Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5]([C:8]2[CH:16]=[C:15]3[C:11]([CH:12]=[CH:13][NH:14]3)=[CH:10][CH:9]=2)=[CH:4][CH2:3]1.[CH3:17][N:18]([CH3:22])[C:19](Cl)=[O:20].C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1>[CH3:17][N:18]([CH3:22])[C:19]([N:14]1[C:15]2[C:11](=[CH:10][CH:9]=[C:8]([C:5]3[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH:4]=3)[CH:16]=2)[CH:12]=[CH:13]1)=[O:20]
Reactant: CN(C)C(=O)Cl
Reactant: CN1CC=C(c2ccc3cc[nH]c3c2)CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CC=C(c2ccc3ccn(C(=O)N(C)C)c3c2)CC1

Procedure:
From 6-(1-Methyl-1,2,5,6-tetrahydropyridin-4-yl)-indole (16.6 mg, 0.0735 mmol), dimethylcarbamyl chloride (15.8 mg. 0.147 mmol) and 1M NaN(TMS)2(0.147ml) in 0.5 ml of THF at 0° C. Yield 12.5 mg (60%), the reaction being carried out according to Example 6.
Reaction SMILES: Cl[C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]1[O:17][C:16]([C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)=[CH:20][C:19]=2[O:30][CH3:31])=[N:15][N:14]=1.[NH:32]1[CH:36]=[CH:35][CH:34]=[N:33]1>>[CH3:31][O:30][C:19]1[CH:20]=[C:21]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[CH:22]=[CH:23][C:18]=1[C:16]1[O:17][C:13]([C:3]2[C:4]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)=[N:5][O:6][C:2]=2[N:32]2[CH:36]=[CH:35][CH:34]=[N:33]2)=[N:14][N:15]=1
Reactant: c1cn[nH]c1
Reactant: COc1cc(N2CCOCC2)ccc1-c1nnc(-c2c(-c3ccccc3)noc2Cl)o1
Product: COc1cc(N2CCOCC2)ccc1-c1nnc(-c2c(-c3ccccc3)noc2-n2cccn2)o1
Yield: 79 %

Procedure:
As described for example 106, 4-{4-[5-(5-chloro-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-3-methoxy-phenyl}-morpholine (100 mg, 0.23 mmol) using pyrazole instead of dimethylamine hydrochloride was converted to the title compound (85 mg, 79%) which was obtained as an off-white solid. MS: m/e 471.3 [M+H]+.
Reaction SMILES: C([O:8][C@@H:9]1[C@@H:13]2[NH:14][C@H:15]([CH2:16][OH:17])[C@H:10]1[O:11][C@@H:12]2[O:18][CH3:19])C1C=CC=CC=1.C(=O)([O-])O.[Na+].Cl[C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27].O>CO.[OH-].[Pd+2].[OH-].[C]>[CH2:29]([O:28][C:26]([N:14]1[C@H:15]([CH2:16][OH:17])[C@@H:10]2[C@H:9]([OH:8])[C@H:13]1[C@H:12]([O:18][CH3:19])[O:11]2)=[O:27])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CO[C@H]1O[C@H]2[C@H](OCc3ccccc3)[C@@H]1N[C@@H]2CO
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Pd+2]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CO[C@@H]1O[C@H]2[C@H](O)[C@@H]1N(C(=O)OCc1ccccc1)[C@@H]2CO
Reaction time: 6 h
Yield: 69.9 %

Procedure:
The compound (930 mg, 3.51 mmol) synthesized in Example 7 (7a) was dissolved in methanol (20 mL) and 20% palladium hydroxide-carbon (280 mg) was added thereto, followed by stirring of the mixture under a hydrogen atmosphere for 6 hours. After the catalyst was removed by celite filtration, the solvent was distilled off under reduced pressure. The residue was dissolved in ethyl acetate:saturated aqueous sodium hydrogencarbonate solution (2:1, 20 mL) and benzyl chloroformate (0.75 mL, 5.27 mmol) was added thereto, followed by stirring of the mixture at 0° C. for 2 hours. After water (20 mL) was added thereto at 0° C. and the mixture was extracted with ethyl acetate, the organic layer was washed with saturated brine (20 mL) and dried with anhydrous sodium sulfate, followed by distilling off of the solvent under reduced pressure. The residue was purified using silica gel flash column chromatography (hexane:ethyl acetate, 1:1-3:1, V/V) to obtain the desired title compound (759 mg, yield 70%) as a colorless solid.
Reaction SMILES: [Br:1][C:2]1[NH:10][C:9]2[C:8](=[O:11])[NH:7][C:6](=[O:12])[N:5]([CH3:13])[C:4]=2[N:3]=1.[C:14](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O>[Br:1][C:2]1[N:10]([CH3:14])[C:9]2[C:8](=[O:11])[NH:7][C:6](=[O:12])[N:5]([CH3:13])[C:4]=2[N:3]=1
Reactant: Cn1c(=O)[nH]c(=O)c2[nH]c(Br)nc21
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cn1c(Br)nc2c1c(=O)[nH]c(=O)n2C
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.4 %

Procedure:
To a stirring suspension of 8-bromo-3-methylxanthine (prepared as described above for CT12440) (12.25 g, 50.0 mmol) and potassium carbonate (8.62 g, 62.5 mmol) in dimethylformamide (150 ml) was added methyl iodide (7.81 g, 55.0 mmol). After stirring overnight at room temperature, the mixture was poured into ice cold water (400 ml) and stirred at 0-5° C. for 1 hour. The precipitate was filtered, rinsed with water (5×25 ml) and dried under vacuum to provide 8-bromo-3,7-dimethylxanthine (12.10 g, 93% yield) as a beige solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:27])[CH2:9][CH2:10][CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:18])[CH2:13][CH2:12]2)=[CH:4][CH:3]=1.[CH2:28](O)[CH2:29][OH:30].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([O:30][CH2:29][CH2:28][O:27]2)[CH2:9][CH2:10][CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)=[O:18])[CH2:13][CH2:12]2)=[CH:6][CH:7]=1
Reactant: OCCO
Reactant: O=C(CCC1CCN(C(=O)OCc2ccccc2)CC1)c1ccc(F)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: O=C(OCc1ccccc1)N1CCC(CCC2(c3ccc(F)cc3)OCCO2)CC1
Reaction time: 1 h
Yield: 84 %

Procedure:
A solution of 71 mg (0.19 mmol) of 4-(3-(4-fluorophenyl)-3-oxo-propyl)-1-(benzyloxycarbonyl) piperidine (from EXAMPLE 189, Step B), 0.05 mL (0.9 mmol) of ethylene glycol and 5 mg (0.26 mmol) of p-toluene sulfonic acid x H2O in 3 mL of toluene was heated at 80° C. After 1 h, and additional 5 mg of p-toluene sulfonic acid×H2O was added and the resulting mixture was heated at reflux. After 2 h, the mixture was cooled and partitioned between 30 mL of ether and 10 mL of 1.0 N NaOH. The organic layer was separated, dried and concentrated. Flash chromatography on 4 g of silica gel using 3:1 v/v hexanes/ether afforded 66 mg of the title compound: 1H NMR (500 MHz, CDCl3) δ 1.00-1.10 (m, 2H), 1.261.36 (3H), 1.50-1.60 (m, 2H), 1.86-1.89 (m, 2H), 2.65-2.75 (m, 2H), 3.71-3.78 (m, 2H), 3.96-4.03 (m, 2H), 4.064.16 (m, 2H), 5.10 (s, 2H), 6.99-7.04 (m, 2H), 7.26-7.40 (7H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[CH:6][C:7]=1[OH:8].S(=O)(=O)(O)O.[CH3:18]O>>[CH3:18][O:11][C:10](=[O:12])[CH2:9][C:4]1[CH:5]=[CH:6][C:7]([OH:8])=[C:2]([F:1])[CH:3]=1
Reactant: O=C(O)Cc1ccc(O)c(F)c1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1ccc(O)c(F)c1
Temperature: 120 °C
Yield: 97.6 %

Procedure:
A solution of (3-fluoro-4-hydroxy-phenyl)-acetic acid (1.0 g, 5.87 mmol) in methanol (20 mL) was treated with a catalytic amount of sulfuric acid. The reaction was heated at 120° C. for 6 h. At this time, the reaction was concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 50/50 hexanes/ethyl acetate) afforded (3-fluoro-4-hydroxy-phenyl)-acetic acid methyl ester (1.05 g, 97.6%) as a white solid: mp 34-36° C.: EI-HRMS m/e calcd for C9H9FO3 (M+) 184.0535, found 184.0533.
Reaction SMILES: [S-:1][C:2]#[N:3].[K+].[Br:5][C:6]1[N:11]=[CH:10][C:9]([NH2:12])=[CH:8][CH:7]=1.BrBr>C(O)(=O)C>[Br:5][C:6]1[N:11]=[C:10]2[S:1][C:2]([NH2:3])=[N:12][C:9]2=[CH:8][CH:7]=1
Reactant: N#C[S-]
Reactant: Nc1ccc(Br)nc1
Agent: BrBr
Agent: [K+]
Solvent: CC(=O)O
Product: Nc1nc2ccc(Br)nc2s1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 77.9 %

Procedure:
To a suspension of potassium thiocyanate (33.8 g, 348 mmol) in acetic acid (150 mL) was added 6-bromopyridin-3-amine (15.2 g, 88.1 mmol), and the mixture was stirred at room temperature for 15 min. A solution of bromine (18.4 g, 115 mmol) in acetic acid (200 mL) was added dropwise to the obtained solution at room temperature for 30 min or more. After the completion of the dropwise addition, the mixture was stirred at room temperature for 6 hr. The yielded yellow solid was filtered off, and the filtrate was concentrated under reduced pressure. The residue was suspended in tetrahydrofuran (200 mL) and ethyl acetate (200 mL), the suspension was washed with saturated aqueous sodium hydrogen carbonate solution (300 mL×2) and saturated brine (200 mL), dried over anhydrous magnesium sulfate, and decolorized with activated carbon. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained crude product was recrystallized from tetrahydrofuran and diisopropyl ether to give the title compound (15.8 g, 78%) as a pale-brown solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[S:10][CH:11]=[C:12]([C:14]([OH:16])=O)[N:13]=1.[NH2:17][C:18]1[C:19]([N:27]2[CH2:32][CH2:31][CH2:30][C@H:29]([NH:33]C(=O)OC(C)(C)C)[CH2:28]2)=[C:20]2[CH2:26][CH2:25][O:24][C:21]2=[N:22][CH:23]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:33][C@H:29]1[CH2:30][CH2:31][CH2:32][N:27]([C:19]2[C:18]([NH:17][C:14]([C:12]3[N:13]=[C:9]([C:3]4[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=4[F:1])[S:10][CH:11]=3)=[O:16])=[CH:23][N:22]=[C:21]3[O:24][CH2:25][CH2:26][C:20]=23)[CH2:28]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCN(c2c(N)cnc3c2CCO3)C1
Reactant: O=C(O)c1csc(-c2c(F)cccc2F)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: N[C@H]1CCCN(c2c(NC(=O)c3csc(-c4c(F)cccc4F)n3)cnc3c2CCO3)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 20.2 %

Procedure:
To a mixture of 2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxylic acid (Example 2, Step 2, 14.5 mg, 0.0601 mmol), tert-butyl [(3S)-1-(5-amino-2,3-dihydrofuro[2,3-b]pyridin-4-yl)piperidin-3-yl]carbamate (19.2 mg, 0.0574 mmol) and HATU (72.5 mg, 0.191 mmol), DMF (1.50 mL) was added, followed by DIPEA (79.6 mg, 0.616 mmol). The reaction mixture was stirred at room temperature for 2 h, and then concentrated under reduced pressure. To the residue, DCM (2.0 mL) was added, followed by TFA (2.0 mL). The mixture was stirred at room temperature for 30 min., and then concentrated under reduced pressure. The resulting residue was purified using RP-HPLC (XBridge™ C18 column, eluting with a gradient of MeCN/water containing 0.15% NH4OH, at flow rate of 30 mL/min.) to afford the title compound as a white solid (5.3 mg, 20%). LCMS calc. for C22H22F2N5O2S (M+H)+: m/z=458.1. found 458.1.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[CH:10][N:9]=[C:8]([NH2:12])[CH:7]=2)C[CH2:2]1>C(O)CC>[CH2:4]([O:5][C:6]1[N:11]=[CH:10][N:9]=[C:8]([NH2:12])[CH:7]=1)[CH2:1][CH3:2]
Reactant: Nc1cc(OCC2CC2)ncn1
Solvent: CCCO
Product: CCCOc1cc(N)ncn1
Yield: 85 %

Procedure:
This was prepared in a manner analogous to 6-(cyclopropylmethoxy)pyrimidin-4-amine, where propan-1-ol was used as the alcohol. 6-propoxypyrimidin-4-amine (0.201 g, 1.312 mmol, 85% yield) was obtained as a white solid. m/z (ESI) 154.2 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:33])[NH:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH:13]([C:17](=O)[NH:18][C:19]2[C:20](=[O:31])[N:21]([CH3:30])[C:22]3[C:27]([C:28]=2[NH2:29])=[CH:26][CH:25]=[CH:24][N:23]=3)[CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C>>[CH2:1]([O:8][C:9](=[O:33])[NH:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH:13]([C:17]2[NH:18][C:19]3[C:20](=[O:31])[N:21]([CH3:30])[C:22]4[C:27](=[CH:26][CH:25]=[CH:24][N:23]=4)[C:28]=3[N:29]=2)[CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cn1c(=O)c(NC(=O)C2CCCC(NC(=O)OCc3ccccc3)C2)c(N)c2cccnc21
Solvent: CC(=O)O
Product: Cn1c(=O)c2[nH]c(C3CCCC(NC(=O)OCc4ccccc4)C3)nc2c2cccnc21
Temperature: 120 °C
Yield: 85.5 %

Procedure:
[3-(4-Amino-1-methyl-2-oxo-1,2-dihydro-[1,8]naphthyridin-3-ylcarbamoyl)-cyclohexyl]-carbamic acid benzyl ester (55 mg, 0.122 mmol) was dissolved in glacial acetic acid (1.32 g, 22.02 mmol) and heated at 120° C. for 15 h. After cooing to room temperature, the solvent was removed under reduced pressure and the crude product was purified by flash chromatography, eluting with 2% MeOH in CH2Cl2 to give 45 mg (85%) of [3-(5-methyl-4-oxo-4,5-dihydro-3H-1,3,5,6-tetraaza-cyclopenta[a]naphthalen-2-yl)-cyclohexyl]-carbamic acid benzyl ester as a white solid. 1H-NMR (CDCl3): δ 8.61 (m, 2H), 7.33 (m, 7H), 5.18 (m, 2H), 4.27 (m, 1H), 4.0 (s, 3H), 3.81 (m, 1H), 3.44 (m, 1H), 2.52 (m, 3H), 2.28 (m, 1H), 2.12 (m, 1H), 1.8 (m, 1H), 1.79 (m, 3H), 1.31 (m, 1H). MS: calculated for C24H25N5O3+H 432.2; found: 432.0.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][CH2:11][NH:10]2)=[CH:5][CH:4]=1.C(N(C(C)C)C(C)C)C.[N:30]([CH:33]1[CH2:37][CH2:36][CH2:35][CH2:34]1)=[C:31]=[O:32]>C(Cl)Cl>[CH:33]1([NH:30][C:31]([N:10]2[CH2:11][CH2:12][C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[C@H:9]2[C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:19])[F:20])=[CH:8][CH:7]=2)=[O:32])[CH2:37][CH2:36][CH2:35][CH2:34]1
Reactant: FC(F)(F)c1ccc([C@H]2NCCc3ccccc32)cc1
Reactant: O=C=NC1CCCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NC1CCCC1)N1CCc2ccccc2[C@H]1c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of (R)-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline (0.100 g, 0.361 mmol), N-ethyl-N-isopropylpropan-2-amine (0.0754 mL, 0.433 mmol), and isocyanatocyclopentane (0.0421 g, 0.379 mmol) in DCM (4 mL) was stirred at RT for 24 h. The mixture was concentrated and purified by ISCO (20% EtOAc/hexanes) to give the white solid. MS (ESI, positive ion) m/z: 389 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]([O:6][C:7]2[CH:18]=[CH:17][C:10]([O:11][CH:12]([CH3:16])[C:13]([OH:15])=[O:14])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[Cl:21][CH2:22][CH2:23][CH2:24][CH2:25]O.S(=O)(=O)(O)O.O>C(Cl)(Cl)Cl>[Cl:21][CH2:22][CH2:23][CH2:24][CH2:25][O:14][C:13](=[O:15])[CH:12]([O:11][C:10]1[CH:17]=[CH:18][C:7]([O:6][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:20][CH:19]=2)=[CH:8][CH:9]=1)[CH3:16]
Reactant: OCCCCCl
Reactant: CC(Oc1ccc(Oc2ccc(Cl)cc2)cc1)C(=O)O
Agent: O=S(=O)(O)O
Solvent: ClC(Cl)Cl
Solvent: O
Product: CC(Oc1ccc(Oc2ccc(Cl)cc2)cc1)C(=O)OCCCCCl

Procedure:
24.4 g=0.08 mol of 2-[4'-(4"-chlorophenoxy)phenoxy]-propionic acid, 10.8 g=0.1 mol of 4-chlorobutanol and 2 ml concentrated sulfuric acid in 50 ml chloroform were refluxed for 6 hours with azeotropic distillation of the reaction water. After cooling, the reaction mixture was washed twice with 100 ml water, neutralized with bicarbonate solution and washed with water until it was free from salt. After drying over calcium chloride and distillation of the solvent, 27.0 g=88% of the theory of 2-[4'-(4"-chlorophenoxy)phenoxy]-propionic acid 4-chlorobut-1-yl ester were obtained having a refractive index nD24 of 1.5517. ##STR16##
Reaction SMILES: Br[C:2]1[C:3]([C:8](O)=O)=[N:4][CH:5]=[CH:6][CH:7]=1.[CH3:11][O:12][C:13]1[C:14]([CH3:28])=[C:15](B2OC(C)(C)C(C)(C)O2)[CH:16]=[CH:17][CH:18]=1>>[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]2[CH2:8][C@H:3]3[C@@H:2]([C:15]=2[C:14]=1[CH3:28])[CH2:7][CH2:6][CH2:5][NH:4]3
Reactant: COc1cccc(B2OC(C)(C)C(C)(C)O2)c1C
Reactant: O=C(O)c1ncccc1Br
Product: COc1ccc2c(c1C)[C@H]1CCCN[C@H]1C2

Procedure:
The title compound is prepared from 3-bromo-pyridine-2-carboxylic acid and 2-(3-methoxy-2-methyl-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (may be prepared as in WO 2001053268 described) following the synthetic sequence and protocols described for Intermediate 41; since 3-bromo-pyridine-2-carboxylic acid instead of 3-bromo-pyridine-2-carbonitrile is used for the Suzuki-Miyaura coupling (Step 1 of Intermediate 41), hydrolysis of the nitrile (Step 2 of Intermediate 41) is omitted.
Reaction SMILES: [CH3:1][C:2]([CH3:12])([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:3][CH:4]=O.[NH2:13][C:14]1[C:19]([C:20]([F:23])([F:22])[F:21])=[CH:18][CH:17]=[CH:16][C:15]=1[C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=O.C(=O)(O)[O-].[Na+]>CC(O)=O>[CH3:12][C:2]([C:3]1[CH:4]=[N:13][C:14]2[C:15]([C:24]=1[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[CH:16][CH:17]=[CH:18][C:19]=2[C:20]([F:23])([F:22])[F:21])([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH3:1]
Reactant: CC(C)(CC=O)c1ccccc1
Reactant: Nc1c(C(=O)c2ccccc2)cccc1C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(C)(c1ccccc1)c1cnc2c(C(F)(F)F)cccc2c1-c1ccccc1
Temperature: 200 °C
Yield: 33.9 %

Procedure:
3,3-Dimethyl-3-phenylpropionaldehyde (0.272 g, 1.67 mmol) and [2-amino-3-(trifluoromethyl)phenyl](phenyl)methanone (0.138 g, 0.52 mmol) are dissolved in AcOH (3 mL) and treated with 1:20H2SO4/AcOH solution (0.10 mL). The mixture is heated in a microwave at 175° C. for 15 min and a further 5 min at 200° C. The reaction is carefully poured into saturated aq sodium bicarbonate and extracted with ethyl acetate. The extracts are washed with saturated aq sodium bicarbonate and dried (MgSO4). The product is chromatographed eluting with 5:95 ethyl acetate:hexane. The partially purified is further purified using Prep HPLC with a gradient of 10-100% acetonitrile/water to afford the title compound (0.069 g). HRMS: calcd for C25H20F3N+H, 392.16261; found (ESI, [M+H]+), 392.1637.
Reaction SMILES: [CH3:1][N:2]1[C:8](=[O:9])[C:7]2[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=2[N:5]2[CH:14]=[N:15][C:16]([C:17]([O:19]CC)=[O:18])=[C:4]2[CH2:3]1.[OH-].[Na+].Cl>C(O)C.O>[CH3:1][N:2]1[C:8](=[O:9])[C:7]2[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=2[N:5]2[CH:14]=[N:15][C:16]([C:17]([OH:19])=[O:18])=[C:4]2[CH2:3]1
Reactant: CCOC(=O)c1ncn2c1CN(C)C(=O)c1ccccc1-2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CN1Cc2c(C(=O)O)ncn2-c2ccccc2C1=O

Procedure:
A solution of 14.26 g (0.05 mol) of ethyl 5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate and 2.2 g (0.055 mol) of sodium hydroxide in 100 ml of ethanol and 20 ml of water is heated to boiling under reflux for 45 minutes and subsequently treated with 55 ml of 1 N hydrochloric acid and 50 ml of water. After distilling off the ethanol, the resulting crystal slurry is filtered off under suction, washed with water and dried. There is obtained 5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylic acid of melting point 287°.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH:10]2[C:18]3[C:13](=[CH:14][C:15]([C:19]4[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=4[C:21]#[N:22])=[CH:16][CH:17]=3)[CH2:12][CH2:11]2)[C:8](=[O:27])[C:7]2([CH2:31][CH2:30][CH2:29][CH2:28]2)[N:6]=1)[CH2:2][CH2:3][CH3:4].C[Sn]([N:36]=[N+:37]=[N-:38])(C)C>C1(C)C(C)=CC=CC=1>[CH2:1]([C:5]1[N:9]([CH:10]2[C:18]3[C:13](=[CH:14][C:15]([C:19]4[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=4[C:21]4[NH:38][N:37]=[N:36][N:22]=4)=[CH:16][CH:17]=3)[CH2:12][CH2:11]2)[C:8](=[O:27])[C:7]2([CH2:28][CH2:29][CH2:30][CH2:31]2)[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: C[Sn](C)(C)N=[N+]=[N-]
Reactant: CCCCC1=NC2(CCCC2)C(=O)N1C1CCc2cc(-c3ccccc3C#N)ccc21
Solvent: Cc1ccccc1C
Product: CCCCC1=NC2(CCCC2)C(=O)N1C1CCc2cc(-c3ccccc3-c3nnn[nH]3)ccc21
Temperature: 25 °C
Yield: 31.2 %

Procedure:
A mixture of 2-[1-(2-butyl-4-oxo-1,3-diaza-spiro[4.4]non-1-en-3-yl)-indan -5yl]-benzonitrile (150 mg, 0.36 mmol) and trimethyltin azide (196 mg, 0.91 mmol) was heated under reflux in xylene (5.0 mL) for 25 hours. The reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was chromatographed on SiO2 -gel using a gradient of 2.5% MeOH/CH2Cl2 to 10% MeOH/CH2Cl2 to give 51 mg of a colorless oil. The oil was dissolved in EtOAc and hexanes were added to precipitate the product. The white solid was filtered and dried. 1H NMR (250 MHz, d4 -MeOH): d 7.58 (m, 2 H), 7.47 (m, 2 H), 7.00 (s, 1 H), 6.85 (s, 2 H), 5.50 (t, 1 H), 2.95 (m, 2 H), 2.35 (m, 4 H), 1.90-1.41 (m), 1.22 (m, 2 H), 0.80 (t, 3 H).
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][N:10]([C:13](Cl)=[O:14])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:16]([O:18][CH:19]([O:32][CH2:33][CH3:34])[CH2:20][CH2:21][CH2:22][NH:23]C(C1CCCCC1)=O)[CH3:17]>>[CH2:33]([O:32][CH:19]([O:18][CH2:16][CH3:17])[CH2:20][CH2:21][CH2:22][NH:23][C:13]([N:10]1[CH2:11][CH2:12][N:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:8][CH2:9]1)=[O:14])[CH3:34]
Reactant: O=C(Cl)N1CCN(c2ccccc2)CC1
Reactant: CCOC(CCCNC(=O)C1CCCCC1)OCC
Product: CCOC(CCCNC(=O)N1CCN(c2ccccc2)CC1)OCC

Procedure:
4-Phenylpiperazine-1-carboxylic acid (4,4-diethoxybutyl)amide (61B) is prepared from 61A as described for 20A. The product is obtained in almost quantitative yield.
Reaction SMILES: CS(O[CH2:6][CH2:7][C@@H:8]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:9]1[CH:14]=[CH:13][C:12]([O:15][CH:16]([F:18])[F:17])=[CH:11][CH:10]=1)(=O)=O.[C-:27]#[N:28].[Na+].[Na+].[I-]>CS(C)=O.O>[C:27]([CH2:6][CH2:7][C@@H:8]([NH:19][C:20](=[O:21])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[C:9]1[CH:14]=[CH:13][C:12]([O:15][CH:16]([F:18])[F:17])=[CH:11][CH:10]=1)#[N:28]
Reactant: [C-]#N
Reactant: CC(C)(C)OC(=O)N[C@H](CCOS(C)(=O)=O)c1ccc(OC(F)F)cc1
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H](CCC#N)c1ccc(OC(F)F)cc1
Temperature: 85 °C
Reaction time: 0.5 h
Yield: 47 %

Procedure:
To a stirred solution of 388 in DMSO (5 mL) was added NaCN (92.0 mg, 1.88 mmol) and NaI (25.6 mg, 0.171 mmol) and the mixture heated at 85° C. overnight. After cooling to RT, the mixture was diluted with H2O (100 mL), stirred for 30 min and filtered to afford a tan solid. The solid was purified by SiO2 chromatography eluting with an EtOAc/hexane gradient (0 to 25% EtOAc) to afford 261 mg (47%) of (R)-tert-butyl 3-cyano-1-(4-(difluoromethoxy)phenyl)propylcarbamate (390) as a white solid.
Reaction SMILES: [Mg].Br[CH2:3][CH2:4][CH2:5][CH2:6][O:7][CH3:8].[C:9]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>CCOCC>[C:17]1([C:9]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)([OH:16])[CH2:3][CH2:4][CH2:5][CH2:6][O:7][CH3:8])[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: COCCCCBr
Reactant: O=C(c1ccccc1)c1ccccc1
Agent: [Mg]
Solvent: CCOCC
Product: COCCCCC(O)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a suspension of 3.9 g. (0.16 mole) of magnesium turnings in 300 ml. of dry ether was added dropwise 26.7 g. (0.16 mole) of 1-bromo-4-methoxybutane in 80 ml. of ether and the mixture refluxed for four hours. The reaction mixture was cooled and 14.6 g. (0.008 mole) of benzophenone in 100 ml. of dry ether was added dropwise. The mixture was stirred at ambient temperature for 18 hours, cautiously quenched with water and the ether layer separated. The aqueous layer was extracted with ether and the combined ether extract was dried and concentrated to give 1,1-diphenyl-5-methoxy-1-pentanol, m.p. 112°-115° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([OH:19])[CH:17]=2)[NH:12][N:11]=1.[N+](C1C=CC([O:29][P:30]([CH3:33])([CH3:32])=O)=CC=1)([O-])=O.N12CCCN=C1CCCCC2>ClCCl>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([O:19][P:30]([CH3:33])([CH3:32])=[O:29])[CH:17]=2)[NH:12][N:11]=1
Reactant: CP(C)(=O)Oc1ccc([N+](=O)[O-])cc1
Reactant: Oc1ccc2[nH]nc(-c3cc4ccccc4[nH]3)c2c1
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: CP(C)(=O)Oc1ccc2[nH]nc(-c3cc4ccccc4[nH]3)c2c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 43 %

Procedure:
The dimethylphosphinic acid 3-(1H-indol-2-yl)-1H-indazol-5-yl ester compound is prepared according to procedure F using 230 mg of 3-(1H-indol-2-yl)-1H-indazol-5-ol (intermediate B) in solution with 245 mg of dimethylphosphinic acid 4-nitrophenyl ester in 5 ml of dichloromethane (stabilized with amylene) to which 170 μl of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in solution in 2 ml of dichloromethane are added. After stirring for 24 h at ambient temperature, the solvent is evaporated off and the crude is purified by preparative LC/MS. The crystals obtained after concentration of the fractions are washed with ethyl acetate and then with isopropyl ether. 129 mg of expected product are collected. Yield=43%.