Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=1[O:19][CH3:20])[CH2:3][CH:4]([CH3:10])[C:5]([O:7]CC)=O.[CH3:21][N:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[C:23]1[CH:31]=O>>[CH3:18][O:17][C:16]1[CH:15]=[CH:14][CH:13]=[C:12]([O:19][CH3:20])[C:11]=1[CH:2]1[N:1]([CH2:31][C:23]2[N:22]([CH3:21])[C:30]3[C:25]([CH:24]=2)=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:5](=[O:7])[CH:4]([CH3:10])[CH2:3]1
Reactant: CCOC(=O)C(C)CC(N)c1c(OC)cccc1OC
Reactant: Cn1c(C=O)cc2ccccc21
Product: COc1cccc(OC)c1C1CC(C)C(=O)N1Cc1cc2ccccc2n1C

Procedure:
Prepared according to the described general procedure 2 (GP2) by reaction of ethyl 4-amino-4-(2,6-dimethoxyphenyl)-2-methylbutanoate with commercially available 1-methyl-1H-indole-2-carbaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.90 min.; [M+H]+: 379.05 g/mol.
Reaction SMILES: [BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[NH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1.[CH2:20]([N:27]1[CH2:31][CH2:30][CH2:29][C:28]1=O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C([O-])(O)=O.[Na+]>C1COCC1.C(O)(=O)C>[CH2:20]([N:27]1[CH2:31][CH2:30][CH:29]([N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[CH2:28]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: C1CCNC1
Reactant: O=C1CCCN1Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: c1ccc(CN2CCC(N3CCCC3)C2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3.82 g (18.0 mmol) NaBH(OAc)3 are added to a solution of 1.23 mL (15.0 mmol) pyrrolidine and 2.41 mL (15.0 mmol) N-benzylpyrrolidinone in 100 mL THF and acidified with 2 mL acetic acid. The reaction is stirred overnight at RT. The reaction solution is combined with 200 mL saturated NaHCO3 solution and extracted twice with 200 mL EtOAc. The organic phase is dried over MgSO4 and the solvent is eliminated i.vac. The purification is carried out by column chromatography on silica gel (EtOAc/MeOH/NH3 8:2:0.2).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@H:10]([CH:13]([CH3:15])[CH3:14])[CH2:11]O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C(=O)N([Br:42])C(=O)C1>C(Cl)Cl>[Br:42][CH2:11][C@@H:10]([CH:13]([CH3:15])[CH3:14])[CH2:9][O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)[C@H](CO)COCc1ccccc1
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)[C@H](CBr)COCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 61 %

Procedure:
To a solution of (R)-2-(benzyloxymethyl)-3-methylbutan-1-ol (54 g, 0.26 mol) in dry CH2Cl2 (2 L) at 0° C., Ph3P (88 g, 0.31 mol) and NBS (55.5 g, 0.31 mol) were added in portions. After stirring for 18 h at rt, the mixture was evaporated and the residue was purified by flash chromatography on silica gel to give (S)-((2-(bromomethyl)-3-methylbutoxy)methyl)benzene (43 g, 61%). 1H NMR (400 MHz, CDCl3): 0.94 (m, 6H), 1.71 (m, 1H), 1.85 (m, 1H), 3.48 (m, 1H), 3.57 (m, 1H), 3.62 (m, 1H), 3.68 (m, 1H), 4.52 (s, 2H), 7.31 (m, 5H)
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[O:8][CH2:9][C@@H:10]1[CH2:14][CH2:13][CH2:12][NH:11]1.[CH:15](O)=O.C=O>>[CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[O:8][CH2:9][C@@H:10]1[CH2:14][CH2:13][CH2:12][N:11]1[CH3:15]
Reactant: O=CO
Reactant: Cc1ccncc1OC[C@@H]1CCCN1
Agent: C=O
Product: Cc1ccncc1OC[C@@H]1CCCN1C

Procedure:
To a 330 mg sample of 4-methyl-3-(2-(S)-pyrrolidinylmethoxy)pyridine (from Example 27 above) was added a solution of formic acid/formaldehyde (1:2, 2 mL). The mixture was heated at reflux for 5 hours, and the volatiles were removed by evaporation. The residue was dissolved in 1 mL of 20% NaOH. The solution was extracted with CH2Cl2 (3×), then the organic layer was dried (Na2SO4) and concentrated. The crude product was purified by chromatography over silica gel to afford 295 mg of the title compound. MS (DCI/NH3) m/e: 207 (M+H)+. 1H NMR (CDCl3, 300 MHz) δ: 8.17 (s, 1H), 8.12 (d, J=5.5 Hz, 1H), 7.06 (d, J=5.5 Hz, 1H), 4.07 (dd, J=3.3, 10.6 Hz, 1H), 3.98 (dd, J=7.4, 10.6 Hz, 1H), 3.15-3.08 (m, 1H), 2.76-2.68 (m, 1H), 2.53 (s, 3H), 2.38-2.25 (m, 1H), 2.26 (s, 3H), 2.12-1.67 (m, 4H).
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=[O:7].S([O-])(O)(=O)=O.[Na+]>C(Cl)Cl.CC(O)C.O>[Cl:3][C:4]1[C:11]([C:12]([F:14])([F:15])[F:13])=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6][OH:7]
Reactant: O=Cc1cccc(C(F)(F)F)c1Cl
Agent: O=S(=O)([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Solvent: ClCCl
Product: OCc1cccc(C(F)(F)F)c1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 92.9 %

Procedure:
Sodium borohydride (2.54 g, 67.1 mmol) was added to a solution of 2-chloro-3-(trifluoromethyl)benzaldehyde (purchased at Interchim, cat. # 21117, 10.0 g, 47.9 mmol) in a mixture of DCM (40 ml) and 2-propanol (20 ml), while the mixture was cooled with a water bath. The reaction mixture was stirred for 16 hours at room temperature. At 0° C., a 10% aqueous solution of sodium hydrogensulphate (20 ml) was added dropwise. The reaction mixture was diluted with DCM (100 ml) and water (100 ml). The phases were separated. The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate (100 ml) and dried over magnesium sulphate. The solvent was removed in vacuo to give 9.37 g of crude (2-chloro-3-(trifluoromethyl)phenyl)methanol, which was used for the next step without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][C@H:15](/[CH:18]=[CH:19]\[CH:20]([CH3:22])[CH3:21])[CH2:14][CH2:13]2)=[O:10])=[CH:4][C:3]=1[O:23][CH3:24]>C(O)C.[Pd]>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][C@H:15]([CH2:18][CH2:19][CH:20]([CH3:21])[CH3:22])[CH2:14][CH2:13]2)=[O:10])=[CH:4][C:3]=1[O:23][CH3:24]
Reactant: COc1cc(CC(=O)N[C@H]2CC[C@H](/C=C\C(C)C)CC2)ccc1O
Agent: [Pd]
Solvent: CCO
Product: COc1cc(CC(=O)N[C@H]2CC[C@H](CCC(C)C)CC2)ccc1O

Procedure:
The compound (200 mg) of Example 14 was dissolved in ethanol (10 ml), 10% palladium/carbon (50 mg) was added to the mixture, and the mixture was hydrogenated at 25° C. The catalyst was removed by filtration from the reaction mixture, and the solvent was evaporated under reduced pressure. The residue was purified by a silica gel chromatography (eluent: chloroform) to give 145 mg of the desired compound.
Reaction SMILES: [C:1]([O:4][C:5]1[C:12]([C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:11][C:8]([CH:9]=O)=[CH:7][C:6]=1[C:17]([CH3:20])([CH3:19])[CH3:18])(=[O:3])[CH3:2].C1C=CC=CC=1.[C:27]([NH:31][OH:32])([CH3:30])([CH3:29])[CH3:28]>C(OCC)(=O)C>[C:1]([O:4][C:5]1[C:12]([C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:11][C:8]([CH:9]=[N+:31]([C:27]([CH3:30])([CH3:29])[CH3:28])[O-:32])=[CH:7][C:6]=1[C:17]([CH3:20])([CH3:19])[CH3:18])(=[O:3])[CH3:2]
Reactant: CC(C)(C)NO
Reactant: CC(=O)Oc1c(C(C)(C)C)cc(C=O)cc1C(C)(C)C
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Product: CC(=O)Oc1c(C(C)(C)C)cc(C=[N+]([O-])C(C)(C)C)cc1C(C)(C)C
Yield: 74.2 %

Procedure:
4-Acetoxy-3,5-di-tert-butylbenzaldehyde (113.16 g, 0.41 mol) was placed in a 2 L round-bottomed flask fitted with a magnetic stirrer. Benzene (500 mL) was added and the mixture was stirred until the solids dissolved. To the resulting red solution was added iert-butylhydroxylamine (43.80 g, 0.49 mol) and silica gel (20 g). The mixture was refluxed overnight at which time TLC showed no remaining startin material (Rf=0.31 for product and 0.80 for starting material using 3:1 hexanes/EtOAc). The benzene was removed in vacuo on a rotovap to provide a grey solid. The solid was dissolved in a minimum amount of ethyl acetate and the flask was left to stand in the freezer. The white crystals which formed were separated, washed with hexanes and dried under vacuum to afford 105.78 g of the title compound as a crystalline white solid (74.4% yield), m.p. 227.0-248.9° C.
Reaction SMILES: [OH:1][CH2:2][C@H:3]([N:5]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:15])[CH3:4].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:35][C:36]1[CH:41]=[CH:40][C:39]([F:42])=[CH:38][C:37]=1O.CCOC(/N=N/C(OCC)=O)=O>>[F:35][C:36]1[CH:41]=[CH:40][C:39]([F:42])=[CH:38][C:37]=1[O:1][CH2:2][C@H:3]([N:5]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:15])[CH3:4]
Reactant: C[C@H](CO)N1C(=O)c2ccccc2C1=O
Reactant: Oc1cc(F)ccc1F
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: C[C@H](COc1cc(F)ccc1F)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.9 %

Procedure:
A solution of 15.8 g (77 mmol) of (R)-2-(2-hydroxy-1-methylethyl)-1H-isoindole-1,3(2H)-dione, 24.2 g (92 mmol) of triphenylphosphine and 10.0 g (77 mmol) of 2,5-difluorophenol was stirred while 18.2 mL (116 mmol) of diethylazodicarboxylate was added dropwise. After stirring at ambient temperature overnight, solvent was removed and the residue was dissolved in ethyl acetate. The ethyl acetate was washed with water and brine. Drying (MgSO4) and removal of solvent gave an oil which was chromatographed on silica gel to give 15.6 g of the title compound of Step C as an oil, 1H NMR (CDCl3) δ 1.55 (d, 3H), 4.25 (m, 1H), 4.8 (m, 1H), 6.55 (m, 1H), 6.65 (m, 1H), 6.9 (m, 1H), 7.7 (m, 2H), 7.85 (m, 2H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12].C([Li])CCC.CN(C)[CH:23]=[O:24]>O1CCCC1>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH:23]=[O:24])[C:3]=1[NH:9][C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)C(=O)Nc1c(F)cccc1Br
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)Nc1c(F)cccc1C=O
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 80 %

Procedure:
N-(2-Bromo-6-fluorophenyl)pivalamide (7.0 g, 25.5 mmol) was dissolved in tetrahydrofuran (200 mL). The mixture was cooled to −78° C., and treated with butyllithium (2 M in cyclohexane, 31.0 mL, 62.0 mmol) dropwise. The reaction mixture was held at −78° C. for 30 minutes. A solution of N,N-dimethylformamide (10.0 mL, 129 mmol) in tetrahydrofuran (30 mL) was added to the reaction mixture dropwise. The reaction was held at −78° C. for 30 minutes and quenched by the addition of aqueous ammonium chloride. The mixture was allowed to warm to room temperature and extracted with ethyl acetate (2×). The combined organic layers were dried (magnesium sulfate), filtered, and concentrated. Silica gel chromatography afforded the desired product as white solid in 80% yield. 1H NMR (300 MHz, CDCl3): δ 9.93 (d, J=1.83, 1H), 9.14 (bs, 1H), 7.56-7.50 (m, 1H), 7.42-7.25 (m, 2H), 1.34 (s, 9H). Mass spec.: 224.2 (MH)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:16]=[C:17]([Cl:19])[CH:18]=1)[O:5][C:6]1[C:14]2[N:13]=[N:12][NH:11][C:10]=2[CH:9]=[CH:8][C:7]=1[Cl:15].[CH3:20][N:21](C=O)C>CCOC(C)=O.[C-]#N.[Zn+2].[C-]#N>[Cl:19][C:17]1[CH:18]=[C:2]([CH:3]=[C:4]([O:5][C:6]2[C:14]3[N:13]=[N:12][NH:11][C:10]=3[CH:9]=[CH:8][C:7]=2[Cl:15])[CH:16]=1)[C:20]#[N:21]
Reactant: CN(C)C=O
Reactant: Clc1cc(Br)cc(Oc2c(Cl)ccc3[nH]nnc23)c1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc3[nH]nnc23)c1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
4-(3-bromo-5-chlorophenoxy)-5-chloro-1H-1,2,3-benzotriazole (5.0 g, 14 mmol), tetrakis triphenylphosphine palladium (0) (4.83 g, 4.83 mmol) and zinc cyanide (1.96 g, 16.7 mmol) were suspended in dry DMF (50 mL) under N2 and placed in an oil bath at 90° C. After 2.5 hours, the reaction was allowed to cool to room temperature. The mixture was diluted with EtOAc (300 mL) and washed with water (4×100 mL), dried (MgSO4), filtered and concentrated with silica gel (20 g). This was purified by automated column chromatography on silica gel (120 g), eluting with 0-30% EtOAc/hexanes to deliver the title compound. LRMS (M+1)=304.8.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[C:11]#[N:12])=[CH:6][CH:5]=1.Cl[CH2:22][N:23]1[CH:27]=[N:26][CH:25]=[N:24]1>CN(C=O)C>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]([C:11]#[N:12])([CH2:13][CH2:14][N:15]2[CH2:16][CH2:17][O:18][CH2:19][CH2:20]2)[CH2:22][N:23]2[CH:27]=[N:26][CH:25]=[N:24]2)=[CH:8][CH:9]=1
Reactant: ClCn1cncn1
Reactant: N#CC(CCN1CCOCC1)c1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CC(CCN1CCOCC1)(Cn1cncn1)c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a flask was added 0.24 g. (5.5 mmoles) of a 55% oil dispersion of sodium hydride. After washing the sodium hydride with hexane to remove the mineral oil, 25 ml. of DMF was added, the solution cooled to 0° C., and then 1.3 g. (5.0 mmoles) of 2-(4-chlorophenyl)-4-(4-morpholinyl)butyronitrile in 15 ml. of DMF was slowly added. The solution was stirred for 30 minutes and then 0.59 g. (5.0 mmoles) of 1-(chloromethyl)-1,2,4-triazole in 10 ml. of DMF was added slowly. The reaction was stirred overnight at room temperature and then was poured into ice water. The organics were extracted into ethyl acetate, washed with water, dried over magnesium sulfate, filtered, and concentrated. The product was purified using chromatography by eluting the impurities with ethyl acetate and the desired 1-[2-(4-chlorophenyl)-2-cyano-4-(4-morpholinyl)butyl]-1,2,4-triazole product with acetone to give 1.0 g. (58% yield) of an orange oil.
Reaction SMILES: Br[C:2]1[S:3][C:4]([NH:32]C(=O)OC(C)(C)C)=[C:5]([C:7](=[O:31])[NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:30])[C:13]=2[C@@H:14]2[CH2:20][CH2:19][C@@H:18]([NH:21]C(OC(C)(C)C)=O)[C@@H:17]([F:29])[CH2:16][O:15]2)[N:6]=1.[F:40][C:41]1[CH:46]=[C:45]([C:47]([F:50])([F:49])[F:48])[CH:44]=[CH:43][C:42]=1B(O)O>>[NH2:32][C:4]1[S:3][C:2]([C:42]2[CH:43]=[CH:44][C:45]([C:47]([F:50])([F:49])[F:48])=[CH:46][C:41]=2[F:40])=[N:6][C:5]=1[C:7]([NH:8][C:9]1[CH:10]=[N:11][N:12]([CH3:30])[C:13]=1[C@@H:14]1[CH2:20][CH2:19][C@@H:18]([NH2:21])[C@@H:17]([F:29])[CH2:16][O:15]1)=[O:31]
Reactant: OB(O)c1ccc(C(F)(F)F)cc1F
Reactant: Cn1ncc(NC(=O)c2nc(Br)sc2NC(=O)OC(C)(C)C)c1[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@@H](F)CO1
Product: Cn1ncc(NC(=O)c2nc(-c3ccc(C(F)(F)F)cc3F)sc2N)c1[C@@H]1CC[C@@H](N)[C@@H](F)CO1

Procedure:
Following the procedure for Example 101 starting from tert-butyl N-[2-bromo-4-[[5-[(2S,5R,6R)-5-(tert-butoxycarbonylamino)-6-fluoro-oxepan-2-yl]-1-methyl-pyrazol-4-yl]carbamoyl]thiazol-5-yl]carbamate (Intermediate 88), and replacing 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester with (2-fluoro-4-(trifluoromethyl)phenyl)boronic acid gave 259. 1H NMR (400 MHz, DMSO-d6) δ 9.54 (s, 1H), 8.31 (q, J=9.1, 8.5 Hz, 1H), 7.93-7.84 (m, 1H), 7.83-7.71 (m, 2H), 7.61 (s, 2H), 5.17-4.82 (m, 2H), 4.31-4.14 (m, 1H), 4.08-3.93 (m, 1H), 3.77 (s, 3H), 3.51-3.37 (m, 1H), 2.19-2.05 (m, 1H), 1.98-1.81 (m, 2H), 1.75-1.67 (m, 1H). LCMS (ES+) m/z 517 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:28])=[C:6]([CH:27]=1)/[CH:7]=[C:8]1/[C:9](=[O:26])[N:10]([S:16]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:11][C:12](=[O:15])[NH:13][CH2:14]/1.ClC1C=CC(S(N)(=O)=O)=CC=1.C(=O)([O-])O.[Na+].[I-].[Na+].Br[CH2:48][C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50]>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:28][CH2:48][C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])=[C:6](/[CH:7]=[C:8]2\[CH2:14][NH:13][C:12](=[O:15])[CH2:11][N:10]([S:16]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)(=[O:18])=[O:17])[C:9]\2=[O:26])[CH:27]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: O=C1CN(S(=O)(=O)c2ccc(Cl)cc2)C(=O)/C(=C/c2cc(Cl)ccc2O)CN1
Agent: NS(=O)(=O)c1ccc(Cl)cc1
Agent: O=C([O-])O
Agent: [I-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)COc1ccc(Cl)cc1/C=C1\CNC(=O)CN(S(=O)(=O)c2ccc(Cl)cc2)C1=O
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To (6E)-6-(5-chloro-2-hydroxybenzylidene)-4-[(4-chlorophenyl)sulfonyl]-1,4-diazepan-2,5-dione (364 mg), synthesized from the compound S21 and 4-chlorobenzenesulfonamide by the similar procedure as with Reference Example 117, Reference Example 122, Example 1, and Example 193, in N,N-dimethylformamide (7.3 ml) solution, sodium hydrogencarbonate (89 mg), sodium iodide (12 mg), and tert-butyl bromoacetate (0.19 ml) were added and the mixture was stirred at room temperature for 17 hours. The reaction solution was diluted with ethyl acetate, then the obtained solution was successively washed with saturated ammonium chloride aqueous solution and saturated saline, dried over with anhydrous sodium sulfate, then concentrated. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/1), then the obtained purified product was recrystallized from hexane/ethyl acetate to obtain the title compound (247 mg).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][N:9]=2)[S:4][C:3]=1[C:11]([NH:13][C:14]1[CH:15]=[C:16]([CH:21]=[CH:22][C:23]=1[CH3:24])[C:17]([O:19]C)=[O:18])=[O:12].Cl>C1COCC1.[OH-].[Na+].O>[NH2:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][N:9]=2)[S:4][C:3]=1[C:11]([NH:13][C:14]1[CH:15]=[C:16]([CH:21]=[CH:22][C:23]=1[CH3:24])[C:17]([OH:19])=[O:18])=[O:12]
Reactant: COC(=O)c1ccc(C)c(NC(=O)c2sc3nccnc3c2N)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(C(=O)O)cc1NC(=O)c1sc2nccnc2c1N
Yield: 100.1 %

Procedure:
A solution of methyl 3-(7-aminothieno[2,3-b]pyrazine-6-carboxamido)-4-methylbenzoate 108 (0.803 mmol, 275 mg) in THF (10 mL) and 2N NaOH (10 mL) stirred for 4 h. The red solution was diluted with water, acidified with 2N HCl solution pH 5-6 and extracted with ethyl acetate. The combined organic layers were washed with brine, dried and evaporated to give 3-(7-aminothieno[2,3-b]pyrazine-6-carboxamido)-4-methylbenzoic acid 109 (264 mg, 100%). NMR (400 MHz, DMSO-d6) 2.31 (s, 3H), 7.08 (s, 2H), 7.41 (d, J=8.2 Hz, 1H), 7.75 (dd, J=7.8 Hz and 1.6 Hz, 1H), 7.93 (d, J=1.2 Hz), 8.78 (d, J=2.3 Hz, 1H), 8.79 (d, J=2.3 Hz, 1H), 9.53 (s, 1H), 12.91 (br s, 1H).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=2)=[CH:5][N:4]=1.[Cl:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24]Br)=[CH:22][C:21]=1[F:28]>>[CH3:18][O:17][C:13]1[CH:12]=[C:11]([CH:16]=[CH:15][CH:14]=1)[CH2:10][CH2:9][C:6]1[CH:7]=[CH:8][C:3](=[O:2])[N:4]([CH2:24][C:23]2[CH:26]=[CH:27][C:20]([Cl:19])=[C:21]([F:28])[CH:22]=2)[CH:5]=1
Reactant: Fc1cc(CBr)ccc1Cl
Reactant: COc1cccc(CCc2ccc(OC)nc2)c1
Product: COc1cccc(CCc2ccc(=O)n(Cc3ccc(Cl)c(F)c3)c2)c1
Yield: 56 %

Procedure:
According to Scheme 8 Step 3: The title compound was prepared from 2-methoxy-5-(2-(3-methoxyphenyl)ethyl)pyridine (1 eq, 0.25 mmol, 0.06 g) and 4-chloro-3-fluorobenzylbromide (2 eq, 0.49 mmol, 0.11 g) according to the procedure described for Example 6 Step 2. Reaction conditions: 12 hours at 100° C. The resulting dark brown oil was purified by flash chromatography (AIT Flashsmart prepacked column 25 g SiO2, CH2Cl2/MeOH 98/2) to afford 5-(3-methoxyphenethyl)-1-(4-chloro-3-fluorobenzyl)pyridin-2(1H)-one (0.14 mmol, 55.0 mg, 60%) as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([OH:10])=O)[CH:3]=1.[CH:11]1([N:14]2[C:18]([C:19]3[N:24]=[C:23]([NH2:25])[CH:22]=[CH:21][CH:20]=3)=[CH:17][N:16]=[CH:15]2)[CH2:13][CH2:12]1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.CN1CCOCC1>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([NH:25][C:23]2[CH:22]=[CH:21][CH:20]=[C:19]([C:18]3[N:14]([CH:11]4[CH2:13][CH2:12]4)[CH:15]=[N:16][CH:17]=3)[N:24]=2)=[O:10])[CH:3]=1
Reactant: O=C(O)c1cc(Cl)ccn1
Reactant: Nc1cccc(-c2cncn2C2CC2)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: O=C(Nc1cccc(-c2cncn2C2CC2)n1)c1cc(Cl)ccn1
Yield: 47.1 %

Procedure:
A solution of 4-chloro-pyridine-2-carboxylic acid (141 mg, 0.895 mmol), 6-(3-cyclopropyl-3H-imidazol-4-yl)-pyridin-2-ylamine (150 mg, 0.750 mmol), (2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) (342 g, 0.899 mmol), and N-methylmorpholine (250 μL, 2.70 mmol) in N,N-dimethylformamide was stirred at room temperature for 12 hours. The solvent was removed under reduced pressure, the residue suspended in acetonitrile, and the solid isolated by filtration, washed with water (80 mL), acetonitrile (80 mL) and diethyl ether (80 mL), and dried under reduced pressure to afford 4-chloro-N-(6-(1-cyclopropyl-1H-imidazol-5-yl)pyridin-2-yl)picolinamide as a white powder (120 mg, 47% yield). M+1=340.1
Reaction SMILES: [CH3:1][N:2]([CH3:7])[S:3](Cl)(=[O:5])=[O:4].[C:8]([NH:11][CH2:12][CH2:13][NH2:14])(=[O:10])[CH3:9].C(N(CC)CC)C>C(Cl)Cl>[CH3:1][N:2]([CH3:7])[S:3]([NH:14][CH2:13][CH2:12][NH:11][C:8](=[O:10])[CH3:9])(=[O:5])=[O:4]
Reactant: CC(=O)NCCN
Reactant: CN(C)S(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)NCCNS(=O)(=O)N(C)C
Reaction time: 0.5 h

Procedure:
A solution of 14.3 g (0.1 mole) of dimethylsulfamoyl chloride in 50 ml of methylene chloride was added dropwise to a rapidly stirred solution of 10.2 g (0.1 mole) of acetylethylene diamine and 10.1 g (0.1 mole) of triethylamine in 150 ml of methylene chloride at 25° C. After the addition was completed, the solution was stirred for 30 min and then washed in a separatory funnel with two 100 ml portions of water. The organic phase was separated, and dried over MgSO4, and then concentrated under reduced pressure to afford N-[2[(dimethylamino)sulfonylamino]ethyl]acetamide as an oil. The N-acetyl group was then removed by treatment of the oil with 100 ml of 15% HCl at 80° C. for 6 h. This solution was concentrated under reduced pressure to provide 12.6 g (73%) of product as an oil. The NMR spectrum was consistent with the assigned structure.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:19][C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:23]=[CH:22][CH:21]=2)[C:8]2[C:13]([C:14]=1[CH2:15][NH:16][CH3:17])=[CH:12][C:11]([F:18])=[CH:10][CH:9]=2)=[O:5])[CH3:2].Cl[C:31]([O:33][CH2:34][CH3:35])=[O:32]>>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:19][C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:23]=[CH:22][CH:21]=2)[C:8]2[C:13]([C:14]=1[CH2:15][N:16]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH3:17])=[CH:12][C:11]([F:18])=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)Cl
Reactant: CCOC(=O)c1c(CNC)c2cc(F)ccc2n1Cc1cccc2ccccc12
Product: CCOC(=O)c1c(CN(C)C(=O)OCC)c2cc(F)ccc2n1Cc1cccc2ccccc12

Procedure:
5-Fluoro-3-methylaminomethyl-1-naphthalen-1-ylmethyl-1H-indole-2-carboxylic acid ethyl ester (from Example 86.1.) was reacted with ethyl chloroformate as described in Example 77.1. to give 3-[(ethoxycarbonyl-methyl-amino)-methyl]-5-fluoro-1-naphthalen-1-ylmethyl-1H-indole-2-carboxylic acid ethyl ester which was hydrolyzed as described in the general procedure B (Exp. 2.2) to give the title compound as a colorless solid. MS: 433.5 ([M−H]−).
Reaction SMILES: C([Li])CCC.[F:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[F:13].[CH3:14][Si:15]([CH3:18])([CH3:17])Cl.C1COCC1>CCCCCC.O>[F:6][C:7]1[C:8]([F:13])=[CH:9][CH:10]=[CH:11][C:12]=1[Si:15]([CH3:18])([CH3:17])[CH3:14]
Reactant: Fc1ccccc1F
Reactant: C[Si](C)(C)Cl
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C[Si](C)(C)c1cccc(F)c1F
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
12.5 ml of a 1.6-molar solution of n-butyllithium in hexane is added dropwise at 0° C. to a mixture of 0.02 mol of 1,2-difluorobenzene, 0.02 mol of trimethylchlorosilane and 25 ml of THF. After stirring at room temperature for 1.5 hours, the reaction mixture is poured into water, the phases are separated, and the aqueous phase is extracted with 2×50 ml of methylene chloride. Drying over magnesium sulfate, evaporation of the solvent and chromatography give the pure product.