Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:8]1[CH:12]=[CH:11][NH:10][C:9]=1[CH2:13][OH:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:15][C:16]1[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][C:17]=1[NH:26][CH:27]([CH:31]([CH3:33])[CH3:32])[C:28](O)=[O:29].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.C(Cl)Cl.CN(C)C=O>[CH3:15][C:16]1[CH:21]=[C:20]([C:22]([F:24])([F:25])[F:23])[CH:19]=[CH:18][C:17]=1[NH:26][CH:27]([CH:31]([CH3:33])[CH3:32])[C:28]([O:14][CH2:13][C:9]1[NH:10][CH:11]=[CH:12][C:8]=1[CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:29]
Reactant: OCc1[nH]ccc1Cc1ccccc1
Reactant: Cc1cc(C(F)(F)F)ccc1NC(C(=O)O)C(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1cc(C(F)(F)F)ccc1NC(C(=O)OCc1[nH]ccc1Cc1ccccc1)C(C)C
Reaction time: 2 h

Procedure:
To a stirred solution of 3-benzylpyrrolylmethyl alcohol (1.8 mmol), 2-(2-methyl-4-trifluoromethylphenylamino)-3-methylbutanoic acid (2.0 mmol) and 4-dimethylaminopyridine (0.65 mmol) in 20 ml of methylene chloride and 2 ml of dimethylformamide is added N,N'-dicyclohexylcarbodiimide (2.0 mml). The reaction mixture is stirred, under nitrogen, for two hours and then filtered and extracted with water. The aqueous phase is extracted with ether. The combined organic phases are washed with saturated aqueous sodium bicarbonate, water and saturated aqueous sodium chloride, dried over calcium sulfate and solvent evaporated. The crude product is chromatographed on a rotary chromatograph eluting with 25% ether/hexane to yield 3-benzylpyrrolylmethyl 2-(2-methyl-4-trifluoromethylphenylamino)-3-methylbutanoate.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][C:9](=[CH2:29])[CH2:10][C:11]1([C:24]([O:26]CC)=[O:25])[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]1>ClCCl>[CH3:8][C:9]1([CH3:29])[CH2:10][C:11]2([CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[C:24](=[O:26])[O:25]1
Reactant: C=C(C)CC1(C(=O)OCC)CCN(C(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)CC2(CCNCC2)C(=O)O1
Reaction time: 8 h
Yield: 87.2 %

Procedure:
Trifluoroacetic acid (50 mL) was added to a solution of 1-(1,1-dimethylethyl) 4-ethyl 4-(2-methyl-2-propenyl)-1,4-piperidinedicarboxylate (Description 89, 10.86 g, 35 mmol) in dichloromethane (10 mL) and the mixture was stirred at 50 C for 8 hours. The mixture was cooled and the solvent was evaporated under reduced pressure. Ether (50 mL) was added and the mixture was extracted with hydrochloric acid (1M, 3×50 mL). The combined aqueous fractions were washed with ether (2×50 mL), adjusted to pH 12 with aqueous sodium hydroxide (4M) and the mixture was extracted with ethyl acetate (6×50 mL). The combined organic fractions were dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was dissolved in ethanol (50 mL), cooled in ice and and ethereal hydrogen chloride (1M, 35 mL) was added slowly. The solvent was evaporated under reduced pressure, ethanol (75 mL) was added and the mixture was heated under reflux for 15 minutes. The mixture was cooled and the solid was collected and dried in vacuo to give the title compound as a colorless solid (5.59 g, 73%), m.p.>280° C. m/z (ES+) 184 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[NH:11][C:10]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[OH:26])=[N:9]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:33](Br)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>C(O)C.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:33]([O:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[C:10]1[NH:9][CH:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[CH:12]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[N:11]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: Oc1ccccc1C1=NC(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1
Reactant: BrCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CCO
Product: Clc1ccc(C2N=C(c3ccccc3OCc3ccccc3)NC2c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Yield: 44 %

Procedure:
To a solution of 2-[4,5-bis-(4-chloro-phenyl)-4,5-dihydro-1H-imidazol-2-yl]-phenol (30 mg, 0.0783 mmol) in 3 mL of ethanol were added potassium carbonate (16 mg, 0.117 mmol), benzyl bromide (11 μL, 0.0940 mmol) and tetrabutylammonium iodide (3 mg, 0.1 mmol). The reaction mixture was heated at gentle reflux for 54 h. Additional benzyl bromide (11 μL) and potassium carbonate (16 mg) were added after every 24-hr. Upon cooling to room temperature, the solvent was removed and the residue was taken in methylene chloride. The solution was washed with water, brine and dried over anhydrous sodium sulfate. The solid was then filtered off, and the filtrate was concentrated in vacuo. Purification of the crude residue by flash chromatography (Biotage, KP-Sil™ 32-63 μm, 60 Å silica gel) eluting with 1-6% methanol in methylene chloride yielded 2-(2-benzyloxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-1H-imidazole (16.3 mg, 44%). HR-MS (ES, m/z) calculated for C28H23N2OCl2 [(M+H)+] 473.1185, observed 473.1183.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:20]([C:21]3[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=3)=[C:19](Cl)[N:18]=[CH:17][N:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH:29][CH2:30][CH2:31][N:32]([CH3:43])[S:33]([C:36]1[C:37]([CH3:42])=[CH:38][CH:39]=[CH:40][CH:41]=1)(=[O:35])=[O:34]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:20]([C:21]3[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=3)=[C:19]([O:29][CH2:30][CH2:31][N:32]([S:33]([C:36]3[C:37]([CH3:42])=[CH:38][CH:39]=[CH:40][CH:41]=3)(=[O:35])=[O:34])[CH3:43])[N:18]=[CH:17][N:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(-c2c(Cl)ncnc2NS(=O)(=O)c2ccc(C(C)(C)C)cc2)cc1
Reactant: Cc1ccccc1S(=O)(=O)N(C)CCO
Product: Cc1ccc(-c2c(NS(=O)(=O)c3ccc(C(C)(C)C)cc3)ncnc2OCCN(C)S(=O)(=O)c2ccccc2C)cc1

Procedure:
According to Example 24d) 100 mg 4-tert.-butyl-N-[6-chloro-5-(p-tolyl)-4-pyrimidinyl]-benzene sulfonamide was reacted with N-(2-hydroxyethyl)-N-methyl-toluenesulfonamide to give 14 mg 4-tert.-butyl-N-{6-[2-(toluene-sulfonyl-methyl-amino)-ethoxy]-5-p-tolyl-pyrimidin-4-yl}-benzenesulfonamide. LC-MS: tR=6.18 min, [M−1]−=607.54.
Reaction SMILES: CO[C:3]([C:5]1[NH:6][N:7]=[C:8]([O:10][CH2:11][C:12]2[C:13]([CH2:18][CH2:19][CH2:20][CH3:21])=[N:14][O:15][C:16]=2[CH3:17])[CH:9]=1)=[O:4].[NH2:22][CH:23]1[CH2:27][CH2:26][O:25][CH2:24]1>>[O:25]1[CH2:26][CH2:27][CH:23]([NH:22][C:3]([C:5]2[NH:6][N:7]=[C:8]([O:10][CH2:11][C:12]3[C:13]([CH2:18][CH2:19][CH2:20][CH3:21])=[N:14][O:15][C:16]=3[CH3:17])[CH:9]=2)=[O:4])[CH2:24]1
Reactant: NC1CCOC1
Reactant: CCCCc1noc(C)c1COc1cc(C(=O)OC)[nH]n1
Product: CCCCc1noc(C)c1COc1cc(C(=O)NC2CCOC2)[nH]n1
Yield: 48 %

Procedure:
As described for example 26d, 5-(3-butyl-5-methyl-isoxazol-4-ylmethoxy)-2H-pyrazole-3-carboxylic acid methyl ester (492 mg, 1.7 mmol) was converted, using rac-3-aminotetrahydrofuran instead of 4-aminotetrahydropyran, to the title compound (280 mg, 48%) which was obtained as a colorless oil. MS: m/e=349.2 [M+H]+.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH:6]2[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)[N:3]=[CH:2]1.C(=O)([O-])[O-].[K+].[K+].[F:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Cl)=[CH:21][CH:20]=1>CN(C)C=O>[F:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][N:9]2[CH2:10][CH2:11][CH:6]([C:4]3[N:3]=[CH:2][NH:1][CH:5]=3)[CH2:7][CH2:8]2)=[CH:21][CH:20]=1
Reactant: c1nc(C2CCNCC2)c[nH]1
Reactant: Fc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Fc1ccc(CN2CCC(c3c[nH]cn3)CC2)cc1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a solution of 1.5 g of 4-(4-imidazolyl)piperidine in 75 cm3 of dimethyl formamide, 2 g of potassium carbonate and 1.5 g of p-fluorobenzyl chloride are added. The mixture is then heated to 80° C. with stirring for 2 hours. The mixture is filtered and the filtrate evaporated under reduced pressure. The residue is recrystallized in acetonitrile. White crystals, M.p. 232° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18](=[O:19])[N:17]2[C:12]([C:13]([CH3:21])([CH3:20])[O:14][CH2:15][CH2:16]2)=[N:11][C:10]=1[C:22]([NH:24][CH:25]([C:34]#[N:35])[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=1)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(Cl)(Cl)[Cl:37].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C(#N)C.CCOCC>[CH2:1]([O:8][C:9]1[C:18](=[O:19])[N:17]2[C:12]([C:13]([CH3:20])([CH3:21])[O:14][CH2:15][CH2:16]2)=[N:11][C:10]=1[C:22]1[NH:24][C:25]([CH2:26][C:27]2[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=2)=[C:34]([Cl:37])[N:35]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClC(Cl)(Cl)Cl
Reactant: CC1(C)OCCn2c1nc(C(=O)NC(C#N)Cc1ccc(F)cc1)c(OCc1ccccc1)c2=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: CC#N
Product: CC1(C)OCCn2c1nc(-c1nc(Cl)c(Cc3ccc(F)cc3)[nH]1)c(OCc1ccccc1)c2=O
Temperature: 45 °C
Reaction time: 18 h
Yield: 64 %

Procedure:
(procedure adapted from Org. Lett. 2004, 6, 629-631). To a solution of 3-(benzyloxy)-N-(1-cyano-2-(4-fluorophenyl)ethyl)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide (0.48 g, 1.01 mmol, 1.0 equiv) and CCl4 (0.24 mL, 2.52 mmol, 2.5 equiv) in acetonitrile (10 mL) under a nitrogen atmosphere, was added PPh3 (0.39 g, 2.52 mmol, 2.5 equiv). The reaction was heated to 45° C. (oil bath). After stirring 18 h, the reaction was cooled to ambient temperature and concentrated in vacuo. The residue was treated with CH2Cl2 (10 mL) and 0.5 M NaOH (20 mL) and stirred vigorously. After stirring 4 h, the mixture was poured into water and extracted with CH2Cl2 (×3). The combined CH2Cl2 extracts were dried (Na2SO4) and concentrated in vacuo. The crude product was purified by silica gel chromatography (20-80% ethyl acetate/hexane) to provide a viscous yellow oil. This oil was taken up in ether and seeded with a crystal of previously isolated material. After crystallization, the solid was filtered to provide the title compound (0.32 g, 64% yield) as an off-white solid. 1H NMR (400 MHz, CDCl3) δ ppm 10.17 (s, 1H), 7.28-7.41 (m, 5H), 6.91-6.96 (m, 4H), 5.27 (s, 2H), 3.95-4.11 (m, 4H), 3.77 (s, 2H), 1.67 (s, 6H); LCMS (ES+, (M+H)+) m/z 495.14.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[C:7]([O:11][C:12]([N:14]1[CH2:19][CH2:18][CH:17]([C:20]([C:23]2[S:24][C:25]([CH2:29][O:30][CH3:31])=[CH:26][C:27]=2Br)=[N:21][OH:22])[CH2:16][CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8]>COCCO.[Cu](I)I>[C:7]([O:11][C:12]([N:14]1[CH2:19][CH2:18][CH:17]([C:20]2[C:23]3[S:24][C:25]([CH2:29][O:30][CH3:31])=[CH:26][C:27]=3[O:22][N:21]=2)[CH2:16][CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8]
Reactant: COCc1cc(Br)c(C(=NO)C2CCN(C(=O)OC(C)(C)C)CC2)s1
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCO
Product: COCc1cc2onc(C3CCN(C(=O)OC(C)(C)C)CC3)c2s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Add cesium carbonate (1.13 g, 3.46 mmol, 1.50 equivalents) and copper iodide (44 mg, 0.23 mmol, 0.10 equivalents) to a stirred solution of 4-[1-(3-bromo-5-methoxymethyl-thiophen-2-yl)-1-hydroxyimino-methyl]-piperidine-1-carboxylic acid tert-butyl ester (1.00 g, 2.31 mmol, 1.00 equivalents) in 2-methoxy ethanol (23.30 mL). Stir the resulting mixture at room temperature overnight or up to 3 days and filter through celite. Evaporate the filtrate, partition the residue between ethyl acetate (70 mL) and water (23 mL) and separate. Extract the aqueous layer with ethyl acetate (3×70 mL), combine the organic layers, dry over magnesium sulfate, filter and evaporate. Purify the residue via flash column chromatography eluting with a mixture of hexane: ethyl acetate (4:1) to yield the desired product as a yellow oil. LC/MS (ESI), m/e 375 (MNa+), retention time 1.98 minutes. Condition II.
Reaction SMILES: [CH2:1]1[N:6](C(OCC)=O)[CH2:5][CH2:4][N:3]2[C:12]3[CH:18]=[CH:17][C:16]([C:19]([O:21]CC)=[O:20])=[CH:15][C:13]=3[N:14]=[C:2]12.[OH-].[Na+].O.Cl>C(O)C>[CH2:1]1[NH:6][CH2:5][CH2:4][N:3]2[C:12]3[CH:18]=[CH:17][C:16]([C:19]([OH:21])=[O:20])=[CH:15][C:13]=3[N:14]=[C:2]12
Reactant: CCOC(=O)c1ccc2c(c1)nc1n2CCN(C(=O)OCC)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1ccc2c(c1)nc1n2CCNC1
Yield: 67 %

Procedure:
Diethyl 3,4-dihydro-1H-benzo[4,5]imidazo[1,2-a]pyrazine-2,8-dicarboxylate (500 mg, 1.58 mmol) prepared in the Step 38-1-3 was suspended in ethanol (3.2 ml), and a 1 mol/L sodium hydroxide aqueous solution (1.6 ml) and then purified water (1.6 ml) were added thereto. The mixture was heated under reflux for 48 hours. After being allowed to cool, the mixture was neutralized with 3-N hydrochloric acid. The precipitate was separated by filtration and dried to give the title compound (230 mg, 67%) as a light-brown powder.
Reaction SMILES: C[O:2][C:3](=O)/[CH:4]=[C:5](\[C:8]1[CH:25]=[CH:24][C:11]2[C:12]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:13]([CH2:15][CH3:16])[O:14][C:10]=2[CH:9]=1)/[CH2:6][CH3:7].[H-].C([Al+]CC(C)C)C(C)C>CCOCC>[CH2:17]([C:12]1[C:11]2[CH:24]=[CH:25][C:8](/[C:5](/[CH2:6][CH3:7])=[CH:4]\[CH2:3][OH:2])=[CH:9][C:10]=2[O:14][C:13]=1[CH2:15][CH3:16])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CC/C(=C/C(=O)OC)c1ccc2c(Cc3ccccc3)c(CC)oc2c1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: CCOCC
Product: CC/C(=C/CO)c1ccc2c(Cc3ccccc3)c(CC)oc2c1
Temperature: -47.5 °C
Reaction time: 1 h

Procedure:
Z-3-(3-Benzyl-2-ethyl-benzofuran-6-yl)-pent-2-enoic acid methyl ester (6.0 g; 0.0173 mol) was dissolved in ether (200 mL) and the mixture was cooled to −45 to −50° C. Diisobutyl-aluminum hydride (100 mL of 1M solution in THF; 0.1 mol) was added dropwise. The mixture was stirred at −45 to −50° C. for 1 hour then at room temperature for 18 hours. The mixture was poured over a mixture of ice/2N HCl solution and extracted with ethyl acetate and ether, washed with 2N HCl and water, dried over anhydrous magnesium sulfate and solvent evaporated. The residue was purified by flash chromatography on silica gel using 4% ethyl acetate in Hexane as an eluent. The title compound was obtained (4.7 g) as an oil. 1HNMR (400 MHz, DMSO-d6): δ 0.88 (t, 2H, J=7.25 Hz), 1.22 (t, 3H, J=7.47 Hz), 2.37 (q, 2H, J=7.47 Hz), 2.84 (q, 3H, J=7.47 Hz), 3.81 (d, 2H, J=6.59 Hz), 3.96 (s, 2H), 4.5 (brs, 1H), 5.56 (t, 1H, J=6.59 Hz), 6.93 (dd, 1H, J=7.9, 1.32 Hz), 7.18-7.2 (m, 1H), 7.22-7.26 (m, 5H), 7.31 (d, 1H, J=7.9 Hz).
Reaction SMILES: Br[C:2]1[C:3]2[O:12][CH:11]=[N:10][C:4]=2[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[CH:13]1([CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][C:19]=2B2OC(C)(C)C(C)(C)O2)[CH2:15][CH2:14]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH:13]1([CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][C:19]=2[C:2]2[C:3]3[O:12][CH:11]=[N:10][C:4]=3[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=2)[CH2:14][CH2:15]1
Reactant: Cn1cc(Br)c2ocnc2c1=O
Reactant: CC1(C)OB(c2cc(S(C)(=O)=O)ccc2OCC2CC2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: Cn1cc(-c2cc(S(C)(=O)=O)ccc2OCC2CC2)c2ocnc2c1=O
Temperature: 60 °C
Yield: 18.4 %

Procedure:
The title compound of step 5 (60 mg, 0.3 mmol) in dioxane (2 mL) and H2O (0.4 mL) was stirred at 15° C. under N2 for 30 min. Pd(dppf)Cl2 (19 mg, 0.026 mmol), the title compound of Example 90, step 1 (120 mg, 0.3 mmol) and K3PO4 (166 mg, 0.8 mmol,) were added at 15° C. under N2. The reaction mixture was heated at 60° C. for 12 h. Purification by silica gel chromatography (EA) and preparative HPLC gave the title compound (20.63 mg, 20%) as a yellow solid. 1H NMR (CDCl3, 400 MHz) δ 8.03 (d, J=2.0 Hz, 1H), 8.02 (s, 1H), 7.96 (dd, J1=8.4 Hz, J2=2.0 Hz, 1H), 7.09 (d, J=8.4 Hz, 1H), 3.96 (d, J=6.8 Hz, 2H), 3.76 (s, 3H), 3.1 (s, 3H), 1.18 (m, 1H), 0.60 (m, 2H), 0.30 (m, 2H). LCMS: 375.1 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:10]=2[OH:17])=[CH:4][CH:3]=1.[NH3:19]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[NH:19])[C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:10]=2[OH:17])=[CH:4][CH:3]=1
Reactant: N
Reactant: COc1ccc(C(=O)c2ccc(Cl)cc2)c(O)c1
Solvent: CO
Product: COc1ccc(C(=N)c2ccc(Cl)cc2)c(O)c1

Procedure:
A suspension of 132 g. of 4'-chloro-2-hydroxy-4-methoxy-benzophenone in 500 ml. of methanol is cooled to -20° C. in a 2l. shaking autoclave and treated with 120 ml. of liquid ammonia. The mixture is then shaken at 120° C. for 20 hours under a nitrogen atmosphere. After cooling, the yellow crude product is filtered off under suction and washed with a small amount of methanol. There is obtained 4'-chloro-2-hydroxy-4-methoxy-benzophenone imine, having a melting point of 210°-212° C., which can be used in the next step without further purification. An analytical sample is obtained by recrystallization from methanol and has a melting point of 212°-214° C.
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([F:16])[CH:14]=2)[C:9](=[O:17])[N:8]([CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C:7]=1[C:23](OCC)=[O:24])[CH2:2][CH2:3][CH3:4].[OH-].[Na+].Cl.C(Cl)(=O)C(Cl)=O.[BH4-].[Na+]>O1CCCC1.C(O)C.CN(C)C=O.COCCOC.O>[CH2:1]([O:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([F:16])[CH:14]=2)[C:9](=[O:17])[N:8]([CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C:7]=1[CH2:23][OH:24])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1c(C(=O)OCC)n(CC(C)(C)C)c(=O)c2ccc(F)cc12
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Agent: [BH4-]
Solvent: COCCOC
Solvent: O
Solvent: CN(C)C=O
Product: CCCCOc1c(CO)n(CC(C)(C)C)c(=O)c2ccc(F)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 57 %

Procedure:
To a solution of ethyl 4-butoxy-6-fluoro-2-neopentyl-1-oxo-1,2-dihydro-3-isoquinolinecarboxylate (3.40 g, 9 mmol) in tetrahydrofuran (20 ml) and ethanol (20 ml) was added sodium hydroxide (1.08 g, 27 mmol). The obtained mixture was refluxed under heating for 12 h. The reaction mixture was poured into water and acidified with 1N hydrochloric acid and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (20 ml) and oxalyl chloride (0.9 ml, 10.8 mmol) and N,N-dimethylformamide (2 drops) were added thereto. The mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in tetrahydrofuran (20 ml). The obtained solution was added dropwise to a suspension of sodium tetrahydroborate (1.13 g, 30 mmol) in 1,2-dimethoxyethane (20 ml) at 0° C. The obtained mixture was stirred at 0° C. for 1 h. The reaction mixture was poured into 1N hydrochloric acid and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography and the component eluted earlier was concentrated to give 4-butoxy-6-fluoro-3-hydroxymethyl-2-neopentyl-1(2H)-isoquinolinone (1.72 g, 57.1%) as crystals.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:13]=[C:14]3[CH2:19][CH2:18][CH2:17][CH2:16][N:15]3[CH:20]=2)=[CH:8][CH:7]=1.[NH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>>[N:21]1([CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]3[N:13]=[C:14]4[CH2:19][CH2:18][CH2:17][CH2:16][N:15]4[CH:20]=3)=[CH:8][CH:7]=2)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: ClCCCOc1ccc(-c2cn3c(n2)CCCC3)cc1
Reactant: C1CCNCC1
Product: c1cc(-c2cn3c(n2)CCCC3)ccc1OCCCN1CCCCC1
Temperature: 25 °C

Procedure:
The product of Step B (83 mg) and piperidine (1.0 mL) were heated at 100° C. for 1.5 hours. The reaction was cooled to ambient temperature and partitioned between ethyl acetate (10 mL) and saturated sodium bicarbonate solution (10 mL). The aqueous portion was extracted with a fresh portion of ethyl acetate (2×10 mL) and the organic portions combined and washed with brine (10 mL). The organic portions were dried over magnesium sulfate, filtered and evaporated. The residue was purified via silica gel chromatography (dichloromethane/methanol) to give the title compound (35 mg). 1H-NMR (CDCl3) δ 7.61 (m, 2H), 7.16 (s, 1H), 6.92 (m, 2H), 4.01 (m, 4H), 2.84 (t, J=6.0 Hz, 2H), 2.72 (m, 6H), 2.00 (m, 6H), 1.68 (m, 4H), 1.56 (m, 2H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12](C=O)=[C:11]([O:17][CH:18]([CH3:20])[CH3:19])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:21]O>OS(O)(=O)=O.CO.O>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([OH:21])=[C:11]([O:17][CH:18]([CH3:20])[CH3:19])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OO
Reactant: CC(C)Oc1cc(OCc2ccccc2)ccc1C=O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CO
Product: CC(C)Oc1cc(OCc2ccccc2)ccc1O

Procedure:
A solution of 4-(benzyloxy)-2-isopropoxybenzaldehyde (2.76 g, 10.21 mmol) and 30 wt % hydrogen peroxide (1.35 mL, 13.07 mmol) in conc. H2SO4 (0.204 mL) and MeOH (20.4 mL) was stirred for 3 h at 25° C. under N2. After this time the mixture was diluted with water (20 mL) and extracted with CH2Cl2 (3×30 mL). The combined extracts were dried (MgSO4) and concentrated in vacuo to afford 4-(benzyloxy)-2-isopropoxyphenol, as a colorless oil. LCMS calc.=281.1; found=281.0 (M+Na)+.
Reaction SMILES: [F:1][C@@H:2]1[C:22]2[C@:17]([CH3:24])([CH:18]=[CH:19][C:20](=[O:23])[CH:21]=2)[C@@H:16]2[C@H:4]([C@H:5]3[C@:13]([CH3:26])([CH2:14][C@@H:15]2[OH:25])[C@@H:8]([C:9](=[O:12])[CH:10]=[O:11])[C@H:7]([CH3:27])[CH2:6]3)[CH2:3]1.ClCC[OH:31]>>[F:1][C@@H:2]1[C:22]2[C@:17]([CH3:24])([CH:18]=[CH:19][C:20](=[O:23])[CH:21]=2)[C@@H:16]2[C@H:4]([C@H:5]3[C@:13]([CH3:26])([CH2:14][C@@H:15]2[OH:25])[C@@H:8]([C:9](=[O:12])[C:10]([OH:31])=[O:11])[C@H:7]([CH3:27])[CH2:6]3)[CH2:3]1
Reactant: OCCCl
Reactant: C[C@@H]1C[C@H]2[C@@H]3C[C@H](F)C4=CC(=O)C=C[C@]4(C)[C@H]3[C@@H](O)C[C@]2(C)[C@H]1C(=O)C=O
Product: C[C@@H]1C[C@H]2[C@@H]3C[C@H](F)C4=CC(=O)C=C[C@]4(C)[C@H]3[C@@H](O)C[C@]2(C)[C@H]1C(=O)C(=O)O

Procedure:
5.0 g. of 6α-fluoro-11β-hydroxy-3,20-dioxo-16α-methyl-1,4-pregnadien-21-al is reacted, under the conditions set forth in Example 46, but with 2-chloroethanol in place of 2-fluoroethanol, and then worked up. The crude product is chromatographed on silica gel. With 25-29% acetone-hexane, 2.19 g. of the 2-chloroethyl ester of 6α-fluoro-11β-hydroxy-3,20-dioxo-16α-methyl-1,4-pregnadien-21-oic acid is obtained, m.p. 174.8° C. [α]D25 = +135°. UV: ε242 = 17,100 (methanol).
Reaction SMILES: C(N(C(C)C)CC)(C)C.[CH2:10]([SH:14])[CH2:11][CH2:12][CH3:13].Br[C:16]1[C:17](=[O:33])[C:18]2[S:22][C:21]([CH3:23])=[N:20][C:19]=2[C:24](=[O:32])[C:25]=1[NH:26][CH2:27][CH2:28][N:29]([CH3:31])[CH3:30]>C(O)C>[CH2:10]([S:14][C:16]1[C:17](=[O:33])[C:18]2[S:22][C:21]([CH3:23])=[N:20][C:19]=2[C:24](=[O:32])[C:25]=1[NH:26][CH2:27][CH2:28][N:29]([CH3:30])[CH3:31])[CH2:11][CH2:12][CH3:13]
Reactant: CCCCS
Reactant: Cc1nc2c(s1)C(=O)C(Br)=C(NCCN(C)C)C2=O
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CCCCSC1=C(NCCN(C)C)C(=O)c2nc(C)sc2C1=O
Temperature: 60 °C
Reaction time: 24 h

Procedure:
20 μl (0.115 mmol; 1.2 eq.) of diisopropylethylamine and 16 μl (0.154 mmol; 1.6 eq.) of butanethiol are added to 33 mg (96 μmol) of the compound of Example 35 in solution in 4 ml of anhydrous ethanol. The reaction mixture is maintained under stirring for 24 hours at 60° C., then after concentration under reduced pressure, the residue is purified by chromatography on a silica column (eluent: dichloromethane/methanol 95/5) and the expected product is obtained, after taking up in ethyl ether, in the form of a violet-coloured powder.