Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:9][C@@H:10]1[C@@H:14]([CH2:15][O:16][C:17](=[O:24])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[O:13][C@@H:12]([N:25]2[C:29]([N:30]3C(=O)C4=CC=CC=C4C3=O)=[C:28]([C:41](=[O:44])[CH2:42][Cl:43])[N:27]=[CH:26]2)[C@H:11]1[F:45])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.NN>ClCCl>[NH2:30][C:29]1[N:25]([C@@H:12]2[O:13][C@H:14]([CH2:15][O:16][C:17](=[O:24])[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[C@@H:10]([O:9][C:1](=[O:8])[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C@@H:11]2[F:45])[CH:26]=[N:27][C:28]=1[C:41](=[O:44])[CH2:42][Cl:43]
Reactant: O=C(OC[C@H]1O[C@@H](n2cnc(C(=O)CCl)c2N2C(=O)c3ccccc3C2=O)[C@@H](F)[C@@H]1OC(=O)c1ccccc1)c1ccccc1
Agent: NN
Solvent: O
Solvent: ClCCl
Product: Nc1c(C(=O)CCl)ncn1[C@@H]1O[C@H](COC(=O)c2ccccc2)[C@@H](OC(=O)c2ccccc2)[C@@H]1F
Reaction time: 1 h
Yield: 95 %

Procedure:
Compound (15) obtained in step (6) above (220 mg) was dissolved in dichloromethane (9 ml), to which was then added hydrazine monohydrate (0.02 ml) under cooling at 0° C., and the resultant mixture was allowed to effect the reaction under stirring at the same temperature for 1 hour to produce the titled compound (16). The reaction solution obtained was filtered and the filtrate was concentrated to leave a solid. The solid was purified by silica gel column chromatography (developer solvent:toluene-ethyl acetate, 1:1), to afford the titled compound (16) as a colorless solid (166 mg). Yield: 95%.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-])=O)[CH:9]=2)[CH2:4][CH2:3]1.C[OH:18]>O.[Pd]>[NH2:14][C:10]1[CH:9]=[C:8]([N:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][C:4]2=[O:18])[CH:13]=[CH:12][CH:11]=1
Reactant: CO
Reactant: CN1CCN(c2cccc([N+](=O)[O-])c2)CC1
Agent: [Pd]
Solvent: O
Product: CN1CCN(c2cccc(N)c2)C(=O)C1
Reaction time: 8 h
Yield: 95 %

Procedure:
Pd/C (10%, 420 mg) was added to a solution of 1-methyl-4-(3-nitrophenyl)piperazine (8.4 g) in methanol (500 mL) and water (20 mL). The reaction mixture was stirred and degassed with nitrogen, and the vessel was charged with H2 gas at atmospheric pressure. The reaction was allowed to proceed overnight after which time the Pd/C was removed by filtration over celite and the methanol and water were removed in vacuo to give 1-(3-aminophenyl)-4-methyl-2-piperazinone as a yellow solid (7.08 g, 95% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.07 (1H, t, J=7.83 Hz) 6.48-6.55 (2H, m) 6.46 (1H, d, J=1.01 Hz) 6.44 (1H, s) 3.88 (4H, s) 3.54 (2H, br. s.) 2.82 (3H, s)
Reaction SMILES: CSC(=S)O[C@@H:5]1[C@@H:12]2[C@@H:8]([O:9][C:10]([CH3:14])([CH3:13])[O:11]2)[O:7][C@@H:6]1[CH:15]1[CH2:19][O:18][C:17]([CH3:21])([CH3:20])[O:16]1.C([SnH](CCCC)CCCC)CCC>C1(C)C=CC=CC=1.N(C(C)(C)C#N)=NC(C)(C)C#N>[CH3:20][C:17]1([CH3:21])[O:16][CH:15]([C@H:6]2[O:7][C@@H:8]3[O:9][C:10]([CH3:14])([CH3:13])[O:11][C@@H:12]3[CH2:5]2)[CH2:19][O:18]1
Reactant: CSC(=S)O[C@@H]1[C@H]2OC(C)(C)O[C@H]2O[C@@H]1C1COC(C)(C)O1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CCCC[SnH](CCCC)CCCC
Solvent: Cc1ccccc1
Product: CC1(C)OCC([C@@H]2C[C@H]3OC(C)(C)O[C@H]3O2)O1
Temperature: 130 °C
Yield: 83.9 %

Procedure:
To a solution of O-[(3aR,5R,6S,6aR)-5-(2,2-dimethyl-1,3-dioxolan-4-yl)-2,2-dimethyl-3a,5,6,6a-tetrahydrofuro[2,3-d][1,3]dioxol-6-yl] methylsulfanylmethanethioate (compound 1a, 14 g, 40 mmol) in toluene was added tri-n-butyltin hydride(23.2 g, 80 mmol) and azodiisobutyronitrile (82 mg, 0.5 mmol), the formed mixture was heated at 130° C. under nitrogen for 3 hours. After the reaction was completed, the reaction mixture was concentrated in vacuo and the residue was purified by column chromatography on silica gel (eluting with 1:10 EtOAc in petroleum ether) to afford 8.2 g of (3aR,5S,6aR)-5-(2,2-dimethyl-1,3-dioxolan-4-yl)-2,2-dimethyl-3a,5,6,6a-tetrahydrofuro[2,3-d][1,3]dioxole (compound 1b) as an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([Cl:12])[C:9]([Cl:13])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].Cl[S:15]([C:18]1[C:26]2[C:22](=[N:23][S:24][N:25]=2)[CH:21]=[CH:20][CH:19]=1)(=[O:17])=[O:16]>CN(C1C=CN=CC=1)C>[CH3:7][O:6][C:4](=[O:5])[C:3]1[CH:8]=[C:9]([Cl:13])[C:10]([Cl:12])=[CH:11][C:2]=1[NH:1][S:15]([C:18]1[C:26]2=[N:25][S:24][N:23]=[C:22]2[CH:21]=[CH:20][CH:19]=1)(=[O:17])=[O:16]
Reactant: O=S(=O)(Cl)c1cccc2nsnc12
Reactant: COC(=O)c1cc(Cl)c(Cl)cc1N
Agent: CN(C)c1ccncc1
Product: COC(=O)c1cc(Cl)c(Cl)cc1NS(=O)(=O)c1cccc2nsnc12
Yield: 50 %

Procedure:
The title compound (0.95 g, 50%) was prepared from methyl 2-amino-4,5-dichlorobenzoate and 4-chlorosulfonyl-2,1,3-benzothiadiazole as in Example 1, Part A (without DMAP). 1H NMR (500 MHz, CDCl3): 11.21 (s, 1H), 8.39 (dd, J=7.1, 1.0, 1H), 8.25 (dd, J=8.8, 1.0, 1H), 7.94 (s, 1H), 7.91 (s, 1H), 7.74 (dd, J=8.8, 7.1, 1H), 3.93 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[N:6]=[C:5]2[CH:12]1[CH2:15][CH2:14][CH2:13]1.C(OC([N:23]1[CH2:28][CH2:27][NH:26][CH2:25][C@@H:24]1[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=O)(C)(C)C>>[CH2:29]([C@@H:24]1[NH:23][CH2:28][CH2:27][N:26]([C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[N:7]([CH3:11])[N:6]=[C:5]3[CH:12]2[CH2:15][CH2:14][CH2:13]2)[CH2:25]1)[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: CC(C)(C)OC(=O)N1CCNC[C@@H]1Cc1ccccc1
Reactant: Cn1nc(C2CCC2)c2cc(Br)ccc21
Product: Cn1nc(C2CCC2)c2cc(N3CCN[C@@H](Cc4ccccc4)C3)ccc21
Yield: 99 %

Procedure:
The title compound was prepared by the method outlined for Example 1 using 5-Bromo-3-cyclobutyl-1-methyl-1H-indazole as the aryl halide and (S)-2-benzyl-piperazine-1-carboxylic acid tert-butyl ester as the amine component to afford the title compound as a brown oil (409 mg, 99%). 1H NMR (MeOH-d4) 8.72 (d, J=8.7 Hz, 1H), 7.79 (d, J=8.8 Hz, 1H), 7.32-7.18 (m, 6H), 4.08 (s, 3H), 3.79-3.46 (m, 3H), 3.35-3.34 (m, 1H), 3.31-3.30 (m, 2H), 3.15-3.07 (m, 4H), 2.88-2.77 (m, 5H), 2.69-2.61 (m, 1H). LC/MS (Method B) 2.49 min, [M+1]+ 361.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH:34]=[O:35])=[CH:5][N:6]2[C@@H:11]1[O:28][C@H:27]([CH2:29][O:30][C:31](=[O:33])[CH3:32])[C@@H:22]([O:23][C:24](=[O:26])[CH3:25])[C@H:17]([O:18][C:19](=[O:21])[CH3:20])[C@H:12]1[O:13][C:14](=[O:16])[CH3:15].[F:36][CH:37]([F:48])[O:38][C:39]1[CH:44]=[CH:43][C:42](B(O)O)=[CH:41][CH:40]=1.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.COCCOC>O>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH:34]([C:42]1[CH:43]=[CH:44][C:39]([O:38][CH:37]([F:48])[F:36])=[CH:40][CH:41]=1)[OH:35])=[CH:5][N:6]2[C@@H:11]1[O:28][C@H:27]([CH2:29][O:30][C:31](=[O:33])[CH3:32])[C@@H:22]([O:23][C:24](=[O:26])[CH3:25])[C@H:17]([O:18][C:19](=[O:21])[CH3:20])[C@H:12]1[O:13][C:14](=[O:16])[CH3:15]
Reactant: OB(O)c1ccc(OC(F)F)cc1
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cc(C=O)c3c(Cl)cccc32)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Solvent: O
Solvent: COCCOC
Product: CC(=O)OC[C@H]1O[C@@H](n2cc(C(O)c3ccc(OC(F)F)cc3)c3c(Cl)cccc32)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C

Procedure:
A mixture solution of 4-chloro-1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)indole-3-carboxaldehyde (50 mg) obtained in Example 29-(1), 4-(difluoromethoxy)benzeneboronic acid (55 mg), hydroxyl(1,5-cyclooctadiene)rhodium(I) dimer (1.3 mg) and tri-tert-butylphosphine (0.6 mg) in H2O (1.0 ml)-1,2-dimethoxy-ethane (2.0 ml) was stirred at 80° C. under argon atmosphere for 19 hours. The reaction mixture was cooled to room temperature, and extracted with ethyl acetate (20 ml). The organic layer was filtered through an aminosilane-treated silica gel pad, and the filtrate was evaporated under reduced pressure to give crude 4-chloro-1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-indol-3-yl 4-(difluoromethoxy)phenyl methanol, which was used in the subsequent step without further purification.
Reaction SMILES: B.C1COCC1.B1(C)OC(C2C=CC=CC=2)(C2C=CC=CC=2)[C@H]2N1CCC2.[F:28][C:29]1[CH:34]=[CH:33][C:32]([C:35](=[O:42])[CH2:36][CH2:37][C:38]([O:40][CH3:41])=[O:39])=[CH:31][CH:30]=1>C1COCC1>[F:28][C:29]1[CH:30]=[CH:31][C:32]([C@H:35]([OH:42])[CH2:36][CH2:37][C:38]([O:40][CH3:41])=[O:39])=[CH:33][CH:34]=1
Reactant: COC(=O)CCC(=O)c1ccc(F)cc1
Agent: B
Agent: CB1OC(c2ccccc2)(c2ccccc2)[C@@H]2CCCN12
Solvent: C1CCOC1
Product: COC(=O)CC[C@@H](O)c1ccc(F)cc1
Reaction time: 0.08 h
Yield: 84.3 %

Procedure:
To a solution of BH3.THF (1M, 5.7 mL, 5.7 mmol) in 40 mL anhydrous THF was dropwise added at room temperature (S)-2-methyl-CBS-oxazaborolidine (952 μL, 0.952 mmol, 1M in toluene). After stirring for 5 minutes, methyl 4-(4-fluorophenyl)-4-oxobutanoate (2.0 g, 9.5 mmol) was added as a solution in 25 mL THF. The reaction mixture was stirred for 30 min at room temperature and then quenched by the slow addition of saturated aqueous ammonium chloride (60 mL) The resulting mixture was extracted with ethyl acetate (3×50 mL) and the combined organic layers washed with brine (2×40 mL) and dried over Na2SO4. The solvent was evaporated under reduced pressure and the product isolated by silica gel Flash chromatography to afford 1.7 g of the title compound as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[C:7]2[C:3]=1[CH2:4][C@@H:5]([OH:29])[C@@H:6]2[N:12]1[C:20]2[CH2:19][CH2:18][NH:17][CH2:16][C:15]=2[C:14]([C:21]2[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=2)[C:24]#[N:25])=[N:13]1.C(N(CC)CC)C.[CH2:37]([N:39]=[C:40]=[O:41])[CH3:38]>C(Cl)Cl>[CH2:37]([NH:39][C:40]([N:17]1[CH2:18][CH2:19][C:20]2[N:12]([C@@H:6]3[C:7]4[C:3](=[C:2]([Cl:1])[CH:10]=[C:9]([Cl:11])[CH:8]=4)[CH2:4][C@H:5]3[OH:29])[N:13]=[C:14]([C:21]3[CH:28]=[CH:27][CH:26]=[C:23]([C:24]#[N:25])[CH:22]=3)[C:15]=2[CH2:16]1)=[O:41])[CH3:38]
Reactant: N#Cc1cccc(-c2nn([C@@H]3c4cc(Cl)cc(Cl)c4C[C@H]3O)c3c2CNCC3)c1
Reactant: CCN=C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCNC(=O)N1CCc2c(c(-c3cccc(C#N)c3)nn2[C@@H]2c3cc(Cl)cc(Cl)c3C[C@H]2O)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88 %

Procedure:
According to Scheme 17: To a solution of 3-[1-((1R,2R)-4,6-dichloro-2-hydroxy-indan-1-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl]-benzonitrile (13e) (0.03 g, 0.071 mmol) in dry CH2Cl2 at 0° C. triethylamine (57 mg, 0.564 mmol) and ethylisocyanate (5.5 mg, 0.077 mmol) was added. The mixture was stirred for 1 h at room temperature and purified by reverse phase HPLC (CH3CN/water gradient with 0.1% trifluoroacetic acid) to give 31 mg of 3-(3-cyano-phenyl)-1-((1R,2R)-4,6-dichloro-2-hydroxy-indan-1-yl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid ethylamide (22a)
Reaction SMILES: [C:1]([Si:5]1([C:13]([CH3:16])([CH3:15])[CH3:14])[O:10][CH2:9][CH:8]([CH2:11]O)[CH2:7][O:6]1)([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.C(Br)(Br)(Br)[Br:24].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[Br:24][CH2:11][CH:8]1[CH2:9][O:10][Si:5]([C:13]([CH3:16])([CH3:15])[CH3:14])([C:1]([CH3:4])([CH3:3])[CH3:2])[O:6][CH2:7]1
Reactant: BrC(Br)(Br)Br
Reactant: CC(C)(C)[Si]1(C(C)(C)C)OCC(CO)CO1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)[Si]1(C(C)(C)C)OCC(CBr)CO1
Temperature: -10 °C
Reaction time: 2 h
Yield: 84.1 %

Procedure:
Compound 19n (123 mg, 0.5 mmol) was dissolved in dichloromethane (10 mL) and cooled to −10° C. with an ethanol-ice bath. Pyridine (1 mL) was added followed by carbon tetrabromide (220 mg, 0.66 mmol). Triphenylphosphine (174 mg, 0.66 mmol) was added in portions and the solution was stirred at −10° C. for 2 hr then raised to room temperature overnight. Solvent was removed under reduced pressure and residue was applied for silica gel column chromatography (10% ethyl acetate in hexane) to afford compound 20n (130 mg, 84%): 1H NMR δ 4.20 (m, 2H), 3.93 (t, 2H), 3.20 (d, 2H, J=6.19 Hz), 2.39 (m, 1H), 1.04 (s, 9H), 1.01 (s, 9H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[CH3:9])N.[S:10]1[CH:14]=[CH:13][CH:12]=[CH:11]1.N(OCCCC)=O>>[C:4]1([C:11]2[S:10][CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:7][C:8]([CH3:9])=[C:2]([CH3:1])[CH:3]=1
Reactant: Cc1ccc(N)cc1C
Reactant: c1ccsc1
Agent: CCCCON=O
Product: Cc1ccc(-c2cccs2)cc1C
Yield: 26.6 %

Procedure:
A solution of 182 g (1.50 moles) of 3,4-dimethylaniline, m.p. 49°-51° C. in 3000 ml (38 moles) of thiophene was treated with 226 ml (2.00 moles) of n-butyl nitrite. The solution was allowed to stand at room temperature for one week. Unreacted thiophene was removed by distillation with a steam bath. The residue was distilled at reduced pressure to give 75 g (27%) of 2-(3,4-xylyl)thiophene, b.p. 107°-122° (0.08 mm). Vapor phase chromatography showed the presence of about 2% of the xylidine starting material, removed by washing first with two 100-ml portions of 10% hydrochloric acid followed by two 150-ml portions of distilled water.
Reaction SMILES: Cl.C[O:3][C:4](=[O:14])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[NH2:6].[CH2:15]([C:19]1[N:20]([CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[Cl:36])[C:21]([CH2:25][C:26](O)=[O:27])=[C:22]([F:24])[N:23]=1)[CH2:16][CH2:17][CH3:18].ClC1C=CC=CC=1CN1C(C(O)=O)=CN=C1SCCC>>[CH2:15]([C:19]1[N:20]([CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[Cl:36])[C:21]([CH2:25][C:26]([NH:6][C@H:5]([C:4]([OH:3])=[O:14])[CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:27])=[C:22]([F:24])[N:23]=1)[CH2:16][CH2:17][CH3:18]
Reactant: CCCCc1nc(F)c(CC(=O)O)n1Cc1ccccc1Cl
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Agent: CCCSc1ncc(C(=O)O)n1Cc1ccccc1Cl
Agent: Cl
Product: CCCCc1nc(F)c(CC(=O)N[C@@H](Cc2ccccc2)C(=O)O)n1Cc1ccccc1Cl

Procedure:
The title compound is prepared following the procedure of Example 1-(iii-iv) using phenylalanine methyl ester hydrochloride in place of glycine methyl ester hydrochloride and using 2-[n-butyl-1-(2-chlorophenyl)methyl-4-fluoro-1H-imidazol-5-yl]acetic acid (prepared as in U.S. Pat. No. 4,340,598) in place of 1-(2-chlorophenyl)methyl-2-propylthio-1H-imidazole-5 carboxylic acid.
Reaction SMILES: [CH:1]1([CH:4]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][NH:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:26]=4[F:33])=[C:21]([CH2:34][C:35]([CH3:38])([CH3:37])[CH3:36])[CH:20]=3)[CH:12]=2)[CH2:5][C:6]([O:8]CC)=[O:7])[CH2:3][CH2:2]1.[OH-].[Na+].Cl>C(O)C>[CH:1]1([CH:4]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][NH:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:26]=4[F:33])=[C:21]([CH2:34][C:35]([CH3:38])([CH3:37])[CH3:36])[CH:20]=3)[CH:12]=2)[CH2:5][C:6]([OH:8])=[O:7])[CH2:2][CH2:3]1
Reactant: CCOC(=O)CC(c1cccc(CNc2ccc(-c3cc(OC)ccc3F)c(CC(C)(C)C)c2)c1)C1CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(F)c(-c2ccc(NCc3cccc(C(CC(=O)O)C4CC4)c3)cc2CC(C)(C)C)c1
Temperature: 0 °C
Reaction time: 5 h
Yield: 89.5 %

Procedure:
To a solution of ethyl 3-cyclopropyl-3-(3-(((2′-fluoro-5′-methoxy-2-neopentyl-[1,1′-biphenyl]-4-yl)amino)methyl)phenyl)propanoate (104 mg) in ethanol (2.0 mL) was added 2N aqueous sodium hydroxide solution (502 μL) at room temperature, and the mixture was stirred for 5 hr. The reaction mixture was further stirred at 50° C. for 1 hr, and the reaction mixture was cooled to 0° C. The mixture was neutralized with 1N hydrochloric acid, and extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure to give the title compound (88 mg) as a pale-yellow gummy substance.
Reaction SMILES: [C:1]1([S:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][NH:13][S:14]([CH2:17][CH2:18][C:19](OC)=O)(=[O:16])=[O:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].C([Al+]CC(C)C)C(C)C.[ClH:33].[NH2:34][CH2:35][CH2:36][C:37]1[C:45]2[S:44][C:43](=[O:46])[NH:42][C:41]=2[C:40]([OH:47])=[CH:39][CH:38]=1.C([BH3-])#N.[Na+]>>[ClH:33].[OH:47][C:40]1[C:41]2[NH:42][C:43](=[O:46])[S:44][C:45]=2[C:37]([CH2:36][CH2:35][NH:34][CH2:19][CH2:18][CH2:17][S:14]([NH:13][CH2:12][CH2:11][O:10][CH2:9][CH2:8][S:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)(=[O:15])=[O:16])=[CH:38][CH:39]=1
Reactant: COC(=O)CCS(=O)(=O)NCCOCCSc1ccccc1
Reactant: NCCc1ccc(O)c2[nH]c(=O)sc12
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [BH3-]C#N
Product: O=c1[nH]c2c(O)ccc(CCNCCCS(=O)(=O)NCCOCCSc3ccccc3)c2s1
Yield: 4.8 %

Procedure:
The title compound (0.106 g) was prepared according to the procedure in example 8 part e using methyl 3-[2-(2-phenylthioethoxy)ethylaminosulphonyl]propanoate (1.4 g), diisobutylaluminiumhydride (1.5M in toluene, 3 ml), 7-(2-aminoethyl)-4-hydroxy-1,3-benzothiazol-2(3H)-one hydrochloride (1.2 g) and sodium cyanoborohydride (0.3 g).
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][CH:5]=[N:4]1.[CH3:8][N:9]([CH3:14])[S:10](Cl)(=[O:12])=[O:11].O>C1COCC1>[CH3:8][N:9]([CH3:14])[S:10]([N:3]1[CH:7]=[CH:6][CH:5]=[N:4]1)(=[O:12])=[O:11]
Reactant: c1cn[nH]c1
Reactant: CN(C)S(=O)(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CN(C)S(=O)(=O)n1cccn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of sodium hydride (5.2 g, 130 mmol, 60% in mineral oil) in anhydrous THF (50 mL) was added a solution of 1H-pyrazole (5.92 g, 87 mmol) in anhydrous THF (100 mL) at 0° C. The mixture was stirred for 30 minutes at room temperature. Dimethylsulfamoyl chloride (13.9 mL, 130 mmol) was added at 0° C., and then the mixture was stirred for 1.5 hours at room temperature. Water was added, and the mixture was extracted 3 times with ethyl acetate. The organic phase was washed with brine and dried over sodium sulfate. After evaporation of the solvent, the oil was passed through a short silica gel column using 20% hexane/ethyl acetate as a solvent. N,N-dimethyl-1H-pyrazole-1-sulfonamide was obtained as a yellow oil and used in the next step without further purification.
Reaction SMILES: C([O:3][C:4]([C:6]1([S:21]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)(=[O:23])=[O:22])[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:8][CH2:7]1)=[O:5])C>C1COCC1.CO.[OH-].[Na+]>[CH3:31][O:30][C:27]1[CH:28]=[CH:29][C:24]([S:21]([C:6]2([C:4]([OH:5])=[O:3])[CH2:7][CH2:8][N:9]([CH2:12][CH2:13][CH2:14][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:10][CH2:11]2)(=[O:23])=[O:22])=[CH:25][CH:26]=1
Reactant: CCOC(=O)C1(S(=O)(=O)c2ccc(OC)cc2)CCN(CCCc2ccccc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(S(=O)(=O)C2(C(=O)O)CCN(CCCc3ccccc3)CC2)cc1

Procedure:
4-(4-Methoxy-benzenesulfonyl)-1-(3-phenyl-propyl)-piperidine-4-carboxylic acid was prepared starting from 4-(4-Methoxy-benzenesulfonyl)-1(3-phenyl-propyl)-piperidine-4-carboxylic acid ethyl ester (10.74 g, 24.13 mmol) dissolved in THF:methanol 3:1 and 10 N NaOH (40 ml). The resulting reaction mixture was worked up as outlined in example 83. Yield 4.67 g (47%); off white powder, mp 203° C.; MS: 418.2 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10](=[O:13])[CH2:11]Cl.[CH3:14][CH:15]1[CH2:20][NH:19][CH2:18][CH:17]([CH3:21])[NH:16]1.C(NC(C)C)(C)C>C(O)C>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10](=[O:13])[CH2:11][N:19]1[CH2:18][CH:17]([CH3:21])[NH:16][CH:15]([CH3:14])[CH2:20]1
Reactant: Cc1cccc(C)c1NC(=O)CCl
Reactant: CC1CNCC(C)N1
Solvent: CC(C)NC(C)C
Solvent: CCO
Product: Cc1cccc(C)c1NC(=O)CN1CC(C)NC(C)C1

Procedure:
To a solution of compound 3 (5 g, 25.2 mmol) in ethanol (100 mL) was added 2,6-dimethylpiperazine 4 (2.1 g, 25.0 mmol) and N,N-diisopropylamine (3.2 g, 25.2 mmol). The reaction mixture was refluxed for 24 h. The mixture was concentrated in vacuo and the residue was purified by column chromatography (10:1, DCM:MeOH) to afford compound 5.
Reaction SMILES: [C:1]([O:4][CH:5]([CH3:9])[C:6]([OH:8])=O)(=[O:3])[CH3:2].[F:10][C:11]([F:33])([F:32])[O:12][C:13]1[CH:14]=[C:15]([C:19]2[C:23]3[CH:24]=[C:25]([C:28]([NH:30][NH2:31])=[O:29])[CH:26]=[CH:27][C:22]=3[O:21][CH:20]=2)[CH:16]=[CH:17][CH:18]=1>>[C:1]([O:4][CH:5]([CH3:9])[C:6](=[O:8])[NH:31][NH:30][C:28]([C:25]1[CH:26]=[CH:27][C:22]2[O:21][CH:20]=[C:19]([C:15]3[CH:16]=[CH:17][CH:18]=[C:13]([O:12][C:11]([F:10])([F:32])[F:33])[CH:14]=3)[C:23]=2[CH:24]=1)=[O:29])(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)C(=O)O
Reactant: NNC(=O)c1ccc2occ(-c3cccc(OC(F)(F)F)c3)c2c1
Product: CC(=O)OC(C)C(=O)NNC(=O)c1ccc2occ(-c3cccc(OC(F)(F)F)c3)c2c1
Yield: 48 %

Procedure:
In the same manner as in Reference Example 1 and using (±)-2-acetoxypropionic acid instead of benzothiazole-6-carboxylic acid and 3-[3-(trifluoromethoxy)phenyl]-1-benzofuran-5-carbohydrazide instead of tert-butyl carbazate, the title compound (yield 48%) was obtained as colorless crystals.
Reaction SMILES: [C:1]([CH2:8][N:9]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16][N:15]([CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:14][CH2:13][N:12]([CH2:29][CH2:30][C:31]2[CH:36]=[CH:35][C:34]([N+:37]([O-])=O)=[CH:33][CH:32]=2)[CH2:11][CH2:10]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CCOCC>C(O)C.[Pd]>[C:1]([CH2:8][N:9]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16][N:15]([CH2:21][C:22]([O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:23])[CH2:14][CH2:13][N:12]([CH2:29][CH2:30][C:31]2[CH:32]=[CH:33][C:34]([NH2:37])=[CH:35][CH:36]=2)[CH2:11][CH2:10]1)([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: CC(C)(C)OC(=O)CN1CCNCCN(CC(=O)OC(C)(C)C)CCN(CCc2ccc([N+](=O)[O-])cc2)CC1
Agent: [Pd]
Solvent: CCO
Solvent: CCOCC
Product: CC(C)(C)OC(=O)CN1CCNCCN(CC(=O)OC(C)(C)C)CCN(CCc2ccc(N)cc2)CC1
Yield: 97.8 %

Procedure:
To a solution of compound (25) (1.35 g, 2.46 mmol) in absolute ethanol (100 ml) was added 10% Pd/C (0.41 g). The resultant mixture was stirred at an ambient temperature in the presence of H2 (g) for 12 hours. The reaction mixture was filtered through a celite pad and washed with ethanol (2×20 ml). The filtrate was evaporated in vacuo to give an oily residue, which was then treated with Et2O to obtain a white solid of compound (26) (1.25 g, 98% yield).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[C:7]([O:11][C:12]([N:14]([C:28]1[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=1)[CH2:15][CH2:16][O:17][C:18]1[CH:19]=[C:20]([CH:24]=[C:25]([Cl:27])[CH:26]=1)[C:21](O)=[O:22])=[O:13])([CH3:10])([CH3:9])[CH3:8].[CH3:34][C:35]1([CH3:52])[O:39][CH:38]([CH2:40][O:41][CH2:42][CH2:43][NH:44][C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=2[F:51])[CH2:37][O:36]1.CCN(C(C)C)C(C)C>ClCCl.CN(C1C=CN=CC=1)C.CN(C=O)C>[C:7]([O:11][C:12](=[O:13])[N:14]([CH2:15][CH2:16][O:17][C:18]1[CH:19]=[C:20]([C:21](=[O:22])[N:44]([CH2:43][CH2:42][O:41][CH2:40][CH:38]2[CH2:37][O:36][C:35]([CH3:52])([CH3:34])[O:39]2)[C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=2[F:51])[CH:24]=[C:25]([Cl:27])[CH:26]=1)[C:28]1[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=1)([CH3:10])([CH3:8])[CH3:9]
Reactant: CC(C)(C)OC(=O)N(CCOc1cc(Cl)cc(C(=O)O)c1)c1ccncc1
Reactant: CC1(C)OCC(COCCNc2ccccc2F)O1
Agent: CN(C)c1ccncc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N(CCOc1cc(Cl)cc(C(=O)N(CCOCC2COC(C)(C)O2)c2ccccc2F)c1)c1ccncc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 35.6 %

Procedure:
2M Oxalyl chloride solution in dichloromethane (0.115 ml), and DMF (0.005 ml) were added to a suspension of 3-[2-(tert-butoxycarbonyl-pyridin-4-yl-amino)-ethoxy]-5-chloro-benzoic acid (0.060 g) in anhydrous dichloromethane (5 ml). The reaction was stirred at room temperature for 1.5 h then [2-(2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-ethyl]-(2-fluoro-phenyl)-amine (0.121 g) as a solution in dichloromethane (0.5 ml), DMAP (0.005 g) and DIPEA (0.080 ml) were added. The reaction mixture was stirred at room temperature for 20 h. The reaction mixture was diluted with further dichloromethane and extracted with saturated aqueous sodium bicarbonate. The aqueous layer was removed and the organic phase washed with water and dried with brine and over sodium sulphate and concentrated under reduced pressure. The residue was purified by flash column chromatography, eluting with ethyl acetate:petroleum ether (1:1, 2:1 and 4:1 v/v) and neat ethyl acetate, to give the title compound as a colourless gum (0.035 g).