Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [BrH:1].CC1C=CC=CC=1O[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17](=[CH:22][CH3:23])[C:18]([O:20][CH3:21])=[O:19]>C(Cl)Cl.C1CCCCC1>[Br:1][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17](=[CH:22][CH3:23])[C:18]([O:20][CH3:21])=[O:19]
Reactant: CC=C(C(=O)OC)c1ccccc1COc1ccccc1C
Reactant: Br
Solvent: C1CCCCC1
Solvent: ClCCl
Product: CC=C(C(=O)OC)c1ccccc1CBr

Procedure:
Hydrogen bromide was passed at -5° C. into a solution of 14.8 g of methyl α-[2-(2-methylphenyloxymethyl)phenyl]but-2-enoate in 250 ml of methylene chloride until it was saturated (about 18 g of HBr). After termination of the reaction (about 2 h at 25° C.), the solvent was distilled off under reduced pressure. The residue thus obtained was taken up in 300 ml of cyclohexane. The solution was washed with 5% strength sodium hydroxide solution and then with water. After drying and concentrating the organic phase, 8 g of the title compound were obtained (m.p.: 64°-66° C.).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1)=[O:5].[NH4+].[Cl-].I[CH2:16][C:17]([CH3:19])=[CH2:18]>C1COCC1.[Zn]>[Cl:1][CH2:2][CH2:3][C:4]([C:6]1[CH:7]=[CH:8][C:9]([F:12])=[CH:10][CH:11]=1)([OH:5])[CH2:18][C:17]([CH3:19])=[CH2:16]
Reactant: O=C(CCCl)c1ccc(F)cc1
Reactant: C=C(C)CI
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: C1CCOC1
Product: C=C(C)CC(O)(CCCl)c1ccc(F)cc1
Reaction time: 1 h
Yield: 70 %

Procedure:
A solution of 3-chloro-1-(4-fluorophenyl)-propan-1-one (18.6 g, 0.1 mol) in THF (50 mL) was added to a well-stirred suspension of zinc power (13 g, 0.2 mol) in a mixture of aqueous saturated NH4Cl solution (260 mL) and THF (65 mL). A solution of 3-iodo-2-methylprop-1-ene (36.4 g, 0.2 mol) in THF (50 mL) was added dropwise. The reaction mixture was mildly exothermic, and began to reflux spontaneously. After the refluxing had ceased, the mixture was stirred for 1 h. TLC showed the 3-chloro-1-(4-fluorophenyl)propan-1-one not reacted completely. A solution of 3-iodo-2-methylprop-1-ene (18.2 g, 0.1 mol) in THF (30 mL) was added, and the mixture was stirred at rt overnight. The mixture was extracted with EtOAc (2×500 mL). The combined organic layer was dried and concentrated. The residue was purified by column chromatography on silica gel eluted with petroleum ether/EtOAc 50:1→30:1→5:1, to give 1-chloro-3-(4-fluorophenyl)-5-methylhex-5-en-3-ol (17 g, yield 76%) as an oil.
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.[CH3:41][O:42][C:43]1[CH:44]=[C:45]([CH:49]=[C:50]([O:54][CH3:55])[C:51]=1[O:52][CH3:53])[C:46](O)=[O:47]>C(Cl)Cl>[C:1]1([CH:7]2[CH2:8][CH2:9][N:10]([C:46]([C:45]3[CH:49]=[C:50]([O:54][CH3:55])[C:51]([O:52][CH3:53])=[C:43]([O:42][CH3:41])[CH:44]=3)=[O:47])[CH2:11][CH2:12]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COc1cc(C(=O)O)cc(OC)c1OC
Reactant: c1ccc(C2CCNCC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: COc1cc(C(=O)N2CCC(c3ccccc3)CC2)cc(OC)c1OC
Reaction time: 8 h

Procedure:
To a mixture of 4-phenylpiperidine 41g (5 mmol), EDCI (6 mmol), HOBt (5.5 mmol) and NMM (6 mmol) in CH2Cl2 (50 mL) was added 3,4,5-trimethoxybenzoic acid (5.3 mmol) and stirring continued at RT for overnight. The reaction mixture was diluted with CH2Cl2 (100 mL) and sequentially washed with water, satd. NaHCO3, brine and dried over MgSO4. The solvent was removed under reduced pressure to yield a crude product, which was purified by column chromatography to obtain pure compound 1g. (57.9%). 1H NMR (CDCl3) δ 7.35-7.21 (m, 5H), 6.66 (s, 2H), 4.84 (br, 1H), 3.95 (br, 1H), 3.88 (s, 6H), 3.86 (s, 3H), 3.20-2.87 (br, 2H), 2.85-2.74 (tt, 1H, J=3.6 Hz, J=15.6 Hz) 1.92 (br, 2H), 1.70 (br, 2H); MS (ESI) m/z 378.1 (M+Na)+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]=[O:11])=[CH:2]1.[OH-].[K+].[C:14]1([S:20](Cl)(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(O)C>[C:14]1([S:20]([N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]([CH:10]=[O:11])=[CH:2]2)(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=Cc1c[nH]c2ccccc12
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=Cc1cn(S(=O)(=O)c2ccccc2)c2ccccc12
Yield: 33 %

Procedure:
To a solution of indole 3-carboxaldehyde (100 mmol) in ethanol (500 mL) at RT was added potassium hydroxide (1.1 equiv). The mixture was stirred until total solubilization. The ethanol was completely removed in vacuum and the residual was dissolved in acetone (250 mL) followed by adding benzenesulfonyl chloride (1.1 equiv, 110 mmol). The reaction mixture was stirred for half hour. The precipitate was filtered off and the filtrate was concentrated and recrystallized from methanol to give a white solid. Yield: 33%. 1H NMR (500 MHz, CDCl3) δ 10.17 (s, 1H), 8.25-8.39 (m, 2H), 7.97-8.09 (m, 3H), 7.69 (t, J=7.33 Hz, 1H), 7.59 (t, J=7.5 Hz, 2H), 7.39-7.54 (m, 2H). MS (ESI) calcd for C15H11NO3S 285.1. found 286.0 [M+H]+.
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:29])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10](=[O:22])[C:9]([C:23]1[CH:28]=[N:27][CH:26]=[CH:25][N:24]=1)=[CH:8]2)=[O:4].[NH2:30][CH2:31][CH2:32][C:33]([OH:35])=[O:34].C[O-].[Na+]>>[CH2:15]([N:11]1[C:12]2[C:7](=[C:6]([OH:29])[C:5]([C:3]([NH:30][CH2:31][CH2:32][C:33]([OH:35])=[O:34])=[O:4])=[N:14][CH:13]=2)[CH:8]=[C:9]([C:23]2[CH:28]=[N:27][CH:26]=[CH:25][N:24]=2)[C:10]1=[O:22])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: NCCC(=O)O
Reactant: COC(=O)c1ncc2c(cc(-c3cnccn3)c(=O)n2Cc2ccccc2)c1O
Agent: C[O-]
Agent: [Na+]
Product: O=C(O)CCNC(=O)c1ncc2c(cc(-c3cnccn3)c(=O)n2Cc2ccccc2)c1O
Temperature: 25 °C
Yield: 62.9 %

Procedure:
A mixture of 1-benzyl-5-hydroxy-2-oxo-3-pyrazin-2-yl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (40 mg, 0.10 mmol), β-alanine (735 mg, 8.25 mmol) and NaOMe solution (12.4 mL, 6.19 mmol, 0.5 M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., the solvent was evaporated in vacuo. The residue was partitioned between EtOAc and water. 1 M HCl was added with vigorous stilling until pH was about 2. The organic layer was dried over MgSO4 and concentrated. The crude solid was dissolved in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH about 1 with 6 M HCl, and the resulting precipitate was isolated by filtration to give 28 mg of the title compound as a light yellow solid. MS: (+) m/z 446.27 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][S:8][C:4]=2[CH:3]=1.Cl[CH2:18][CH2:19][CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([C:28](=[O:30])[CH3:29])=[CH:24][C:23]=1[OH:31].C([O-])(O)=O.[Na+].CC#N>O>[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:18][CH2:19][CH2:20][O:21][C:22]4[CH:27]=[CH:26][C:25]([C:28](=[O:30])[CH3:29])=[CH:24][C:23]=4[OH:31])[CH2:13][CH2:14]3)=[N:7][S:8][C:4]=2[CH:3]=1
Reactant: CC(=O)c1ccc(OCCCCl)c(O)c1
Reactant: Fc1ccc2c(C3CCNCC3)nsc2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CC(=O)c1ccc(OCCCN2CCC(c3nsc4cc(F)ccc34)CC2)c(O)c1
Yield: 97 %

Procedure:
A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisothiazole (2.4 g, 10.1 mmol), 1-[4-(3-chloropropoxy)-3-hydroxyphenyl]ethanone (2.5 g, 11.1 mmol), NaHCO3, (0.94 g, 11.1 mmol), KI (100 mg) and CH3CN (100 ml) was stirred at reflux under N2 for 65 hours. The cooled reaction was poured into H2O and the aqueous mixture was extracted with EtOAc. The EtOAc extract was washed with H2O (1×) and brine (3×) and after drying with MgSO4 the solvent was evaporated to give 4.2 g of a dark solid. Three consecutive recrystallizations from EtOH provided 2.1 g (48%) of glittery beige crystals m.p.=135°-137° C.
Reaction SMILES: C(N(CCCC)CCCC)CCC.[CH2:14](Cl)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[Cl:22][SiH:23]([Cl:25])[Cl:24]>>[CH2:14]([Si:23]([Cl:25])([Cl:24])[Cl:22])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Cl[SiH](Cl)Cl
Reactant: ClCc1ccccc1
Solvent: CCCCN(CCCC)CCCC
Product: Cl[Si](Cl)(Cl)Cc1ccccc1
Yield: 28.4 %

Procedure:
In the same apparatus and procedure as Example 1 above, 0.090 g (0.5 mmol) of tri-n-butylamine, 0.63 g (5.0 mmol) of benzyl chloride, and 3.41 g (25.2 mmol) of trichlorosilane were reacted at 150° C. for 6 hrs. The resulting mixture was distilled to give 0.32 g of benzyltrichlorosilane (yield; 29%).
Reaction SMILES: [CH:1]1([Mg]Br)[CH2:5][CH2:4][CH2:3][CH2:2]1.CC1(C)[O:13][C@@H:12]([C@H:14]2[CH2:16][N:15]2[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:11][O:10]1.C(OC(OC(OC(C)(C)C)=O)=O)(C)(C)C>C1COCC1>[CH:1]1([CH2:16][C@H:14]([NH:15][C:17](=[O:18])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[C@H:12]([OH:13])[CH2:11][OH:10])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1C[C@@H]1[C@H]1COC(C)(C)O1
Reactant: Br[Mg]C1CCCC1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](CC1CCCC1)[C@H](O)CO
Temperature: -25 °C
Reaction time: 0.33 h
Yield: 84 %

Procedure:
Cyclopentyl magnesium bromide (8 mL of 2M ethereal solution) was added to cuprous bromide/dimethylsulfide complex (0.33 g, 1.6 mmol) in 10 mL of dry THF cooled to −25° C. under nitrogen. After 20 min, a solution of tert-butyl (2R)-2-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]aziridine-1-carboxylate (1.95 g, 8 mmol) in 4 mL of dry THF was introduced. The mixture was allowed to warm to ambient temperature overnight. It was quenched with saturated aqueous NH4Cl and extracted with ethyl ether. The organic phase was washed with aqueous saturated NH4Cl, 1 N NaHCO3, and brine. It was dried over anhydrous Na2SO4 and concentrated to 2.38 g of a solid. This material was dissolved in 70 mL of methanol, 12 g of Dowex 50WX2-400 was added, and the mixture was refluxed for 2 h. The mixture was filtered, washing with methanol and dichloromethane. A clean receiver was attached, and the resin was washed with 100 mL of 1:1 concentrated NH4OH: ethanol. The filtrate was concentrated to 1.16 g of tan crystals. The crystals were dissolved in 30 mL of dry THF, and 1.5 g (6.9 mmol) of di-t-butyldicarbonate was introduced. The mixture was stirred under nitrogen overnight. It was concentrated, extracted with ether and the ether was washed with several portions of water and brine. Drying over Na2SO4 and concentration afforded 1.8 g (6.7 mmol, 84% from tert-butyl (2R)-2-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]aziridine-1-carboxylate) of tert-butyl (1S,2S)-1-[cyclopentylmethy]-2,3-dihydroxypropylcarbamate: 1H NMR (CDCl3) δ 4.5 (d, 1H, NH), 3.7 (m, 1H), 3.6–3.49 (m, 2H), 3.36 (m, 1H), 3.26 (t, 1H, OH), 2.76 (d, 1H, OH), 1.45 (s, 9H), 1.88–1.36 (m, 9H), 1.17–1.08 (m, 2H).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:14]N.[N:16]1C=CC=[CH:18][CH:17]=1>>[CH3:18][C:17]1[N:3]2[CH:4]=[CH:5][CH:6]=[C:7]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=3)[C:2]2=[N:14][N:16]=1
Reactant: c1ccncc1
Reactant: NN
Reactant: Clc1ncccc1-c1ccccn1
Product: Cc1nnc2c(-c3ccccn3)cccn12

Procedure:
A mixture of 0.5 g of 2'-chloro-2,3'-bipyridine, 5 ml of anhydrous hydrazine and 50 ml of dry pyridine was refluxed for 24 hours, then concentrated under vacuum and the residue dissolved in methylene chloride. The solution was dried and passed through a short pad of hydrous magnesium silicate. The filtrate was concentrated under vacuum to a gum which is 2'-hydrazino-2,3'-bipyridine. To this gum was added 50 ml of triethyl orthoacetate, the mixture was heated on a steam bath for 2.5 hours and concentrated under vacuum. The residue was dissolved in methylene chloride and while boiling, hexane was added. Cooling gave crystals which were recrystallized from methylene chloride-hexane, giving the desired product, mp 142°-143° C.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:10]([CH3:12])=[CH:9][CH2:8][CH2:7][C:6]=2[CH:5]=[CH:4][C:3]=1[NH:13][S:14]([C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)(=[O:16])=[O:15].C1C=C(Cl)C=C(C(OO)=[O:32])C=1>C(Cl)Cl.C(OCC)(=O)C.C(OCC)C.[I-].[Zn+2].[I-]>[Br:1][C:2]1[C:11]2[CH:10]([CH3:12])[C:9](=[O:32])[CH2:8][CH2:7][C:6]=2[CH:5]=[CH:4][C:3]=1[NH:13][S:14]([C:17]1[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=1)(=[O:16])=[O:15]
Reactant: CC1=CCCc2ccc(NS(=O)(=O)c3ccc(F)cc3)c(Br)c21
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: [I-]
Agent: [Zn+2]
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC1C(=O)CCc2ccc(NS(=O)(=O)c3ccc(F)cc3)c(Br)c21
Temperature: 25 °C
Reaction time: 2 h
Yield: 79 %

Procedure:
A mixture of Example 132A (170 mg, 0.43 mmol) in CH2Cl2 (5 mL) at 0° C. was treated with mCPBA (136 mg, 0.47 mmol), warmed to room temperature, stirred for 2 hours, diluted with ethyl acetate, washed with NaHCO3 and brine, dried (Na2SO4), filtered, and concentrated. The concentrate was dissolved in toluene (5 mL), treated with activated-zinc iodide (37 mg, 0.12 mmol), heated to reflux for 1 hour, diluted with diethyl ether, washed with brine, dried (Na2SO4), filtered, and concentrated to provide the desired product (140 mg, 79% yield). MS (ESI) m/e 410 (M−H)−; 1H NMR (300 MHz, DMSO-d6) δ 9.92 (s, 1H), 7.73 (m, 2H), 7.4 (m, 2H), 7.24 (d, 1H), 7.0 (d, 1H), 3.6 (q, 1H), 3.15 (m, 1H), 2.93 (m, 1H), 2.59 (m, 1H), 2.41 (m, 1H), 1.2 (d, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH2:11][C:12](=[O:18])[NH:13]3)=[CH:5][CH:4]=1.[CH3:19][C:20]1[CH:24]=[C:23]([CH3:25])[NH:22][C:21]=1[CH:26]=O>C(O)C.N1CCCCC1>[CH3:19][C:20]1[CH:24]=[C:23]([CH3:25])[NH:22][C:21]=1[CH:26]=[C:11]1[C:10]2[C:14](=[CH:15][CH:16]=[CH:17][C:9]=2[C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[NH:13][C:12]1=[O:18]
Reactant: Cc1cc(C)c(C=O)[nH]1
Reactant: COc1ccc(-c2cccc3c2CC(=O)N3)cc1
Solvent: C1CCNCC1
Solvent: CCO
Product: COc1ccc(-c2cccc3c2C(=Cc2[nH]c(C)cc2C)C(=O)N3)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 66.2 %

Procedure:
To a solution of 4-(4-methoxy-phenyl)-1,3-dihydro-indol-2-one (59.8 mg, 0.25 mmol) and 3,5-dimethyl-1H-pyrrole-2-carbaldehyde (32 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 3-(3,5-Dimethyl-1H-pyrrol-2-ylmethylene)-4-(4-methoxy-phenyl)-1,3-dihydro-indol-2-one as a yellow solid (57 mg, 66%).
Reaction SMILES: Cl[C:2]1[NH:11][C:10](=[O:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH3:13])[CH:8]=2)[N:3]=1.[S:14]1(=[O:25])[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[CH2:18][NH:17][CH2:16][CH2:15]1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:13][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([N:17]1[CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[S:14](=[O:25])[CH2:15][CH2:16]1)[NH:11][C:10]2=[O:12]
Reactant: Cc1ccc2nc(Cl)[nH]c(=O)c2c1
Reactant: O=S1CCNCc2ccccc21
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Cc1ccc2nc(N3CCS(=O)c4ccccc4C3)[nH]c(=O)c2c1
Temperature: 25 °C
Yield: 80 %

Procedure:
To a stirred solution of 2-chloro-6-methylquinazolin-4(3H)-one (15 g, 77.3 mmol) and 2,3,4,5-tetrahydro-1,4-benzothiazepine 1-oxide (16.8 g, 103 mmol) in toluene (200 mL) was added triethylamine (16.1 mL, 116 mmol). After being refluxed overnight, the reaction mixture was cooled to room temperature. The formed solid was collected by filtration, washed with ethanol (50 mL) and ethyl acetate (100 mL), and then dried in vacuo to afford 21.0 g of the desired product as a white solid (yield was 80%).
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][C:5]2[N:6]3[C:10]([CH2:11][N:12]([CH2:15][C:16]4[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:17]=4[O:24][CH3:25])[C:13](=[O:14])[C:4]=2[CH:3]=1)=[C:9]([C:26]#[N:27])[N:8]=[CH:7]3.Cl.[NH2:31][OH:32].C[O-].[Na+].CO>CN(C=O)C.O>[Cl:1][C:2]1[CH:29]=[CH:28][C:5]2[N:6]3[C:10]([CH2:11][N:12]([CH2:15][C:16]4[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:17]=4[O:24][CH3:25])[C:13](=[O:14])[C:4]=2[CH:3]=1)=[C:9]([C:26]([NH:31][OH:32])=[NH:27])[N:8]=[CH:7]3
Reactant: NO
Reactant: COc1ccc(CN2Cc3c(C#N)ncn3-c3ccc(Cl)cc3C2=O)c(OC)c1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(CN2Cc3c(C(=N)NO)ncn3-c3ccc(Cl)cc3C2=O)c(OC)c1
Reaction time: 8 h

Procedure:
8-Chloro-5-(2,4-dimethoxy-benzyl)-6-oxo-5,6-dihydro-4H-2,5,10b-triaza-benzo[e]azulene-3-carbonitrile (2 g, 4.9 mmol) and hydroxylamine HCl (1 g, 14.6 mmol) were suspended in DMF (10 mL) and treated slowly with a 5.4 M solution of sodium methylate in methanol (2.7 mL, 14.6 mmol). The yellow suspension was stirred overnight. The suspension was cooled in ice and diluted with water (20 mL) and stirred for 1 h in ice. The crystals were filtered off and washed with cold water (5 mL). One obtained white crystals (1.9 g, 89%). m/z 442 (MH+).
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:15]=[CH:14][C:13]([O:16]C)=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.B(Br)(Br)Br.O>C(Cl)Cl>[C:1]1([S:7]([C:10]2[CH:11]=[CH:12][C:13]([OH:16])=[CH:14][CH:15]=2)(=[O:8])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COc1ccc(S(=O)(=O)c2ccccc2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: O=S(=O)(c1ccccc1)c1ccc(O)cc1
Yield: 95.8 %

Procedure:
1-Benzenesulfonyl-4-methoxy-benzene (5.92 g, 23.8 mmol) was dissolved in methylene chloride and stirred. A solution of BBr3 (6.77 g, 71.68 mg) in 120 mL of methylene chloride was added dropwise to the reaction mixture, after which the mixture was stirred for 4 hours at room temperature. Water (150 mL) was then added to the reaction mixture, and the organic layer was separated. The aqueous layer was extracted three times with 45 mL methylene chloride, and the combined organic layers were dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash chromatography (30-50% EtOAc in hexanes) to afford 5.348 g of 4-benzenesulfonyl-phenol (22.8 mmol, 99%) as an oil. MS: 235 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([OH:20])=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[C:27]([C:29]1[CH:36]=[CH:35][C:32]([CH2:33]Br)=[CH:31][CH:30]=1)#[N:28]>CS(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([O:20][CH2:33][C:32]3[CH:35]=[CH:36][C:29]([C:27]#[N:28])=[CH:30][CH:31]=3)=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(O)c2CC1
Reactant: N#Cc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(OCc3ccc(C#N)cc3)c2CC1
Temperature: 25 °C

Procedure:
Combine 3-tert-butoxycarbonyl-7-chloro-6-hydroxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (200 mg, 0.67 mmol), potassium carbonate (111 mg, 0.8 mmol), and 4-cyanobenzyl bromide (263 mg, 1.34 mmol) in DMSO (5 mL) and heat the stirred mixture to 100° C. for 24 h. Cool to ambient temperature and partition the mixture between water and EtOAc/hexane (1:1). Wash the organic layer with brine and dry over Na2SO4, filter and concentrate in vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc (5:1) to give 3-tert-butoxycarbonyl-7-chloro-6-(4-cyanobenzyloxy)-2,3,4,5-tetrahydro-1H-benzo[d]azepine as an oil.
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:8])=[N:4][CH:5]=[CH:6][CH:7]=1.Br[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12].C(=O)([O-])[O-].[K+].[K+].CCCCCCC>C(OCC)(=O)C>[CH2:14]([O:13][C:11](=[O:12])[CH2:10][N:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[C:3]1=[O:8])[CH3:15]
Reactant: CCOC(=O)CBr
Reactant: Oc1ncccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: CCOC(=O)Cn1cccc(Br)c1=O
Yield: 55 %

Procedure:
As described for example 320a, 3-bromo-2-hydroxy-pyridine was reacted with ethyl bromoacetate and potassium carbonate. Extractive workup followed by chromatography (SiO2, heptane:ethyl acetate=100:0 to 50:50) afforded the title compound as a light yellow oil (yield: 55%), which was directly used in the next step.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[CH:14]=[CH:13][CH:12]=[CH:11]1)([O-:3])=[O:2].I[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18].OO>CS(C)=O.O>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[CH:14]=[CH:13][CH:12]=[C:11]1[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])([O-:3])=[O:2]
Reactant: CCOC(=O)CI
Reactant: O=[N+]([O-])c1ccccc1-n1cccc1
Agent: OO
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)Cc1cccn1-c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 24 h
Yield: 10.9 %

Procedure:
To a stirred mixture of 1.88 g of 1-(2-nitrophenyl)pyrrole, 4.80 g of ethyl iodoacetate and 2.22 g of FeSO4.7H2O in 40 ml of dimethyl sulfoxide is added dropwise 10 ml of 30% hydrogen peroxide while keeping the reaction mixture at room temperature with a cold water bath. The mixture is stirred at room temperature for one day. An additional 2.4 g of ethyl iodoacetate, 1.1 g of FeSO4.7H2O and 5 ml of 30% hydrogen peroxide is added and the mixture stirred at room temperature for 1 day. The mixture is diluted with water and extracted with diethyl ether. The organic extract is washed with water, brine and dried (Na2SO4). The solvent is removed and the residue (2.12 g) chromatographed on silica gel with ethyl acetate-hexane (1:4) as solvent to give 0.30 g of product as a brown gum.
Reaction SMILES: C1C=C2C=CC(O)=C(C3C4C(=CC=CC=4)C=CC=3O)C2=CC=1.[F:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30](=[CH2:34])[CH2:31][CH2:32][CH3:33])[C:25]=1[O:35][CH3:36].[F:37][C:38]([F:47])([F:46])[C:39](=[O:45])[C:40]([O:42][CH2:43][CH3:44])=[O:41]>C1(C)C=CC=CC=1.CC(C)[O-].CC(C)[O-].CC(C)[O-].CC(C)[O-].[Ti+4]>[F:23][C:24]1[C:25]([O:35][CH3:36])=[C:26]([C:30](=[CH:31][CH2:32][CH3:33])[CH2:34][C:39]([OH:45])([C:38]([F:46])([F:47])[F:37])[C:40]([O:42][CH2:43][CH3:44])=[O:41])[CH:27]=[CH:28][CH:29]=1
Reactant: C=C(CCC)c1cccc(F)c1OC
Reactant: CCOC(=O)C(=O)C(F)(F)F
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: Oc1ccc2ccccc2c1-c1c(O)ccc2ccccc12
Solvent: Cc1ccccc1
Product: CCC=C(CC(O)(C(=O)OCC)C(F)(F)F)c1cccc(F)c1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.9 %

Procedure:
698 mg (2.56 mmol) of 1,1′-bi-2-naphthol are admixed with 2.56 ml (1.28 mmol) of a 0.5 M titanium tetraisopropoxide solution in toluene and the red solution is stirred at room temperature for 2 hours. 4.26 g (21.9 mmol) of 2-fluoro-6-(1-methylenbutyl)anisole and 5.7 ml (44 mmol) of ethyl trifluoropyruvate are added and the mixture is heated at 140° C. for 18 hours. After cooling it is immediately purified by column chromatography on silica gel (hexane/ethyl acetate 0-15%) to give 5.82 g of ethyl 4-(3-fluoro-2-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)hept-4-enoate. 2.6 g (7.1 mmol) of ethyl 4-(3-fluoro-2-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)hept-4-enoate are dissolved in 65 ml of methanol and the solution is admixed with 260 mg of palladium on carbon (10%). The suspension is shaken under a hydrogen atmosphere at atmospheric pressure for 4 hours until the hydrogen uptake is 155 ml. The mixture is filtered through Celite, the filter bed being rinsed thoroughly with ethyl acetate. Removal of the solvent gives 2.6 g of ethyl 4-(3-fluoro-2-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)heptanoate. 2.6 g (7.1 mmol) of ethyl 4-(3-fluoro-2-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)-heptanoate in 150 ml of diethyl ether are cooled to −10° C. and over 15 minutes 520 g (14.2 mmol) of solid lithium aluminum hydride are added in portions. The mixture is stirred at −15° C. for 1.5 hours, followed by dropwise addition in succession of ethyl acetate and water and by a further hour of stirring until a readily filterable precipitate is formed. The suspension is filtered through Celite, the filter bed being rinsed thoroughly with ethyl acetate. The phases of the filtrate are separated and extraction is carried out again with ethyl acetate. The extracts are washed with saturated sodium chloride solution and dried over sodium sulphate and the solvent is removed in vacuo. Separation by column chromatography on silica gel (hexane/diisopropyl ether 0-15%) yields 2.1 g of 4-(3-fluoro-2-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)heptanal as a mixture of the diastereomers.