Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]([N:23]2[CH2:27][CH2:26][CH2:25][C:24]2=[O:28])=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=3)=[C:7]([C:17]([O:19]CC)=[O:18])[C:6]=2[CH:22]=1.[Li+].[OH-]>O1CCOCC1.O>[Br:1][C:2]1[C:3]([N:23]2[CH2:27][CH2:26][CH2:25][C:24]2=[O:28])=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=3)=[C:7]([C:17]([OH:19])=[O:18])[C:6]=2[CH:22]=1
Reactant: CCOC(=O)c1c(-c2ccc(F)cc2)oc2cc(N3CCCC3=O)c(Br)cc12
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)c1c(-c2ccc(F)cc2)oc2cc(N3CCCC3=O)c(Br)cc12
Temperature: 90 °C
Reaction time: 1 h
Yield: 90.7 %

Procedure:
A solution of ethyl 5-bromo-2-(4-fluorophenyl)-6-(2-oxopyrrolidin-1-yl)benzofuran-3-carboxylate (2.5 g, 5.8 mmol) and LiOH (0.5 g, 21.0 mmol) in dioxane (30 mL) and water (10 mL) was allowed to stir at 90° C. for 1 hour. The mixture was cooled to room temperature and extracted with dichloromethane, the organic extract was washed with brine, dried over Na2SO4 and concentrated to provide 5-bromo-2-(4-fluorophenyl)-6-(2-oxopyrrolidin-1-yl)benzofuran-3-carboxylic acid (2.2 g, yield: 91%). 1H-NMR (CDCl3, 400 MHz) δ 8.08 (s, 1H), 7.81˜7.84 (m, 2H), 7.34 (s, 1H), 6.89˜6.93 (m, 2H), 3.79˜3.82 (m, 2H), 2.66˜2.70 (m, 2H), 2.26˜2.31 (m, 2H). MS (M+H)+: 418/420.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[N:5]=[CH:4][C:3]=1[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13]>[Pd].C(O)C>[CH3:1][C:2]1[CH:7]=[C:6]([NH2:8])[N:5]=[CH:4][C:3]=1[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)Cc1cnc([N+](=O)[O-])cc1C
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)Cc1cnc(N)cc1C
Reaction time: 2 h

Procedure:
A mixture of ethyl (4-methyl-6-nitropyridin-3-yl)acetate (1.65 g, 7.36 mmol) and palladium on carbon (10%, 1.57 g, 1.47 mmol) in Ethanol (10 mL) was evacuated and refilled with nitrogen (3×), then stirred under an atmosphere of hydrogen for 2 h. The reaction mixture was filtered through celite and concentrated in vacuoto provide title compound which was used directly in the next reaction without further purification: LC-MS (IE, m/z): 195 [M+1]+.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH:5]([N:8]1[C:12]([C:13]([F:16])([F:15])[F:14])=[C:11]([CH2:17]O)[CH:10]=[N:9]1)([CH3:7])[CH3:6]>C(Cl)Cl>[Cl:3][CH2:17][C:11]1[CH:10]=[N:9][N:8]([CH:5]([CH3:7])[CH3:6])[C:12]=1[C:13]([F:16])([F:15])[F:14]
Reactant: O=S(Cl)Cl
Reactant: CC(C)n1ncc(CO)c1C(F)(F)F
Solvent: ClCCl
Product: CC(C)n1ncc(CCl)c1C(F)(F)F
Reaction time: 2 h
Yield: 86 %

Procedure:
Thionyl chloride (5.26 mL, 72 mmol) was added to [1-isopropyl-5-(trifluoromethyl)-1H-pyrazol-4-yl]methanol (Preparation 183, 7.5 g, 36 mmol) in DCM (75 mL) at 0° C. and the mixture was stirred for 2 hours. The mixture was diluted with DCM (30 mL) and the organic phase was washed with water (75 mL), brine (75 mL) and dried over sodium sulphate. The filtrate was evaporated in vacuo to afford 4-(chloromethyl)-1-isopropyl-5-(trifluoromethyl)-1H-pyrazole in 86% yield, 7 g.
Reaction SMILES: [Mg].[CH3:2]I.[CH3:4][CH:5]1[CH2:10][CH:9]([CH2:11][CH2:12][CH:13]([CH3:15])[CH3:14])[CH2:8][CH:7]([CH3:16])[C:6]1=[O:17]>CCOCC>[CH3:2][C:6]1([OH:17])[CH:7]([CH3:16])[CH2:8][CH:9]([CH2:11][CH2:12][CH:13]([CH3:15])[CH3:14])[CH2:10][CH:5]1[CH3:4]
Reactant: CC(C)CCC1CC(C)C(=O)C(C)C1
Reactant: CI
Agent: [Mg]
Solvent: CCOCC
Product: CC(C)CCC1CC(C)C(C)(O)C(C)C1
Reaction time: 1 h
Yield: 62.8 %

Procedure:
To a Grignard solution prepared from magnesium (14.5 g, 0.6 g-atom) and methyl iodide (85.2 g, 0.6 mol) in anhydrous ether (500 mL) was added 2,6-dimethyl-4-(3-methylbutyl)cyclohexanone (59 g, 0.3 mol, produced according to Example 8) over 1 h at 15°-20° C. The mixture was stirred for an additional 1 h and then quenched into saturated ammonium chloride solution. The layers were separated and the aqueous solution was extracted with ether. The combined extracts were washed with 5% sodium bicarbonate solution, brine and then dried. Solvent removal and distillation gave 40 g of the alcohol, bp 92° C. (1 mm). NMR (CDCl3) δ0.8-1.1 (12H, m), 1.1-2.2 (16H, complex pattern with a singlet at 1.2). IR (film) 3550, 1025, 920, 890 cm-1. MS (m/e) 212 (M+), 85, 43, 57, 86.
Reaction SMILES: [CH2:1]([C:3]([C:16]1[CH:29]=[CH:28][C:19]([O:20][CH2:21][C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24])=[C:18]([CH3:30])[CH:17]=1)([C:6]1[O:7][C:8]2[CH:14]=[C:13]([OH:15])[CH:12]=[CH:11][C:9]=2[CH:10]=1)[CH2:4][CH3:5])[CH3:2].CCN(CC)CC.[CH3:38][S:39](Cl)(=[O:41])=[O:40]>C(Cl)Cl>[CH3:26][C:23]([CH3:25])([CH3:24])[C:22](=[O:27])[CH2:21][O:20][C:19]1[CH:28]=[CH:29][C:16]([C:3]([C:6]2[O:7][C:8]3[CH:14]=[C:13]([O:15][S:39]([CH3:38])(=[O:41])=[O:40])[CH:12]=[CH:11][C:9]=3[CH:10]=2)([CH2:4][CH3:5])[CH2:1][CH3:2])=[CH:17][C:18]=1[CH3:30]
Reactant: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1cc2ccc(O)cc2o1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1cc2ccc(OS(C)(=O)=O)cc2o1
Reaction time: 0.5 h
Yield: 93.4 %

Procedure:
A solution of 1-{4-[1-ethyl-1-(6-hydroxy-benzofuran-2-yl)-propyl]-2-methyl-phenoxy}-3,3-dimethyl-butan-2-one (116 mg, 0.407 mmol) and Et3N (0.20 mL) in CH2Cl2 (5.0 mL) at 0° C. is added methanesulfonic chloride (70 mg, 0.610 mmol). The resulting mixture is stirred for 30 min and quenched with MeOH (1.0 mL). The mixture is purified on column chromatography (25% EtOAc/Hex) to afford the title compound (185 mg, 93%).
Reaction SMILES: [O:1]=[C:2]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4][CH2:3]1.[Br:16]Br.CCN(CC)CC.CC(OC(OC(OC(C)(C)C)=O)=O)(C)C>C(Cl)(Cl)Cl>[Br:16][CH:8]1[C:2](=[O:1])[CH2:3][CH2:4][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:6][CH2:7]1
Reactant: CC(C)(C)OC(=O)N1CCCC(=O)CC1
Reactant: BrBr
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCC(=O)C(Br)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 26.5 %

Procedure:
To a solution tert-butyl 4-oxoazepane-1-carboxylate (429.2, 11.0 g, 51.6 mmol, 1.00 equiv) in chloroform (220 mL) 0° C. was added dropwise solution of Br2 (12.4 g, 77.6 mmol, 1.50 equiv) in chloroform (110 mL). The resulting mixture was stirred at room temperature overnight. The formed solids were collected by filtration and taken up in 200 mL of dichloromethane. Et3N (12.2 g) and (Boc)2O (8.70 g, 40.3 mmol, 1.00 equiv) were added to the mixture at 0° C. The resulting solution was stirred for 3 h at room temperature, and then concentrated under pressure. The crude residue was purified by silica gel chromatography using ethyl acetate/petroleum ether (1:10) as eluent to give 4.00 g (27%) of the title compound as a yellow oil.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]3[CH:15]=[CH:14][CH:13]=[CH:12][C:6]3=[CH:7][CH:8]=2)[N:3]=1.C([Li])CCC.CCCCCC.CN(C)[C:29](=[O:31])[CH3:30].Cl>C1COCC1>[N:3]1[C:4]2[C:9](=[CH:8][CH:7]=[C:6]3[CH:12]=[CH:13][CH:14]=[CH:15][C:5]3=2)[CH:10]=[CH:11][C:2]=1[C:29](=[O:31])[CH3:30]
Reactant: CC(=O)N(C)C
Reactant: Brc1ccc2ccc3ccccc3c2n1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(=O)c1ccc2ccc3ccccc3c2n1
Temperature: -78 °C
Reaction time: 1 h
Yield: 76.7 %

Procedure:
A solution of 2-bromobenzo[h]quinoline (1.52 g, 5.89 mmol) in THF (36 ml) was cooled to −78° C. After 10 minutes a solution of 2.5 M n-butyllithium in n-hexane (2.47 ml, 6.18 mmol) was added. The resulting dark red solution was again stirred at −78° C. for 1 hour after which N,N-dimethylacetamide (0.60 ml, 6.45 mmol) was added drop-wise. The solution was stirred for 1 h at −78° C. and allowed to warm slowly to ambient temperature. A solution of 1 M HCl (7.4 ml, 7.4 mmol) was then added, the organic phase was separated and the aqueous phase was extracted with Et2O (2×15 ml). The organic phases were combined, dried over anhydrous Na2SO4 and the solvent evaporated under reduced pressure. The residue was purified by flash chromatography (petroleum ether/acetate=95/5) to give 1.00 g (77% yield) of 1-(benzo[h]quinolin-2-yl)ethanone in the form of a yellow solid: mp 113-115° C.
Reaction SMILES: [Sn](Cl)Cl.[CH2:4]([O:6][C:7]([C:9]1[CH:10]=[N:11][N:12]([CH3:25])[C:13]=1[NH:14][C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][C:16]=1[N+:22]([O-])=O)=[O:8])[CH3:5]>CO>[CH2:4]([O:6][C:7]([C:9]1[CH:10]=[N:11][N:12]([CH3:25])[C:13]=1[NH:14][C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][C:16]=1[NH2:22])=[O:8])[CH3:5]
Reactant: CCOC(=O)c1cnn(C)c1Nc1ccc(C)cc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Solvent: CO
Product: CCOC(=O)c1cnn(C)c1Nc1ccc(C)cc1N
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 52 %

Procedure:
Tin (II) chloride (86.65 g, 457.0 mmol) was added to a solution of 1-methyl-5-(4-methyl-2-nitro-phenylamino)-1H-pyrazole-4-carboxylic acid ethyl ester from Example E2.1 (28.00 g, 91.4 mmol) in methanol and the mixture heated at reflux for 3 days. The solvent was removed in vacuo and the residue taken up in EtOAc (400 ml) and cooled to 0° C. 35% Ammonia solution was added to pH 14, and the mixture was stirred for 15 min before being filtered through Celite® filter agent. The filtrate was washed with 2M NH3 and brine and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; 6% methanol:94% dichloromethane rising to 10% methanol:90% dichloromethane) to yield the title compound (12.8 g, 52%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8]CC(C)=C)=[CH:4][CH:3]=1.[C:13](OC)([CH3:16])([CH3:15])[CH3:14]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:8])=[C:6]([CH2:15][C:13]([CH3:16])=[CH2:14])[CH:7]=1
Reactant: C=C(C)COc1ccc(Br)cc1
Reactant: COC(C)(C)C
Solvent: CN(C)C=O
Product: C=C(C)Cc1cc(Br)ccc1O
Temperature: 25 °C
Yield: 65 %

Procedure:
A solution of 1-bromo-4-(2-methylallyloxy)benzene (6) (1.0 g, 4.4 mmol) in DMF (8 mL) was heated in a microwave reactor at 190° C. for 2 h. After cooling to room temperature, the reaction mixture was diluted with methyl tert-butyl ether (50 mL), and washed with H2O (25 mL), brine (25 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, eluting with 5% ethyl acetate in hexanes) to give the title compound (7) (0.7 g, 65%) as a liquid. 1H NMR (CDCl3, 400 MHz) δ 7.27-7.25 (m, 2H), 6.72 (d, J=8.4 Hz, 1H), 4.95 (s, 1H), 4.86 (s, 1H), 3.34 (s, 2H), 1.74 (s, 3H); MS (ESI, M+H+) C10H12BrO, calcd. 227.1. found 227.0, 229.0.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][O:8][C:9]2[C:13]([CH2:14][CH2:15][C:16]([O:18]CC)=[O:17])=[CH:12][N:11]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]4[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=4)=[CH:24][CH:23]=3)[N:10]=2)[CH:2]=1.[OH-].[Na+].O1CCCC1.C(O)C>Cl>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][O:8][C:9]2[C:13]([CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[CH:12][N:11]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]4[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=4)=[CH:24][CH:23]=3)[N:10]=2)[CH:2]=1
Reactant: CCOC(=O)CCc1cn(Cc2ccc(OCc3cccnc3)cc2)nc1OCc1cccnc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(O)CCc1cn(Cc2ccc(OCc3cccnc3)cc2)nc1OCc1cccnc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.8 %

Procedure:
A mixture of ethyl 3-[3-(3-pyridylmethoxy)-1-[4-(3-pyridylmethoxy)benzyl]-1H-pyrazol-4-yl]propionate (529 mg), 1 N aqueous sodium hydroxide solution (3 ml), tetrahydrofuran (6 ml), and ethanol (6 ml) was stirred at room temperature for one hour, diluted with 1 N hydrochloric acid (3 ml), and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The obtained colorless crystals were collected by filtration, and 3-[3-(3-pyridylmethoxy)-1-[4-(3-pyridylmethoxy)benzyl]-1H-pyrazol-4-yl]propionic acid (427 mg, yield: 86%) was obtained. This was recrystallized from ethanol-hexane. Melting point: 116–117° C.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[O:3][C:4]1[CH:11]=[CH:10][C:7]([CH2:8]Br)=[CH:6][CH:5]=1.[OH:14][C:15]1[CH:23]=[CH:22][C:18]([CH2:19][C:20]#[N:21])=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.O>[F:1][C:2]([F:13])([F:12])[O:3][C:4]1[CH:11]=[CH:10][C:7]([CH2:8][O:14][C:15]2[CH:23]=[CH:22][C:18]([CH2:19][C:20]#[N:21])=[CH:17][CH:16]=2)=[CH:6][CH:5]=1
Reactant: FC(F)(F)Oc1ccc(CBr)cc1
Reactant: N#CCc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: N#CCc1ccc(OCc2ccc(OC(F)(F)F)cc2)cc1
Yield: 89.5 %

Procedure:
A mixture of 4-(trifluoromethoxy)benzyl bromide (2.5 g, 10 mmol), 4-hydroxybenzyl cyanide (1.1 g, 8 mmol) and potassium carbonate (1.4 g, 10 mmol) in acetone (25 mL) was heated to reflux for 7 hours. The mixture was then diluted with H2O (100 mL) and extracted with EtOAc (2×150 mL). Organics portions were combined and washed with brine and then dried with Na2SO4. The mixture was then filtered and the solvent was removed in vacuo affording 2.5 g of crude product. Purification by flash chromatography eluting with 30 percent ether/pentane over silica gel yielded 2.2 g of a white solid.
Reaction SMILES: C([O:8][C:9]1[C:23]([O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[F:31])=[CH:22][C:12]2[NH:13][C:14]([C:16]3[CH:21]=[N:20][CH:19]=[CH:18][N:17]=3)=[N:15][C:11]=2[CH:10]=1)C1C=CC=CC=1.[H][H]>[OH-].[Pd+2].[OH-].[C].CO.O1CCCC1>[F:31][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[O:24][C:23]1[C:9]([OH:8])=[CH:10][C:11]2[NH:15][C:14]([C:16]3[CH:21]=[N:20][CH:19]=[CH:18][N:17]=3)=[N:13][C:12]=2[CH:22]=1
Reactant: [H][H]
Reactant: Fc1ccccc1Oc1cc2[nH]c(-c3cnccn3)nc2cc1OCc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Oc1cc2[nH]c(-c3cnccn3)nc2cc1Oc1ccccc1F

Procedure:
500 mg of 20% palladium hydroxide-carbon catalyst was added to a suspension of 697 mg of 5-benzyloxy-6-(2-fluorophenoxy)-2-pyrazin-2-yl-1H-benzimidazole obtained in Example 250, in 10 ml of methanol and 10 ml of tetrahydrofuran, and the reaction liquid was stirred in a hydrogen atmosphere at room temperature for 1 hour. The catalyst was removed through filtration through Celite, the solvent was evaporated away under reduced pressure, and the residue was purified through silica gel column chromatography (developing solvent: ethyl acetate) to obtain the entitled compound as a yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:30])[CH2:5][N:6]1[CH2:11][CH2:10][NH:9][C@@H:8]([CH2:12][CH2:13][C:14]([NH:16][CH2:17][NH:18][S:19]([C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=2)(=[O:21])=[O:20])=[NH:15])[C:7]1=[O:29])[CH3:2].[CH2:31]([O:38][C:39](ON1C(=O)CCC1=O)=[O:40])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C(N(CC)CC)C>CN(C=O)C.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([CH2:5][N:6]1[CH2:11][CH2:10][N:9]([C:39]([O:38][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:40])[C@@H:8]([CH2:12][CH2:13][C:14]([NH:16][CH2:17][NH:18][S:19]([C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=2)(=[O:20])=[O:21])=[NH:15])[C:7]1=[O:29])=[O:30])[CH3:2]
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Reactant: CCOC(=O)CN1CCN[C@@H](CCC(=N)NCNS(=O)(=O)c2ccc(C)cc2)C1=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCOC(=O)CN1CCN(C(=O)OCc2ccccc2)[C@@H](CCC(=N)NCNS(=O)(=O)c2ccc(C)cc2)C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.1 %

Procedure:
A mixture of the compound of Example 10 (0.43 mmol), N-(benzyloxycarbonyloxy)succinimide (107 mg, 0.43 mmol) and triethylamine (0.24 mL, 1.72 mmol) in DMF (3 mL) was stirred at room temperature overnight. The mixture was diluted with ethyl acetate and the organic layer was washed with water three times, dried over anhydrous Na2SO4, filtered and evaporated to give the title compound (195 mg).
Reaction SMILES: [C:1]1([NH:7][S:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH:17]=[CH:18][C:19]([OH:21])=O)(=[O:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:22]CCl>CN(C)C=O>[C:1]1([NH:7][S:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH:17]=[CH:18][C:19]([Cl:22])=[O:21])(=[O:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: ClCCl
Reactant: O=C(O)C=Cc1ccccc1S(=O)(=O)Nc1ccccc1
Solvent: CN(C)C=O
Product: O=C(Cl)C=Cc1ccccc1S(=O)(=O)Nc1ccccc1
Temperature: 40 °C
Reaction time: 1 h
Yield: 100.1 %

Procedure:
To a suspension of 3-(2-phenylsulfamoyl-phenyl)acrylic acid (35a) (0.18 g, 0.59 mmol) in dichloromethane (3.0 ml) oxalyl chloride (0.18 ml, 2.06 mmol) and one drop of dimethylformamide were added. The reaction mixture was stirred at 40° C. for one hour and concentrated under reduced pressure to give crude title compound (0.19 g, 99%).
Reaction SMILES: C(OC([NH:11][C@H:12]([C:14]([NH:16][C@H:17]([C:19]([NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:20])[CH3:18])=[O:15])[CH3:13])=O)C1C=CC=CC=1.CCOCC.[BrH:33]>C(O)(=O)C>[BrH:33].[NH2:11][C@H:12]([C:14]([NH:16][C@H:17]([C:19]([NH:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)=[O:20])[CH3:18])=[O:15])[CH3:13]
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](C)C(=O)Nc1ccccc1
Agent: Br
Solvent: CCOCC
Solvent: CC(=O)O
Product: C[C@H](N)C(=O)N[C@@H](C)C(=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88 %

Procedure:
5.5 g (0.0149 g) of N-benzyloxycarbonyl-L-alanyl-L-alanine anilide were dissolved in 30 ml of 4-N hydrogen bromide in acetic acid and the solution was stirred at room temperature for 1 hour. 300 ml of dry ether were then added. A white solid separated out and was allowed to settle. The solution was decanted off and the solid washed with two 150 ml portions of ether. Recrystallisation of the solid from methanol/ethyl acetate yielded 4.1 g (88%) of L-alanyl-L-alanine anilide hydrobromide.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]2[O:6][C:7]3[CH:22]=[CH:21][CH:20]=[CH:19][C:8]=3[CH2:9][N:10]([C:11]([NH:13][CH2:14][C:15](=[O:18])[CH:16]=[CH2:17])=[O:12])[C:4]=2[CH:3]=1.[CH2:25]([SH:27])[CH3:26].N1CCCCC1.[OH-].C([N+](C)(C)C)C1C=CC=CC=1>C(Cl)Cl.CO>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]2[O:6][C:7]3[CH:22]=[CH:21][CH:20]=[CH:19][C:8]=3[CH2:9][N:10]([C:11]([NH:13][CH2:14][C:15](=[O:18])[CH2:16][CH2:17][S:27][CH2:25][CH3:26])=[O:12])[C:4]=2[CH:3]=1
Reactant: C=CC(=O)CNC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21
Reactant: CCS
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Solvent: C1CCNCC1
Solvent: CO
Solvent: ClCCl
Product: CCSCCC(=O)CNC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21

Procedure:
A solution of 8-chloro-N-(2-oxo-3-butenyl)dibenz[b,f][1,4]oxazepin-10(11H)-carboxamide (1.00 gram), ethanethiol (0.23 mL), piperidine (0.092 mL), and N-benzyltrimethylammonium hydroxide (0.092 mL) in methylene chloride (16 mL) and methanol (4 mL) was stirred at room temperature for 5 hours. The reaction was diluted with methylene chloride (100 mL), washed with 100 mL each of 1N HCl (two times), water, saturated aqueous sodium bicarbonate, and brine, dried over MgSO4, and evaporated in vacuo. The crude product was purified by flash chromatography through silica gel 60 (350 mL) using 92:8 methylene chloride: ethyl acetate to yield a colorless oil. The yield of the title compound was 0.38 gram. (32%).
Reaction SMILES: I[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-:24])=[O:23])[CH:17]=2)=[N:4][N:5]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)[CH:6]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[F:31][C:32]1[C:37](B(O)O)=[CH:36][CH:35]=[CH:34][N:33]=1>O1CCOCC1.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>[F:31][C:32]1[CH:37]=[C:36]([C:2]2[C:3]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-:24])=[O:23])[CH:17]=3)=[N:4][N:5]([CH2:7][C:8]3[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=3)[CH:6]=2)[CH:35]=[CH:34][N:33]=1
Reactant: OB(O)c1cccnc1F
Reactant: COc1ccc(Cn2cc(I)c(-c3cccc([N+](=O)[O-])c3)n2)cc1
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: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(Cn2cc(-c3ccnc(F)c3)c(-c3cccc([N+](=O)[O-])c3)n2)cc1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
1 g (2.3 mmol) of 4-iodo-1-(4-methoxybenzyl)-3-(3-nitrophenyl)-1H-pyrazole (prepared as described in Example 27) were dissolved in a mixture of 20 ml of dioxane and 5 ml of water in a nitrogen atmosphere. 750 mg (2.3 mmol) of cesium carbonate, 350 mg (0.3 mmol) of palladium tetrakis and 486 mg (3.45 mmol) of 2-fluoro-pyridyl boronic acid were added and the reaction stirred at 100° C. for 4 hours. The mixture was then filtered through a celite pad and the filtrate evaporated under reduced pressure. The residue was re-dissolved with dichloromethane and washed with water. The organic layer was dried over sodium sulphate and evaporated. 680 mg (73%) of the title compound crystallized from diethylether.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:12])[CH:8]=2)[N:3]=1.[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1.Cl>C(O)C>[Cl:12][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)[CH:11]=[CH:10]2
Reactant: Clc1ccc2nc(Cl)ccc2c1
Reactant: Nc1ccc(O)cc1
Agent: Cl
Solvent: CCO
Product: Oc1ccc(Nc2ccc3cc(Cl)ccc3n2)cc1
Yield: 33 %

Procedure:
A mixture of 2,6-dichloroquinoline (6.0 g), 4-aminophenol (3.3 g), hydrochloric acid (3 g) and ethanol (100 ml) was stirred and refluxed for 10 hours. The solvent was removed under reduced pressure and the residue partitioned between ethyl acetate and water. The ethyl acetate extracts on evaporation gave 4-[N-(6-chloro-2-quinolinyl)-amino]phenol (2.7 g) as a brown solid.
Reaction SMILES: [C:1]([N:5]1[C:9](=[O:10])[C:8](Cl)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])([CH3:4])([CH3:3])[CH3:2].[O:20]1[CH2:25][CH2:24][N:23]([C:26]2[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][CH:27]=2)[CH2:22][CH2:21]1.CCOC(C)=O>CN(C=O)C>[C:1]([N:5]1[C:9](=[O:10])[C:8]([NH:30][C:29]2[CH:28]=[CH:27][C:26]([N:23]3[CH2:24][CH2:25][O:20][CH2:21][CH2:22]3)=[CH:32][CH:31]=2)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])([CH3:4])([CH3:3])[CH3:2]
Reactant: Nc1ccc(N2CCOCC2)cc1
Reactant: CC(C)(C)N1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)N1C(=O)C(Nc2ccc(N3CCOCC3)cc2)=C(c2ccccc2)S1(=O)=O
Yield: 55.9 %

Procedure:
A solution of 2-tert-butyl-4-chloro-5-phenylisothiazol-3(2H)-one 1,1-dioxide (0.400 g, 1.33 mmol) and 4-morpholinoaniline (0.476 g, 2.67 mmol) in DMF (4 mL) was heated at 140° C. for 15 mins in a microwave reactor. EtOAc was then added, and the resulting mixture was washed with brine and evaporated. The residue was purified by silica gel column chromatography using a 1:1 mixture of petroleum ether and EtOAc as eluant, to give the title compound (0.328 g, 56%) as a solid; 1H NMR (500 MHz, CDCl3): δ 7.23-7.18 (m, 1H), 7.15-7.09 (m, 4H), 6.62 (d, 2H), 6.52 (d, 2H), 3.83 (t, 4H), 3.00 (t, 4H), 1.79 (s, 9H); Mass Spectrum: M−H+ 440.