Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:3]([C:8]#[N:9])=[N:4][CH:5]=[CH:6][CH:7]=1.[C:10]([O:14][CH3:15])(=[O:13])[CH2:11][SH:12].C([O-])([O-])=O.[K+].[K+]>C(#N)C>[CH3:15][O:14][C:10]([C:11]1[S:12][C:2]2[C:3](=[N:4][CH:5]=[CH:6][CH:7]=2)[C:8]=1[NH2:9])=[O:13]
Reactant: N#Cc1ncccc1Cl
Reactant: COC(=O)CS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1sc2cccnc2c1N

Procedure:
To a solution of compound 145-C (23.41 g, 169.0 mmol) in acetonitrile (170 mL) was added methyl thioglycolate (16.2 mL, 178 mmol) and K2CO3 (46.72 g, 338 mmol). The mixture was heated under reflux for 3 h then filtered hot and the filter cake rinsed with acetonitrile. The filter cake was suspended in refluxing acetonitrile, filtered hot, and rinsed with additional acetonitrile. The combined filtrates were evaporated in vacuo, the residue triturated with warm water (250 mL), filtered, and rinsed with water. The solid was dissolved in warm methanol (500 mL), treated with charcoal, filtered, and evaporated in vacuo. The residue was triturated with ethanol (25 mL), filtered, washed with ethanol (25 mL), and dried in vacuo to afford compound 145-D as a brown powder (21.65 g, 62%). 1H-NMR (DMSO-d6): δ 3.83 (s, 3H), 6.91 (s, 2H), 7.52-7.59 (m, 1H), 8.40 (dd, 1H), 8.69 (dd, 1H); MS: m/z 209.1 (MH+).
Reaction SMILES: [C:1]([C:5]1[CH:11]=[C:10]([SH:12])[CH:9]=[C:8]([CH3:13])[C:6]=1[NH2:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:21]([O:32][CH2:33][CH2:34][CH2:35][CH3:36])(=[O:31])/[CH:22]=[CH:23]\[C:24]([O:26][CH2:27][CH2:28][CH2:29][CH3:30])=[O:25]>C1(C)C=CC=CC=1>[NH2:7][C:6]1[C:8]([CH3:13])=[CH:9][C:10]([S:12][CH:22]([CH2:23][C:24]([O:26][CH2:27][CH2:28][CH2:29][CH3:30])=[O:25])[C:21]([O:32][CH2:33][CH2:34][CH2:35][CH3:36])=[O:31])=[CH:11][C:5]=1[C:1]([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCCOC(=O)/C=C\C(=O)OCCCC
Reactant: Cc1cc(S)cc(C(C)(C)C)c1N
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCCCOC(=O)CC(Sc1cc(C)c(N)c(C(C)(C)C)c1)C(=O)OCCCC
Temperature: 25 °C
Reaction time: 18 h
Yield: 27.8 %

Procedure:
To a stirred solution of 1.00 g (5.1 mmol) of 2-tert-butyl-4-mercapto-6-methylaniline and 0.05 g (0.5 mmol) of triethylamine in 5 mL of toluene at room temperature is added dropwise a solution of 1.16 g (5.1 mmol) of di-n-butyl maleate in 5 mL of toluene. The reaction mixture is stirred for 18 hours at room temperature. The solvent is removed in vacuo and the crude product is purified by flash column chromatography (silica gel, 85:15, heptane:ethylacetate eluent) to give 0.60 g (28%) of the title compound as a colorless liquid.
Reaction SMILES: [OH:1][NH:2][C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6].[CH2:10]([N:12]([CH2:16][CH3:17])[C:13](Cl)=[O:14])[CH3:11]>>[CH2:10]([N:12]([CH2:16][CH3:17])[C:13](=[O:14])[O:1][NH:2][C:3]([O:4][C:5]([CH3:8])([CH3:7])[CH3:6])=[O:9])[CH3:11]
Reactant: CC(C)(C)OC(=O)NO
Reactant: CCN(CC)C(=O)Cl
Product: CCN(CC)C(=O)ONC(=O)OC(C)(C)C

Procedure:
[(tert-Butoxy)carbonyl]amino N,N-diethylcarbamate is prepared from tert-butyl N-hydroxycarbamate and diethyl carbamoyl chloride according to Scheme 1. (0.67 g, 39%), 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 7.84 (1H, br. s.), 3.33 (4H, q, 7.1 Hz), 1.48 (9H, s), 1.11-1.28 (6H, m).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][CH:6]=[CH:5]2.C(OCC)(=O)C.O.[CH3:19][N:20](C)C=O>[C-]#N.[Zn+2].[C-]#N.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>[CH:8]1[C:9]2[C:4](=[CH:3][C:2]([C:19]#[N:20])=[CH:11][CH:10]=2)[CH:5]=[CH:6][N:7]=1
Reactant: CN(C)C=O
Reactant: Brc1ccc2cnccc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Solvent: CCOC(C)=O
Product: N#Cc1ccc2cnccc2c1
Temperature: 100 °C
Reaction time: 1 h
Yield: 83 %

Procedure:
Next, to a solution of 6-bromoisoquinoline (382 mg, 1.84 mmol) in N,N-dimethylformamide (3.8 mL) were added zinc cyanide (431 mg, 3.67 mmol) and tetrakis(triphenylphosphine)palladium(0) (42 mg, 0.0367 mmol) under nitrogen atmosphere, and the mixture was stirred at 100° C. for 1 hour. Tetrakis(triphenylphosphine)palladium(0) (42 mg, 0.0367 mmol) was further added, and the mixture was stirred for 2.5 hours at 100° C. The reaction mixture was allowed to room temperature, ethyl acetate and water were added for extraction, the organic layer was washed with water and dried over anhydrous magnesium sulfate. The residue was purified by silica gel column chromatography (hexane:ethyl acetate), and isoquinoline-6-carbonitrile (234 mg, 83%) was obtained as a yellow solid.
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[N:7][C:8]([O:11][CH2:12][C:13]2[C:14]([CH2:19][CH2:20][CH2:21][CH3:22])=[N:15][O:16][C:17]=2[CH3:18])=[CH:9][CH:10]=1)=[O:4].[NH2:23][CH2:24][C:25]([CH3:28])([OH:27])[CH3:26]>C1(C)C=CC=CC=1>[OH:27][C:25]([CH3:28])([CH3:26])[CH2:24][NH:23][C:3]([C:5]1[N:6]=[N:7][C:8]([O:11][CH2:12][C:13]2[C:14]([CH2:19][CH2:20][CH2:21][CH3:22])=[N:15][O:16][C:17]=2[CH3:18])=[CH:9][CH:10]=1)=[O:4]
Reactant: CCCCc1noc(C)c1COc1ccc(C(=O)OC)nn1
Reactant: CC(C)(O)CN
Solvent: Cc1ccccc1
Product: CCCCc1noc(C)c1COc1ccc(C(=O)NCC(C)(C)O)nn1
Temperature: 25 °C
Reaction time: 15 h
Yield: 69 %

Procedure:
A mixture of 6-(3-butyl-5-methyl-isoxazol-4-ylmethoxy)-pyridazine-3-carboxylic acid methyl ester (110 mg, 0.36 mmol), 1-amino-2-methyl-propan-2-ol (39 mg, 0.43 mmol) and TBD (15 mg, 0.11 mmol) in toluene (0.5 mL) was stirred for 15 h at room temperature under argon. The reaction mixture was concentrated onto silica then purified by chromatography (silica, 0 to 5% methanol in dichloromethane) to afford the title compound (90 mg, 69%) as a colourless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:16][CH:17]2[CH2:20][C:19](=[O:21])[CH2:18]2)[C:13](Cl)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].[NH2:22][C:23]1[CH:27]=[CH:26][N:25]([CH2:28][C:29]([CH3:32])([OH:31])[CH3:30])[N:24]=1.N1C(C)=CC=CC=1C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:16][CH:17]2[CH2:20][C:19](=[O:21])[CH2:18]2)[C:13]([NH:22][C:23]2[CH:27]=[CH:26][N:25]([CH2:28][C:29]([OH:31])([CH3:30])[CH3:32])[N:24]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9]
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CC(=O)C2)C(=O)Cl)cc1Cl
Reactant: CC(C)(O)Cn1ccc(N)n1
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CC(C)(O)Cn1ccc(NC(=O)[C@H](CC2CC(=O)C2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 63 %

Procedure:
A solution of 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-(3-oxo-cyclobutyl)-propionyl chloride in methylene chloride (0.036 M solution, 5 mL, 0.18 mmol) was slowly added to a cooled to 0° C. solution of 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (prepared in Example 80, 31 mg, 0.20 mmol) and 2,6-lutidine (31 μl, 0.27 mmol) in methylene chloride (6 ml). The reaction continued to stir at 0° C. for 15 min and then at 25° C. for 4 h. After concentration in vacuo it was purified on an AnaLogix Intelliflash system (40 g column, 100% ethyl acetate) to afford 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-3-(3-oxo-cyclobutyl)-propionamide (54 mg, 63%) as an off-white solid: [α]30589=−6.60° (c=5.9, CHCl3); 1H NMR (300 MHz, DMSO-d6) δ ppm 1.03, 1.04 (2×s, 6H, 2×CH3), 1.93-2.40 (m, 3H, CH and CH2), 2.66-2.85 (m, 2H, 2×CH or 2×CH2), 2.98-3.12 (m, 2H, 2×CH or 2×CH2), 3.34 (s, 3H, SO2CH3), 3.87 (s, 2H, NCH2), 3.85-3.91 (m, 1H, ArCHCO2), 6.46 (d, J=2.3 Hz, 1H, Ar), 7.52 (d, J=2.3 Hz, 1H, Ar), 7.61 (dd, Jm=1.6 Hz, Jo=8.3 Hz, 1H, Ar), 7.73 (d, Jm=1.6 Hz, 1H, Ar), 8.02 (d, Jo=8.3 Hz, 1H, Ar), 10.84 (s, 1H, NH).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][C:8]2=O)[CH:2]=1.[NH2:14][N:15]1[CH2:19][CH2:18][CH2:17][C@H:16]1[CH2:20][O:21][CH3:22].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.C(OCC)C>[CH3:22][O:21][CH2:20][C@@H:16]1[CH2:17][CH2:18][CH2:19][N:15]1[N:14]=[C:8]1[CH2:9][CH2:10][CH2:11][CH2:12][CH:7]1[C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1
Reactant: O=C1CCCCC1c1cccnc1
Reactant: COC[C@@H]1CCCN1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: COC[C@@H]1CCCN1N=C1CCCCC1c1cccnc1

Procedure:
A mixture of 2-(pyrid-3-yl)cyclohexanone (20.6 g, 117.6 mmol), [S]-(-)-1-amino-2-(methoxymethyl)pyrrolidine (`SAMP`) (15.4 g, 118 mmol) and p-toluenesulphonic acid (316 mg) was refluxed in toluene (475 ml) for 4 hours. The toluene was removed in vacuo to afford an oil which was dissolved in diethyl ether (340ml) and washed with aqueous saturated sodium bicarbonate solution (2×170 ml). The organic phase was dried over magnesium sulphate then filtered and concentrated in vacuo to afford [2S]-2-(methoxymethyl)-1-[2-(pyrid-3-yl)cyclohexylidenamino]pyrrolidine (30.8 g, 113 mmol) as a 50:50 mixture of diastereoisomers;
Reaction SMILES: [CH2:1]([O:3][C:4](Cl)=[O:5])[CH3:2].[CH2:7]1[O:22][CH:10]([C:11]2[C:16]([O:17][CH3:18])=[C:15]([O:19][CH3:20])[CH:14]=[CH:13][C:12]=2[NH2:21])[O:9][CH2:8]1.[OH-].[Na+]>O1CCCC1.O>[CH2:8]1[O:9][CH:10]([C:11]2[C:16]([O:17][CH3:18])=[C:15]([O:19][CH3:20])[CH:14]=[CH:13][C:12]=2[NH:21][C:4]([O:3][CH2:1][CH3:2])=[O:5])[O:22][CH2:7]1
Reactant: CCOC(=O)Cl
Reactant: COc1ccc(N)c(C2OCCO2)c1OC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)Nc1ccc(OC)c(OC)c1C1OCCO1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Ethylchloroformate (1.9 g, 17.5 mM) is added with stirring to 2-amino-5,6-dimethoxybenzaldehyde-ethyleneketal (1.6 g, 7.1 mM) dissolved in tetrahydrofuran (50 ml). A solution of sodium hydroxide in H2O (0.72 g in 3.5 ml H2O) is added and the resulting solution is stirred for 2 hours at room temperature. The tetrahydrofuran is removed in vacuo and the residue extracted with CHCl3 (2×100 ml). The extracts are dried over Na2SO4, filtered, and the solvent removed in vacuo. The crude product is recrystallized from n-hexane; yield 1.2 g (57.1%); m.p. 95°-96° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4]([Cl:9])[CH:3]=1.[Mg].CON(C)[C:14]([C@@H:16]1[CH2:21][CH2:20][CH2:19][N:18]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:17]1)=[O:15]>C1COCC1>[Cl:9][C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][C:5]=1[F:8])[C:14]([C@@H:16]1[CH2:21][CH2:20][CH2:19][N:18]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:17]1)=[O:15]
Reactant: Fc1ccc(Br)cc1Cl
Reactant: CON(C)C(=O)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Agent: [Mg]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@@H](C(=O)c2ccc(F)c(Cl)c2)C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 92.2 %

Procedure:
A solution of 4-bromo-2-chloro-1-fluoro-benzene (31.3 g, 0.15 mol) in anhydrous THF (150 mL) was added dropwise to Mg (4.8 g, 0.2 mol) in THF (50 mL) at rt under nitrogen. The mixture was stirred at 50-60° C. for 1 hr at which time most of the magnesium was consumed. The resulting Grignard reagent was used for the next step. The Grignard reagent was added dropwise to a solution of (R)-tert-butyl 3-(methoxy(methyl)carbamoyl)piperidine-1-carboxylate (27.2 g, 0.1 mol) in anhydrous THF (300 mL) at −78° C. under nitrogen. After addition, the mixture was allowed to stir at rt for 1.5 hr. The mixture was quenched with saturated NH4Cl solution (300 mL) and extracted with EtOAc (3×200 mL). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo to give crude (R)-tert-butyl 3-(3-chloro-4-fluorobenzoyl)piperidine-1-carboxylate (31.5 g, 92%), which was used immediately for next step without purification.
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][C:10]=2[CH3:12])[N:5]([C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20]3[N:24](COCC[Si](C)(C)C)[C:23]4[CH:33]=[CH:34][CH:35]=[CH:36][C:22]=4[N:21]=3)=[CH:15][CH:14]=2)[C:4]1=[O:37])[CH3:2].[ClH:38]>CCO>[ClH:38].[ClH:38].[NH:21]1[C:22]2[CH:36]=[CH:35][CH:34]=[CH:33][C:23]=2[N:24]=[C:20]1[O:19][C:16]1[CH:17]=[CH:18][C:13]([N:5]2[C:6]3=[N:7][CH:8]=[CH:9][C:10]([CH3:12])=[C:11]3[N:3]([CH2:1][CH3:2])[C:4]2=[O:37])=[CH:14][CH:15]=1
Reactant: CCn1c(=O)n(-c2ccc(Oc3nc4ccccc4n3COCC[Si](C)(C)C)cc2)c2nccc(C)c21
Agent: Cl
Solvent: CCO
Product: CCn1c(=O)n(-c2ccc(Oc3nc4ccccc4[nH]3)cc2)c2nccc(C)c21
Temperature: 60 °C
Reaction time: 10 h

Procedure:
A mixture of 1-ethyl-7-methyl-3-{4-[(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazol-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (0.090 g) and 2N HCl in EtOH (5.0 ml) was stirred at 60° C. for 10 h. After cooling to room temperature, the solvent was removed. The residue was recrystallized from EtOH—AcOEt to give 3-[4-(1H-benzimidazol-2-yloxy)phenyl]-1-ethyl-7-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one dihydrochloride (0.040 g).
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[NH:6][C:5](=[O:7])[NH:4][C:3]1=[O:8].[Cl-].[Li+].CN(C)C=O.[CH:17]12[O:23][CH:18]1[CH2:19][CH2:20][CH2:21][CH2:22]2>CC(C)=O>[OH:23][CH:18]1[CH2:19][CH2:20][CH2:21][CH2:22][CH:17]1[N:4]1[C:3](=[O:8])[C:2]([CH3:9])([CH3:1])[NH:6][C:5]1=[O:7]
Reactant: CC1(C)NC(=O)NC1=O
Reactant: C1CCC2OC2C1
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: CC1(C)NC(=O)N(C2CCCCC2O)C1=O
Temperature: 60 °C

Procedure:
A mixture of 128.1 g of 5,5-dimethylhydantoin (1 mol), 1 g of lithium chloride and 200 ml of dimethylformamide is stirred at 100° C in a 500 ml glass apparatus having a stirrer, thermometer, dropping funnel and reflux condenser. 100 g of cyclohexene oxide (1.02 mols) are added dropwise to this solution over the course of 120 minutes, whilst stirring. Thereafter the mixture is stirred for a further 5 hours at 125°-130° C. After cooling to about 60° C, the reaction mixture is filtered and is concentrated to dryness on a rotary evaporator at 70° C under a waterpump vacuum. Thereafter the residue is dried to constant weight at 90° C/0.1 Hg. 217.8 g of a yellowish, crystalline material (96.4% of theory) are obtained, and this can be recrystallised, for example from acetone. The purified product melts at 159°-161° C. Elementary analysis shows the following values:
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH3:9][C:10]1[CH:11]=[C:12]([CH:14]=[C:15]([C:17]2[S:21][CH:20]=[N:19][CH:18]=2)[CH:16]=1)[NH2:13].[CH3:22][C:23]1([CH3:34])[CH:28]([CH3:29])[C:27](=[O:30])[CH2:26][CH2:25][CH:24]1[C:31]([OH:33])=[O:32]>C1COCC1.CCOC(C)=O>[NH2:13][C:12]1[CH:14]=[C:15]([C:17]2[S:21][C:20]([C:27]3([OH:30])[CH2:26][CH2:25][CH:24]([C:31]([OH:33])=[O:32])[C:23]([CH3:22])([CH3:34])[CH:28]3[CH3:29])=[N:19][CH:18]=2)[CH:16]=[C:10]([CH3:9])[CH:11]=1
Reactant: CC1C(=O)CCC(C(=O)O)C1(C)C
Reactant: Cc1cc(N)cc(-c2cncs2)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1cc(N)cc(-c2cnc(C3(O)CCC(C(=O)O)C(C)(C)C3C)s2)c1
Temperature: -60 °C
Reaction time: 0.5 h
Yield: 12.3 %

Procedure:
Lithium diisopropylamide (5110 μl, 9.20 mmol) was added to a −78° C. solution of 3-methyl-5-(1,3-thiazol-5-yl)aniline (500 mg, 2.63 mmol) in THF (7 mL). The reaction was allowed to warm to −60° C. while aging for 30 min. The solution was cooled to −78° C. and 2,2,3-trimethyl-4-oxocyclohexanecarboxylic acid (600 mg, 3.26 mmol) in THF (6 mL) was added portionwise, maintaining an internal temperature below −65° C. After 5 min at −78° C. the reaction was warmed to room temperature, diluted with EtOAc and washed with aqueous saturated ammonium chloride (3×). The combined aqueous portion was extracted with 10% IPA:CHCl3 (3×). The combined organic layers were dried under reduced pressure to yield 4-[5-(3-amino-5-methylphenyl)-1,3-thiazol-2-yl]-4-hydroxy-2,2,3-trimethylcyclohexanecarboxylic acid (121 mg, 12%) as a yellow oil. MS ESI: [M+H]+ m/z 375.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]=[C:10]([N:18]3[CH:22]=[C:21](I)[N:20]=[CH:19]3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:24]([NH:28][S:29]([C:32]1[S:33][C:34](B2OC(C)(C)C(C)(C)O2)=[CH:35][CH:36]=1)(=[O:31])=[O:30])([CH3:27])([CH3:26])[CH3:25]>>[C:24]([NH:28][S:29]([C:32]1[S:33][C:34]([C:21]2[N:20]=[CH:19][N:18]([C:10]3[N:9]=[C:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=4)[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]=3)[CH:22]=2)=[CH:35][CH:36]=1)(=[O:30])=[O:31])([CH3:27])([CH3:25])[CH3:26]
Reactant: FC(F)(F)c1cc(-c2cccc(Cl)c2)nc(-n2cnc(I)c2)n1
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)s1
Product: CC(C)(C)NS(=O)(=O)c1ccc(-c2cn(-c3nc(-c4cccc(Cl)c4)cc(C(F)(F)F)n3)cn2)s1

Procedure:
5-{1-[4-(3-Chloro-phenyl)-6-trifluoromethyl-pyrimidin-2-yl]-1H-imidazol-4-yl}-thiophene-2-sulfonic acid tert-butyl amide was prepared from 4-(3-chloro-phenyl)-2-(4-iodo-imidazol-1-yl)-6-trifluoromethyl-pyrimidine (example E.72) (0.68 g, 1.5 mmol) and N-tert-butyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-thiophene-2-sulfonamide (example F.1) (0.62 g, 1.8 mmol) according to the general procedure VI. Obtained as a light yellow solid (0.4 g), which was subsequently deprotected.
Reaction SMILES: [CH:1]([O:4][C@H:5]1[CH2:22][C@@:21]2([CH3:23])[C@@H:8]([CH2:9][CH2:10][C@@H:11]3[C@@H:20]2[CH2:19][CH2:18][C@@:16]2([CH3:17])[C@H:12]3[CH2:13][CH2:14][C:15]2=O)[CH2:7][C@@H:6]1[OH:25])([CH3:3])[CH3:2].[C:26]1([CH3:37])[CH:31]=[CH:30][C:29]([S:32]([NH:35][NH2:36])(=[O:34])=[O:33])=[CH:28][CH:27]=1.C(O)C>C(Cl)Cl>[S:32]([NH:35][N:36]=[C:15]1[CH2:14][CH2:13][C@H:12]2[C@H:11]3[C@H:20]([CH2:19][CH2:18][C@:16]12[CH3:17])[C@:21]1([CH3:23])[C@H:8]([CH2:7][C@H:6]([OH:25])[C@@H:5]([O:4][CH:1]([CH3:3])[CH3:2])[CH2:22]1)[CH2:9][CH2:10]3)([C:29]1[CH:28]=[CH:27][C:26]([CH3:37])=[CH:31][CH:30]=1)(=[O:33])=[O:34]
Reactant: Cc1ccc(S(=O)(=O)NN)cc1
Reactant: CC(C)O[C@H]1C[C@@]2(C)[C@@H](CC[C@@H]3[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]32)C[C@@H]1O
Solvent: ClCCl
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)NN=C2CC[C@H]3[C@@H]4CC[C@H]5C[C@H](O)[C@@H](OC(C)C)C[C@]5(C)[C@H]4CC[C@]23C)cc1
Yield: 107.7 %

Procedure:
To a mixture of 2β-isopropoxy-3α-hydroxy-5α-androstan-17-one (700 mg, 2.0 mmol) and p-toluenesulfonhydrazide (450 mg, 2.4 mmol) was added ethanol (2 mL) and the mixture obtained was heated to reflux for 12 h. Then the reaction mixture was dissolved in CH2Cl2 (150 mL) and washed with water (4×45mL). It was then dried over Na2SO4 and removal of the solvent in vacuo resulted in the crude 2β-isopropoxy-3α-hydroxy-5α-androstan-17-one tosylhydrazone (1.113 g), which was used without further purification for the next step.
Reaction SMILES: [CH2:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([CH2:11][CH2:12][CH:13]([CH2:16][OH:17])[CH2:14][OH:15])[CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4].[F:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][CH:20]=1>ClCCl.CC1C=CC(S(O)(=O)=O)=CC=1>[F:18][C:19]1[CH:26]=[CH:25][C:22]([C@H:23]2[O:15][CH2:14][C@H:13]([CH2:12][CH2:11][C@H:8]3[CH2:7][CH2:6][C@H:5]([CH2:1][CH2:2][CH2:3][CH3:4])[CH2:10][CH2:9]3)[CH2:16][O:17]2)=[CH:21][CH:20]=1
Reactant: CCCC[C@H]1CC[C@H](CCC(CO)CO)CC1
Reactant: O=Cc1ccc(F)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: CCCC[C@H]1CC[C@H](CC[C@H]2CO[C@H](c3ccc(F)cc3)OC2)CC1

Procedure:
A solution of 2.4 g (0.01 mol) of 2-[2'-(trans-4"- butylcyclohexyl)ethyl]propane-1,3-diol, 1.8 g (0.01 mol) of 4-fluorobenzaldehyde (manufactured by Aldrich) and 0.1 g of TsOH in 50 cm3 of dichloromethane was refluxed for 3 hours over a hot water bath with a Dean-Stark trap. The resulting solution was washed with water and the dichloromethane was distilled off. The residue was recrystallized from a solvent mixture of acetone and methanol to yield 3.0 g (0.008 mol) of trans-2-(4'-fluorophenyl)-5-[2'-(trans-4"-butylcyclohexyl)ethyl]-1,3-dioxane. The phase transition temperature of this compound, measured by DSC, was: ##STR41## wherein C is the crystal phase, N is the nematic phase, and I is the isotropic liquid phase.
Reaction SMILES: [C:1]([O:6][CH2:7][CH3:8])(=[O:5])[CH:2]([CH3:4])[OH:3].[CH2:9](O)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]CC.S(=O)(=O)(O)O>>[C:1]([O:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])(=[O:5])[CH:2]([CH3:4])[OH:3]
Reactant: CCCCCCCCO
Reactant: CCOC(=O)C(C)O
Agent: O=S(=O)(O)O
Product: CCCCCCCCOC(=O)C(C)O
Yield: 43.8 %

Procedure:
A 500 mL one neck round bottom flask equipped with a distillation apparatus and nitrogen inlet/outlet was charged with 100.0 g (0.847 moles) of ethyl lactate, 220.49 g (1.69 moles) of octyl alcohol and 0.423 g of sulfuric acid (based on 0.5 g sulfuric acid/one mole ethyl lactate). The reaction was refluxed for 8 hours and ethanol was collected as formed. The acid was neutralized by washing three times with 100 mL saturated sodium bicarbonate solution. Approximately 50 mL ether was needed to break the emulsion. The organic layer was collected and dried over magnesium sulfate. Excess octyl alcohol was removed by high vacuum distillation, and three fractional distillations led to 75.0 g (44% yield) of clear colorless oil. According to GC, the product is 95% pure.
Reaction SMILES: [CH2:1]([S:17][CH2:18][CH:19]([CH2:22]OS(C)(=O)=O)[O:20][CH3:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[Br-:28].[Li+]>CC(C)=O>[CH2:1]([S:17][CH2:18][CH:19]([O:20][CH3:21])[CH2:22][Br:28])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: [Br-]
Reactant: CCCCCCCCCCCCCCCCSCC(COS(C)(=O)=O)OC
Agent: [Li+]
Solvent: CC(C)=O
Product: CCCCCCCCCCCCCCCCSCC(CBr)OC
Temperature: 25 °C
Yield: 87.2 %

Procedure:
Into a flask equipped with a magnetic stir bar, drying tube, and a reflux condenser, a solution of 3.0 grams (0.007 mole) (±)-1-S-hexadecyl-2-O-methyl-3-O-mesylthioglycerol and 2.5 grams (0.029 mole) of lithium bromide in 150 milliliters of acetone was refluxed for 24 hours with continuous stirring. The reaction was cooled to room temperature, the sodium mesylate filtered and the solvent evaporated in vacuo. The residue was dissolved in 300 milliliters of ether and extracted three times with 500 milliliter portions of sodium thiosulfate, twice with 500 milliliter portions of water, and the organic layer dried over anhydrous sodium sulfate. Filtration of the drying agent, evaporation of the ether in vacuo and subsequent silica gel chromatography (hexane:ether 9:1 as eluent) afforded 2.5 grams (87%) of an oily product. 1H-NMR (CDCl3): delta, 0.87 (t, 3H, terminal methyl), 1.2-1.6 [m, 28H, (CH2)14 ], 2.58 (m, 2H, S--CH2), 2.62 (m, 2H, CH--CH2 --S), 3.38(S, 3H, O--CH3), 3.48 (m, 3H, CH--CH2Br).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:12][CH2:13][CH3:14])[C:5]1[CH:10]=[CH:9][C:8](Br)=[CH:7][CH:6]=1)[CH3:2].[Li]CCCC.[CH3:20][O:21][CH2:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([C:30](=[O:40])[CH:31]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:32][CH3:33])=[CH:26][CH:25]=1.O>C1COCC1>[CH2:1]([O:3][CH:4]([O:12][CH2:13][CH3:14])[C:5]1[CH:10]=[CH:9][C:8]([C:30]([C:27]2[CH:26]=[CH:25][C:24]([O:23][CH2:22][O:21][CH3:20])=[CH:29][CH:28]=2)([OH:40])[CH:31]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:32][CH3:33])=[CH:7][CH:6]=1)[CH3:2]
Reactant: CCC(C(=O)c1ccc(OCOC)cc1)c1ccccc1
Reactant: CCOC(OCC)c1ccc(Br)cc1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CCOC(OCC)c1ccc(C(O)(c2ccc(OCOC)cc2)C(CC)c2ccccc2)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 122.8 %

Procedure:
To a stirred solution of 4-bromobenzaldehyde diethyl acetal (107 g, 0.41 mol) in anhydrous THF (750 mL) was added n-BuLi (1.6 M in hexanes, 268 mL, 0.43 mol) dropwise at −78° C. After stirring for 1 h at −78° C., a solution of 15 (97.6 g, 0.34 mol) in THF (750 mL) was cannulated into the reaction mixture portionwise. The mixture was stirred overnight at RT, H2O (500 mL) was added, and the volatiles were removed under reduced pressure. The residue was extracted with Et2O (3×500 mL) and the combined extracts washed with H2O (500 mL) and brine (500 mL). The mixture was dried over MgSO4 and concentrated to afford 194 g of 16 that was used without further purification. 1HNMR (400 MHz, DMSO-d6): δ 0.58 (t, J=7.3 Hz, 3H), 1.12 (m, 6H), 1.52 (m, 1H), 1.70 (m, 1H), 3.23 (s, 3H), 3.40-3.65 (m, 5H), 4.98 (s, 2H), 5.41 (s, 1H), 5.51 (s, 1H), 6.62 (d, J=8.8 Hz, 2H), 6.96-7.06 (m, 3H), 7.17-7.23 (m, 4H), 7.31 (d, J=8.0 Hz, 2H), 7.61 (d, J=8.4 Hz, 2H).