Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]1[C:10]([CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:9][NH:8][N:7]=1)[CH3:4].Cl[CH2:19][C:20]1[CH:39]=[CH:38][C:23]([O:24][CH2:25][C:26]2[N:27]=[C:28]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[O:29][C:30]=2[CH3:31])=[C:22]([O:40][CH2:41][CH3:42])[CH:21]=1.O>CN(C)C=O>[CH2:3]([O:5][C:6]1[C:10]([CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:9][N:8]([CH2:19][C:20]2[CH:39]=[CH:38][C:23]([O:24][CH2:25][C:26]3[N:27]=[C:28]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[O:29][C:30]=3[CH3:31])=[C:22]([O:40][CH2:41][CH3:42])[CH:21]=2)[N:7]=1)[CH3:4]
Reactant: CCOc1cc(CCl)ccc1OCc1nc(-c2ccccc2)oc1C
Reactant: CCOC(=O)CCc1c[nH]nc1OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCc1cn(Cc2ccc(OCc3nc(-c4ccccc4)oc3C)c(OCC)c2)nc1OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.3 %

Procedure:
Sodium hydride (60%, oily, 50.0 mg) was added to a solution of ethyl 3-(3-ethoxy-1H-pyrazol-4-yl)propionate (265 mg) and 4-(4-chloromethyl-2-ethoxyphenoxymethyl)-5-methyl-2-phenyloxazole (447 mg) in N,N-dimethylformamide (10 ml) at 0° C., and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 3-[3-ethoxy-1-[3-ethoxy-4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-1H-pyrazol-4-yl]propionate (548 mg, yield: 82%) as a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1:1, volume ratio).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][N:5]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[N:3]=1.[Br:19]Br>C(O)(=O)C>[Br:19][CH2:1][C:2]1[C:7]([CH3:8])=[CH:6][N:5]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[N:3]=1
Reactant: BrBr
Reactant: Cc1cnc(-c2ccc(C(F)(F)F)cc2)nc1C
Solvent: CC(=O)O
Product: Cc1cnc(-c2ccc(C(F)(F)F)cc2)nc1CBr
Temperature: 80 °C
Yield: 95.9 %

Procedure:
The title compound of Step B (2.0 g, 8 mmol) was dissolved in 10 mL of acetic acid and treated with bromine (0.4 mL, 8 mmol). The mixture was heated at 80° C. until the orange color was discharged (1 h). The mixture was evaporated under reduced pressure, diluted with 50 mL of ether and washed twice with 50 mL of sodium bicarbonate and then 50 mL of brine. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure to yield 2.54 g of the title compound of Step C as a tan solid which was used immediately in the next step without further purification. 1H NMR (CDCl3): δ2.44 (s, 3H), 4.54 (s, 2H), 7.74 (d, 2H), 8.56 (d, 2H), 8.62 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[S:9][CH:10]=[C:11]([CH3:13])[CH:12]=2)[CH:5]=[CH:4][C:3]=1[S:14]([NH:17][C:18]1[N:23]=[C:22]([N:24]2[CH2:29][C@H:28]([CH3:30])[N:27](C(OC(C)(C)C)=O)[C@H:26]([CH3:38])[CH2:25]2)[CH:21]=[CH:20][C:19]=1[O:39][CH3:40])(=[O:16])=[O:15].Cl.O1CCOCC1>O1CCOCC1>[ClH:1].[Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[S:9][CH:10]=[C:11]([CH3:13])[CH:12]=2)[CH:5]=[CH:4][C:3]=1[S:14]([NH:17][C:18]1[C:19]([O:39][CH3:40])=[CH:20][CH:21]=[C:22]([N:24]2[CH2:29][C@H:28]([CH3:30])[NH:27][C@H:26]([CH3:38])[CH2:25]2)[N:23]=1)(=[O:16])=[O:15]
Reactant: COc1ccc(N2C[C@@H](C)N(C(=O)OC(C)(C)C)[C@@H](C)C2)nc1NS(=O)(=O)c1ccc(-c2cc(C)cs2)cc1Cl
Agent: Cl
Solvent: C1COCCO1
Product: COc1ccc(N2C[C@@H](C)N[C@@H](C)C2)nc1NS(=O)(=O)c1ccc(-c2cc(C)cs2)cc1Cl
Temperature: 25 °C
Reaction time: 24 h
Yield: 193.7 %

Procedure:
1,1-Dimethylethyl (2R,6S)-4-[6-({[2-chloro-4-(4-methyl-2-thienyl)phenyl]sulfonyl}amino)-5-(methyloxy)-2-pyridinyl]-2,6-dimethyl-1-piperazinecarboxylate (D14) (0.128 g) was dissolved in dioxane (5 mL) and 4N HCl/dioxane (5 mL) added and the reaction stirred at rt for 24 hours. The reaction mixture was evaporated to give the title compound as a pale yellow solid (E6) (0.111 g). MS (ES+) m/e 507/509 [M+H]+.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:8]([CH3:11])[C:9]#[N:10])[CH:5]=[CH:6][CH:7]=1.C([O-])([O-])=O.[Na+].[Na+].[O:18]1[CH:22]=[CH:21][N:20]=[C:19]1B(O)O>C1COCC1>[O:18]1[CH:22]=[CH:21][N:20]=[C:19]1[C:2]1[CH:3]=[C:4]([CH:8]([CH3:11])[C:9]#[N:10])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C#N)c1cccc(I)c1
Reactant: OB(O)c1ncco1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C#N)c1cccc(-c2ncco2)c1
Temperature: 25 °C
Yield: 78.1 %

Procedure:
To a solution of 2-(3-iodophenyl)propionitrile (0.6 g, 2.33 mmol) in dry THF (10 mL) Pd(PPh3)4 (4% mol, 0.108 mg) and Na2CO3 (0.493 g, 4.66 mmol) were added sequentially under nitrogen atmosphere. After stirring 20 min commercial 1,3-oxazole-2-boronic acid (0.289 g 2.56 mmol) was added. The reaction mixture was stirred at reflux 4 h. After cooling at room temperature, THF was evaporated under reduced pressure and EtOAc (10 mL) was added to the crude and the organic phase was washed with water (3×10 mL) and brine (3×10 mL). After drying over Na2SO4 and solvent evaporation a residue was obtained that, after flash chromatography (eluent mixture n-hexane/EtOAc 8:2), afforded 2-(3-oxazol-2-ylphenyl) propionitrile as yellow oil (0.360 g, 1.82 mmol). Yield 78%.
Reaction SMILES: [OH:1][CH2:2][C:3]([CH3:17])([CH3:16])[C:4]([NH:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1)=[O:5].[N+:18]([C:21]1[CH:28]=[CH:27][CH:26]=[C:25]([N+]([O-])=O)[C:22]=1[C:23]#[N:24])([O-:20])=[O:19]>>[C:23]([C:22]1[C:21]([N+:18]([O-:20])=[O:19])=[CH:28][CH:27]=[CH:26][C:25]=1[O:1][CH2:2][C:3]([CH3:17])([CH3:16])[C:4]([NH:6][CH2:7][C:8]1[CH:9]=[CH:10][C:11]([O:14][CH3:15])=[CH:12][CH:13]=1)=[O:5])#[N:24]
Reactant: N#Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Reactant: COc1ccc(CNC(=O)C(C)(C)CO)cc1
Product: COc1ccc(CNC(=O)C(C)(C)COc2cccc([N+](=O)[O-])c2C#N)cc1
Yield: 95 %

Procedure:
Prepared as in Example 215c from 3-hydroxy-N-(4-methoxybenzyl)-2,2-dimethylpropanamide (Example 220d) and 2,6-dinitrobenzonitrile in 95% yield as a pale yellow solid. MS 384 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:6]2[C:7]([O:9][C:10](=O)[NH:11][C:5]2=[CH:4][CH:3]=1)=[O:8].[NH:14]([CH2:16]C(O)=O)[CH3:15]>CS(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:9])[CH2:15][N:14]([CH3:16])[C:7](=[O:8])[C:6]=2[CH:13]=1
Reactant: O=c1[nH]c2ccc(Cl)cc2c(=O)o1
Reactant: CNCC(=O)O
Solvent: CS(C)=O
Product: CN1CC(=O)Nc2ccc(Cl)cc2C1=O
Temperature: 150 °C

Procedure:
A mixture of 5-chloroisatoic anhydride 401 (20 g, 101 mmol) and sarcosine (9.02 g, 101 mmol) in DMSO (160 mL) was heated at 150° C. for 5 hr, cooled to room temperature and poured into ice water (750 mL) to furnish a light brown precipitate. This solid was collected by filtration, washed with water (3×200 mL) and dried. The benzodiazepine 402 was obtained as a light brown solid (19 g, 84% yield). This material was used directly in the next experiment.
Reaction SMILES: [C:1]([O:9][CH2:10][C@@H:11]1[CH2:15][C@H:14](OS(C(F)(F)F)(=O)=O)[CH:13]([O:24][CH3:25])[O:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:26]=[N+:27]=[N-:28].[Na+]>CN(C=O)C.O>[C:1]([O:9][CH2:10][C@@H:11]1[CH2:15][C@@H:14]([N:26]=[N+:27]=[N-:28])[C@H:13]([O:24][CH3:25])[O:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC1O[C@H](COC(=O)c2ccccc2)C[C@@H]1OS(=O)(=O)C(F)(F)F
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CO[C@@H]1O[C@H](COC(=O)c2ccccc2)C[C@H]1N=[N+]=[N-]
Temperature: 25 °C
Reaction time: 16 h
Yield: 141.7 %

Procedure:
To a solution of [(2S,4S)-5-methoxy-4-(trifluoromethylsulfonyloxy)tetrahydrofuran-2-yl]methyl benzoate (compound 32c, 1.1 g, 2.8 mmol) in DMF (5 mL) was added sodium azide (372 mg, 5.7 mmol) at room temperature and the mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with water and extracted with EtOAc, the organic layers were combined and concentrated in vacuo to afford 1.1 g crude product of [(2S,4R,5R)-4-azido-5-methoxy-tetrahydrofuran-2-yl]methyl benzoate (compound 33a) as an oil, which was used in next step without further purification.
Reaction SMILES: [CH2:1]([N:3]([CH2:8][CH3:9])[CH2:4][CH2:5][NH:6][CH3:7])[CH3:2].Cl[CH2:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C)C=O>[CH2:1]([N:3]([CH2:8][CH3:9])[CH2:4][CH2:5][N:6]([CH2:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][CH:13]=1)[CH3:7])[CH3:2]
Reactant: O=C(O)c1ccc(CCl)cc1
Reactant: CCN(CC)CCNC
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCN(CC)CCN(C)Cc1ccc(C(=O)O)cc1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
Into a 1000-mL round bottom flask, was placed a solution of N1,N1-diethyl-N2-methylethane-1,2-diamine (10 g, 69.23 mmol, 1.20 equiv, 90%) in N,N-dimethylformamide (500 mL), 4-(chloromethyl)benzoic acid (11.5 g, 67.65 mmol, 1.00 equiv), potassium carbonate (10 g, 71.94 mmol, 3.00 equiv), and potassium iodide (1.95 g, 11.75 mmol, 0.20 equiv). The resulting solution was stirred for 2 h at 90° C. in an oil bath. The solids were filtered out. The resulting mixture was concentrated under vacuum. The crude product (10 g) was purified by reverse phase chromatography eluting with a water/methanol gradient. This resulted in 5 g (27%) of 4-(((2-(diethylamino)ethyl)(methyl)amino)methyl)benzoic acid as a white solid. 1H-NMR (300 MHz, CDCl3, ppm): δ 8.00 (d, J=8.4 Hz, 2H), 7.39 (d, J=8.1 Hz, 2H), 3.68 (s, 2H), 3.23-3.15 (m, 6H), 2.91 (m, 2H), 2.33 (s, 3H), 1.33-1.27 (m, 6H). MS (ES, m/z): 265 [M+H]+.
Reaction SMILES: [C:1]([CH:4]([CH2:10][CH3:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6])(=[O:3])[CH3:2].[Br:12]C(Cl)(Cl)Cl.O.O.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>>[C:1]([C:4]([Br:12])([CH2:10][CH3:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6])(=[O:3])[CH3:2]
Reactant: CCOC(=O)C(CC)C(C)=O
Reactant: ClC(Cl)(Cl)Br
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Product: CCOC(=O)C(Br)(CC)C(C)=O
Yield: 56.5 %

Procedure:
In a 10 mL round-bottom flask, 1.58 g of ethyl 2-acetylbutyrate (10 mmol), 2.1 g bromotrichloromethane (10.5 mmol), and 200 mg of tetra-n-butylammonium fluoride trihydrate (0.632 mmol) were mixed at 24° C. for 1 h. Gas chromatographic analysis of the resulting mixture showed the presence of 1.34 g of ethyl 2-acetyl-2-bromobutyrate (56% yield).
Reaction SMILES: [C:1]([Si:5]([CH3:12])([CH3:11])[O:6][C@@H:7]([CH3:10])[CH2:8][OH:9])([CH3:4])([CH3:3])[CH3:2].O[N:14]1[C:18](=[O:19])[C:17]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:16]2[C:15]1=[O:24].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[C:1]([Si:5]([CH3:12])([CH3:11])[O:6][C@@H:7]([CH3:10])[CH2:8][O:9][N:14]1[C:18](=[O:19])[C:17]2[C:16](=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:15]1=[O:24])([CH3:3])([CH3:4])[CH3:2]
Reactant: C[C@@H](CO)O[Si](C)(C)C(C)(C)C
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C[C@@H](CON1C(=O)c2ccccc2C1=O)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C

Procedure:
To a suspension of (S)-2-(tert-butyl-dimethyl-silanyloxy)-propan-1-ol (53.0 g, 0.28 mol), N-hydroxyphthalimide (47.0 g, 0.29 mol) and triphenylphosphine (77.9 g, 0.30 mol) in THF (200 ml) at 0° C. was added dropwise DIAD (56.8 ml, 0.29 mol). During the addition the reagents dissolved and the solution turned a dark red colour before fading to pale yellow colour on completion of the addition. The reaction mixture was stirred and allowed to warm to room temperature overnight. The reaction mixture was concentrated in vacuo and the resultant residue re-dissolved in diethyl ether. The suspension was filtered and the filtrate was concentrated in vacuo to yield the crude title compound as a pale yellow oil. The material was used without further purification in the subsequent step.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[C:14](B2OC(C)(C)C(C)(C)O2)[CH:13]=[CH:12][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.I[C:26]1[CH:39]=[N:38][C:29]2[NH:30][C:31]3[CH:36]=[N:35][C:34]([Br:37])=[CH:33][C:32]=3[C:28]=2[CH:27]=1>C(=O)([O-])[O-].[Na+].[Na+].CC1CCCO1.C(Cl)Cl>[Br:37][C:34]1[N:35]=[CH:36][C:31]2[NH:30][C:29]3[N:38]=[CH:39][C:26]([C:14]4[CH:13]=[CH:12][C:4]([CH2:5][N:6]5[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]5)=[C:3]([O:2][CH3:1])[CH:15]=4)=[CH:27][C:28]=3[C:32]=2[CH:33]=1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1CN1CCCCC1
Reactant: Brc1cc2c(cn1)[nH]c1ncc(I)cc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC1CCCO1
Product: COc1cc(-c2cnc3[nH]c4cnc(Br)cc4c3c2)ccc1CN1CCCCC1
Temperature: 85 °C
Yield: 60.8 %

Procedure:
A degassed mixture of 1-[2-methoxy-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzyl]-piperidine (885 mg, 2.7 mmol), 3-iodo-6-bromo-9H-dipyrido[2,3-b;4′,3′-d]pyrrole (500 mg, 1.3 mmol), 1,1′-[bis(diphenylphosphino)-ferrocene]dichloropalladium(II) (163 mg, 0.2 mmol) in 2N aqueous sodium carbonate solution (10 mL) and 2-methyltetrahydrofuran (20 mL) was heated at 85° C. for 18 h. The cooled reaction mixture was diluted with DCM (100 mL) and washed with water (75 mL). The organic phase was separated, dried over sodium sulfate, filtered and evaporated in vacuo to afford a residue (357 mg, 61%) that was used in the next step without purification. 1H NMR (CDCl3, 300 MHz): 8.83 (d, J=2.0 Hz, 1H), 8.70 (s, 1H), 8.63 (d, J=2.0 Hz, 1H), 8.24 (s, 1H), 7.45 (d, J=7.8 Hz, 1H), 7.25 (d, J=7.8 Hz, 1H), 7.14 (s, 1H), 3.96 (s, 3H), 3.65 (s, 2H), 2.56-2.48 (m, 4H), 1.67-1.59 (m, 4H), 1.52-1.41 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH2:24][C:25]([F:28])([F:27])[F:26])[C:4](=[O:23])[C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13](Br)[CH:14]=3)[O:9][CH:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:7]2)[N:6]=1.[C:29]([C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][CH:36]=1)#[N:30]>O1CCOCC1.C([O-])([O-])=O.[Cs+].[Cs+].Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:1][C:2]1[N:3]([CH2:24][C:25]([F:28])([F:27])[F:26])[C:4](=[O:23])[C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:35]4[CH:36]=[C:31]([CH:32]=[CH:33][CH:34]=4)[C:29]#[N:30])[CH:14]=3)[O:9][CH:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:7]2)[N:6]=1
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: NC1=NC2(CC(c3ccccc3)Oc3ccc(Br)cc32)C(=O)N1CC(F)(F)F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: N#Cc1cccc(-c2ccc3c(c2)C2(CC(c4ccccc4)O3)N=C(N)N(CC(F)(F)F)C2=O)c1
Temperature: 120 °C
Yield: 17.6 %

Procedure:
Pd(PPh3)2Cl2 (10 mg) in a 10 mL of tube under Ar2 was treated sequentially with 2′-amino-6-bromo-2-phenyl-1′-(2,2,2-trifluoroethyl)spiro[chroman-4,4′-imidazol]-5′(1′H)-one (20 mg, 0.044 mmol) in 1,4-dioxane (1 mL), Cs2CO3 (2 M, 0.3 mL) and 3-cyanophenylboronic acid (13 mg, 0.088 mmol). The mixture was heated at 120° C. under microwave reactor for 0.5 h. The reaction mixture was concentrated in vacuo to give the residue, which was purified by preparative TLC to give pure 3-(2′-amino-5′-oxo-2-phenyl-1′-(2,2,2-trifluoroethyl)-1′,5′-dihydrospiro[chroman-4,4′-imidazole]-6-yl)benzonitrile (3.7 mg, 12%). 1H-NMR (MeOD): 2.27 (m, 1H), 2.35 (m, 1H), 3.87 (m, 2H), 5.83 (m, 1H), 7.01 (d, 1H), 7.26(m, 1H), 7.32 (m, 5H), 7.59 (m, 3H), 7.76 (m, 1H), 7.81 (m, 1H).
Reaction SMILES: [N+](C[C:5](=[O:14])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])([O-])=O.[CH3:15][N:16]([CH2:18][CH2:19][OH:20])[CH3:17]>C1C=CC=CC=1>[C:5]([O:20][CH2:19][CH2:18][N:16]([CH3:17])[CH3:15])(=[O:14])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCCCCCC(=O)C[N+](=O)[O-]
Reactant: CN(C)CCO
Solvent: c1ccccc1
Product: CCCCCCCCC(=O)OCCN(C)C
Yield: 72 %

Procedure:
In accordance with practice of the process of this invention, ten parts of 1-nitro-2-decanone, 5.0 parts of dimethylaminoethanol, and 110 parts of dry benzene are admitted to a reaction vessel wherein they are refluxed for four hours. At the end of this time, there are distilled off from the reaction mixture 44 parts by weight of benzene solvent and 2.0 parts by weight of nitromethane. The remaining benzene is then distilled at atmospheric pressure and 80°C. Thereafter the residual dark oil is distilled at 106°-110°C, at 2mm Hg to yield 8.2 parts by weight of N,N-dimethylaminoethyl nonanoate, a pale yellow liquid having a boiling point of 106°-110°C/2mm and a refractive index ND24 1.4355. (Yield 72%)
Reaction SMILES: [Br:1][C@H:2]([CH2:6][CH:7]([CH3:9])[CH3:8])[C:3]([OH:5])=[O:4].[CH3:10][C:11]([CH3:13])=[CH2:12].S(=O)(=O)(O)O>C(Cl)Cl>[C:11]([O:4][C:3](=[O:5])[C@H:2]([Br:1])[CH2:6][CH:7]([CH3:9])[CH3:8])([CH3:13])([CH3:12])[CH3:10]
Reactant: C=C(C)C
Reactant: CC(C)C[C@@H](Br)C(=O)O
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: CC(C)C[C@@H](Br)C(=O)OC(C)(C)C
Yield: 88 %

Procedure:
33 g of 2(R)-bromo-4-methylpentanoic acid (prepared from D-leucine) was dissolved in 100 ml of methylene chloride. To this solution, at -40° C. was introduced 47 g of 2-methylpropene while stirring, and after the addition of 0.8 ml of sulfuric acid the mixture was stirred overnight at room temperature. The reaction mixture was concentrated to 1/2 in vacuo and washed with 10% sodium carbonate aqueous solution and dried over anhydrous magnesium sulfate. The solution was then evaporated in vacuo, yielding 37.4 g of 2(R)-bromo-4-methylpentanoic acid t-butyl ester.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]2[C:3]=1[CH2:4][CH:5]([CH3:13])[C:6]2=[O:12].C(O)C>>[F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]2[C:3]=1[CH2:4][CH:5]([CH3:13])[CH:6]2[OH:12]
Reactant: CC1Cc2c(F)cc(F)cc2C1=O
Solvent: CCO
Product: CC1Cc2c(F)cc(F)cc2C1O
Temperature: 25 °C
Reaction time: 18 h
Yield: 50.6 %

Procedure:
According to Scheme 3, step 2: to a solution 4,6-Difluoro-2-methyl-indan-1-one (7a) (1.27 g, 6.97 mmol) in ethanol (30 ml) NaBH4 (0.26 g, 6.97 mmol) was added in portions at 0° C. and then the mixture was stirred at room temperature for 18 h. After evaporation of solvents in vacuo, water was added to the residue, the solution was extracted 3 times with ethyl acetate, then 2N aqueous HCl was added and the combined organic layers were washed with saturated aq. NaHCO3 and water. After drying over Na2SO4 and filtration, solvents were evaporated in vacuo to give 650 mg 4,6-Difluoro-2-methyl-indan-1-ol (8a) which was used immediately in the next step without purification.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([S:7]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]([O:20][CH:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[C:17]([OH:19])=O)=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH2:3][CH2:2]1.[N:27]1[C:35]2[C:30](=[N:31][CH:32]=[CH:33][CH:34]=2)[S:29][C:28]=1[NH2:36].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.CN1CCOCC1>CN(C=O)C>[O:1]1[CH2:6][CH2:5][N:4]([S:7]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]([O:20][CH:21]3[CH2:22][CH2:23][O:24][CH2:25][CH2:26]3)[C:17]([NH:36][C:28]3[S:29][C:30]4[C:35]([N:27]=3)=[CH:34][CH:33]=[CH:32][N:31]=4)=[O:19])=[CH:12][CH:11]=2)(=[O:8])=[O:9])[CH2:3][CH2:2]1
Reactant: O=C(O)C(OC1CCOCC1)c1ccc(S(=O)(=O)N2CCOCC2)cc1
Reactant: Nc1nc2cccnc2s1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: O=C(Nc1nc2cccnc2s1)C(OC1CCOCC1)c1ccc(S(=O)(=O)N2CCOCC2)cc1
Yield: 21.6 %

Procedure:
The compound of example A4 was obtained by similar method described in example A2 using 2-(4-morpholinosulfonylphenyl)-2-tetrahydropyran-4-yloxy-acetic acid (Preparation 11, 0.1 g, 0.25 mmol), thiazolo[5,4-b]pyridin-2-ylamine (0.050 g, 0.31 mmol), HOBt (0.042 g, 0.31 mmol), and EDCl (0.060 g, 0.31 mmol), N-methyl morpholine (0.065 g, 0.64 mmol) in DMF (5 mL) to provide the title compound (0.028 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:17](=[O:18])[C:16]2[C:11](=[N:12][C:13](S(C)=O)=[N:14][CH:15]=2)[N:10]2[CH:22]=[CH:23][N:24]=[C:9]12.[NH2:25][C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=1.C([O-])(O)=O.[Na+]>[Cl-].[Na+].O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:17](=[O:18])[C:16]2[CH:15]=[N:14][C:13]([NH:25][C:26]3[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=3)=[N:12][C:11]=2[N:10]2[CH:22]=[CH:23][N:24]=[C:9]12
Reactant: CS(=O)c1ncc2c(=O)n(-c3ccccc3Cl)c3nccn3c2n1
Reactant: Cc1ccc(N)cc1
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: Cc1ccc(Nc2ncc3c(=O)n(-c4ccccc4Cl)c4nccn4c3n2)cc1

Procedure:
A mixture of Example 1E (132.0 mg, 0.367 mmol) and p-toluidine (86 mg, 0.807 mmol) was heated in a capped vial at 90° C. for 1 hour. After cooling, the residue was treated with saturated aqueous NaHCO3 and brine and extracted with ethyl acetate (twice). The combined organic layers were dried over MgSO4, filtered, concentrated, and purified on a 12 g column using the ISCO Companion flash system eluting with CH2Cl2/ethyl acetate (8:2 to 7:3) to provide the title compound. 1H NMR (400 MHz, CDCl3) δ 2.39 (s, 3H), 7.08 (d, J=1.8 Hz, 1H), 7.26-7.23 (m, 2H), 7.49-7.47 (m, 3H), 7.57-7.55 (m, 2H), 7.66-7.61 (m, 1H), 7.72-7.67 (m, 1H), 7.88-7.72 (m, 1H), 9.24 (s, 1H). MS (ESI+) m/z 403.2 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].C[Al](C)C.C([O:15][C:16]([C:18]1[C:27]2[C:26]3[N:28]=[CH:29][N:30]=[CH:31][C:25]=3[CH2:24][CH2:23][CH2:22][C:21]=2[NH:20][CH:19]=1)=O)C.O>C(Cl)Cl.[NH4+].[Cl-]>[F:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH:4][C:16]([C:18]1[C:27]2[C:26]3[N:28]=[CH:29][N:30]=[CH:31][C:25]=3[CH2:24][CH2:23][CH2:22][C:21]=2[NH:20][CH:19]=1)=[O:15]
Reactant: Nc1ccccc1F
Reactant: CCOC(=O)c1c[nH]c2c1-c1ncncc1CCC2
Agent: C[Al](C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: O
Product: O=C(Nc1ccccc1F)c1c[nH]c2c1-c1ncncc1CCC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 72 %

Procedure:
To a solution of 2-fluoroaniline (108 mg, 0.972 mmol) in CH2Cl2 (2.0 mL) at 0° C. under N2 is slowly added AlMe3 (0.49 mL, 2.0 M in toluene). The resulting solution is stirred at room temperature for 1 h. Next, 3,4,5,6-tetrahydro-3,8,10-triaza-benzo[e]azulene-1-carboxylic acid ethyl ester (50 mg, 0.194 mmol) is added in one portion. The resulting mixture is then stirred at reflux for 2 h. After cooling, the reaction mixture is carefully diluted with saturated aq NH4Cl (˜5 mL) and some H2O. The mixture is stirred vigorously for 15 min. and then extracted three times with CH2Cl2. The combined extracts are dried over K2CO3 and concentrated. The crude material is purified by flash chromatography on silica gel. Elution with 40:1 CHCl3—MeOH followed by 30:1 CHCl3—MeOH and finally 20:1 CHCl3—MeOH afforded 45 mg (72%) of 3,4,5,6-tetrahydro-3,8,10-triaza-benzo[e]azulene-1-carboxylic acid (2-fluoro-phenyl)-amide as a light yellow solid. Electrospray mass spectrum: m/z 321 [M−1].
Reaction SMILES: [C:1]1([C:7]2([CH2:13][O:14][CH2:15][C:16]3[CH:17]=[C:18]([C:26]4[CH:31]=[CH:30][C:29]([C:32]#[N:33])=[CH:28][CH:27]=4)[CH:19]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:21]=3)[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C=O.[C:36]([BH3-])#N.[Na+]>C(#N)C.C(O)(=O)C>[CH3:36][N:10]1[CH2:11][CH2:12][C:7]([CH2:13][O:14][CH2:15][C:16]2[CH:17]=[C:18]([C:26]3[CH:31]=[CH:30][C:29]([C:32]#[N:33])=[CH:28][CH:27]=3)[CH:19]=[C:20]([C:22]([F:24])([F:25])[F:23])[CH:21]=2)([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8][CH2:9]1
Reactant: [BH3-]C#N
Reactant: N#Cc1ccc(-c2cc(COCC3(c4ccccc4)CCNCC3)cc(C(F)(F)F)c2)cc1
Agent: C=O
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)O
Product: CN1CCC(COCc2cc(-c3ccc(C#N)cc3)cc(C(F)(F)F)c2)(c2ccccc2)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
3′-(((4-Phenylpiperidin-4-yl)methoxy)methyl)-5′-(trifluoromethyl)biphenyl-4-carbonitrile (18.3 mg, 0.04 mmol) and formaldehyde (37 wt. % solution in water, 86.4 μL, 3.22 mmol) were combined in acetonitrile (1.0 mL) and cooled to 0° C. The reaction was treated with sodium cyanoborohydride (12.6 mg, 0.2 mmol) and a few drops of acetic acid. The reaction was stirred at 0° C. for 30 min and at room temperature for 1 h. The solvent was removed in vacuo and the resulting crude mixture passed through a strong cation exchange column. After washing the column with several volumes of methanol, the product was eluted by washing the column with 2 M ammonia in methanol. The solvents were evaporated to afford 12.1 mg (65%). 1H-NMR (CDCl3, 500 MHz) δ 7.74-7.76 (m, 2H), 7.66 (s, 1H), 7.58-7.60 (m, 2H), 7.44 (s, 1H), 7.41 (s, 1H), 7.36-7.38 (m, 2H), 7.30-7.33 (m, 2H), 7.18-7.21 (m, 1H), 4.45 (s, 2H), 3.48 (s, 2H), 2.58-2.60 (m, 2H), 2.17-2.28 (m, 4H), 2.21 (s, 3H), 1.98-2.08 (m, 2H). Mass spec.: 465.11 (MH)+.