Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:2]1.[CH:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][C:13]=1[S:22](Cl)(=[O:24])=[O:23]>>[CH:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][C:13]=1[S:22]([N:1]1[CH2:6][CH2:5][CH2:4][CH:3]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:2]1)(=[O:23])=[O:24]
Reactant: CCOC(=O)C1CCCNC1
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Product: CCOC(=O)C1CCCN(S(=O)(=O)c2ccc3ccccc3c2)C1
Yield: 62 %

Procedure:
Using an analogous procedure to that described in Example 2, ethyl piperidine-3-carboxylate was reacted with 2-naphthylsulphonyl chloride to give ethyl 1-(2-naphthylsulphonyl)piperidine-3-carboxylate in 62% yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][N:4]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC.[Cl:33][C:34]1[CH:35]=[C:36]([CH:41]2[CH2:45][NH:44][CH2:43][CH:42]2[C:46](=[O:48])[CH3:47])[CH:37]=[CH:38][C:39]=1[Cl:40]>C(Cl)Cl>[Cl:33][C:34]1[CH:35]=[C:36]([CH:41]2[CH2:45][N:44]([C:7]([C:6]3[CH:5]=[N:4][C:3]([O:2][CH3:1])=[CH:11][CH:10]=3)=[O:9])[CH2:43][CH:42]2[C:46](=[O:48])[CH3:47])[CH:37]=[CH:38][C:39]=1[Cl:40]
Reactant: COc1ccc(C(=O)O)cn1
Reactant: CC(=O)C1CNCC1c1ccc(Cl)c(Cl)c1
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: ClCCCl
Product: COc1ccc(C(=O)N2CC(C(C)=O)C(c3ccc(Cl)c(Cl)c3)C2)cn1
Yield: 56.1 %

Procedure:
To a stirred solution of 6-methoxy-nicotinic acid (0.53 g, 3.40 mmol) in CH2Cl2 (15 mL) were added EDC (0.659 g, 3.40 mmol), HOBt (0.465 g, 3.40 mmol) and Et3N (0.59 mL, 4.3 mmol). After one hour at RT was added 1-[(3SR,4RS)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-ethanone (XIII-1) (0.74 g, 2.90 mmol) and stirring was continued over night. The reaction mixture was then poured onto water and extracted with CH2Cl2. The combined organic phases were dried over Na2SO4 and concentrate under vacuo. Flash chromatography (SiO2, EtOAc/H, 1:1) afforded 0.64 g (57%) of the title product as a white solid. ES-MS m/e: 393.1 (M+H+).
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[C:6]3[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][N:7]3[C:15]=2[CH3:16])[CH2:3][CH2:2]1.[F:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:25]=[N:26][C:27]([C:30](O)=[O:31])=[N:28][CH:29]=2)=[CH:20][CH:19]=1.[ClH:33].C(OCC)(=O)C>C(OCC)(=O)C>[ClH:33].[CH:1]1([C:4]2[N:5]=[C:6]3[CH:11]=[CH:10][C:9]([NH:12][C:30]([C:27]4[N:26]=[CH:25][C:24]([C:21]5[CH:22]=[CH:23][C:18]([F:17])=[CH:19][CH:20]=5)=[CH:29][N:28]=4)=[O:31])=[CH:8][N:7]3[C:15]=2[CH3:16])[CH2:3][CH2:2]1
Reactant: Cc1c(C2CC2)nc2ccc([N+](=O)[O-])cn12
Reactant: O=C(O)c1ncc(-c2ccc(F)cc2)cn1
Agent: Cl
Solvent: CCOC(C)=O
Product: Cc1c(C2CC2)nc2ccc(NC(=O)c3ncc(-c4ccc(F)cc4)cn3)cn12

Procedure:
2-cyclopropyl-3-methyl-6-nitroimidazo[1,2-a]pyridine and 5-(4-fluorophenyl)-2-pyrimidinecarboxylic acid. The resulting solid was dissolved in ethyl acetate, followed by addition of 4N hydrochloric acid-ethyl acetate solution and concentration under reduced pressure. The title compound was obtained as white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][N:12]=3)[CH2:10][O:9]2)=[N:6][CH:7]=1.[NH:18]1[CH:22]=[N:21][CH:20]=[N:19]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][N:12]=2)([OH:9])[CH2:10][N:18]2[CH:22]=[N:21][CH:20]=[N:19]2)=[N:6][CH:7]=1
Reactant: c1nc[nH]n1
Reactant: Clc1ccc(C2(c3ccc(Cl)cn3)CO2)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: OC(Cn1cncn1)(c1ccc(Cl)cn1)c1ccc(Cl)cn1
Temperature: 85 °C
Yield: 47.7 %

Procedure:
2,2-Bis(5-chloro-pyrid-2-yl)oxirane (0.8 g), 1,2,4-triazole (1.0 g) and anhydrous potassium carbonate (3.0 g) were stirred in dry N,N-dimethylformamide (30 ml) and the mixture was heated at 85° C. for 1.5 hours. The solvent was then evaporated under vacuum, with the addition of xylene to remove final traces of N,N-dimethylformamide as an azeotrope, and the residue was dissolved in water (20 ml) and extracted with ethyl acetate (3×20 ml). The combined organic extracts were dried over megnesium sulfate and evaporated. The residue was chromatographed on silica, eluting with ethyl acetate. Evaporation of the relevant fractions gave a viscous oil which solidified on trituration with petroleum ether (b.p. 60°-80° C.). Recrystallization from hexane gave the title compound as white crystals (0.48 g, 38%) m.p. 98°-100° C.
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([N:17]3[C:25]4[C:20](=[CH:21][C:22]([F:27])=[C:23]([F:26])[CH:24]=4)[CH:19]=[N:18]3)[N:15]=2)[N:10](COCC[Si](C)(C)C)[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O>ClCCl>[C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([N:17]3[C:25]4[C:20](=[CH:21][C:22]([F:27])=[C:23]([F:26])[CH:24]=4)[CH:19]=[N:18]3)[N:15]=2)[NH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-n3ncc4cc(F)c(F)cc43)nc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)NC(=O)c1c[nH]c2ncc(-n3ncc4cc(F)c(F)cc43)nc12
Reaction time: 15 h
Yield: 16.2 %

Procedure:
To a stirred solution of N-tert-butyl-2-(5,6-difluoro-1H-indazol-1-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (120 mg, 240 μmol) in dichloromethane (3 mL) was added trifluoroacetic acid (1 mL). After 15 h, the mixture was concentrated in vacuo then 25 mL of a Jan. 10, 1960 mixture of ammonium hydroxide/methanol/dichloromethane added. After 1 h the mixture was concentrated in vacuo. Purification by chromatography (silica, 24 g Analogix column, 0 to 4% of a solution of methanol containing 10% ammonium hydroxide)/dichloromethane gave 2-(5,6-difluoro-indazol-1-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid tert-butylamide (14.4 mg, 16%). MS: (M+H)+=371; 1H NMR (DMSO-d6) δ: 9.02 (s, 1H), 8.53-8.60 (m, 2H), 8.44 (s, 1H), 8.06 (dd, J=10.0, 7.8 Hz, 1H), 7.56 (s, 1H), 1.50 (s, 9H).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:17]=[CH:16][CH:15]=[CH:14][C:6]=1[O:7][S:8]([N:11]=[C:12]=[O:13])(=[O:10])=[O:9].[NH2:18][C:19]1[N:24]=[C:23]([O:25][CH3:26])[CH:22]=[C:21]([O:27][CH3:28])[N:20]=1>ClCCl>[Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:17]=[CH:16][CH:15]=[CH:14][C:6]=1[O:7][S:8]([NH:11][C:12]([NH:18][C:19]1[N:20]=[C:21]([O:27][CH3:28])[CH:22]=[C:23]([O:25][CH3:26])[N:24]=1)=[O:13])(=[O:10])=[O:9]
Reactant: COc1cc(OC)nc(N)n1
Reactant: O=C=NS(=O)(=O)Oc1ccccc1OCCCl
Solvent: ClCCl
Product: COc1cc(OC)nc(NC(=O)NS(=O)(=O)Oc2ccccc2OCCCl)n1
Reaction time: 24 h
Yield: 88.9 %

Procedure:
A solution of 5.6 g (0.02 mol) of the product of Example 1 in 20 ml of dichloromethane is added dropwise at 0° C. to 3.1 g (0.02 mol) of 2-amino-4,6-dimethoxypyrimidine in 30 ml of dichloromethane. The reaction mixture is allowed to reach room temperature, and stirring is continued for 24 hours. The reaction solution is diluted using 100 ml of dichloromethane and washed with 50 ml of 1N hydrochloric acid and 50 ml of water. The organic phase is dried using sodium sulfate, and the solvent is removed on a rotary evaporator. The viscous oil which remains is crystallized by trituration with diethyl ether. 7.7 g (89% of theory) of 1-[2-(2-chloroethoxy)phenoxy-sulfonyl]-3-(4,6-dimethoxypyrimidin-2-yl)urea of melting point 132°-134° C. are obtained.
Reaction SMILES: [CH3:1][C:2]1[N:7]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[C:6](=[O:13])[C:5]([N+:14]([O-:16])=[O:15])=[C:4](OS(C(F)(F)F)(=O)=O)[CH:3]=1.[C:25]1([S:31]([O-:33])=[O:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[Na+]>O1CCCC1>[CH3:1][C:2]1[N:7]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[C:6](=[O:13])[C:5]([N+:14]([O-:16])=[O:15])=[C:4]([S:31]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)(=[O:33])=[O:32])[CH:3]=1
Reactant: O=S([O-])c1ccccc1
Reactant: COC(=O)Cn1c(C)cc(OS(=O)(=O)C(F)(F)F)c([N+](=O)[O-])c1=O
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)Cn1c(C)cc(S(=O)(=O)c2ccccc2)c([N+](=O)[O-])c1=O
Reaction time: 3 h

Procedure:
5.24 g (14 mmol) of methyl 6-methyl-3-nitro-2-oxo-4-[[(trifluoromethyl)sulphonyl]oxy]-1,2-dihydropyridine-1-acetate in solution in 50 ml of tetrahydrofuran are added dropwise to 2.38 g (14.5 mmol) of sodium benzenesulphinate in suspension in 100 ml of tetrahydrofuran and the mixture is left for 3 hours at room temperature. The solvent is evaporated off, the residue is taken up in 200 ml of dichloromethane and washed with 50 ml of a 1 N aqueous hydrochloric acid solution. The organic phase is recovered, it is dried over magnesium sulphate and evaporated off.
Reaction SMILES: C([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C@@H:7]([CH2:8][CH2:9][C@:10]3([CH3:44])[C@@H:19]2[CH2:18][CH2:17][C@H:16]2[C@@:11]3([CH3:43])[CH2:12][CH2:13][C@@:14]3([C:30]([N:32]4[CH2:37][CH2:36][C:35]([CH2:41][CH3:42])([C:38]([OH:40])=[O:39])[CH2:34][CH2:33]4)=[O:31])[CH2:26][CH2:25][C@@H:24]([C:27]([CH3:29])=[CH2:28])[C@@H:15]32)[C:6]1([CH3:46])[CH3:45])(=O)C.C1COCC1.[OH-].[Na+]>CO>[CH2:41]([C:35]1([C:38]([OH:40])=[O:39])[CH2:34][CH2:33][N:32]([C:30]([C@:14]23[CH2:26][CH2:25][C@@H:24]([C:27]([CH3:29])=[CH2:28])[C@@H:15]2[C@@H:16]2[C@@:11]([CH3:43])([CH2:12][CH2:13]3)[C@@:10]3([CH3:44])[C@@H:19]([C@:20]4([CH3:23])[C@@H:7]([CH2:8][CH2:9]3)[C:6]([CH3:46])([CH3:45])[C@@H:5]([OH:4])[CH2:22][CH2:21]4)[CH2:18][CH2:17]2)=[O:31])[CH2:37][CH2:36]1)[CH3:42]
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)N3CCC(CC)(C(=O)O)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](OC(C)=O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)N3CCC(CC)(C(=O)O)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 25 °C
Reaction time: 6 h
Yield: 77.6 %

Procedure:
1-((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-9-acetoxy-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysene-3a-carbonyl)-4-ethylpiperidine-4-carboxylic acid (Example 83, 2.0 g) was taken in MeOH:THF (8:8 ml) and cooled the contents to 0° C. then sodium hydroxide (1.5 g in 4 ml water) was added and the contents were stirred for 6 hours at room temperature. Completion of the reaction was monitored by TLC. The reaction mixture was evaporated under reduced pressure and the residue was taken in water and extracted with DCM, the organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using 5% methanol in DCM as eluent to furnish the title compound (1.45 g) as a white solid. 1H NMR (300 MHz, CDCl3): 0.57-0.97 (m, 19H); 1.18-1.21 (m, 8H); 1.25-1.41 (m, 12H); 1.49-1.62 (m, 10H); 1.65-1.82 (m, 10H); 1.85-1.98 (m, 4H); 2.56-2.69 (m, 2H); 3.29-3.38 (m, 1H); 3.89-3.90 (m, 1H); 4.15-4.18 (m, 2H); 4.56 (s, 1H); 4.71 (s, 1H); MASS: 595 (100%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[S:28][C:27]3[C:22](=[N:23][CH:24]=[CH:25][C:26]=3[O:29][C:30]3[CH:35]=[CH:34][C:33]([NH:36][CH:37]([CH:42]([C:48]([O:50]CC)=[O:49])[C:43]([O:45]CC)=[O:44])[C:38]([F:41])([F:40])[F:39])=[CH:32][C:31]=3[F:53])[CH:21]=2)=[N:18][CH:19]=1)[CH2:9][CH2:10][O:11][CH3:12])=[O:7])([CH3:4])([CH3:3])[CH3:2]>CCO>[C:1]([O:5][C:6]([N:8]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[S:28][C:27]3[C:22](=[N:23][CH:24]=[CH:25][C:26]=3[O:29][C:30]3[CH:35]=[CH:34][C:33]([NH:36][CH:37]([CH:42]([C:43]([OH:45])=[O:44])[C:48]([OH:50])=[O:49])[C:38]([F:41])([F:39])[F:40])=[CH:32][C:31]=3[F:53])[CH:21]=2)=[N:18][CH:19]=1)[CH2:9][CH2:10][O:11][CH3:12])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)C(C(=O)OCC)C(Nc1ccc(Oc2ccnc3cc(-c4ccc(CN(CCOC)C(=O)OC(C)(C)C)cn4)sc23)c(F)c1)C(F)(F)F
Solvent: CCO
Product: COCCN(Cc1ccc(-c2cc3nccc(Oc4ccc(NC(C(C(=O)O)C(=O)O)C(F)(F)F)cc4F)c3s2)nc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 16 (1.794 g, 2.346 mmol) in a mixture of EtOH/1N NaOH (25 mL/11.7 mL) was stirred at RT overnight. The reaction mixture was then concentrated, diluted with water and the pH was adjusted to 3-4 by addition of 1N HCl. The resulting suspension was stirred for 30 min, and the solid was collected by filtration, rinsed with water, air-dried and dried under high vacuum to afford the title compound 17 (1.217 g; mixed with the acid 18) as a pale yellow fluffy solid. MS (m/z): 665.5 and 709.5 (M+H).
Reaction SMILES: [NH2:1][C@@H:2]([CH3:5])[CH2:3][OH:4].[Cl:6][CH2:7][C:8](Cl)=[O:9]>O.ClCCl.[OH-].[Na+]>[Cl:6][CH2:7][C:8]([NH:1][C@@H:2]([CH3:5])[CH2:3][OH:4])=[O:9]
Reactant: O=C(Cl)CCl
Reactant: C[C@H](N)CO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: C[C@@H](CO)NC(=O)CCl
Yield: 82.2 %

Procedure:
To a stirred solution of (S)-2-aminopropan-1-ol (10 g, 0.13 mol) in water at 0° C. was added simultaneously a solution of chloroacetyl chloride (18 g, 0.16 mol) in dichloromethane (50 mL) and 1.6M aqueous sodium hydroxide (100 mL) dropwise over 1 h. The dichloromethane was removed under reduced pressure then the aqueous layer was extracted with ethyl acetate. The separated organic layer was dried (Na2SO4) and concentrated to afford (S)-2-chloro-N-(1-hydroxypropan-2-yl)acetamide (16.2 g, 83%) as a colourless oil which was used in the next step without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[S:14][C:15]([C:17]([OH:19])=O)=[CH:16][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O1CCCC1.[CH3:25][NH:26][CH3:27]>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[S:14][C:15]([C:17](=[O:19])[N:26]([CH3:27])[CH3:25])=[CH:16][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCc2sc(C(=O)O)cc2C1
Reactant: CNC
Solvent: C1CCOC1
Product: CN(C)C(=O)c1cc2c(s1)CCN(C(=O)OC(C)(C)C)C2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5-t-Butoxycarbonyl-4,5,6,7-tetrahydro-thieno[3,2-c]pyridine-2-carboxylic acid (570 mg, 2.0 mmol) was dissolved in anhydrous tetrahydrofuran (10 ml), and the solution was mixed with 1,1-carbonyldiimidazole (320 mg, 2.0 mmol) and stirred at room temperature for 1 hour. The reaction solution was mixed with dimethylamine tetrahydrofuran solution (2.0 M, 4.0 ml, 2.0 mmol) and the stirring was continued for 15 hours. The solvent was removed by evaporation from the reaction solution under a reduced pressure, and the residue was mixed with ethyl acetate and washed with water, hydrochloric acid (1 N), sodium hydroxide aqueous solution (1 N) and saturated brine. The organic layer was dried with anhydrous sodium sulfate, and the solvent was removed by evaporation under a reduced pressure to obtain 470 mg (1.5 mmol, 77% in yield) of the title compound.
Reaction SMILES: [CH2:1]([C:3]1[N:4]([C:8]2[CH:41]=[CH:40][CH:39]=[CH:38][C:9]=2[C:10]([NH:12][C:13]2[CH:37]=[CH:36][C:16]([C:17]([N:19]3[C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=4/[C:23](=[CH:30]/[C:31]([OH:33])=O)/[C:22]([F:35])([F:34])[CH2:21][CH2:20]3)=[O:18])=[CH:15][CH:14]=2)=[O:11])[CH:5]=[CH:6][N:7]=1)[CH3:2].[CH3:42][NH2:43]>>[CH2:1]([C:3]1[N:4]([C:8]2[CH:41]=[CH:40][CH:39]=[CH:38][C:9]=2[C:10]([NH:12][C:13]2[CH:14]=[CH:15][C:16]([C:17]([N:19]3[C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=4/[C:23](=[CH:30]/[C:31](=[O:33])[NH:43][CH3:42])/[C:22]([F:34])([F:35])[CH2:21][CH2:20]3)=[O:18])=[CH:36][CH:37]=2)=[O:11])[CH:5]=[CH:6][N:7]=1)[CH3:2]
Reactant: CCc1nccn1-c1ccccc1C(=O)Nc1ccc(C(=O)N2CCC(F)(F)/C(=C\C(=O)O)c3ccccc32)cc1
Reactant: CN
Product: CCc1nccn1-c1ccccc1C(=O)Nc1ccc(C(=O)N2CCC(F)(F)/C(=C\C(=O)NC)c3ccccc32)cc1

Procedure:
Using 0.5 g of (Z)-[1-[4-[2-(2-ethyl-1H-imidazol-1-yl)benzoylamino]benzoyl]-4,4-difluoro-2,3,4,5-tetrahydro-1H-1-benzazepin-5-ylidene]acetic acid and 40% methylamine aqueous solution, a similar procedure as in Example 11 was repeated to obtain 425 mg of (Z)-2-(2-ethyl-1H-imidazol-1-yl)-4'-[[4,4-difluoro-5-[(N-methylcarbamoyl)methylene]-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl]carbonyl]benzanilide.
Reaction SMILES: [O:1]([CH2:8][CH2:9][S:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([OH:26])=O)=[CH:20][CH:19]=2)=[CH:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:39][N:40]([CH3:45])[CH2:41][CH2:42][CH2:43][NH2:44]>C1COCC1>[CH3:39][N:40]([CH3:45])[CH2:41][CH2:42][CH2:43][NH:44][C:24]([C:21]1[CH:20]=[CH:19][C:18]([C:15]2[CH:14]=[CH:13][C:12]([CH2:11][S:10][CH2:9][CH2:8][O:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:17][CH:16]=2)=[CH:23][CH:22]=1)=[O:26]
Reactant: O=C(O)c1ccc(-c2ccc(CSCCOc3ccccc3)cc2)cc1
Reactant: CN(C)CCCN
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CN(C)CCCNC(=O)c1ccc(-c2ccc(CSCCOc3ccccc3)cc2)cc1
Yield: 74.3 %

Procedure:
4′-(2-Phenoxy-ethylsulfanylmethyl)-biphenyl-4-carboxylic acid (3-dimethylamino-propyl)-amide was prepared as described in example 1. 4′-(2-Phenoxy-ethylsulfanylmethyl)-biphenyl-4-carboxylic acid (0.6 g, 1.65 mmol, 1 eq.) in THF was treated with 1,1′-carbonyldiimidazole (0.27 g, 1.68 mmol, 1.02 eq.). The resulting acyl imidazole was then treated with 3-(dimethylamino)propylamine (0.20 g, 1.98 mmol, 1.2 eq.). When complete, the reaction was worked up and the resulting yellow oil purified as described in example 3 to give 4′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl4-carboxylic acid (3-dimethylamino-propyl)-amide (0.55 g, 74% yield) as a white solid.
Reaction SMILES: [O:1]=[C:2]([CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:3][CH2:4][NH:5][CH:6]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:7]([O:9]CC)=O.[O-:28][C:29]#[N:30].[K+].Cl>>[CH2:21]([O:20][C:18]([CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH:6]1[N:5]([CH2:4][CH2:3][C:2](=[O:1])[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[C:29](=[O:28])[NH:30][C:7]1=[O:9])=[O:19])[CH3:22]
Reactant: CCCCCC(=O)CCNC(CCCCCCC(=O)OCC)C(=O)OCC
Reactant: N#C[O-]
Agent: Cl
Agent: [K+]
Product: CCCCCC(=O)CCN1C(=O)NC(=O)C1CCCCCCC(=O)OCC

Procedure:
Diethyl 2-(3-oxooctylamino)nonanedioate (7.7 g) prepared by the method described in Example 1B was treated with potassium cyanate and hydrochloric acid to give 5-(6-ethoxycarbonylhexyl)-1-(3-oxo-octyl)hydantoin. Hydrolysis of this ester using sodium hydroxide solution gave 5-(6-carboxyhexyl)-1-(3-oxooctyl)hydantoin as a viscous oil, which crystallised to a low-melting solid.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][OH:9])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:10][Si:11]([CH3:26])([CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[CH2:12][CH2:13][CH2:14][O:15][CH2:16][CH:17]1[CH2:19][O:18]1>C(O)C>[CH3:10][Si:11]([CH3:26])([CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[CH2:12][CH2:13][CH2:14][O:15][CH2:16][CH:17]([OH:18])[CH2:19][N:4]1[CH2:5][CH2:6][N:1]([CH2:7][CH2:8][OH:9])[CH2:2][CH2:3]1
Reactant: C[Si](C)(C)CC[Si](C)(C)CCCOCC1CO1
Reactant: OCCN1CCNCC1
Solvent: CCO
Product: C[Si](C)(C)CC[Si](C)(C)CCCOCC(O)CN1CCN(CCO)CC1
Temperature: 70 °C

Procedure:
2-piperazin-1-yl-ethanol (0.95 g; 7.28 mMol) and 20 mL of ethanol were charged to a 100 ml RB flask equipped with a magnetic stirrer. The mixture was stirred and heated to 70° C. 2-{3-[Dimethyl-(2-trimethylsilanyl-ethyl)-silanyl]-propoxymethyl}-oxirane 8 (2 g; 7.28 mMol) was placed in an addition funnel and added dropwise to the flask. The mixture was stirred and maintained at 70° C. for additional 4 hours. After the reaction was complete, ethanol was stripped off on the rotovap. The mixture was distilled under vacuum.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[CH:12]=[C:13]([NH:17][CH:18]([CH:27]([CH3:29])[CH3:28])[C:19]([NH:21][CH2:22][C:23]([F:26])([F:25])[F:24])=[O:20])[CH:14]=[N:15][CH:16]=3)=[CH:9][N:8](COCC[Si](C)(C)C)[C:5]2=[N:6][CH:7]=1.C(O)(C(F)(F)F)=O.C(N)CN.[OH-].[Na+]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[CH:12]=[C:13]([NH:17][CH:18]([CH:27]([CH3:29])[CH3:28])[C:19]([NH:21][CH2:22][C:23]([F:24])([F:25])[F:26])=[O:20])[CH:14]=[N:15][CH:16]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CC(C)C(Nc1cncc(-c2cn(COCC[Si](C)(C)C)c3ncc(F)cc23)c1)C(=O)NCC(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: NCCN
Solvent: O=C(O)C(F)(F)F
Product: CC(C)C(Nc1cncc(-c2c[nH]c3ncc(F)cc23)c1)C(=O)NCC(F)(F)F
Reaction time: 1 h

Procedure:
2-(5-(5-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-3-ylamino)-3-methyl-N-(2,2,2-trifluoroethyl)butanamide 1-2a (78 mg, 0.145 mmol) was dissolved in DCM (2 ml). TFA (1.114 ml, 14.45 mmol) was added and mixture allowed to stir for 1 hr. Reaction concentrated then resuspended in MeOH (4 ml) and ethylenediamine (0.020 ml, 0.289 mmol) and sodium hydroxide (10 M aqueous) (0.101 ml, 1.012 mmol) added. After 30 min the reaction was treated with HCL (1.012 ml, 1.012 mmol) concentrated in vacuo and the residue was purified by preparative HPLC Reverse phase (C-18). (5-95% Acetonitrile/0.1% TFA/water). Product fractions were treated with aq. NaHCO3, concentrated and product extracted into DCM and ethyl acetate. Extracts dried over sodium sulfate, filtered and concentrated to give white solid 1-2. (40 mg).
Reaction SMILES: O=P(Cl)(Cl)[Cl:3].[N+:6]([C:9]1[C:10]2[N:11]([N:20]=[N:21][N:22]=2)[C:12]2[C:17]([C:18]=1O)=[CH:16][CH:15]=[CH:14][CH:13]=2)([O-:8])=[O:7]>CN(C)C=O>[Cl:3][C:18]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]2[N:20]=[N:21][N:22]=[C:10]2[C:9]=1[N+:6]([O-:8])=[O:7]
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=[N+]([O-])c1c(O)c2ccccc2n2nnnc12
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1c(Cl)c2ccccc2n2nnnc12
Temperature: 0 °C

Procedure:
Under a nitrogen atmosphere, POCl3 (16.42 ml, 0.17 mol) was slowly added to a chilled (0° C.) flask containing N,N-dimethylformamide (100 ml). The resulting solution was slowly warmed to room temperature and then added dropwise to a suspension of 4-nitro-tetrazolo[1,5-a]quinolin-5-ol in N,N-dimethylformamide (300 ml). The reaction was heated to 100° C. for 30 minutes. The orange/red solution was quenched by pouring over 1 liter of ice water. A yellow precipitate formed and was collected by filtration, redissolved in chloroform (approx. 750 ml), dried (Na2SO4), filtered, and concentrated in vacuo to yield 33.74 g of 5-chloro-4-nitrotetrazolo[1,5-a]quinoline as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.[CH3:11][N:12]([CH3:18])[CH:13]1[CH2:17][CH2:16][NH:15][CH2:14]1.CN(C)CCCN=C=NCC>C(Cl)Cl>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:15]2[CH2:16][CH2:17][CH:13]([N:12]([CH3:18])[CH3:11])[CH2:14]2)=[O:8])=[CH:9][CH:10]=1
Reactant: Nc1ccc(C(=O)O)cc1
Reactant: CN(C)C1CCNC1
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Product: CN(C)C1CCN(C(=O)c2ccc(N)cc2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 47.1 %

Procedure:
A mixture of 4-aminobenzoic acid (1.4 g, 10 mmol), 3-(dimethylamino)-pyrrolidine (1.5 g, 13 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (2.5 g, 13 mmol) in CH2Cl2 is stirred at room temperature for 16 h, diluted with CH2Cl2, washed with water, dried over MgSO4 and concentrated in vacuo to give the title compound (1.1 g), identified by NMR analysis.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:28][C:29]1[CH:38]=[CH:37][C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=1)[C:3]([NH:5][CH2:6][CH2:7][CH2:8][CH2:9][C@H:10]([N:13]([S:18]([C:21]1[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][CH:22]=1)(=[O:20])=[O:19])[CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:11][OH:12])=[O:4].[C:39](O)(=[O:46])[C:40]1[CH:45]=[CH:44][N:43]=[CH:42][CH:41]=1>>[NH2:27][C:24]1[CH:23]=[CH:22][C:21]([S:18]([N:13]([CH2:14][CH:15]([CH3:17])[CH3:16])[C@H:10]([CH2:11][OH:12])[CH2:9][CH2:8][CH2:7][CH2:6][NH:5][C:3]([C@@H:2]([NH:1][C:39](=[O:46])[C:40]2[CH:45]=[CH:44][N:43]=[CH:42][CH:41]=2)[CH2:28][C:29]2[CH:38]=[CH:37][C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH:30]=2)=[O:4])(=[O:20])=[O:19])=[CH:26][CH:25]=1
Reactant: CC(C)CN([C@H](CO)CCCCNC(=O)[C@@H](N)Cc1ccc2ccccc2c1)S(=O)(=O)c1ccc(N)cc1
Reactant: O=C(O)c1ccncc1
Product: CC(C)CN([C@H](CO)CCCCNC(=O)[C@H](Cc1ccc2ccccc2c1)NC(=O)c1ccncc1)S(=O)(=O)c1ccc(N)cc1

Procedure:
The title compound was prepared from (2S,5S)-2-amino-N-{5-[(4-amino-benzenesulfonyl)-isobutyl-amino]-6-hydroxy-hexyl}-3-naphthalen-2-yl-propionamide (product of example 49) as described in general procedure E using isonicotinic acid. The final product was obtained in 46% yield.