Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH:10]([C:11]([CH2:13][CH3:14])=[CH2:12])[O:9][CH:8]=[N:7]1)=[O:5])[CH3:2].C([OH:17])C.O>>[CH2:1]([O:3][C:4](=[O:5])[CH:6]([NH:7][CH:8]=[O:17])[CH:10]([OH:9])[C:11]([CH2:13][CH3:14])=[CH2:12])[CH3:2]
Reactant: CCO
Reactant: C=C(CC)C1OC=NC1C(=O)OCC
Solvent: O
Product: C=C(CC)C(O)C(NC=O)C(=O)OCC

Procedure:
The starting material is manufactured as follows: Reaction of 2-methylene-butyraldehyde with isocyanoacetic acid ethyl ester in a manner analogous to that described in Example 1 yields 5-(buten-2-yl)-2-oxazoline-4-carboxylic acid ethyl ester. A solution of 16 g of 5-(buten-2-yl)-2-oxazoline-4-carboxylic acid ethyl ester in 100 ml of ethanol/water (1:1) is heated at the boil, under reflux, for 15 hours. The whole is concentrated by evaporation in vacuo, the residue is taken up in 200 ml of dichloromethane, dried over sodium sulphate and filtered, and the filtrate is concentrated by evaporation to yield 2-formylamino-3-hydroxy-4-ethyl-4-pentenoic acid ethyl ester.
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.[OH:15][CH2:16][C@@H:17]1[O:21][C:20](=[O:22])[N:19]([C:23]2[CH:28]=[CH:27][C:26]([C:29]3[CH2:30][CH2:31][O:32][CH2:33][CH:34]=3)=[C:25]([F:35])[CH:24]=2)[CH2:18]1.O[C:37]1[CH:41]=[N:40][S:39][N:38]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[S:39]1[N:40]=[CH:41][C:37]([O:15][CH2:16][C@@H:17]2[O:21][C:20](=[O:22])[N:19]([C:23]3[CH:28]=[CH:27][C:26]([C:29]4[CH2:30][CH2:31][O:32][CH2:33][CH:34]=4)=[C:25]([F:35])[CH:24]=3)[CH2:18]2)=[N:38]1
Reactant: O=C1O[C@@H](CO)CN1c1ccc(C2=CCOCC2)c(F)c1
Reactant: Oc1cnsn1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1O[C@@H](COc2cnsn2)CN1c1ccc(C2=CCOCC2)c(F)c1
Reaction time: 1.5 h
Yield: 72.9 %

Procedure:
Diisopropylazodicarboxylate (0.22 g, 1.1 mmol) was added dropwise at ambient temperature to a stirred solution of 5(R)-hydroxymethyl-3-(4-[3,6-dihydro-(2H)-pyran-4-yl]-3-fluorophenyl)oxazolidin-2-one (WO97/09328; 0.275 g, 0.93 mmol), 3-hydroxy1,2,5-thiadiazole (Weinstock et al. Journal of Organic Chemistry 32, 2823 [1967]; 0.1 12 g, 1.1 mmol) and triphenylphosphine (0.288 g, 1.1 mmol) in dry THF (7 ml). The solution was kept for 1.5 hours. Solvent was evaporated and the residue was purified by flash column chromatography, eluting with EtOAc/isohexane (1:1) to give the title product (0.256 g , 73%) as a solid (mp 146-148 ° C.). MS: 378 (MH+); NMR: 2.4 (1H, bs); 3.78 (3H, t); 3.96 (1H, m); 4.2 (3H, m); 4.66 (2H, m); 5.1 (1H, m); 6.05 (1H, s); 7.27-7.5 (3H, m); 8.41 (1H, s).
Reaction SMILES: CC1C=CC(C[S:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=CC=1.Br[CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.CC[O-].[Na+].SCC(OCC)=O>C(O)C>[CH2:17]([S:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: BrCCc1ccccc1
Reactant: CCOC(=O)CSCc1ccc(C)cc1
Agent: CCOC(=O)CS
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)CSCCc1ccccc1

Procedure:
The procedure is as in Example 29 for the preparation of ethyl (4-methylbenzylthio)acetate, starting with (2-bromoethyl)benzene (20 g), a 2M ethanolic solution of sodium ethylate (25 cc) and ethyl 2-mercaptoacetate (13 g) in ethanol (150 cc). Ethyl (phenethylthio)acetate (21.7 g) is thereby obtained, and is used in the crude state in the subsequent syntheses.
Reaction SMILES: C(O)(=O)C1C=CC=CC=1.S(=O)(=O)(O)O.S(=O)(=O)=O.[S:19]([C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=1)[C:26]([OH:28])=[O:27])([OH:22])(=[O:21])=[O:20].[N+:32]([O-])([OH:34])=[O:33]>>[N+:32]([C:30]1[CH:29]=[C:25]([CH:24]=[C:23]([S:19]([OH:22])(=[O:21])=[O:20])[CH:31]=1)[C:26]([OH:28])=[O:27])([O-:34])=[O:33]
Reactant: O=C(O)c1cccc(S(=O)(=O)O)c1
Reactant: O=[N+]([O-])O
Agent: O=C(O)c1ccccc1
Agent: O=S(=O)(O)O
Agent: O=S(=O)=O
Product: O=C(O)c1cc([N+](=O)[O-])cc(S(=O)(=O)O)c1

Procedure:
Benzoic acid was sulfonated by heating it with concentrated sulfuric acid in the presence of sulfur trioxide. The 3-sulfobenzoic acid was nitrated with fuming nitric acid to yield 3-nitro-5-sulfobenzoic acid. Hydrogenation of this in 50% ethanol/water over palladium on charcoal easily afforded 3-amino-5-sulfobenzoic acid in good yield. Structural verification was obtained by carbon magnetic resonance, proton magnetic resonance and infra-red analysis.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]1[CH2:15][O:14][CH2:13][CH2:12][N:11]1CC1C=CC=CC=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(Cl)(Cl)[Cl:24]>C(O)C.[C].[Pd]>[ClH:24].[Si:1]([O:8][CH2:9][C@@H:10]1[CH2:15][O:14][CH2:13][CH2:12][NH:11]1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H]1COCCN1Cc1ccccc1
Reactant: ClC(Cl)Cl
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)[Si](C)(C)OC[C@@H]1COCCN1
Product: Cl

Procedure:
(3S)-3-(t-Butyldimethylsilyloxy)methyl-4-benzylmorpholine (1.19 g, 3.7 mmol) was treated for hydrogenation in the presence of 10% palladium-carbon (0.36 g) in 5 mL of ethanol and 0.32 mL of chloroform for 4 hours (one atmosphere). The catalyst was removed by filtration, and the filtrate was concentrated. The precipitated crystalline matter was washed with ether to obtain (3S)-3-(t-butyldimethylsilyloxy)methylmorpholine hydrochloride (0.96 g (96%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[CH2:9](OC(OCC)OCC)C.[N-:19]=[N+:20]=[N-:21].[Na+]>C(O)(=O)C>[N:1]1([C:2]2[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=2)[CH:9]=[N:21][N:20]=[N:19]1
Reactant: [N-]=[N+]=[N-]
Reactant: CCOC(OCC)OCC
Reactant: Nc1ccc(O)cc1
Agent: [Na+]
Solvent: CC(=O)O
Product: Oc1ccc(-n2cnnn2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 30 %

Procedure:
To a stirred solution of p-amino-phenol (0.1 mol) in glacial acetic acid (140 ml) at 70°-75° under nitrogen atmosphere was added triethylorthoformate (0.1 mol). The mixture was stirred at this temperature for 4 h, then, sodium azide (0.32 mol) was added portionwise and the reaction was continued for 18 h, cooled to room temperature and poured into ice water (400 ml) and extracted with diethyl ether (3×400 ml) and ethyl acetate (1×400 ml), dried (MgSO4), filtered and concentrated to give a dark brown residue which was triturated with 200 ml of a mixture of ethanol:diethyl ether (1:1 v/v) and filtered to afford the title compound in 30% yield. T.l.c. (ether) Rf 0.65
Reaction SMILES: [CH2:1]([C:4]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[O:9][C:8](=[O:10])[N:7]([C:11]2[CH:12]=[C:13]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=3[F:24])[CH:14]=[CH:15][CH:16]=2)[CH2:6][CH2:5]1)[CH:2]=C.[O:31]=[O+][O-].[BH4-].[Na+]>C(Cl)Cl>[F:24][C:18]1[CH:19]=[C:20]([F:23])[CH:21]=[CH:22][C:17]=1[C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([N:7]2[CH2:6][CH2:5][C:4]([CH2:1][CH2:2][OH:31])([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[O:9][C:8]2=[O:10])[CH:12]=1
Reactant: O=[O+][O-]
Reactant: C=CCC1(c2ccccc2)CCN(c2cccc(-c3ccc(F)cc3F)c2)C(=O)O1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Product: O=C1OC(CCO)(c2ccccc2)CCN1c1cccc(-c2ccc(F)cc2F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 25 %

Procedure:
A solution of 6-allyl-3-(2′,4′-difluorobiphenyl-3-yl)-6-phenyl-1,3-oxazinan-2-one (600 mg, 1.47 mmol) in dry CH2Cl2 (10 mL) was treated with ozone at −78° C. until the mixture turned blue. The system was then flushed with oxygen to remove excess ozone. NaBH4 (450 mg, 11.7 mmol) was added to the mixture in portions at −20° C. The mixture was stirred overnight at rt. The mixture was quenched with water and the layers were separated. The aqueous layer was extracted with CH2Cl2 (2×). The organic layers were combined, washed with brine, dried over anhydrous Na2SO4 and concentrated to give 3-(2′,4′-difluorobiphenyl-3-yl)-6-(2-hydroxyethyl)-6-phenyl-1,3-oxazinan-2-one (150 mg, 25%). 1H NMR (400 MHz, CDCl3): δ=2.12-2.35 (m, 2H), 2.51 (m, 2H), 3.26 (m, 1H), 3.47-3.6 (m, 2H), 4.25 (m, 1H), 6.83 (m, 2H), 7.06 (m, 1H), 7.26-7.51 (m, 8H).
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:15]=[C:16]([NH:20][C:21]([C:23]4[CH:24]=[N:25][N:26]([CH3:29])[C:27]=4[Cl:28])=[O:22])[CH:17]=[CH:18][CH:19]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:30].C1COCC1.[NH2:36][C:37]1[CH:42]=[CH:41][C:40]([CH2:43][CH2:44][C:45]([OH:47])=[O:46])=[CH:39][CH:38]=1>CCOC(C)=O.CCCCCC>[Cl:28][C:27]1[N:26]([CH3:29])[N:25]=[CH:24][C:23]=1[C:21]([NH:20][C:16]1[CH:15]=[C:14]([CH:19]=[CH:18][CH:17]=1)[C:12]([C:8]1[CH:7]=[C:6]2[C:11]([C:3](=[CH:2][NH:36][C:37]3[CH:38]=[CH:39][C:40]([CH2:43][CH2:44][C:45]([OH:47])=[O:46])=[CH:41][CH:42]=3)[C:4](=[O:30])[NH:5]2)=[CH:10][CH:9]=1)=[O:13])=[O:22]
Reactant: Nc1ccc(CCC(=O)O)cc1
Reactant: Cn1ncc(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4=CO)c2)c1Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Cn1ncc(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4=CNc3ccc(CCC(=O)O)cc3)c2)c1Cl
Temperature: 65 °C
Reaction time: 24 h
Yield: 57 %

Procedure:
A small screw cap test tube was charged with 5-Chloro-1-methyl-1H-pyrazole-4-carboxylic acid [3-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (as prepared in Example 328, 100 mg, 0.2365 mmol) and THF (2.5 mL). To the resulting solution was added 3-(4-Amino-phenyl)-propionic acid (39.1 mg, 0.237 mmol), and the mixture was stirred for 24 h at 65° C. Subsequently, the reaction mixture was cooled to room temperature and diluted with EtOAc (˜5 mL) and Hexane (˜50 mL). The precipitate that formed was collected by filtration and washed with acetone (˜15 mL) to afford the title compound in 57% yield (0.077 g, 0.1351 mmol).
Reaction SMILES: C[Mg]Br.[CH:4]([C:6]1[N:11]=[C:10]([C:12]([NH2:14])=[O:13])[CH:9]=[CH:8][CH:7]=1)=[O:5].O.[C:16](OCC)(=O)C>O1CCCC1>[OH:5][CH:4]([C:6]1[N:11]=[C:10]([C:12]([NH2:14])=[O:13])[CH:9]=[CH:8][CH:7]=1)[CH3:16]
Reactant: NC(=O)c1cccc(C=O)n1
Reactant: CCOC(C)=O
Agent: C[Mg]Br
Solvent: O
Solvent: C1CCOC1
Product: CC(O)c1cccc(C(N)=O)n1

Procedure:
An ethereal solution of methyl magnesium bromide (3 mol/l) (546 ml) was added dropwise to a solution of 6-formyl-2-pyridinecarboxamide (61.5 g) in tetrahydrofuran (900 ml) at 0°-13° C. with stirring. After the mixture was stirred at the same temperature for 2 hours and cold water was dropped to the reaction mixture under ice-cooling. To the mixture was added ethyl acetate and adjusted to pH 7 with N-hydrochloric acid. The separated organic layer was washed with brine, dried over magnesium sulfate and evaporated in vacuo to give 6-(1-hydroxyethyl)-2-pyridinecarboxamide (63.2 g) as an oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:17]3[CH:18]=[N:19][C:20]([NH:32][C:33]([NH:35][CH2:36][CH3:37])=[O:34])=[CH:21][C:22]=3[C:23]3[S:24][CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[N:27]=3)[CH:13]=2)[N:8]([CH2:38][C@@H:39]2[CH2:44][O:43][CH2:42][CH2:41][N:40]2[C:45]([O:47]C(C)(C)C)=[O:46])[CH:7]=1)=[O:5])[CH3:2].[CH2:52]1[CH2:56]OC[CH2:53]1.[Li+].[OH-].[CH3:59]O>>[C:52]([C@@:39]1([CH2:38][N:8]2[C:9]3[C:14](=[CH:13][C:12]([C:17]4[CH:18]=[N:19][C:20]([NH:32][C:33]([NH:35][CH2:36][CH3:37])=[O:34])=[CH:21][C:22]=4[C:23]4[S:24][CH:25]=[C:26]([C:28]([F:30])([F:29])[F:31])[N:27]=4)=[CH:11][CH:10]=3)[C:15](=[O:16])[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:7]2)[CH2:44][O:43][CH2:42][CH2:41][N:40]1[C:45]([OH:47])=[O:46])([CH3:53])([CH3:56])[CH3:59]
Reactant: CO
Reactant: C1CCOC1
Reactant: CCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(-c2ccc3c(c2)c(=O)c(C(=O)OCC)cn3C[C@@H]2COCCN2C(=O)OC(C)(C)C)cn1
Agent: [Li+]
Agent: [OH-]
Product: CCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(-c2ccc3c(c2)c(=O)c(C(=O)OCC)cn3C[C@]2(C(C)(C)C)COCCN2C(=O)O)cn1
Temperature: 100 °C
Reaction time: 1 h
Yield: 36 %

Procedure:
(R)-tert-butyl 3-((3-(ethoxycarbonyl)-6-(6-(3-ethylureido)-4-(4-(trifluoromethyl)thiazol-2-yl)pyridin-3-yl)-4-oxoquinolin-1(4H)-yl)methyl)morpholine-4-carboxylate (Example 254, 0.150 g, 0.20 mmol) was suspended in MeOH (6 mL) in a microwave vessel (CEM). THF (3.00 mL) was added. A 2.0 M aq solution of LiOH (0.381 mL, 0.76 mmol) was added. The microwave vessel was heated in the microwave at 100° C. for 15 min After cooling to room temperature solvent was removed in vacuo and residue was taken up in dichloromethane (2 ml) and 4N HCl in dioxane (1 ml) was added. The mixture was stirred at room temperature for 1 h, then diluted with water (3 ml) and neutralized with saturate NaHCO3. The mixture was extracted with DCM three times, and the combined organic layers were dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo, and the residue was purified by flash column chromatography on silica gel using (dichloromethane-methanol) to give (R)-tert-butyl 3-((3-(ethoxycarbonyl)-6-(6-(3-ethylureido)-4-(4-(trifluoromethyl)thiazol-2-yl)pyridin-3-yl)-4-oxoquinolin-1(4H)-yl)methyl)morpholine-4-carboxylic acid (0.042 g, 36%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.CN(C)CCCN=C=NCC.[F:29][C:30]([F:47])([F:46])[O:31][C:32]1[CH:45]=[CH:44][C:35]([O:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=2[NH2:43])=[CH:34][CH:33]=1>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14](=[O:16])[NH:43][C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=2[O:36][C:35]2[CH:44]=[CH:45][C:32]([O:31][C:30]([F:29])([F:46])[F:47])=[CH:33][CH:34]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Reactant: Nc1ccccc1Oc1ccc(OC(F)(F)F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(C(=O)Nc2ccccc2Oc2ccc(OC(F)(F)F)cc2)CC1

Procedure:
Piperidine-1,4-dicarboxylic acid mono-tert-butyl ester (HVB01062, 1.19 g, 5.2 mmol) was dissolved in anhydrous DCM (40 ml), and stirred under nitrogen. To this was added N N-4-dimethylaminopyridine (cat.), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (3.0 g, 4.2 mmol) and TEA (0.84 ml). Stirred for 30 min. 2-(4-Trifluoromethoxy-phenoxy)-phenylamine (HVB01053, 1.4 g, 5.2 mmol) was added and stirred under nitrogen for 20 h. Diluted with DCM, washed with HCl (1M, 20 ml), Sodium hydrogen carbonate (sat. 20 ml), and brine (20 ml). Organic layers combined and dried over anhydrous magnesium sulphate, and evaporated in-vacuo. The crude mixture was purified using flash chromatography (DCM/hexane, 0 to 100%), to afford a yellow solid, 1.59 g, 57%. m.p. 45-48° C., Rf. 0.65 (DCM), 1HNMR: (CDCl3, 270 MHz) δ 1.44 (9H, s, CH3), 1.67 (2H, td, J=13.4, 4.4 Hz, CH2), 1.80 (2H, dd, J=1.8 Hz, CH2), 2.36 (1H, m, CH), 2.74 (2H, t, J=11.9 Hz, CH2N), 4.12 (2H, d, J=11.6 Hz, CH2N), 6.85 (1H, dd, J=6.7, 1.5 Hz, Ar HD), 7.03 (2H, d, Ar HF), 7.04 (1H, m, Ar HB), 7.13 (1H, td, J=1.5, 6.4 Hz, Ar HC), 7.20 (2H, d, J=1.5, 6.4 Hz Ar HF), 7.64 (1H, s, NH), 8.40 (1H, d, J=8.2 Hz, Ar HA.
Reaction SMILES: [C:1]1([C:7]2[C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:9][NH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:16](Cl)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.Cl>C(Cl)Cl>[C:1]1([C:7]2[C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:9][NH:10][C:11]=2[C:16](=[O:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)c1c[nH]cc1-c1ccccc1
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Solvent: ClCCl
Product: COC(=O)c1c[nH]c(C(=O)c2ccccc2)c1-c1ccccc1
Reaction time: 1.5 h

Procedure:
Methyl 4-phenylpyrrole-3-carboxylate (920 mg., 4.6 mmoles) and benzoyl chloride (0.53 ml., 4.6 mmoles) were combined in 50 ml. methylene chloride and stirred under nitrogen at room temperature. Stannic chloride (1.15 ml., 10 mmoles) was added. The resulting solution was stirred for 1.5 hours. Hydrochloric acid (1 N 25 ml.) was added slowly. The mixture was stirred for 10 minutes, the methylene chloride layer separated, back-washed with two 20 ml. portions of water, approximately 50 mg. of solids removed by filtration, and the filtrate evaporated to dryness. Recrystallization of the residue from acetone afforded purified methyl 4-phenyl-5-benzoylpyrrole-3-carboxylate (673 mg., m.p. 201°-203° C.).
Reaction SMILES: [NH3:1].[Br:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]#[N:10])[C:4]=1[S:11](Cl)(=[O:13])=[O:12].O>CO.O1CCCC1>[Br:2][C:3]1[C:4]2[S:11](=[O:13])(=[O:12])[N:10]=[C:9]([NH2:1])[C:5]=2[CH:6]=[CH:7][CH:8]=1
Reactant: N#Cc1cccc(Br)c1S(=O)(=O)Cl
Reactant: N
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: NC1=NS(=O)(=O)c2c(Br)cccc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2.1 ml of ammonia in methanol (7M) is added at ambient temperature to a solution of 1.85 g of 2-bromo-6-cyano-benzenesulfonyl chloride in 40 ml of tetrahydrofurane. The reaction mixture is stirred for 16 hours at ambient temperature. Then the mixture is poured into water and extracted with ethylacetate. The organic layer is washed with water, dried over sodium sulfate, filtered and concentrated. Chromatography of the residue with cyclohexane—ethyl acetate (1:1) affords 730 mg of 7-bromo-1,1-dioxo-1H-1λ6-benzo[d]isothiazol-3-ylamine (P1.1).
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:30]([NH2:32])=[O:31])[CH:17]=[C:18](B4OC(C)(C)C(C)(C)O4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2].C(=O)([O-])[O-].[Na+].[Na+].Br[C:40]1[CH:41]=[N:42][N:43]([CH2:45][CH2:46][Cl:47])[CH:44]=1>O1CCOCC1.O.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:47][CH2:46][CH2:45][N:43]1[CH:44]=[C:40]([C:18]2[CH:19]=[C:20]3[C:15](=[C:16]([C:30]([NH2:32])=[O:31])[CH:17]=2)[NH:14][CH:13]=[C:12]3[CH:9]2[CH2:10][CH2:11][N:6]([S:3]([CH2:1][CH3:2])(=[O:5])=[O:4])[CH2:7][CH2:8]2)[CH:41]=[N:42]1
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(B4OC(C)(C)C(C)(C)O4)cc23)CC1
Reactant: ClCCn1cc(Br)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cnn(CCCl)c4)cc23)CC1
Temperature: 120 °C
Yield: 23.9 %

Procedure:
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-7-carboxamide (40 mg, 0.090 mmol) in dioxane (750 μL) and H2O (250 μL) was added sodium carbonate (53 mg, 0.50 mmol), and 4-bromo-1-(2-chloroethyl)-1H-pyrazole (26 mg, 0.126 mmol). The reaction mixture was flushed under Argon for 10 min before addition of tetrakis(triphenylphosphine)palladium (0) (5 mg, 0.004 mmol). The reaction was heated in a microwave at 120° C. for 20 min. It was then diluted with EtOAc (10 mL), filtered thru celite, followed by an aqueous work-up. The compound was purified by Gilson Preparatory HPLC to give 10 mg of 5-[1-(2-chloroethyl)-1H-pyrazol-4-yl]-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide (24%).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].C(OC1CCCCC1C(C)(C)C)(=O)C.[H][H]>>[C:1]([C@H:5]1[CH2:10][CH2:9][CH2:8][CH2:7][C@H:6]1[OH:11])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccccc1O
Reactant: [H][H]
Agent: CC(=O)OC1CCCCC1C(C)(C)C
Product: CC(C)(C)[C@H]1CCCC[C@H]1O

Procedure:
A pressurized container fitted with stirrer is charged with 2-tertiary-butylphenol, 2-tertiary-butylcyclohexyl acetate and the catalyst. Hydrogenation is carried out at the chosen reaction temperature and hydrogen pressure. The resulting cis-2-tertiary-butylcyclohexanol is obtained following removal of the catalyst by filtration, decantation or centrifugation.
Reaction SMILES: [C:1](=[O:6])([O:4][CH3:5])OC.C[O-].[Na+].[NH2:10][C:11]1[CH:15]=[C:14]([CH3:16])[O:13][N:12]=1.Cl>C(OCC)(=O)C.O>[CH3:16][C:14]1[O:13][N:12]=[C:11]([NH:10][C:1](=[O:6])[O:4][CH3:5])[CH:15]=1
Reactant: Cc1cc(N)no1
Reactant: COC(=O)OC
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)Nc1cc(C)on1

Procedure:
Dimethyl carbonate (2.38 g) and sodium methoxide (0.30 g) are added to 3-amino-5-methylisoxazole (0.49 g), and the resultant mixture is stirred at 100° C for 3 hours. After cooling, the reaction mixture is combined with water (15 ml), adjusted to pH 1 with a small amount of c. hydrochloric acid and shaken twice with ethyl acetate. The organic layer is washed with water, dried over anhydrous sodium sulfate and evaporated to remove the solvent. The resulting light yellow crystals (0.52 g) are chromatographed on a column of silica gel, whereby methyl N-(5-methyl-3-isoxazolyl)carbamate is obtained as crystals melting at 136.0° to 137.0° C.
Reaction SMILES: [CH3:1][CH:2]1[CH2:8][CH:7]=[CH:6][CH2:5][N:4]([S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)(=[O:11])=[O:10])[CH2:3]1.C([O-])(O)=[O:19].[Na+].C1C=C(Cl)C=C(C(OO)=O)C=1>C(Cl)Cl>[CH3:1][CH:2]1[CH2:8][CH:7]2[CH:6]([O:19]2)[CH2:5][N:4]([S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)(=[O:11])=[O:10])[CH2:3]1
Reactant: CC1CC=CCN(S(=O)(=O)c2ccccn2)C1
Reactant: O=C([O-])O
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: ClCCl
Product: CC1CC2OC2CN(S(=O)(=O)c2ccccn2)C1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To the solution of 3-methyl-1-(pyridine-2-sulfonyl)-2,3,4,7-tetrahydro-1H-azepine (1.3 g, 5.16 mmol) in CH2Cl2 (50 ml) was added NaHCO3 (1.3 g, 15.5 mmol) and then mCPBA (2.67 g, 15.5 mmol) in portions. Stirred at RT for 4 h before worked up by washing with 15% NaOH, saturated K2CO3 and brine. Dried over Na2SO4. The reaction miixture was concentrated by rotary evaporation and two insomers were seperated on column chromatography (30%–40% EtoAc/Hexane). The first elution (trans-isomer, 230 mg) was used in next steps, the second elution (cis-insomer 200 mg) was saved.: MS (M+H+): 269.0; 1H-NMR (400 Hz, CDCl3): d=8.70(d, 1H), 8.0–7.75(m, 2H), 7.50 (m, 1H) 4.39(m, 1H), 3.92(m, 1H), 3.34–2.00(m, 6H), 1.40(m, 1H), 0.88(d, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:33])=[C:6]([C:8]2[C:12]([C:13]#[C:14][C:15]3[CH:20]=[CH:19][C:18]([NH:21][C:22]([C@H:24]4[CH2:29][CH2:28][CH2:27][CH2:26][NH:25]4)=[O:23])=[CH:17][CH:16]=3)=[CH:11][N:10]([CH2:30][CH2:31][OH:32])[N:9]=2)[CH:7]=1.C(OC(N1CCCC[C@H]1C(=O)NC1C=CC(C#CC2C(C3C=C(Cl)C=CC=3O)=NN(CCO)C=2)=CC=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:33])=[C:6]([C:8]2[C:12]([C:13]#[C:14][C:15]3[CH:16]=[CH:17][C:18]([NH:21][C:22]([C@@H:24]4[CH2:29][CH2:28][CH2:27][CH2:26][NH:25]4)=[O:23])=[CH:19][CH:20]=3)=[CH:11][N:10]([CH2:30][CH2:31][OH:32])[N:9]=2)[CH:7]=1
Reactant: O=C(Nc1ccc(C#Cc2cn(CCO)nc2-c2cc(Cl)ccc2O)cc1)[C@H]1CCCCN1
Agent: CC(C)(C)OC(=O)N1CCCC[C@H]1C(=O)Nc1ccc(C#Cc2cn(CCO)nc2-c2cc(Cl)ccc2O)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1ccc(C#Cc2cn(CCO)nc2-c2cc(Cl)ccc2O)cc1)[C@@H]1CCCCN1

Procedure:
Using the same procedure for the preparation of 5A, treatment compound 9A with TFA in methylene chloride to give compound 10A in quantitative yield. Its 1H NMR and LCMS data are identical with those of compound 5A.
Reaction SMILES: [C:1](Cl)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[OH:8][C:9]1[C:26]([O:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[CH:25][C:24]2[C:23]3[C:18](=[CH:19][C:20]([O:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])=[C:21]([O:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH:22]=3)[C:17]3[C:12](=[CH:13][C:14]([O:51][CH2:52][CH2:53][CH2:54][CH2:55][CH3:56])=[C:15]([O:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])[CH:16]=3)[C:11]=2[CH:10]=1>N1C=CC=CC=1.C(OCC)C>[C:1]([O:8][C:9]1[C:26]([O:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[CH:25][C:24]2[C:23]3[C:18](=[CH:19][C:20]([O:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])=[C:21]([O:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH:22]=3)[C:17]3[C:12](=[CH:13][C:14]([O:51][CH2:52][CH2:53][CH2:54][CH2:55][CH3:56])=[C:15]([O:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])[CH:16]=3)[C:11]=2[CH:10]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)C(=O)Cl
Reactant: CCCCCOc1cc2c(cc1O)c1cc(OCCCCC)c(OCCCCC)cc1c1cc(OCCCCC)c(OCCCCC)cc21
Solvent: CCOCC
Solvent: c1ccncc1
Product: CCCCCOc1cc2c3cc(OCCCCC)c(OCCCCC)cc3c3cc(OC(=O)C(C)(C)C)c(OCCCCC)cc3c2cc1OCCCCC
Temperature: 80 °C

Procedure:
181 mg (1.5 mmol) pivaloyl chloride was added to a solution of 673 mg (1 mmol) 2-hydroxy-3,6,7,10,11-pentapentyloxytriphenylene (see Henderson et al., Liquid Crystals 18 (1995) 191) in 1 mL pyridine. The mixture was heated for one hour at 80° C., diluted with diethyl ether and extracted repeatedly with dilute HCl and sodium carbonate solution. Purification was performed by crystallization from ethanol.