Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:3][OH:4].[CH3:11][O:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=1>C1(C)C=CC=CC=1>[CH3:11][O:12][C:13]1[CH:20]=[CH:19][C:16](/[CH:17]=[N:1]/[C@H:2]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:3][OH:4])=[CH:15][CH:14]=1
Reactant: N[C@@H](CO)c1ccccc1
Reactant: COc1ccc(C=O)cc1
Solvent: Cc1ccccc1
Product: COc1ccc(/C=N/[C@@H](CO)c2ccccc2)cc1

Procedure:
A solution of (2R)-2-amino-2-phenylethanol (148 g, 1.08 mol) and 4-methoxybenzaldehyde (147 g, 1.08 mol) in toluene (2 L) was heated at reflux to remove water by Dean-Stark trap for 3 hr. The mixture was concentrated and the residue was dried which gave the title compound XIa (265 g, 96%) as a white solid, which was used for next reaction without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:21][CH3:22])=[CH:4][C:5]2[CH2:11][N:10]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:9][C:8](=[O:19])[NH:7][C:6]=2[CH:20]=1.Cl[C:24]1[N:29]=[C:28]([NH:30][C@@H:31]2[CH2:36][CH2:35][CH2:34][CH2:33][C@H:32]2[NH:37][S:38]([CH3:41])(=[O:40])=[O:39])[C:27]([Cl:42])=[CH:26][N:25]=1.Cl.O1CCOCC1>COCCO>[CH2:12]([N:10]1[CH2:11][C:5]2[CH:4]=[C:3]([O:21][CH3:22])[C:2]([NH:1][C:24]3[N:29]=[C:28]([NH:30][C@@H:31]4[CH2:36][CH2:35][CH2:34][CH2:33][C@H:32]4[NH:37][S:38]([CH3:41])(=[O:39])=[O:40])[C:27]([Cl:42])=[CH:26][N:25]=3)=[CH:20][C:6]=2[NH:7][C:8](=[O:19])[CH2:9]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COc1cc2c(cc1N)NC(=O)CN(Cc1ccccc1)C2
Reactant: CS(=O)(=O)N[C@@H]1CCCC[C@H]1Nc1nc(Cl)ncc1Cl
Agent: Cl
Solvent: C1COCCO1
Solvent: COCCO
Product: COc1cc2c(cc1Nc1ncc(Cl)c(N[C@@H]3CCCC[C@H]3NS(C)(=O)=O)n1)NC(=O)CN(Cc1ccccc1)C2
Temperature: 25 °C

Procedure:
To a solution of 8-amino-4-benzyl-7-methoxy-1,3,4,5-tetrahydro-benzo[e][1,4]diazepin-2-one (55 mg, 0.19 mmol) and N-[(1R,2R)-2-(2,5-dichloro-pyrimidin-4-ylamino)-cyclohexyl]-methanesulfonamide (63 mg, 0.19 mmol) in 2-methoxyethanol (2 mL) was added 4N HCl-dioxane (0.20 mL). The mixture was heated to reflux for two hours whereupon LCMS showed complete consumption of the aniline. After being cooled to room temperature, triethylamine was added to pH 9 and the crude product was purified by preparative tlc (5% MeOH-DCM) to afford N-{(1R,2R)-2-[2-(4-benzyl-7-methoxy-2-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-8-ylamino)-5-chloro-pyrimidin-4-ylamino]-cyclohexyl}-methanesulfonamide as a mustard yellow solid; 1H NMR (400 MHz, DMSO-d6) δ 9.68 (s, 1H), 7.96 (s, 2H), 7.73 (s, 1H), 7.35 (m, 5H), 7.05 (d, J=7 Hz, 1H), 6.93 (s, 1H), 6.85 (d, J=8.5 Hz, 1H), 4.55 (m, 1H), 3.86 (s, 3H), 3.70 (s, 2H), 3.64 (s, 2H), 3.06 (s, 2H), 2.88 (s, 3H), 1.97 (m, 2H), 1.63 (m, 2H), 1.38 (m, 2H), 1.23 (m, 2H); MS (m/e) 601 (M+1); mp 214° C. (dec.).
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[CH:9][C:8]=2[C:15]2[C:16]3[NH:23][C:22]([CH3:24])=[C:21]([C:25]([NH:27][CH:28]4[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]4)=[O:26])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:4][CH2:3]1.C([O:37][CH2:38][C:39](Cl)=[O:40])(=O)C>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[CH:9][C:8]=2[C:15]2[C:16]3[NH:23][C:22]([CH3:24])=[C:21]([C:25]([NH:27][CH:28]4[CH2:29][CH2:30][N:31]([C:38](=[O:37])[CH2:39][OH:40])[CH2:32][CH2:33]4)=[O:26])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:4][CH2:3]1
Reactant: COc1ccc(-c2ncnc3c(C(=O)NC4CCNCC4)c(C)[nH]c23)c(OCC2CC2)c1
Reactant: CC(=O)OCC(=O)Cl
Agent: Cl
Product: COc1ccc(-c2ncnc3c(C(=O)NC4CCN(C(=O)CO)CC4)c(C)[nH]c23)c(OCC2CC2)c1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-4-methoxyphenyl]-6-methyl-N-piperidin-4-yl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f18) and commercially available 2-chloro-2-oxoethyl acetate the title compound is obtained as colorless solid.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:21][C:22]2[CH:23]=[C:24]3[C:28](=[CH:29][CH:30]=2)[N:27]([CH3:31])[N:26]=[CH:25]3)[C:5]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:6]=2[N:7]=1.[NH2:32][C:33]1[CH:34]=[C:35]2[C:40](=[CH:41][CH:42]=1)[NH:39][C:38](=[O:43])[CH2:37][CH2:36]2.C[Si](Cl)(C)C>C(O)CCC>[CH3:31][N:27]1[C:28]2[C:24](=[CH:23][C:22]([NH:21][C:4]3[C:5]4[CH:10]=[CH:9][N:8]([S:11]([C:14]5[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=5)(=[O:13])=[O:12])[C:6]=4[N:7]=[C:2]([NH:32][C:33]4[CH:34]=[C:35]5[C:40](=[CH:41][CH:42]=4)[NH:39][C:38](=[O:43])[CH2:37][CH2:36]5)[N:3]=3)=[CH:30][CH:29]=2)[CH:25]=[N:26]1
Reactant: Nc1ccc2c(c1)CCC(=O)N2
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Nc4ccc5c(cnn5C)c4)nc(Cl)nc32)cc1
Agent: C[Si](C)(C)Cl
Solvent: CCCCO
Product: Cc1ccc(S(=O)(=O)n2ccc3c(Nc4ccc5c(cnn5C)c4)nc(Nc4ccc5c(c4)CCC(=O)N5)nc32)cc1
Yield: 12.4 %

Procedure:
A mixture of 2-chloro-N-(1-methyl-1H-indazol-5-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (1158 mg, 0.349 mmol), 6-amino-3,4-dihydroquinolin-2(1H)-one (113 mg, 0.697 mmol) and TMSCl (0.300 mL, 2.37 mmol) in nBuOH (3 mL) was stirred at 135° C. for 44 h. nBuOH was removed in vacuo. The residue was purified by HPLC to give 6-(4-(1-methyl-1H-indazol-5-ylamino)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-3,4-dihydroquinolin-2(1H)-one (25 mg).
Reaction SMILES: [CH3:1][C@H:2]1[NH:7][C@@H:6]([CH3:8])[CH2:5][N:4]([C:9]2[CH:10]=[CH:11][C:12]([Cl:16])=[C:13]([CH:15]=2)[NH2:14])[CH2:3]1.[Br:17][C:18]1[S:22][C:21]([S:23](Cl)(=[O:25])=[O:24])=[CH:20][CH:19]=1>N1C=CC=CC=1.ClCCl>[Br:17][C:18]1[S:22][C:21]([S:23]([NH:14][C:13]2[CH:15]=[C:9]([N:4]3[CH2:5][C@H:6]([CH3:8])[NH:7][C@H:2]([CH3:1])[CH2:3]3)[CH:10]=[CH:11][C:12]=2[Cl:16])(=[O:25])=[O:24])=[CH:20][CH:19]=1
Reactant: C[C@@H]1CN(c2ccc(Cl)c(N)c2)C[C@H](C)N1
Reactant: O=S(=O)(Cl)c1ccc(Br)s1
Solvent: ClCCl
Solvent: c1ccncc1
Product: C[C@@H]1CN(c2ccc(Cl)c(NS(=O)(=O)c3ccc(Br)s3)c2)C[C@H](C)N1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 5-(cis-3,5-Dimethyl-1-piperazinyl)-2-chloroaniline (D34) (100 mg, 0.42 mmol) in pyridine:dichloromethane (1:1, 4 ml) was treated with 5-bromo-2-thiophenesulfonyl chloride (132 mg, 0.51 mmol). The solution was stirred at room temperature for 2 hours, quenched with methanol and concentrated in vacuo. The residue was applied to a SCX cartridge (Varian bond-elute, 5 g) and washed with methanol and 2M ammonia in methanol. The combined basic fractions were concentrated in vacuo and the resulting residue was purified by column chromatography (FlashMaster) (gradient of dichloromethane to 4% metlianol:dichloromethane) to afford the title product (D36). MS (ES+) m/e 464/466/468 [M+H]+.
Reaction SMILES: C([NH:5][S:6]([C:9]1[S:10][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]3[N:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[C:22]([C:30]4[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=4)[N:21]=3)[CH:15]=2)=[CH:12][CH:13]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[F:36][C:33]1[CH:32]=[CH:31][C:30]([C:22]2[CH:23]=[C:24]([C:26]([F:28])([F:29])[F:27])[N:25]=[C:20]([C:16]3[CH:15]=[C:14]([C:11]4[S:10][C:9]([S:6]([NH2:5])(=[O:8])=[O:7])=[CH:13][CH:12]=4)[CH:19]=[CH:18][CH:17]=3)[N:21]=2)=[CH:35][CH:34]=1
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(-c2cccc(-c3nc(-c4ccc(F)cc4)cc(C(F)(F)F)n3)c2)s1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NS(=O)(=O)c1ccc(-c2cccc(-c3nc(-c4ccc(F)cc4)cc(C(F)(F)F)n3)c2)s1
Temperature: 25 °C
Reaction time: 15 h
Yield: 51.3 %

Procedure:
To a cooled and stirred solution of N-tert-butyl-5-{3-[6-(4-fluoro-phenyl)-4-trifluoromethyl-pyrimidin-2-yl]-phenyl}-thiophene-2-sulfonic acid amide (0.37 g) in dichloromethane (6 ml) was added TFA (6 ml) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness, poured into 2N NaHCO3 solution (25 ml) and extracted with ethyl acetate (3×50 ml). The combined organic layers were washed with brine (50 ml), dried (MgSO4) and evaporated. Further purification by flash chromatography on silica gel (ethyl acetate/heptane) and crystallization (ethyl acetate/heptane) yielded the title compound as a light yellow solid (0.17 g, 35%). MS (ISP) 480.0 [(M+H)+]; mp 228.5° C.
Reaction SMILES: [CH3:1][O:2][C@H:3]1[C@@H:8]([NH:9][C@@H:10]2[CH2:17][C@H:13]3[CH2:14][NH:15][CH2:16][C@@:12]3([C:18]([N:20]3[CH2:29][CH2:28][C:27]4[N:26]=[CH:25][C:24]([C:30]([F:33])([F:32])[F:31])=[CH:23][C:22]=4[CH2:21]3)=[O:19])[CH2:11]2)[CH2:7][CH2:6][O:5][CH2:4]1.[CH:34](OCC)=[O:35]>>[CH3:1][O:2][C@H:3]1[C@@H:8]([NH:9][C@@H:10]2[CH2:17][C@H:13]3[CH2:14][N:15]([CH:34]=[O:35])[CH2:16][C@@:12]3([C:18]([N:20]3[CH2:29][CH2:28][C:27]4[N:26]=[CH:25][C:24]([C:30]([F:33])([F:31])[F:32])=[CH:23][C:22]=4[CH2:21]3)=[O:19])[CH2:11]2)[CH2:7][CH2:6][O:5][CH2:4]1
Reactant: CCOC=O
Reactant: CO[C@@H]1COCC[C@@H]1N[C@@H]1C[C@H]2CNC[C@@]2(C(=O)N2CCc3ncc(C(F)(F)F)cc3C2)C1
Product: CO[C@@H]1COCC[C@@H]1N[C@@H]1C[C@H]2CN(C=O)C[C@@]2(C(=O)N2CCc3ncc(C(F)(F)F)cc3C2)C1
Temperature: 25 °C

Procedure:
A mixture of Example 1 (70.28 mg, 0.15 mmol) in ethyl formate (1 mL) in a sealed tube was heated at 70° C. overnight. After cooling to rt, the mixture was concentrated and purified by CombiFlash (eluent: 8% methanol in DCM) gave the product as a yellowish gel. 1H-NMR (400 MHz, CDCl3): δ 1.50-1.97 (m, 5H), 2.28 (br. s., 1H), 2.72 (br. s., 1H), 2.92-3.51 (m, 11H), 3.59-4.16 (m, 8H), 4.61-5.02 (m, 2H), 7.70 (br. s., 1H), 8.08-8.24 (m, 1H), 8.73 (br. s., 1H); LC/MS: C24H31F3N4O4: m/z 497.2 (M+H).
Reaction SMILES: [C:1]1(C)C=CC=CC=1.[C:8]([CH2:10][CH:11]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:12]1=[O:18])#[N:9].CI>C1C=CC=CC=1>[C:8]([CH2:10][C:11]1([CH3:1])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:12]1=[O:18])#[N:9]
Reactant: N#CCC1CCCCCC1=O
Reactant: Cc1ccccc1
Solvent: c1ccccc1
Solvent: CI
Product: CC1(CC#N)CCCCCC1=O
Temperature: 65 °C
Reaction time: 4 h

Procedure:
A solution of sodium tert.-amylate in toluene (340 ml, 0.297 mole) is added dropwise with stirring under nitrogen to a solution of 2-cyanomethylcycloheptanone (44.6 g, 0.297 mole, obtained as described above) and methyl iodide (42.6 g, 0.3 mole) in dry benzene (200 ml), and the mixture is stirred at 65° C for 4 hrs. and allowed to stand overnight at room temperature. The reaction mixture is washed with 1% aqueous hydrochloric acid, water, saturated sodium chloride solution, dried over magnesium sulfate, and the solvent is evaporated. Distillation of the residue under reduced pressure yields 2-cyanomethyl-2-methylcycloheptanone, bp. 152°-158° C/14 mm, nmr (CDCl3) δ1.27 (s, 3H).
Reaction SMILES: O[C:2]1[CH:17]=[C:16]([OH:18])[CH:15]=[CH:14][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][C:7]=1[OH:13])=O.C([O-])(=O)C.[Na+].Cl.[F:25][C:26]([F:37])([F:36])[O:27][C:28]1[CH:33]=[CH:32][C:31]([NH:34][NH2:35])=[CH:30][CH:29]=1>>[OH:18][C:16]1[CH:17]=[C:2]2[C:3]([C:4]([C:6]3[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][C:7]=3[OH:13])=[N:35][N:34]2[C:31]2[CH:32]=[CH:33][C:28]([O:27][C:26]([F:25])([F:37])[F:36])=[CH:29][CH:30]=2)=[CH:14][CH:15]=1
Reactant: O=C(c1ccc(O)cc1O)c1ccc(O)cc1O
Reactant: NNc1ccc(OC(F)(F)F)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Product: Oc1ccc(-c2nn(-c3ccc(OC(F)(F)F)cc3)c3cc(O)ccc23)c(O)c1
Yield: 22.4 %

Procedure:
Prepared according to Method B from 2,2′,4,4′-tetrahydroxybenzophenone (0.123 g, 0.5 mmol), sodium acetate (0.041 g, 0.5 mmol) and 4-trifluoromethoxyphenylhydrazine hydrochloride (0.114 g, 0.5 mmol) to give 0.045 g of product as a tan solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([OH:10])[CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4].N1C=CC=CC=1.[C:24]1([CH3:34])[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1>C(Cl)Cl>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([O:10][S:30]([C:27]2[CH:28]=[CH:29][C:24]([CH3:34])=[CH:25][CH:26]=2)(=[O:32])=[O:31])[CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)[C@@H]1C[C@@H](OS(=O)(=O)c2ccc(C)cc2)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 88.4 %

Procedure:
To a solution of (2S,4R)-4-hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (10 g, 40.77 mmol) in methylene chloride (56 mL) at 0° C. was added pyridine (30 mL), followed by dropwise addition of a solution of p-toluenesulfonyl chloride (9.4 g, 49.30 mmol) in methylene chloride. The reaction mixture was warmed to room temperature and then refluxed for 16 h. The reaction mixture was concentrated, re-dissolved in methylene chloride, and washed with water and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to give (2S,4R)-4-(toluene-4-sulfonyloxy)-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (14.4 g, 88.4% yield) as a light yellow sticky solid. The crude was used in the next step without further purification. MS calcd. for C18H26NO7S [(M+H)+] 400.0, obsd. 400.0.
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[N:14]2[C:8]([CH2:9][N:10]([C:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[CH3:33])=[C:23]([CH3:34])[CH:22]=3)=[O:20])[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13]2)=[CH:7][CH:6]=1)=[O:4].[CH2:37]([NH2:44])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>>[CH2:37]([NH:44][C:3]([C:5]1[N:14]2[C:8]([CH2:9][N:10]([C:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[CH3:33])=[C:23]([CH3:34])[CH:22]=3)=[O:20])[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13]2)=[CH:7][CH:6]=1)=[O:4])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: NCc1ccccc1
Reactant: Cc1ccccc1-c1ccc(C(=O)N2Cc3ccc(C(=O)C(Cl)(Cl)Cl)n3Cc3ccccc32)cc1C
Product: Cc1ccccc1-c1ccc(C(=O)N2Cc3ccc(C(=O)NCc4ccccc4)n3Cc3ccccc32)cc1C

Procedure:
The title compound was synthesized in the manner of Example 13 from 2,2,2-trichloro-1-{10-[(2,2′-dimethyl-1,1′-biphenyl-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}ethanone of Example 6 and benzylamine, m.p. 138-141° C. MS [(+)ESI, m/z]: 524 [M+H]+
Reaction SMILES: [C:1]([CH2:3][C:4]1[N:5]=[C:6]([NH:9][C:10](=[O:45])[CH2:11][NH:12][C:13]2[N:18]=[C:17]([N:19]3[CH:24]=[C:23]([CH:25]4[C:31]5[CH:32]=[CH:33][C:34]([CH2:36][CH3:37])=[CH:35][C:30]=5[CH:29]=[CH:28][C:27]5[CH:38]=[C:39]([CH3:42])[CH:40]=[CH:41][C:26]4=5)[C:22](=[O:43])[NH:21][C:20]3=[O:44])[CH:16]=[CH:15][N:14]=2)[S:7][CH:8]=1)#[N:2].C[Sn]([N:50]=[N+:51]=[N-:52])(C)C.CO>C1(C)C=CC=CC=1>[CH2:36]([C:34]1[CH:33]=[CH:32][C:31]2[CH:25]([C:23]3[C:22](=[O:43])[NH:21][C:20](=[O:44])[N:19]([C:17]4[CH:16]=[CH:15][N:14]=[C:13]([NH:12][CH2:11][C:10]([NH:9][C:6]5[S:7][CH:8]=[C:4]([CH2:3][C:1]6[NH:52][N:51]=[N:50][N:2]=6)[N:5]=5)=[O:45])[N:18]=4)[CH:24]=3)[C:26]3[CH:41]=[CH:40][C:39]([CH3:42])=[CH:38][C:27]=3[CH:28]=[CH:29][C:30]=2[CH:35]=1)[CH3:37]
Reactant: C[Sn](C)(C)N=[N+]=[N-]
Reactant: CCc1ccc2c(c1)C=Cc1cc(C)ccc1C2c1cn(-c2ccnc(NCC(=O)Nc3nc(CC#N)cs3)n2)c(=O)[nH]c1=O
Solvent: CO
Solvent: Cc1ccccc1
Product: CCc1ccc2c(c1)C=Cc1cc(C)ccc1C2c1cn(-c2ccnc(NCC(=O)Nc3nc(Cc4nnn[nH]4)cs3)n2)c(=O)[nH]c1=O

Procedure:
A mixture of the product of step (iv) (0.35 g) and trimethyltin azide (0.5 g) in toluene (10 ml) was heated at reflux for 48 hours. Methanol was added and the resultant precipitate filtered off. The solution was evaporated to dryness and the residue purified by reverse phase chromatography. The fraction containing product was concentrated under reduced pressure, acidified with 2N HCl and extracted with ethyl acetate. The extract was evaporated to dryness and the residue triturated with diethyl ether. The product was collected by filtration. Yield 0.16 g.
Reaction SMILES: C([O:3][C:4](=[O:20])[C@@H:5]([O:18][CH3:19])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH2:16]Br)=[CH:9][CH:8]=1)C.[NH:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][C:28]=2[OH:30])[CH:23]=[CH:22]1.[OH-].[Na+]>>[NH:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][C:28]=2[O:30][CH2:16][CH2:15][CH2:14][O:13][C:10]2[CH:9]=[CH:8][C:7]([CH2:6][C@H:5]([O:18][CH3:19])[C:4]([OH:3])=[O:20])=[CH:12][CH:11]=2)[CH:23]=[CH:22]1
Reactant: Oc1cccc2cc[nH]c12
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCCBr)cc1)OC
Agent: [Na+]
Agent: [OH-]
Product: CO[C@@H](Cc1ccc(OCCCOc2cccc3cc[nH]c23)cc1)C(=O)O

Procedure:
(2S)-3-[4-(3-Bromo-propoxy)-phenyl]-2-methoxy-propionic acid ethyl ester from Example 173, Step A was treated with 1H-Indol-7-ol under the Standard Procedure J. The compound thus obtained was allowed to react under Standard hydrolysis procedure C (NaOH) to give the title compound. MS(ES) for C21H23NO5 [M+Na]+: 392; [M+H]+: 370.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[O:15][C:14]([NH:16][CH2:17][C:18]4[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=4)=[N:13][N:12]=3)[CH:9]=2)[N:4]([S:26]([C:29]2[CH:35]=[CH:34][C:32]([CH3:33])=[CH:31][CH:30]=2)(=[O:28])=[O:27])[CH:3]=1.[Cl:36][C:37]1[CH:42]=[CH:41][N:40]=[C:39]([Sn](CCCC)(CCCC)CCCC)[N:38]=1.N#N>CN(C=O)C.[Cu]I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:36][C:37]1[CH:42]=[CH:41][N:40]=[C:39]([C:2]2[C:10]3[C:5](=[CH:6][CH:7]=[C:8]([C:11]4[O:15][C:14]([NH:16][CH2:17][C:18]5[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=5)=[N:13][N:12]=4)[CH:9]=3)[N:4]([S:26]([C:29]3[CH:30]=[CH:31][C:32]([CH3:33])=[CH:34][CH:35]=3)(=[O:27])=[O:28])[CH:3]=2)[N:38]=1
Reactant: COc1ccc(CNc2nnc(-c3ccc4c(c3)c(I)cn4S(=O)(=O)c3ccc(C)cc3)o2)cc1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccc(Cl)n1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Solvent: CN(C)C=O
Product: COc1ccc(CNc2nnc(-c3ccc4c(c3)c(-c3nccc(Cl)n3)cn4S(=O)(=O)c3ccc(C)cc3)o2)cc1
Temperature: 80 °C
Yield: 52.4 %

Procedure:
A solution of 5-(3-iodo-1-tosyl-1H-indol-5-yl)-N-(4-methoxybenzyl)-1,3,4-oxadiazol-2-amine (3.0 g, 5.20 mmol) and 4-chloro-2-(tributylstannyl)pyrimidine (2.5 g, 6.00 mmol) in DMF was bubbled with N2 for 15 min. To the above mixture was added CuI (476 mg; 2.50 mmol) and Pd(PPh3)4 (577 mg, 0.52 mmol) and N2 gas was bubbled for another 15 min. The reaction was heated at 80° C. for 1 h. The reaction was quenched with H2O and the resulting precipitate was filtered, washed with H2O and dried. The crude material was purified with silica gel chromatography (eluting with 30% EtOAc in Hex) to give 5-(3-(4-chloropyrimidin-2-yl)-1-tosyl-1H-indol-5-yl)-N-(4-methoxybenzyl)-1,3,4-oxadiazol-2-amine (1.6 g, 53.3%). MS (ESI, pos. ion) m/z: 586.6 (M+1); 1H-NMR (400 MHz, DMSO-d6): δ 8.96 (s, 1H), 8.91 (d, J=4 Hz, 1H), 8.62 (s, 1H), 8.35 (m, 1H), 8.17 (d, J=8 Hz, 1H), 8.10 (d, J=8 Hz, 2H), 7.91 (d, J=8 Hz, 1H), 7.65-7.62 (m, 2H), 7.45-7.43 (m, 6H), 7.33 (d, J=8 Hz, 2H), 6.90 (d, J=8 Hz, 2H), 4.38 (d, J=5.6 Hz, 2H), 3.72 (s, 3H), 2.33 (s, 3H).
Reaction SMILES: [CH:1](=[CH:8][C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:17]([O:19][C:20](=[O:25])[CH2:21][C:22](=[NH:24])[NH2:23])[CH3:18]>C(O)C>[CH2:17]([O:19][C:20]([C:21]1[CH:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:8]=[C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[NH:23][C:22]=1[NH2:24])=[O:25])[CH3:18]
Reactant: CCOC(=O)CC(=N)N
Reactant: O=C(C=Cc1ccccc1)c1ccccc1
Solvent: CCO
Product: CCOC(=O)C1=C(N)NC(c2ccccc2)=CC1c1ccccc1
Yield: 69 %

Procedure:
Upon heating a solution of 20.8 of benzylideneacetophenone and 13.0 g of amidinoacetic acid ethyl ester in 250 ml of ethanol for 2 hours, 2-amino-4,6-diphenyl-1,4-dihydropyridine-3-carboxylic acid ethyl ester of melting point 159°C (ethanol) is obtained. Yield: 69 percent of theory.
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:10]([C:12]1[C:17]([F:18])=[CH:16][CH:15]=[CH:14][C:13]=1[F:19])O.C([SiH](CC)CC)C.FC(F)(F)C(O)=O.[OH-].[Na+]>ClCCl>[F:18][C:17]1[CH:16]=[CH:15][CH:14]=[C:13]([F:19])[C:12]=1[CH2:10][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([O:8][CH3:9])[C:2]=1[NH2:1]
Reactant: COc1cccc(C(O)c2c(F)cccc2F)c1N
Agent: CC[SiH](CC)CC
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cccc(Cc2c(F)cccc2F)c1N
Temperature: 40 °C
Yield: 69.7 %

Procedure:
The reaction mixture composed of 5.8 g of (2-amino-3-methoxyphenyl)(2,6-difluorophenyl)methanol, 11 ml of triethylsilane (3 eq.), 10 ml of trifluoroacetic acid (3.9 eq.) in 90 ml of dichloromethane is heated for 6 hours at 40° C. After one night at room temperature, the reaction medium is slowly hydrolyzed in the cold state with 6N sodium hydroxide, the organic phase is dried over anhydrous sodium sulfate and concentrated. The residue is purified by filtration on silica H, eluting with dichloromethane, in order to obtain 3.8 g of the expected product.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:19][CH2:20][CH2:21][CH2:22][OH:23]>CN(C)C=O>[OH:23][CH2:22][CH2:21][CH2:20][CH2:19][NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: OCCCCBr
Reactant: N#Cc1ccc(-c2ccc(N)cc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(-c2ccc(NCCCCO)cc2)cc1

Procedure:
4′-amino-(1,1′-Biphenyl)-4-carbonitrile is dissolved in dimethyl formamide. Sodium hydride is added to the solution followed by 4-bromo-1-hydroxybutane to provide 4′-(4-hydroxybutylamino)-(1,1′-Biphenyl)-4-carbonitrile. 4′-(4-hydroxybutylamino)-(1,1′-Biphenyl)-4-carbonitrile is suspended in dichloromethane.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH:23]=O)[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.[CH2:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C@@H:28]([NH2:35])[C@H:27]1[OH:36].C([BH3-])#N.[Na+]>C(O)(=O)C.C(Cl)Cl.C([O-])(O)=O.[Na+]>[CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:21])([F:22])[F:20])=[CH:15][C:14]=2[CH2:23][NH:35][C@@H:28]2[C:29]3[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:26][C@@H:27]2[OH:36])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1
Reactant: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2C=O)c1
Reactant: N[C@@H]1c2ccccc2C[C@@H]1O
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN[C@@H]2c3ccccc3C[C@@H]2O)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
(2′-Formyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid methyl ester (0.153 g, 0.43 mmol), (1R,2S)-(+)-cis-1-amino-2-indanol (0.065 g, 0.43 mmol), sodium cyanoborohydride (0.041 g, 0.65 mmol), and acetic acid (3 drops) were combined in CH2Cl2 (1.5 mL), and the reaction was stirred for 30 minutes at room temperature. The mixture was diluted with CH2Cl2 and saturated aqueous NaHCO3, and the aqueous layer was extracted with CH2Cl2. The combined organic layers were dried over MgSO4, filtered, and concentrated to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8]O)[S:5][C:6]=1[Cl:7].[C:10]1(=[O:20])[NH:14][C:13](=[O:15])[C:12]2=[CH:16][CH:17]=[CH:18][CH:19]=[C:11]12.N(C(OCC)=O)=NC(OCC)=O.O>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][N:14]2[C:10](=[O:20])[C:11]3[C:12](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:13]2=[O:15])[S:5][C:6]=1[Cl:7]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: OCc1cc(Cl)c(Cl)s1
Agent: CCOC(=O)N=NC(=O)OCC
Solvent: C1CCOC1
Solvent: O
Product: O=C1c2ccccc2C(=O)N1Cc1cc(Cl)c(Cl)s1
Temperature: 25 °C
Yield: 68.7 %

Procedure:
To a stirred solution of (4,5-Dichloro-thiophen-2-yl)-methanol (0.660 grams, 3.60 mmole), Phthalimide (0.636 grams, 4.32 mmole), and triphenyl phosphene (1.1 grams, 4.32 mmole) in tetrahydrofuran (20 ml) at room temperature was added diethyl azodicarboxylate (0.395 grams, 12.3 mmole) and stirred at room temperature over night. The mixture was poured into 100 ml water and extracted with diethyl ether. The combined extracts were washed with 1 N NaOH, water and brine, dried over MgSO4, filtered, and concentrated to an oil from which triphenylphosphine was crystalized out using diethyl ether/hexane. The mother liquor was concentrated to give a solid which was purified via flash chromatography on silica using 30% ethyl acetate/hexane as eluent to give a yellow solid. This was triturated in hexane to give a white solid (0.772 g). MW 312.18; MS (m/e) 313 (M++1).