Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O-2].[Zn+2:2].[C:3]([OH:26])(=[O:25])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]>O>[C:3]([O-:26])(=[O:25])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].[Zn+2:2].[C:3]([O-:26])(=[O:25])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCCCCCCCCCCCCCCCCCCC(=O)O
Agent: [O-2]
Agent: [Zn+2]
Solvent: O
Product: CCCCCCCCCCCCCCCCCCCCCC(=O)[O-]
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
A suspension consisting of 8.5 g zinc oxide (95% active, precipitated, particle size 50μ, density 5.4 g/cm3) and 67.8 g behenic acid (AN 165, titer 75° C., particle size 0.2-0.3 mm.) which has been obtained as a granulate from an aqueous dispersion as described in Example 1 and is contained in 1.3 liters of water, is stirred first for 30 minutes at 60° C. and then heated to 100° C. After agitation for one hour at this temperature the granulate still contains 4.4% free fatty acid. After 2 hours this is reduced to 2.7% and after 3 hours only 2.0% free fatty acid remains.
Reaction SMILES: [CH3:1][CH:2]1[CH2:4][CH:3]1[CH2:5][C:6]1[NH:7][C:8](=[O:21])[N:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:17]([F:20])([F:19])[F:18])[N:10]=1.[C:22]([NH:26][S:27]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[C:36]1[CH:41]=[CH:40][C:39]([CH2:42]Br)=[CH:38][CH:37]=1)(=[O:29])=[O:28])([CH3:25])([CH3:24])[CH3:23]>>[C:22]([NH:26][S:27]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[C:36]1[CH:41]=[CH:40][C:39]([CH2:42][N:7]2[C:6]([CH2:5][CH:3]3[CH2:4][CH:2]3[CH3:1])=[N:10][N:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[C:17]([F:20])([F:19])[F:18])[C:8]2=[O:21])=[CH:38][CH:37]=1)(=[O:29])=[O:28])([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)(C)NS(=O)(=O)c1ccccc1-c1ccc(CBr)cc1
Reactant: CC1CC1Cc1nn(-c2ccccc2C(F)(F)F)c(=O)[nH]1
Product: CC1CC1Cc1nn(-c2ccccc2C(F)(F)F)c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(C)(C)C)cc1

Procedure:
The title compound was prepared from 2,4-dihydro-5-[(2-methylcylopropyl)methyl]-2-[2-(trifluoromethyl)phenyl]-3H-1,2,4-triazol-3-one (from Step E) and [2'-(N-t-butylsulfamoyl)biphenyl-4-yl]methyl bromide (from Example 12, Step D) according to the procedure of Example 13, Step A. The crude material was purified by flash chromatography over silica gel (gradient elution using 0.3-1.0% MeOH/CH2Cl2) to give a 64% yield of the desired material as a cream-colored solid, homogeneous by TLC in 2% MeOH/CH2Cl2 ; mass spectrum (FAB) m/e 599 (M+1)+ ; mp 128°-130° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[CH2:5]Cl.[I:13][C:14]1[C:15]([C:19]([F:22])([F:21])[F:20])=[N:16][NH:17][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[I:13][C:14]1[C:15]([C:19]([F:22])([F:21])[F:20])=[N:16][N:17]([CH2:5][C:4]2[CH:7]=[CH:8][C:9]([N+:10]([O-:12])=[O:11])=[C:2]([CH3:1])[CH:3]=2)[CH:18]=1
Reactant: Cc1cc(CCl)ccc1[N+](=O)[O-]
Reactant: FC(F)(F)c1n[nH]cc1I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cc(Cn2cc(I)c(C(F)(F)F)n2)ccc1[N+](=O)[O-]
Yield: 64.4 %

Procedure:
3-Methyl-4-nitrobenzyl chloride (0.77 g), 4-iodo-3-trifluoromethyl-1H-pyrazole (0.99 g) and potassium carbonate (0.63 g) were stirred in DMF (10 ml) at 60° C. for 1 hour. After cooling, the reaction solution was diluted with ethyl acetate and washed with water and saturated aqueous solution of sodium chloride. After drying the organic layer with magnesium sulfate, the solvent was distilled off under the reduced pressure and the obtained residue was purified by silica gel column chromatography to obtain 4-iodo-1-(3-methyl-4-nitrobenzyl)-3-trifluoromethyl-1H-pyrazole (1.0 g).
Reaction SMILES: [C:1]1([CH3:12])[CH:6]=[CH:5][C:4]([S:7]([C:10]#[N:11])(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH3:13][N:14]=[N+:15]=[N-:16]>C1C=CC=CC=1>[CH3:13][N:14]1[C:10]([S:7]([C:4]2[CH:3]=[CH:2][C:1]([CH3:12])=[CH:6][CH:5]=2)(=[O:8])=[O:9])=[N:11][N:16]=[N:15]1
Reactant: Cc1ccc(S(=O)(=O)C#N)cc1
Reactant: CN=[N+]=[N-]
Solvent: c1ccccc1
Product: Cc1ccc(S(=O)(=O)c2nnnn2C)cc1

Procedure:
A mixture of 36.2 g. (0.2 mol.) of p-toluenesulfonyl cyanide [M. J. Cox and R. Ghosh, Tet. Letters, 3351 (1969)] and 50 g. (0.9 mol.) of methyl azide [O. Dimroth, Ber., 38, 1572 (1905)] in 100 ml. of benzene is heated in a sealed bomb at 80° for 4 hours. The reaction mixture is filtered and allowed to cool to give 42 g. of crystallize product, m.p. 110°-111° C.
Reaction SMILES: [C:1]([C:4]1[CH:34]=[CH:33][C:7]([CH2:8][N:9]2[CH2:14][CH2:13][CH:12]([CH2:15][NH:16][C:17](=[O:32])[CH2:18][NH:19][C:20](=[O:31])[C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=3)[CH2:11][CH2:10]2)=[CH:6][CH:5]=1)(O)=[O:2].S(Cl)([Cl:37])=O>>[Cl:37][C:1]([C:4]1[CH:34]=[CH:33][C:7]([CH2:8][N:9]2[CH2:14][CH2:13][CH:12]([CH2:15][NH:16][C:17](=[O:32])[CH2:18][NH:19][C:20](=[O:31])[C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=3)[CH2:11][CH2:10]2)=[CH:6][CH:5]=1)=[O:2]
Reactant: O=S(Cl)Cl
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NCC1CCN(Cc2ccc(C(=O)O)cc2)CC1
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NCC1CCN(Cc2ccc(C(=O)Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of 1-(4-carboxybenzyl)-4-[{N-(3-(trifluoromethyl)benzoyl)glycyl}aminomethyl]piperidine (240 mg) and thionyl chloride (1 mL) was stirred at room temperature for 12 h and the excess thionyl chloride was removed under reduced pressure to give desired 1-[4-(chloroformyl)benzyl]-4-[{N-(3-(trifluoromethyl)benzoyl)glycyl}aminomethyl]piperidine. The acid chloride was used without further purification.
Reaction SMILES: OC(C(F)(F)F)=O.OC(C(F)(F)F)=O.[CH:15]12[O:22][CH:19]([CH2:20][CH2:21]1)[CH2:18][N:17]([C:23]1[N:28]=[C:27]([N:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)[N:26]=[C:25]([C:35]3[CH:40]=[CH:39][C:38]([NH:41][C:42]([NH:44][C:45]4[CH:50]=[CH:49][N:48]=[CH:47][CH:46]=4)=[O:43])=[CH:37][CH:36]=3)[N:24]=1)[CH2:16]2.[N:51]1[CH:56]=[CH:55][CH:54]=[C:53]([CH:57]=O)[CH:52]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.C(N(CC)CC)C>[CH:19]12[O:22][CH:15]([CH2:21][CH2:20]1)[CH2:16][N:17]([C:23]1[N:28]=[C:27]([N:29]3[CH2:34][CH2:33][N:32]([CH2:57][C:53]4[CH:52]=[N:51][CH:56]=[CH:55][CH:54]=4)[CH2:31][CH2:30]3)[N:26]=[C:25]([C:35]3[CH:36]=[CH:37][C:38]([NH:41][C:42]([NH:44][C:45]4[CH:46]=[CH:47][N:48]=[CH:49][CH:50]=4)=[O:43])=[CH:39][CH:40]=3)[N:24]=1)[CH2:18]2
Reactant: O=C(Nc1ccncc1)Nc1ccc(-c2nc(N3CCNCC3)nc(N3CC4CCC(C3)O4)n2)cc1
Reactant: O=Cc1cccnc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(Nc1ccncc1)Nc1ccc(-c2nc(N3CCN(Cc4cccnc4)CC3)nc(N3CC4CCC(C3)O4)n2)cc1

Procedure:
1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(piperazin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea-2TFA (150 mg) in dichloromethane (4 mL) and triethylamine (0.12 mL) was treated with 3-pyridinecarboxaldehyde (0.1 mL), followed by sodium triacetoxyborohydride (80 mg). The mixture was concentrated to dryness and purified on HPLC to give the title compound as its tri-TFA salt; MS (ES+) 579.3 (M+H)+
Reaction SMILES: [C:1]([O:9][C@H:10]1[C@H:14]([OH:15])[CH2:13][N:12]([C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[C@H:11]1[CH2:26][F:27])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC(Cl)(Cl)C(=N)O[CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.FC(F)(F)S(O)(=O)=O.C(=O)([O-])O.[Na+]>C(Cl)Cl.C1CCCCC1.C(OCC)(=O)C>[C:1]([O:9][C@H:10]1[C@@H:14]([O:15][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:13][N:12]([C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[C@H:11]1[CH2:26][F:27])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N=C(OCc1ccccc1)C(Cl)(Cl)Cl
Reactant: O=C(O[C@H]1[C@H](O)CN(C(=O)OCc2ccccc2)[C@H]1CF)c1ccccc1
Agent: O=C([O-])O
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Na+]
Solvent: C1CCCCC1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C(O[C@H]1[C@@H](OCc2ccccc2)CN(C(=O)OCc2ccccc2)[C@H]1CF)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 72 %

Procedure:
The compound (344 mg, 0.92 mmol) synthesized in Example 10 (10a) was dissolved in methylene chloride:cyclohexane (1:2, 10 mL) and benzyl trichloroacetoimidate (0.68 mL, 3.68 mmol) and trifluoromethane sulfonic acid (16 μL, 0.18 mmol) were added thereto, followed by stirring of the mixture at room temperature for 4 hours. After saturated aqueous sodium hydrogencarbonate (1 mL) was added to the reaction mixture at 0° C. and the mixture was diluted with ethyl acetate (20 mL), the mixture was washed with water (20 mL) and 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, 8:1-5:1, V/V) to obtain a colorless oil (307 mg, 68%).
Reaction SMILES: [N+](C1C=C(C)C=CC=1)([O-])=O.[Na].[N+:12]([C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=[O:20])=[CH:17][CH:16]=1)([O-])=O>>[NH2:12][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=[O:20])=[CH:17][CH:16]=1
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Agent: Cc1cccc([N+](=O)[O-])c1
Agent: [Na]
Product: Nc1ccc(C(=O)O)cc1

Procedure:
In place of 3-nitrotoluene of Example 7 there is charged the sodium salt of p-nitrobenzoic acid. A ca. 90% conversion of the nitro compound to p-aminobenzoic acid is obtained.
Reaction SMILES: [CH3:1][C:2]([OH:6])([C:4]#[CH:5])[CH3:3].FC(F)(F)C(OC(=O)C(F)(F)F)=O.O[C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][CH:30]=1)[N:27]=[CH:26][CH:25]=[CH:24]2.Cl>C(#N)C.[Cu]Cl>[CH3:1][C:2]([O:6][C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][CH:30]=1)[N:27]=[CH:26][CH:25]=[CH:24]2)([CH3:3])[C:4]#[CH:5]
Reactant: C#CC(C)(C)O
Reactant: Oc1ccc2ncccc2c1
Agent: Cl[Cu]
Agent: Cl
Solvent: CC#N
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: C#CC(C)(C)Oc1ccc2ncccc2c1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
A solution of 2-methyl-3-butyn-2-ol (2.45 mL, 25.1 mmol) and 1,8-diazabicyclo-[5.4.0]-7-undecene (4.25 mL, 28.4 mmol) in acetonitrile (15.5 mL) was stirred 0° C. for 30 minutes, and trifluoroacetic anhydride (3.55 mL, 25.1 mmol) was added dropwise. The resulting mixture was added dropwise to a mixed solution of 6-hydroxyquinoline (2.43 g, 16.7 mmol), copper (I) chloride (8.3 mg, 0.0835 mmol), acetonitrile (15.5 mL) and 1,8-diazabicyclo-[5.4.0]-7-undecene (4.25 mL, 28.4 mmol) at 0° C., and stirred at 0° C. for 3 hours. The resulting solution was acidified with 1 mol/L HCl and extracted with ethyl acetate, and the resulting aqueous phase was neutralized with aqueous sodium hydrogencarbonate solution, extracted with ethyl acetate, and dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue was purified by column chromatography (hexane/ethyl acetate=1/1 to 1/3) and the aimed product was obtained.
Reaction SMILES: [CH:1]1[C:11]2[C:10]3=[CH:12][C:13]4[CH:14]=[CH:15][C:16]([C:19]([O:21]C)=[O:20])=[CH:17][C:18]=4[N:9]3[CH2:8][CH:7]=[CH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.N1(C2N=CC=CN=2)CCNCC1.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[CH:1]1[C:11]2[C:10]3=[CH:12][C:13]4[CH:14]=[CH:15][C:16]([C:19]([OH:21])=[O:20])=[CH:17][C:18]=4[N:9]3[CH2:8][CH:7]=[CH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)c1ccc2cc3n(c2c1)CC=Cc1ccccc1-3
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: c1cnc(N2CCNCC2)nc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)c1ccc2cc3n(c2c1)CC=Cc1ccccc1-3
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a stirred solution of methyl 7H-indolo[2,1-a][2]benzazepine-10-carboxylate, 13-cyclohexyl, 6-carboxylic acid (150 mg, 0.36 mmol), 2-(piperazin-1-yl)pyrimidine (63 mg, 0.38 mmol) and triethylamine (0.10 mL) in DMF (2 mL) was added HATU (160 mg, 0.42 mmol). The reaction mixture was stirred at rt for 15 min., diluted with H2O (˜4 mL) and the solids were collected by filtration washed with H2O and dried under vacuum overnight to yield 7H-indolo[2,1-a][2]benzazepine-10-carboxylic acid, 13-cyclohexyl-6-[[4-(2-pyrimidinyl)-1-piperazinyl]carbonyl]-, methyl ester (168 mg, 0.30 mmol, 83%) as a yellow solid. 1H NMR (500 MHz, CDCl3) δ 8.28 (d, J=4.9 Hz, 2H), 8.16 (br s, 1H), 7.89 (d, J =8.6 Hz, 1H), 7.74 (dd, J=8.6 Hz, 1H), 7.59 (dd, J=7.6, 1.5 Hz, 1H), 7.52-7.45 (m, 2H), 7.40 (dd, J=7.3, 1.5 Hz, 1H), 7.25 (s, 1H), 6.51 (t, J=4.9 Hz, 1H), 5.15 (br s, 1H), 4.43(br s, 1H), 3.91 (s, 3H), 3.80-3.29 (m, 8H), 2.91-2.82 (m, 1H), 2.17-1.14 (m, 10H). LCMS: m/e 562 (M+H)+, ret time 2.07 min, column A, 2 minute gradient.
Reaction SMILES: [NH2:1][C:2]1(C#N)[CH2:7][C:6]([Cl:8])=[C:5]([F:9])[C:4](=[O:10])[N:3]1[CH3:11].S(=O)(=O)(O)O>C(O)=O>[Cl:8][C:6]1[C:7]2[C:4](=[O:10])[NH:3][CH:2]=[N:1][C:2]=2[N:3]([CH3:11])[C:4](=[O:10])[C:5]=1[F:9]
Reactant: CN1C(=O)C(F)=C(Cl)CC1(N)C#N
Agent: O=S(=O)(O)O
Solvent: O=CO
Product: Cn1c(=O)c(F)c(Cl)c2c(=O)[nH]cnc21
Temperature: 80 °C
Reaction time: 20 h

Procedure:
Combine 2-amino-5-fluoro-4-chloro-1-methyl-6-oxo-1,6-dihydropyridine-carbonitrile (4.97 g, 246 mmol) and 99% formic acid (40 mL, 8 volumes) in a dried vessel. Heat to 80° C. When a solution is formed add aqueous 9 N sulfuric acid (25 mL, 5 volumes). After 20 hours, cool ambient temperature and add ice-water (50 mL, 10 volumes) with stirring. Cool in an ice bath to give a solid. After 30 minutes, collect the solid by filtration, rinse with water (2×5 mL), and dry in vacuo to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]([CH3:17])([CH3:16])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][C:8]=1[CH:14]=O.[Cl:19][C:20]1[CH:28]=[C:27]2[C:23]([CH2:24][C:25](=[O:29])[NH:26]2)=[CH:22][CH:21]=1.N1CCCC1>CO>[CH3:1][O:2][C:3](=[O:18])[C:4]([CH3:17])([CH3:16])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][C:8]=1/[CH:14]=[C:24]1\[C:25](=[O:29])[NH:26][C:27]2[C:23]\1=[CH:22][CH:21]=[C:20]([Cl:19])[CH:28]=2
Reactant: COC(=O)C(C)(C)COc1ccc(Br)cc1C=O
Reactant: O=C1Cc2ccc(Cl)cc2N1
Solvent: CO
Solvent: C1CCNC1
Product: COC(=O)C(C)(C)COc1ccc(Br)cc1/C=C1\C(=O)Nc2cc(Cl)ccc21
Yield: 53.8 %

Procedure:
In a manner similar to the method described in Example 227b, 3-(4-bromo-2-formyl-phenoxy)-2,2-dimethyl-propionic acid methyl ester (3.4 g, 10.8 mmol) was reacted with 6-chlorooxindole (1.8 g, 10.8 mmol) and pyrrolidine (0.84 g, 11.8 mmol) in methanol to give E/Z-3-[4-Bromo-2-(6-chloro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-phenoxy]-2,2-dimethyl-propionic acid methyl ester as a yellow solid (2.7 g).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:8][CH2:9][CH2:10][N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[N:6][CH:7]=1.[Li]CCCC.[CH3:21][O:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][CH:32]=1)[C:29](=[O:33])[CH2:28][CH2:27][CH2:26]2.C([O-])(O)=O.[Na+]>C1COCC1>[CH3:21][O:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][CH:32]=1)[C:29]([C:2]1[CH:7]=[N:6][C:5]([O:8][CH2:9][CH2:10][N:11]3[CH2:15][CH2:14][CH2:13][CH2:12]3)=[CH:4][CH:3]=1)([OH:33])[CH2:28][CH2:27][CH2:26]2
Reactant: COc1ccc2c(c1)CCCC2=O
Reactant: Brc1ccc(OCCN2CCCC2)nc1
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc2c(c1)CCCC2(O)c1ccc(OCCN2CCCC2)nc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 44.5 %

Procedure:
To a solution of 5-Bromo-2-(2-pyrrolidin-1-ylethoxy)pyridine (7.0 g, 26 mmol) in dry THF (50 mL) at −78° C. was added n-BuLi (2.5 M in hexanes, 12.4 mL, 31.0 mmol) dropwise. After 30 min, 6-methoxy-1-tetralone (4.55 g, 25.8 mmol) in dry THF was added. After stirring for 15 min at −78° C., the reaction was allowed to warm to room temperature. After 30 min, the reaction was poured into aq NaHCO3 (satd). The aqueous layer was extracted with EtOAc (2×). The combined organic solutions were dried (MgSO4), filtered, and concentrated. Flash chromatography (CHCl3:MeOH, 95:5) provided the alcohol (4.23 g, 44%) as a white solid. 1H NMR (250 MHz, CDCl3): δ8.07 (d, J=2.5Hz, 1H), 7.49 (dd, J=2.5, 8.7 Hz, 1H), 7.00 (d, J=8.5 Hz, 1H), 6.73 (m, 3H), 4.45 (t, J=5.7 Hz, 2H), 3.79 (s, 3H), 2.92 (t, J=5.7 Hz, 2H), 2.76 (m, 2H), 2.67 (m, 4H), 2.11 (s, 1H), 2.08 (m, 3H), 1.82 (m, 5H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([F:10])[C:8]=1[F:9])[NH2:5].Cl[C:12]1([C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH2:17][CH2:16][CH2:15][N:14]2[C:18]([C:21]3[CH:26]=[CH:25][C:24]([C:27]4[O:31][C:30]([CH3:32])=[N:29][CH:28]=4)=[C:23]([O:33][CH3:34])[CH:22]=3)=[N:19][N:20]=[C:13]12>C(=O)([O-])O.[Na+]>[CH3:34][O:33][C:23]1[CH:22]=[C:21]([C:18]2[N:14]3[CH2:15][CH2:16][CH2:17][C:12]([NH:5][C:4]4[CH:3]=[C:2]([F:1])[C:8]([F:9])=[C:7]([F:10])[CH:6]=4)([C:35]([O:37][CH2:38][CH3:39])=[O:36])[C:13]3=[N:20][N:19]=2)[CH:26]=[CH:25][C:24]=1[C:27]1[O:31][C:30]([CH3:32])=[N:29][CH:28]=1
Reactant: Nc1cc(F)c(F)c(F)c1
Reactant: CCOC(=O)C1(Cl)CCCn2c(-c3ccc(-c4cnc(C)o4)c(OC)c3)nnc21
Agent: O=C([O-])O
Agent: [Na+]
Product: CCOC(=O)C1(Nc2cc(F)c(F)c(F)c2)CCCn2c(-c3ccc(-c4cnc(C)o4)c(OC)c3)nnc21
Temperature: 100 °C
Reaction time: 8 h
Yield: 56.8 %

Procedure:
To 3,4,5-trifluoroaniline (2.1 g) was added ethyl 8-chloro-3-[3-methoxy-4-(2-methyl-1,3-oxazol-5-yl)phenyl]-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyridine-8-carboxylate (1 g) at room temperature, and the mixture was stirred at 100° C. overnight under a nitrogen atmosphere. The reaction mixture was diluted with saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (719 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH3:11])(=[NH:10])=[O:9])=[C:4]([O:12][CH3:13])[CH:3]=1.[Br:14][C:15]1[C:16]([O:22][C@H:23]([CH3:27])[C@H:24]([OH:26])[CH3:25])=[N:17][C:18](Cl)=[N:19][CH:20]=1.Cl.C(O)CCC.CO>C(#N)C.O1CCOCC1>[Br:14][C:15]1[C:16]([O:22][C@H:23]([CH3:27])[C@H:24]([OH:26])[CH3:25])=[N:17][C:18]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([S:8]([CH3:11])(=[NH:10])=[O:9])=[C:4]([O:12][CH3:13])[CH:3]=2)=[N:19][CH:20]=1
Reactant: COc1cc(N)ccc1S(C)(=N)=O
Reactant: C[C@@H](O)[C@@H](C)Oc1nc(Cl)ncc1Br
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Solvent: CCCCO
Product: COc1cc(Nc2ncc(Br)c(O[C@H](C)[C@@H](C)O)n2)ccc1S(C)(=N)=O

Procedure:
220 mg (1.1 mmol) of (RS)-S-(4-amino-2-methoxyphenyl)-S-methyl sulfoximide and 280 mg (1.0 mmol) of (2R,3R)-3-[(5-bromo-2-chloropyrimidin-4-yl)oxy]-butan-2-ol in 10 ml of acetonitrile are mixed with 0.28 ml of a 4N solution of HCl in dioxane and stirred under reflux overnight. It is mixed with 1 ml of a solution of n-butanol/methanol (9:1) and stirred under reflux for another 5 days. The batch is concentrated by evaporation, and the residue is purified by chromatography (DCM/ethanol 8:2). 36 mg (0.1 mmol, corresponding to 8% of theory) of the product is obtained.
Reaction SMILES: [C:1]([N:8]1[C@H:12]([CH3:13])[CH2:11][CH2:10][C@H:9]1[CH2:14][OH:15])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[C:36]1[CH:45]=[CH:44][C:39]([C:40]([O:42][CH3:43])=[O:41])=[CH:38][CH:37]=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>>[C:1]([N:8]1[C@H:12]([CH3:13])[CH2:11][CH2:10][C@H:9]1[CH2:14][O:15][C:36]1[CH:45]=[CH:44][C:39]([C:40]([O:42][CH3:43])=[O:41])=[CH:38][CH:37]=1)([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: C[C@@H]1CC[C@@H](CO)N1C(=O)OC(C)(C)C
Reactant: COC(=O)c1ccc(O)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: COC(=O)c1ccc(OC[C@@H]2CC[C@@H](C)N2C(=O)OC(C)(C)C)cc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 99.2 %

Procedure:
To a stirred solution of N-Boc-2-(S)-hydroxymethyl-5-(R)-methylpyrrolidine (820 mg, 3.81 mmol), triphenylphosphine (1.10 g, 4.19 mmol) and methyl 4-hydroxybenzoate (580 mg, 3.81 mmol) was added diisopropyl azodicarboxylate (841 ml, 4.19 mmol) at rt, and the resulting mixture was stirred at 60° C. for 1 h. The mixture was concentrated in vacuo, and the residue was chromatographed on silica gel with hexane-EtOAc (5:1) as eluent to give methyl 4-[N-Boc-5-(R)-methyl-2-(S)-pyrrolidinylmethoxy]benzoate (1.32 g, 80%) as a colorless oil. 1H-NMR (CDCl3) δ1.24 (brs, 3 H), 1.49 (s, 9 H), 1.55-1.70 (m, 2 H), 1.94-2.11 (m, 2 H), 3.88 (s, 3 H), 3.88 (overlap, 1H), 4.06-4.20 (m, 2H), 6.93-6.96 (m, 2H), 7.97 (d, J=8.8 Hz, 2 H); MS (ESI) m/z, 350 (M++H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]([C:13]3[CH:18]=[CH:17][C:16]([C@:19]4([C:35](=[O:37])[NH2:36])[CH2:23][CH2:22][CH2:21][N:20]4[C:24](=[O:34])[C@@H:25]([NH:29][C:30](=[O:33])[O:31][CH3:32])[CH:26]([CH3:28])[CH3:27])=[CH:15][CH:14]=3)[CH2:11][CH2:10][CH:9]2[C:38]2[CH:43]=[CH:42][C:41]([C@:44]3([C:60](=[O:62])[NH2:61])[CH2:48][CH2:47][CH2:46][N:45]3[C:49](=[O:59])[C@@H:50]([NH:54][C:55](=[O:58])[O:56][CH3:57])[CH:51]([CH3:53])[CH3:52])=[CH:40][CH:39]=2)=[CH:4][CH:3]=1.[C:63]1(B(O)O)[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1COCC1.O.[Pd](Cl)Cl.C(P(C(C)(C)C)[C-]1C=CC=C1)(C)(C)C.[C-]1(P(C(C)(C)C)C(C)(C)C)C=CC=C1.[Fe+2]>[C:2]1([C:63]2[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=2)[CH:7]=[CH:6][C:5]([N:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([C@:19]4([C:35](=[O:37])[NH2:36])[CH2:23][CH2:22][CH2:21][N:20]4[C:24](=[O:34])[C@@H:25]([NH:29][C:30](=[O:33])[O:31][CH3:32])[CH:26]([CH3:28])[CH3:27])=[CH:15][CH:14]=3)[CH2:11][CH2:10][C@@H:9]2[C:38]2[CH:43]=[CH:42][C:41]([C@:44]3([C:60](=[O:62])[NH2:61])[CH2:48][CH2:47][CH2:46][N:45]3[C:49](=[O:59])[C@@H:50]([NH:54][C:55](=[O:58])[O:56][CH3:57])[CH:51]([CH3:53])[CH3:52])=[CH:40][CH:39]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@@]1(C(N)=O)c1ccc(C2CCC(c3ccc([C@]4(C(N)=O)CCCN4C(=O)[C@@H](NC(=O)OC)C(C)C)cc3)N2c2ccc(Br)cc2)cc1)C(C)C
Reactant: OB(O)c1ccccc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(C)(C)P([c-]1cccc1)C(C)(C)C
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)N[C@H](C(=O)N1CCC[C@@]1(C(N)=O)c1ccc([C@H]2CC[C@H](c3ccc([C@]4(C(N)=O)CCCN4C(=O)[C@@H](NC(=O)OC)C(C)C)cc3)N2c2ccc(-c3ccccc3)cc2)cc1)C(C)C
Yield: 75.4 %

Procedure:
The product from Example 86C (24.9 mg, 0.027 mmole) dissolved in a THF (1 mL) and water (0.3 mL) solution was combined in a microwave tube with phenylboronic acid (6.90 mg, 0.054 mmole), tribasic potassium phosphate (13.37 mg, 0.063 mmole) and 1,1′-bis(di-tert-butylphosphino)ferrocene palladium dichloride (1.42 mg, 2.17 μmole). The tube was sealed and nitrogen bubbled through at room temperature for five minutes. All gas lines were subsequently removed and the reaction vessel immersed in a 50° C. oil bath and heated for two and one half hours. The contents of the tube were partitioned between ethylacetate (5 mL) and brine (1 mL). The organic phase was washed with brine (2×1 mL) then dried over MgSO4, filtered and concentrated. The crude product was purified by silica gel chromatography eluting with 5% EtOAc-hexane and progressing to (75% EtOAc-hexane)+3% methanol to provide as a 1:1 mixture of (trans) diastereomers the title compound (18.6 mg, 75% yield) as a cream colored solid. 1H NMR (400 MHz, DMSO-D6) δ ppm 0.76-0.99 (m, 12H) 1.67 (s, 2H) 1.77-2.19 (m, 11H) 3.52 (s, 6H) 3.58-3.65 (m, 2H) 3.74-3.86 (m, 2H) 3.96-4.08 (m, 2H) 4.44 (d, J=4.99 Hz, 2H) 5.25 (s, 2H) 6.35 (d, J=8.02 Hz, 2H) 7.17 (d, J=7.26 Hz, 5H) 7.24-7.34 (m, 6H) 7.45 (d, J=7.92 Hz, 2H) 7.52 (d, J=7.81 Hz, 4H) 10.00 (s, 2H). MS ESI(+) m/z@915.1 (M+H)+, m/z@972.3 (M+CH3CN+NH4)+.