Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=O.[H-].[Na+].ClCC(Cl)=[O:17].[NH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>O1CCCC1.C(=O)(O)[O-].[Na+]>[O:17]=[C:7]1[CH2:6][O:5][C:3]([N:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)=[C:2]1[C:1]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: O=C(Cl)CCl
Reactant: CCOC(=O)CC(=O)OCC
Reactant: C1CCNCC1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C1=C(N2CCCCC2)OCC1=O
Reaction time: 1 h

Procedure:
Diethyl malonate (5.0 mL, 0.033 mol) was added dropwise to a solution of sodium hydride (60% w/w in oil, 2.7 g, 0.066 mol) in anhydrous tetrahydrofuran (50 mL) that cooled with ice bath. The mixture was refluxed for 5 min. The reaction mixture was cooled with ice bath, chloroacetyl chloride (2.8 mL, 0.035 mol) was added dropwise to the reaction mixture and the mixture was stirred for 1 h then stirred at 45° C. for 1 h. The reaction mixture was cooled with ice bath again then piperidine (3.9 mL, 0.040 mol) was added dropwise and stirred at ambient temperature for further 12 h. The reaction mixture was diluted with aqueous saturated sodium bicarbonate solution, and extracted with ethyl acetate for 2 times then extracted with chloroform. The organic layer was washed with brine, dried over sodium sulfate and concentrated. The residue was purified by chromatography on silica gel(chloroform/methanol) to afford ethyl 4-oxo-2-piperidino-4,5-dihydrofuran-3-carboxylate as solid (3.5 g, y. 45%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9]O)=[CH:4][CH:3]=1.[OH:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[CH:14][C:13]=1[O:20][CH3:21].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([O:11][C:12]2[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[CH:14][C:13]=2[O:20][CH3:21])[CH3:9])=[CH:6][CH:7]=1
Reactant: COc1cc(C=O)ccc1O
Reactant: OCCc1ccc(Cl)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1cc(C=O)ccc1OC(C)c1ccc(Cl)cc1
Reaction time: 2 h

Procedure:
4-Chlorophenylmethylcarbinol (76, 0.668 mL, 6.57 mmol) was dissolved in tetrahydrofuran (60.0 mL) at 0° C. under an atmosphere of nitrogen. 4-Hydroxy-3-methoxybenzaldehyde (21, 1.00 g, 6.57 mmol) and triphenylphosphine (2.07 g, 7.89 mmol) were added to the reaction, followed by diisopropyl azodicarboxylate (1.55 mL, 7.89 mmol) over 10 minutes. The reaction was stirred for 2 hours. The mixture was adsorbed onto silica and purified by silica gel chromatography, ethyl acetate:hexanes, to provide the desired compound, (77, 1.14 g, 60%). 1H-NMR was consistent with the desired compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:19]=[C:18]([OH:20])[C:17]([F:21])=[CH:16][C:11]=1[C:12]([O:14]C)=[O:13].[OH-].[Na+].C(OCC)(=O)C.O>CO>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:19]=[C:18]([OH:20])[C:17]([F:21])=[CH:16][C:11]=1[C:12]([OH:14])=[O:13]
Reactant: COC(=O)c1cc(F)c(O)nc1Nc1ccc(F)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(O)c1cc(F)c(O)nc1Nc1ccc(F)cc1F
Yield: 93.7 %

Procedure:
In 30 ml of methanol was suspended 3.00 g of methyl 2-(2,4-difluorophenylamino)-5-fluoro-6-hydroxynicotinate, and 16.1 ml of 2N aqueous sodium hydroxide solution was added thereto at room temperature, after which the resulting mixture was subjected to reaction under reflux for 4 hours. Subsequently, the reaction mixture was added to a mixture of 60 ml of ethyl acetate and 60 ml of water, and the aqueous layer was separated. The aqueous layer was adjusted to pH 1.0 with 6N hydrochloric acid, and the crystals thus deposited were collected by filtration, washed successively with 15 ml of water and 25 ml of isopropyl alcohol to obtain 2.68 g (yield 93.7%) of 2-(2,4-difluorophenylamino)-5-fluoro-6-hydroxynicotinic acid having a melting point of 213°-216° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:8]=[C:9]=[O:10])[CH:5]=[CH:6][CH:7]=1.[NH2:11][C:12]1[C:13]([F:43])=[CH:14][C:15]([F:42])=[C:16]([C:18]2[C:19](=[O:41])[N:20]([CH2:39][CH3:40])[C:21]3[C:26]([CH:27]=2)=[CH:25][N:24]=[C:23]([N:28]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[CH3:29])[CH:22]=3)[CH:17]=1.[N-]=C=O>C1COCC1.CCOC(C)=O>[CH3:38][O:37][C:34]1[CH:33]=[CH:32][C:31]([CH2:30][N:28]([CH3:29])[C:23]2[CH:22]=[C:21]3[C:26]([CH:27]=[C:18]([C:16]4[C:15]([F:42])=[CH:14][C:13]([F:43])=[C:12]([NH:11][C:9]([NH:8][C:4]5[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=5)=[O:10])[CH:17]=4)[C:19](=[O:41])[N:20]3[CH2:39][CH3:40])=[CH:25][N:24]=2)=[CH:36][CH:35]=1
Reactant: O=C=Nc1cccc(F)c1
Reactant: CCn1c(=O)c(-c2cc(N)c(F)cc2F)cc2cnc(N(C)Cc3ccc(OC)cc3)cc21
Agent: [N-]=C=O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCn1c(=O)c(-c2cc(NC(=O)Nc3cccc(F)c3)c(F)cc2F)cc2cnc(N(C)Cc3ccc(OC)cc3)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.3 %

Procedure:
3-Fluorophenyl isocyanate (81 mg, 0.444 mmol) was added to a solution of Example A7 (200 mg, 0.444 mmol) in THF (5 mL) and the mixture was stirred at RT overnight. The reaction was treated with additional isocyanate (10 mg) and stirred at RT for a further 4 h. The mixture was diluted with EtOAc, washed successively with water, satd. NaHCO3, and brine, dried (Na2SO4), concentrated in vacuo, purified by reverse phase chromatography (MeCN/water with 0.1% TFA) and partially concentrated to give an aqueous solution. The solution was diluted with satd. NaHCO3, extracted with EtOAc (2×) and the combined organics were washed with brine, dried (Na2SO4) and evaporated at reduced pressure to give 1-(5-(7-((4-methoxybenzyl)(methyl)amino)-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2,4-difluorophenyl)-3-(3-fluorophenyl)urea (207 mg, 79% yield, ˜75% pure) as a light yellow solid, which was used without further purification. MS (ES-API) m/z: 588.2 [M+H]+.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2].CO[CH:12](OC)[N:13]([CH3:15])[CH3:14]>C1C=CC=CC=1>[CH2:12]([N:13]([CH2:15][CH2:7][CH2:8][CH3:9])[CH:14]=[CH:2][C:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1)=[O:3])[CH2:2][CH2:1][CH3:4]
Reactant: CC(=O)c1cccnc1
Reactant: COC(OC)N(C)C
Solvent: c1ccccc1
Product: CCCCN(C=CC(=O)c1cccnc1)CCCC

Procedure:
A mixture of 0.10 mole of 3-acetylpyridine and 0.10 mole of N,N-dimethylformamide dimethylacetal in 100 ml of benzene was refluxed for 12 hours. The solvent was removed, giving 3-dibutylamino-1-(3-pyridinyl)-2-propen-1-one.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]2[NH:6][C:7](=[O:9])[NH:8][C:4]=2[CH:3]=1.Cl[CH2:13][C:14]([N:16]1[CH2:21][CH2:20][CH:19]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:18][CH2:17]1)=[O:15]>C(OCC)C>[CH2:22]([CH:19]1[CH2:18][CH2:17][N:16]([C:14](=[O:15])[CH2:13][NH:1][C:2]2[CH:11]=[CH:10][C:5]3[NH:6][C:7](=[O:9])[NH:8][C:4]=3[CH:3]=2)[CH2:21][CH2:20]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(CCl)N1CCC(Cc2ccccc2)CC1
Reactant: Nc1ccc2[nH]c(=O)[nH]c2c1
Solvent: CCOCC
Product: O=C(CNc1ccc2[nH]c(=O)[nH]c2c1)N1CCC(Cc2ccccc2)CC1

Procedure:
The title compound is prepared from 5-amino-1,3-dihydro-benzimidazol-2-one and 2-chloro-1-(4-benzyl-piperidin-1-yl)-ethanone (Example 200a) according to the method described in Example 142b. Melting Point: 237-238° C. (diethylether)
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][CH:4]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(C)([O-])C.[K+].[CH:37]([C:39]1[N:40]=[C:41]([NH:44][C:45](=[O:47])[CH3:46])[S:42][CH:43]=1)=O>CN(C)C=O>[N+:9]([C:6]1[CH:7]=[CH:8][C:3](/[CH:2]=[CH:37]\[C:39]2[N:40]=[C:41]([NH:44][C:45](=[O:47])[CH3:46])[S:42][CH:43]=2)=[CH:4][CH:5]=1)([O-:11])=[O:10]
Reactant: CC(=O)Nc1nc(C=O)cs1
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CC(=O)Nc1nc(/C=C\c2ccc([N+](=O)[O-])cc2)cs1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 62.5 %

Procedure:
1-(Bromomethyl)-4-nitrobenzene (1.9 g), triphenylphosphine (2.31 g) and N,N-dimethylformamide (20 ml) were combined under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 2.5 hours. Then potassium tert-butoxide (1.19 g) and N-(4-formyl-1,3-thiazol-2-yl)acetamide (1.5 g) were added and the mixture was stirred at room temperature for 14 hours. The reaction mixture was poured into ice-water and extracted with ethyl acetate. The organic layer was washed with 1N-hydrochloric acid, water and saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residue was purified by flash column chromatography over silica gel with n-hexane/ethyl acetate (1:1)→(1:2) as an eluent, and triturated with ethyl ether to give N-{4-[(Z)-2-(4-nitrophenyl)ethenyl]-1,3-thiazol-2-yl}acetamide (1.59 g) as a yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([NH:13][NH2:14])[CH:8]=1)[CH3:2].[CH3:16][C:17]([CH3:24])([CH3:23])[C:18](=O)[CH2:19][C:20]#[N:21]>CCO>[C:17]([C:18]1[CH:19]=[C:20]([NH2:21])[N:13]([C:9]2[CH:8]=[C:7]([CH2:6][CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:15])[CH:12]=[CH:11][CH:10]=2)[N:14]=1)([CH3:24])([CH3:23])[CH3:16]
Reactant: CC(C)(C)C(=O)CC#N
Reactant: CCOC(=O)CCc1cccc(NN)c1
Solvent: CCO
Product: CCOC(=O)CCc1cccc(-n2nc(C(C)(C)C)cc2N)c1
Yield: 85.1 %

Procedure:
A mixture of 3-(3-hydrazinophenyl)propionic acid ethyl ester (13 g, 53.3 mmol) and 4,4-dimethyl-3-oxopentanenitrile (6.9 g, 55 mol) in EtOH (150 mL) was heated at reflux overnight. The reaction solution was evaporated under vacuum. The residue was purified by column chromatography to yield ethyl 3-(3-(3-t-butyl-5-amino-1H-pyrazol-1-yl)phenyl)propanoate (14.3 g, 85% yield) as a white solid. 1H NMR (300 MHz, DMSO-d6); δ 7.50-7.42 (m, 4H), 5.63 (s, 1H), 5.14 (s, 2H), 4.04 (q, J=6.9 Hz, 2H), 2.92 (t, J=7.5 Hz, 2H), 2.66 (t, J=7.5 Hz, 2H), 1.27 (s, 9H), 1.16 (t, J=7.5 Hz, 3H); MS (ESI) m/z: 316 (M+H+).
Reaction SMILES: [N:1]1[N:2]=[C:3]([S:6]([O:9][C:10]2[CH:11]=[C:12]([CH3:26])[C:13]3[CH:17]([CH2:18][C:19]([O:21]CC)=[O:20])[O:16][B:15]([OH:24])[C:14]=3[CH:25]=2)(=[O:8])=[O:7])[NH:4][CH:5]=1.[Li+].[OH-].Cl>CCO>[N:1]1[N:2]=[C:3]([S:6]([O:9][C:10]2[CH:11]=[C:12]([CH3:26])[C:13]3[CH:17]([CH2:18][C:19]([OH:21])=[O:20])[O:16][B:15]([OH:24])[C:14]=3[CH:25]=2)(=[O:7])=[O:8])[NH:4][CH:5]=1
Reactant: CCOC(=O)CC1OB(O)c2cc(OS(=O)(=O)c3nnc[nH]3)cc(C)c21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(OS(=O)(=O)c2nnc[nH]2)cc2c1C(CC(=O)O)OB2O
Temperature: 0 °C
Reaction time: 3 h
Yield: 36.2 %

Procedure:
To a solution of ethyl 2-(6-(4H-1,2,4-triazol-3-ylsulfonyloxy)-1-hydroxy-4-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)acetate (100 mg, 0.25 mmol) in EtOH (4 ml) was added aqueous LiOH (1 ml, 10% aq). The mixture was stirred at 0° C. for 3 h. The reaction was acidified with 1N HCl to pH=2-4, extracted with DCM, washed with brine. The organic layer was dried over Na2SO4 and concentrated. Purify via prep. HPLC to get white solid 32 mg. NMR: 1H NMR (DMSO-d6, 400 MHz): δ=12.3 (br, 1H), 9.15 (br, 1H), 8.99 (s, 1H), 7.20 (d, J=2 Hz, 1H), 7.042 (d, J=2 Hz, 1H), 5.48 (dd, J=2.4, 9.2 Hz, 1H), 3.65 (s, 1H), 3.03 (dd, J=2.8, 16.6 Hz, 1H), 2.14 (s, 3H), and 2.1 (q, 1H) ppm. MS (ESI) m/z=352.0 [M−H]−.
Reaction SMILES: [C:1]([CH:3]([CH:7]1[C:11]([Cl:12])=[C:10](Cl)C(=O)O1)[C:4]([NH2:6])=[O:5])#[N:2].Cl.[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([S:25]([CH3:28])(=[O:27])=[O:26])=[C:21]([CH2:23][NH2:24])[CH:22]=1.C(N(CC)C(C)C)(C)C.O>C(O)C>[ClH:12].[Cl:12][C:11]1[CH:7]=[C:3]([C:4]([NH2:6])=[O:5])[C:1](=[NH:2])[N:24]([CH2:23][C:21]2[CH:22]=[C:17]([Cl:16])[CH:18]=[CH:19][C:20]=2[S:25]([CH3:28])(=[O:27])=[O:26])[CH:10]=1
Reactant: N#CC(C(N)=O)C1OC(=O)C(Cl)=C1Cl
Reactant: CS(=O)(=O)c1ccc(Cl)cc1CN
Agent: Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CS(=O)(=O)c1ccc(Cl)cc1Cn1cc(Cl)cc(C(N)=O)c1=N
Temperature: 70 °C
Reaction time: 1 h
Yield: 89.9 %

Procedure:
(Step 4) To a suspension of 2-cyano-2-(3,4-dichloro-5-oxo-2,5-dihydrofuran-2-yl)acetamide (0.28 g) and 1-[5-chloro-2-(methylsulfonyl)phenyl]methanamine hydrochloride obtained in Step 3 (0.26 g) in ethanol (3 ml) was added N,N-diisopropylethylamine (0.44 ml) at room temperature, and the resulting mixture was heated under reflux for 4 hr. The reaction mixture was treated with water and stirred at 70° C. for 1 hr. After cooling to room temperature, the precipitate was collected by filtration and dried. The precipitate was suspended in methanol, and treated with a 2 M hydrogen chloride-methanol solution (0.3 ml). The resulting mixture was stirred at room temperature overnight. The precipitate was collected by filtration and dried to give the title compound (0.22 g) as white crystals.
Reaction SMILES: [O:1]=[C:2]1[CH:6]2[CH2:7][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:9][CH2:10][N:5]2[CH2:4][CH:3]1C(OC)=O.CS(C)=O.[Na+].[Cl-]>O>[O:1]=[C:2]1[CH:6]2[CH2:7][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:9][CH2:10][N:5]2[CH2:4][CH2:3]1
Reactant: COC(=O)C1CN2CCN(C(=O)OC(C)(C)C)CC2C1=O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN2CCC(=O)C2C1
Temperature: 130 °C

Procedure:
A mixture of 2-tert-butyl 7-methyl 8-oxohexahydro pyrrolo[1,2-a]pyrazine-2,7(1H)-dicarboxylate (Example 100B, 131 g, 0.44 mol), dimethyl sulfoxide (530 mL), NaCl (25.6 g, 0.44 mol) and water (32 g, 1.75 mol) was heated to 130° C. and maintained at that temperature for 2 hours. The reaction mixture was cooled, diluted with water (1 L) and extracted with ethyl acetate (1 L×2). The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was chromatographed over silica gel eluting with 30-40% ethyl acetate in petroleum ether to afford the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 1.48 (s, 9H), 2.23-2.42 (m, 3H), 2.47-2.60 (m, 1H), 2.60-2.78 (m, 1H), 2.82-2.98 (m, 1H), 3.02-3.10 (m, 1H), 3.32-3.40 (m, 1H), 3.65-3.85 (m, 1H), 3.99-4.20 (bs, 1H), 4.20-4.45 (bs, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][O:17]CC3C=CC=CC=3)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.C(O)C.[H][H]>[Pd].O1CCOCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][OH:17])=[CH:11][CH:10]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2ccc(CCOCc3ccccc3)cc2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1COCCO1
Solvent: CCO
Product: COc1ccc(-c2ccc(CCO)cc2)cc1
Yield: 92 %

Procedure:
2,59 g (7.85 mol) of 2-{4-(4-methoxyphenyl) phenyl}ethylbenzylether, 0.4 g of 5% palladium activated carbon, 70 ml of ethanol and 6 ml of dioxane were injected and stirred at room temperature for 7 hours under presence of hydrogen. After the reactions had been completed, the catalyst was removed by tuck filtration and the solvent was removed by filtration so that 1.64 g of 2-{4-(4-methoxyphenyl) phenyl}ethanol was obtained (yield 92%).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][SH:5].[CH2:6](Cl)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C>[CH2:6]([S:5][CH2:4][CH2:3][NH2:2])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: ClCc1ccccc1
Reactant: NCCS
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: NCCSCc1ccccc1
Reaction time: 8 h

Procedure:
A suspension of 2-aminoethanethiol hydrochloride (2.27 g, 20.0 mmol), benzyl chloride (2.42 mL, 21.0 mmol) and cesium carbonate (19.5 g, 60 mmol) in DMF (100 mL) was stirred overnight. The reaction mixture was then diluted with ethyl acetate (200 mL) and filtered into a separation funnel. The solid residue was washed with ether (50 mL×3). The combined filtrates were then washed with water (80 mL×5) and brine (50 mL), dried over potassium carbonate and filtered. The filtrate was concentrated first with rotary evaporator (water bath at 80° C.), then by high vacuum (1 mm Hg) to give 2-benzylthioethylamine in good purity. The crude product was used for next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[CH2:7][OH:8].[Br:9]N1C(=O)CCC1=O.S([O-])([O-])(=O)=S.[Na+].[Na+]>CN(C)C=O.C(OCC)(=O)C>[Br:9][C:4]1[S:3][C:2]([Cl:1])=[C:6]([CH2:7][OH:8])[CH:5]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: OCc1ccsc1Cl
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: OCc1cc(Br)sc1Cl
Reaction time: 2 h
Yield: 80.6 %

Procedure:
To a solution of 3.0 g of (2-chlorothiophen-3-yl)methanol in 60 mL of dimethylformamide was added 3.59 g of N-bromosuccinimide at room temperature, and stirred at this temperature for 2 hours. Adding 10 mL of 10% sodium thiosulfate, and the resultant solution was diluted with ethyl acetate. The organic layer was washed successively with saturated aqueous ammonium chloride and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated, to afford 3.7 g of the title compound as a colorless oil.
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:9][CH2:10][C:11]([CH2:13][Cl:14])=[O:12].C(O)(=O)C.O>CCOCC>[Cl:9][CH2:10][C:11]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([OH:12])[CH2:13][Cl:14]
Reactant: Br[Mg]c1ccccc1
Reactant: O=C(CCl)CCl
Solvent: CCOCC
Solvent: O
Solvent: CC(=O)O
Product: OC(CCl)(CCl)c1ccccc1
Reaction time: 0.17 h
Yield: 51 %

Procedure:
289 ml (0.866 mol) of a 3M solution of phenylmagnesium bromide in ether are run, over a period of 1.50 h, into a solution of 100 g (0.787 mol) of 1,3-dichloroacetone in 1000 ml of anhydrous ether under a nitrogen atmosphere and at -60° C. After 10 minutes, a solution of 83.5 g of acetic acid in 126 ml of ether is added to the reaction medium. The temperature is allowed to rise to +4° C. and 315 ml of water are run in. The ether phase is decanted, washed with water and dried over MgSO4. It is filtered, the filtrate is evaporated to dryness and the evaporation residue is distilled in vacuo to give 82.3 g (yield: 51%) of 1,3-dichloro-2-phenylpropan-2-ol. B.p. (0.5 mm Hg)=102° C. (0.5 mm Hg corresponds to 66.6 Pa).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][S:16]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([S:25](=[O:42])(=[O:41])[NH:26][C:27]3[CH:32]=[CH:31][C:30]([N:33]([CH3:35])[CH3:34])=[C:29]([C:36]4[O:37][CH:38]=[CH:39][CH:40]=4)[CH:28]=3)[CH:20]=2)(=[O:18])=[O:17])[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH3:34][N:33]([CH3:35])[C:30]1[CH:31]=[CH:32][C:27]([NH:26][S:25]([C:21]2[CH:20]=[C:19]([S:16]([NH:15][CH2:14][CH:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)(=[O:18])=[O:17])[CH:24]=[CH:23][CH:22]=2)(=[O:42])=[O:41])=[CH:28][C:29]=1[C:36]1[O:37][CH:38]=[CH:39][CH:40]=1
Reactant: CN(C)c1ccc(NS(=O)(=O)c2cccc(S(=O)(=O)NCC3CCN(C(=O)OC(C)(C)C)CC3)c2)cc1-c1ccco1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C)c1ccc(NS(=O)(=O)c2cccc(S(=O)(=O)NCC3CCNCC3)c2)cc1-c1ccco1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 103 %

Procedure:
To a solution (10 ml) of Y244 (332 mg, 0.53 mmol) produced in Example 5 in dichloromethane was added trifluoroacetic acid (3 ml), and the mixture was stirred at room temperature for 20 min. Then, the reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent; chloroform:methanol (8:1-3:1)) to give the title compound (283 mg, 87%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([S:8]([NH:11][CH2:12][CH:13]2[CH2:15][CH2:14]2)(=[O:10])=[O:9])=[C:6]([OH:16])[C:5]([N+:17]([O-])=O)=[CH:4][CH:3]=1.[H][H]>[Pd]>[NH2:17][C:5]1[C:6]([OH:16])=[C:7]([S:8]([NH:11][CH2:12][CH:13]2[CH2:15][CH2:14]2)(=[O:9])=[O:10])[C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)NCC2CC2)c1O
Agent: [Pd]
Product: Nc1ccc(Cl)c(S(=O)(=O)NCC2CC2)c1O
Yield: 9 %

Procedure:
Following the general hydrogenation procedure outlined in example 15, 6-chloro-N-cyclopropylmethyl-2-hydroxy-3-nitrobenzenesulfonamide (0.1 g, 3.2 mmol) was reduced with hydrogen and 10% Pd/C (0.1 g) to form the desired product (0.08 g, 89%). LC-MS m/z 277 (M+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[NH:7][CH:8]1[C:14](=[O:15])[N:13]([CH2:16][CH2:17][O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:12]2[CH:26]=[CH:27][CH:28]=[CH:29][C:11]=2[NH:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[C:31](=[O:34])([O-])[O-:32].[Cs+].[Cs+].FC(F)(F)S(O[CH2:43][C:44]([F:47])([F:46])[F:45])(=O)=O>CN(C)C=O>[F:45][C:44]([F:47])([F:46])[CH2:43][O:32][C:31]([N:10]1[CH2:9][C@H:8]([NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:30])[C:14](=[O:15])[N:13]([CH2:16][CH2:17][O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:12]2[CH:26]=[CH:27][CH:28]=[CH:29][C:11]1=2)=[O:34]
Reactant: O=C([O-])[O-]
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: CC(C)(C)OC(=O)NC1CNc2ccccc2N(CCOCc2ccccc2)C1=O
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H]1CN(C(=O)OCC(F)(F)F)c2ccccc2N(CCOCc2ccccc2)C1=O
Temperature: 60 °C
Reaction time: 18 h

Procedure:
A solution of 301 mg of [(RS)-1-(2-benzyloxy-ethyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl]-carbamic acid tert-butyl ester in 6 ml of N,N-dimethylformamide was treated with 477 mg of cesium carbonate, 350 mg of 2,2,2-trifluoroethyl trifluoromethanesulphonate, and about 300 mg of solid carbondioxide. The reaction mixture was stirred in a sealed tube at 60° C. for 18 hours. For the working-up, the solvent was evaporated under reduced pressure, and the residue was distributed between 10 ml of a saturated sodium hydrogencarbonate solution and 30 ml of ethyl acetate. The aqueous layer was separated and extracted twice with 30 ml of ethyl acetate. The combined organic layers were dried over sodium sulphate and evaporated under reduced pressure. For purification, the light brown oil was separated on silica gel using a gradient of heptane/ethyl acetate=100/0 to 60/20 as the eluent. There were obtained 325 mg (83% of theory) of the title compound as a white foam [MS (m/e): 538 (M+H)+].
Reaction SMILES: [C:1](Cl)(=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[C:12]1([CH:19]=[CH:18][C:16]([OH:17])=[CH:15][CH:14]=1)[OH:13].Cl>N1C=CC=CC=1>[CH2:2]([C:1]([O:13][C:12]1[CH:19]=[CH:18][C:16]([OH:17])=[CH:15][CH:14]=1)=[O:10])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: Oc1ccc(O)cc1
Reactant: CCCCCCCCC(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Product: CCCCCCCCC(=O)Oc1ccc(O)cc1

Procedure:
After adding 17 g of nonanic acid chloride to 200 ml of pyridine dissolved with 47 g of hydroquinone, the mixture was heated for 2 hours. Following neutralization of hydrogen chloride, the crude of 4-octylcarbonyloxyphenol was obtained by extracting with chloroform. The crude compound was purified by passing through silica-gel column to obtain pure 4-octylcarbonyloxyphenol (J). (I) was reacted with (J) to obtain the compound (G) same procedure as example 14. (G) was a smectic liquid crystal compound having the SC* phase. The phase transition points of (G) were shown in table 4.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:27]=[CH:26][C:6]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([S:15][C:16]3[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=3)=[C:11]([N+:23]([O-])=O)[CH:10]=2)=[CH:5][CH:4]=1.[Cl-].[NH4+].O1CCCC1.O>CO.[Fe]>[NH2:23][C:11]1[CH:10]=[C:9]([O:8][CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:27][CH:26]=2)[CH:14]=[CH:13][C:12]=1[S:15][C:16]1[CH:17]=[CH:18][C:19]([OH:22])=[CH:20][CH:21]=1
Reactant: COc1ccc(COc2ccc(Sc3ccc(O)cc3)c([N+](=O)[O-])c2)cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(COc2ccc(Sc3ccc(O)cc3)c(N)c2)cc1
Yield: 101.5 %

Procedure:
A solution of the product of Example 9D (1.06 g, 2.76 mmol), iron powder (0.63 g, 11.04 mmol) and ammonium chloride (0.18 g, 3.31 mmol) in a methanol (18 mL), tetrahydrofuran (18 mL), and water (6 mL) solution was heated to reflux for 3 hours. The resultant mixture was diluted with methanol (50 mL) and filtered through a pad of celite. The filtrate was concentrated under vacuum to a volume of 10 mL, the solution diluted with water (50 mL) and extracted with ethyl acetate (2×50 mL). The combined extracts were dried over magnesium sulfate, filtered and concentrated under vacuum to provide the title compound (0.99 g, 100%).