Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[CH:18]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27]C)[CH:22]=1)C#N)=[CH:15][CH:14]=[CH:13][C:12]=2[C:29]([F:32])([F:31])[F:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[NH4+]>Br.O>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[CH2:18][C:21]1[CH:22]=[C:23]([OH:27])[CH:24]=[CH:25][CH:26]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:29]([F:31])([F:32])[F:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cccc(C(C#N)c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Agent: Br
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: Oc1cccc(Cc2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Yield: 83.7 %

Procedure:
[3-Benzyl-8-(trifluoromethyl)quinolin-4-yl](3-methoxyphenyl)acetonitrile (5.14 g, 11.88 mmol) in 48% HBr (75 mL) is heated at 90° C. for 65 h. Cooled reaction is poured into concentrated ammonium hydroxide (50 mL) diluted with water and ice. The mixture is extracted with ethyl acetate and the combined extracts are dried (MgSO4) and concentrated. The residue is purified via column chromatography using 15:85 ethyl acetate:hexane as the eluent to afford the title compound as a yellow powder (3.91 g, 84%). HRMS: calcd for C24H18F3NO+H+, 394.14132; found (ESI, [M+H]+), 394.1404.
Reaction SMILES: [Na+].[OH:2][C:3]1[C:4]([S:20]([O-:23])(=O)=[O:21])=[CH:5][C:6]2[C:7](=[O:19])[C:8]3[C:13]([C:14](=[O:18])[C:15]=2[C:16]=1[OH:17])=[CH:12][CH:11]=[CH:10][CH:9]=3.[Cl:24]S(O)(=O)=O>>[OH:2][C:3]1[C:4]([S:20]([Cl:24])(=[O:23])=[O:21])=[CH:5][C:6]2[C:7](=[O:19])[C:8]3[C:13]([C:14](=[O:18])[C:15]=2[C:16]=1[OH:17])=[CH:12][CH:11]=[CH:10][CH:9]=3
Reactant: O=S(=O)(O)Cl
Reactant: O=C1c2ccccc2C(=O)c2c1cc(S(=O)(=O)[O-])c(O)c2O
Agent: [Na+]
Product: O=C1c2ccccc2C(=O)c2c1cc(S(=O)(=O)Cl)c(O)c2O
Temperature: 90 °C
Yield: 66 %

Procedure:
3,4-dihydroxy-9,10-dioxo-2-anthracenesulfonic acid sodium salt (1.4 g, 3.9 mmoles) was combined with 30 mL of chlorosulfonic acid and heated to 90° C. for 5 hours, after which the solution was cooled to 0° C. and poured into 100 g of ice. After the ice melted the solution was extracted with CH2Cl2 (3×100 mL), methylene chloride extracts were combined, dried with Na2SO4 and evaporated to produce 0.87 g of solid (Yield 66%).
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH2:13][Cl:14])(=O)=O)=CC=1.[OH:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH:18]=[O:19].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[Cl:14][CH2:13][CH2:12][O:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH:18]=[O:19]
Reactant: O=Cc1ccccc1O
Reactant: Cc1ccc(S(=O)(=O)OCCCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1ccccc1OCCCl
Temperature: 45 °C
Reaction time: 12 h
Yield: 79.1 %

Procedure:
A mixture of 2-chloroethyl 4-methylbenzenesulfonate (39; 27.0 g, 0.115 mol), 2-hydroxybenzaldehyde (25; 14.0 g, 0.115 mol) and K2CO3 (31.7 g, 0.23 mol) in DMF (100 mL) was stirred at 45° C. for 12 h. Water (200 mL) was added and the mixture was extracted with ethyl acetate (3×150 mL). The combined organic layers were washed saturated brine (3×50 mL), dried (Na2SO4) and concentrated under reduced pressure. The resulting residue was purified by chromatography (petroleum ether:ethyl acetate=10:1) to give 2-(2-chloroethoxy)benzaldehyde 40 (16.8 g, 0.091 mol, 79%) as a pale yellow solid.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[I:25]I.[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]2([CH2:37]O)[CH2:36][CH2:35]2)=[CH:30][CH:29]=1>ClCCl>[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]2([CH2:37][I:25])[CH2:36][CH2:35]2)=[CH:30][CH:29]=1
Reactant: II
Reactant: OCC1(c2ccc(Cl)cc2)CC1
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Clc1ccc(C2(CI)CC2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of triphenylphosphine (3.45 g, 13 mmol) and imidazole (0.90 g, 13 mmol) in dichloromethane (25 ml) under an argon atmosphere was added slowly iodine (3.33 g, 13 mmol) and [1-(4-chlorophenyl)-cyclopropyl]-methanol (2.00 g, 11 mmol). The mixture was stirred for 2 hours at room temperature, then dichloromethane (75 ml) was added and mixture was extracted with saturated sodium thiosulfate solution (100 ml) and hydrochloric acid (1N, 50 ml). The organic layer was dried over MgSO4 and evaporated. The residue was suspended in ether and filtered to remove insoluble triphenylphosphine oxide. The ether was evaporated and the residue was purified by column chromatography (SiO2, heptane/EtOAc=9:1) to yield a light yellow oil, (2.30 g, 72%); MS (EI): 292.0 (M+.).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:9]=[CH:10][CH:11]=1)[NH2:8])([CH3:4])([CH3:3])[CH3:2].[N-]=[C:13]=[O:14]>C(Cl)Cl>[C:1]([C:5]1[CH:11]=[CH:10][CH:9]=[C:7]([N:8]=[C:13]=[O:14])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: [N-]=C=O
Reactant: CC(C)(C)c1cccc(N)c1
Solvent: ClCCl
Product: CC(C)(C)c1cccc(N=C=O)c1
Reaction time: 8 h

Procedure:
3-t-Butyl-aniline (150 mg, 1 mmol) was converted to the isocyanate as described above and then dissolved in 4 mL DCM. Hydrazate (104 mg, 1 mmol) was added and the reaction was continued at rt overnight. Preparative LC-MS purification afforded 181 mg of the target compound as a white solid.
Reaction SMILES: [O:1]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([C:11]([OH:13])=[O:12])[C:5]=2[CH:4]=[CH:3][CH2:2]1>CO.[Pd]>[O:1]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([C:11]([OH:13])=[O:12])[C:5]=2[CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)c1cccc2c1C=CCO2
Agent: [Pd]
Solvent: CO
Product: O=C(O)c1cccc2c1CCCO2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 2H-chromene-5-carboxylic acid (1.42 mmol) in MeOH (5.0 mL) is treated with Pd/C (10%, 50 mg) and stirred at RT under a hydrogen atmosphere (1 bar) for 16 h. After filtration through celite and removal of the solvents the desired product is obtained which is used without further purification. 1H-NMR (DMSO-d6): δ=1.90 (m, 2H); 2.98 (m, 2H); 4.13 (m, 2H); 6.89-6.94 (m, 1H); 7.11-7.17 (m, 1H); 7.31-7.36 (m, 1H); 12.8 (bs, 1H).
Reaction SMILES: N1C=CN=C1.[CH2:6]([OH:11])[CH2:7][CH2:8][CH2:9][OH:10].[Si:12](Cl)([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13].C(OCC)C>CN(C=O)C.ClCCl.O>[Si:12]([O:10][CH2:9][CH2:8][CH2:7][CH2:6][OH:11])([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13]
Reactant: OCCCCO
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCCCCO
Reaction time: 3 h

Procedure:
Imidazole (6.77 g) was added to a solution containing 1,4-butanediol (58.8 mL) in DMF (60.0 mL) at room temperature. A solution of tert-butyldimethylsilyl chloride (10.0 g) in dichloromethane (5.0 mL) was added dropwise, and the mixture was stirred at the same temperature for three hours. Diethyl ether and water were added to the reaction solution. The organic layer was separated, washed with water and a saturated sodium chloride solution and then dried over anhydrous magnesium sulfate. The insoluble matter was separated by filtration and the filtrate was concentrated to obtain the title compound (13.4 g).
Reaction SMILES: [C:1]1(C)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:9]1[CH:10]=[CH:11][C:12]([O:17][C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=2)=[C:13]([CH:16]=1)[CH:14]=[O:15].C1(B(O)O)C=CC=CC=1.C([O-])([O-])=O.[Na+].[Na+]>O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(O)C>[Cl:25][C:20]1[CH:19]=[C:18]([CH:23]=[CH:22][C:21]=1[Cl:24])[O:17][C:12]1[CH:11]=[CH:10][C:9]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:16][C:13]=1[CH:14]=[O:15]
Reactant: Cc1ccccc1
Reactant: O=Cc1cc(Br)ccc1Oc1ccc(Cl)c(Cl)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: OB(O)c1ccccc1
Solvent: O
Solvent: CCO
Product: O=Cc1cc(-c2ccccc2)ccc1Oc1ccc(Cl)c(Cl)c1

Procedure:
Under N2 in a 50 mL round bottomed flask fitted with a magnetic stirrer were placed the following reactants in order: 15 mL of toluene, 500 mg (1.4 mmol) of 5-bromo-2-(3,4-dichlorophenoxy)-benzaldehyde (from Preparation 1), 341 mg (2.8 mmol) of phenylboronic acid (Aldrich Chem. Co.), 1.5 mL of ethanol and 774 mg (5.6 mmol) of Na2CO3 in 3 mL of water. To this was added 45 mg (0.04 mmol) of tetrakis(triphenylphosphine)palladium (0) (Aldrich Chem. Co.), and the mixture was degassed with N2. The reaction was next heated to reflux for 4 hr, at which time a thin layer chromatography (tlc), using 1:1 CH2Cl2: hexane on silica gel coated plates, showed the absence of the starting aldehyde. After cooling, the mixture was diluted with 100 mL of EtOAc, washed twice with water, twice with 2 N NaOH, twice with water and finally with saturated aqueous NaCl. After drying over MgSO4, the solvent was removed in vacuo to give an oily residue, 690 mg. This was chromatographed on silica gel, eluting with CH2Cl2:hexane (1:1) to give the title product as an oil, 462 mg.
Reaction SMILES: [P:1]([O:13][CH2:14][C:15]([N:17]([CH2:22][C:23]1[CH:24]=[N:25][C:26]([C:29]2[S:37][C:36]3[C:31](=[N:32][CH:33]=[CH:34][C:35]=3[O:38][C:39]3[CH:44]=[CH:43][C:42]([NH:45][C:46]([NH:48][CH:49]4[CH2:51][CH2:50]4)=[O:47])=[CH:41][C:40]=3[F:52])[CH:30]=2)=[CH:27][CH:28]=1)[CH2:18][CH2:19][O:20][CH3:21])=[O:16])([O:8]C(C)(C)C)([O:3]C(C)(C)C)=[O:2].Cl.O1CCOCC1>C(Cl)Cl>[P:1]([OH:8])([OH:3])([O:13][CH2:14][C:15]([N:17]([CH2:22][C:23]1[CH:24]=[N:25][C:26]([C:29]2[S:37][C:36]3[C:31](=[N:32][CH:33]=[CH:34][C:35]=3[O:38][C:39]3[CH:44]=[CH:43][C:42]([NH:45][C:46]([NH:48][CH:49]4[CH2:51][CH2:50]4)=[O:47])=[CH:41][C:40]=3[F:52])[CH:30]=2)=[CH:27][CH:28]=1)[CH2:18][CH2:19][O:20][CH3:21])=[O:16])=[O:2]
Reactant: COCCN(Cc1ccc(-c2cc3nccc(Oc4ccc(NC(=O)NC5CC5)cc4F)c3s2)nc1)C(=O)COP(=O)(OC(C)(C)C)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: COCCN(Cc1ccc(-c2cc3nccc(Oc4ccc(NC(=O)NC5CC5)cc4F)c3s2)nc1)C(=O)COP(=O)(O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 60 %

Procedure:
To a stirred solution of 33 from the previous step in DCM (15 mL) was added a solution of 4M HCl in 1,4-dioxane (0.44 mL, 1.75 mmol). The reaction mixture (suspension) was stirred at RT for 1 h. The solid was collected by filtration, rinsed with DCM and dried under high vacuum. The residue was suspended in MeOH, concentrated and triturated with a minimum of methanol/water to afford the title compound 34 (136 mg, 0.21 mmol, 60% over 3 steps) as an off-white fluffy solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): mixture of rotamers, 8.71 (s, 1H), 8.58-8.48 (m, 2H), 8.37 and 8.33 (2 s, 1H), 8.29 and 8.24 (2d, J=8.2 Hz, 1H), 7.86-7.77 (m, 1H), 7.73 (dd, J=13.6, 2.4 Hz, 1H), 7.38 (t, J=9.1 Hz, 1H), 7.20 (bd, J=9.0 Hz, 1H), 6.64 (d, J=5.3 Hz, 1H), 6.57 (d, J=2.5 Hz, 1H), 4.74-4.50 (m, 4H), 3.47 (bs, 4H), 3.24 and 3.21 (2s, 3H), 2.59-2.51 (m, 1H), 0.73-0.58 (m, 2H), 0.50-0.36 (m, 2H). MS (m/z): 646.7 (M+H).
Reaction SMILES: N.[CH3:2][N:3]1[CH:8]2[CH2:9][CH2:10][CH:4]1[CH2:5][CH:6]([N:11]1[CH:15]=[C:14]([N+:16]([O-])=O)[CH:13]=[N:12]1)[CH2:7]2>CO.[Ni]>[CH3:2][N:3]1[CH:8]2[CH2:9][CH2:10][CH:4]1[CH2:5][CH:6]([N:11]1[CH:15]=[C:14]([NH2:16])[CH:13]=[N:12]1)[CH2:7]2
Reactant: CN1C2CCC1CC(n1cc([N+](=O)[O-])cn1)C2
Agent: [Ni]
Agent: N
Solvent: CO
Product: CN1C2CCC1CC(n1cc(N)cn1)C2
Reaction time: 2 h
Yield: 74.1 %

Procedure:
Ammonia was bubbled for 15 min in a solution of 8-Methyl-3-(4-nitro-1H-pyrazol-1-yl)-8-azabicyclo[3.2.1]octane (3.4 g, 14.4 mmol) in MeOH (300 mL). The solution was then hydrogenated (3 bars) in presence of Ra—Ni (2 g) at RT. After 2 h, the catalyst was filtered off and the filtrate was concentrated under reduced pressure. The solid was purified by trituration in acetonitrile (25 mL) to give the title compound as a white solid (2.2 g, 75%). 1H NMR (400 MHz, DMSO-d6) δ 7.08 (brs, 1H), 6.87 (brs, 1H), 4.49 (brs, 1H), 3.84 (s, 2H), 2.61 (s, 3H), 2.42-2.36 (m, 2H), 2.19-2.16 (t, 2H), 2.06-1.97 (m, 4H).
Reaction SMILES: [CH2:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[N:15]=[CH:14][C:13]([NH2:16])=[CH:12][N:11]=2)[CH2:6][CH2:5]1)[CH:2]=[CH2:3].[CH:17]([C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1)([CH3:19])[CH3:18].C(N(CC)CC)C>O1CCCC1>[CH2:1]([N:4]1[CH2:5][CH2:6][N:7]([C:10]2[N:15]=[CH:14][C:13]([NH:16][S:26]([C:23]3[CH:24]=[CH:25][C:20]([CH:17]([CH3:19])[CH3:18])=[CH:21][CH:22]=3)(=[O:28])=[O:27])=[CH:12][N:11]=2)[CH2:8][CH2:9]1)[CH:2]=[CH2:3]
Reactant: C=CCN1CCN(c2ncc(N)cn2)CC1
Reactant: CC(C)c1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=CCN1CCN(c2ncc(NS(=O)(=O)c3ccc(C(C)C)cc3)cn2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
216 mg (0.98 mmol) of 2-(4-Allylpiperazin-1-yl)pyrimidin-5-ylamine from Example 16.2 and 215 mg (0.98 mmol) of 4-isopropylbenzenesulfonyl chloride were dissolved in 20 ml of tetrahydrofuran at room temperature, after which 0.4 ml (3.0 mmol) of triethylamine was added dropwise and the mixture was stirred at room temperature overnight. After the solvent had been evaporated down to dryness, water was added to the resulting residue. The aqueous reaction mixture was made acid using 1N aqueous hydrochloric acid and extracted twice with diethyl ether. The aqueous phase was made alkaline to pH 9-10, using a 1N solution of sodium hydroxide and then extracted three times with diethyl ether. The combined organic phases were dried over sodium sulfate. The residue which was obtained after filtering off the drying agent and evaporating the solvent down to dryness was thoroughly stirred with a mixture composed of heptane and diethyl ether, filtered off with suction and dried, with 71 mg (18% of theory) of the title compound being obtained.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7](=[N:14][O:15][CH2:16][C:17]2[N:22]=[C:21]([CH:23]=O)[CH:20]=[CH:19][CH:18]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:5][N:4]=[N:3]1.Cl.[NH2:26][OH:27]>N1C=CC=CC=1>[OH:27][N:26]=[CH:23][C:21]1[N:22]=[C:17]([CH2:16][O:15][N:14]=[C:7]([C:6]2[N:2]([CH3:1])[N:3]=[N:4][N:5]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:18]=[CH:19][CH:20]=1
Reactant: NO
Reactant: Cn1nnnc1C(=NOCc1cccc(C=O)n1)c1ccccc1
Agent: Cl
Solvent: c1ccncc1
Product: Cn1nnnc1C(=NOCc1cccc(C=NO)n1)c1ccccc1
Reaction time: 6 h
Yield: 88.2 %

Procedure:
To a solution of 6-[({[(1-methyl-1H-tetrazol-5-yl)(phenyl)methylene]amino}oxy)methyl]pyridine-2-carbaldehyde (1.8 g, 5.58 mmol, 1 eq.) in 10 ml of pyridine was added hydroxylamine hydrochloride 0.427 g, 6.14 mmol, 1.1 eq.). The reaction was stirred for 6 hrs and stood overnight. The pyridine was evaporated, and the residue was partitioned between EtOAc and water. The organic layer was separated, dried over MgSO4 and concentrated to give N-({6-[(hydroxyimino)methyl]pyridin-2-yl}methoxy)-1-(1-methyl-1H-tetrazol-5-yl)-1-phenylmethanimine (1.66 g, 88% yield) as a pale brown solid.
Reaction SMILES: C([Si](C)(C)[O:6][CH2:7][CH:8]([CH:17]1[CH:21]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=2)[CH2:20][N:19]([C:30]([C:32]2[CH:37]=C(C)N=[N:34][CH:33]=2)=[O:31])[CH2:18]1)[O:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][N:11]=1)(C)(C)C.CC[CH2:43][CH2:44][N+:45](CCCC)(CCCC)CCCC.[F-]>C1COCC1.C(OCC)(=O)C>[Cl:16][C:13]1[CH:14]=[CH:15][C:10]([O:9][CH:8]([CH:17]2[CH:21]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=3)[CH2:20][N:19]([C:30]([C:32]3[CH:33]=[N:34][C:44]([CH3:43])=[N:45][CH:37]=3)=[O:31])[CH2:18]2)[CH2:7][OH:6])=[N:11][CH:12]=1
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Reactant: Cc1cc(C(=O)N2CC(c3ccc(Cl)c(Cl)c3)C(C(CO[Si](C)(C)C(C)(C)C)Oc3ccc(Cl)cn3)C2)cnn1
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1ncc(C(=O)N2CC(c3ccc(Cl)c(Cl)c3)C(C(CO)Oc3ccc(Cl)cn3)C2)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93 %

Procedure:
To a solution of [(3RS,4SR)-3-[(RS)-2-(tert-butyl-dimethyl-silanyloxy)-1-(5-chloro-pyridin-2-yloxy)-ethyl]-4-(3,4-dichloro-phenyl)-pyrrolidin-1-yl]-(6-methyl-pyridazin-4-yl)-methanone 0.024 g (0.038 mmol) dissolved in THF (4 mL) was added 0.05 mL of TBAF (1.0M in THF). The reaction mixture was stirred for 30 minutes at room temperature. The mixture was diluted with ethyl acetate and washed with water and aq. sodium bicarbonate solution subsequently. The separated organic phase was dried over sodium sulfate and concentrated in vaccuo after filtration. The residue was purified by TLC (SiO2, MeOH/DCM, 1:10) yielded 18 mg (93%) of the title compound as a light yellow oil. ES-MS m/e: 509.2 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1([C:14]2[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=2)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)(=O)C(Cl)=O.CN(C)C=O.[CH:34](O)([CH3:36])[CH3:35]>ClCCl.CN(C)C1C=CN=CC=1.C1C=CC=CC=1>[C:1]([O:5][C:6]([C:8]1([C:14]2[CH:15]=[CH:16][C:17]([C:18]([O:20][CH:34]([CH3:36])[CH3:35])=[O:19])=[CH:21][CH:22]=2)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)C1(c2ccc(C(=O)O)cc2)CCCCC1
Reactant: CC(C)O
Agent: CN(C)c1ccncc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: c1ccccc1
Product: CC(C)OC(=O)c1ccc(C2(C(=O)OC(C)(C)C)CCCCC2)cc1
Temperature: 40 °C
Reaction time: 1 h
Yield: 90.6 %

Procedure:
To a solution of 4-[1-(tert-butoxycarbonyl)cyclohexyl]benzoic acid (12) (0.219 g, 0.72 mmol) in dichloromethane (5 ml) under argon atmosphere at ice bath temperature oxalyl chloride (0.3 ml, 3.44 mmol) and a drop of dimethylformamide were added. The reaction mixture was stirred at ambient temperature for 15 minutes and at 40° C. for 1 hour, then the volatiles were evaporated and the residue was dried in vacuo. The residue (0.247 g) was dissolved in tetrahydrofuran (4 ml) and 4-dimethylaminopyridine (0.176 g, 1.43 mmol) and isopropanol (0.35 ml, 4.57 mmol) were added to the resulting solution. The mixture was stirred overnight, supplemented with benzene (50 ml), successively washed with water (30 ml), brine (20 ml), and dried (Na2SO4). The solvents were evaporated and the residue was chromatographed on silica gel with toluene-ethyl acetate (97:3) as eluent to give the title compound (0.226 g, 91%) as an oil. 1H NMR (CDCl3, HMDSO) δ: 1.01-1.87 (8H, m); 1.34 (6H, d, J=6.5 Hz); 1.34 (9H, s); 2.17-2.61 (2H, m); 5.23 (1H, sept, J=6.5 Hz); 7.46 (2H, d, J=8.8 Hz); 7.98 (2H, d, J=8.8 Hz).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([C:22]([F:25])([F:24])[F:23])=[C:5]([C:20]#[N:21])[C@@H:6]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[NH:15][N:14]=[C:13]3[CH3:19])[C:7]=1[C:8]#[N:9].[OH-].[K+:27]>C1COCC1>[C:8]([C:7]1[C@H:6]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[NH:15][N:14]=[C:13]3[CH3:19])[C:5]([C:20]#[N:21])=[C:4]([C:22]([F:23])([F:25])[F:24])[N-:3][C:2]=1[CH3:1])#[N:9].[K+:27]
Reactant: CC1=C(C#N)[C@H](c2ccc3[nH]nc(C)c3c2)C(C#N)=C(C(F)(F)F)N1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC1=C(C#N)[C@H](c2ccc3[nH]nc(C)c3c2)C(C#N)=C(C(F)(F)F)[N-]1
Temperature: 25 °C
Reaction time: 120 h

Procedure:
To a suspension of 60 mg (0.175 mmol) (4S)-2-methyl-4-(3-methyl-1H-indazol-5-yl)-6-(trifluoromethyl)-1,4-dihydropyridine-3,5-dicarbonitrile (Example 6) in THF (6 ml) under argon atmosphere was added 175 μl (0.175 mmol) 1 N aqueous potassium hydroxide solution, and the mixture was stirred under a weak argon stream for 5 days at room temperature. The resulting precipitate was dried in vacuo to yield 66 mg (100% of th.) of the title compound as a solid.
Reaction SMILES: [OH:1][C:2]1[C:19](=[O:20])[CH2:18][CH2:17][C@@:16]2([CH3:21])[C:3]=1[C:4](=[CH2:23])[CH2:5][C@@H:6]1[C@@H:15]2[CH2:14][CH2:13][C@@:11]2([CH3:12])[C@H:7]1[CH2:8][CH2:9][C:10]2=[O:22].[CH:24]1C=CC=CC=1.IC>>[CH3:24][O:1][C:2]1[C:19](=[O:20])[CH2:18][CH2:17][C@@:16]2([CH3:21])[C:3]=1[C:4](=[CH2:23])[CH2:5][C@@H:6]1[C@@H:15]2[CH2:14][CH2:13][C@@:11]2([CH3:12])[C@H:7]1[CH2:8][CH2:9][C:10]2=[O:22]
Reactant: c1ccccc1
Reactant: C=C1C[C@@H]2[C@H](CC[C@]3(C)C(=O)CC[C@@H]23)[C@@]2(C)CCC(=O)C(O)=C12
Solvent: CI
Product: C=C1C[C@@H]2[C@H](CC[C@]3(C)C(=O)CC[C@@H]23)[C@@]2(C)CCC(=O)C(OC)=C12
Reaction time: 2 h
Yield: 75.2 %

Procedure:
To a solution of 4-hydroxy-6-methylenandrost-4-ene-3,17-dione (0.315 g, 1 mmole) in benzene (10 ml) potassium tert-butoxide (0.224 g, 2 mmole) is added and the mixture heated to reflux for 30 minutes. After cooling, iodomethane (0.710 g, 5 mmole) is added and the mixture boiled for a further 2 hours. Then the organic solution is washed with water, dried and evaporated in vacuum. Flash column chromatography of the residue on silica gel using n-hexane/ethyl acetate 60:40 affords 0.247 g (75% yield) of the title compound, m.p. 196°-198° C.
Reaction SMILES: [F:1][C:2]1[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:3]=1[O:4][C:5]1[C:13]2[N:12]=[N:11][NH:10][C:9]=2[CH:8]=[CH:7][C:6]=1[C:14]1[C:15]2[CH:24]=[CH:23][N:22](S(C3C=CC(C)=CC=3)(=O)=O)[C:16]=2[C:17](=[O:21])[N:18]([CH3:20])[CH:19]=1.[OH-].[Na+].O>C(O)C>[F:1][C:2]1[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:3]=1[O:4][C:5]1[C:13]2[N:12]=[N:11][NH:10][C:9]=2[CH:8]=[CH:7][C:6]=1[C:14]1[C:15]2[CH:24]=[CH:23][NH:22][C:16]=2[C:17](=[O:21])[N:18]([CH3:20])[CH:19]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(-c4ccc5[nH]nnc5c4Oc4ccc(F)cc4F)cn(C)c(=O)c32)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cn1cc(-c2ccc3[nH]nnc3c2Oc2ccc(F)cc2F)c2cc[nH]c2c1=O
Temperature: 20 °C
Reaction time: 15 h
Yield: 57 %

Procedure:
A solution of 4-[4-(2,4-difluorophenoxy)-1H-1,2,3-benzotriazol-5-yl]-6-methyl-1-[(4-methylphenyl)sulfonyl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (32 mg, 0.058 mmol) in ethanol (3.4 mL) was treated with 3.0 M sodium hydroxide in water (195 μL, 0.584 mmol) and stirred at 20° C. for 15 h. The reaction mixture was purified via preparative LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water 0.1% ammonium hydroxide, at flow rate of 60 mL/min) to give the desired product (13 mg, 56%). 1H NMR (400 MHz, DMSO-d6) δ 12.05 (s, 1H), 7.77 (br s, 1H), 7.53 (d, J=8.5 Hz, 1H), 7.37-7.19 (m, 3H), 6.77 (br s, 2H), 6.23-6.07 (m, 1H), 3.50 (s, 3H); LCMS calculated for C20H14F2N5O2 (M+H)+: m/z=394.1. found: 394.0.
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:20]2[CH:36]=[CH:35][C:23]([CH2:24][O:25][C:26]3([C:30]([O:32]CC)=[O:31])[CH2:29][CH2:28][CH2:27]3)=[CH:22][CH:21]=2)[C:4]2[C:9]([C:10]=1[C:11](=[O:19])[C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.C1COCC1.[OH-].[Na+]>CO.O>[CH3:1][C:2]1[N:3]([C:20]2[CH:36]=[CH:35][C:23]([CH2:24][O:25][C:26]3([C:30]([OH:32])=[O:31])[CH2:29][CH2:28][CH2:27]3)=[CH:22][CH:21]=2)[C:4]2[C:9]([C:10]=1[C:11](=[O:19])[C:12]1[CH:13]=[CH:14][C:15]([CH3:18])=[CH:16][CH:17]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: CCOC(=O)C1(OCc2ccc(-n3c(C)c(C(=O)c4ccc(C)cc4)c4ccccc43)cc2)CCC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)c2c(C)n(-c3ccc(COC4(C(=O)O)CCC4)cc3)c3ccccc23)cc1
Yield: 44.1 %

Procedure:
The compound of Example 86-1 (36 mg, 0.07 mmol) was dissolved in methanol (1 ml) and THF (1 ml) and thereto was added 1N aqueous sodium hydroxide solution (1 ml), followed by stirring under reflux for 20 hours. The mixture was diluted with water and washed with ethyl ether. The aqueous layer was adjusted to around pH 4 with 5% aqueous potassium hydrogen sulfate solution and the solution was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and filtered. The solvent was removed in vacuo to give the subject compound (14 mg, 43%).
Reaction SMILES: [CH3:1][NH2:2].C1COCC1.[I:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N:15]=[C:16]=[O:17]>>[I:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C:16]([NH:2][CH3:1])=[O:17]
Reactant: CN
Reactant: O=C=Nc1ccccc1I
Solvent: C1CCOC1
Product: CNC(=O)Nc1ccccc1I
Reaction time: 0.5 h

Procedure:
A solution of methylamine in THF (2 M, 19 mL, 39 mmol) was cooled to 0° C. and 2-iodophenylisocyanate (0.68 g, 12.6 mmol) was added dropwise over 5 minutes. The solution was stirred for 30 minutes, after which it was evaporated to dryness in vacuo to yield a white solid (2.05 g) 1H NMR (400 MHz, d6-DMSO): δ 7.81-7.77 (2H, m), 7.53 (1H, s), 7.30-7.26 (1H, m), 6.87 (1H, d, J=4.3 Hz), 6.77-6.73 (1H, m), 2.65 (3H, d, J=4.6 Hz).