Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([O:11][CH3:12])=[O:10])=[C:6]([CH3:16])[N:5]=[C:4]([N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[N:3]=1.C(N(CC)C(C)C)(C)C.[Cl:32][C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[C:35]([F:42])[CH:34]=1>COCCOC.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cl:32][C:33]1[CH:38]=[CH:37][C:36]([C:2]2[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([O:11][CH3:12])=[O:10])=[C:6]([CH3:16])[N:5]=[C:4]([N:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[N:3]=2)=[C:35]([F:42])[CH:34]=1
Reactant: CCCC(C(=O)OC)c1c(C)nc(N2CCCCC2)nc1Cl
Reactant: OB(O)c1ccc(Cl)cc1F
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCCC(C(=O)OC)c1c(C)nc(N2CCCCC2)nc1-c1ccc(Cl)cc1F
Temperature: 100 °C
Yield: 46.7 %

Procedure:
A suspension of methyl 2-(4-chloro-6-methyl-2-(piperidin-1-yl)pyrimidin-5-yl)pentanoate (0.081 g; 0.25 mmol), tetrakis(triphenylphosphine) palladium(0) (0.029 g; 0.025 mmol), N,N-diisopropylethylamine (0.172 mL; 1.00 mmol) and 4-chloro-2-fluorophenylboronic acid (0.065 g; 0.375 mmol) in a mixture of DME-water (3:1, 1 mL) was heated at 100° C. for 2.5 h. The mixture was partitioned between brine and dichloromethane, filtered over a phase separator filter (1PS) and concentrated under reduced pressure. Purification by flash-chromatography on silica gel using a gradient of ethyl acetate (1-10%) in heptane furnished 0.049 g (38%) of the title compound as a colorless oil.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.CCCCCC.[F:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[S:27][CH:28]=[CH:29][N:30]=2)=[CH:22][CH:21]=1.[C:31]([C:34]1[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=1)(=[O:33])[CH3:32]>C1COCC1>[F:19][C:20]1[CH:21]=[CH:22][C:23]([C:26]2[S:27][C:28]([C:31]([C:34]3[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=3)([OH:33])[CH3:32])=[CH:29][N:30]=2)=[CH:24][CH:25]=1
Reactant: CC(=O)c1ccncc1
Reactant: Fc1ccc(-c2nccs2)cc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC(O)(c1ccncc1)c1cnc(-c2ccc(F)cc2)s1
Temperature: -5 °C
Reaction time: 0.5 h
Yield: 56.8 %

Procedure:
To a stirred solution of diisopropylamine (0.283 mL, 2.01 mmol) in THF (15 mL) at −78° C. under nitrogen atmosphere was added 1.6M n-BuLi in hexane (1.25 mL, 2.01 mmol) slowly. The reaction mixture was stirred for 30 min at −5° C., cooled to −78° C., 2-(4-fluorophenyl)thiazole (300 mg, 1.67 mmol) in THF (5 mL) added, and then 4-acetyl pyridine (300 mg, 1.67 mmol) in THF (5 mL) added. The resulting mixture was stirred at −78° C. for 2 h. The reaction mixture was quenched with saturated NH4Cl solution (40 mL) and extracted with ethyl acetate (4×150 mL). The organic layer was dried over Na2SO4 and concentrated to obtain crude product. The crude product was purified by flash chromatography (100-200μ; 80% ethyl acetate in hexane) to afford 1-(2-(4-fluorophenyl)thiazol-5-yl)-1-(pyridin-4-yl)ethanol as off-white solid (285 mg, 57% yield), HPLC purity 99.9%, mp 229-232° C. 1H NMR (400 MHz, DMSO-d6): δ 8.53 (d, 2H), 7.92 (t, 2H), 7.81 (s, 1H), 7.49 (d, 2H), 7.30 (t, 2H), 6.66 (s, 1H), 1.93 (s, 3H); LC-MS m/z calculated for [M+H]+ 301.07. found 301.6.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[C:16]2[CH2:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8]=2[CH:7]=[CH:6][CH:5]=1.C([Li])CCC.[C:22](=[O:24])=[O:23]>C1COCC1.O.C(OCC)(=O)C>[CH3:1][O:2][CH2:3][C:4]1[C:16]2[CH:15]([C:22]([OH:24])=[O:23])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8]=2[CH:7]=[CH:6][CH:5]=1
Reactant: COCc1cccc2c1Cc1ccccc1-2
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: COCc1cccc2c1C(C(=O)O)c1ccccc1-2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 33.1 %

Procedure:
A solution of 1-methoxymethylfluorene (4.5 g, 21.4 mmol) in 100 mL of THF at -78° C. was charged with butyl lithium (10.0 mL, 23.5 mmol). The reaction mixture was stirred for 15 min, then CO2 gaseous (5g, 113.6 mmol) was introduced via cannula over a period 15 min at -78° C. The reaction mixture was warmed up to room temperature and stirred for additional 2 hr until colorless, diluted with water (100 mL) and ethyl acetate (50 mL). The layers were separated, the water layer was washed with ethyl acetate (3×50 mL), then acidified with conc. HCl. The resulting precipitate was collected, washed with water and dried to give 1-methoxymethyl-9-fluorenecarboxylic acid (1.8 g, 33.1%).
Reaction SMILES: [OH:1][C:2]1[C:3]([N+:13]([O-:15])=[O:14])=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]2.[N:16]1([CH2:21][C@@H:22]([C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)O)[CH:20]=[CH:19][N:18]=[CH:17]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[N:16]1([CH2:21][C@H:22]([C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)[O:1][C:2]2[C:3]([N+:13]([O-:15])=[O:14])=[C:4]3[C:9](=[CH:10][CH:11]=2)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]3)[CH:20]=[CH:19][N:18]=[CH:17]1
Reactant: O[C@@H](Cn1ccnc1)c1cccnc1
Reactant: O=C1CCCc2c1ccc(O)c2[N+](=O)[O-]
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1CCCc2c1ccc(O[C@H](Cn1ccnc1)c1cccnc1)c2[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 95 %

Procedure:
To a solution of 6-hydroxy-5-nitro-1-tetralone (0.957 g, 4.62 mmol) in dry THF (20 mL) was added (R)-2-imidazol-1-yl-1-pyridin-3-yl-ethanol (0.875 g, 4.62 mmol) followed by triphenylphospine (1.33 g, 5.08 mmol). After approximately 10 min, diethylazodicarboxylate (0.80 mL, 5.08 mmol) was added slowly. The reaction became homogenous. The reaction was allowed to stir at RT overnight. The reaction mixture was concentrated under reduced pressure and the residue was triturated with Et2O to remove some of the phospine by-products. The residue was dissolved in EtOAc and washed with H2O, saturated aqueous NaHCO3 and brine, dried over Na2SO4, and concentrated to give a foam/oil. Purification by chromatography (SiO2, 4-10% MeOH/CH2Cl2) afforded the title compound as a tan foam (1.66 g, 4.39 mmol, 95%). The structure was confirmed by NMR and mass spectrometry. MS m/z 379 (M++H).
Reaction SMILES: [CH3:1][CH:2]([CH3:39])[CH2:3][C@H:4]([NH:17][C:18](=[O:38])[C@@H:19]([NH:28][C:29](=[O:37])[CH2:30][N:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1)[CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:5]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1)=[O:6].C[Si]([N-][Si](C)(C)C)(C)C.[K+].[CH3:50][C:51]([O:58][CH2:59][C:60]#[CH:61])([CH3:57])[C:52]([O:54][CH2:55]I)=[O:53]>C1COCC1>[CH3:1][CH:2]([CH3:39])[CH2:3][C@H:4]([N:17]([CH2:55][O:54][C:52](=[O:53])[C:51]([CH3:50])([O:58][CH2:59][C:60]#[CH:61])[CH3:57])[C:18](=[O:38])[C@@H:19]([NH:28][C:29](=[O:37])[CH2:30][N:31]1[CH2:32][CH2:33][O:34][CH2:35][CH2:36]1)[CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:5]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1)=[O:6]
Reactant: COc1ccc(COC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCc2ccccc2)NC(=O)CN2CCOCC2)cc1
Reactant: C#CCOC(C)(C)C(=O)OCI
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: C#CCOC(C)(C)C(=O)OCN(C(=O)[C@H](CCc1ccccc1)NC(=O)CN1CCOCC1)[C@@H](CC(C)C)C(=O)OCc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 68.5 %

Procedure:
To a light yellow solution of (S)-4-methoxybenzyl 4-methyl-2-((S)-2-(2-morpholinoacetamido)-4-phenylbutanamido)pentanoate (2.16 g, 4.0 mmol) in THF (15 mL) at −50° C. was added KHMDS solution (1 M in THF, 5.0 mL, 5.0 mmol) dropwise maintaining the internal reaction temperature below −50° C. The mixture was stirred for 10 min and a solution of iodomethyl 2-methyl-2-(prop-2-ynyloxy)propanoate (1.58 g, 5.6 mmol) in THF (5.0 mL) was added dropwise. The reaction mixture was allowed to warm to room temperature and stirred for 3 h. The reaction was quenched with methanol (3 mL) and then diluted with ethyl acetate. The resulting mixture was washed with brine and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting oil was purified by flash column chromatography on silica gel (hexanes/ethyl acetate=9:1 to 7:3) to afford compound (major spot, 1.9 g, 68.5% yield) as a colorless oil.
Reaction SMILES: [OH-].[Na+].[NH2:3][C:4]1[CH:5]=[C:6]([SH:10])[CH:7]=[CH:8][CH:9]=1.[CH2:11](Cl)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>O.C(O)C>[CH2:11]([S:10][C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=1)[NH2:3])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Nc1cccc(S)c1
Reactant: ClCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Nc1cccc(SCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 81.9 %

Procedure:
To a stirred solution of sodium hydroxide (2.1 g, 52.5 mmol) in water (4 ml) cooled in an ice bath, a solution of 3-aminothiophenol (4.8 g, 38.4 mmol) in ethanol (20 ml) was added drop wise, followed by the addition of solution of benzyl chloride (5 g, 39.5 mmol) in ethanol (5 ml). After the addition, the reaction mixture was stirred at room temperature for 4 hours and became a brown solution with white precipitate. After filtering off the precipitate, the filtrate was concentrated and residue was taken by dichloromethane (40 ml). The dichloromethane solution was washed with aqueous sodium hydroxide solution three times (0.5 M, 3×40 ml) and water once (40 ml). After dried over MgSO4 and filtered, dichloromethane solution was then concentrated in vacuo to afford thick yellow oil as crude product. It was further purified by flash chromatography (SiO2, hexanes/CH2Cl2, 0-100%) to afford 3-(benzylthio)aniline (6.77 g, 82%) as a pale yellow oil, which solidified into white solid after staying at room temperature. Thin layer chromatography: Dichloromethane, Rf=0.37; 1H-NMR (CDCl3) δ(ppm) 6.6-7.4 (m, 9H, Ar—H), 4.15 (s, 2H, S—CH2).
Reaction SMILES: CS([O:5][CH2:6][C:7]1[C:8]([C:19]2[CH:24]=[CH:23][C:22]([CH2:25][CH3:26])=[CH:21][CH:20]=2)=[N:9][S:10][C:11]=1[C:12]([F:18])([F:17])[C:13]([F:16])([F:15])[F:14])(=O)=O.O[C:28]1[CH:33]=[CH:32][C:31]([CH2:34][CH2:35][C:36]([O:38]CC)=[O:37])=[C:30]([CH3:41])[C:29]=1[CH3:42]>>[CH2:25]([C:22]1[CH:23]=[CH:24][C:19]([C:8]2[C:7]([CH2:6][O:5][C:28]3[CH:33]=[CH:32][C:31]([CH2:34][CH2:35][C:36]([OH:38])=[O:37])=[C:30]([CH3:41])[C:29]=3[CH3:42])=[C:11]([C:12]([F:18])([F:17])[C:13]([F:16])([F:15])[F:14])[S:10][N:9]=2)=[CH:20][CH:21]=1)[CH3:26]
Reactant: CCOC(=O)CCc1ccc(O)c(C)c1C
Reactant: CCc1ccc(-c2nsc(C(F)(F)C(F)(F)F)c2COS(C)(=O)=O)cc1
Product: CCc1ccc(-c2nsc(C(F)(F)C(F)(F)F)c2COc2ccc(CCC(=O)O)c(C)c2C)cc1

Procedure:
The title compound was prepared according to the procedure described in Example 1 following Step 5 and 6 by coupling [3-(4-ethylphenyl)-5-(pentafluoroethyl)-1,2-thiazol-4-yl]methyl methanesulfonate and ethyl 3-(4-hydroxy-2,3-dimethylphenyl)propanoate to afford the desired product as an off-white solid. 1H-NMR (300 MHz, CD3OD) δ 7.60 (d, J=8.1 Hz, 2H), 7.26 (d, J=8.1 Hz, 2H), 6.97 (d, J=8.4 Hz, 1H), 6.69 (d, J=8.4 Hz, 1H), 5.03 (s, 2H), 2.91 (t, J=8.1 Hz, 2H), 2.68 (q, J1=15.3 Hz, J2=7.5 Hz, 2H), 2.51 (t, J=8.4 Hz, 2H), 2.23 (s, 3H), 2.03 (s, 3H), 1.02 (t, J=7.8 Hz, 3H). Mass spectrum (ESI, m/z): Calcd. for C25H24F5NO3S, 514.1 (M+H). found 514.1.
Reaction SMILES: [CH2:1]([O:13][C:14]1[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=1[C:16](O)=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].CN(C)C=O.S(Cl)([Cl:30])=O>C(Cl)Cl>[CH2:1]([O:13][C:14]1[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=1[C:16]([Cl:30])=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: O=S(Cl)Cl
Reactant: CCCCCCCCCCCCOc1ccccc1C(=O)O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCCCCCCCCCCCOc1ccccc1C(=O)Cl
Reaction time: 2 h

Procedure:
29.1 g of the dodecyloxybenzoic acid was dissolved in 300 ml of methylene chloride, 1 ml of N,N-dimethylformamide was added, and 24 g of thionyl chloride was added dropwise over about 30 min under heating and reflux. After the addition the heating and refluxing were continued for 2 hours further, and concentration was conducted, to obtain 2-dodecyloxybenzoic acid chloride.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[N:16][N:15]4[C:18]([C:21]5[CH:22]=[C:23]([NH:27][C:28]([NH:30][CH2:31][C:32]([F:35])([F:34])[F:33])=[O:29])[CH:24]=[CH:25][CH:26]=5)=[CH:19][N:20]=[C:14]4[CH:13]=3)[CH:9]=[N:8]2)[CH2:3][CH2:2]1.[N:36]([C:39]1[CH:40]=[N:41][CH:42]=[CH:43][CH:44]=1)=[C:37]=[O:38]>>[N:41]1[CH:42]=[CH:43][CH:44]=[C:39]([NH:36][C:37]([N:1]2[CH2:6][CH2:5][CH:4]([N:7]3[CH:11]=[C:10]([C:12]4[CH:17]=[N:16][N:15]5[C:18]([C:21]6[CH:26]=[CH:25][CH:24]=[C:23]([NH:27][C:28]([NH:30][CH2:31][C:32]([F:33])([F:35])[F:34])=[O:29])[CH:22]=6)=[CH:19][N:20]=[C:14]5[CH:13]=4)[CH:9]=[N:8]3)[CH2:3][CH2:2]2)=[O:38])[CH:40]=1
Reactant: O=C(NCC(F)(F)F)Nc1cccc(-c2cnc3cc(-c4cnn(C5CCNCC5)c4)cnn23)c1
Reactant: O=C=Nc1cccnc1
Product: O=C(NCC(F)(F)F)Nc1cccc(-c2cnc3cc(-c4cnn(C5CCN(C(=O)Nc6cccnc6)CC5)c4)cnn23)c1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 30 (Step 6) starting from N-{3-[7-(1-piperidin-4-yl-1H-pyrazol-4-yl)imidazo[1,2-b]pyridazin-3-yl]phenyl}-N′-(2,2,2-trifluoroethyl)urea and 3-isocyanatopyridine (Oakwood, Cat. No. 022077). LCMS (M+H)+: m/z=605.3.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10]([C:20]3[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=3)=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[N:12]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:33][S:34](Cl)(=[O:36])=[O:35].C([O-])(O)=O.[Na+]>C(Cl)Cl>[F:19][C:16]1[CH:15]=[CH:14][C:13]([C:11]2[N:12]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:1][S:34]([CH3:33])(=[O:36])=[O:35])=[CH:3][CH:4]=3)[NH:9][C:10]=2[C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)=[CH:18][CH:17]=1
Reactant: Nc1ccc(-c2nc(-c3ccc(F)cc3)c(-c3ccncc3)[nH]2)cc1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)Nc1ccc(-c2nc(-c3ccc(F)cc3)c(-c3ccncc3)[nH]2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 35.7 %

Procedure:
To a suspension of 2-(4-aminophenyl)-4-(4-fluorophenyl)-5-(4-pyridyl)-1H-imidazole (80 mg, 0.24 mmol) [See Ex. 28 above] and triethylamine (0.12 mL, 0.86 mmol) in CH2Cl2 (5 mL) was added methanesulfonyl chloride (55 mL, 0.72 mmol). After stirring at rt for 1 h, the mixture was poured into aqueous NaHCO3 and extracted with EtOAc. The organic extract was washed with saturated aqueous NaCl, dried (MgSO4) and concentrated under reduced pressure. The residue was purified by flash chromatography, eluting with a solvent gradient of 2-10% MeOH/CHCl3 to afford the title compound as a tan solid (35 mg, 36%): ESMS (m/z): 409 (M+ +H).
Reaction SMILES: [CH:1]([C:3]1[N:8]=[N:7][C:6]2[O:9][CH2:10][CH2:11][S:12][C:5]=2[CH:4]=1)=C.I([O-])(=O)(=O)=[O:14].[Na+]>O1CCOCC1.O.[Os](=O)(=O)(=O)=O>[N:7]1[C:6]2[O:9][CH2:10][CH2:11][S:12][C:5]=2[CH:4]=[C:3]([CH:1]=[O:14])[N:8]=1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=Cc1cc2c(nn1)OCCS2
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: O=Cc1cc2c(nn1)OCCS2
Temperature: 25 °C
Yield: 35.9 %

Procedure:
A solution of 3-ethenyl-6,7-dihydro[1,4]oxathiino[2,3-c]pyridazine (320 mg) in 1,4-dioxane/water (20 ml/5 ml) was treated with an aqueous solution of osmium tetroxide (4% w/v, 2 ml) and sodium periodate (1.0 g), initially stirred in an ice-bath, then allowed to warm to rt. After 2.5 h the mixture was evaporated to dryness and dissolved in 1,4-dioxane and chloroform. Silica gel was added and the mixture was evaporated to dryness, added to a silica column (50 g) and chromatographed, eluting with 0-100% ethyl acetate in hexane, to afford a white solid (116 mg, 36%).
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([C:12]([OH:14])=O)[O:7][C:8]=1[CH:9]([CH3:11])[CH3:10])([CH3:3])[CH3:2].N1C(Cl)=NC(Cl)=NC=1Cl.C(N(CC)CC)C.[NH2:31][C:32]1[CH:41]=[CH:40][C:35]([C:36]([O:38][CH3:39])=[O:37])=[CH:34][CH:33]=1>CC(C)=O.CN(C)C1C=CN=CC=1>[CH:1]([C:4]1[CH:5]=[C:6]([C:12]([NH:31][C:32]2[CH:33]=[CH:34][C:35]([C:36]([O:38][CH3:39])=[O:37])=[CH:40][CH:41]=2)=[O:14])[O:7][C:8]=1[CH:9]([CH3:10])[CH3:11])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccc(N)cc1
Reactant: CC(C)c1cc(C(=O)O)oc1C(C)C
Agent: CN(C)c1ccncc1
Agent: Clc1nc(Cl)nc(Cl)n1
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: COC(=O)c1ccc(NC(=O)c2cc(C(C)C)c(C(C)C)o2)cc1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 89.3 %

Procedure:
A solution of 4,5-diisopropylfuran-2-carboxylic acid (50 mg, 0.255 mmol) and cyanuric chloride (71 mg, 0.385 mmol) in acetone (3 ml) was added with triethylamine (142 μl, 1.021 mmol), and the mixture was stirred at room temperature for 3.5 hours. The reaction mixture was added with methyl 4-aminobenzoate (77 mg, 0.510 mmol), and the mixture was further stirred for 14 hours. The reaction solvent was evaporated, then the residue was dissolved in pyridine (1 ml), the solution was added with 4-dimethylaminopyridine (1 mg, 8.20 μmol), and the mixture was stirred at room temperature for 4 hours. Pyridine was evaporated, and then the reaction mixture was dissolved in 10% methanol-chloroform, the solution was added with silica gel (1.0 g), and the mixture was evaporated to dryness. The residue was purified by silica gel chromatography [hexane-ethyl acetate (6:1)] to obtain methyl 4-[(4,5-diisopropylfuran-2-carbonyl)amino]benzoate (75 mg, 89%) as colorless prisms.
Reaction SMILES: [S:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[CH:3]=[CH:2]1.C([Li])CCC.[B:15](OC(C)C)([O:20]C(C)C)[O:16]C(C)C>O1CCCC1>[S:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[CH:3]=[C:2]1[B:15]([OH:20])[OH:16]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: c1cc2sccc2cn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OB(O)c1cc2cnccc2s1
Reaction time: 0.08 h

Procedure:
To a stirring mixture consisting of thieno[3,2-c]pyridine (2.0 g) in anhydrous tetrahydrofuran (25 mL) at −40° C. was added a solution consisting of 1.6 M n-butyllithium in hexanes (10 mL) over several minutes (dropwise at first followed by a slow, steady stream). The reaction mixture was stirred for five minutes and triisopropyl borate (4.2 mL) was subsequently added. The cold bath was removed and the mixture was allowed to stir for one hour. Water (2 mL) was added to the stirring mixture, which caused a pale yellow solid to precipitate instantly. The precipitate was collected by vacuum filtration and the solids were rinsed lightly with water (giving a cloudy yellow filtrate) and subsequently with diethyl ether (giving a dark orange filtrate). The aqueous portion of the filtrate was separated from the organic solvent, and then diluted with 1,4-dioxane (100 mL) and the solution was concentrated under reduced pressure. Addition of 1,4-dioxane (100 mL) to the concentrate and subsequent concentration under reduced pressure was repeated twice to afford a yellow powder (0.8 g) upon final evaporation.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11]Br)=[CH:6][CH:5]=1.[F:15][CH2:16][CH2:17][CH:18]1[CH2:23][CH2:22][CH:21]([CH:24]2[CH2:29][CH2:28][C:27](=O)[CH2:26][CH2:25]2)[CH2:20][CH2:19]1.Cl>CCOCC>[F:15][CH2:16][CH2:17][CH:18]1[CH2:19][CH2:20][CH:21]([CH:24]2[CH2:29][CH2:28][C:27]([CH2:11][CH2:10][C:7]3[CH:8]=[CH:9][C:4]([O:3][C:2]([F:14])([F:13])[F:1])=[CH:5][CH:6]=3)=[CH:26][CH2:25]2)[CH2:22][CH2:23]1
Reactant: O=C1CCC(C2CCC(CCF)CC2)CC1
Reactant: FC(F)(F)Oc1ccc(CCBr)cc1
Agent: Cl
Solvent: CCOCC
Product: FCCC1CCC(C2CC=C(CCc3ccc(OC(F)(F)F)cc3)CC2)CC1
Temperature: 0 °C
Reaction time: 3 h
Yield: 46.4 %

Procedure:
A Grignard reagent prepared from the above 2-(4-trifluoromethoxyphenyl)bromoethane (7.0 g, 30.3 mmol) and dried Mg (0.74 g, 30.4 mmol) in an ether solvent (40 ml) was cooled down to 0° C., followed by dropwise adding thereto a 30 ml ether solution of 4-(4-(2-fluoroethyl)cyclohexyl)cyclohexanone (2.2 g, 9.7 mmol) prepared at the third step, stirring the mixture at 0° C. for 3 hours, adding 6N HCl to the reaction solution, extracting the resulting product with toluene, washing the extraction solution successively with a saturated aqueous solution of sodium bicarbonate and water, drying over magnesium sulfate, distilling off the solvent, adding toluene (100 ml) and Amberlist (500 mg) to the resulting yellow oily substance, refluxing the mixture for 4 hours, while removing water formed by the reaction by means of Dean-Stark, filtering off Amberlist, distilling off the solvent, purifying the residue according to column chromatography treatment using toluene as a developing solvent, on silica gel, to isolate 4-(4-(2-fluoroethyl)cyclohexyl)-1-(2-(4-trifluoromethoxyphenyl)ethyl)-1-cyclohexene (1.8 g, 4.5 mmol), hydrogenating this product (1.2 g, 3.0 mmol) in the presence of 5% Pd/C catalyst (0.12 g) in ethanol solution, filtering off the catalyst, distilling off the solvent under reduced pressure, and recrystallizing the residue, to isolate only trans-form of colorless 1-(2-(4-(4-(2-fluoroethyl)-cyclohexyl)cyclohexyl)ethyl-4-trifluoromethoxybenzene (0.37 g, 0.90 mmol) exhibiting smectic phase. The yield of this product from 4-(4-(2-fluoroethyl)chclohexyl)cyclohexanone was 9.3%.
Reaction SMILES: [Br:1][C:2]1[N:6]2[CH2:7][CH2:8][N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:10][C:5]2=[C:4]([C:18]([O:20]C)=[O:19])[N:3]=1.[Li+].[OH-]>CO.O>[Br:1][C:2]1[N:6]2[CH2:7][CH2:8][N:9]([C:11]([O:13][C:14]([CH3:15])([CH3:16])[CH3:17])=[O:12])[CH2:10][C:5]2=[C:4]([C:18]([OH:20])=[O:19])[N:3]=1
Reactant: COC(=O)c1nc(Br)n2c1CN(C(=O)OC(C)(C)C)CC2
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCn2c(Br)nc(C(=O)O)c2C1
Temperature: 50 °C
Reaction time: 8 h
Yield: 75.9 %

Procedure:
The product Intermediate 1H (0.85 g, 2.36 mmol) was dissolved in methanol (50 mL) and LiOH (0.79 g, 18.88 mmol) in water (10 mL) was added. The resulting solution was stirred at 50° C. overnight. The reaction mixture was concentrated, cooled on ice and brought to pH 3 using 1N HCl. The resulting white precipitate was filtered, washed with water and air dried to give the desired acid Intermediate 1I as a white solid (0.62 g, 76%).
Reaction SMILES: [H-].[Na+].[NH2:3]/[C:4](/[C:11]([F:14])([F:13])[F:12])=[CH:5]\[C:6]([O:8]CC)=O.[CH2:15]([O:17][N:18]=[CH:19][C:20]1[CH:25]=[C:24]([N:26]=[C:27]=[O:28])[C:23]([Cl:29])=[CH:22][C:21]=1[Cl:30])[CH3:16]>>[CH2:15]([O:17][N:18]=[CH:19][C:20]1[CH:25]=[C:24]([N:26]2[C:6](=[O:8])[CH:5]=[C:4]([C:11]([F:12])([F:13])[F:14])[NH:3][C:27]2=[O:28])[C:23]([Cl:29])=[CH:22][C:21]=1[Cl:30])[CH3:16]
Reactant: CCON=Cc1cc(N=C=O)c(Cl)cc1Cl
Reactant: CCOC(=O)/C=C(\N)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Product: CCON=Cc1cc(-n2c(=O)cc(C(F)(F)F)[nH]c2=O)c(Cl)cc1Cl

Procedure:
9.2 g (0.31 mol) of sodium hydride, 51.3 g (0.28 mol) of ethyl 3-amino-4,4,4-trifluorocrotonate and 72.6 g (0.28 mol) of 2,4-dichloro-5-isocyanatobenzaldehyde (O-ethyl)oxime were reacted in the manner described for precursor 3.2. Yield: 72.0 g; m.p.: 205-209° C.
Reaction SMILES: C(C1C(N[C@@H]2C3C(=CC=CC=3)C[C@@H]2O)=NC(CC)=CN=1)C.[CH2:22]([C@H:24]1[C@H:32]([NH2:33])[C:28]2[CH:29]=[CH:30][S:31][C:27]=2[CH2:26][CH2:25]1)[CH3:23].Br[C:35]1[C:40]([CH2:41][CH3:42])=[N:39][C:38]([C:43]2[CH:48]=[CH:47][C:46]([Cl:49])=[CH:45][C:44]=2[Cl:50])=[C:37]([CH2:51][CH3:52])[N:36]=1>>[Cl:50][C:44]1[CH:45]=[C:46]([Cl:49])[CH:47]=[CH:48][C:43]=1[C:38]1[N:39]=[C:40]([CH2:41][CH3:42])[C:35]([NH:33][C@@H:32]2[C:28]3[CH:29]=[CH:30][S:31][C:27]=3[CH2:26][CH2:25][C@H:24]2[CH2:22][CH3:23])=[N:36][C:37]=1[CH2:51][CH3:52]
Reactant: CC[C@@H]1CCc2sccc2[C@H]1N
Reactant: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1Br
Agent: CCc1cnc(CC)c(N[C@@H]2c3ccccc3C[C@@H]2O)n1
Product: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1N[C@@H]1c2ccsc2CC[C@H]1CC

Procedure:
Following the procedure for the preparation of (1R,2S)-1-[(3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol but substituting trans-5-ethyl-4,5,6,7-tetrahydro-1-benzothiophen-4-amine and 2-bromo-5-(2,4-dichlorophenyl)-3,6-diethylpyrazine and making non-critical variations provided the title compound as a oil: 1H NMR (400 MHz, CDCl3) δ) 7.50, 7.35–7.28, 7.11, 6.91, 5.27, 4.58, 2.85, 2.64, 2.49, 2.08, 1.93, 1.84, 1.66, 1.41, 1.26, 1.18, 1.06; HRMS (FAB) calcd for C24H27Cl2N3S+H 460.1381, found 460.1398. Anal. Calcd for C24H27Cl2N3S: C, 62.60; H, 5.91; N, 9.13. Found: C, 62.36; H, 5.94; N, 8.91.