Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH2:7][CH:6]([C:8]2[S:9][C:10]([CH3:13])=[CH:11][CH:12]=2)[CH2:5][C:4](=[O:14])[CH:3]=1.[OH-].[K+]>C(O)C.C1(C)C=CC=CC=1>[CH3:4][C:3]1[C:3]2[C:4](=[O:14])[CH2:5][CH:6]([C:8]3[S:9][C:10]([CH3:13])=[CH:11][CH:12]=3)[CH2:7][C:2]=2[N:1]=[CH:7][CH:2]=1
Reactant: Cc1ccc(C2CC(=O)C=C(N)C2)s1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: Cc1ccccc1
Product: Cc1ccc(C2CC(=O)c3c(C)ccnc3C2)s1
Temperature: 115 °C
Yield: 172.7 %

Procedure:
In a mixture of ethanol (30 ml) and toluene (90 ml) was dissolved 1-amino-5-(5-methyl-2-thienyl)cyclohexen-3-one (1.66 g). To the solution were added 3-oxobutylaldehydedimethylacetal (2.6 g) and granulated potassium hydroxide (430 mg), and the mixture was stirred at 115° C. (bath temperature). To the mixture were added granulated potassium hydroxide (80 mg), 30 minutes later; 1 hour later; 1.5 hours later; respectively. The reaction solution was stirred at the same temperature for 1 hour and cooled. Under reduced pressure, the solvent was evaporated, and to the residue were added ethyl acetate (50 ml) and water (10 ml). The mixture was shaken, and the separated upper layer was washed with saturated brine and concentrated under reduced pressure. The residue was purified with silica gel column chromatography (EtOAc/hexane) and eluted with ethyl acetate/hexane to give 4-methyl-7-(5-methyl-2-thienyl)-5,6,7,8-tetrahydroquinolin-5-one (1.78 g) as pale yellow oil.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:28]([CH3:29])=[CH:27][C:15]2[N:16]=[C:17]([C:19]3[C:24]([CH3:25])=[CH:23][N:22]=[C:21](Cl)[CH:20]=3)[S:18][C:14]=2[C:13]=1[C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2].[CH3:37][N:38]1[C:46]2[C:41](=[CH:42][C:43](B(O)O)=[CH:44][CH:45]=2)[CH:40]=[N:39]1.C([O-])([O-])=O.[K+].[K+]>CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:5][C@@H:6]([C:12]1[C:28]([CH3:29])=[CH:27][C:15]2[N:16]=[C:17]([C:19]3[C:24]([CH3:25])=[CH:23][N:22]=[C:21]([C:43]4[CH:42]=[C:41]5[C:46](=[CH:45][CH:44]=4)[N:38]([CH3:37])[N:39]=[CH:40]5)[CH:20]=3)[S:18][C:14]=2[C:13]=1[C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:3])([CH3:4])[CH3:2]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3cc(Cl)ncc3C)sc2c1-c1ccc(Cl)cc1
Reactant: Cn1ncc2cc(B(O)O)ccc21
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: CCOC(C)=O
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3cc(-c4ccc5c(cnn5C)c4)ncc3C)sc2c1-c1ccc(Cl)cc1
Temperature: 120 °C

Procedure:
A microwave vial containing (S)-ethyl 2-(tert-butoxy)-2-(2-(2-chloro-5-methylpyridin-4-yl)-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)acetate (68 mg, 0.13 mmol) was charged with (1-methyl-1H-indazol-5-yl)boronic acid (44 mg, 0.25 mmol), then Pd(PPh3)4 (24 mg, 0.02 mmol). The vial was flushed with argon, diluted with dioxane (2.0 mL) and to this was added 2M aqueous K2CO3 (0.20 mL, 0.40 mmol). The vial was sealed, heated to 120° C. for 3 hours, and then allowed to cool to room temperature. The mixture was diluted with EtOAc, dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified by silica gel column chromatography (10-45% EtOAc/Hex gradient) to afford the desired product. LCMS-ESI+: calc'd for C36H36ClN4O3S: 639.2 (M+H+); Found: 639.2 (M+H+).
Reaction SMILES: [CH3:1][Si:2]([C:5]#[CH:6])([CH3:4])[CH3:3].C([Li])CCC.[Cl:12][CH2:13][CH2:14][CH2:15]I.O>O1CCCC1>[Cl:12][CH2:13][CH2:14][CH2:15][C:6]#[C:5][Si:2]([CH3:4])([CH3:3])[CH3:1]
Reactant: C#C[Si](C)(C)C
Reactant: ClCCCI
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: C[Si](C)(C)C#CCCCCl
Reaction time: 0.5 h

Procedure:
A solution of trimethylsilylacetylene (12.0 g., Aldrich) in dry tetrahydrofuran (100 ml.) was stirred at 0°, under a current of nitrogen and n-butyllithium (76.5 ml. of 1.6M solution in hexane) was added dropwise. The solution was stirred for 30 minutes and a solution of 1-chloro-3-iodopropane (25.0 g.) in dry tetrahydrofuran (75 ml.) was added. The reaction mixture was allowed to warm to 20° and stirred for 18 hours. The mixture was poured into water and the aqueous mixture was extracted with diethyl ether. The ethereal extracts were washed with water and dried over anhydrous magnesium sulphate. The solvent was removed in vacuo and the residue distilled. 5-Chloro-1-trimethylsilylpent-1-yne was obtained as a colourless oil (12.7 g., b.p. 67°-27°, 15 mm. Hg.).
Reaction SMILES: [F:1][C:2]([F:44])([F:43])[C:3]1[CH:4]=[C:5]([C:13]([CH3:42])([CH3:41])[C:14]([N:16]([C:18]2[C:19]([C:33]3[CH:38]=[CH:37][C:36]([F:39])=[CH:35][C:34]=3[CH3:40])=[CH:20][C:21]([N:24]3[CH2:29][CH2:28][CH:27]([CH2:30][S:31][CH3:32])[CH2:26][CH2:25]3)=[N:22][CH:23]=2)[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.ClC1C=CC=C(C(OO)=[O:53])C=1.S([O-])(O)=O.[Na+]>ClCCl>[F:44][C:2]([F:1])([F:43])[C:3]1[CH:4]=[C:5]([C:13]([CH3:41])([CH3:42])[C:14]([N:16]([C:18]2[C:19]([C:33]3[CH:38]=[CH:37][C:36]([F:39])=[CH:35][C:34]=3[CH3:40])=[CH:20][C:21]([N:24]3[CH2:25][CH2:26][CH:27]([CH2:30][S:31]([CH3:32])=[O:53])[CH2:28][CH2:29]3)=[N:22][CH:23]=2)[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSCC1CCN(c2cc(-c3ccc(F)cc3C)c(N(C)C(=O)C(C)(C)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)cn2)CC1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cc(F)ccc1-c1cc(N2CCC(CS(C)=O)CC2)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Yield: 89.7 %

Procedure:
To a solution of 0.25 g (0.39 mmol) 2-(3,5-bis-trifluoromethyl-phenyl)-N-[4′-(4-fluoro-2-methyl-phenyl)-4-methylsulfanylmethyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl]-N-methyl-isobutyramide in 10 ml dichloromethane were added 95 mg (70%, 0.39 mmol) 3-chloroperbenzoic acid at 0° C. After completed addition, the reaction mixture was allowed to warm to room temperature and stirred over night. An aqueous solution of sodium hydrogensulfite was added and the mixture was stirred for 10 min. Basification with 1 N aqueous sodium hydroxide solution was followed by extraction with three portions of dichloromethane. The combined organic extracts were dried over sodium sulphate and concentrated. Flash column chromatography gave 0.23 g (89%) of the title compound as a white solid.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH:10]([N:12]1[C:20]2[CH:19]=[CH:18][N:17]=[CH:16][C:15]=2[C:14](I)=[CH:13]1)[CH3:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Br:22][C:23]1[CH:28]=[CH:27][N:26]=[C:25]([C:29](N(OC)C)=[O:30])[CH:24]=1>>[Br:22][C:23]1[CH:28]=[CH:27][N:26]=[C:25]([C:29]([C:14]2[C:15]3[CH:16]=[N:17][CH:18]=[CH:19][C:20]=3[N:12]([CH:10]([CH3:11])[CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[CH:13]=2)=[O:30])[CH:24]=1
Reactant: CC(CO[Si](C)(C)C(C)(C)C)n1cc(I)c2cnccc21
Reactant: CON(C)C(=O)c1cc(Br)ccn1
Product: CC(CO[Si](C)(C)C(C)(C)C)n1cc(C(=O)c2cc(Br)ccn2)c2cnccc21

Procedure:
Prepared according to the method described for Preparation 37 using 1-(2-{[tert-butyl(dimethyl)silyl]oxy}-1-methylethyl)-3-iodo-1H-pyrrolo[3,2-c]pyridine (Preparation 55) and 4-bromo-N-methoxy-N-methylpyridine-2-carboxamide. Purified using silica gel column chromatography eluting with 35-40% EtOAc in hexane.
Reaction SMILES: [C:1]([C:3]1[CH:20]=[CH:19][C:6]([C:7]([NH:9][C:10]2[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=2)[C:13]([OH:15])=O)=[O:8])=[CH:5][CH:4]=1)#[N:2].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH2:32][C@H:33]([C:42]([O:44][CH3:45])=[O:43])[CH2:34][C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38]>CN(C=O)C>[CH3:45][O:44][C:42](=[O:43])[C@H:33]([CH2:34][C:35]([O:36][C:37]([CH3:39])([CH3:38])[CH3:40])=[O:41])[NH:32][C:13](=[O:15])[C:12]1[CH:16]=[CH:17][CH:18]=[C:10]([NH:9][C:7](=[O:8])[C:6]2[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:20][CH:19]=2)[CH:11]=1
Reactant: N#Cc1ccc(C(=O)Nc2cccc(C(=O)O)c2)cc1
Reactant: COC(=O)[C@@H](N)CC(=O)OC(C)(C)C
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Solvent: CN(C)C=O
Product: COC(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)c1cccc(NC(=O)c2ccc(C#N)cc2)c1
Yield: 65 %

Procedure:
m-(p-Cyanobenzamido)benzoic acid is activated in the same manner as described under a) and coupled with the p-toluenesulphonate of H-Asp(OtBu)OMe in DMF at room temperature. There is isolated 3-(t-butoxycarbonyl)-N-[m-(p-cyanobenzamido)benzoyl]-L-alanine methyl ester in the form of colourless crystals. Yield: 65%, m.p. 83°-84° C. (hexane).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([N+:18]([O-])=O)[C:10]([O:16][CH3:17])=[C:11]([O:14][CH3:15])[CH:12]=3)[C:7](=[O:21])[C:6]([C:22]([OH:24])=[O:23])=[CH:5]2)[CH2:3][CH2:2]1.O.O.O.O.O.O.O.O.O.[S-2].[Na+].[Na+]>C(O)C.O>[NH2:18][C:9]1[C:10]([O:16][CH3:17])=[C:11]([O:14][CH3:15])[CH:12]=[C:13]2[C:8]=1[C:7](=[O:21])[C:6]([C:22]([OH:24])=[O:23])=[CH:5][N:4]2[CH:1]1[CH2:2][CH2:3]1
Reactant: COc1cc2c(c([N+](=O)[O-])c1OC)c(=O)c(C(=O)O)cn2C1CC1
Agent: [Na+]
Agent: [S-2]
Solvent: CCO
Solvent: O
Product: COc1cc2c(c(N)c1OC)c(=O)c(C(=O)O)cn2C1CC1
Yield: 97.7 %

Procedure:
Under N2, 1-cyclopropyl-6,7-dimethoxy-5-nitro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (10 g, 29.9 mmol) was treated with sodium sulfide nonahydrate (71.9 g, 299 mmol) in a mixture of Ethanol (100 mL) and Water (100 mL) for 2 h at 100° C. LCMS showed completion of reaction. After cooling down, the mixture was poured into cold water and the solution was adjusted to pH 2. The yellow precipitate was collected by filtration, washed with water and dried to afford 5-amino-1-cyclopropyl-6,7-dimethoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (8.9 g, 29.2 mmol, 98% yield) as a yellow solid.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5]([C:7]1[CH:8]=[C:9]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:10]=[C:11]([C:13](=[O:18])[NH:14][CH2:15][CH2:16][CH3:17])[CH:12]=1)=[O:6]>CO.CC(C)=O.O.Cl>[CH2:15]([NH:14][C:13]([C:11]1[CH:12]=[C:7]([C:5]([OH:6])=[O:4])[CH:8]=[C:9]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:10]=1)=[O:18])[CH2:16][CH3:17]
Reactant: CCCNC(=O)c1cc(C(=O)OC)cc(-c2ccccc2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: CC(C)=O
Product: CCCNC(=O)c1cc(C(=O)O)cc(-c2ccccc2)c1
Reaction time: 72 h

Procedure:
A solution of NaOH (44 mg, 1.1 mmol) in 372 μL of MeOH was added to a solution of 68D (284 mg, 0.96 mmol) in 1.8 mL of acetone. The reaction was stirred at room temperature for 16 hrs after which time 10 mg of NaOH and 200 μL of MeOH were added. The reaction was stirred for 72 hrs. The reaction mixture was then concentrated in vacuo and the residue obtained was dissolved in water and a few drops of concentrated HCl were added till pH ˜1. An off-white solid appeared. It was collected by filtration and extensively rinsed with water. The solid was then dried in vacuo (194 mg, 72%). NMR 1H (ppm, CD3OD): 8.43 (t., J4=1.63 Hz, 1H), 8.38 (t., J4=1.73 Hz, 1H), 8.27 (t., J4=1.78 Hz, 1H), 7.71-7.67 (m, 2H), 7.48 (m, 2H), 7.39 (t.t., J3=7.34 Hz, J4=1.36 Hz 1H), 3.39-3.34 (m, 2H), 1.65 (sext., J3=7.18 Hz, 2H), 0.98 (t., J3=7.34 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([CH2:8][CH2:9][OH:10])[CH:5]=[CH:4][CH:3]=1.F[C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=1.[H-].[Na+]>O1CCCC1>[CH3:1][C:2]1[N:7]=[C:6]([CH2:8][CH2:9][O:10][C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(F)cc1
Reactant: Cc1cccc(CCO)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cccc(CCOc2ccc(C#N)cc2)n1
Temperature: 0 °C

Procedure:
To a mixture of 6-methyl-2-pyridineethanol (97.2 g), p-fluorobenzonitrile (85.8 g) and dry tetrahydrofuran (600 ml) was added 60% sodium hydride in oil (29.0 g) in small portions with ice-cooling and stirring and the mixture was further stirred for 2 hours. The reaction mixture was poured in ice-water and extracted with ethyl ether. The ethyl ether layer was washed with water, dried (MgSO4) and concentrated, and the residue was crystallized from hexane to give 4-[2-(6-methyl-2-pyridyl)ethoxy]benzonitrile. Yield: 85.9 g (50.1%); m.p.: 66°-67° C.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:20][O:21][CH2:22][CH3:23])[N:14]([CH2:15][C:16]([CH3:19])([OH:18])[CH3:17])[C:10]=2[C:9]2[N:8]=[CH:7][C:6](Br)=[CH:5][C:4]=2[N:3]=1.[N:25]1([C:30]([C:32]2[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][CH:37]=2)=[O:31])[CH2:29][CH2:28][CH2:27][CH2:26]1.C(=O)([O-])[O-].[K+].[K+].COCCOC>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:20][O:21][CH2:22][CH3:23])[N:14]([CH2:15][C:16]([CH3:19])([OH:18])[CH3:17])[C:10]=2[C:9]2[N:8]=[CH:7][C:6]([C:36]3[CH:35]=[CH:34][CH:33]=[C:32]([C:30]([N:25]4[CH2:26][CH2:27][CH2:28][CH2:29]4)=[O:31])[CH:37]=3)=[CH:5][C:4]=2[N:3]=1
Reactant: O=C(c1cccc(B(O)O)c1)N1CCCC1
Reactant: CCOCc1nc2c(N)nc3cc(Br)cnc3c2n1CC(C)(C)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: CCOCc1nc2c(N)nc3cc(-c4cccc(C(=O)N5CCCC5)c4)cnc3c2n1CC(C)(C)O
Temperature: 110 °C
Yield: 27.5 %

Procedure:
A suspension of 1-[4-amino-7-bromo-2-(ethoxymethyl)-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl]-2-methylpropan-2-ol (1.2 g, 3.0 mmol), (3-pyrrolidinylcarbonylphenyl)boronic acid (0.800 g, 3.65 mmol), potassium carbonate (1.4 g, 10.0 mmol), dichlorobis(triphenylphosphine)palladium(II)(0.021 g, 0.030 mmol), DME (13 mL), and water (7 mL) was stirred under a nitrogen atmosphere in a pressure vessel. The vessel was then sealed and heated at 110° C. for 16.5 hours and allowed to cool to room temperature. The volatiles were removed under reduced pressure. The residue was diluted with methanol, and silica gel was added. The mixture was concentrated under reduced pressure. The residue was purified by automated flash chromatography (FLASH 40+M silica cartridge, eluting with 10% to 25% methanol in ethyl acetate). The resulting material was concentrated twice from acetonitrile and then triturated with acetonitrile (100 mL) to provide a solid. The solid was isolated by filtration, washed with acetonitrile, and dried in a vacuum oven at 65° C. to provide 403 mg of 1-{4-amino-2-(ethoxymethyl)-7-[3-(pyrrolidin-1-ylcarbonyl)phenyl]-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl}-2-methylpropan-2-ol as a white solid, mp 185-187° C.
Reaction SMILES: CO[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13](OC)=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.I[C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=1.C(O[Na])(C)(C)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C(C)=CC=CC=1>[C:22]1([CH3:25])[CH:23]=[CH:24][C:19]([N:9]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:6]2[CH:7]=[CH:8][CH:3]=[CH:4][CH:5]=2)=[CH:20][CH:21]=1
Reactant: COc1ccc(Nc2ccc(OC)cc2)cc1
Reactant: Cc1ccc(I)cc1
Agent: CC(C)(C)O[Na]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1C
Product: Cc1ccc(N(c2ccccc2)c2ccccc2)cc1

Procedure:
9.70 g (57.3 mmols) of N,N-diphenylamine (31a), 12.5 g (57.3 mmols) of 4-iodotoluene (32b), 6.61 g (68.8, mmols) of t-BuONa, 260 mg (1.15 mmols) of Pd(CH3COO)2 and 1.20 g (4.58 mmols) of triphenylphosphine were dissolved in xylene and refluxed in an atmosphere of nitrogen for 4 hours.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]2[C:5]([O:6][CH2:7][C:8]3[N:14]=[C:13]([NH:15][C:16](=[O:18])C)[S:12][C:9]=32)=[CH:4][N:3]=1.C(C1N=CC2CCC3N=C(NC([N:39]4[CH:43]=[CH:42][N:41]=[CH:40]4)=O)SC=3C=2N=1)(C)(C)C>>[CH3:1][C:2]1[CH:11]=[C:10]2[C:5]([O:6][CH2:7][C:8]3[N:14]=[C:13]([NH:15][C:16]([N:39]4[CH:43]=[CH:42][N:41]=[CH:40]4)=[O:18])[S:12][C:9]=32)=[CH:4][N:3]=1
Reactant: CC(=O)Nc1nc2c(s1)-c1cc(C)ncc1OC2
Reactant: CC(C)(C)c1ncc2c(n1)-c1sc(NC(=O)n3ccnc3)nc1CC2
Product: Cc1cc2c(cn1)OCc1nc(NC(=O)n3ccnc3)sc1-2

Procedure:
Imidazole-1-carboxylic acid (8-methyl-4H-5-oxa-1-thia-3,7-diaza-cyclopenta[a]naphthalen-2-yl)-amide was prepared from N-(8-methyl-4H-5-oxa-1-thia-3,7-diaza-cyclopenta[a]naphthalen-2-yl)-acetamide (Stage 40.2) using synthetic methodology as described for the preparation of intermediate A.
Reaction SMILES: CO.[NH2:3][OH:4].[C-]#N.[K+].[C:8](O)(=O)[CH2:9][C:10]([CH2:15][C:16]([OH:18])=O)(C(O)=O)O.[CH2:21]1[CH2:25]O[CH2:23][CH2:22]1>>[OH:4][NH:3][C:16](=[O:18])[CH2:15][CH2:10][C:9]1[CH:8]=[CH:25][CH:21]=[CH:22][CH:23]=1
Reactant: NO
Reactant: C1CCOC1
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [C-]#N
Agent: [K+]
Solvent: CO
Product: O=C(CCc1ccccc1)NO
Temperature: 25 °C
Yield: 67 %

Procedure:
To methyl 3-phenyl propionate (0.328 g, 2.0 mmol) in THF:MeOH:50% aqueous NH2OH (1:1:0.5, 2.5 mL) was added KCN (5 mg, 0.08 mmol, 4 mol %)) and the mixture was stirred at ambient temperature. After 3 h the reaction was complete by HPLC and saturated aqueous citric acid was added (25 mL) followed by extraction with EtOAc (3×25 mL). The organic phase was isolated, dried (MgSO4), filtered, and the filtrate was concentrated in vacuo to give a residue. The residue was purified by reverse phase HPLC (C-18, 5μ 100×30 mm column), eluting with a gradient of acetonitrile: water (0.05% TFA). Following lyophilization of the product fractions there was obtained pure N-hydroxy-3-phenylpropionamide (IIc) as a fluffy solid (0.220 g, 67% yield): LRMS (M+H)+: 166.0 m/z; 1H NMR (DMSO-d6) δ: 10.31(s, 1H), 8.68(br, 1H), 7.17(m, 5H), 2.79(t, 2H), 2.21(t, 2H); Anal (C,H,N): % C (calc) 65.44, (found) 65.38; % H (calc.) 6.71, (found) 6.61; % N (calc.) 8.48, (found) 8.08.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([C:6]([C:8]2[NH:12][C:11]([CH2:13][C:14]([OH:16])=[O:15])=[C:10](C(O)=O)[C:9]=2[CH3:20])=[O:7])=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>>[Cl:1][C:2]1[CH:22]=[CH:21][C:5]([C:6]([C:8]2[NH:12][C:11]([CH2:13][C:14]([OH:16])=[O:15])=[CH:10][C:9]=2[CH3:20])=[O:7])=[CH:4][CH:3]=1
Reactant: Cc1c(C(=O)c2ccc(Cl)cc2)[nH]c(CC(=O)O)c1C(=O)O
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(CC(=O)O)[nH]c1C(=O)c1ccc(Cl)cc1

Procedure:
The acidic decarboxylation is conducted under mild conditions. For example, 5-(p-chlorobenzoyl)-3-hydroxycarbonyl-4-methylpyrrole-2-acetic acid is treated with refluxing trifluoroacetic acid to afford 5-(p-chlorobenzoyl)-4-methylpyrrole-2-acetic acid. Other acids may also be used. For example, those listed below in Table I.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:7]#[N:8])=[CH:5][N:6]=1.[C:9](OC(=O)C)(=[O:11])[CH3:10]>C(O)(=O)C>[C:9]([NH:1][C:2]1[S:3][C:4]([C:7]#[N:8])=[CH:5][N:6]=1)(=[O:11])[CH3:10]
Reactant: N#Cc1cnc(N)s1
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CC(=O)Nc1ncc(C#N)s1
Yield: 80 %

Procedure:
2.14 g 2-Amino-5-cyanothiazole was dissolved in 10 ml acetic acid, and 1.8 ml acetic anhydride was added to carry out reaction at 100° C. for 30 min. The reaction product was cooled down, and filtered to obtain 2.5 g of a clay-solid having metallic luster (yield 80%), 1H NMR (DMSO-d6) 2.22 (3H, s), 8.36 (1H, s), 12.95 (1H, s).
Reaction SMILES: [C:1]([CH2:4][O:5][C:6]1[CH:16]=[CH:15][CH:14]=[CH:13][C:7]=1[O:8][CH2:9][C:10]([NH2:12])=[O:11])(=[O:3])[NH2:2].[Cl:17][S:18](O)(=[O:20])=[O:19].ClCCl>O>[C:10]([CH2:9][O:8][C:7]1[CH:13]=[CH:14][C:15]([S:18]([Cl:17])(=[O:20])=[O:19])=[CH:16][C:6]=1[O:5][CH2:4][C:1]([NH2:2])=[O:3])(=[O:11])[NH2:12]
Reactant: NC(=O)COc1ccccc1OCC(N)=O
Reactant: O=S(=O)(O)Cl
Solvent: O
Solvent: ClCCl
Product: NC(=O)COc1ccc(S(=O)(=O)Cl)cc1OCC(N)=O
Temperature: 0 °C
Yield: 77.5 %

Procedure:
2-Carbamoylmethoxyphenoxyacetamide (Intermediate A84, 112 g, 0.50 mol) was added portion-wise over 15 min to rapidly stirred chlorosulfonic acid (582.5 g, 5.0 mol) cooled to 0° C. Dichloromethane (120 mL) was then added, and the mixture was heated in a 60°-70° C. bath for 3 hr. The mixture was slowly poured into 1.5 Kg of crushed ice, and then water (500 mL) was added. The resulting solid was collected, washed with water (3×500 mL) and acetone (3×500 mL), resuspended in acetone (1 L), again collected, washed with acetone (500 mL), and air dried to yield 125 g (77%) of the title compound.
Reaction SMILES: [CH2:1]([C@@H:3]1[C@@H:16]2[C@:7]3([CH2:19][CH2:18][N:17]([CH3:20])[C@@H:15]2[CH2:14][C:13]2[CH:12]=[CH:11][C:10]([O:21][CH3:22])=[CH:9][C:8]3=2)[CH2:6][C:5](=[O:23])[CH2:4]1)[CH3:2].[N:24]#CBr>>[C:20]([N:17]1[CH2:18][CH2:19][C@@:7]23[C:8]4[CH:9]=[C:10]([O:21][CH3:22])[CH:11]=[CH:12][C:13]=4[CH2:14][C@@H:15]1[C@@H:16]2[C@@H:3]([CH2:1][CH3:2])[CH2:4][C:5](=[O:23])[CH2:6]3)#[N:24]
Reactant: N#CBr
Reactant: CC[C@H]1CC(=O)C[C@]23CCN(C)[C@H](Cc4ccc(OC)cc42)[C@H]13
Product: CC[C@H]1CC(=O)C[C@]23CCN(C#N)[C@H](Cc4ccc(OC)cc42)[C@H]13
Yield: 73 %

Procedure:
To a rapidly stirred solution of 8β-ethyl-3-methoxy-17-methylmorphinan-6-one (prepared in Part A) was added cyanogen bromide as in Example 1B. The product, mp. 141°-145° C., was obtained in 73% yield.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:14])[CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1)([O-:3])=[O:2].[CH3:15][N:16]1[CH2:20][CH2:19][CH:18](O)[CH2:17]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[CH3:15][N:16]1[CH2:20][CH2:19][CH:18]([O:14][C:6]2[CH:7]=[C:8]([C:10]([F:11])([F:12])[F:13])[CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[CH2:17]1
Reactant: CN1CCC(O)C1
Reactant: O=[N+]([O-])c1cc(O)cc(C(F)(F)F)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CN1CCC(Oc2cc([N+](=O)[O-])cc(C(F)(F)F)c2)C1
Yield: 67.1 %

Procedure:
Add 3-nitro-5-(trifluoromethyl)phenol (1.6 g, 7.7 mmol), 1-methylpyrrolidin-3-ol (940 mg, 9.3 mmol), triphenylphosphine (3.4 g, 11.6 mmol) in THF (20 mL), stir on ice bath, then add diethyl azodicarboxylate (DEAD, 2.0 g, 11.6 mmol). Stir the mixture at ambient temperature for 15 hrs. Add water (100 mL), then extract the mixture with ethyl acetate (100 mL×3), combine the organic layers and dry over anhydrous sodium sulfate. Filter and concentrate the filtrate to get the crude product. Purify by flash chromatography (silica gel, DCM:MeOH=20:1) to afford the target product (1.5 g, 67%). MS: (M+1): 291.1.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:9](B2OC(C)(C)C(C)(C)O2)=[CH:8][C:5]=1[CH:6]=[O:7])([O-:3])=[O:2].Br[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH2:28][CH2:29][NH:30][S:31]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)(=[O:33])=[O:32]>COCCOC.C([O-])([O-])=O.[Na+].[Na+]>[CH:6]([C:5]1[CH:8]=[C:9]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH2:28][CH2:29][NH:30][S:31]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)(=[O:32])=[O:33])[CH:10]=[CH:11][C:4]=1[N+:1]([O-:3])=[O:2])=[O:7]
Reactant: CC1(C)OB(c2ccc([N+](=O)[O-])c(C=O)c2)OC1(C)C
Reactant: O=S(=O)(NCCc1ccccc1Br)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: O=Cc1cc(-c2ccccc2CCNS(=O)(=O)c2ccccc2)ccc1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 3 h

Procedure:
A mixture of 2-nitro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzaldehyde (0.001 mol), N-[2-(2-bromo-phenyl)-ethyl]-benzenesulfonamide (0.0012 mol) and Pd(PCy3)2Cl2 (0.00005 mol) in DME (5 mL) and 1M Na2CO3 (2 mL) in a reaction vial was stirred for 3 hours at 80° C., then DME was removed under a stream of N2 and the resulting mixture was extracted with CH2Cl2. The mixture was filtered through Extrelut, and the organic layer was blown dry, then the desired product was isolated by FAST-synthesis to yield the title compound as a residue.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[C:10]=1[N+:16]([O-])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[Sn]Cl>CCOC(C)=O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[C:10]=1[NH2:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc(OCc2ccccc2)c1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Solvent: CCOC(C)=O
Product: Cc1cccc(OCc2ccccc2)c1N
Temperature: 60 °C

Procedure:
To a solution of 1-benzyloxy-3-methyl-2-nitrobenzene (5.0 g, 20.6 mmol) in EtOAc (150 mL) is added SnCl2 (23.2 g, 103 mmol) and the mixture is heated at 60° C. for 72 h. The mixture is then filtered and to the filtrate is added saturated NaHCO3 and solid Na2CO3. It is then filtered again. EtOAc layer is separated and washed with brine, dried and concentrated. The residue is purified by flash chromatography to give the title compound as a yellow oil.