Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=O)[CH2:4][NH:5][C:6](=O)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(Cl)(Cl)Cl.[SH2:19]>>[CH3:1][O:2][C:3]1[S:19][C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:5][CH:4]=1
Reactant: COC(=O)CNC(=O)c1ccccc1
Reactant: S
Solvent: ClC(Cl)Cl
Product: COc1cnc(-c2ccccc2)s1
Temperature: 80 °C

Procedure:
1.0 g (5.2 mmol) of benzoylglycin methyl ester and 1.4 g (6.4 mmol) of diphosphorous pentasulfide was added quickly into a reaction vessel. After that, anhydrous chloroform (15 ml) was also added and heated to around 80° C. When decrease in hydrogen sulfide generation and white precipitate formation in the reaction solution were observed, an argon balloon was attached and the solution was refluxed for 24 hours. After completion of reaction, the precipitate was dissolved by adding an aqueous solution of strong alkali to the solution, and the organic phase was extracted with dichloromethane, followed by drying with addition of magnesium sulfate and removal of solvent. The product was developed with ethyl acetate:hexane=5:5 solvent on a silica column to give 5-methoxy-2-phenylthiazole (Rf=0.40). The yield was 566 mg in weight and 57% in percentage.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1C=[CH:11][C:10]([B:13]2[O:17][C:16]([CH3:19])([CH3:18])[C:15]([CH3:21])([CH3:20])[O:14]2)=[CH:9][N:8]=1)=[O:5])[CH3:2].CC1(C)C(C)(C)OB(C2C=[N:32]C(N)=NC=2)O1.C(N=C=O)C>>[CH2:1]([NH:3][C:4]([NH:6][C:7]1[N:8]=[CH:9][C:10]([B:13]2[O:14][C:15]([CH3:20])([CH3:21])[C:16]([CH3:18])([CH3:19])[O:17]2)=[CH:11][N:32]=1)=[O:5])[CH3:2]
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Reactant: CCNC(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: CCN=C=O
Product: CCNC(=O)Nc1ncc(B2OC(C)(C)C(C)(C)O2)cn1

Procedure:
The title compound was synthesized by a method analogous to Intermediate 1 synthesis starting with 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine and ethyl isocyanate. NMR (CDCl3): 1.23 (t, 3H), 1.32 (s, 12H), 3.41 (m, 2H), 7.95 (s, 1H), 8.76 (s, 2H), 9.10 (s, 1H).
Reaction SMILES: NC1C(C)=CC=CC=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[F:17])=[O:10].[Cl:18][C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][C:25]=1[Cl:26])[NH2:22].FC1C=CC=CC=1C#N>>[NH2:22][C:21]1[CH:20]=[C:19]([Cl:18])[C:25]([Cl:26])=[CH:24][C:23]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[F:17])=[O:10]
Reactant: Nc1ccc(Cl)c(Cl)c1
Reactant: Cc1cccc(C(=O)c2ccccc2F)c1N
Agent: N#Cc1ccccc1F
Product: Nc1cc(Cl)c(Cl)cc1C(=O)c1ccccc1F
Yield: 17 %

Procedure:
In a manner similar to that described above for compound 1b, 3,4-dichloroaniline and 2-fluorobenzonitrile were converted to 1ad (17% yield) MS m/z=284 (M+H).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:42]=[CH:43][C:44]=1[CH3:45])[CH2:7][O:8][CH:9]1[CH:14]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][CH2:24][O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[O:33][CH3:34])=[CH:17][CH:16]=2)[CH2:13][CH2:12][N:11]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:10]1)(O)=[O:2].C(Cl)(=O)C([Cl:49])=O.CN(C)C=O>ClCCl>[Cl:49][C:1]([C:4]1[CH:5]=[C:6]([CH:42]=[CH:43][C:44]=1[CH3:45])[CH2:7][O:8][CH:9]1[CH:14]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][CH2:24][O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[O:33][CH3:34])=[CH:17][CH:16]=2)[CH2:13][CH2:12][N:11]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:10]1)=[O:2]
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCc2ccc(C)c(C(=O)O)c2)cc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCc2ccc(C)c(C(=O)Cl)c2)cc1
Reaction time: 1 h

Procedure:
The solution of 0.474 g of tertbutyl 3-(3-carboxy-4-methylbenzyloxy)-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate in 12 ml of dichloromethane is admixed at 0° C. successively with 0.132 ml of oxalyl chloride and 0.005 ml of N,N-dimethylformamide. The reaction mixture is stirred over 1 hour and then concentrated by evaporation. The residue is dissolved once more in 20 ml of dichloromethane and concentrated by evaporation. This gives the crude title compound.
Reaction SMILES: [H-].[Na+].[Si:3]([O:20][CH2:21][CH2:22][O:23][CH2:24][C@H:25]([OH:36])[C:26]([NH:28][C:29]1[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][N:30]=1)=[O:27])([C:16]([CH3:19])([CH3:18])[CH3:17])([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl[C:38]1[N:43]=[CH:42][N:41]=[C:40]2[N:44]([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=3[Cl:53])[N:45]=[CH:46][C:39]=12.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1>[Si:3]([O:20][CH2:21][CH2:22][O:23][CH2:24][C@H:25]([O:36][C:38]1[N:43]=[CH:42][N:41]=[C:40]2[N:44]([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=3[Cl:53])[N:45]=[CH:46][C:39]=12)[C:26]([NH:28][C:29]1[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][N:30]=1)=[O:27])([C:16]([CH3:19])([CH3:18])[CH3:17])([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: Cc1ccc(NC(=O)[C@@H](O)COCCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)nc1
Reactant: Clc1ccccc1-n1ncc2c(Cl)ncnc21
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(NC(=O)[C@H](COCCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)Oc2ncnc3c2cnn3-c2ccccc2Cl)nc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 99 %

Procedure:
Sodium hydride (14.21 mg, 0.36 mmol) was added to (S)-3-(2-(tert-butyldiphenylsilyloxy)ethoxy)-2-hydroxy-N-(5-methylpyridin-2-yl)propanamide (Intermediate AU2) (85 mg, 0.18 mmol) in anhydrous THF (5 mL) at 0° C. under nitrogen. The resulting solution was stirred at 0° C. for 10 minutes and then 4-chloro-1-(2-chlorophenyl)-1H-pyrazolo[3,4-d]pyrimidine (47.1 mg, 0.18 mmol) was added. The reaction mixture was allowed to warm to room temperature and stirred for 1 hour. The reaction mixture was neutralised with 1M citric acid and the majority of the THF removed in vacuo. The reaction mixture was diluted with water (20 mL) and EtOAc (50 mL). The organic layer was separated and the aqueous layer re-extracted with EtOAc (2×20 mL). The combined organics were washed with saturated brine (10 mL), dried (MgSO4) and evaporated. The crude product was purified by flash silica chromatography, eluting with 0 to 20% EtOAc in isohexane to give (2S)-3-(2-(tert-butyldiphenylsilyloxy)ethoxy)-2-(1-(2-chlorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)-N-(5-methylpyridin-2-yl)propanamide (126 mg, 100%). 1H NMR (400 MHz, CDCl3) δ0.99 (s, 9H), 2.29 (s, 3H), 3.67-3.73 (m, 2H), 3.77-3.84 (m, 2H), 4.13-4.25 (m, 2H), 6.07 (t, 1H), 7.29-7.54 (m, 10H), 7.59-7.69 (m, 5H), 8.06-8.16 (m, 2H), 8.38 (s, 1H), 8.58 (s, 1H), 8.66 (s, 1H); m/z (ES+), (M+H)=707.62; HPLC tR=3.81 min
Reaction SMILES: CC(C)([O-])C.[K+].C(O)(C)(C)C.[CH3:12][O:13][C:14](=[O:20])[CH2:15][C:16](=[O:19])[CH2:17][CH3:18].Br[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([S:29]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)(=[O:31])=[O:30])=[CH:25][CH:24]=1>O1CCCC1>[CH3:12][O:13][C:14](=[O:20])[CH:15]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([S:29]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)(=[O:31])=[O:30])=[CH:25][CH:24]=1)[C:16](=[O:19])[CH2:17][CH3:18]
Reactant: O=S(=O)(c1ccc(CBr)cc1)N1CCOCC1
Reactant: CCC(=O)CC(=O)OC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: C1CCOC1
Product: CCC(=O)C(Cc1ccc(S(=O)(=O)N2CCOCC2)cc1)C(=O)OC
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
A suspension of potassium tert-butoxide (0.26 g) in anhydrous tetrahydrofuran (40 mL) at 0° C. was treated with a mixture of tert-butanol (1.0 mL) and 3-oxopentanoic acid methyl ester (0.25 mL). The mixture was stirred at 0° C. for 45 minutes and then a solution of 4-(4-bromomethylbenzenesulfonyl)morpholine (0.53 g) in tetrahydrofuran (10 mL) was added and the resulting mixture warmed to room temperature over 1 hour and then stirred at this temperature for 17 hours. The mixture was concentrated under reduced pressure and the residue diluted with water and extracted with ethyl acetate. The combined extracts were washed with saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solvent was removed under reduced pressure and the residue purified by column chromatography on silica gel, eluting with a mixture of ethyl acetate and cyclohexane (1:1 by volume) to afford title compound, 0.41 g.
Reaction SMILES: [CH2:1]([CH:3]1[C:11]2[C:10](O)=[N:9][CH:8]=[N:7][C:6]=2[CH2:5][S:4]1)[CH3:2].C(C1SC2C(O)=NC=NC=2C1)C.O=P(Cl)(Cl)[Cl:27]>ClCCCl.C(N(C(C)C)CC)(C)C>[Cl:27][C:10]1[C:11]2[CH:3]([CH2:1][CH3:2])[S:4][CH2:5][C:6]=2[N:7]=[CH:8][N:9]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCC1SCc2ncnc(O)c21
Agent: CCC1Cc2ncnc(O)c2S1
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCC1SCc2ncnc(Cl)c21
Yield: 28 %

Procedure:
To a solution of a mixture of 5-ethyl-5,7-dihydrothieno[3,4-d]pyrimidin-4-ol and 6-ethyl-6,7-dihydrothieno[3,2-d]pyrimidin-4-ol (2.32 g, 12.8 mmol) in 1,2-dichloroethane (50 mL) and diisopropylethylamine (4 mL) was added POCl3 (4 mL), and the mixture was refluxed overnight. The solvent was removed and the residue was purified by silica gel chromatography, eluting with Hexane/ethyl acetate (9:1-4:1) to give 4-chloro-5-ethyl-5,7-dihydrothieno[3,4-d]pyrimidine (0.49 g, 28%). 1H NMR (CDCl3, 400 MHz) δ 8.73 (s, 1H), 4.44 (m, 1H), 4.32-4.00 (m, 2H), 2.08 (m, 1H), 1.75 (m, 1H), 0.93 (m, 3H).
Reaction SMILES: O[CH2:2][C:3]1[O:7][N:6]=[C:5]([O:8][CH3:9])[CH:4]=1.S(Cl)([Cl:12])=O>>[Cl:12][CH2:2][C:3]1[O:7][N:6]=[C:5]([O:8][CH3:9])[CH:4]=1
Reactant: COc1cc(CO)on1
Reactant: O=S(Cl)Cl
Product: COc1cc(CCl)on1
Temperature: 25 °C
Reaction time: 20 h
Yield: 87.5 %

Procedure:
A mixture of 1.0 g 5-hydroxymethyl-3-methoxy-isoxazole and 10 g thionyl chloride was stirred at room temperature for 20 h. The excess thionylchloride was removed in vacuo, dissolved in toluene and the solvent evaporated. 1.0 g of an oil was obtained.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[O:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1.C(O)(=O)[CH2:15][C:16]([OH:18])=[O:17]>>[F:1][C:2]([F:13])([F:12])[O:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[CH:15][C:16]([OH:18])=[O:17])=[CH:6][CH:5]=1
Reactant: O=Cc1ccc(OC(F)(F)F)cc1
Reactant: O=C(O)CC(=O)O
Product: O=C(O)C=Cc1ccc(OC(F)(F)F)cc1

Procedure:
According to the previously described general procedure (GP1), Knoevenagel condensation (75° C.; 6 h) between 4-(trifluoromethoxy)benzaldehyde (10.000 g; 52.598 mmol) and malonic acid (10.399 g; 99.937 mmol) gave the product 3-(4-trifluoromethoxy-phenyl)-acrylic acid as a colorless solid (12.080 g; 99%). LC-MS: tR=0.96 min.; [M+H]+: no ionisation.
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:5][CH:6]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[CH:8]=1)=[O:4].[C:21](O)(=[O:28])[C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1>>[F:20][C:16]1[CH:15]=[C:14]([CH:6]([NH:5][C:3]([CH2:2][NH:1][C:21](=[O:28])[C:22]2[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=2)=[O:4])[C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[CH:8]=2)[CH:19]=[CH:18][CH:17]=1
Reactant: O=C(O)c1ccncc1
Reactant: NCC(=O)NC(c1cccc(F)c1)c1cccc(F)c1
Product: O=C(CNC(=O)c1ccncc1)NC(c1cccc(F)c1)c1cccc(F)c1

Procedure:
Prepared in analogy to example 1.12 from 2-amino-N-[bis-(3-fluoro-phenyl)-methyl]-acetamide (example 3.4) and isonicotinic acid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][C@H:8]([CH2:13][OH:14])[CH2:9][CH:10]([CH3:12])[CH3:11])([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.[CH3:25][S:26](Cl)(=[O:28])=[O:27]>ClCCl>[C:1]([O:5][C:6]([NH:7][C@@H:8]([CH2:9][CH:10]([CH3:11])[CH3:12])[CH2:13][O:14][S:26]([CH3:25])(=[O:28])=[O:27])=[O:15])([CH3:3])([CH3:2])[CH3:4]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)C[C@@H](CO)NC(=O)OC(C)(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)C[C@@H](COS(C)(=O)=O)NC(=O)OC(C)(C)C
Temperature: 25 °C

Procedure:
To a solution of ((1S)-1-hydroxymethyl-3-methyl-butyl)-carbamic acid tert-butyl ester (25 g, 115 mmol) in dichloromethane (500 ml) cooled by an ice-water bath was successively added diisopropylethylamine (35.7 g, 276 mmol) and methanesulphonyl chloride (15.81 g, 138 mmol). The resulting solution was stirred over night during which time the mixture was allowed to gradually warm up to ambient temperature. The mixture was washed successively with water, 10% citric acid (aq), water and saturated NaHCO3 (aq), then dried with Na2SO4 and concentrated to a brown solid (32.6 g, 96%) which was used in the next reaction without further purification.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:29][C:30]2[CH:42]=[CH:41][C:33]([C:34]([O:36]C(C)(C)C)=[O:35])=[CH:32][CH:31]=2)[C:7](/[CH:10]=[C:11]2\[N:12]([CH2:22][C:23]3[S:24][C:25]([CH3:28])=[CH:26][CH:27]=3)[C:13](=[O:21])[N:14]([CH2:17][CH2:18][CH2:19][CH3:20])[C:15]\2=[O:16])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4]>C(Cl)Cl.FC(F)(F)C(O)=O>[CH2:1]([C:5]1[N:6]([CH2:29][C:30]2[CH:31]=[CH:32][C:33]([C:34]([OH:36])=[O:35])=[CH:41][CH:42]=2)[C:7](/[CH:10]=[C:11]2\[N:12]([CH2:22][C:23]3[S:24][C:25]([CH3:28])=[CH:26][CH:27]=3)[C:13](=[O:21])[N:14]([CH2:17][CH2:18][CH2:19][CH3:20])[C:15]\2=[O:16])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ncc(/C=C2/C(=O)N(CCCC)C(=O)N2Cc2ccc(C)s2)n1Cc1ccc(C(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCc1ncc(/C=C2/C(=O)N(CCCC)C(=O)N2Cc2ccc(C)s2)n1Cc1ccc(C(=O)O)cc1
Reaction time: 16 h

Procedure:
1,1-dimethylethyl Z-4-[[2-butyl-5-[[1-butyl-3-[(5-methyl-2-thienyl)methyl]-2,5-dioxo-4-imidazolidinylidene]methyl]-1H-imidazol-1-yl]methyl]benzoate (0.56 g, 0.948 mmol) was dissolved in methylene chloride (10 mL) and trifluoroacetic acid (5 mL). After stirring for 16 hours the reaction mixture was evaporated in vacuo. pH 7 buffer was added and the mixture extracted with ethyl acetate. This extract was dried over MgSO4 and then evaporated in vacuo and crystallized from THF/ether.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([S:21](=[O:35])(=[O:34])[N:22]([CH:30]3[CH2:33][CH2:32][CH2:31]3)[C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:30]1([N:22]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=2)[S:21]([C:18]2[CH:19]=[CH:20][C:15]([O:14][CH:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)=[CH:16][CH:17]=2)(=[O:35])=[O:34])[CH2:33][CH2:32][CH2:31]1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(S(=O)(=O)N(c3cccc(F)c3)C3CCC3)cc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=S(=O)(c1ccc(OC2CCNCC2)cc1)N(c1cccc(F)c1)C1CCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73.7 %

Procedure:
To a solution of 4-{4-[cyclobutyl-(3-fluoro-phenyl)-sulfamoyl]-phenoxy}-piperidine-1-carboxylic acid tert-butyl ester (330 mg, 655 μmol) in DCM (9 mL) was added TFA (1 mL) and then the reaction was stirred at room temperature for 30 minutes. The reaction was concentrated and then purified by SCX eluting with 2 M NH3 in MeOH to give N-cyclobutyl-N-(3-fluoro-phenyl)-4-(piperidin-4-yloxy)-benzenesulfonamide (195 mg, 483 μmol). To a solution of N-cyclobutyl-N-(3-fluoro-phenyl)-4-(piperidin-4-yloxy)-benzenesulfonamide in DCM (10 mL) was added DIPEA (168 μL, 965 μmol) and methanesulfonyl chloride (41 μL, 531 μmol) and the reaction was stirred at room temperature for 30 minutes. Water was added and then extracted with DCM, filtered through a phase separator and concentrated. Purification by silica gel column chromatography (0-50% EtOAc in cyclohexane) followed by preparative reverse a phase HPLC gave the title compound (169 mg). 1H NMR δ (DMSO): 7.46 (2H, d, J=8.8 Hz), 7.38-7.39 (1H, m), 7.16-7.17 (3H, m), 6.77-6.78 (2H, m), 4.69-4.71 (1H, m), 4.20-4.22 (1H, m), 3.33-3.38 (4H, m), 3.13 (2H, ddd, J=12.1, 8.09, 3.4 Hz), 2.91 (3H, s), 2.03-2.06 (4H, m), 1.77-1.81 (4H, m), 1.53-1.56 (2H, m). LCMS (m/z, Method B) ES+ 482.9 [M+1]+.
Reaction SMILES: [CH2:1]([NH:8][C@H:9]([CH3:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[CH2:22]([O:24][C:25](=[O:41])[CH:26]=[CH:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[C:30]([F:40])[CH:29]=1)[CH3:23]>C1COCC1>[CH2:22]([O:24][C:25](=[O:41])[CH2:26][CH:27]([N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C@@H:9]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH3:16])[C:28]1[CH:33]=[CH:32][C:31]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)=[C:30]([F:40])[CH:29]=1)[CH3:23]
Reactant: C[C@@H](NCc1ccccc1)c1ccccc1
Reactant: CCOC(=O)C=Cc1ccc(-c2ccccc2)c(F)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)CC(c1ccc(-c2ccccc2)c(F)c1)N(Cc1ccccc1)[C@H](C)c1ccccc1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
A cooled (0° C.) solution of (R)-(+)-N-benzyl-α-methylbenzylamine (8.9 mL, 42.6 mmol) in THF (100 mL) was treated with n-butyllithium (26.6 mL of a 1.6 M soln in hexanes; 42.6 mmol). After stirring for 10 min, the purple solution was cooled to -78° C. and treated with a solution of ester 12-2 (5.76 g, 21.3 mmol) in THF (10 mL). After stirring for 20 min, the solution was quenched with satd aq NH4Cl soln (5 mL), and the cold bath removed. The reaction mixture was diluted with Et2O (100 mL), and washed with 10% aq citric acid (50 mL), satd aq NaHCO3 (50 mL), 5% aq acetic acid (30 mL), 10% aq K2CO3 (50 mL), and brine (50 mL). The solution was dried over MgSO4, filtered and concentrated. The residue was purified by flash chromatography (90:10 hexanes/EtOAc) to give adduct 12-3.
Reaction SMILES: [N+:1]([C:4]1[CH:20]=[CH:19][C:7]([C:8]([C:10]2[N:14]([CH3:15])[C:13]([CH2:16][C:17]#[N:18])=[CH:12][CH:11]=2)=[O:9])=[CH:6][CH:5]=1)([O-])=O>[Pd].C(OCC)(=O)C>[NH2:1][C:4]1[CH:20]=[CH:19][C:7]([C:8]([C:10]2[N:14]([CH3:15])[C:13]([CH2:16][C:17]#[N:18])=[CH:12][CH:11]=2)=[O:9])=[CH:6][CH:5]=1
Reactant: Cn1c(CC#N)ccc1C(=O)c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Cn1c(CC#N)ccc1C(=O)c1ccc(N)cc1

Procedure:
A solution of 7 g. (0.026 mole) of 5-(p-nitrobenzoyl)-1-methylpyrrole-2-acetonitrile in 450 ml. of ethyl acetate containing 1 g. palladium-on-carbon catalyst is hydrogenated in a Parr shaker under 44 p.s.i. of hydrogen until the theoretical amount of hydrogen is consumed. The catalyst is filtered off, and the solvent evaporated in vacuo. A yellow solid, 5-(p-aminobenzoyl)-1-methylpyrrole-2-acetonitrile remains, m.p. 137-142° C.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][C:9]([OH:11])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.[NH2:18][C:19]1[N:26]=[C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[O:33][Si:34]([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35])[CH:24]=[C:23]([C:41]2[CH:46]=[CH:45][CH:44]=[C:43]([NH2:47])[CH:42]=2)[C:20]=1[C:21]#[N:22]>ClCCl.C(#N)C>[NH2:18][C:19]1[C:20]([C:21]#[N:22])=[C:23]([C:41]2[CH:42]=[C:43]([NH:47][C:9](=[O:11])[CH2:8][CH2:7][N:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)[CH:44]=[CH:45][CH:46]=2)[CH:24]=[C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[O:33][Si:34]([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:35])[CH3:36])[N:26]=1
Reactant: O=C(O)CCN1CCCCC1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccccc1-c1cc(-c2cccc(N)c2)c(C#N)c(N)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CC#N
Product: CC(C)(C)[Si](C)(C)Oc1ccccc1-c1cc(-c2cccc(NC(=O)CCN3CCCCC3)c2)c(C#N)c(N)n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 43 %

Procedure:
To a cold (0° C.) solution of 3-(1-piperidinyl)-propanoic acid (0.676 g, 3.601 mmol) in dichloromethane was added oxalyl chloride (0.471 mL, 5.401 mmol) and stirred at room temperature for 12 hrs. The mixture was concentrated under reduced pressure. The residue was added to the solution of 2-amino-4-(3-aminophenyl)-6-(2-{[tert-butyl(dimethyl)silyl]oxy}-phenyl)nicotinonitrile (starting compound 2, 1.500 g, 3.601 mmol) in acetonitrile (3 mL), and the resulting mixture was stirred at 0° C. for 1 hr. The reaction mixture was extracted with ethyl acetate and water. The separated organic phase was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. Purification was carried out by silica gel column chromatography (chloroform/methanol=10/1) to give N-{3-[2-amino-6-(2-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-3-cyano-4-pyridinyl]phenyl}-3-(1-piperidinyl)propanamide as a white solid (0.860 g, yield 45%).
Reaction SMILES: [C:1]([C:4]1[C:5]([C:34]([F:37])([F:36])[F:35])=[N:6][C:7]([N:10]2[CH2:15][CH2:14][N:13]3[C:16]4[CH:22]=[C:21]([S:23]([CH3:26])(=[O:25])=[O:24])[C:20]([C:27](OC)=[O:28])=[CH:19][C:17]=4[N:18]=[C:12]3[C@H:11]2[CH:31]([CH3:33])[CH3:32])=[N:8][CH:9]=1)(=[O:3])[CH3:2].CC(C[AlH]CC(C)C)C.[NH4+].[Cl-]>C(Cl)Cl>[OH:28][CH2:27][C:20]1[C:21]([S:23]([CH3:26])(=[O:24])=[O:25])=[CH:22][C:16]2[N:13]3[CH2:14][CH2:15][N:10]([C:7]4[N:6]=[C:5]([C:34]([F:37])([F:36])[F:35])[C:4]([CH:1]([OH:3])[CH3:2])=[CH:9][N:8]=4)[CH:11]([CH:31]([CH3:32])[CH3:33])[C:12]3=[N:18][C:17]=2[CH:19]=1
Reactant: COC(=O)c1cc2nc3n(c2cc1S(C)(=O)=O)CCN(c1ncc(C(C)=O)c(C(F)(F)F)n1)[C@@H]3C(C)C
Agent: CC(C)C[AlH]CC(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Product: CC(O)c1cnc(N2CCn3c(nc4cc(CO)c(S(C)(=O)=O)cc43)C2C(C)C)nc1C(F)(F)F
Temperature: -78 °C
Reaction time: 3 h
Yield: 56.7 %

Procedure:
To a 50 mL three-necked flask containing (R)-methyl 2-(5-acetyl-4-(trifluoromethyl)pyrimidin-2-yl)-1-isopropyl-7-(methylsulfonyl)-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazine-8-carboxylate (150 mg, 0.278 mmol) in DCM (3 mL) was added DIBAL-H (1.10 mL, 1.11 mmol, 1.0 M in toluene) dropwise at −78° C. under N2. The mixture was stirred at −78° C. for 3 h. Sat. NH4Cl solution (10 mL) was added at −78° C. and the mixture was filtered. The aqueous layer was extracted with DCM (3×20 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by preparative TLC to give the racemic mixture (81.0 mg, 56.7% yield) as a white solid. The racemic mixture was purified by SFC separation to give isomer 1 (10.60 mg, 47.1% yield) as a white solid, isomer 2 (7.10 mg, 31.6% yield) as a white solid, isomer 3 (4.70 mg, 26.1% yield) as a white solid and isomer 4 (6.00 mg, 33.3% yield) as a white solid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([N:10]3[C:14]4=[N:15][C:16]([CH:19]=[CH2:20])=[CH:17][CH:18]=[C:13]4[N:12]=[CH:11]3)=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[Cl:21][CH2:22][CH2:23][CH2:24][S:25](Cl)(=[O:27])=[O:26].C(N(CC)C(C)C)(C)C>ClCCl>[Cl:21][CH2:22][CH2:23][CH2:24][S:25]([N:1]1[C:9]2[C:4](=[CH:5][C:6]([N:10]3[C:14]4=[N:15][C:16]([CH:19]=[CH2:20])=[CH:17][CH:18]=[C:13]4[N:12]=[CH:11]3)=[CH:7][CH:8]=2)[CH2:3][CH2:2]1)(=[O:27])=[O:26]
Reactant: O=S(=O)(Cl)CCCCl
Reactant: C=Cc1ccc2ncn(-c3ccc4c(c3)CCN4)c2n1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=Cc1ccc2ncn(-c3ccc4c(c3)CCN4S(=O)(=O)CCCCl)c2n1

Procedure:
A solution of 3-(2,3-dihydro-1H-indol-5-yl)-5-vinyl-3H-imidazo[4,5-b]pyridine (270 mg, 1.03 mmol) (Intermediate 10.1), 3-chloropropanesulfonyl chloride (0.25 ml, 2.06 mmol), and N,N-diisopropylethylamine (1.08 ml, 6.18 mmol) in dichloromethane (15 ml) is stirred for 10 min at ambient temperature. The mixture is successively extracted with saturated aqueous ammonium chloride and saturated aqueous sodium bicarbonate. The organic layer is dried over sodium sulfate and concentrated in vacuo to render 351 mg (85%) of the respective sulfonamide. HPLC (over 10 min 10-85% MeCN/100 mM aq. NaOAc): 92% purity, tR 8.44 min (tR(SM) 6.59 min). MS (ESI) m/z (C19H19ClN4O2S) 403.0 (M, 100), 294.9 (65) Finnegan LCQ.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3](B(O)O)=[CH:2]1.[N+:9]([C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=1)[CH2:15]Br)([O-:11])=[O:10]>>[N+:9]([C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=1)[CH2:15][C:3]1[CH:4]=[CH:5][O:1][CH:2]=1)([O-:11])=[O:10]
Reactant: OB(O)c1ccoc1
Reactant: O=[N+]([O-])c1cccc(CBr)c1
Product: O=[N+]([O-])c1cccc(Cc2ccoc2)c1
Yield: 84 %

Procedure:
Using the same method as in Example 19-(ii), 3-furanboronic acid was reacted with the 3-nitrobenzyl bromide to give 3-(3-nitrobenzyl)furan (yield: 84%).