Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH2:23][N:24]([CH3:31])[CH:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[CH:19][CH:18]=3)=[O:15])=[CH:7][C:6]=2[CH:32]=1.B([O-])([O-])O[C:35]1[CH:40]=[CH:39][C:38]([CH2:41][CH2:42][CH2:43][O:44][CH2:45][CH3:46])=[CH:37][CH:36]=1.C(=O)([O-])[O-].[K+].[K+].C(O)C>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.C1(C)C=CC=CC=1>[CH2:45]([O:44][CH2:43][CH2:42][CH2:41][C:38]1[CH:39]=[CH:40][C:35]([C:2]2[CH:3]=[CH:4][C:5]3[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([NH:16][C:17]4[CH:18]=[CH:19][C:20]([CH2:23][N:24]([CH3:31])[CH:25]5[CH2:30][CH2:29][O:28][CH2:27][CH2:26]5)=[CH:21][CH:22]=4)=[O:15])=[CH:7][C:6]=3[CH:32]=2)=[CH:36][CH:37]=1)[CH3:46]
Reactant: CCOCCCc1ccc(OB([O-])[O-])cc1
Reactant: CN(Cc1ccc(NC(=O)C2=Cc3cc(Br)ccc3S(=O)(=O)CC2)cc1)C1CCOCC1
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: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCOCCCc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCS3(=O)=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.8 %

Procedure:
A mixture of 7-bromo-N-[4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (0.3 g), 4-(3-ethoxypropyl)phenyl borate (0.18 g), 1M potassium carbonate solution (1.3 ml), ethanol (1.3 ml) and toluene (25 ml) was stirred under argon atmosphere at room temperature for 30 minutes. To the mixture was added tetrakistriphenylphosphinepalladium (0.03 g), and the mixture was refluxed under argon atmosphere for 6 hours and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried with anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified with silica gel column chromatography (ethyl acetate/methanol/triethylamine) to give crude crystals, which were recrystallized from ethanol to give 7-[4-(3-ethoxypropyl)phenyl]-N-[4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 123) (0.25 g) as colorless crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9].C(N(CC)CC)C.[CH3:17][S:18](Cl)(=[O:20])=[O:19]>ClCCl>[CH3:17][S:18]([O:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[O:2][CH3:1])(=[O:20])=[O:19]
Reactant: COc1ccccc1O
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccccc1OS(C)(=O)=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To a solution of 2-methoxyphenol (50 g, 402.8 mmol) and triethylamine (84.2 mL, 604.2 mmol) in anhydrous dichloromethane (300 mL), was added methanesulfonyl chloride (37.6 mL, 483.3 mmol) at 0° C. under nitrogen. The reaction mixture was stirred at 0° C. for 2 hours, quenched with ice water (250 mL) and transferred to a separatory funnel. The organic phase was washed with a solution of NaOH (8 g) in ice water (200 mL), brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound as a colorless liquid (81.44 g, 100%). 1H NMR (400 MHz, DMSO-d6) δ 3.32 (s, 3H), 3.83 (s, 3H), 6.96-7.0 (m, 1H), 7.18-7.2 (m, 1H), 7.27-7.33 (m, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[O:5][C:6]1[C:11]([Cl:12])=[CH:10][C:9]([C:13]([F:16])([F:15])[F:14])=[CH:8][N:7]=1.[Br:20]Br>C(Cl)(Cl)Cl>[OH:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[Br:20])[O:5][C:6]1[C:11]([Cl:12])=[CH:10][C:9]([C:13]([F:16])([F:15])[F:14])=[CH:8][N:7]=1
Reactant: Oc1cccc(Oc2ncc(C(F)(F)F)cc2Cl)c1
Reactant: BrBr
Solvent: ClC(Cl)Cl
Product: Oc1cc(Oc2ncc(C(F)(F)F)cc2Cl)ccc1Br
Yield: 42.9 %

Procedure:
In 150 ml of chloroform, 5.5 g of 2-(3-hydroxyphenoxy)-3-chloro-5-trifluoromethyl pyridine was dissolved and then, 3.5 g of bromine was added dropwise to the solution at a temperature of 10° to 15° C. After the reaction, the reaction product was washed with water, with a sodium bicarbonate aqueous solution, with a saturated sodium thiosulfate solution and then, with water and dried over anhydrous sodium sulfate. Chloroform was distilled off under a reduced pressure and the resulting crystals were washed with hexane and dried to obtain 3.0 g of 2-(3-hydroxy-4-bromophenoxy)-3-chloro-5-trifluoromethyl pyridine having a melting point of 124° to 127° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([CH:17]([CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)[OH:18])=[C:15]3[C:10]([CH:11]=[C:12]([F:26])[C:13]([F:25])=[CH:14]3)=[N:9]2)=[CH:4][CH:3]=1.C[O:28][C:29]([C:31]1([O:34][C:35]2[CH:40]=[CH:39][C:38](O)=[CH:37][CH:36]=2)[CH2:33][CH2:32]1)=[O:30].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]([CH:17]([CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)[O:18][C:38]3[CH:39]=[CH:40][C:35]([O:34][C:31]4([C:29]([OH:30])=[O:28])[CH2:33][CH2:32]4)=[CH:36][CH:37]=3)=[C:15]3[C:10]([CH:11]=[C:12]([F:26])[C:13]([F:25])=[CH:14]3)=[N:9]2)=[CH:6][CH:7]=1
Reactant: OC(c1c2cc(F)c(F)cc2nn1-c1ccc(Cl)cc1)C1CCCCC1
Reactant: COC(=O)C1(Oc2ccc(O)cc2)CC1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C(O)C1(Oc2ccc(OC(c3c4cc(F)c(F)cc4nn3-c3ccc(Cl)cc3)C3CCCCC3)cc2)CC1

Procedure:
In analogy to the procedure described in example 29.2, [rac]-[2-(4-chloro-phenyl)-5,6-difluoro-2H-indazol-3-yl]-cyclohexyl-methanol (example 24.4) was reacted with 1-(4-hydroxy-phenoxy)-cyclopropanecarboxylic acid methyl ester (Hazeldine, Stuart T.; Polin, Lisa; Kushner, Juiwanna; White, Kathryn; Corbett, Thomas H.; Horwitz, Jerome P. Bioorganic & Medicinal Chemistry (2005), 13(12), 3910-3920) in the presence of tri-phenylphosphine and di-tert-butyl azodicarboxylate in THF to give the title compound as white solid. MS: m/e=567.4 [M+H4].
Reaction SMILES: [F:1][CH:2]([F:27])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:11][CH:12]=[C:13]([CH2:15][NH:16][C:17](=[O:25])[C:18]3[C:23]([CH3:24])=[CH:22][CH:21]=[CH:20][N:19]=3)[N:14]=2)=[CH:6][C:5]=1[OH:26].Br[CH:29]([CH2:32][CH3:33])[CH2:30][CH3:31]>>[F:27][CH:2]([F:1])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:11][CH:12]=[C:13]([CH2:15][NH:16][C:17](=[O:25])[C:18]3[C:23]([CH3:24])=[CH:22][CH:21]=[CH:20][N:19]=3)[N:14]=2)=[CH:6][C:5]=1[O:26][CH:29]([CH2:32][CH3:33])[CH2:30][CH3:31]
Reactant: CCC(Br)CC
Reactant: Cc1cccnc1C(=O)NCc1coc(-c2ccc(OC(F)F)c(O)c2)n1
Product: CCC(CC)Oc1cc(-c2nc(CNC(=O)c3ncccc3C)co2)ccc1OC(F)F

Procedure:
Using the compound obtained in Example 97 and 3-bromopentane, colorless oily N-{2-[4-difluoromethoxy-3-(1-ethylpropoxy)phenyl]oxazol-4-ylmethyl}-3-methylpicolinamide was obtained following the procedure of Example 3.
Reaction SMILES: [C:1]([O:5][C:6](=[O:39])[NH:7][CH2:8][C:9]1[C:10]([Br:38])=[N:11][C:12]([N:15]2[CH2:19][CH2:18][C:17]([C:24]3[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[C:26]([C:34]([F:37])([F:36])[F:35])[CH:25]=3)([C:20]([F:23])([F:22])[F:21])[CH2:16]2)=[CH:13][CH:14]=1)([CH3:4])([CH3:3])[CH3:2].C(#N)C.[N+]([O-])([O-])=[O:44].[NH4+].[Ce]>C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:39])[NH:7][CH2:8][C:9]1[C:10]([Br:38])=[N:11][C:12]([N:15]2[CH2:19][CH2:18][C:17]([C:24]3[CH:29]=[C:28]([C:30]([F:31])([F:32])[F:33])[CH:27]=[C:26]([C:34]([F:37])([F:35])[F:36])[CH:25]=3)([C:20]([F:22])([F:23])[F:21])[CH:16]2[OH:44])=[CH:13][CH:14]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCc1ccc(N2CCC(c3cc(C(F)(F)F)cc(C(F)(F)F)c3)(C(F)(F)F)C2)nc1Br
Reactant: O=[N+]([O-])[O-]
Agent: [Ce]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(C)(C)OC(=O)NCc1ccc(N2CCC(c3cc(C(F)(F)F)cc(C(F)(F)F)c3)(C(F)(F)F)C2O)nc1Br
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a mixture of t-butyl[(6-{3-[3,5-bis(trifluoromethyl)phenyl]-3-(trifluoromethyl)-pyrrolidin-1-yl}-2-bromopyridin-3-yl)methyl]carbamate (0.5 g) and acetonitrile (30 ml), which had been stirred in ice water bath, a 1 M aqueous solution of cerium ammonium nitrate (IV) (1.6 ml) was added, stirred approximately for 10 minutes and the reaction mixture was diluted with ethyl acetate. After that, the mixture was washed with an aqueous solution of sodium thiosulfate and then an aqueous saturated brine solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel chromatography to obtain t-butyl[(6-{3-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxy-3-(trifluoromethyl)pyrrolidin-1-yl}-2-bromopyridin-3-yl)methyl]carbamate (0.35 g).
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[C:11]4[CH2:19][CH2:18][O:17][C:16](=[O:20])[C:12]4=[N:13][CH:14]=3)[CH:9]=[CH:8]2)=[CH:4][CH:3]=1.[OH-:23].[Na+].Cl>CO.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:15]3=[CH:14][N:13]=[C:12]([C:16]([OH:17])=[O:20])[C:11]([CH2:19][CH2:18][OH:23])=[C:10]3[CH:9]=[CH:8]2)=[CH:21][CH:22]=1
Reactant: O=C1OCCc2c1ncc1c2ccn1Cc1ccc(F)cc1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: O=C(O)c1ncc2c(ccn2Cc2ccc(F)cc2)c1CCO
Temperature: 60 °C
Yield: 94.6 %

Procedure:
To 7-(4-fluorobenzyl)-1,7-dihydropyrano[3,4-b]pyrrolo[3,2-d]pyridin-4(2H)-one (0.11 g, 0.37 mmol) in methanol (10 mL) was added sodium hydroxide (0.066 g, 1.65 mmol) in water (2.0 mL). The reaction was heated to 60° C. for 3 hours. After cooling down, the reaction mixture was neutralized with 4N hydrochloric acid (0.42 mL, 1.65 mmol). It was concentrated and dried in vacuo to provide the crude title compound as a white powder (0.11 g, 94%). 1H NMR (DMSO-d6) δ; 8.93 (d, 1H, J=1.9 Hz), 8.06 (s, 1H), 7.36 (m, 2H), 7.16 (t, 2H, J=6.6 Hz), 6.96 (s, 1H), 5.63 (s, 2H), 3.66 (t, 2H, J=6.8 Hz), 3.44 (t, 2H, J=6.8 Hz). LCMS (APCl, M+H+): 315.1.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:8]([N:10]=[C:11]=[S:12])=[O:9])[CH:5]=[CH:6][CH:7]=1.[CH3:13][O:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][C:24]=1[O:25][CH3:26])[N:21]=[CH:20][CH:19]=[C:18]2[O:27][C:28]1[CH:34]=[CH:33][C:31]([NH2:32])=[C:30]([CH3:35])[C:29]=1[CH3:36].C1(C)C=CC=CC=1>C(O)C>[CH3:13][O:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][C:24]=1[O:25][CH3:26])[N:21]=[CH:20][CH:19]=[C:18]2[O:27][C:28]1[CH:34]=[CH:33][C:31]([NH:32][C:11]([NH:10][C:8](=[O:9])[C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[CH:3]=2)=[S:12])=[C:30]([CH3:35])[C:29]=1[CH3:36]
Reactant: Cc1cccc(C(=O)N=C=S)c1
Reactant: COc1cc2nccc(Oc3ccc(N)c(C)c3C)c2cc1OC
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4cccc(C)c4)c(C)c3C)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 83 %

Procedure:
Commercially available 3-methyl-1-benzenecarbonyl isothiocyanate (50 μl) was dissolved in ethanol (1 ml) to prepare a solution. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,3-dimethylaniline (50 mg), toluene (5 ml), and ethanol (1 ml) were added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (64 mg, yield 83%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:10])[CH:5]=[CH:6][C:7]=1[NH2:8].CO.[CH:19](=O)[CH:20]=O>O>[C:11]1([C:9]([C:4]2[CH:3]=[C:2]3[C:7](=[CH:6][CH:5]=2)[N:8]=[CH:20][CH:19]=[N:1]3)=[O:10])[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=CC=O
Reactant: Nc1ccc(C(=O)c2ccccc2)cc1N
Solvent: O
Solvent: CO
Product: O=C(c1ccccc1)c1ccc2nccnc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 59.3 %

Procedure:
To a stirred solution of 30 parts of (3,4-diaminophenyl) phenylmethanone in 240 parts of methanol were added 30 parts of an ethanedial solution in water 40%. The reaction mixture was stirred for 3 hours at reflux temperature. After cooling to room temperature, the precipitated product was filtered off, washed with methanol and dried, yielding 20 parts (59.3%) of phenyl (6-quinoxalinyl)methanone; mp. 120° C. (interm. 2).
Reaction SMILES: NC1(C2C=CC(C3C(C4C=CC=CC=4)=CC4C(=O)CCCC=4N=3)=CC=2)CCC1.C(OC(=O)[NH:35][C:36]1([C:40]2[CH:45]=[CH:44][C:43]([C:46]3[C:47]([C:58]4[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=4)=[CH:48][C:49]4[N:54]([CH3:55])[C:53](=[O:56])[CH2:52][O:51][C:50]=4[N:57]=3)=[CH:42][CH:41]=2)[CH2:39][CH2:38][CH2:37]1)(C)(C)C>>[NH2:35][C:36]1([C:40]2[CH:41]=[CH:42][C:43]([C:46]3[C:47]([C:58]4[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=4)=[CH:48][C:49]4[N:54]([CH3:55])[C:53](=[O:56])[CH2:52][O:51][C:50]=4[N:57]=3)=[CH:44][CH:45]=2)[CH2:37][CH2:38][CH2:39]1
Reactant: CN1C(=O)COc2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)cc21
Agent: NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)C(=O)CCC4)cc2)CCC1
Product: CN1C(=O)COc2nc(-c3ccc(C4(N)CCC4)cc3)c(-c3ccccc3)cc21
Yield: 81.1 %

Procedure:
Following the procedure for 2-(4-(1-aminocyclobutyl)phenyl)-3-phenyl-7,8-dihydroquinolin-5(6H)-one, tert-butyl(1-(4-(1-methyl-2-oxo-7-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)phenyl)cyclobutyl)carbamate (37 mg, 0.08 mmol) was reacted to afford the title compound (25 mg, 78%). LCMS (Method A): RT=3.90 min, M+2H+=387. 1H NMR (500 MHz, MeOD): 7.54 (1H, S), 7.40 (2H, d), 7.37 (2H, d), 7.29-7.27 (3H, m), 7.23-7.21 (m, 2H), 4.95 (2H, s), 3.42 (3H, s), 2.77-2.71 (m, 2H), 2.59-2.53 (m, 2H), 2.26-2.17 (m, 1H), 1.99-1.90 (m, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]([N:18]([CH3:22])[CH:19]([CH3:21])[CH3:20])=[N:16][C:15]3[C:10](=[CH:11][C:12]([O:27][CH3:28])=[C:13]([C:23]([O:25]C)=[O:24])[CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1.[OH-].[Na+]>CO.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]([N:18]([CH3:22])[CH:19]([CH3:21])[CH3:20])=[N:16][C:15]3[C:10](=[CH:11][C:12]([O:27][CH3:28])=[C:13]([C:23]([OH:25])=[O:24])[CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1cc2nc(N(C)C(C)C)c(-c3ccc(F)cc3)nc2cc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1cc2nc(-c3ccc(F)cc3)c(N(C)C(C)C)nc2cc1C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 33.4 %

Procedure:
To a solution of methyl 2-(4-fluorophenyl)-7-methoxy-3-[methyl(propan-2-yl)amino]quinoxaline-6-carboxylate (120 mg, 0.31 mmol) in methanol (30 mL) and water (1.0 mL) was added sodium hydroxide (50 mg, 1.25 mmol) with stirring overnight at room temperature. The reaction mixture was concentrated in vacuo, dissolved in water (30 mL), and adjusted to pH 5 with hydrochloric acid (3N) to give the precipitate, which was collected by filtration to afford 2-(4-fluorophenyl)-7-methoxy-3-[methyl(propan-2-yl)amino]quinoxaline-6-carboxylic acid as a light yellow solid (38.2 mg, 88%).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]1[C:7]([CH3:12])=[N:8][NH:9][C:10]=1[CH3:11])C.[NH:14]1C=C(CC(O)=O)C=[N:15]1.O.NN>C(O)CCC>[CH3:12][C:7]1[C:6]([CH2:5][C:4]([NH:14][NH2:15])=[O:3])=[C:10]([CH3:11])[NH:9][N:8]=1
Reactant: O=C(O)Cc1cn[nH]c1
Reactant: CCOC(=O)Cc1c(C)n[nH]c1C
Agent: NN
Solvent: O
Solvent: CCCCO
Product: Cc1n[nH]c(C)c1CC(=O)NN
Yield: 68 %

Procedure:
As described for example 112a, (3,5-dimethyl-1H-pyrazol-4-yl)-acetic acid ethyl ester (Rainer, Georg. 4-Pyrazoleacetic acid derivatives. U.S. (1979), U.S. Pat. No. 4,146,721) in butanol was reacted with hydrazine hydrate (3 equivalents) and the resulting mixture was heated under reflux for 6 h. Evaporation of all volatiles afforded the title compound as a colourless oil (yield: 68%). MS: m/e=183.3 [M+H]+.
Reaction SMILES: [CH3:1][NH:2][S:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N+:12]([O-:14])=[O:13])(=[O:5])=[O:4].[F:15][C:16]([F:20])=[C:17]([F:19])[F:18].[OH-].[K+].O>CN(C)C=O>[CH3:1][N:2]([C:17]([F:19])([F:18])[CH:16]([F:20])[F:15])[S:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N+:12]([O-:14])=[O:13])(=[O:5])=[O:4]
Reactant: CNS(=O)(=O)c1ccccc1[N+](=O)[O-]
Reactant: FC(F)=C(F)F
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C(F)(F)C(F)F)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Yield: 80.8 %

Procedure:
A solution of 72 g of N-methyl-2-nitrobenzenesulfonamide, 35 g of tetrafluoroethylene and 4 g of powdered potassium hydroxide in 150 ml of dimethylformamide was heated at 85° for 3 hours in a pressure vessel. The reaction mixture was cooled to 25° and poured into 800 ml of water. A heavy oil was separated and the aqueous layer extracted with 150 ml of 1-chlorobutane. The heavy oil, the 1-chlorobutane extract and an additional 300 ml of 1-chlorobutane were combined and washed three times with water. The organic solution was dried over magnesium sulfate and concentrated in-vacuo to yield 85.1 g of N-methyl-N-(1,1,2,2-tetrafluoroethyl)-2-nitrobenzenesulfonamide as a viscous orange oil.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:17])=[C:4]([C:8]2[CH:9]=[C:10]([Br:16])[C:11](=[O:15])[N:12]([CH3:14])[CH:13]=2)[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[C:25]([C:29]1[CH:37]=[CH:36][C:32]([C:33](Cl)=[O:34])=[CH:31][CH:30]=1)([CH3:28])([CH3:27])[CH3:26]>C(Cl)Cl>[Br:16][C:10]1[C:11](=[O:15])[N:12]([CH3:14])[CH:13]=[C:8]([C:4]2[C:3]([CH3:17])=[C:2]([NH:1][C:33](=[O:34])[C:32]3[CH:36]=[CH:37][C:29]([C:25]([CH3:27])([CH3:26])[CH3:28])=[CH:30][CH:31]=3)[CH:7]=[CH:6][CH:5]=2)[CH:9]=1
Reactant: Cc1c(N)cccc1-c1cc(Br)c(=O)n(C)c1
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1c(NC(=O)c2ccc(C(C)(C)C)cc2)cccc1-c1cc(Br)c(=O)n(C)c1
Temperature: 0 °C
Reaction time: 18 h
Yield: 75.2 %

Procedure:
A 25-mL round bottomed flask was cooled to 0° C. with an ice/water bath and charged with 5-(3-amino-2-methylphenyl)-3-bromo-1-methylpyridin-2-one (12) (0.71 g, 2.20 mmol), triethylamine (489 mg, 4.84 mmol), methylene chloride (10 mL) and 4-tert-butyl-benzoyl chloride (0.48 g, 2.42 mmol) and the reaction mixture stirred at room temperature for 18 h. After this time the reaction was partitioned between water (25 mL) and ethyl acetate (50 mL). The organic layer was separated and washed with saturated aqueous sodium bicarbonate (2×25 mL), brine (50 mL) and dried over magnesium sulfate. The drying agent was removed by filtration and the filtrate concentrated under reduced pressure. The resulting residue was subjected to flash chromatography to afford 0.75 g (75%) of N-(3-(5-bromo-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2-methylphenyl)-4-tert-butylbenzamide (13) as a white solid: mp 149-151° C.; 1H NMR (300 MHz, CDCl3) 7.87 (dd, 1H, J=2.4 Hz), 7.86 (d, 2H, J=8.4 Hz), 7.71 (br s, 1H), 7.54 (d, 2H, J=8.7 Hz), 7.30 (t, 1H, J=7.8 Hz), 7.27 (d, 1H, J=1.8 Hz), 3.75 (br s, 2H), 7.05 (dd, 1H, J=7.8, 1.5 Hz), 3.67 (s, 3H), 2.24 (s, 3H), 1.37 (s, 9H); MS (ESI+) m/z 453 (M+H).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5]Br.[C:7]([NH:12][NH:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])([O:9][CH2:10][CH3:11])=[O:8].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[N:12]1([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2][N:13]1[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: BrCCCCBr
Reactant: CCOC(=O)NNC(=O)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)N1CCCCN1C(=O)OCC
Temperature: 25 °C
Yield: 69.4 %

Procedure:
1,4-Dibromobutane (81.4 mL, 0.682 mol) is added over 1 hour to a mixture of 1,2-dicarbethoxyhydrazine (100 g, 0.568 mol) and potassium carbonate (158 g, 1.14 mol) in acetonitrile (600 mL). The resultant reaction mixture is refluxed for 6 hours, cooled to room temperature, and filtered. The filtrate is concentrated in vacuo to obtain a yellow liquid which is distilled under reduced pressure to give the title product as a colorless liquid (90.8 g, bp 115°-120° C. at 0.9 mm Hg).
Reaction SMILES: [C:1]1(=[O:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.CC([O-])(C)C.[K+].C(O)(C)(C)C>C(O)(C)C>[C@H:1]1([OH:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: O=C1CCCc2ccccc21
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)O
Solvent: CC(C)(C)O
Product: O[C@@H]1CCCc2ccccc21
Temperature: 60 °C
Reaction time: 20 h
Yield: 98 %

Procedure:
General procedure for hydrogenation: Hydrogenation of 28 illustrates the typical reaction procedure: To a mixture of 1-tetralone, 28, (10.0 g, 66.4 mmol) and RuCl2[(2R,2′R,3S,3′S)-MeO-BIBOP](amqui), 27, (1.0 mg, 0.001 mmol, 0.002 mol %) was added isopropanol (40 mL) and a 1 M solution of t-BuOK in tert-butanol (1.33 mL, 1.33 mmol, 0.02 equiv). The autoclave reactor was first purged with nitrogen, then with hydrogen, and then the reaction mixture was stirred at 60° C. under 400 psi of hydrogen for 20 h. After venting the hydrogen gas, the solvent was removed under reduced pressure. The residue was purified by silica-gel column chromatography with ethyl acetate/hexane (0-50%) as eluent to give (R)-1,2,3,4-tetrahydro-1-naphthol, 29, (colorless oil, 9.6 g, 98% yield, 96:4 er). The er of 1,2,3,4-tetrahydro-1-naphthol was determined by HPLC analysis: column, Chiralcel OJ-3, 4.6×150 mm; eluent, heptane/isopropanol (95:5); flow rate, 1 mL/min; column temperature, 25° C.; retention time (tR) of (R)-1,2,3,4-tetrahydro-1-naphthol, 7.45 min (95.8%); tR of (S)-1,2,3,4-tetrahydro-1-naphthol, 5.75 min (4.2%). [α]D=−31.2 (c=2.0, MeOH).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[CH2:4][C:5]1[CH:10]=[C:9]([Br:11])[C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[C:15](I)[CH:14]=2)=[C:7]([Br:21])[CH:6]=1.[C:23]1([C:29]#[CH:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N(CC)CC)C>ClCCl.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I>[CH3:1][O:2][C:3](=[O:22])[CH2:4][C:5]1[CH:10]=[C:9]([Br:11])[C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16]3[O:19][C:29]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:30][C:15]=3[CH:14]=2)=[C:7]([Br:21])[CH:6]=1
Reactant: COC(=O)Cc1cc(Br)c(Oc2ccc(O)c(I)c2)c(Br)c1
Reactant: C#Cc1ccccc1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)Cc1cc(Br)c(Oc2ccc3oc(-c4ccccc4)cc3c2)c(Br)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.4 %

Procedure:
Methyl[3,5-dibromo-4-(4-hydroxy-3-iodophenoxy)phenyl]acetate (730 mg, 1.3 mmol), phenylacetylen (210 mg, 2.1 mmol) and bis(triphenylphosphine)palladium (II) chloride (82 mg, 0.12 mmol), copper (I) iodide (32 mg, 0.17 mmol) and triethylamine (11 mL) was stirred at reflux. After 2 hours, dichloromethane (2 mL) was added to the reaction mixture, followed by further heating for 16 hours. The reaction mixture was allowed to cool down to room temperature, dissolved in dichloromethane and washed once with a saturated solution of aqueous ammonium chloride. The organic phase was dried over sodium sulphate and concentrated. The residue was purified on column (silica gel, gradient elution from chloroform/heptane 1:2, to chloroform/methanol 5:1), to give 600 mg (86%) of methyl[3,5-dibromo-4-(2-phenyl-5-benzofuranyloxy)phenyl]acetate as a pale yellow solid mass. 1H-NMR (300 MHz, DMSO-d6): δ 7.87 (d, J=7.4 Hz, 2H), 7.76 (s, 2H), 7.61 (d, J=9.2 Hz, 1H), 7.53 (t, 3H), 7.42 (d, J=7.1 Hz, 1H), 7.35 (s, 1H), 6.90 (s, 1H), 3.82 (s, 2H), 3.67 (s, 3H).