Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][CH:3]=1.[Br:9]N1C(=O)CCC1=O>C(#N)C>[Br:9][C:3]1[CH:4]=[CH:5][C:6]([NH2:8])=[N:7][C:2]=1[F:1]
Reactant: Nc1cccc(F)n1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: Nc1ccc(Br)c(F)n1
Reaction time: 1 h
Yield: 170.2 %

Procedure:
To a stirred solution of 6-fluoro-pyridin-2-ylamin (1.0 g, 8.93 mmol) in acetonitrile (50 mL), protected from light and under nitrogen atmosphere, N-bromosuccinimide (0.79 g, 4.46 mmol) was added. After 1 hour, an additional portion of N-bromosuccinimide (0.79 g, 4.46 mmol) was added and the stirring was continued for 3 hours. The volatiles were removed under reduced pressure and the crude material was purified by flash column chromatography using a gradient of 25% to 30% ethyl acetate in hexane to give 5-bromo-6-fluoro-pyridin-2-ylamine (1.45 g) as a white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ: 7.60 (t, J=8.59 Hz, 1 H) 6.15-6.36 (m, 1 H) 4.58 (br. s., 2 H)
Reaction SMILES: [CH3:1][CH:2]([CH3:22])[CH2:3][CH2:4][NH:5][CH2:6][C:7]1[CH:21]=[CH:20][C:10]([O:11][C:12]2[S:16][C:15]([C:17]([NH2:19])=[O:18])=[CH:14][CH:13]=2)=[CH:9][CH:8]=1.[O:23]1[CH2:28]CC(CCN)C[CH2:24]1.[BH4-].[Na+]>CO>[O:23]1[CH2:28][CH2:22][CH:2]([CH2:3][CH2:4][NH:5][CH2:6][C:7]2[CH:21]=[CH:20][C:10]([O:11][C:12]3[S:16][C:15]([C:17]([NH2:19])=[O:18])=[CH:14][CH:13]=3)=[CH:9][CH:8]=2)[CH2:1][CH2:24]1
Reactant: NCCC1CCOCC1
Reactant: CC(C)CCNCc1ccc(Oc2ccc(C(N)=O)s2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: NC(=O)c1ccc(Oc2ccc(CNCCC3CCOCC3)cc2)s1
Reaction time: 8 h

Procedure:
Place 5-(4-formylphenoxy)thiophene-2-carboxamide (Example 10, Part C) (0.235 g, 0.948 mmol), 2-(tetrahydropyran-4-yl)ethylamine (0.122 g, 0.996 mmol) and 3 Å molecular sieves in a vial. Add methanol (4.7 mL), cap and stir overnight. Add NaBH4 (0.0359 g, 0.948 mmol) and stir until the gasses stop evolving. Load the reaction mixture directly onto a 25 g ISCO® pre-load column. Dry the column in a vacuum oven at room temperature. Purify by eluting through a 40 g ISCO® column with 5% to 30% (2.0 M NH3 in methanol) in ethyl acetate over 45 minutes to give the title compound: TOF MS ES+ 361.2 (M+H)+, HRMS calcd for C19H25N2O3S 361.1586 (M+H)+, found 361.1604, time 0.36 min; HPLC [YMC-Pro pack C-18 (150×4.6 mm, S-5 microm), 0.05% TFA/acetonitrile in 0.05% TFA/water at 1.0 mL/min, 10-20% over 5 min, 20-95% over 18], tR=9.4 min, 100% purity.
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:23])=[CH:13][CH:12]=[CH:11][C:10]=2[OH:24])(=[O:5])[CH2:2][CH2:3][CH3:4].[Na].OC1C=CC2C(=CC=CC=2)N=1.Cl.Cl[CH2:39][CH2:40][CH2:41][N:42]([CH3:52])[CH2:43][CH2:44][CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1>C(O)C>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:23])=[CH:13][CH:12]=[CH:11][C:10]=2[O:24][CH2:39][CH2:40][CH2:41][N:42]([CH3:52])[CH2:43][CH2:44][CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CN(CCCCl)CCCc1ccccc1
Reactant: CCCC(=O)c1cnc2c(O)cccc2c1Nc1ccccc1C
Agent: Cl
Agent: Oc1ccc2ccccc2n1
Agent: [Na]
Solvent: CCO
Product: CCCC(=O)c1cnc2c(OCCCN(C)CCCc3ccccc3)cccc2c1Nc1ccccc1C
Yield: 31 %

Procedure:
3-Butyryl-4-(2-methylphenylamino)-8-hydroxyquinoline (3.2 g, 10 mmol) was dried by azeotroping with toluene, then dissolved in dry ethanol (20 ml). Sodium (0.23 g, 10 mmol) was dissolved in ethanol (15 ml), and added to the hydroxyquinoline. The resulting solution was evaporated, and the solid redissolved in toluene (50 ml). 3-chloro-N-methyl-N-(3-phenylpropyl)-1-propylamine hydrochloride (1.5 g, 5.7 mmol) was added and the mixture heated at reflux under nitrogen for 3 hours. Evaporation of the solvent, chromatography (silica gel, 0-3% methanolic ammonia in chloroform) and crystallisation from ether gave 3-butyryl-4-(2-methylphenylamino)-8-(3-(N-methyl-N-(3-phenylpropyl)amino)propoxy)quinoline (0.9 g, 18%), m.p. 79°-81°.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][N:11]1[C:15]2[CH:16]=[CH:17][C:18]([C:20](O)=[O:21])=[CH:19][C:14]=2[N:13]=[C:12]1[NH:23][C:24]1[S:25][C:26]2[CH:32]=[C:31]([O:33][C:34]([F:37])([F:36])[F:35])[CH:30]=[CH:29][C:27]=2[N:28]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN.[CH3:40][N:41](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][CH2:10][N:11]1[C:15]2[CH:16]=[CH:17][C:18]([C:20](=[O:21])[NH:41][CH3:40])=[CH:19][C:14]=2[N:13]=[C:12]1[NH:23][C:24]1[S:25][C:26]2[CH:32]=[C:31]([O:33][C:34]([F:35])([F:36])[F:37])[CH:30]=[CH:29][C:27]=2[N:28]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: CC(C)(C)OC(=O)NCCn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)O)ccc21
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1ccc2c(c1)nc(Nc1nc3ccc(OC(F)(F)F)cc3s1)n2CCNC(=O)OC(C)(C)C
Yield: 50.8 %

Procedure:
{2-[5-Methylcarbamoyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-benzoimidazol-1-yl]-ethyl}-carbamic acid tert-butyl ester (39.0 mg) was prepared by following General Procedure F starting from 1-(2-tert-butoxycarbonylamino-ethyl)-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (75.0 mg), methylamine (2.0 M solution in THF, 0.5 mL), HBTU (80.0 mg) and DIEA (0.05 mL) in DMF (1.0 mL).
Reaction SMILES: Br[C:2]1[C:10]2[O:9][C:8]([CH3:12])([CH3:11])[CH2:7][C:6]=2[C:5]([CH3:13])=[C:4]([NH:14][C:15](=[O:21])[CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C:3]=1[CH3:22].[CH3:23][C:24]1[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=1>CCCCCC>[CH3:18][C:17]([CH3:20])([CH3:19])[CH2:16][C:15]([NH:14][C:4]1[C:3]([CH3:22])=[C:2]([O:30][C:27]2[CH:28]=[CH:29][C:24]([CH3:23])=[CH:25][CH:26]=2)[C:10]2[O:9][C:8]([CH3:12])([CH3:11])[CH2:7][C:6]=2[C:5]=1[CH3:13])=[O:21]
Reactant: Cc1ccc(O)cc1
Reactant: Cc1c(Br)c2c(c(C)c1NC(=O)CC(C)(C)C)CC(C)(C)O2
Solvent: CCCCCC
Product: Cc1ccc(Oc2c(C)c(NC(=O)CC(C)(C)C)c(C)c3c2OC(C)(C)C3)cc1
Yield: 19 %

Procedure:
Using N-(7-bromo-2,2,4,6-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide obtained in Example 343 and 4-methylphenol, the title compound was synthesized in the same manner as in Example 344. Yield: 19%. Melting point: 182-184° C. (hexane).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:10])[CH:5]=[CH:6][C:7]=1[S:8][CH3:9].[Cl:11][C:12]1[CH:17]=[C:16]([N+]([O-])=O)[CH:15]=[CH:14][N:13]=1.C([O-])([O-])=O.[K+].[K+].O>C(#N)C>[Cl:11][C:12]1[CH:17]=[C:16]([O:10][C:4]2[CH:5]=[CH:6][C:7]([S:8][CH3:9])=[C:2]([CH3:1])[CH:3]=2)[CH:15]=[CH:14][N:13]=1
Reactant: O=[N+]([O-])c1ccnc(Cl)c1
Reactant: CSc1ccc(O)cc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CSc1ccc(Oc2ccnc(Cl)c2)cc1C
Reaction time: 3 h

Procedure:
A solution of 17 gm (0.1 mol) of 3-methyl-4-methylmercaptophenol and 15.9 gm (0.1 mol) of 2-chloro-4-nitropyridine in 150 ml of acetonitrile was mixed with 13.8 gm (0.1 mol) of K2CO3 and stirred for 3 hours under reflux. It was then cooled and poured into 300 ml of water. The oil which separated out was separated off and taken up in methylene chloride, and the solution was washed with dilute sodium hydroxide solution and with water. The organic solution was then dried over Na2SO4 and concentrated by evaporation. The oil which remained was crystallized from hexane.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[N:13]([CH3:14])[C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:11][C:10]=2[C:21]2C=CC(C#N)=[CH:23][CH:22]=2)=[CH:4][CH:3]=1.[CH3:29][Mg+].[Br-].Cl.[CH2:33]1[CH2:37][O:36][CH2:35][CH2:34]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][C:9]2[N:13]([CH3:14])[C:12]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)=[N:11][C:10]=2[C:21]2[CH:35]=[CH:34][C:33]([C:37](=[O:36])[CH3:29])=[CH:23][CH:22]=2)=[CH:6][CH:7]=1
Reactant: Cn1c(-c2ccccc2)nc(-c2ccc(C#N)cc2)c1Sc1ccc(Cl)cc1
Reactant: C1CCOC1
Reactant: C[Mg+]
Agent: Cl
Agent: [Br-]
Product: CC(=O)c1ccc(-c2nc(-c3ccccc3)n(C)c2Sc2ccc(Cl)cc2)cc1
Temperature: 25 °C

Procedure:
To 4-{5-[(4-chlorophenyl)thio]-1-methyl-2-phenyl-1H-imidazol-4-yl}benzonitrile (Example 2, 35 mg, 0.087 mmol) in 0.75 mL of THF was added MeMgBr (3M in ether, 0.44 mmol) at 0° C. After heating at reflux for 2 hr, the reaction was cooled to rt and 5 mL 2N HCl was added, and was stirred for another hour. The reaction was quenched with aqueous sodium bicarbonate (pH=ca 7). The product was extracted with EtOAc, the combined extracts were washed with water and brine, dried over MgSO4, filtered, and concentrated to dryness to give 1-(4-{5-[(4-chlorophenyl)thio]-1-methyl-2-phenyl-1H-imidazol-4-yl}phenyl)ethanone, which was used in the next step without further purification.
Reaction SMILES: FC(F)(F)C(O)=O.C([O:12][C:13](=[O:45])[CH2:14][CH:15]([NH:20][C:21]([CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][N:24]1[C:29]([N:31]1[C:44]2[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=2[S:38][C:37]2[C:32]1=[CH:33][CH:34]=[CH:35][CH:36]=2)=[O:30])=[O:22])[C:16](=[O:19])[CH2:17][F:18])(C)(C)C>C(Cl)Cl>[F:18][CH2:17][C:16](=[O:19])[CH:15]([NH:20][C:21]([CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][N:24]1[C:29]([N:31]1[C:44]2[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=2[S:38][C:37]2[C:32]1=[CH:33][CH:34]=[CH:35][CH:36]=2)=[O:30])=[O:22])[CH2:14][C:13]([OH:45])=[O:12]
Reactant: CC(C)(C)OC(=O)CC(NC(=O)C1CCCCN1C(=O)N1c2ccccc2Sc2ccccc21)C(=O)CF
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CC(NC(=O)C1CCCCN1C(=O)N1c2ccccc2Sc2ccccc21)C(=O)CF
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 66.1 %

Procedure:
Trifluoroacetic acid (5 mL) was added to a stirred ice cold solution of [3S/R, (2S)]-5-fluoro-4-oxo-3-{[1-(phenothiazine-10-carbonyl)piperidine-2-carbonyl]amino}-pentanoic acid tert-butyl ester (130 mg, 0.24 mmol) in anhydrous DCM (5 mL). The mixture was stirred at 0° C. for 0.5 h then at room temperature for 0.5 h. The mixture was concentrated under reduced pressure and then the residue was dissolved in dry DCM. This process was repeated several times in order to remove excess trifluoroacetic acid. The gum was lyophilized twice from HPLC grade water to afford the title compound as a white powder (77 mg, 66%): IR (solid) 1670, 1716, 1782 cm−1; 1H NMR (400 MHz, d6-DMSO) δ 0.96-0.99 (1H, m), 1.23-1.26 (2H, m), 1.42-1.44 (1H, m), 1.60 (1H, m), 1.91-1.98 (1H, m), 2.51-2.89 (2H, m), 3.11-3.22 (1H, m), 3.57-3.60 (1H, m), 4.30-4.72 and 5.05-5.29 (4H, 2m), 7.11-7.17 (2H, m), 7.24-7.30 (2H, m), 7.34-7.38 (2H, m), 7.57-7.63 (2H, m), 8.07-8.61 (1H, m); 13C NMR (100 MHz, DMSO) δ (DMSO+TFA) 18.8/18.9 (CH2), 22.2/22.3 (CH2), 25.8/26.1 (CH2), 31.5/33.2 (CH2), 43.2 (CH2), 50.6/51.1 (CH), 54.4/54.5 (CH), 82.8/82.9 (2d, J 178.6/178.1, CH2F), 119.9/120.0 (CH), 120.4/120.5 (CH), 124.0/124.1 m(CH), 125.9/126.0 (C), 126.4/126.5 (CH), 139.6/139.7 (C), 156.0/156.4 (CO), 170.3 (CO), 170.7/170.8 (CO), 202.2/202.3 (2d, J 14.6/15.1, CO).; 19F (376 MHz, DMSO) δ chemical shift (multiplicity, relative intensity)-226.7 (t, 3), −226.9 (t, 3), −230.4 (t, 1), −231.2 (t, 1), −232.7 (t, 10), −233.0 (t, 10).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([C:15]#[N:16])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.Br[CH:18]([CH3:24])[C:19]([O:21][CH2:22][CH3:23])=[O:20]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([C:15]#[N:16])([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:24][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(C)Br
Reactant: CCOC(=O)C(C#N)Cc1ccc(Cl)cc1
Product: CCOC(=O)CCC(C#N)(Cc1ccc(Cl)cc1)C(=O)OCC

Procedure:
In the same manner as Example 1-(b), 47.5 g of ethyl 3-(4-chlorophenyl)-2-cyanopropionate was reacted with ethyl 2-bromopropionate to obtain ethyl 5-(4-chlorophenyl)-4-cyano-4-ethoxycarbonylvalerate.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][C:7]([CH:11]=[O:12])=[CH:8][CH:9]=2)[N:4]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[N:3]=1.CC1(C)C(C)(C)OB([C:29]2[CH:30]=[CH:31][C:32]([N:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)=[N:33][CH:34]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.O.CCO>[O:38]1[CH2:39][CH2:40][N:35]([C:32]2[N:33]=[CH:34][C:29]([C:2]3[C:10]4[C:5](=[CH:6][C:7]([CH:11]=[O:12])=[CH:8][CH:9]=4)[N:4]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[N:3]=3)=[CH:30][CH:31]=2)[CH2:36][CH2:37]1
Reactant: C[Si](C)(C)CCOCn1nc(I)c2ccc(C=O)cc21
Reactant: CC1(C)OB(c2ccc(N3CCOCC3)nc2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: COCCOC
Solvent: O
Product: C[Si](C)(C)CCOCn1nc(-c2ccc(N3CCOCC3)nc2)c2ccc(C=O)cc21
Temperature: 125 °C
Reaction time: 4 h
Yield: 97.8 %

Procedure:
A mixture 3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-6-carbaldehyde (25 mg, 0.62 mmol), 4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)morpholine (22 mg, 0.75 mmol), PdCl2 (PPh3)2 (4 mg, 0.006 mmol) and 2M Na2CO3 (0.31 mL, 0.62 mmol) in DME/H2O/EtOH (2.8 mL/0.8 mL/0.4 mL) was sealed and heated with stirring under microwave irradiation at 125° C. for 4 h. Solvent was removed and the crude product was purified by silica gel chromatography (95:5 CH2Cl2/MeOH) to yield a bright yellow foam (266 mg, 97%). 1H NMR (400 MHz, CD3OD) δ 10.02 (s, 1H), 8.60 (d, J=2.3 Hz, 1H), 8.13 (s, 1H), 7.99 (dd, J=8.9, 2.5 Hz, 1H), 7.94 (d, J=8.6 Hz, 1H), 7.64 (dd, J=8.7, 1.1 Hz, 1H), 6.80 (d, J=9.1 Hz, 1H), 5.78 (s, 2H), 3.76 (t, J=4.7 Hz, 4H), 3.61 (t, J=8.0 Hz, 2H), 3.49 (t, J=5.1 Hz, 4H), 0.84 (t, J=8.0 Hz, 2H), −0.12 (s, 9H); MS ESI 439.3 [M+H]+, calcd for [C23H30N4O3Si+H]+ 439.21.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:22])[C:12]3[S:19][C:18]([CH2:20]Cl)=[CH:17][C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1.[CH3:25][NH:26][CH2:27][CH:28]([C:30]1[N:35]=[CH:34][CH:33]=[CH:32][N:31]=1)[OH:29].C(N(C(C)C)CC)(C)C>CN(C=O)C.O>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:22])[C:12]3[S:19][C:18]([CH2:20][N:26]([CH2:27][CH:28]([OH:29])[C:30]4[N:31]=[CH:32][CH:33]=[CH:34][N:35]=4)[CH3:25])=[CH:17][C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2sc(CCl)cc21
Reactant: CNCC(O)c1ncccn1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CN(Cc1cc2c(s1)c(=O)c(C(=O)NCc1ccc(Cl)cc1)cn2C)CC(O)c1ncccn1
Temperature: 60 °C
Reaction time: 7 h
Yield: 46.3 %

Procedure:
A mixture of N-(4-chlorobenzyl)-2-(chloromethyl)-4-methyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide (100 mg, 0.26 mmol), 2-(methylamino)-1-pyrimidin-2-ylethanol (Preparation 23)(59 mg, 0.39 mmol) and diisopropylethylamine (67 μL, 0.38 mmol) in dry DMF (5 mL) was heated to 60° C., becoming a solution. The reaction was stirred for 7 hours at that temperature. After cooling to room temperature, the solution was diluted with water (10 mL). The resulting milky suspension was stirred vigorously for 30 minutes, and then left standing overnight in the refrigerator. The mixture was filtered, and the collected solid was washed with water and dried in vacuo, leaving a white solid. Recrystallization from acetonitrile/water (dissolved with warming 5 mL of acetonitrile, then cooled to 0° C. and then diluted with 2 mL of water, left overnight) gave the title compound (60 mg) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][C:6]([Cl:9])=[CH:5][C:3]=1[NH2:4].Cl[CH2:11][CH:12]1[O:16][CH2:15][CH2:14][O:13]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[O:13]1[CH2:14][CH2:15][O:16][CH:12]1[CH2:11][NH:4][C:3]1[CH:5]=[C:6]([Cl:9])[CH:7]=[CH:8][C:2]=1[CH3:1]
Reactant: ClCC1OCCO1
Reactant: Cc1ccc(Cl)cc1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(Cl)cc1NCC1OCCO1
Reaction time: 26 h

Procedure:
2-Methyl-5-chloroaniline (75 grams), 2-chloromethyl1,3-dioxolane (25 grams), potassium carbonate (22 grams) and dimethylformamide (50 ml) were charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer, and reflux condenser. The reaction mixture was heated, with stirring, for a period of about 26 hours. After this time the reaction mixture was filtered and then distilled to yield the desired product N-(1,3-dioxolan-2-ylmethyl)-2-methyl-5chloroaniline having a boiling point of 116° to 118°C at 0.1 mm of Hg pressure.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[C:17]([N:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)#[N:18]>C1C(O)=CC=CC=1C>[CH3:10][O:9][C:6]1[CH:7]=[CH:8][C:3]([NH:2][C:17]([N:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)=[NH:18])=[C:4]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:5]=1
Reactant: N#CN1CCCCC1
Reactant: COc1ccc(N)c(-c2ccccc2)c1
Agent: Cl
Solvent: Cc1cccc(O)c1
Product: COc1ccc(NC(=N)N2CCCCC2)c(-c2ccccc2)c1

Procedure:
2-Amino-5-methoxybiphenyl hydrochloride (0.9 g) was heated with N-cyanopiperidine (0.45 g) in m-cresol (1 ml) at 140° C. for 8 hours to give N-(5-methoxy-2-biphenylyl)piperidine-1-carboxamidine which was crystallised from a 1:9 mixture of ethylacetate and hexane to furnish N-(5-methoxy-2-biphenylyl)piperidine-1-carboxamidine as a pale brown crystals (m.p. 155° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](SCC)=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:31])([F:30])[F:29])[CH:3]=1.[CH3:32][N:33]1[CH2:38][CH2:37][NH:36][CH2:35][C:34]1([CH3:40])[CH3:39]>>[Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:36]5[CH2:37][CH2:38][N:33]([CH3:32])[C:34]([CH3:40])([CH3:39])[CH2:35]5)=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:31])([F:29])[F:30])[CH:3]=1
Reactant: CN1CCNCC1(C)C
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Product: CN1CCN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)S2)CC1(C)C

Procedure:
5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2-(3,3,4-trimethylpiperazin-1-yl)-1,3-thiazol-4(5H)-one was prepared from 5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-one and 1,2,2-Trimethyl-piperazine following General Procedure C.
Reaction SMILES: [Zn:1].[OH:2][S:3]([C:6]([F:9])([F:8])[F:7])(=[O:5])=[O:4]>O>[O-:5][S:3]([C:6]([F:9])([F:8])[F:7])(=[O:4])=[O:2].[Zn+2:1].[O-:5][S:3]([C:6]([F:9])([F:8])[F:7])(=[O:4])=[O:2]
Reactant: O=S(=O)(O)C(F)(F)F
Reactant: [Zn]
Solvent: O
Product: O=S(=O)([O-])C(F)(F)F
Product: [Zn+2]
Reaction time: 48 h

Procedure:
0.5 g of zinc powder and 70 ml of water are introduced with stirring into a 250 ml glass flask. The suspension obtained is brought to 80° C., then 22.2 ml of an aqueous solution of 0.57N triflic acid is added drop by drop. This mixture is maintained with stirring at 80° C. for 2 hours, then at ambient temperature for 48 hours. The zinc triflate obtained may then be isolated by eliminating the excess zinc by filtration and evaporating the water at 100° C. under atmospheric pressure. In this way, one recovers 3 g of zinc triflate, having the formula Zn(CF3SO3)2, in the form of a white powder.
Reaction SMILES: [SH:1][C:2]1[O:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[OH-].[Na+].Cl[CH2:14][CH2:15][CH2:16][NH2:17]>C(O)C.O>[O:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=[C:2]1[S:1][CH2:14][CH2:15][CH2:16][NH2:17]
Reactant: NCCCCl
Reactant: Sc1nc2ccccc2o1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: NCCCSc1nc2ccccc2o1
Yield: 71.6 %

Procedure:
2-Mercaptobenzoxazole (15.2 g; 0.1 mol) was dissolved in ethanol (200 ml); NaOH (4.0 g; 0.1 mol) dissolved in water was added thereto. The reaction mixture was refluxed for 30 minutes, then 3-chloropropylamine (9.3 g; 0.1 mol) dissolved in ethanol (50 ml) was added. The mixture was refluxed for 90 minutes, cooled, filtered from the salt and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography, eluting with methanol/ether (1:3), (15.0 g; 71.6% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][N:7]2[C:15](=[O:16])[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:17]([OH:19])=O)[CH:13]=3)[C:8]2=[O:20])=[CH:4][CH:3]=1.[N:23]1([CH2:28][CH2:29][CH2:30][NH2:31])[CH2:27][CH2:26][CH2:25][CH2:24]1>>[Cl-:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:15](=[O:16])[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:17]([NH:31][CH2:30][CH2:29][CH2:28][NH+:23]4[CH2:27][CH2:26][CH2:25][CH2:24]4)=[O:19])[CH:13]=3)[C:8]2=[O:20])=[CH:21][CH:22]=1
Reactant: O=C(O)c1ccc2c(c1)C(=O)N(Cc1ccc(Cl)cc1)C2=O
Reactant: NCCCN1CCCC1
Product: O=C(NCCC[NH+]1CCCC1)c1ccc2c(c1)C(=O)N(Cc1ccc(Cl)cc1)C2=O
Product: [Cl-]

Procedure:
2-(4-chloro-benzyl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-carboxylic acid (100 mg, 0.316 mmol) and 3-pyrrolidin-1-yl-propylamine (100 μL, 0.792 mmol) were reacted with each other. Target compound in the amount of 57 mg (39%) was obtained by following the procedure described in Example 1.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:40])[C:4]([NH:7][C:8](=[O:39])[C@@H:9]([NH:31]C(OC(C)(C)C)=O)[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17]CC2C=CC=CC=2)=[C:13]([O:25][C:26](=[O:30])[NH:27][CH2:28][CH3:29])[CH:12]=1)([CH3:6])[CH3:5].CCOCC.[ClH:46].O1CCOCC1>>[Cl-:46].[CH2:28]([NH:27][C:26]([O:25][C:13]1[CH:12]=[C:11]([CH2:10][C@H:9]([NH3+:31])[C:8](=[O:39])[NH:7][C:4]([C:3]([O:2][CH3:1])=[O:40])([CH3:6])[CH3:5])[CH:16]=[CH:15][C:14]=1[OH:17])=[O:30])[CH3:29]
Reactant: CCNC(=O)Oc1cc(C[C@H](NC(=O)OC(C)(C)C)C(=O)NC(C)(C)C(=O)OC)ccc1OCc1ccccc1
Reactant: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: CCNC(=O)Oc1cc(C[C@H]([NH3+])C(=O)NC(C)(C)C(=O)OC)ccc1O
Product: [Cl-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-[(S)-3-(4-Benzyloxy-3-ethylcarbamoyloxy-phenyl)-2-tert-butoxycarbony lamino-propionylamino]-2-methyl-propionic acid methyl ester (380 mg) was dissolved in 4M HCl-dioxane (10 ml) and stirred at room temperature for 1 hour. The solution was evaporated to dryness and the resulting gum was redissolved on methanol (10 ml) containing 5% Pd—C (60 mg). The mixture was stirred under an atmosphere of hydrogen for 2 hours. The catalyst was removed by filtration and the filtrate evaporated to dryness giving a gum. Repeated trituration with ether gave (S)-2-(3-ethylcarbamoyloxy-4-hydroxy-phenyl)-1-(1-methoxycarbonyl-1-methyl-ethylcarbamoyl)-ethyl-ammonium chloride as a white solid, 240 mg; NMR (500 MHz, d6 DMSO) 1.07 (ca 3H, t J 7), 1.32 (3H, s), 1.38 (3H, s), 2.85 (1H, dd J 14, 7), 2.98 (1H, dd J 14, 5), 3.05-3.09 (2H, m), 3.58 (3H, s), 3.91 (1H, br t), 6.83 (1H, d J 8), 6.91 (1H, dd J 8, 2), 6.94 (1H, d J 2), 7.55 (1H, br t), 8.15 (3H, br s exch D2O), 8.82 (1H, exch D2O), 9.51 (1H, s, exch D2O); HPLC/MS retention time 4.29 min, m/z 368 (MH+).
Reaction SMILES: C[O:2][C:3](=[O:35])[CH2:4][CH2:5][CH2:6][CH2:7][CH:8]([C@@H:10]1[C@:27]2([CH3:28])[C@H:13]([C@H:14]3[C@H:24]([CH2:25][C@@H:26]2[O:29]C=O)[C@:22]2([CH3:23])[C@@H:17]([CH2:18][C@H:19]([O:32]C=O)[CH2:20][CH2:21]2)[CH2:16][CH2:15]3)[CH2:12][CH2:11]1)[CH3:9].CO.[OH-].[Na+]>O>[OH:32][C@@H:19]1[CH2:20][CH2:21][C@@:22]2([CH3:23])[C@H:17]([CH2:16][CH2:15][C@@H:14]3[C@@H:24]2[CH2:25][C@H:26]([OH:29])[C@@:27]2([CH3:28])[C@H:13]3[CH2:12][CH2:11][C@@H:10]2[CH:8]([CH2:7][CH2:6][CH2:5][CH2:4][C:3]([OH:35])=[O:2])[CH3:9])[CH2:18]1
Reactant: COC(=O)CCCCC(C)[C@H]1CC[C@H]2[C@@H]3CC[C@@H]4C[C@H](OC=O)CC[C@]4(C)[C@H]3C[C@H](OC=O)[C@]12C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(CCCCC(=O)O)[C@H]1CC[C@H]2[C@@H]3CC[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3C[C@H](O)[C@]12C
Yield: 64.8 %

Procedure:
A solution of 7.2 g of 5-(3α,12α-diformyloxy-5β-pregnane-20-yl)pentanoic acid methyl ester, 50 ml of methanol, 50 ml of 2N methanolic sodium hydroxide solution and 10 ml of water was refluxed for 2 hr. At the end of this time, the methanol was removed under reduced pressure and 300 ml of water was added to the residue. The solution was treated with charcoal and filtered through a bed of diatomaceous earth. The solution was then cooled to 0° and with stirring acidified (pH3) by the dropwise addition of concentrated aqueous hydrochloric acid. The precipitate was filtered and dried overnight under house vacuum. Crystallization from methyl ethyl ketone gave 4 g of 5-(3α,12α-dihydroxy-5β-pregnane-20-yl)pentanoic acid, mp 191°-193°.