Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[C:8]([CH2:32][CH2:33][C:34]([O:36]CC)=[O:35])=[CH:9][N:10]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]4[N:22]=[C:23]([C:26]5[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=5)[S:24][CH:25]=4)=[CH:15][CH:14]=3)[CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].O1CCCC1.Cl>C(O)C>[C:1]1([C:7]2[C:8]([CH2:32][CH2:33][C:34]([OH:36])=[O:35])=[CH:9][N:10]([CH2:12][C:13]3[CH:14]=[CH:15][C:16]([O:19][CH2:20][C:21]4[N:22]=[C:23]([C:26]5[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=5)[S:24][CH:25]=4)=[CH:17][CH:18]=3)[CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)CCc1cn(Cc2ccc(OCc3csc(-c4cccnc4)n3)cc2)cc1-c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(O)CCc1cn(Cc2ccc(OCc3csc(-c4cccnc4)n3)cc2)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 86.6 %

Procedure:
A mixture of ethyl 3-[4-phenyl-1-[4-[2-(3-pyridyl)-4-thiazolylmethoxy]benzyl]-3-pyrrolyl]propionate (655 mg), 1N aqueous sodium hydroxide solution (2.5 ml), tetrahydrofuran (5 ml), and ethanol (5 ml) was stirred at room temperature for 6 hours, and 1N hydrochloric acid (2.5 ml) was added to the mixture, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), then concentrated. The colorless crystals obtained were collected by filtration to yield 3-[4-phenyl-1-[4-[2-(3-pyridyl)-4-thiazolylmethoxy]benzyl]-3-pyrrolyl]propionic acid (537 mg, yield: 92%). This was recrystallized from ethanol. Melting point: 118–119° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH3:19])[C:5]2[N:9]=[C:8]([C:10]3[C:11](=[O:17])[NH:12][CH:13]=[CH:14][C:15]=3Cl)[NH:7][C:6]=2[CH:18]=1.[NH2:20][C@@H:21]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:22][OH:23].CN1CCOCC1>CN(C=O)C>[CH2:24]([C@H:21]([NH:20][C:15]1[CH:14]=[CH:13][NH:12][C:11](=[O:17])[C:10]=1[C:8]1[NH:7][C:6]2[CH:18]=[C:2]([Br:1])[CH:3]=[C:4]([CH3:19])[C:5]=2[N:9]=1)[CH2:22][OH:23])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: Cc1cc(Br)cc2[nH]c(-c3c(Cl)cc[nH]c3=O)nc12
Reactant: N[C@H](CO)Cc1ccccc1
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: Cc1cc(Br)cc2[nH]c(-c3c(N[C@H](CO)Cc4ccccc4)cc[nH]c3=O)nc12
Temperature: 80 °C
Yield: 73.5 %

Procedure:
To a solution of 3-(6-bromo-4-methyl-1H-benzimidazol-2-yl)-4-chloro-1H-pyridin-2-one (1.42 g, 3.78 mmol) in DMF (15 mL) were added (S)-(−)-2-amino-3-phenyl-1-propanol (1.43 g, 9.45 mmol) and N-methyl morpholine (1.5 mL). The reaction mixture was heated to 80° C. for 6 h and cooled to room temperature. The solvent was removed with high vacuum and the residue was purified by flash chromatography (5% MeOH/CH2Cl2) to yield the title compound (1.26 g, 74%) as a yellow foam. 1H NMR (300 MHz, CDCl3) δ 6.9–7.2 (8H, m), 5.86 (1H, d, J=7.1 Hz), 3.7–3.9 (3H, m), 2.9–3.1(2H, m), 2.57 (3H, s). LCMS (M+H)+ m/z 453 (t=2.03 min.).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]([C:12]2[C:13]([O:19]C)=[N:14][CH:15]=[CH:16][C:17]=2I)=[N:9][C:10]=1[CH3:11])=[O:5])[CH3:2].Cl.C(N(CC)CC)C.[NH2:29][CH2:30][C@H:31]([C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[CH:34]=1)[OH:32]>C(O)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]([C:12]2[C:13](=[O:19])[NH:14][CH:15]=[CH:16][C:17]=2[NH:29][CH2:30][CH:31]([C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[CH:34]=2)[OH:32])=[N:9][C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: NC[C@@H](O)c1cccc(Cl)c1
Reactant: CCOC(=O)c1[nH]c(-c2c(I)ccnc2OC)nc1C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Product: CCOC(=O)c1[nH]c(-c2c(NCC(O)c3cccc(Cl)c3)cc[nH]c2=O)nc1C
Temperature: 65 °C
Yield: 13.8 %

Procedure:
2-(4-Iodo-2-methoxy-pyridin-3-yl)-5-methyl-3H-imidazole-4-carboxylic acid ethyl ester (0.020 g, 0.052 mmol) was dissolved in acetic acid (1 mL) and concentrated hydrochloric acid (1 mL) and this mixture was stirred at reflux for 2 hours. The mixture was then evaporated and the residue was dissolved in N,N-dimethylformamide (2 mL) and treated with triethylamine (˜22 μL, 0.155 mmol) and the hydrochloric acid salt of (S)-2-amino-1-[3-chlorophenyl]ethanol (0.020 g, 0.096 mmol). The mixture was heated at 65° C. overnight, then the solvent was evaporated and the residue was purified by Prep HPLC (ammonium acetate/acetonitrile/water) to give the title compound (0.003 g, 14%) as a white solid. HPLC 100% (220 nm), LCMS (+ESI, M+H+) m/z 417; 1H NMR (400 MHz, methanol-d4) δ (ppm) (mixture of tautomers): 1.40 and 1.43 (3H, 2t, J=7.1 Hz), 2.49 and 2.61 (3H, 2s), 3.61-3.72 (2H, m), 4.35 and 4.39 (2H, q, J=7.1 Hz), 4.95-4.97 (1H, m), 6.21 and 6.23 (1H, 2d, J=7.6 Hz), 7.19-7.55 (5H, m).
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:15]=2[Cl:21])=[O:12])[N:7]([C:22]2[CH:31]=[C:30]3[C:25]([CH2:26][CH2:27][NH:28][C:29]3=S)=[CH:24][CH:23]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].O.[NH3:34].O1CCOCC1>>[NH2:34][C:29]1[C:30]2[C:25](=[CH:24][CH:23]=[C:22]([N:7]3[C:8]([NH:10][C:11]([NH:13][C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:15]=4[Cl:21])=[O:12])=[CH:9][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[N:6]3)[CH:31]=2)[CH2:26][CH2:27][N:28]=1
Reactant: N
Reactant: CC(C)(C)c1cc(NC(=O)Nc2cccc(Cl)c2Cl)n(-c2ccc3c(c2)C(=S)NCC3)n1
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)c1cc(NC(=O)Nc2cccc(Cl)c2Cl)n(-c2ccc3c(c2)C(N)=NCC3)n1
Temperature: 80 °C
Reaction time: 18 h
Yield: 15 %

Procedure:
1-[3-t-Butyl-1-(1-thioxo-1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-pyrazol-5-yl]-3-(2,3-dichlorophenyl)urea (0.170 g, 0.348 mmol) was dissolved in 0.5M NH3/dioxane (30 mL). Mercuric chloride (0.142 g, 0.522 mmol) was added and the mixture was stirred at 80° C. After 18 h, H2O (2 mL) was added. The mixture was stirred for 30 min and filtered through a pad of Celite®. The solvent was removed under vacuum and the residue was purified by reverse-phase chromatography to yield 1-[1-(1-amino-3,4-dihydroisoquinolin-7-yl)-3-t-butyl-1 H-pyrazol-5-yl]-3-(2,3-dichlorophenyl)urea (25 mg, 15% yield). 1H NMR (400 MHz, CD3OD): □ 8.14 (d, J=2.0 Hz, 1H), 7.99-7.96 (m, 1H), 7.84 (dd, J=8.0, and 2.0 Hz, 1H), 7.63 (d, J=8.0 Hz, 1H), 7.23-7.21 (m, 2H), 6.46 (s, 1H), 3.62 (t, J=6.8 Hz, 2H), 3.14 (t, J=6.8 Hz, 2H), 1.35 (s, 9H); MS (ESI) m/z: 471.3 (M+H+).
Reaction SMILES: C(Cl)(=O)[C:2](Cl)=[O:3].[C:7]([O:10][C:11]1[C:19]([O:20][C:21](=[O:23])[CH3:22])=[CH:18][CH:17]=[CH:16][C:12]=1[C:13]([NH2:15])=[O:14])(=[O:9])[CH3:8]>ClCCCl>[C:7]([O:10][C:11]1[C:19]([O:20][C:21](=[O:23])[CH3:22])=[CH:18][CH:17]=[CH:16][C:12]=1[C:13]([N:15]=[C:2]=[O:3])=[O:14])(=[O:9])[CH3:8]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(=O)Oc1cccc(C(N)=O)c1OC(C)=O
Solvent: ClCCCl
Product: CC(=O)Oc1cccc(C(=O)N=C=O)c1OC(C)=O

Procedure:
Oxalyl chloride (5.3 g) was added to a solution of 2,3-diacetoxybenzamide (4.0 g) in 1,2-dichloroethane (40 ml) with stirring under cooling. The mixture was gradually heated to a reflux temperature and allowed to react under reflux for 10 hours. Then, the solvent and excess oxalyl chloride were distilled off under reduced pressure to give 2,3-diacetoxybenzoyl isocyanate, which was dissolved in anhydrous dichloromethane (40 ml) for the subsequent reaction.
Reaction SMILES: N#N.[F:3][C:4]([F:18])([CH3:17])[CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[O:10][CH:11]=[C:12]([C:14](O)=[O:15])[N:13]=1.CN(C=O)C.C(Cl)(=O)C([Cl:27])=O>C1(C)C=CC=CC=1>[F:3][C:4]([F:18])([CH3:17])[CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[O:10][CH:11]=[C:12]([C:14]([Cl:27])=[O:15])[N:13]=1
Reactant: CC(F)(F)CCCCc1nc(C(=O)O)co1
Reactant: O=C(Cl)C(=O)Cl
Agent: N#N
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CC(F)(F)CCCCc1nc(C(=O)Cl)co1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a suspension of 2-(5,5-difluoro-hexyl)-oxazole-4-carboxylic acid (280 mg, 1.20 mmol) in toluene (12 mL) was treated at 0° C. with a drop of DMF followed by oxalyl chloride (0.13 mL, 1.44 mmol) and the resulting yellow solution was stirred at rt for 1 h. The solvent was then removed under reduced pressure (coevaporation with toluene) to give 2-(5,5-difluoro-hexyl)-oxazole-4-carbonyl chloride as a brown oil.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]2[NH:6][C:7]([CH2:9][NH:10][C:11]3[CH:15]=[CH:14][NH:13][C:12]=3[C:16]([O:18]CC)=O)=[N:8][C:4]=2[CH:3]=1.CN(C=O)C.C([N:36]=[C:37]=[S:38])(=O)C1C=CC=CC=1>C(Cl)Cl>[Cl:1][C:2]1[CH:22]=[CH:21][C:5]2[NH:6][C:7]([CH2:9][N:10]3[C:11]4[CH:15]=[CH:14][NH:13][C:12]=4[C:16](=[O:18])[NH:36][C:37]3=[S:38])=[N:8][C:4]=2[CH:3]=1
Reactant: CCOC(=O)c1[nH]ccc1NCc1nc2cc(Cl)ccc2[nH]1
Reactant: O=C(N=C=S)c1ccccc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=c1[nH]c(=S)n(Cc2nc3cc(Cl)ccc3[nH]2)c2cc[nH]c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 43.2 %

Procedure:
A solution of ethyl 3-{[(5-chloro-1H-benzimidazol-2-yl)methyl]amino}-1H-pyrrole-2-carboxylate (0.074 g, 0.23 mmol) in CH2Cl2 was stirred for 5 minutes. DMF (0.2 mL) was added to enhance solubility. Benzoyl isothiocyanate (0.045 g, 0.28 mmol) was added and the mixture was stirred for 1 h then concentrated in vacuo. The crude intermediate was taken up in ammonia (7N in methanol, 2 mL) and was stirred at 70° C. for 1.5 h in a sealed vessel. After cooling to r.t. the precipitated product was collected by vacuum filtration, washed with diethyl ether and dried, obtaining 0.033 g (43%) of the title product as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([C:13]3[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][C:14]=3[O:20][CH3:21])=[CH:11][CH:12]=2)=[C:4]([O:22][CH3:23])[CH:3]=1.[C:24]1([NH2:35])[C:29](F)=[C:28](F)[C:27](F)=[C:26]([NH2:33])C=1F.Cl.Cl>CCOC(C)=O.CCOCC>[CH3:21][O:20][C:14]1[CH:15]=[C:16]([N:19]=[N:33][C:26]2[CH:27]=[CH:28][CH:29]=[CH:24][N:35]=2)[CH:17]=[CH:18][C:13]=1[C:10]1[O:9][C:8]([C:5]2[CH:6]=[CH:7][C:2]([N:1]=[N:33][C:26]3[CH:27]=[CH:28][CH:29]=[CH:24][N:35]=3)=[CH:3][C:4]=2[O:22][CH3:23])=[CH:12][CH:11]=1
Reactant: COc1cc(N)ccc1-c1ccc(-c2ccc(N)cc2OC)o1
Reactant: Nc1c(F)c(N)c(F)c(F)c1F
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: COc1cc(N=Nc2ccccn2)ccc1-c1ccc(-c2ccc(N=Nc3ccccn3)cc2OC)o1
Yield: 75 %

Procedure:
2,5-Bis[2-methoxy-4-(2-pyridylimino)aminophenyl]furan (41, DB709) was prepared according to the procedure for 4f using diamine 3c and S-(2-naphthylmethyl)-2-pyridylthioimidate hydrobromide as starting materials. Free base: Bright yellow crystalline solid, mp 196-197° C. (EtOAc/Et2O). Yield: 75%. 1H NMR (DMSO-d6): 3.92 (s, 6H), 6.64 and 6.67 (d, 2H and s, 2H, overlapping a broad NH signal), 6.89 (s, 2H), 7.55 (dd, 2H), 7.86 (d, 2H), 7.95 (m, 2H), 8.32 (d, 2H), 8.63 (d, 2H). Dihydrochloride: brick orange solid, mp >180° C. dec. 1H NMR (DMSO-d6): 4.00 (s, 6H), 7.16 (s, 2H), 7.18 (d, 2H), 7.34 (s, 2H), 7.85 (dd, 2H), 8.13 (d, 2H), 8.22 (t, 2H), 8.49 (d, 2H), 8.89 (d, 2H), 9.39 (br s, 2H), 10.15 (br s, 2H), 11.89 (br s, 2H), MS (EI): m/z 518 (M+, 100), 414 (90.0), 371 (13.3), 310 (12.7), 267 (9.7), 155 (6.02), 104 (25.9), 77 (9.6), 43 (13.6). Anal Calcd. for C30H26N6O.2.0HCl.2.0H2O (627.51): C, H, N, Cl.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[F:19])[C:3]=1[CH3:20].[NH2:21][C:22]1[CH:29]=[C:28]([N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)[CH:27]=[CH:26][C:23]=1[C:24]#[N:25].Cl.O1CCOCC1>CO>[F:12][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([NH:21][C:22]3[CH:29]=[C:28]([N:30]4[CH2:31][CH2:32][O:33][CH2:34][CH2:35]4)[CH:27]=[CH:26][C:23]=3[C:24]#[N:25])=[C:3]([CH3:20])[C:4]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[F:19])=[N:5]2)=[CH:10][CH:9]=1
Reactant: N#Cc1ccc(N2CCOCC2)cc1N
Reactant: Cc1c(-c2ccccc2F)nc2cc(F)ccc2c1Cl
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: Cc1c(-c2ccccc2F)nc2cc(F)ccc2c1Nc1cc(N2CCOCC2)ccc1C#N

Procedure:
Prepared according to general Procedure K using 4-chloro-7-fluoro-2-(2-fluorophenyl)-3-methylquinoline (70 mg, 0.24 mmol), 2-amino-4-morpholinobenzonitrile (49 mg, 0.24 mmol) and a 4.0M solution of HCl in dioxane (0.030 mL, 0.121 mmol) in MeOH (1.0 mL) and heating in the microwave for 2 h at 150° C. After purification 2-((7-fluoro-2-(2-fluorophenyl)-3-methyl-4-quinolinyl)amino)-4-(4-morpholinyl)benzonitrile was obtained as a yellow film. 1H NMR (500 MHz, chloroform-d) δ ppm 7.94-8.03 (1H, m), 7.82 (1H, dd, J=9.8, 2.7 Hz), 7.60-7.66 (1H, m), 7.43-7.52 (2H, m), 7.32-7.40 (2H, m), 7.13-7.22 (1H, m), 6.56 (1H, br. s.), 6.41 (1H, dd, J=8.8, 2.2 Hz), 5.81 (1H, d, J=2.7 Hz), 3.68-3.77 (4H, m), 2.98-3.15 (4H, m), 2.12-2.26 (3H, s). Mass Spectrum (ESI) m/e=457.0 (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]#[N:28])=[CH:17][CH:16]=2)=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH2:29]([N:31]=[C:32]=[S:33])[CH3:30].C(O)C>C(OCC)(=O)C>[C:27]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[C:18]1[CH:19]=[CH:20][C:15]([CH2:14][NH:13][C:3]2[C:2]([NH:1][C:32]([NH:31][CH2:29][CH3:30])=[S:33])=[CH:12][CH:11]=[CH:10][C:4]=2[C:5]([O:7][CH2:8][CH3:9])=[O:6])=[CH:16][CH:17]=1)#[N:28]
Reactant: CCN=C=S
Reactant: CCOC(=O)c1cccc(N)c1NCc1ccc(-c2ccccc2C#N)cc1
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCNC(=S)Nc1cccc(C(=O)OCC)c1NCc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of ethyl 3-amino-2-[[(2′-cyanobiphenyl-4-yl)methyl]amino]benzoate (1.61 g), ethyl isothiocyanate (1.5 ml) and ethanol (1 ml) was stirred at room temperature for 3 days. The reaction mixture was dissolved in ethyl acetate and the solution was washed with water, dried and concentrated to dryness to give crystals. Recrystallization from ethyl acetate-hexane afforded pale yellow crystals (1.92 g, 91%), m.p. 108-110° C.
Reaction SMILES: [CH2:1]([N:4]([CH2:17][C:18]([OH:20])=O)[NH:5][C:6](=[O:16])[NH:7][C@H:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH3:9])[CH:2]=[CH2:3].[NH2:21][C@@H:22]([CH2:46][C:47]1[CH:52]=[CH:51][C:50]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[CH:49][CH:48]=1)[C:23]([N:25]([C@@H:37]([CH3:45])[CH:38]([O:42][CH2:43][CH3:44])[O:39][CH2:40][CH3:41])[CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[C:31]2[C:36]=1[N:35]=[CH:34][CH:33]=[CH:32]2)=[O:24]>>[CH2:1]([N:4]([CH2:17][C:18]([NH:21][C@@H:22]([CH2:46][C:47]1[CH:52]=[CH:51][C:50]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[CH:49][CH:48]=1)[C:23]([N:25]([C@@H:37]([CH3:45])[CH:38]([O:39][CH2:40][CH3:41])[O:42][CH2:43][CH3:44])[CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[C:31]2[C:36]=1[N:35]=[CH:34][CH:33]=[CH:32]2)=[O:24])=[O:20])[NH:5][C:6]([NH:7][C@H:8]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[CH3:9])=[O:16])[CH:2]=[CH2:3]
Reactant: C=CCN(CC(=O)O)NC(=O)N[C@@H](C)c1ccccc1
Reactant: CCOC(OCC)[C@H](C)N(Cc1cccc2cccnc12)C(=O)[C@@H](N)Cc1ccc(OC(C)(C)C)cc1
Product: C=CCN(CC(=O)N[C@@H](Cc1ccc(OC(C)(C)C)cc1)C(=O)N(Cc1cccc2cccnc12)[C@@H](C)C(OCC)OCC)NC(=O)N[C@@H](C)c1ccccc1
Yield: 81.5 %

Procedure:
According to the procedure described in the synthesis method of Compound II-1, (S)-2-(1-allyl-2-(1-phenylethylcarbamoyl)hydrazinyl)acetic acid (Compound VI-5) 133 mg (0.48 mmol) was coupled with (S)-2-amino-3-(4-tert-butoxyphenyl)-N—((S)-1,1-diethoxy-propan-2-yl)-N-(quinolin-8-ylmethyl)propanamide (Compound IV-3) 203 mg (0.4 mmol) and purified on silica gel column chromatography (chloroform:methanol=100:0 to 95:5) to obtain the title compound 250 mg (81%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([CH2:12][NH:13][CH3:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[O:15]1[CH2:18][C:17](=O)[CH2:16]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.O>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([CH2:12][N:13]([CH3:14])[CH:17]2[CH2:16][O:15][CH2:18]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C1COC1
Reactant: CNCC1CN(C(=O)OC(C)(C)C)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CN(CC1CN(C(=O)OC(C)(C)C)C1)C1COC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 68.5 %

Procedure:
A mixture of 3-(methylamino)methylazetidine-1-carboxylic acid tert-butyl ester (450 mg, 2.25 mmol), oxetan-3-one (135 mg, 1.88 mmol), in dichloromethane (10 mL) was stirred at RT for 1.5 h. Sodium triacetoxyborohydride (797 mg, 3.76 mmol) was added and the resulting reaction mixture was stirred at RT under nitrogen atmosphere for 18 h. The mixture was diluted with water, the phases were separated and the aqueous phase was extracted with EtOAc (2×25 mL). The combined organic layers were dried over sodium sulfate, filtered and the solvents reduced in vacuo The residue was purified by column chromatography (Si—PPC, MeOH:DCM, gradient 0:100 to 5:95) to afford the title compound as a colourless oil (330 mg, 69%). 1H NMR (400 MHz, CDCl3): δ 4.64 (2H, t, J=6.58 Hz), 4.57 (2H, t, J=6.26 Hz), 4.01 (2H, t, J=8.40 Hz), 3.57-3.55 (3H, m), 2.71-2.61 (1H, m), 2.41 (2H, d, J=7.57 Hz), 2.08 (3H, s), 1.44 (9H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2([CH3:40])[C@:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[NH:11][C:10]([C:21]3[C:22]([O:37][CH2:38][CH3:39])=[CH:23][C:24]([C:33]([CH3:36])([CH3:35])[CH3:34])=[C:25]([S:27]([N:30]([CH3:32])[CH3:31])(=[O:29])=[O:28])[CH:26]=3)=[N:9]2)=[CH:4][CH:3]=1.[C:41](Cl)([Cl:43])=[O:42]>C(N(CC)CC)C>[C:33]([C:24]1[C:25]([S:27](=[O:28])(=[O:29])[N:30]([CH3:31])[CH3:32])=[CH:26][C:21]([C:10]2[N:9]([C:41]([Cl:43])=[O:42])[C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)([CH3:40])[C:12]([C:14]3[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=3)([CH3:13])[N:11]=2)=[C:22]([O:37][CH2:38][CH3:39])[CH:23]=1)([CH3:34])([CH3:36])[CH3:35]
Reactant: O=C(Cl)Cl
Reactant: CCOc1cc(C(C)(C)C)c(S(=O)(=O)N(C)C)cc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1
Solvent: CCN(CC)CC
Product: CCOc1cc(C(C)(C)C)c(S(=O)(=O)N(C)C)cc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl

Procedure:
In a manner analogous to the method described in example 3, rac-5-[(4S*,5R*)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-1H-imidazol-2-yl]-2-tert-butyl-4-ethoxy-N,N-dimethyl-benzenesulfonamide was reacted with phosgene in the presence of triethylamine to give rac-(4S*,5R*)-2-(4-tert-butyl-5-dimethylsulfamoyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride. The carbamoyl chloride was then reacted with 1-(3-methanesulfonyl-propyl)-piperazine dihydrochloride (prepared as described in Fotouhi, N. et al. WO 2005110996) in the presence of triethylamine to give the title compound as a racemic mixture. The enantiomers were then separated by supercritical fluid chromatography (Berger Instrument Multi-Gram II, Daicel ChiralPak OD-H 3×25 cm, 35° C. at 100 bar, eluting with 30% methanol in carbon dioxide). HR-MS (ES, m/z) calculated for C40H53N5O6S2Cl2 [(M+H)+] 834.2887, observed 834.2878.
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]1(=[C:14]([C:31]2[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][CH:32]=2)[C:15]2[CH:20]=[CH:19][C:18](/[CH:21]=[CH:22]/[C:23]([O:25]C(C)(C)C)=[O:24])=[C:17]([CH3:30])[CH:16]=2)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1>C(Cl)Cl>[C:8]1(=[C:14]([C:31]2[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][CH:32]=2)[C:15]2[CH:20]=[CH:19][C:18](/[CH:21]=[CH:22]/[C:23]([OH:25])=[O:24])=[C:17]([CH3:30])[CH:16]=2)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: Cc1cc(C(=C2CCCCC2)c2ccc(O)cc2)ccc1/C=C/C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C(=C2CCCCC2)c2ccc(O)cc2)ccc1/C=C/C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 76.3 %

Procedure:
Trifluoroacetic acid (2.0 mL) was added dropwise to 68 (210 mg, 0.519 mmol) dissolved in CH2Cl2 (2 mL) at 0° C. The reaction mixture was stirred at RT for 3 h and the volatiles were removed under reduced pressure. The residue was chromatographed on silica gel (20:1 CH2Cl2:MeOH) and recrystallized (EtOAc:hexanes) to afford 138 mg (76%) of 69 as a pale yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 1.51 (br s, 6H), 2.13 (m, 4H), 2.30 (s, 3H), 6.35 (d, J=16.0 Hz, 1H), 6.66 (d, J=8.2 Hz, 2H), 6.82-6.91 (m, 4H), 7.59 (d, J=7.9 Hz, 1H), 7.75 (d, J=16.0 Hz, 1H), 9.31 (s, 1H), 12.36 (br s, 1H). LRMS (ESI): m/z 349 (M+H)+.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N:11]([S:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[S:28]([CH3:31])(=[O:30])=[O:29])(=[O:21])=[O:20])C(OC(C)(C)C)=O)[CH:9]=2)[N:4](C(OC(C)(C)C)=O)[N:3]=1.[O:39]1[CH:43]=[CH:42][C:41](B(O)O)=[CH:40]1.C(=O)([O-])O.[Na+]>CN(C)C=O>[O:39]1[CH:43]=[CH:42][C:41]([C:2]2[C:10]3[C:5](=[CH:6][CH:7]=[C:8]([NH:11][S:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[S:28]([CH3:31])(=[O:30])=[O:29])(=[O:21])=[O:20])[CH:9]=3)[NH:4][N:3]=2)=[CH:40]1
Reactant: CC(C)(C)OC(=O)N(c1ccc2c(c1)c(I)nn2C(=O)OC(C)(C)C)S(=O)(=O)c1ccccc1S(C)(=O)=O
Reactant: OB(O)c1ccoc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccccc1S(=O)(=O)Nc1ccc2[nH]nc(-c3ccoc3)c2c1
Yield: 35.7 %

Procedure:
N-(3-Furan-3-yl-1H-indazol-5-yl)-2-methylsulfonylbenzenesulfonamide can be obtained as described in Example 47 from of 2 g of tert-butyl 3-iodo-5-(N-tert-butoxycarbonyl-2-methylsulfonylbenzenesulfonylamino)indazole-1-carboxylate, 660 mg of 3-furanboronic acid, 80 ml of dimethylformamide, 6.4 ml of a saturated aqueous sodium hydrogencarbonate solution and 85.4 mg of tetrakis(triphenylphosphine)palladium[0]. 440 mg of N-(3-furan-3-yl-1H-indazol-5-yl)-2-methylsulfonylbenzenesulfonamide are thus obtained in the form of a white solid melting at 249° C. (analysis C18H15N3O5S2 % calculated C, 51.79; H, 3.62; N, 10.07; O, 19.16; S, 15.36. % found C, 51.63; H, 3.55; N, 10.00; S, 15.13).
Reaction SMILES: FC(F)(F)OC1C=CC(CN)=CC=1.FC1C=C(C=CC=1[N+]([O-])=O)OCC1C=CN(C)N=1.[CH3:32][N:33]1[CH:37]=[CH:36][C:35]([CH2:38][O:39][C:40]2[CH:45]=[C:44]([NH:46][CH2:47][C:48]3[CH:53]=[CH:52][C:51]([O:54][C:55]([F:58])([F:57])[F:56])=[CH:50][CH:49]=3)[C:43]([NH2:59])=[CH:42][CH:41]=2)=[N:34]1.[CH3:60][C:61]1([CH3:69])[C@@H:66]2[C@H:62]1[C:63](=[O:68])[O:64][C:65]2=O>>[CH3:60][C:61]1([CH3:69])[C@H:66]([C:65]2[N:46]([CH2:47][C:48]3[CH:53]=[CH:52][C:51]([O:54][C:55]([F:56])([F:57])[F:58])=[CH:50][CH:49]=3)[C:44]3[CH:45]=[C:40]([O:39][CH2:38][C:35]4[CH:36]=[CH:37][N:33]([CH3:32])[N:34]=4)[CH:41]=[CH:42][C:43]=3[N:59]=2)[C@@H:62]1[C:63]([OH:68])=[O:64]
Reactant: CC1(C)[C@@H]2C(=O)OC(=O)[C@@H]21
Reactant: Cn1ccc(COc2ccc(N)c(NCc3ccc(OC(F)(F)F)cc3)c2)n1
Agent: Cn1ccc(COc2ccc([N+](=O)[O-])c(F)c2)n1
Agent: NCc1ccc(OC(F)(F)F)cc1
Product: Cn1ccc(COc2ccc3nc([C@@H]4[C@H](C(=O)O)C4(C)C)n(Cc4ccc(OC(F)(F)F)cc4)c3c2)n1

Procedure:
The title compound was prepared using analogous conditions described for Example 1 using (4-(trifluoromethoxy)phenyl)methanamine and 3-((3-fluoro-4-nitrophenoxy)methyl)-1-methyl-1H-pyrazole in Step A then for Intermediate I using 5-((1-methyl-1H-pyrazol-3-yl)methoxy)-N1-(4-(trifluoromethoxy)benzyl)benzene-1,2-diamine and cis-6,6-dimethyl-3-oxabicyclo[3.1.0]hexane-2,4-dione followed by the hydrolysis according to Example Example 111. MS (ESI): mass calcd. for C26H25F3N4O4, 514.18; m/z found, 515.1 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 7.60 (d, J=8.9, 1H), 7.33 (d, J=2.2, 1H), 7.21 (d, J=8.1, 2H), 7.09 (d, J=8.8, 2H), 7.06 (dd, J=8.9, 2.3, 1H), 6.94 (d, J=2.2, 1H), 6.31 (d, J=2.2, 1H), 5.39 (d, J=16.9, 1H), 5.31 (d, J=16.9, 1H), 5.09 (s, 2H), 3.86 (s, 3H), 2.31 (d, J=8.2, 1H), 2.04 (d, J=8.3, 1H), 1.20 (s, 3H), 0.97 (s, 3H).