Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[CH2:10][CH2:9][CH:8]([C:11]([N:13]3[CH2:17][CH:16]([NH:18][CH3:19])[CH:15]([C:20]4[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=4)[CH2:14]3)=[O:12])[CH2:7][CH2:6]2)[CH2:3][CH2:2]1.[Cl:28][C:29]1[CH:37]=[CH:36][C:32]([C:33]([OH:35])=O)=[CH:31][C:30]=1[C:38]([F:41])([F:40])[F:39]>>[Cl:28][C:29]1[CH:37]=[CH:36][C:32]([C:33]([N:18]([CH:16]2[CH:15]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=3)[CH2:14][N:13]([C:11]([CH:8]3[CH2:9][CH2:10][N:5]([CH2:4][CH:1]4[CH2:3][CH2:2]4)[CH2:6][CH2:7]3)=[O:12])[CH2:17]2)[CH3:19])=[O:35])=[CH:31][C:30]=1[C:38]([F:41])([F:40])[F:39]
Reactant: CNC1CN(C(=O)C2CCN(CC3CC3)CC2)CC1c1ccc(Cl)c(Cl)c1
Reactant: O=C(O)c1ccc(Cl)c(C(F)(F)F)c1
Product: CN(C(=O)c1ccc(Cl)c(C(F)(F)F)c1)C1CN(C(=O)C2CCN(CC3CC3)CC2)CC1c1ccc(Cl)c(Cl)c1

Procedure:
In analogy to the procedure described for the synthesis of example 87 (step c), the title compound 4-chloro-N-[(3RS,4SR)-1-(1-cyclopropylmethyl-piperidine-4-carbonyl)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-N-methyl-3-trifluoromethyl-benzamide was prepared from (1-cyclopropylmethyl-piperidin-4-yl)-[(3SR,4RS)-3-(3,4-dichloro-phenyl)-4-methylamino-pyrrolidin-1-yl]-methanone instead of N-[(3RS,4SR)-4-(4-chloro-phenyl)-pyrrolidin-3-yl]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide using 4-chloro-3-(trifluoromethyl)benzoic acid instead of 1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carboxylic acid and was obtained as a white foam. MS m/e: 616.3 [M]+.
Reaction SMILES: FC1C=CC(N[C:9]([C:11]2(C(NC3C=CC(OC4C5C(=CC(OC)=C(OC)C=5)N=C(C)N=4)=CC=3)=O)CC2)=[O:10])=CC=1.[CH3:39][O:40][C:41](=[O:53])[C:42]1[CH:47]=[C:46]([O:48][CH3:49])[C:45]([O:50][CH3:51])=[CH:44][C:43]=1[NH2:52].C(OC(=O)C)(=O)C>CCCCCCC>[CH3:39][O:40][C:41](=[O:53])[C:42]1[CH:47]=[C:46]([O:48][CH3:49])[C:45]([O:50][CH3:51])=[CH:44][C:43]=1[NH:52][C:9](=[O:10])[CH3:11]
Reactant: COC(=O)c1cc(OC)c(OC)cc1N
Reactant: COc1cc2nc(C)nc(Oc3ccc(NC(=O)C4(C(=O)Nc5ccc(F)cc5)CC4)cc3)c2cc1OC
Solvent: CCCCCCC
Solvent: CC(=O)OC(C)=O
Product: COC(=O)c1cc(OC)c(OC)cc1NC(C)=O

Procedure:
′N-(4-fluorophenyl)-N′-(4-{[2-methyl-6,7-bis(methyloxy)quinazolin-4-yl]oxy}phenyl)cyclopropane-1,1-dicarboxamide. Commercially available 2-amino-4,5-dimethoxy-benzoic acid methyl ester (3 g, 0.014 mol) and acetic anhydride (4.03 mL, 0.0426 mol) were heated in heptane at 100° C. for 3 hours. After removal of heptane in vacuo, the crude product of 2-acetylamino-4,5-dimethoxy-benzoic acid methyl ester was obtained and used without further purification. LC/MS: m/z 254 (M+H).
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[O:6][CH2:5]1.[CH3:28][N:29]1[CH2:34][CH2:33][CH:32]([C:35](O)=[O:36])[CH2:31][CH2:30]1>>[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:35]([CH:32]5[CH2:33][CH2:34][N:29]([CH3:28])[CH2:30][CH2:31]5)=[O:36])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[O:6][CH2:5]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3cccc4c3OCO4)CC2)CC1
Reactant: CN1CCC(C(=O)O)CC1
Agent: Cl
Product: CN1CCC(C(=O)N[C@H]2CC[C@H](CCN3CCN(c4cccc5c4OCO5)CC3)CC2)CC1

Procedure:
The title compound, white solid (26.2 mg, 67.5%), MS (ISP) m/z=457.3 [(M+H)+], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexylamine hydrochloride (Intermediate A) (30 mg, 92.5 mmol) and 1-methylpiperidine-4-carboxylic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[CH2:11][CH2:10]2)[C:5]([NH2:21])=[CH:4][C:3]=1[C:22]([F:25])([F:24])[F:23].[C:26](C1NC=CN=1)(C1NC=CN=1)=[O:27].C(OCC)(=O)C>O1CCCC1>[Cl:1][C:2]1[C:3]([C:22]([F:23])([F:25])[F:24])=[CH:4][C:5]2[NH:21][C:26](=[O:27])[N:8]([CH:9]3[CH2:10][CH2:11][N:12]([CH:15]4[CH2:20][CH2:19][O:18][CH2:17][CH2:16]4)[CH2:13][CH2:14]3)[C:6]=2[CH:7]=1
Reactant: Nc1cc(C(F)(F)F)c(Cl)cc1NC1CCN(C2CCOCC2)CC1
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=c1[nH]c2cc(C(F)(F)F)c(Cl)cc2n1C1CCN(C2CCOCC2)CC1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A stirred solution of 5-chloro-N-[1-(tetrahydro-2H-pyran-4-yl)-4-piperidinyl]-4-trifluoromethyl-1,2-benzenediamine (D52) (0.34 g, 0.9 mmol) in anhydrous tetrahydrofuran (40 ml) was treated with carbonyl diimidazole (0.29 g, 1.80 mmol)—added in portion over 5 minutes. The mixture was stirred at room temperature under argon for 4 hours. The mixture was warmed to a gentle reflux. After 18 hours, a further 0.29 g, 1.8 mmole of carbonyl diimidazole was added and the mixture maintained at reflux for another 24 hours. The mixture was cooled to room temperature and was treated with ethyl acetate (40 ml) and washed with water and brine then dried over MgSO4 and concentrated to dryness. The residue was purified by silica gel chromatography eluting with 1 to 10% methanol in dichloromethane to afford 6-chloro-5-trifluoromethyl-1-[1-(tetrahydro-2H-pyran-4-yl)-4-piperidinyl]-1,3-dihydro-2H-benzimidazol-2-one, which was subsequently converted to the hydrochloride salt and isolated as a cream powder. 0.25 g, 73%. MH+=404 and 406
Reaction SMILES: O=[C:2]1[CH:8]([NH:9][S:10]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)(=[O:12])=[O:11])[CH2:7][CH2:6][CH2:5][CH2:4][NH:3]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[NH:3]1[CH2:4][CH2:5][CH2:6][CH2:7][CH:8]([NH:9][S:10]([C:13]2[CH:14]=[CH:15][C:16]([CH3:19])=[CH:17][CH:18]=2)(=[O:11])=[O:12])[CH2:2]1
Reactant: Cc1ccc(S(=O)(=O)NC2CCCCNC2=O)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)NC2CCCCNC2)cc1

Procedure:
N-(2-Oxoazepan-3-yl)-4-methylbenzenesulfonamide (6A) (4.24 g, 15 mmol) was dissolved in 250 ml of dry THF under a nitrogen atmosphere, and lithium aluminium hydride (1.11 g, 30 mmol) was added slowly. The reaction was heated to reflux for 20 hours and then quenched with water until the effervescence ceased. Solid potassium carbonate was added until a white suspension appeared, and the mixture was allowed to stir for half an hour. The suspension was filtered through celite, which was washed with 3×50 ml of EtOAc. The solvents were evaporated and the residue was dissolved in 100 ml of EtOAc and 100 ml of water. The layers were separated and the aqueous layer was extracted with 2×100 ml of EtOAc. The combined organic layer was washed with brine, dried over sodium sulphate, and evaporated to give compound (6B) as an oil.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[C:10]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([NH2:23])(=[O:22])=[O:21])=[CH:16][CH:15]=1)[N:9]=[CH:8]2)=O.[CH3:24][O:25][CH2:26][CH2:27][NH:28][CH3:29].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CN1C(=O)CCC1.C(O)(=O)C>[CH3:24][O:25][CH2:26][CH2:27][N:28]([CH2:1][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[C:10]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([NH2:23])(=[O:22])=[O:21])=[CH:16][CH:15]=1)[N:9]=[CH:8]2)[CH3:29]
Reactant: CNCCOC
Reactant: NS(=O)(=O)c1ccc(Nc2ncc3cccc(C=O)c3n2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CC(=O)O
Product: COCCN(C)Cc1cccc2cnc(Nc3ccc(S(N)(=O)=O)cc3)nc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To the solution of 4-(8-formylquinazolin-2-ylamino)benzenesulfonamide (11 mg, 30 umole) and 2-methoxy-N-methylethanamine (37 ul, 30 umole) in 500 ul of NMP was added a few drops of acetic acid. The reaction solution was stirred at room temperature for overnight. Sodium triacetoxy borohydride (7 mg, 33 umole) was added. The reaction mixture was stirred for 2 hr at ambient temperature. The reductive amination went to completion to give 4-(8-(((2-methoxyethyl)(methyl)amino)methyl)quinazolin-2-ylamino)benzenesulfonamide that was then purified on prep HPLC to give product as powder. ES/MS m/z 402.2 (MH+).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[Cl:13][C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[CH:16]=O.C(O)(C(F)(F)F)=O>>[Cl:13][C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[CH:16]1[C:5]2[NH:6][C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:4]=2[CH2:3][CH2:2][NH:1]1
Reactant: O=Cc1ccccc1Cl
Reactant: NCCc1c[nH]c2ccccc12
Solvent: O=C(O)C(F)(F)F
Product: Clc1ccccc1C1NCCc2c1[nH]c1ccccc21
Yield: 69 %

Procedure:
This product was prepared using the same procedure as for Intermediate 1 with tryptamine (1.0 g, 6.2 mmol), 2-chlorobenzaldehyde (0.7 mL, 1.0 equiv.) and TFA (1.0 mL, 2 equiv.) to give the title compound (1.2 g, 69%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:15]([N:16]2[CH:20]=[CH:19][CH:18]=[CH:17]2)=[CH:14][C:6]([CH:7](O)CS(C)(=O)=O)=[CH:5][C:4]=1[N:21]1[CH:25]=[CH:24][CH:23]=[CH:22]1.C[O-].[Na+].[NH:29]([CH2:36][CH2:37][C:38]#[N:39])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>CS(C)=O>[NH:29]([CH:36]=[C:37]([CH2:7][C:6]1[CH:5]=[C:4]([N:21]2[CH:25]=[CH:24][CH:23]=[CH:22]2)[C:3]([O:2][CH3:1])=[C:15]([N:16]2[CH:20]=[CH:19][CH:18]=[CH:17]2)[CH:14]=1)[C:38]#[N:39])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: N#CCCNc1ccccc1
Reactant: COc1c(-n2cccc2)cc(C(O)CS(C)(=O)=O)cc1-n1cccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1c(-n2cccc2)cc(CC(C#N)=CNc2ccccc2)cc1-n1cccc1

Procedure:
A mixture of 1.8 g. of 4-methoxy- α -[(methylsulfonyl)methyl]-3,5-di-(pyrrol-1-yl)benzyl alcohol, 0.41 g. of sodium methylate and 1.1 g. of β-anilinopropionitrile in 12 ml. of dimethylsulfoxide was stirred with the exclusion of moisture for 3 hours at room temperature. The mixture was diluted with 100 ml. of water, the precipitated oil extracted with ethyl acetate, the ethyl acetate solution dried over sodium sulfate and evaporated. By purification of the residue over aluminum oxide with benzene and recrystallization from ethyl acetate/petroleum ether, there was obtained α -(anilinomethylene)-4-methoxy-3,5-di(pyrrol-1-yl)hydrocinnamonitrile, having a melting point of 152° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([CH3:11])[C:3]=1[NH2:12].[CH:13]1([CH2:18][C:19](Cl)=[O:20])[CH2:17][CH2:16][CH2:15][CH2:14]1>C(#N)C>[Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([CH3:11])[C:3]=1[NH:12][C:19](=[O:20])[CH2:18][CH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: Cc1cc([N+](=O)[O-])cc(Cl)c1N
Reactant: O=C(Cl)CC1CCCC1
Solvent: CC#N
Product: Cc1cc([N+](=O)[O-])cc(Cl)c1NC(=O)CC1CCCC1
Temperature: 150 °C
Yield: 57.6 %

Procedure:
2-Chloro-6-methyl-4-nitro-phenylamine (6.0 g) and cyclopentylacetyl chloride (5.1 g) were dissolved in acetonitrile (45 mL) and heated to 150° C. for 20 minutes in a sealed microwave process vessel. The reaction mixture was cooled to 0° C. and the precipitated product collected by filtration and washed with cold acetonitrile to furnish 5.5 g (58%) of the title compound as a yellow solid. 1H NMR (500 MHz, DMSO-d6): 1.24 (m, 2H), 1.58 (m, 4H), 1.78 (m, 2H), 2.27 (m, 1H), 2.30 (s, 3H), 2.38 (d, 2H), 8.15 (d, 1H), 8.18 (d, 1H), 9.83 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][C:4]=1[C:12]([F:15])([F:14])[F:13].[CH2:16]([N:23]1[CH2:27][C@@H:26]([C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[C:30]([Cl:35])[CH:29]=2)[C@H:25]([NH:36][CH3:37])[CH2:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(C(C)C)C(C)C)C>C(Cl)Cl>[CH2:16]([N:23]1[CH2:27][C@@H:26]([C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[C:30]([Cl:35])[CH:29]=2)[C@H:25]([N:36]([CH3:37])[C:7](=[O:8])[C:6]2[CH:10]=[CH:11][C:3]([O:2][CH3:1])=[C:4]([C:12]([F:15])([F:14])[F:13])[CH:5]=2)[CH2:24]1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CN[C@@H]1CN(Cc2ccccc2)C[C@H]1c1ccc(Cl)c(Cl)c1
Reactant: COc1ccc(C(=O)Cl)cc1C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(C(=O)N(C)[C@@H]2CN(Cc3ccccc3)C[C@H]2c2ccc(Cl)c(Cl)c2)cc1C(F)(F)F
Reaction time: 4 h
Yield: 86 %

Procedure:
A solution of 4-methoxy-3-trifluoromethyl-benzoyl chloride (commercially available) (0.88 g, 2.76 mmol) in CH2Cl2 (10 ml) was added drop wise to a stirred solution of rac-[(3S,4R)-1-benzyl-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-methyl-amine (0.80 g, 2.38 mmol) and ethyl-diisopropyl-amine (0.61 ml, 3.58 mmol) in CH2Cl2 (10 ml). The reaction mixture was stirred 4 h, concentrated under vacuo and purification by flash chromatography (SiO2, CH2Cl2/MeOH, 99:1) yielded 1.09 g (86%) of the title product as colorless oil. ES-MS m/e: 537.5 (M+H+).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5]([C:8]1[CH:9]=[CH:10][C:11]2[O:16][CH:15]=[C:14]([C:17]#[N:18])[C:13](=[O:19])[C:12]=2[CH:20]=1)(=[O:7])[CH3:6].[N-:21]=[N+:22]=[N-:23].[Na+]>O1CCCC1>[C:5]([C:8]1[CH:20]=[C:12]2[C:11](=[CH:10][CH:9]=1)[O:16][CH:15]=[C:14]([C:17]1[NH:23][N:22]=[N:21][N:18]=1)[C:13]2=[O:19])(=[O:7])[CH3:6]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(=O)c1ccc2occ(C#N)c(=O)c2c1
Agent: [Al+3]
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)c1ccc2occ(-c3nnn[nH]3)c(=O)c2c1

Procedure:
To 40 parts by volume of tetrahydrofuran are added under cooling 4.0 parts of anhydrous aluminum chloride, 3.20 parts of 6-acetyl-4-oxo-4H-1-benzopyran-3-carbonitrile and 2.93 parts of sodium azide in the order mentioned and, under stirring, the mixture is refluxed for 30 minutes. After cooled, the reaction mixture is concentrated to dryness. To the residue are added 100 parts by volume of 1N-hydrochloric acid and 3.10 parts of sodium nitrite, and the insoluble material is recovered by filtration and recrystallized four times from dimethylformamide to obtain 0.380 part of 6-acetyl-3-(1H-tetrazol-5-yl)-chromone as colorless crystals.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[C:10]3[C:16](I)=[CH:15][N:14]([S:18]([C:21]4[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=4)(=[O:20])=[O:19])[C:11]3=[N:12][CH:13]=2)[CH:5]=[CH:4][C:3]=1[CH:28]1[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30][CH2:29]1.[F:41][C:42]1[CH:43]=[C:44]([CH:61]=[CH:62][CH:63]=1)[CH2:45][N:46]1[CH:50]=[C:49](C2OC(C)(C)C(C)(C)O2)[C:48]([CH3:60])=[N:47]1.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:41][C:42]1[CH:43]=[C:44]([CH:61]=[CH:62][CH:63]=1)[CH2:45][N:46]1[CH:50]=[C:49]([C:16]2[C:10]3[C:11](=[N:12][CH:13]=[C:8]([C:6]4[CH:7]=[CH:2][C:3]([CH:28]5[CH2:29][CH2:30][N:31]([C:34]([O:36][C:37]([CH3:39])([CH3:40])[CH3:38])=[O:35])[CH2:32][CH2:33]5)=[CH:4][CH:5]=4)[CH:9]=3)[N:14]([S:18]([C:21]3[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=3)(=[O:20])=[O:19])[CH:15]=2)[C:48]([CH3:60])=[N:47]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(-c4ccc(C5CCN(C(=O)OC(C)(C)C)CC5)c(F)c4)cnc32)cc1
Reactant: Cc1nn(Cc2cccc(F)c2)cc1C1OC(C)(C)C(C)(C)O1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cn(Cc4cccc(F)c4)nc3C)c3cc(-c4ccc(C5CCN(C(=O)OC(C)(C)C)CC5)cc4)cnc32)cc1
Yield: 76.3 %

Procedure:
Using similar reaction conditions as described in step-i of example-1, tert-butyl 4-(4-(3-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperidine-1-carboxylate (intermediate 67B) (120 mg, 0.182 mmol) was coupled with 1-(3-fluorobenzyl)-3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (intermediate 12) (64 mg, 0.200 mmol) using Pd(PPh3)2Cl2 (6 mg, 0.009 mol) and sodium carbonate (58 mg, 0.547 mmol) in acetonitrile/water (3/2 ml) to afford 100 mg (76% yield) of the titled compound.
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:11]=[CH:10][C:9]3[CH:12]=[C:13]([Cl:16])[CH:14]=[CH:15][C:8]=3[CH:7]([C:17]3[C:18](=[O:25])[NH:19][C:20](=[O:24])[N:21]([CH3:23])[CH:22]=3)[C:5]=2[N:6]=1>C(O)(=O)C.[Zn]>[Cl:16][C:13]1[CH:14]=[CH:15][C:8]2[CH:7]([C:17]3[C:18](=[O:25])[NH:19][C:20](=[O:24])[N:21]([CH3:23])[CH:22]=3)[C:5]3[N:6]=[CH:2][S:3][C:4]=3[CH:11]=[CH:10][C:9]=2[CH:12]=1
Reactant: Cn1cc(C2c3ccc(Cl)cc3C=Cc3sc(Cl)nc32)c(=O)[nH]c1=O
Agent: [Zn]
Solvent: CC(=O)O
Product: Cn1cc(C2c3ccc(Cl)cc3C=Cc3scnc32)c(=O)[nH]c1=O

Procedure:
Zinc powder (4 g) was added to a solution of the product from example 44 step (viii) (0.5 g) in acetic acid. After 24 h the solvent was evaporated under reduced pressure and the residue partitioned between saturated sodium bicarbonate solution and dichloromethane. The organic phase was collected, dried, (MgSO4) and solvent evaporated to leave as a beige foam. Purification by trituration and filtration from isohexane/ethyl acetate mixtures gave the title product.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:5]=[C:4]([C:20]([F:23])([F:22])[F:21])[N:3]=1.[N-:24]=[N+:25]=[N-:26].[Na+]>C(O)C>[N:24]([C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:5]=[C:4]([C:20]([F:23])([F:22])[F:21])[N:3]=1)=[N+:25]=[N-:26]
Reactant: [N-]=[N+]=[N-]
Reactant: FC(F)(F)c1nc(Cl)c(-c2ccccc2)c(-c2ccccc2)n1
Agent: [Na+]
Solvent: CCO
Product: [N-]=[N+]=Nc1nc(C(F)(F)F)nc(-c2ccccc2)c1-c1ccccc1
Temperature: 25 °C
Yield: 87.9 %

Procedure:
4-Chloro-5,6-diphenyl-2-(trifluoromethyl)pyrimidine (0.5 g, 1.5 mmol) (synthesized according to the procedure described in example 1) was refluxed in ethanol (10 ml) containing sodium azide (0.1 g, 1.5 mmol) for 8 hours and allowed to cool to room temperature. The reaction mixture was poured onto ice-water mixture. The solid thus separated was extracted with ethyl acetate. The organic extract was washed with water, dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford the title compound (0.45 g, 88.3%, HPLC purity 98.5%), mp: 126-128° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([OH:11])=[CH:9][N:8]([CH3:12])[C:7]=1[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:5])[CH3:2].[Cl:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=1.FC(F)(F)S(O)(=O)=O.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[Cl:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([C:9]2[N:8]([CH3:12])[C:7]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[C:10]=2[OH:11])=[O:25])=[CH:22][CH:21]=1
Reactant: CCOC(=O)Cc1c(C(=O)OCC)c(O)cn1C
Reactant: O=C(Cl)c1ccc(Cl)cc1
Agent: O=C([O-])O
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)Cc1c(C(=O)OCC)c(O)c(C(=O)c2ccc(Cl)cc2)n1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.8 %

Procedure:
Ethyl 3-ethoxycarbonyl-4-hydroxy-1-methylpyrrole-2-acetate (255 mg, 1.0 mmol) is mixed with p-chlorobenzoyl chloride (385 μl, 3.0 mmol) under nitrogen, and 2.0 ml anhydrous trifluoromethanesulfonic acid is added. The reaction mixture is stirred at room temperature for one hour followed by dilution with methylene chloride (50 ml). Solid sodium bicarbonate is slowly added until the acid is neutralized. The solids are filtered off and washed with an additional 50 ml methylene chloride. The combined methylene chloride solutions are washed with water (20 ml) and saturated brine (50 ml). Subsequently, the washed layers are dried with sodium sulfate and the solvent is removed in vacuo to give a red solid which is recrystallized from ethanol to give 275 mg (70%) of ethyl 5-(p-chlorobenzoyl)-3-ethoxycarbonyl-4-hydroxy-1-methylpyrrole-2-acetate, m.p. 145°-147° C.
Reaction SMILES: [CH3:1][O:2][C@@H:3]([CH3:22])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]([NH:14]C(=O)OC(C)(C)C)[CH3:13])=[CH:8][CH:7]=1.FC(F)(F)C(O)=O>ClCCl>[CH3:1][O:2][C@@H:3]([CH3:22])[CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([CH:12]([NH2:14])[CH3:13])=[CH:10][CH:11]=1
Reactant: CO[C@@H](C)COc1ccc(C(C)NC(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CO[C@@H](C)COc1ccc(C(C)N)cc1

Procedure:
tert-Butyl [1-(4-{[(2S)-2-methoxypropyl]oxy}phenyl)ethyl]carbamate (0.29 g, 0.94 mmol) was treated with trifluoroacetic acid (2 mL) in dichloromethane (18 mL) for 25 minutes, the volatiles removed under reduced pressure and the residue purified by silica gel column chromatography using dichloromethane:methanol:triethylamine 98:1:1 giving the title compound in 0.12 g (59%) yield. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.14 (s, 2 H) 7.34-7.41 (m, J=8.78 Hz, 2 H) 6.97-7.03 (m, 2 H) 4.35 (q, J=6.78 Hz, 1 H) 3.93 (d, J=5.02 Hz, 2 H) 3.60-3.70 (m, 1 H) 3.30 (s, 3 H) 2.96 (q, J=7.11 Hz, 1 H) 1.45 (d, J=6.78 Hz, 3 H) 1.16 (d, J=6.27 Hz, 3 H)
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([N:18]1[CH2:27][CH2:26][C:25]2[C:20](=[CH:21][C:22]([O:28][CH2:29][CH:30]3[CH2:35][CH2:34][N:33]([C:36]4[CH:41]=[CH:40][C:39]([NH2:42])=[CH:38][N:37]=4)[CH2:32][CH2:31]3)=[CH:23][CH:24]=2)[CH2:19]1)=[N:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:43](OC(=O)C)(=[O:45])[CH3:44].N1C=CC=CC=1>O1CCCC1>[C:14]([O:13][C:11]([NH:10][C:9]([N:18]1[CH2:27][CH2:26][C:25]2[C:20](=[CH:21][C:22]([O:28][CH2:29][CH:30]3[CH2:31][CH2:32][N:33]([C:36]4[CH:41]=[CH:40][C:39]([NH:42][C:43](=[O:45])[CH3:44])=[CH:38][N:37]=4)[CH2:34][CH2:35]3)=[CH:23][CH:24]=2)[CH2:19]1)=[N:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[O:12])([CH3:16])([CH3:17])[CH3:15]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)N1CCc2ccc(OCC3CCN(c4ccc(N)cn4)CC3)cc2C1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc(N2CCC(COc3ccc4c(c3)CN(C(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)CC4)CC2)nc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of N,N′-di-tert-butoxycarbonyl-7-[1-(5-aminopyridin-2-yl)piperidin-4-ylmethoxy]-1,2,3,4-tetrahydroisoquinoline-2-carboxamidine (100 mg) in tetrahydrofuran (1.5 ml) were added acetic anhydride (0.017 ml) and pyridine (0.017 ml), and the mixture was stirred at room temperature for 2 hours. After completion of the reaction, the mixture was extracted with ethyl acetate and washed successively with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated. The obtained residue was purified by silica gel column chromatography (hexane:acetone=2:1). The obtained residue was dissolved in methanol and treated with active charcoal, and dried under reduced pressure to give the title compound (75 mg).
Reaction SMILES: [H-].[Na+].[C:3]([O:10][CH3:11])(=[O:9])[CH2:4][C:5]([O:7][CH3:8])=[O:6].[CH2:12]1[O:22][C:21]2[CH:20]=[CH:19][C:16]([CH2:17]Cl)=[CH:15][C:14]=2[O:13]1>C1COCC1>[CH2:12]1[O:22][C:21]2[CH:20]=[CH:19][C:16]([CH2:17][C:4]([CH2:17][C:16]3[CH:19]=[CH:20][C:21]4[O:22][CH2:12][O:13][C:14]=4[CH:15]=3)([C:3]([O:10][CH3:11])=[O:9])[C:5]([O:7][CH3:8])=[O:6])=[CH:15][C:14]=2[O:13]1
Reactant: ClCc1ccc2c(c1)OCO2
Reactant: COC(=O)CC(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)C(Cc1ccc2c(c1)OCO2)(Cc1ccc2c(c1)OCO2)C(=O)OC
Reaction time: 0.5 h
Yield: 68.5 %

Procedure:
A suspension of 6.6 g (0.165 mol) of NaH.oil (60%) in 200 mL THF was cooled in ice and treated dropwise with 10 g (0.075 mol) of dimethyl malonate. After stirring for 0.5 hour, the solution was treated with a solution of 27.3 g (0.16 mol) of 3,4-methylenedioxybenzyl chloride (50% in CH2Cl2). After stirring at room temperature overnight, the solution was heated at reflux overnight. The mixture was filtered and the solvent removed under reduced pressure. The residue was taken up in EtOAc and washed with 1N HCl, then saturated NaCl. Drying over MgSO4 and removal of the solvent under reduced pressure gave the crude product. Recrystallization from EtOAc/hexane gave 20.58 g (68.6% yield) of the product as a solid. The structure was confirmed by NMR spectroscopy.