Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(=[O:7])O[C:4](=[O:5])[CH:3]=[CH:2]1.[CH:8]1([NH2:14])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.CN(C)C=O.C(Cl)([Cl:22])=O>C1(C)C=CC=CC=1.O>[CH:8]1([N:14]2[C:4](=[O:5])[CH2:3][CH:2]([Cl:22])[C:1]2=[O:7])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: O=C1C=CC(=O)O1
Reactant: NC1CCCCC1
Reactant: O=C(Cl)Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: Cc1ccccc1
Product: O=C1CC(Cl)C(=O)N1C1CCCCC1
Reaction time: 2 h

Procedure:
Using the same apparatus as described in Example 1, 34.7 g (0.354 mole) of maleic anhydride was dissolved in 260 g of toluene and 34.7 g (0.350 mole) of cyclohexylamine was added to the resulting solution over 0.5 hour at 10°-50° C. After stirring the reaction mixture for 0.5 hour at the same temperature, 1.27 g (0.0175 mole) of dimethylforamide was added and 38.1 g (0.385 mole) of phosgene was then blown into the reaction mixture over 4 hours at 35°-40° C. After raising the temperature to 70°-75° C., nitrogen gas was blown through the reaction mixture for 2 hours to carry out phosgene degassing and water was added to wash the reaction mixture. The reaction mixture was dried. Solvent was removed and the residue was vacuum distilled at 138°-140° C., 1-2 mmHg. The N-Cyclohexylmonochlorosuccinimide thus obtained (72.7 g, 96.6% of theoretical yield) had a melting point of 63°-64° C.
Reaction SMILES: [NH2:1][S:2]([CH:5]1[CH2:10][CH2:9][N:8](C(OCC2C=CC=CC=2)=O)[CH2:7][CH2:6]1)(=[O:4])=[O:3].C(O)(=O)C>CO.[Pd]>[NH:8]1[CH2:9][CH2:10][CH:5]([S:2]([NH2:1])(=[O:4])=[O:3])[CH2:6][CH2:7]1
Reactant: NS(=O)(=O)C1CCN(C(=O)OCc2ccccc2)CC1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: NS(=O)(=O)C1CCNCC1
Reaction time: 18 h

Procedure:
Benzyl 4-(aminosulfonyl)piperidine-1-carboxylate (the product from step i), 3.3 g) was dissolved in MeOH (20 ml). To this solution was added acetic acid (0.5 ml) and a catalytic amount of Pd/C. The reaction mixture was subjected to a pressure of 5 bar under an atmosphere of hydrogen gas for 18 h at RT. The reaction was filtered through celite and the filtrate was reduced in vacuo to give the subtitle compound as a white solid. Yield 1.7 g
Reaction SMILES: C[O:2][C:3]1[CH:21]=[CH:20][C:6]([N:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.B(Br)(Br)Br.CO.O>C(Cl)Cl>[C:8]1([N:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:6]2[CH:20]=[CH:21][C:3]([OH:2])=[CH:4][CH:5]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: COc1ccc(N(c2ccccc2)c2ccccc2)cc1
Agent: BrB(Br)Br
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: Oc1ccc(N(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81 %

Procedure:
To a solution of 4-methoxy-N,N-diphenylaniline (6.0 g, 21.8 mmol) in DCM (40 mL) was slowly added BBr3 (23 mL, 23 mmol) at about −78° C. The mixture was then stirred overnight under argon while it slowly warmed up to room temperature. To the resulting mixture, methanol (70 mL) was added slowly, then stirred for about 3 hours. The mixture was then poured into water and extracted with DCM (2×200 mL). The organic phases were then combined and washed with brine, dried over Na2SO4, loaded on silica gel, and purified by short plug using hexane/ethyl acetate (9:1 to 8:1). The desired fraction was concentrated and washed with hexanes to give a white solid (Compound 7) (4.59 g, in 81% yield).
Reaction SMILES: C(O)=O.[NH2:4][CH2:5][CH2:6][C:7]1[CH:31]=[CH:30][C:10]([NH:11][CH:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][C:22]3[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=3[F:29])=[O:19])[CH2:14][CH2:13]2)=[CH:9][CH:8]=1.C([Si]([O:49][C:50]1[CH:55]=[CH:54][C:53]([O:56][CH2:57][CH:58]2[CH2:60][O:59]2)=[CH:52][CH:51]=1)(C1C=CC=CC=1)C1C=CC=CC=1)(C)(C)C>>[F:29][C:23]1[CH:24]=[CH:25][C:26]([F:28])=[CH:27][C:22]=1[CH2:21][O:20][C:18]([N:15]1[CH2:16][CH2:17][CH:12]([NH:11][C:10]2[CH:9]=[CH:8][C:7]([CH2:6][CH2:5][NH:4][CH2:60][C@H:58]([OH:59])[CH2:57][O:56][C:53]3[CH:54]=[CH:55][C:50]([OH:49])=[CH:51][CH:52]=3)=[CH:31][CH:30]=2)[CH2:13][CH2:14]1)=[O:19]
Reactant: NCCc1ccc(NC2CCN(C(=O)OCc3cc(F)ccc3F)CC2)cc1
Reactant: CC(C)(C)[Si](Oc1ccc(OCC2CO2)cc1)(c1ccccc1)c1ccccc1
Solvent: O=CO
Product: O=C(OCc1cc(F)ccc1F)N1CCC(Nc2ccc(CCNC[C@H](O)COc3ccc(O)cc3)cc2)CC1

Procedure:
2,5-Difluorobenzyl 4-[4-(2-aminoethyl)anilino]-1-piperidinecarboxylate formate (0.609 g, 1.4 mmol) was reacted with tert-butyl-(4-oxiranylmethoxy-phenoxy)-diphenyl-silane according to Procedure G to yield the title compound (0.260 g, 0.3 mmol).
Reaction SMILES: [NH2:1][C:2]1[CH:6]([O:7][CH2:8][CH3:9])[O:5][C:4](=[O:10])[CH:3]=1.[C:11]([O:15][C:16]([N:18]1[CH2:22][CH2:21][CH2:20][C@H:19]1[C:23](O)=[O:24])=[O:17])([CH3:14])([CH3:13])[CH3:12].C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>ClCCl.C(OCC)(=O)C>[C:11]([O:15][C:16]([N:18]1[CH2:22][CH2:21][CH2:20][C@@H:19]1[C:23](=[O:24])[NH:1][C:2]1[CH:6]([O:7][CH2:8][CH3:9])[O:5][C:4](=[O:10])[CH:3]=1)=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Reactant: CCOC1OC(=O)C=C1N
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCOC1OC(=O)C=C1NC(=O)[C@H]1CCCN1C(=O)OC(C)(C)C
Reaction time: 72 h
Yield: 8.8 %

Procedure:
A solution of 4-amino-5-ethoxy-5H-furan-2-one (0.04 g, 0.30 mmol), (S)-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (0.07 g, 0.30 mmol), diisopropylethylamine (0.12 mL, 0.66 mmol) and O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HBTU) (0.14 g, 0.38 mmol) in dichloromethane (3 mL) was stirred 24 h, was evaporated, was redissolved in 1-methyl-pyrrolidinone (3 mL) and was stirred 3 d. The reaction was diluted with ethyl acetate, was washed with 10% sodium bisulfate, saturated sodium bicarbonate, and brine, was dried over sodium sulfate, and was evaporated. Purification by two flash chromatographies (SiO2), eluted first with 4:6, then with 35:65 ethyl acetate:hexanes afforded (R )-2-(2-ethoxy-5-oxo-2,5-dihydrofuran-3-ylcarbamoyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (0.009 g, 9% yield) as a film. 1H-NMR (500 MHz, CDCl3) δ 10.2 (br s, 0.7H), 10.1 (br s, 0.3H), 6.21 (br s, 0.7H), 6.17 (br s, 0.3H), 5.68 (s, 0.7H), 5.60 (br s, 0.3H), 4.38 (br s, 1H), 3.85 (m, 1H), 3.72 (m, 1H), 3.25-3.45 (m, 2H), 2.53 (br d, 12.5 Hz, 0.7H), 2.1 (br, 0.3H), 1.87 (br m, 3H), 1.44 (s, 9H), 1.21 (m, 3H) ppm. MS (ES+): m/e=341 (M+H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:6][CH2:7][CH2:8][N:9]([S:12]([C:15]3[CH:16]=[C:17]([CH3:21])[CH:18]=[CH:19][CH:20]=3)(=[O:14])=[O:13])[C:10]=2[N:11]=1.N1[C:35]2[C:26](=[CH:27][CH:28]=[C:29]3[C:34]=2N=CC=C3)[CH:25]=CC=1.C([O-])([O-])=[O:37].[Cs+].[Cs+]>C(O)C1C=CC=CC=1.[Cu]I>[CH2:25]([O:37][C:2]1[CH:3]=[CH:4][C:5]2[O:6][CH2:7][CH2:8][N:9]([S:12]([C:15]3[CH:16]=[C:17]([CH3:21])[CH:18]=[CH:19][CH:20]=3)(=[O:14])=[O:13])[C:10]=2[N:11]=1)[C:26]1[CH:35]=[CH:34][CH:29]=[CH:28][CH:27]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1cccc(S(=O)(=O)N2CCOc3ccc(Br)nc32)c1
Reactant: c1cnc2c(c1)ccc1cccnc12
Agent: [Cu]I
Agent: [Cs+]
Solvent: OCc1ccccc1
Product: Cc1cccc(S(=O)(=O)N2CCOc3ccc(OCc4ccccc4)nc32)c1
Temperature: 130 °C

Procedure:
To 6-bromo-4-(toluene-3-sulfonyl)-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine (50 mg, 140 mmol) in benzyl alcohol (400 μL) was added CuI (15 mg, 79 mmol), 1,10-phenanthroline (15 mg, 83 mmol), and Cs2CO3 (70 mg, 210 mmol). The resulting mixture was heated to 130° C. for 2 hours. Next, the reaction mixture was cooled to room temperature and quenched with a small amount of water, then extracted with ethyl acetate. The aqueous phase was discarded and the organic phase concentrated under reduced pressure. The resulting residue was purified by HPLC to afford 6-benzyloxy-4-(toluene-3-sulfonyl)-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine. LCMS (ESI): calc. C21H20N2O4S=396; obs. M+H=397.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6]([S:13]([OH:16])(=[O:15])=[O:14])=[CH:7][C:8]=2O)[C:3]=1[S:17]([OH:20])(=[O:19])=[O:18].FC1N=NN=C(F)C=1F.C(N)CN.FC1N=NN=C(F)C=1>>[NH2:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6]([S:13]([OH:16])(=[O:14])=[O:15])=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]=1[S:17]([OH:20])(=[O:19])=[O:18]
Reactant: Nc1ccc2c(O)cc(S(=O)(=O)O)cc2c1S(=O)(=O)O
Agent: Fc1cc(F)nnn1
Agent: Fc1nnnc(F)c1F
Solvent: NCCN
Product: Nc1ccc2c(S(=O)(=O)O)cccc2c1S(=O)(=O)O
Reaction time: 2.5 h
Yield: 100 %

Procedure:
31.9 g of 2-amino-5-hydroxynaphthalene-1,7-disulphonic acid are condensed with trifluorotriazine by the procedure of Example 1.5.0 g of ethylenediamine is added to the solution of the resulting difluorotriazine compound at 0° while maintaining a pH of 5.5 to 6.5. After 2 to 3 hours, condensation is complete. A diazo compound obtained in the usual manner by diazotisation of 30.3 g of 2-aminonaphthalene-1,5-disulphonic acid is added to the reaction product of the formula ##STR18## which is largely present as a suspension, while simultaneously maintaining the pH at 7.0 to 7.5 by sprinkling in sodium bicarbonate. After coupling is complete, the dyestuff of the formula ##STR19## which has precipitated as a sparingly soluble compound, is filtered off with suction and stirred again in 1 l of water. 16.9 g of 2,4,6-trifluoro-5-chloropyrimidine are added dropwise at 0° to 5° while maintaining a pH of 7.5 to 8.0 with dilute sodium hydroxide solution. During condensation, the dyestuff goes into solution. After condensation is complete (thin-layer chromatogram), the dyestuff is salted out, filtered off with suction, dried and milled. The orange-coloured powder is readily soluble in water and dyes cotton in clear orange shades (colour indicator number 5).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][CH2:16][CH2:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([OH:24])=O)=[CH:20][CH:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC[N:29](CC)CC.C1C=CC(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)=CC=1>O1CCOCC1>[N-:29]=[C:22]=[O:24].[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][CH2:16][CH2:17][C:18]1[CH:26]=[CH:25][CH:21]=[CH:20][CH:19]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc(CCCc2ccccc2OCc2ccccc2)cc1
Reactant: CCN(CC)CC
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: C1COCCO1
Product: [N-]=C=O
Product: c1ccc(CCCc2ccccc2OCc2ccccc2)cc1

Procedure:
The solution of 4-[3-(2-benzyloxyphenyl)propyl]benzene isocyanate in dioxane was prepared by heating a mixture of 4-[3-(2-benzyloxyphenyl)propyl]benzoic acid (2.0 g), Et3N (1.61 ml) and DPPA (1.31 ml) in dioxane (20 ml) for 3 hours.
Reaction SMILES: [Si]([O:8][C:9]1[CH:10]=[C:11]([S:15]([C:18]2[CH:35]=[CH:34][C:21]3[CH2:22][CH2:23][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:25][CH2:26][C:20]=3[CH:19]=2)(=[O:17])=[O:16])[CH:12]=[CH:13][CH:14]=1)(C(C)(C)C)(C)C.O1CCCC1>[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C>[OH:8][C:9]1[CH:10]=[C:11]([S:15]([C:18]2[CH:35]=[CH:34][C:21]3[CH2:22][CH2:23][N:24]([C:27]([O:29][C:30]([CH3:31])([CH3:32])[CH3:33])=[O:28])[CH2:25][CH2:26][C:20]=3[CH:19]=2)(=[O:16])=[O:17])[CH:12]=[CH:13][CH:14]=1
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(S(=O)(=O)c3cccc(O[Si](C)(C)C(C)(C)C)c3)cc2CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCc2ccc(S(=O)(=O)c3cccc(O)c3)cc2CC1
Reaction time: 1 h

Procedure:
7-(3-t-Butyldimethysilyloxyphenylsulfonyl)-3-(t-butoxycarbonyl)-2,3,4,5-tetrahydro-1H-3-benzazepine (5.4 g, 10.5 mmol) was dissolved in a solution of tetra-n-butylammonium fluoride in tetrahydrofuran (15 mL, 1M, 15 mmol). The solution was stirred for 1 h then diluted with ethyl acetate (100 mL) and washed with saturated aqueous sodium hydrogen carbonate (100 mL), and brine (100 mL), dried (MgSO4), and evaporated.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:10][C@H:9]1[C:19]([OH:21])=O)=[O:7])(C)(C)C.[N:22]([C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH3:32])[CH:26]=1)=C=O.[CH3:33][O:34][CH2:35][CH2:36][NH2:37]>>[C:15]([O:14][N:13]=[C:11]1[CH2:12][N:8]([C:6]([NH:22][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH3:32])[CH:26]=2)=[O:7])[C@H:9]([C:19]([NH:37][CH2:36][CH2:35][O:34][CH3:33])=[O:21])[CH2:10]1)([CH3:16])([CH3:17])[CH3:18]
Reactant: COCCN
Reactant: COc1cccc(N=C=O)c1
Reactant: CC(C)(C)ON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Product: COCCNC(=O)[C@@H]1CC(=NOC(C)(C)C)CN1C(=O)Nc1cccc(OC)c1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(tert-butoxyimino)-2-pyrrolidinecarboxylic acid, 1-isocyanato-3-methoxybenzene, and 2-methoxyethylamine the title compound was obtained in 76% purity by LC/MS. MS(ESI+): m/z=407.2.
Reaction SMILES: Cl.[CH3:2][NH:3][O:4][CH3:5].[CH:6]1([C:9](Cl)=[O:10])[CH2:8][CH2:7]1>C(Cl)Cl>[CH3:5][O:4][N:3]([CH3:2])[C:9]([CH:6]1[CH2:8][CH2:7]1)=[O:10]
Reactant: O=C(Cl)C1CC1
Reactant: CNOC
Agent: Cl
Solvent: ClCCl
Product: CON(C)C(=O)C1CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 70 %

Procedure:
N,O-dimethylhydroxylamine hydrochloride (11.2 g, 114.79 mmol) and TEA (19.36 g, 191.32 mmol) were dissolved in CH2Cl2 (60 ml). Cyclopropanecarbonyl chloride (10 g, 95.66 mmol) was added dropwise at 0° C. After addition, the mixture was allowed to warm to 25° C. and stirred for 18 h. After the reaction completed, the solution was washed with H2O, saturated NaHCO3, 1 N HCl and brine. The organic layer was dried over Na2SO4 and evaporated under reduced pressure to get N-methoxy-N-methylcyclopropanecarboxamide as a yellow oil. (8.6 g, yield 70%).
Reaction SMILES: [CH:1]1([N:4]([CH3:21])[CH:5]2[CH2:14][CH2:13][C:12]([CH3:16])([CH3:15])[C:11]3[CH:10]=[C:9]([C:17]#[CH:18])[CH:8]=[C:7]([O:19][CH3:20])[C:6]2=3)[CH2:3][CH2:2]1.[CH2:22]([O:29][C:30](=[O:40])[CH:31]=[CH:32][C:33]1[CH:38]=[CH:37][C:36](O)=[CH:35][CH:34]=1)C1C=CC=CC=1.C(N(CC)CC)C.C(OCC)(=O)C>CCCCCC.[Cu]I.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>[CH3:22][O:29][C:30](=[O:40])/[CH:31]=[CH:32]/[C:33]1[CH:34]=[CH:35][C:36]([C:18]#[C:17][C:9]2[CH:8]=[C:7]([O:19][CH3:20])[C:6]3[CH:5]([N:4]([CH:1]4[CH2:3][CH2:2]4)[CH3:21])[CH2:14][CH2:13][C:12]([CH3:15])([CH3:16])[C:11]=3[CH:10]=2)=[CH:37][CH:38]=1
Reactant: C#Cc1cc(OC)c2c(c1)C(C)(C)CCC2N(C)C1CC1
Reactant: O=C(C=Cc1ccc(O)cc1)OCc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)/C=C/c1ccc(C#Cc2cc(OC)c3c(c2)C(C)(C)CCC3N(C)C2CC2)cc1

Procedure:
Following General Procedure B and using 5-(cyclopropyl-methyl-amino)-2-ethynyl-8,8-dimethyl-4-methoxy-5,6,7,8-tetrahydro-naphthalene (Intermediate 81, 0.095 g, 0.336 mmol), methyl-4-iodocinnamate (Reagent 4, 0.097 g, 0.336 mmol), triethyl amine (8 mL), copper(I)iodide (0.019 g, 0.1 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.07 g, 0.1 mmol) followed by flash column chromatography over silica gel (230-400 mesh) using 5-15% ethyl acetate in hexane as the eluent, the title compound was obtained as a white solid (0.12 g, 80%).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][CH:17]=1)[O:6][C:7]1[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][N:8]=1.[OH:18][C:19]1[C:24]([CH2:25][CH2:26][CH3:27])=[C:23](O)[CH:22]=[CH:21][C:20]=1[C:29](=[O:31])[CH3:30].C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C(OCC)C.C1(C)C=CC=CC=1.ClCCl>[C:29]([C:20]1[CH:21]=[CH:22][C:23]([O:1][CH2:2][C:3]2[CH:4]=[C:5]([CH:15]=[CH:16][CH:17]=2)[O:6][C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][N:8]=2)=[C:24]([CH2:25][CH2:26][CH3:27])[C:19]=1[OH:18])(=[O:31])[CH3:30]
Reactant: CCCc1c(O)ccc(C(C)=O)c1O
Reactant: N#Cc1ccc(Oc2cccc(CO)c2)nc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Solvent: CCOCC
Solvent: ClCCl
Product: CCCc1c(OCc2cccc(Oc3ccc(C#N)cn3)c2)ccc(C(C)=O)c1O
Temperature: -20 °C
Reaction time: 0.08 h
Yield: 33.1 %

Procedure:
Mix 6-(3-hydroxymethyl-phenoxy)-nicotinonitrile (1.63 g, 7.18 mmol) and 1-(2,4-dihydroxy-3-propyl-phenyl)-ethanone (1.33 g, 6.84 mmol) in 2:1 toluene/dichloromethane (24 mL). Cool to −20° C. and add tributylphosphine (2.6 mL, 10.26 mmol) dropwise. After stirring for 5 minutes, add 1,1′-(azodicarbonyl)dipiperidine in three batches. Allow the reaction mixture to warm to ambient temperature overnight. Concentrate under reduced pressure to give a yellow solid. Dilute with diethyl ether (50 mL) and cool to 0° C. Filter the white precipitate and concentrate the filtrate under reduced pressure to give a residue. Purification by flash chromatography, using 5% ethyl acetate/hexanes to 30% ethyl acetate/hexanes as a gradient eluent yields the title compound (0.91 g, 33%): MS (m/z): 401.2 (M−1). 1H NMR (CDCl3) 12.78 (s, 1H), 8.50 (s, 1H), 7.97 (dd, J=2.2 Hz, 8.8 Hz, 1H), 7.62 (d, J=8.8 Hz, 1H), 7.51 (t, J=8.0 Hz, 1H), 7.36 (d, J=7.8 Hz, 1H), 7.25 (s, 1H), 7.16 (d, J=8.0 Hz, 1H), 7.09 (d, J=8.8 Hz, 1H), 6.51 (d, J=8.8 Hz, 1H), 5.22 (s, 2H), 2.72 (t, J=7.6 Hz, 2H), 2.60 (s, 3H), 1.62-1.53 (m, 2H), 0.94 (t, J=7.6 Hz, 3H).
Reaction SMILES: [CH3:1]N(C)C=O.CS(O[C@@H:11]([C@:13]1([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=2[F:23])[O:15][CH2:14]1)C)(=O)=O.[NH:24]1[CH:28]=[CH:27][N:26]=[CH:25]1.[H-].[Na+]>O>[F:23][C:17]1[CH:18]=[C:19]([F:22])[CH:20]=[CH:21][C:16]=1[C@@:13]1([CH2:11][N:24]2[CH:28]=[CH:27][N:26]=[CH:25]2)[C@H:14]([CH3:1])[O:15]1
Reactant: CN(C)C=O
Reactant: c1c[nH]cn1
Reactant: C[C@@H](OS(C)(=O)=O)[C@@]1(c2ccc(F)cc2F)CO1
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: C[C@@H]1O[C@@]1(Cn1ccnc1)c1ccc(F)cc1F
Reaction time: 0.17 h

Procedure:
To a N,N-dimethylformamide (35 ml) solution containing (2R,3R)-3-(2,4-difluorophenyl)-3,4-epoxy-2-butyl methanesulfonate (3.5 g) and imidazole (1.2 g) was added 60% sodium hydride in mineral oil (0.70 g) at 0° C. with constant stirring. After 10 minutes, the temperature was adjusted to 20° C. and the mixture was stirred for 20 hours. The reaction mixture was then poured into water (100 ml) and extracted with ethyl acetate (30 ml×4). The ethyl acetate layers were combined, washed with saturated aqueous sodium chloride solution (30 ml), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (3 cm×15 cm) using methanol-ethyl acetate (5:95) as the eluent. The desired fraction was concentrated under reduced pressure and the residue was crystallized by addition of isopropyl ether and n-hexane to give (2R,3S)-2-(2,4-difluorophenyl)-2-(1-imidazolyl)methyl-3-methyloxirane (1.7 g) as colorless prisms. m.p. 73°-76° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:26])=[C:14]([C:21](OCC)=[O:22])[C:15](=[O:20])[N:16]3[CH3:19])=[N:11][CH:10]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl.[CH3:35][S:36]([CH2:39][CH2:40][NH2:41])(=[O:38])=[O:37]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:26])=[C:14]([C:21]([NH:41][CH2:40][CH2:39][S:36]([CH3:35])(=[O:38])=[O:37])=[O:22])[C:15](=[O:20])[N:16]3[CH3:19])=[N:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(C)c1=O
Reactant: CS(=O)(=O)CCN
Agent: Cl
Solvent: CCN(CC)CC
Product: Cn1c(=O)c(C(=O)NCCS(C)(=O)=O)c(O)c2ncc(Cc3ccc(F)cc3)cc21
Yield: 30.2 %

Procedure:
In a similar manner to that described in example 196, from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate (30 mg, 0.084 mmol) described in example 92, triethylamine (0.05 mL, 0.364 mmol) and [2-(methylsulfonyl)ethyl]amine hydrochloride (174 mg, 1.08 mmol) was prepared 7-[(4-fluorophenyl)methyl]-4-hydroxy-1-methyl-N-[2-(methylsulfonyl)ethyl]-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide (11 mg, 22% yield) as a white solid after purification by reverse phase HPLC. 1H NMR (CDCl3) δ 10.61 (br s, 1 H), 8.56 (s, 1 H), 7.39 (s, 1 H), 7.16-7.12 (m, 2 H), 7.04-6.99 (m, 2 H), 4.13 (s, 2 H), 3.95 (m, 2 H), 3.57 (s, 3 H), 3.37 (m, 2 H), 2.98 (s, 3 H); MS m/z 434 (M+1).
Reaction SMILES: C1N(S(F)(F)[F:8])CCOC1.[Br:11][C:12]1[CH:13]=[CH:14][C:15]2[N:16]([CH2:26][CH:27](O)[CH2:28][N:29]([C:37]3[CH:42]=[CH:41][CH:40]=[C:39]([O:43][CH2:44]C)[CH:38]=3)[S:30]([C:33]([F:36])([F:35])[F:34])(=[O:32])=[O:31])[C:17]3[C:22]([C:23]=2[CH:24]=1)=[CH:21][C:20]([Br:25])=[CH:19][CH:18]=3.C(=O)(O)[O-]>C(Cl)Cl>[Br:25][C:20]1[CH:19]=[CH:18][C:17]2[N:16]([CH2:26][CH:27]([F:8])[CH2:28][N:29]([C:37]3[CH:42]=[CH:41][CH:40]=[C:39]([O:43][CH3:44])[CH:38]=3)[S:30]([C:33]([F:34])([F:35])[F:36])(=[O:32])=[O:31])[C:15]3[C:23]([C:22]=2[CH:21]=1)=[CH:24][C:12]([Br:11])=[CH:13][CH:14]=3
Reactant: FS(F)(F)N1CCOCC1
Reactant: CCOc1cccc(N(CC(O)Cn2c3ccc(Br)cc3c3cc(Br)ccc32)S(=O)(=O)C(F)(F)F)c1
Agent: O=C([O-])O
Solvent: ClCCl
Product: COc1cccc(N(CC(F)Cn2c3ccc(Br)cc3c3cc(Br)ccc32)S(=O)(=O)C(F)(F)F)c1
Reaction time: 8 h
Yield: 104 %

Procedure:
Morpho-Dast (14.0 ml, 115 mmol) was added to a solution of N-(3-(3,6-dibromo-9H-carbazol-9-yl)-2-hydroxypropyl)-1,1,1-trifluoro-N-(3-ethoxyphenyl)methanesulfonamide (20.6 g, 32.4 mmol) in anhydrous methylene chloride (315 ml) and stirred overnight. The solution, in a water bath at ambient temperature, was neutralized by dropwise addition of 375 ml saturated bicarbonate solution. The biphasic mixture was extracted with methylene chloride twice. The combined organics were dried over MgSO4, filtered and condensed to give 21.5 g of off-white foam in quantitative yield.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH2:7])=[C:3]([NH2:8])[CH:2]=1.[C:9](=S)=[S:10].[Cl-].[Cl-].[Ca+2]>CCO>[NH:7]1[C:4]2[CH:5]=[CH:6][N:1]=[CH:2][C:3]=2[N:8]=[C:9]1[SH:10]
Reactant: S=C=S
Reactant: Nc1ccncc1N
Agent: [Ca+2]
Agent: [Cl-]
Solvent: CCO
Product: Sc1nc2cnccc2[nH]1
Temperature: 25 °C

Procedure:
To a solution of pyridine-3,4-diamine (5 g) in EtOH (80 ml) was added carbon disulfide (10 mL) at room temperature. The mixture was stirred at 40° C. under a dry atmosphere (CaCl2 tube) for 10 h. The mixture was cooled to room temperature. The resulting white solid was collected by filtration and washed with ether to give 1H-imidazo[4,5-c]pyridine-2-thiol (6.1 g) as a white solid.
Reaction SMILES: [CH2:1]([CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C:11]1=O)[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=O.[NH2:17][C:18]1[CH:19]=[C:20]([OH:27])[C:21](=[CH:25][CH:26]=1)[C:22]([OH:24])=[O:23]>C(O)(=O)C>[C:22]([C:21]1[CH:25]=[CH:26][C:18]([N:17]2[C:11]3[CH2:12][CH2:13][CH2:14][CH2:15][C:10]=3[CH:1]=[C:2]2[C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)=[CH:19][C:20]=1[OH:27])([OH:24])=[O:23]
Reactant: O=C(CC1CCCCC1=O)c1ccccc1
Reactant: Nc1ccc(C(=O)O)c(O)c1
Solvent: CC(=O)O
Product: O=C(O)c1ccc(-n2c(-c3ccccc3)cc3c2CCCC3)cc1O

Procedure:
A solution of 32.4 g. (0.15 mole) of 2-phenacylcyclohexanone, 23.0 g. (0.15 mole) of 4-aminosalicylic acid and 90 ml. of glacial acetic acid was heated under reflux for 7 hours, cooled, diluted with 90 ml. of water and extracted with ether. The ether solution was dried over sodium sulfate and concentrated. The residue was recrystallized from benzene-ethanol to provide 3.36 g. (7%) of yellow crystals, m.p. 193°-195°.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([N+:13]([O-])=O)=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7].CCOC(C)=O>C1COCC1.CO.[Pd]>[NH2:13][C:4]1[C:3]([O:2][CH3:1])=[CH:12][CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1cccc(OC)c1[N+](=O)[O-]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc(OC)c1N
Temperature: 25 °C
Reaction time: 18 h
Yield: 99.7 %

Procedure:
A suspension of compound 52 (26.2 g, 124 mmol) and Pd/C (10 wt. %, 6.0 g) in THF (400 mL) and MeOH (200 mL) was stirred under an atmosphere of H2 at room temperature for 18 hours. EtOAc (300 mL) was added to the mixture and filtered through a Celite pad. The filtrate was concentrated in vacuo to provide the crude product 53 (22.4 g, 99%) as colorless oil.