Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[C:12]([O:14][CH3:15])=[O:13].[N:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[S:22](Cl)(=[O:24])=[O:23].N1C=CC=CC=1>ClCCl>[N:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[S:22]([NH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[C:12]([O:14][CH3:15])=[O:13])(=[O:24])=[O:23]
Reactant: O=S(=O)(Cl)c1ccccn1
Reactant: COC(=O)c1c(N)ccc2ccccc12
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1c(NS(=O)(=O)c2ccccn2)ccc2ccccc12
Reaction time: 0.25 h
Yield: 83.5 %

Procedure:
A solution of methyl 2-amino-1-naphthoate (85 mg, 0.42 mmol) and 2-pyridinesulfonyl chloride (244 mg, 1.3 mmol) in dichloromethane (1.0 mL) was treated with pyridine (0.15 mL, 1.3 mmol), stirred for 15 minutes, treated with dichloromethane (30 mL), washed with 1N HCl (2×20 mL), and concentrated. The crude product was chromatographed on a silica gel column eluting with 30% ethyl acetate/hexanes to provide the desired product (120 mg, 83.5%). 1H NMR (CDCl3) δ 4.09 (s, 3H), 7.35-7.55 (m, 3H), 7.75-7.96 (m, 5H), 8.16 (d, 1H), 8.59 (d, 1H), 9.46 (s, 1H); MS (DCI/NH3) m/e 343 (M+H)+.
Reaction SMILES: S(=O)(=O)(O)O.[C:6]([NH:9][CH2:10][CH2:11][CH2:12][C:13]([C:15]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:16]=1[CH2:17][CH2:18][C:19]([OH:21])=[O:20])=[O:14])(=[O:8])[CH3:7].[CH3:27][C:28](=[CH2:30])[CH3:29]>O1CCCC1>[C:6]([NH:9][CH2:10][CH2:11][CH2:12][C:13]([C:15]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:16]=1[CH2:17][CH2:18][C:19]([O:21][C:28]([CH3:30])([CH3:29])[CH3:27])=[O:20])=[O:14])(=[O:8])[CH3:7]
Reactant: C=C(C)C
Reactant: CC(=O)NCCCC(=O)c1ccc(Cl)cc1CCC(=O)O
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Product: CC(=O)NCCCC(=O)c1ccc(Cl)cc1CCC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 720 h

Procedure:
0.3 ml of concentrated sulfuric acid is added to a solution of 10.00 g (0.032 mol) of 2-(4-acetamidobutyryl)-5-chlorohydrocinnamic acid in 40 ml of tetrahydrofuran in a steel autoclave and about 60 ml of isobutylene are condensed. The mixture is stirred at room temperature for 30 days. The solution is concentrated, extracted with methylene chloride/water, dried with magnesium sulfate and the solvent is distilled in a vacuum. Chromatography with ethyl acetate on aluminum oxide and then on silica gel gives t-butyl 2-(4-acetamidobutyryl)-5-chlorohydrocinnamate as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=[N:10]2)=[C:4]([N+:20]([O-])=O)[C:3]=1[OH:23]>C(O)(=O)C.[Fe]>[NH2:20][C:4]1[C:3]([OH:23])=[C:2]([Cl:1])[CH:7]=[C:6]([F:8])[C:5]=1[N:9]1[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=[N:10]1
Reactant: O=c1cc(C(F)(F)F)cnn1-c1c(F)cc(Cl)c(O)c1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Product: Nc1c(O)c(Cl)cc(F)c1-n1ncc(C(F)(F)F)cc1=O
Reaction time: 4 h
Yield: 93.6 %

Procedure:
To a stirred solution of 2-(4-chloro-6-fluoro-3-hydroxy-2-nitrophenyl)-5-trifluoromethylpyridazin-3-one (0.601 g) in acetic acid (6 ml) was added 0.38 g of iron powder at ambient temperature and stirred for 4 hours. The reaction mixture was partitioned between ethyl acetate and water. The organic phase was dried over anhydrous sodium sulfate. After removing the solvent under reduced pressure, the residue was purified by silica gel column chromatography, eluted with hexane-ethyl acetate (2:1) to give 0.515 g of the title compound.
Reaction SMILES: [O:1]=[C:2]1[C:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:11][CH:10]=2)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]2[N:26]=[CH:27][N:28]=[C:4]2[N:3]1[CH:29]1[CH2:34][CH2:33][CH:32]([O:35][CH2:36][CH:37]=C)[CH2:31][CH2:30]1.I([O-])(=O)(=O)=[O:40].[Na+].CC(C)=O.C(#N)C>C(OCC)(=O)C.O.[Os]=O>[OH:40][CH2:37][CH2:36][O:35][C@@H:32]1[CH2:33][CH2:34][C@H:29]([N:3]2[C:2](=[O:1])[C:7]([CH2:8][C:9]3[CH:14]=[CH:13][C:12]([C:15]4[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=4)=[CH:11][CH:10]=3)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]3[N:26]=[CH:27][N:28]=[C:4]23)[CH2:30][CH2:31]1
Reactant: C=CCOC1CCC(n2c(=O)c(Cc3ccc(-c4ccccc4C#N)cc3)c(CCC)n3ncnc23)CC1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@@H](OCCO)CC2)c2ncnn12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 4′-({5-oxo-4-[4-(prop-2-en-1-yloxy)cyclohexyl]-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile (1.1 g), osmium oxide (7% immobilized catalyst, 0.48 g), sodium periodate (2.4 g), acetone (15 mL), acetonitrile (15 mL) and water (15 mL) was stirred at room temperature for 3 hr. The reaction mixture was diluted with ethyl acetate and water, and the insoluble material was filtered off through celite. The obtained organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was dissolved in methanol (20 mL), sodium borohydride (0.13 g) was added, and the mixture was stirred at room temperature for 1 hr. After evaporation of the solvent under reduced pressure, the residue was extracted with water and ethyl acetate. The obtained ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.29 g, 26%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][C:17]=1[C:23](=[O:25])[CH3:24].[CH2:26](I)[CH3:27].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:26][CH3:27])=[CH:18][C:17]=1[C:23](=[O:25])[CH3:24]
Reactant: COc1cc2nccc(Oc3ccc(O)cc3C(C)=O)c2cc1OC
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1ccc(Oc2ccnc3cc(OC)c(OC)cc23)c(C(C)=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.6 %

Procedure:
1-[2-(6,7-Dimethoxy-quinolin-4-yloxy)-5-hydroxy-phenyl]-ethanone (compound 176) (75 mg) was dissolved in N,N-dimethylformamide (2 ml) to prepare a solution. Ethyl iodide (103 mg) and potassium carbonate (153 mg) were added to the solution, and the mixture was stirred at room temperature overnight. The solvent was removed by distillation under the reduced pressure, water was then added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and was dried over anhydrous magnesium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using acetone-hexane to give the title compound (50 mg, yield 62%).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[F:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH:18]=[CH:17][N:16]=[C:15]([N:19](O)[C:20](=[NH:29])[CH2:21][O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:14]2=[O:31])=[CH:9][CH:8]=1.C([O-])([O-])=O.[Na+].[Na+]>C1COCC1>[F:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH:18]=[CH:17][N:16]3[N:29]=[C:20]([CH2:21][O:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[N:19]=[C:15]3[C:14]2=[O:31])=[CH:9][CH:8]=1
Reactant: N=C(COc1ccccc1)N(O)c1nccn(-c2ccc(F)cc2)c1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: C1CCOC1
Product: O=c1c2nc(COc3ccccc3)nn2ccn1-c1ccc(F)cc1
Temperature: 100 °C
Reaction time: 0.08 h
Yield: 6.3 %

Procedure:
Phosphorus oxychloride (0.28 mL, 3.0 mmol) was added to a solution of N-[4-(4-fluoro-phenyl)-3-oxo-3,4-dihydro-pyrazin-2-yl]-N-hydroxy-2-phenoxy-acetamidine (0.35 g. 1.51 mmol) in THF (8 mL) at 0° C. The reaction was stirred at 100° C. for 5 minutes under microwave irradiation. The reaction mixture was basified with a saturated solution of Na2CO3. The organic layer was separated, dried (Na2SO4), filtered and the solvent evaporated in vacuo. The crude product was purified by flash column chromatography (silica; AcOEt in DCM 1/99 to 10/90). The desired fractions were collected and the solvents evaporated in vacuo and treated with DIPE to yield 7-(4-fluoro-phenyl)-2-phenoxymethyl-7H-[1,2,4]triazolo[1,5-a]pyrazin-8-one (32 mg, 6% yield). 1H NMR (500 MHz, DMSO-d6) δ ppm 5.33 (s, 2H), 6.97 (t, J=7.4 Hz, 1H), 7.07 (d, J=7.8 Hz, 2H), 7.26-7.36 (m, 2H), 7.36-7.44 (m, 2H), 7.45 (d, J=6.1 Hz, 1H), 7.50-7.62 (m, 2H), 8.03 (d, J=5.8 Hz, 1H).
Reaction SMILES: CC1C=CC(S(OCC2CC3C=CC=C(C4C=CC(OC)=CC=4)C=3O2)(=O)=O)=CC=1.[N-]=[N+]=[N-].[Na+].[N:34]([CH2:37][CH:38]1[CH2:42][C:41]2[CH:43]=[CH:44][CH:45]=[C:46]([C:47]3[CH:52]=[CH:51][C:50]([O:53][CH3:54])=[CH:49][CH:48]=3)[C:40]=2[O:39]1)=[N+]=[N-].[N-]=[N+]=[N-]>[Pd]>[CH3:54][O:53][C:50]1[CH:51]=[CH:52][C:47]([C:46]2[C:40]3[O:39][CH:38]([CH2:37][NH2:34])[CH2:42][C:41]=3[CH:43]=[CH:44][CH:45]=2)=[CH:48][CH:49]=1
Reactant: COc1ccc(-c2cccc3c2OC(CN=[N+]=[N-])C3)cc1
Agent: [Pd]
Agent: COc1ccc(-c2cccc3c2OC(COS(=O)(=O)c2ccc(C)cc2)C3)cc1
Agent: [N-]=[N+]=[N-]
Product: COc1ccc(-c2cccc3c2OC(CN)C3)cc1
Yield: 58 %

Procedure:
Treatment of (±)-[7-(4-methoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (2.1 g, 5.11 mmol) with sodium azide (1.33 g, 20.96 mmol) generally according to the procedure described for Intermediate 98 afforded (±)-2-(azidomethyl)-7-(4-methoxyphenyl)-2,3-dihydro-1-benzofuran. Treatment of the azide with palladium on carbon (0.125 g, 10 wt. %) generally according to the procedure described for Example 1 provided 0.860 g (58%) of (±)-1-[7-(4-methoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine as a white solid, hydrochloride salt. mp 176-178° C.; Anal. calcd. for C16H17NO2HCl: C, 65.86; H, 6.22; N, 4.80. Found: C, 65.02; H, 6.13; N, 4.57.
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]([NH:10][C:11]([C:14]2[CH:15]=[CH:16][C:17]([C:20]3[CH:25]=[CH:24][C:23]([P:26](=[O:33])([O:30]CC)[O:27]CC)=[CH:22][CH:21]=3)=[N:18][CH:19]=2)([CH3:13])[CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([C:34]2[N:35]=[N:36][CH:37]=[CH:38][CH:39]=2)[N:3]=1.C[Si](Br)(C)C>C(Cl)Cl>[OH:1][C:2]1[C:7]([C:8]([NH:10][C:11]([C:14]2[CH:15]=[CH:16][C:17]([C:20]3[CH:21]=[CH:22][C:23]([P:26](=[O:27])([OH:30])[OH:33])=[CH:24][CH:25]=3)=[N:18][CH:19]=2)([CH3:13])[CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([C:34]2[N:35]=[N:36][CH:37]=[CH:38][CH:39]=2)[N:3]=1
Reactant: CCOP(=O)(OCC)c1ccc(-c2ccc(C(C)(C)NC(=O)c3cnc(-c4cccnn4)nc3O)cn2)cc1
Agent: C[Si](C)(C)Br
Solvent: ClCCl
Product: CC(C)(NC(=O)c1cnc(-c2cccnn2)nc1O)c1ccc(-c2ccc(P(=O)(O)O)cc2)nc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of diethyl 4-(5-(2-(4-hydroxy-2-(pyridazin-3-yl)pyrimidine-5-carboxamido) propan-2-yl)pyridin-2-yl)phenylphosphonate (180 mg, 0.33 mmol) in DCM (5 ml) was added dropwise TMSBr (1.50 g, 9.85 mmol) at 0° C., the reaction mixture was stirred at room temperature for overnight. Then evaporated the solution and diluted with 20 ml MeOH, and stirred at room temperature for 30 mins, concentrated under vacuo, purified by Pre-HPLC to give product 33-1. 1H NMR (CDCl3-d6, 300 MHz,): δ 9.50 (s, 1H), 8.71 (s, 1H), 8.50 (d, 1H), 8.11 (m, 2H), 7.72-8.02 (m, 5H), 3.15 (s, 1H), 1.76 (s, 6H). (M+H)+=493.1.
Reaction SMILES: [I-].[CH3:2][S+](C)C.[H-].[Na+].[C:8]([O:12][C:13](=[O:21])[NH:14][C@H:15]([CH3:20])[CH:16]=[CH:17][C:18]#[N:19])([CH3:11])([CH3:10])[CH3:9]>CS(C)=O.O.C(OCC)(=O)C>[C:8]([O:12][C:13](=[O:21])[NH:14][C@@H:15]([CH:16]1[CH2:2][CH:17]1[C:18]#[N:19])[CH3:20])([CH3:11])([CH3:9])[CH3:10]
Reactant: C[S+](C)C
Reactant: C[C@H](C=CC#N)NC(=O)OC(C)(C)C
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: O
Product: C[C@@H](NC(=O)OC(C)(C)C)C1CC1C#N
Temperature: 25 °C
Reaction time: 48 h

Procedure:
DMSO was added to trimethylsulfonium iodide (1.79 g, 8.15 mmol) and sodium hydride (60% in mineral oil, 326 mg, 8.15 mmol) at 0° C. Then a 3:1 E:Z mixture of ((R)-3-cyano-1-methyl-allyl)-carbamic acid tert-butyl ester (0.4 g, 2.04 mmol) in DMSO was added. The reaction mixture was left to warm up to room temperature overnight. The reaction was stirred at room temperature for 2 days then diluted with water and ethyl acetate. The organic layers were dried over MgSO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 80 g, 20% to 50% EtOAc in hexanes) to provide [(R)-1-(2-cyanocyclopropyl)-ethyl]-carbamic acid tert-butyl ester as two discreet diastereomers (arbitrarily assigned). Diastereomer A (250 mg, 58%) as a colorless oil; MS: (M+H)+=211. Diastereomer B (130 mg, 30%) as a white powder; M+Na)+=233.
Reaction SMILES: [NH2:1][CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=1)[CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[N:6]=1)[OH:4].[F:23][C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27]([C:34](O)=[O:35])=[CH:26][CH:25]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>C(#N)C.O>[Cl:11][C:7]1[N:6]=[C:5]([CH:3]([OH:4])[CH:2]([NH:1][C:34]([C:27]2[C:28]3[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:24]([F:23])=[CH:25][CH:26]=2)=[O:35])[CH2:12][C:13]2[CH:14]=[CH:15][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:17][CH:18]=2)[CH:10]=[CH:9][CH:8]=1
Reactant: O=C(O)c1ccc(F)c2ccccc12
Reactant: NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1cccc(Cl)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: O
Product: O=C(NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1cccc(Cl)n1)c1ccc(F)c2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.9 %

Procedure:
To a solution of (1RS,2RS)-2-amino-1-(6-chloro-2-pyridyl)-3-(4-(trifluoromethyl)phenyl)-1-propanol (250 mg, 0.76 mmol) in acetonitrile (15 ml) were added 4-fluoronaphthalenecarboxylic acid (144 mg, 0.76 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (218 mg, 1.14 mmol) and 1-hydroxy-1H-benzotriazole (116 mg, 0.76 mmol), and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1). Recrystallization from ethyl acetate-hexane gave the title compound (267 mg, 70%).
Reaction SMILES: COC1C=CC(N2CCN(CCC3C=CC=CC=3)CC2)=CC=1.[CH:23]1([CH2:29][CH2:30][CH2:31][CH:32]2[CH2:37][CH2:36][N:35]([C:38]3[CH:43]=[C:42]([F:44])[C:41]([O:45]C)=[CH:40][C:39]=3[F:47])[CH2:34][CH2:33]2)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>>[CH:23]1([CH2:29][CH2:30][CH2:31][CH:32]2[CH2:37][CH2:36][N:35]([C:38]3[C:39]([F:47])=[CH:40][C:41]([OH:45])=[C:42]([F:44])[CH:43]=3)[CH2:34][CH2:33]2)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: COc1cc(F)c(N2CCC(CCCC3CCCCC3)CC2)cc1F
Agent: COc1ccc(N2CCN(CCc3ccccc3)CC2)cc1
Product: Oc1cc(F)c(N2CCC(CCCC3CCCCC3)CC2)cc1F
Yield: 253.6 %

Procedure:
Production Example 2 was repeated except that 1-(4-methoxyphenyl)-4-phenethylpiperazine was replaced with 4-(3-cyclohexylpropyl)-1-(2,5-difluoro-4-methoxyphenyl)piperidine (246 mg), to provide crude 4-[4-(3-cyclohexylpropyl)piperidino]-2,5-difluorophenol (599 mg).
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].[CH2:7]([C:11]1[O:15][C:14]([C:16]2[CH:17]=[CH:18][C:19]([CH3:26])=[C:20]([CH2:22][C:23]([OH:25])=[O:24])[CH:21]=2)=[N:13][N:12]=1)[CH:8]([CH3:10])[CH3:9].IC>CN(C)C=O>[CH3:1][O:24][C:23](=[O:25])[CH2:22][C:20]1[CH:21]=[C:16]([C:14]2[O:15][C:11]([CH2:7][CH:8]([CH3:10])[CH3:9])=[N:12][N:13]=2)[CH:17]=[CH:18][C:19]=1[CH3:26]
Reactant: Cc1ccc(-c2nnc(CC(C)C)o2)cc1CC(=O)O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)Cc1cc(-c2nnc(CC(C)C)o2)ccc1C
Temperature: 25 °C
Reaction time: 48 h
Yield: 50.9 %

Procedure:
A suspension of potassium carbonate (0.56 g, 4.05 mmol), [5-(5-isobutyl-[1,3,4]oxadiazol-2-yl)-2-methyl-phenyl]-acetic acid (1.01 g, 3.68 mmol) and iodomethane (0.33 mL, 5.26 mmol) in N,N-dimethylformamide (10 mL) was stirred at room temperature for 2 days. The reaction mixture was partitioned between ethyl acetate and water. The combined organic phase was washed with water and brine, dried (magnesium sulfate), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with 0-40% ethyl acetate in hexanes to give [5-(5-isobutyl-[1,3,4]oxadiazol-2-yl)-2-methyl-phenyl]-acetic acid methyl ester (Yield: 0.54 g, 51%).
Reaction SMILES: [N+:1]([C:4]1[CH:26]=[CH:25][C:7]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:6][C:5]=1[Br:27])([O-])=O.[N+](C1C=CC(C(O)=O)=CC=1Br)([O-])=O.ClC1C=CC(CCN2CCNCC2)=CC=1>[Ni]>[NH2:1][C:4]1[CH:26]=[CH:25][C:7]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:6][C:5]=1[Br:27]
Reactant: O=C(c1ccc([N+](=O)[O-])c(Br)c1)N1CCN(CCc2ccc(Cl)cc2)CC1
Agent: [Ni]
Agent: Clc1ccc(CCN2CCNCC2)cc1
Agent: O=C(O)c1ccc([N+](=O)[O-])c(Br)c1
Product: Nc1ccc(C(=O)N2CCN(CCc3ccc(Cl)cc3)CC2)cc1Br

Procedure:
In a manner analogous to that described in Example 2, 1-(4-nitro-3-bromobenzoyl)-4-[2-(4-chlorophenyl)ethyl]-piperazine is prepared from 4.7 g of 4-nitro-3-bromobenzoic acid and 1-[2-(4-chlorophenyl)ethyl]-piperazine and, as described in Example 3, reduced in the presence of Raney nickel to form 1-(4-amino-3-bromobenzoyl)-4-[2-(4-chlorophenyl)ethyl]-piperazine having a melting point of 120°-123°.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7](=[O:9])[CH3:8])[CH:4]=[N:3]1.[Br-:10].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.S([O-])([O-])=O.[Na+].[Na+]>ClCCl.C(O)C.O>[Br:10][CH2:8][C:7]([C:5]1[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=1)=[O:9]
Reactant: [Br-]
Reactant: CC(=O)c1cnn(C)c1
Agent: O=S([O-])[O-]
Agent: [Na+]
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: CCO
Solvent: ClCCl
Product: Cn1cc(C(=O)CBr)cn1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 1-(1-methyl-1H-pyrazol-4-yl)ethanone (28.5 g, 230 mmol) in dichloromethane (400 mL) was diluted with absolute ethanol (100 mL) and treated portion-wise with pyridinium tribromide (95%, 77.3 g, 230 mmol). The reaction was stirred at room temperature for 3 hours, during which time it solidified; the mixture was diluted with dichloromethane (300 mL) and water (400 mL), treated with sodium sulfite (5 g) and stirred for 10 minutes. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was washed with water (200 mL), collected by filtration, washed again with water, and dried to afford the product as an off-white solid. Yield: 41.6 g, 205 mmol, 89%. 1H NMR (500 MHz, CDCl3) δ 7.97-7.98 (m, 1H), 7.95 (br s, 1H), 4.17 (s, 2H), 3.95-3.96 (m, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([I:10])[CH:7]=[CH:6][C:3]=1[CH2:4]Br.[CH3:11][S-:12].[Na+]>CN(C)C=O.C(OCC)(=O)C>[CH3:11][S:12][CH2:4][C:3]1[CH:6]=[CH:7][C:8]([I:10])=[CH:9][C:2]=1[Cl:1]
Reactant: Clc1cc(I)ccc1CBr
Reactant: C[S-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CSCc1ccc(I)cc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 97.7 %

Procedure:
A solution of 2-chloro-4-iodobenzyl bromide (4.82 g, 14.54 mmol) in N,N-dimethylformamide (30 mL) was treated with sodium thiomethoxide (2.04 g, 29.08 mmol). After the addition, the solution became cloudy and turned to a yellow color. The resulting reaction mixture was stirred for 3 h at 25° C. The reaction mixture was then diluted with ethyl acetate (100 mL). The organic layer was washed successively with water (2×100 mL) and a saturated aqueous sodium chloride solution (1×100 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to afford 2-chloro-4-iodobenzyl methyl sulfide (4.24 g, 97%) as a colorless oil which was used without further purification: EI-HRMS m/e calcd for C8H8CIIS (M+) 297.9080, found 297.9078.
Reaction SMILES: [CH3:1][N:2]([CH3:10])[C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1.[S:11]([O-:15])([O-:14])(=[O:13])=[S:12]>>[NH2:9][C:6]1[CH:7]=[CH:8][C:3]([N:2]([CH3:10])[CH3:1])=[CH:4][C:5]=1[S:12][S:11](=[O:14])(=[O:13])[OH:15]
Reactant: O=S([O-])([O-])=S
Reactant: CN(C)c1ccc(N)cc1
Product: CN(C)c1ccc(N)c(SS(=O)(=O)O)c1

Procedure:
In one embodiment, an N,N-dimethyl-1,4-diamino-benzene, 3′, is oxidized in the presence of a thiosulfate to give a thiosulfuric acid S-{2-(amino)-5-(dimethylamino)-phenyl}ester, 4′, as illustrated in the following scheme:
Reaction SMILES: [F:1][C:2]1[C:24]([S:25][CH:26]2[CH2:31][CH2:30][N:29]([C:32]([CH3:37])([CH3:36])[C:33]([NH2:35])=[O:34])[CH2:28][CH2:27]2)=[CH:23][C:5]2[C:6]3[N:10]([CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1)[CH:9]=[C:8]([C:14]1[N:15]([CH:20]([CH3:22])[CH3:21])[N:16]=[C:17]([CH3:19])[N:18]=1)[N:7]=3.C(O)(C(F)(F)F)=[O:39].C1C=C(Cl)C=C(C(OO)=O)C=1>C(Cl)Cl>[F:1][C:2]1[C:24]([S:25]([CH:26]2[CH2:31][CH2:30][N:29]([C:32]([CH3:37])([CH3:36])[C:33]([NH2:35])=[O:34])[CH2:28][CH2:27]2)=[O:39])=[CH:23][C:5]2[C:6]3[N:10]([CH:9]=[C:8]([C:14]4[N:15]([CH:20]([CH3:22])[CH3:21])[N:16]=[C:17]([CH3:19])[N:18]=4)[N:7]=3)[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1
Reactant: Cc1nc(-c2cn3c(n2)-c2cc(SC4CCN(C(C)(C)C(N)=O)CC4)c(F)cc2OCC3)n(C(C)C)n1
Reactant: O=C(O)C(F)(F)F
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cc1nc(-c2cn3c(n2)-c2cc(S(=O)C4CCN(C(C)(C)C(N)=O)CC4)c(F)cc2OCC3)n(C(C)C)n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 59.3 %

Procedure:
To an ice-cooled solution of 2-{4-[8-fluoro-2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulen-9-ylsulfanyl]piperidin-1-yl}isobutyramide from Example 8 (96 mg, 0.183 mmol) in DCM (10 mL) was added TFA (42 μL, 0.548 mmol) followed by a solution of m-CPBA (35 mg, 0.201 mmol) in DCM (2 mL). The resulting mixture was stirred for 30 min at 0° C. then volatiles were removed under reduced pressure. The crude material was purified by column chromatography (C18, gradient 10-50% MeOH in 0.5% TFA/H2O) and then loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH and the product was eluted with 0.5M NH3 in MeOH. The product containing fractions were concentrated in vacuo and further purified by column chromatography (Si-PCC, gradient 2-12% MeOH in DCM) affording 220 as a white solid (59 mg, 60%). LCMS: RT 2.54 min [M+H]+ 544.1. 1H NMR (DMSO, 400 MHz): δ 8.72 (1H, d, J=7.98 Hz), 7.93 (1H, s), 7.17-7.09 (2H, m), 6.86 (1H, s), 5.68-5.56 (1H, m), 4.67-4.50 (4H, m), 2.88-2.74 (3H, m), 2.26 (3H, s), 2.19-2.04 (2H, m), 1.92-1.84 (1H, m), 1.76-1.51 (3H, m), 1.50-1.42 (6H, m), 1.03 (6H, d, J=4.44 Hz)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][N:9]=1)[C:5]#[N:6].CCN(CC)CC>CCO.[Pd]>[NH2:6][CH2:5][C:4]1[CH:7]=[CH:8][N:9]=[C:2]([NH2:1])[CH:3]=1
Reactant: N#Cc1ccnc(N)c1
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CCO
Product: NCc1ccnc(N)c1
Reaction time: 12 h
Yield: 88.9 %

Procedure:
In a sealed flask, a well stirred mixture of 2-amino-isonicotinonitrile (12.6 g, 106.0 mmol), Et3N (98 mL) and Pd/C 10% (15.0 g) in EtOH (400 mL) was placed under an H2 atmosphere (50 psi) and hydrogenated at RT for 12 h. The catalyst was filtered through a Celite pad and washed with MeOH. The filtrate was concentrated to dryness to yield the title compound (11.6 g, 94.2 mmol, 89%) as a white solid, which was used without further purification. MS: 122 [M−1]+; HPLC: AtRet=0.16.
Reaction SMILES: O[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].[CH3:11][C:12]1[CH:13]=[C:14]([CH:18]=O)O[C:16]=1[CH3:17].O(C)[Na]>C1COCC1>[C:12]1([CH:11]=[CH:2][C:3]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)=[O:4])[CH:13]=[CH:14][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(CO)c1ccccc1
Reactant: Cc1cc(C=O)oc1C
Agent: CO[Na]
Solvent: C1CCOC1
Product: O=C(C=Cc1ccccc1)c1ccccc1
Yield: 58.2 %

Procedure:
2.0 g (14.7 mmol) of 2-hydroxyacetophenone, 1.75 g of 4,5-dimethylfuran-2-carbaldehyde (14.1 mmol), and 10 ml of 25% wt NaOCH3 were reacted in 50 ml of dry THF to give 1.71 g (50%) of chalcone after purification. 1H NMR (300 MHz, CDCl3): δ 13.07 (s, 1H), 7.95 (d, J=7.8 Hz, 1H), 7.61 (d, J=15.0 Hz, 1H), 7.51-7.42 (m, 2H), 7.02 (d, d, J=0.9, 8.4 Hz, 1H), 6.94 (d, d, d, J=1.2, 8.4, 9.0 Hz, 1H), 6.60 (s, 1H), 2.34 (s, 3H), 2.00 (s, 3H).