Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: BrCC(C1C=C(C)C([N+]([O-])=O)=CC=1C)=O.C(=S)(N)C.[CH3:20][C:21]1[CH:26]=[C:25]([N+:27]([O-])=O)[C:24]([CH3:30])=[CH:23][C:22]=1[C:31]1[N:32]=[C:33]([CH3:36])[S:34][CH:35]=1>C(O)C.CO.[Pd]>[CH3:30][C:24]1[CH:23]=[C:22]([C:31]2[N:32]=[C:33]([CH3:36])[S:34][CH:35]=2)[C:21]([CH3:20])=[CH:26][C:25]=1[NH2:27]
Reactant: Cc1nc(-c2cc(C)c([N+](=O)[O-])cc2C)cs1
Agent: [Pd]
Agent: CC(N)=S
Agent: Cc1cc([N+](=O)[O-])c(C)cc1C(=O)CBr
Solvent: CO
Solvent: CCO
Product: Cc1nc(-c2cc(C)c(N)cc2C)cs1
Temperature: 150 °C
Reaction time: 8 h

Procedure:
A mixture of 2-bromo-1-(2,5-dimethyl-4-nitrophenyl)ethanone (70 mg, 0.26 mmol) and ethanethioamide (30 mg, 0.4 mmol) in ethanol (2 mL) was heated in a microwave at 150° C. for 20 min. The obtained 4-(2,5-dimethyl-4-nitrophenyl)-2-methylthiazole was dissolved in methanol (10 mL). To the solution was added Pd/C (10%). The reaction mixture was degassed and purged with H2 for several times and stirred under 1 atm. hydrogen gas overnight. The mixture was filtered and concentrated to afford 2,5-dimethyl-4-(2-methylthiazol-4-yl)aniline. ESMS m/z 219 (M+H+).
Reaction SMILES: [CH:1]1([CH2:7][CH:8]2[CH2:13][CH:12]([C:14](=[O:21])[CH2:15][C:16](OCC)=[O:17])[CH2:11][CH2:10][N:9]2[C:22]([O:24][CH3:25])=[O:23])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].Cl.[NH2:29]O.Cl>CO.CO.O.O>[CH:1]1([CH2:7][C@@H:8]2[CH2:13][C@@H:12]([C:14]3[O:21][NH:29][C:16](=[O:17])[CH:15]=3)[CH2:11][CH2:10][N:9]2[C:22]([O:24][CH3:25])=[O:23])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NO
Reactant: CCOC(=O)CC(=O)C1CCN(C(=O)OC)C(CC2CCCCC2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COC(=O)N1CC[C@H](c2cc(=O)[nH]o2)C[C@H]1CC1CCCCC1
Reaction time: 0.5 h
Yield: 8.1 %

Procedure:
A solution of methyl 2-(cyclohexylmethyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (1.5 g, 4.2 mmol) in MeOH (4 mL) was added to a solution of NaOH (221 mg, 5.5 mmol) in MeOH/H2O (4 mL/0.25 mL) at −30° C. After 10 minutes was added hydroxylamine-HCl (0.59 g, 8.5 mmol) and NaOH (0.339 g, 8.5 mmol) in MeOH (5 mL) and H2O (5 mL). Stirring was continued at −30° C. for 30 minutes. The reaction solution was poured into 6M HCl (6 mL) at 80° C. and heated for 30 minutes. The reaction mixture was partitioned between water and ethyl acetate. The organic phase was isolated, dried with Na2SO4, filtered through Celite® and the solvent was evaporated. Crude 1.7 g. Purification using reversed phase chromatography, which gave 0.3 g, yield 22%. Chiral separation using Chiralcel OJ, mobile phase heptane/ethanol 80/20 at 40° C. gave of (2R,4S)-methyl 2-(cyclohexylmethyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (0.11 g). 1H NMR (600 MHz, cdcl3) δ 0.91 (d, 2H), 1.06-1.39 (m, 5H), 1.68 (dt, 7H), 1.85 (s, 2H), 1.94 (s, 1H), 2.99 (t, 2H), 3.68 (s, 3H), 4.11 (d, 1H), 4.50 (d, 1H), 5.60 (s, 1H). [α]20D +3.2 (MeCN, c=1).
Reaction SMILES: [CH2:1]([N:4]([CH2:8][C:9](OC)([O:11]C)[CH3:10])[C:5](=[O:7])[CH3:6])[CH:2]=[CH2:3]>C(O)=O>[CH2:1]([N:4]([CH2:8][C:9](=[O:11])[CH3:10])[C:5](=[O:7])[CH3:6])[CH:2]=[CH2:3]
Reactant: C=CCN(CC(C)(OC)OC)C(C)=O
Solvent: O=CO
Product: C=CCN(CC(C)=O)C(C)=O
Temperature: 0 °C

Procedure:
85.5 g (0.425 mol) of N-allyl-N-(2,2-dimethoxypropyl)-acetamide are heated under reflux with 212 ml of formic acid for one hour. The mixture is poured onto 500 g of ice and extracted several times with methylene chloride, the organic phases are washed with sodium bicarbonate solution, dried over magnesium sulphate and concentrated and the residue is distilled.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[N+](C1C=CC=CC=1)([O-])=O.[C:15]1(=[O:21])[O:20][C:18](=[O:19])[CH2:17][CH2:16]1.[Cl-].[Al+3].[Cl-].[Cl-].Cl>>[O:21]=[C:15]([C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)[CH2:16][CH2:17][C:18]([OH:20])=[O:19]
Reactant: c1ccsc1
Reactant: O=C1CCC(=O)O1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Product: O=C(O)CCC(=O)c1cccs1
Reaction time: 8 h
Yield: 53 %

Procedure:
A solution of 0.3 mole of thiophene in 100 ml. of nitrobenzene is added dropwise with stirring to a cooled mixture of 30 g. (0.3 mole) of succinic anhydride, 87.8 g. (0.66 mole) of aluminum chloride and 300 ml. of nitrobenzene. The mixture is cooled and stirred for 30 minutes and then allowed to stand at room temperature overnight. The mixture is poured onto ice and 50 ml. of concentrated hydrochloric acid. The nitrobenzene is removed by steam distillation. The aqueous layer is decanted and the residue is mixed with 650 ml. of water and 20 g. of sodium carbonate. The mixture is heated, mixed with diatomaceous earth and filtered. The filtrate is acidified with concentrated hydrochloric acid and the solid which separates is filtered and washed with water. Recrystallization from water gives 53% of 4-oxo-4-(2-thienyl)butyric acid, m.p. 121°-123° C.
Reaction SMILES: Cl[C:2]([CH2:4][CH2:5][CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:3].[NH2:12][CH:13]([CH2:20][O:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1)[CH2:14][N:15]1[CH:19]=[CH:18][N:17]=[CH:16]1.C(N(CC)CC)C>ClCCl>[N:15]1([CH2:14][CH:13]([NH:12][C:2](=[O:3])[CH2:4][CH2:5][CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:20][O:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)[CH:19]=[CH:18][N:17]=[CH:16]1
Reactant: COc1ccc(COCC(N)Cn2ccnc2)cc1
Reactant: CCOC(=O)CCCC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CCCC(=O)NC(COCc1ccc(OC)cc1)Cn1ccnc1
Reaction time: 12 h

Procedure:
A solution of ethyl 4-(chloroformyl)butyrate (0.714 g, 0.004 mol) in dichloromethane (5 ml) was added dropwise to a stirred solution of 1-[2-amino-3-[(4-methoxyphenyl)methoxy]propyl]-1H-imidazole (Example 32c; 1.0 g, 0.0038 mol) and triethylamine (0.4 g, 0.004 mol) in dichloromethane (20 ml) at room temperature. The solution was stirred for 12 hours, washed with an aqueous saturated solution of ammonium chloride and dried (Na2SO4). The solvent was evaporated off under reduced pressure and the crude product was purified by column chromatography (silica gel, 2% ethanol in chloroform) to give ethyl 5-[[2-(1H-imidazol-1-yl)-1-[[(4-methoxyphenyl)methoxy]methyl]ethyl]amino]-5-oxopentanoate as a pale-yellow oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.Cl[C:10]1[CH:11]=[CH:12][C:13]([N+:25]([O-:27])=[O:26])=[C:14]([N:16]([CH3:24])[C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH:15]=1.[H-].[Na+]>CN(C)C=O>[CH3:24][N:16]([C:14]1[CH:15]=[C:10]([S:8][C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=2)[CH:11]=[CH:12][C:13]=1[N+:25]([O-:27])=[O:26])[C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:20])[CH3:21]
Reactant: Cc1ccc(S)cc1
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Cl)ccc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(Sc2ccc([N+](=O)[O-])c(N(C)C(=O)OC(C)(C)C)c2)cc1
Yield: 98 %

Procedure:
In a similar manner to that described in Reference Example 6, a reaction was carried out using 4-methylthiophenol (0.98 g), t-butyl N-(5-chloro-2-nitrophenyl)-N-methylcarbamate (2.00 g), sodium hydride (55 wt. %, 0.31 g) and anhydrous N,N-dimethylformamide (60 ml) and the reaction mixture was purified to give the title compound (2.56 g).
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:19][C:20]2[CH:24]=[C:23]([CH:25]3[CH2:27][CH2:26]3)[NH:22][N:21]=2)=[CH:4][C:5]([NH:8][C@H:9]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[CH2:10][OH:11])=[N:6][CH:7]=1.[C:28](O)(=O)C.C(N)=N.C([O-])(O)=O.[Na+].CCOC(C)=O>CCO>[CH:25]1([C:23]2[NH:22][N:21]=[C:20]([N:19]3[C:3]4[CH:4]=[C:5]([NH:8][C@H:9]([C:12]5[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=5)[CH2:10][OH:11])[N:6]=[CH:7][C:2]=4[N:1]=[CH:28]3)[CH:24]=2)[CH2:27][CH2:26]1
Reactant: Nc1cnc(N[C@@H](CO)c2ccc(F)cc2)cc1Nc1cc(C2CC2)[nH]n1
Reactant: CC(=O)O
Agent: N=CN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: OC[C@H](Nc1cc2c(cn1)ncn2-c1cc(C2CC2)[nH]n1)c1ccc(F)cc1
Temperature: 25 °C
Yield: 153 %

Procedure:
A mixture of (R)-2-(5-amino-4-(5-cyclopropyl-1H-pyrazol-3-ylamino)pyridin-2-ylamino)-2-(4-fluorophenyl)ethanol (Method 93, 0.14 g, 0.38 mmol) and formamidine acetate (0.079 g, 0.76 mmol) in EtOH (5 ml) was heated at reflux for 2 hours. After cooling to 25° C., the reaction mixture was treated with saturated NaHCO3 solution (10 ml) and EtOAc (30 ml). The organic layer was separated, washed with brine (10 ml), and dried over sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by column chromatography (EtOAc-MeOH=20:1) to give the title compound as an off-white solid (0.22 g, 32%). 1H NMR (400 MHz) 12.76 (s, 1H), 8.40 (s, 1H), 8.34 (s, 1H), 7.43 (m, 2H), 7.10 (m, 2H), 6.92 (s, 1H), 6.72 (d, J=7.2 Hz, 1H), 6.25 (s, 1H), 4.92 (m, 2H), 3.62 (m, 2H), 1.97 (m, 1H), 1.02 (m, 2H), 0.77 (m, 2H). MS: Calcd.: 378; Found: [M+H]+ 379.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([C@H:12]([CH2:30][CH2:31][CH2:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C@H:13]([CH2:21][CH2:22][O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:14]([O:16]C(C)(C)C)=[O:15])(=[O:11])=[O:10])=[CH:5][CH:4]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([S:9]([C@H:12]([CH2:30][CH2:31][CH2:32][CH2:33][C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[C@H:13]([CH2:21][CH2:22][O:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:14]([OH:16])=[O:15])(=[O:11])=[O:10])=[CH:7][CH:8]=1
Reactant: COc1ccc(S(=O)(=O)[C@H](CCCCc2ccccc2)[C@H](CCOc2ccccc2)C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)[C@H](CCCCc2ccccc2)[C@H](CCOc2ccccc2)C(=O)O)cc1
Temperature: 0 °C
Reaction time: 4 h
Yield: 70.9 %

Procedure:
(±)-t-Butyl (2R*,3R*)-3-(4-methoxybenzenesulfonyl)-7-phenyl-2-(2-phenoxyethyl)heptanoate (0.3 g, 0.54 mmol) is dissolved in CH2Cl2 (7 mL), cooled to 0° C. and TFA (1 mL) is added slowly. The bath is removed and the reaction is stirred for 4 hours. The reaction is concentrated in vacuo and the residue purified by reverse phase HPLC (50-100% CH3CN in 0.1% TFA/H2O) to yield (±)-(2R*,3R*)-3-(4-methoxybenzenesulfonyl)-7-phenyl-2-(2-phenoxyethyl)heptanoic acid (0.19 g, 70%). 1H NMR (300 MHz, CDCl3) δ 7.81 (d, J=8.8 Hz, 2H), 7.29-7.15 (m, 5H), 7.08 (d, J=7.3 Hz, 2H), 6.98-6.91 (m, 3H), 6.81 (d, J=8.3 Hz, 2H), 4.17-4.03 (m, 2H), 3.83 (s, 3H), 3.80-3.75 (m, 1H), 3.17-3.14 (m, 1H), 2.58-2.50 (m, 3H), 2.30-2.18 (m, 1H), 1.90-1.77 (m, 2H), 1.60-1.45 (m, 3H), 1.41-1.30 (m, 1H); MS (FAB) m/e 497 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:15])[CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[C:7]=1[OH:8].[C:22](Cl)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>O1CCCC1>[C:22]([O:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:15])[CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[C:7]=1[O:8][C:14](=[O:15])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: O=C(C=Cc1cc(O)c(O)c([N+](=O)[O-])c1)c1ccccc1
Solvent: C1CCOC1
Product: O=C(C=Cc1cc(OC(=O)c2ccccc2)c(OC(=O)c2ccccc2)c([N+](=O)[O-])c1)c1ccccc1

Procedure:
1.0 g of the product obtained in Example 8 and 2.0 ml of benzoylchloride were dissolved in 5 ml of tetrahydrofuran. Tetrahydrofuran was distilled off to a great extent and the residue was refluxed for 2 h. After cooling ether was added to the mixture and the product was filtered and triturated with ethylmethylketone. Yield 0.50 g (29%), m.p. 206°-210° C.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([NH:7][C:8]([NH2:10])=[NH:9])[CH:4]=[N:3]1.[C:11]([CH:13]([CH2:19][CH:20](OCC)OCC)[C:14](OCC)=[O:15])#[N:12].CO[Na].CO.Cl.[OH-].[Na+]>CCO.CO>[CH3:1][N:2]1[CH:6]=[C:5]([NH:7][C:8]2[N:10]=[C:14]([OH:15])[C:13]3[CH:19]=[CH:20][NH:12][C:11]=3[N:9]=2)[CH:4]=[N:3]1
Reactant: Cn1cc(NC(=N)N)cn1
Reactant: CCOC(=O)C(C#N)CC(OCC)OCC
Agent: CO[Na]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CCO
Product: Cn1cc(Nc2nc(O)c3cc[nH]c3n2)cn1
Temperature: 100 °C
Reaction time: 20 h
Yield: 36.2 %

Procedure:
To a solution of crude 1-(1-methyl-1H-pyrazol-4-yl)guanidine (17.5 g, crude) and ethyl 2-cyano-4,4-diethoxybutanoate (13.08 g, 0.06 mol) in EtOH (50 mL) was added CH3ONa/CH3OH (150 mL, 0.06 mol) at 20° C., and the reaction mixture was stirred at 100° C. for 20 hrs. The pH was adjusted to 2 by HCl (6 M) and stirred for 30 min. Then pH was adjusted to 7-8 by aqueous NaOH (1 M). The reaction mixture was filtered and the filter cake was dried in vacuo to afford a first batch of pure product. The filtrate was concentrated in vacuo and the residue was purified by column chromatography eluted with CH2Cl2:MeOH=13:1 to afford the title compound (combined batches yielded 5 g, 43.5% yield over two steps). 1H NMR: (400 MHz, DMSO) δ ppm 11.21 (s, 1H), 10.28 (s, 1H), 8.44 (s, 1H), 7.88 (s, 1H), 7.50 (s, 1H), 6.67-6.68 (m, 1H), 6.22-6.24 (m, 1H), 3.79 (s, 3H).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH3:6][CH:7]([CH3:26])[CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[CH:13][CH:12]=1.C(N(CC)CC)C.Cl>ClCCl>[CH3:6][CH:7]([CH3:26])[CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:18][C:19]([O:21][C:22]([CH3:23])([CH3:25])[CH3:24])=[O:20])=[CH:13][CH:12]=1
Reactant: CC(C)CCOc1ccc(NCC(=O)OC(C)(C)C)cc1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)CCOc1ccc(N(CC(=O)OC(C)(C)C)S(C)(=O)=O)cc1
Reaction time: 3 h
Yield: 55.4 %

Procedure:
Methanesulfonylchloride (93 mg, 63 μL, 0.82 mmol) was added in one portion to a stirred solution of 1,1-dimethylethyl N-{4-[(3-methylbutyl)oxy]phenyl}glycinate (intermediate 6, 0.20 g, 0.68 mmol) and triethylamine (138 mg, 189 μL, 1.36 mmol) in dichloromethane (2 mL) at room temperature under a nitrogen atmosphere. Stirring was continued for 3 h then aqueous hydrochloric acid (1.0 M; 2 mL) was added. The organic phase was separated and the aqueous phase washed with dichloromethane (3×5 mL). The organic phases were combined, dried (magnesium sulfate) then evaporated to dryness. The residue was chromatographed on silica gel (30% diethyl ether:cyclohexane) to give the title compound as a white solid (140 mg, 56%). LC/MS: 3.72 min; z/e 389, calcd (M+18) 389. 1H NMR (400 MHz; CDCl3): 0.95 (6H), 1.45 (9H), 1.70 (2H), 1.85 (1H), 3.10 (3H), 3.95 (2H), 4.30 (2H), 6.85 (2H), 7.35 (2H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][C:24]=2[CH3:25])[C:21](=[O:26])[N:20](CC2C=CC(OC)=CC=2)[CH:19]=[CH:18]3)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>>[CH3:25][C:24]1[CH:23]=[C:22]2[C:17]([CH:18]=[CH:19][NH:20][C:21]2=[O:26])=[CH:16][C:15]=1[O:14][CH:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: COc1ccc(Cn2ccc3cc(OC4CCN(C(=O)OC(C)(C)C)CC4)c(C)cc3c2=O)cc1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc2c(=O)[nH]ccc2cc1OC1CCNCC1
Temperature: 150 °C

Procedure:
6.4 g (13.4 mmol) 4-[2-(4-methoxy-benzyl)-7-methyl-1-oxo-1,2-dihydro-isoquinolin-6-yloxy]-piperidine-1-carboxylic acid tert-butyl ester were dissolved in 30.5 g (267.4 mmol) trifluoroacetic acid. After 1 h at room temperature the mixture was heated for 2 h in a microwave oven at 150° C. Then the excess trifluoroacetic acid was distilled off in vacuo and the residue was diluted with 130 mL of 1 M hydrochloric acid. The aqueous phase was washed with methylene chloride 3 times and then it was freeze dried to give a hydrochloride, which was crystallized from isopropanol. This furnished 3.2 g 7-methyl-6-(piperidin-4-yloxy)-2H-isoquinolin-1-one (16) as hydrochloride.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[S:10][CH2:9][CH2:8][C:7](=[O:11])[C:6]=2[CH:12]=1.Cl.[NH2:14]O.C([O-])(=O)C.[Na+].O>C(O)C>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[S:10][CH2:9][CH2:8][C:7](=[O:11])[NH:14][C:6]=2[CH:12]=1
Reactant: NO
Reactant: Cc1ccc2c(c1)C(=O)CCS2
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1ccc2c(c1)NC(=O)CCS2
Reaction time: 1 h
Yield: 23.7 %

Procedure:
6-Methyl-2,3-dihydro-4H-1-benzothiopyran-4-one (2g, 10.9 mmol) was dissloved in 80% ethanol (73 mL) and to this was added hydroxylamine hydrochloride (840 mg, 12.05 mmol) and sodium acetate (990 mg, 12.03 mmol). This mixture was heated at reflux for 3 hours. Water (150 mL) was added and then extracted with dichloromethane (3×100 mL), washed with brine (75 mL), water (75 mL), dried (sodium sulfate) and concentrated to residue. The residue was taken up in polyphosphoric acid (10 mL) and heated at reflux for 1 hour. Ice chips were added and water was added (100 mL) this was stirred for 1 hour. A solid formed and was filtered and purified by flashcolumn chromatography on 20 g of silica gel, eluting with (50%, 60%, and 70%) ethyl acetate in hexanes to give 7-methyl-2,3,4,5-tetrahydrobenzo[b]1,4-thiazepin-4-one (500 mg, 30%). 1H NMR (CDCl3, 300 MHz): δ7.87 (s-broad, 1H), 7.47 (d, 1H, J=7.7 Hz), 6.98 (d, 1H, J=8.1 Hz), 6.91 (s, 1H), 3.42 (t, 2H, J=6.9 Hz), 2.62 (t, 2H, J=6.9 Hz), 2.35 (s, 3H) ppm.
Reaction SMILES: B.C1COCC1.[Cl:7][C:8]1[CH:13]=[C:12]([C:14](O)=[O:15])[CH:11]=[C:10]([CH3:17])[N:9]=1.Cl.C(=O)(O)[O-].[Na+]>C1COCC1>[Cl:7][C:8]1[CH:13]=[C:12]([CH2:14][OH:15])[CH:11]=[C:10]([CH3:17])[N:9]=1
Reactant: Cc1cc(C(=O)O)cc(Cl)n1
Agent: B
Agent: Cl
Agent: O=C([O-])O
Solvent: C1CCOC1
Product: Cc1cc(CO)cc(Cl)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.3 %

Procedure:
Borane-THF complex (16.5 mL, 1.06 M solution in THF) was added to a solution of 2-chloro-6-methylpyridine-4-carboxylic acid (2 g) in THF (10 mL), and the mixture was heated under reflux for 12 hours. 5 M hydrochloric acid was added to the reaction mixture, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was neutralized by adding a saturated aqueous sodium bicarbonate solution, followed by extraction with ethyl acetate. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/n-heptane, 10% to 50%) to give the title compound (1.75 g).
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([NH2:8])[CH:5]=[N:4]1)[CH3:2].Br[C:10]1[C:11](=[O:18])[N:12]([CH3:17])[CH:13]=[C:14]([Br:16])[N:15]=1>>[Br:16][C:14]1[N:15]=[C:10]([NH:8][C:6]2[CH:5]=[N:4][N:3]([CH2:1][CH3:2])[CH:7]=2)[C:11](=[O:18])[N:12]([CH3:17])[CH:13]=1
Reactant: CCn1cc(N)cn1
Reactant: Cn1cc(Br)nc(Br)c1=O
Product: CCn1cc(Nc2nc(Br)cn(C)c2=O)cn1
Yield: 75.3 %

Procedure:
Following Example 111b, reaction of 1-ethyl-1H-pyrazol-4-amine (500 mg, 4.50 mmol) and 3,5-dibromo-1-methylpyrazin-2(1H)-one (1.33 g, 4.95 mmol) afforded a 75% yield (1.01 g) of 131b as an off-white solid: mp 237-239° C.; 1H NMR (300 MHz, DMSO-d6) d 9.90 (s, 1H), 8.02 (s, 1H), 7.73 (s, 1H), 7.20 (s, 1H), 4.11 (q, 2H, J=7.5 Hz), 3.41 (s, 3H), 1.34 (t, 3H, J=7.3 Hz); MS (ESI+) m/z 298.0 (M+H).
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1[NH:12][C:13]([CH:16]=[O:17])=[CH:14][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P([O-])(O)(O)=[O:19].[Na+].Cl([O-])=O.[Na+].C=C(C)C>C(O)CCC.O>[CH2:1]([O:8][C:9]([C:11]1[NH:12][C:13]([C:16]([OH:19])=[O:17])=[CH:14][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(C(=O)OCc2ccccc2)[nH]1
Reactant: O=P([O-])(O)O
Agent: C=C(C)C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Solvent: CCCCO
Product: O=C(O)c1ccc(C(=O)OCc2ccccc2)[nH]1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 5-formyl-1H-pyrrole-2-carboxylic acid benzyl ester (8.0 g) in n-butanol (300 mL) and water (112 mL) was added sodium dihydrogen phosphate (6.28 g), sodium chlorite (9.47 g) and isobutene (58g). The mixture was stirred for 20 h at RT after which it was concentrated. After purification of the residue by flash column chromatography on silica (DCM/MeOH 15:1 to 1:1) 10.0 g of 1H-pyrrole-2,5-dicarboxylic acid monobenzyl ester were obtained.
Reaction SMILES: [CH:1]([C:3]1[N:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[N:6]=[C:5]([O:13][CH:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]2)[CH:4]=1)=O.[NH:27]1[CH2:30][CH:29]([OH:31])[CH2:28]1>>[OH:31][CH:29]1[CH2:30][N:27]([CH2:1][C:3]2[N:8]=[C:7]([C:9]([F:11])([F:10])[F:12])[N:6]=[C:5]([O:13][CH:14]3[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]3)[CH:4]=2)[CH2:28]1
Reactant: OC1CNC1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cc(C=O)nc(C(F)(F)F)n2)CC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2cc(CN3CC(O)C3)nc(C(F)(F)F)n2)CC1

Procedure:
This compound was prepared according to the method of Example 41, Step 2 using tert-butyl 4-{[6-formyl-2-(trifluoromethyl)pyrimidin-4-yl]oxy}piperidine-1-carboxylate and azetidin-3-ol as starting materials. LCMS (M+H)+: 433.3.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7]2[C:3]=1[CH2:4][CH:5]([C:12]([O:14][CH3:15])=[O:13])[NH:6]2.[OH:16]O>CO>[OH:16][N:6]1[C:7]2[C:3](=[C:2]([CH3:1])[CH:10]=[CH:9][C:8]=2[CH3:11])[CH:4]=[C:5]1[C:12]([O:14][CH3:15])=[O:13]
Reactant: OO
Reactant: COC(=O)C1Cc2c(C)ccc(C)c2N1
Solvent: CO
Product: COC(=O)c1cc2c(C)ccc(C)c2n1O
Temperature: 0 °C
Reaction time: 3 h
Yield: 35.5 %

Procedure:
A flask was charged with 1.0 g (4.9 mmol) of methyl 4,7-dimethylindoline-2-carboxylate and 64 mg (0.193 mmol) of sodium tungstate-dihydrate, and the air in the reaction system was substituted with nitrogen. Methanol (15 ml) was added and the reaction mixture was cooled to 0° C. Then 1.25 g of 30% aqueous hydrogen peroxide solution was added and the reaction mixture was stirred for 3 hours. Yield: 35.5%
Reaction SMILES: [CH2:1]([N:8]([CH2:10][CH2:11][N:12]1[C:33](=[O:34])[N:15]2[C:16]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:17]=3[N:18]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:19](=[O:21])[CH:20]=[C:14]2[NH:13]1)C)C1C=CC=CC=1.[CH2:35](O)C>[Pd]>[CH3:1][NH:8][CH:10]([CH3:35])[CH2:11][N:12]1[C:33](=[O:34])[N:15]2[C:16]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:17]=3[N:18]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:19](=[O:21])[CH:20]=[C:14]2[NH:13]1
Reactant: CN(CCN1NC2=CC(=O)N(c3ccccc3)c3cc(Cl)ccc3N2C1=O)Cc1ccccc1
Reactant: CCO
Agent: [Pd]
Product: CNC(C)CN1NC2=CC(=O)N(c3ccccc3)c3cc(Cl)ccc3N2C1=O

Procedure:
4 g of 2-[2-(N-benzyl-N-methylamino)ethyl]-8-chloro-6-phenyl-1H-s-triazolo[4,3-a][1,5]benzodiazepine-1,5-dione in 100 ml of ethanol containing 0.4 g of 5% palladium on charcoal is hydrogenated at 50 p.s.i. hydrogen pressure until 1 molar equivalent of hydrogen is absorbed. The suspension is filtered and the filtrate is evaporated. The residue is triturated with a small amount of cold ether and the title compound is filtered off and dried.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][CH:13]=1)[CH:8]=[CH:7]2.[CH:22]([C:25]1[CH:31]=[CH:30][CH:29]=[C:28]([CH:32]([CH3:34])[CH3:33])[C:26]=1[NH2:27])([CH3:24])[CH3:23].C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2N(C)C)CCCCC1.CC([O-])(C)C.[Na+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].O.C1(C)C=CC=CC=1>[CH:32]([C:28]1[CH:29]=[CH:30][CH:31]=[C:25]([CH:22]([CH3:24])[CH3:23])[C:26]=1[NH:27][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][CH:13]=1)[CH:8]=[CH:7]2)([CH3:34])[CH3:33]
Reactant: CC(C)c1cccc(C(C)C)c1N
Reactant: Brc1cccc2ccc(-c3cccc4ccccc34)nc12
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)c1cccc(C(C)C)c1Nc1cccc2ccc(-c3cccc4ccccc34)nc12
Temperature: 105 °C
Reaction time: 8 h

Procedure:
A mixture of 8-bromo-2-(1-naphthyl)quinoline (2.03 g, 6 mmol), 2,6-diisopropylaniline (1.3 ml, 7 mmol), Pd(dba)2 (72 mg, 0.12 mmol), L=(N-[2′-(dicyclohexylphosphino)[1,1′-biphenyl]-2-yl]-N,N-dimethylamine (94 mg, 0.24 mmol), NaOtBu (0.72 g, 7.2 mol) and toluene (15 mL) is stirred for 8 h under an argon atmosphere at 105° C. in an oil bath. The mixture is then poured into water and extracted with benzene (3×50 mL). The combined organic phase is washed with water and brine, and is then concentrated. The residue is purified by column chromatography (silica gel 40, hexane/toluene 2:1). Yield: 1.7 g (66%).