Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11]C=C2[C:5]=1[CH:6]=[CH:7]N2)([O-:3])=[O:2].[CH3:13][N:14]([CH:16]=[O:17])C.C[OH:19]>>[CH:11]([C:12]1[C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=[CH:7][C:13]=1[NH:14][CH:16]=[O:17])=[O:19]
Reactant: O=[N+]([O-])c1cccc2[nH]ccc12
Reactant: CO
Reactant: CN(C)C=O
Product: O=CNc1cccc([N+](=O)[O-])c1C=O
Yield: 55 %

Procedure:
A stirred solution of 4-nitro-1H-indole (4a, 93.8 g, 0.56 mol) in DMF-MeOH (1:2, 2.7 L) cooled in a dry ice-acetone bath was bubbled with ozone (generated from oxygen gas, 22 g/m3, flow rate 500 L/hr, ozone generator: Tokyo Keiso, 11 g/hr) for 3.5 h. The mixture was kept cool in the dry ice-acetone bath for 1 h without stirring. The precipitate generated was filtered and washed with H2O to give N-(2-formyl-3-nitrophenyl)-formamide (5a, 62.0 g, 55%), 1H NMR (270 MHz) δ (DMSO-d6) 7.82 (t, J=7.9 Hz, 1H), 7.91 (d, J=7.9 Hz, 1H), 8.15 (m, 1H), 8.37 (br, 1H), 10.07 (s, 1H), 10.71 (br, 1H); MS (EI) m/z 194 (M+).
Reaction SMILES: Br.[C:2]([N:5]1[CH2:10][CH2:9][C:8](=O)[CH:7](Br)[CH2:6]1)(=[O:4])[CH3:3].C(N(CC)CC)C.[C:20]([NH2:23])(=[S:22])[CH3:21]>CC(C)=O>[C:2]([N:5]1[CH2:10][CH2:9][C:8]2[N:23]=[C:20]([CH3:21])[S:22][C:7]=2[CH2:6]1)(=[O:4])[CH3:3]
Reactant: CC(=O)N1CCC(=O)C(Br)C1
Reactant: CC(N)=S
Agent: Br
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: CC(=O)N1CCc2nc(C)sc2C1

Procedure:
N-Acetyl-3-bromo-4-piperidone hydrobromide (5.0 g, 16.6 mmol) in acetone (160 ml) was heated to 60° and treated with triethylamine (2.31 ml, 33.1 mmol) and thioacetamide (1.24 g, 16.6 mmol). The reaction mixture was heated to reflux for 24 hours, then cooled and filtered, to provide a yellow solid which was purified by column chromatography (eluant:89:10:1 chloroform: methanol: concentrated aqueous ammonium hydroxide). The title product was obtained as a yellow oil (995 mg, 5.1 mmol, 31% yield).
Reaction SMILES: [I:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.Cl[C:10]1[N:15]=[C:14]([O:16][CH3:17])[CH:13]=[C:12]([O:18][CH3:19])[N:11]=1.[H-].[Na+]>>[I:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:10]2[N:15]=[C:14]([O:16][CH3:17])[CH:13]=[C:12]([O:18][CH3:19])[N:11]=2)=[CH:4][CH:3]=1
Reactant: COc1cc(OC)nc(Cl)n1
Reactant: Nc1ccc(I)cc1
Agent: [H-]
Agent: [Na+]
Product: COc1cc(OC)nc(Nc2ccc(I)cc2)n1
Yield: 39.3 %

Procedure:
In the same manner as in Reference Example 24-(1), 4-iodoaniline (220 mg) and 2-chloro-4,6-dimethoxypyrimidine (200 mg) were reacted in the presence of sodium hydride to obtain N-(4-iodophenyl)-4,6-dimethoxypyrimidin-2-amine (141 mg). (2) In the same manner as in Reference Example 24-(2), sodium hydride (16 mg), N-(4-iodophenyl)-4,6-dimethoxypyrimidin-2-amine (140 mg) and methyl iodide (0.024 ml) were reacted to obtain N-(4-iodophenyl)-4,6-dimethoxy-N-methylpyrimidin-2-amine (118 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[N:11]=[N:12][C:13]([CH:16]([NH:18][C:19](=[O:28])[CH:20](C3C=CC=CC=3)[CH3:21])[CH3:17])=[CH:14][N:15]=2)=[CH:5][CH:4]=1.NC(C1N=N[C:35]([NH:38][C:39]2[CH:44]=[CH:43][C:42](OC)=[CH:41][CH:40]=2)=NC=1)C.CN1C2C(=CC=CC=2)C=C1C(O)=O>>[CH3:35][N:38]1[C:39]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH:21]=[C:20]1[C:19]([NH:18][CH:16]([C:13]1[N:12]=[N:11][C:10]([NH:9][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)=[N:15][CH:14]=1)[CH3:17])=[O:28]
Reactant: COc1ccc(Nc2ncc(C(C)N)nn2)cc1
Reactant: COc1ccc(Nc2ncc(C(C)NC(=O)C(C)c3ccccc3)nn2)cc1
Agent: Cn1c(C(=O)O)cc2ccccc21
Product: COc1ccc(Nc2ncc(C(C)NC(=O)c3cc4ccccc4n3C)nn2)cc1

Procedure:
In a similar manner as described for Intermediate 55, using 6-(1-aminoethyl)-N-[4-(methyloxy)phenyl]-1,2,4-triazin-3-amine (Intermediate 47) (100 mg, 0.41 mmol), and 1-methylindole-2-carboxylic acid (79 mg, 0.45 mmol), to give 1-methyl-N-[1-(3-{[4-(methyloxy)phenyl]amino}-1,2,4-triazin-6-yl)ethyl]-1H-indole-2-carboxamide (158 mg) as a yellow solid. MS m/z 403 (M+1).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH2:23][N:24]([CH3:31])[CH:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[CH:19][CH:18]=3)=[O:15])=[CH:7][C:6]=2[CH:32]=1.C1(C)C=CC=CC=1.C(O)C.O.B([O-])([O-])O[C:46]1[CH:51]=[CH:50][C:49]([S:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH3:58])=[CH:48][CH:47]=1.C(=O)([O-])[O-].[K+].[K+]>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.O>[CH2:53]([S:52][C:49]1[CH:48]=[CH:47][C:46]([C:2]2[CH:3]=[CH:4][C:5]3[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([NH:16][C:17]4[CH:22]=[CH:21][C:20]([CH2:23][N:24]([CH3:31])[CH:25]5[CH2:30][CH2:29][O:28][CH2:27][CH2:26]5)=[CH:19][CH:18]=4)=[O:15])=[CH:7][C:6]=3[CH:32]=2)=[CH:51][CH:50]=1)[CH2:54][CH2:55][CH2:56][CH2:57][CH3:58]
Reactant: CN(Cc1ccc(NC(=O)C2=Cc3cc(Br)ccc3S(=O)(=O)CC2)cc1)C1CCOCC1
Reactant: CCCCCCSc1ccc(OB([O-])[O-])cc1
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: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: CCCCCCSc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCS3(=O)=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.4 %

Procedure:
To 7-bromo-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (320 mg) was added toluene/ethanol/water (10/1/1, 12 ml) and then were added 4-(hexylthio)phenyl borate (199 mg) and potassium carbonate (187 mg), and the mixture was stirred at room temperature for 30 minutes. To the mixture was added tetrakistriphenylphosphinepalladium (36 mg), and the mixture was stirred at 100° C. for 14 hours and cooled to room temperature. The mixture was added to water, and the mixture was extracted with ethyl acetate/THF, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column chromatography (ethyl acetate/ethanol=3/1) and recrystallized from ethanol to give 7-(4-hexylthiophenyl)-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 79) (298 mg).
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[CH2:10][CH:9]1[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:7].[O:36]1[CH2:38][CH:37]1[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>CO>[F:35][C:2]([F:34])([F:1])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:31])[F:32])[CH:29]=1)[C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([N:14]2[CH2:15][CH2:16][N:17]([CH2:38][CH:37]([OH:36])[C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[CH2:18][CH2:19]2)[CH2:10][C@@H:9]1[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:7].[F:35][C:2]([F:34])([F:1])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:31])[F:32])[CH:29]=1)[C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([N:14]2[CH2:15][CH2:16][N:17]([CH:37]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[CH2:38][OH:36])[CH2:18][CH2:19]2)[CH2:10][C@@H:9]1[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:7]
Reactant: c1ccc(C2CO2)cc1
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCC(N2CCNCC2)CC1Cc1ccccc1
Solvent: CO
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CC[C@H](N2CCN(C(CO)c3ccccc3)CC2)C[C@@H]1Cc1ccccc1
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CC[C@H](N2CCN(CC(O)c3ccccc3)CC2)C[C@@H]1Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 23 %
Yield: 7 %

Procedure:
A mixture of compound 15 (0.005 mol) and 1,2-epoxyethylbenzene (0.006 mol) in methanol (50 ml) was stirred at RT for 1 hour. The mixture was stirred and refluxed for 3 hours. The solvent was evaporated and the residue was purified over silica gel on a glass filter (eluent: CH2Cl2/CH3OH 100/0, 99/1 and 98/2). The pure fractions were collected and the solvent was evaporated. The residue was purified by HPLC over silica gel (eluent: CH2Cl2/CH3OH 98/2 to 95/5). Two pure fractions were collected and their solvents were evaporated. Each residue was dried, yielding 0.7 g (23%) of (±)-cis-1-[3,5-bis(trifluoromethyl)benzoyl]-4-[4-(2-hydroxy-2-phenylethyl)-1-piperazinyl]-2-(phenylmethyl)piperidine (compound 60) and 0.23 g (7%) of (±)-cis-1-[3,5-bis(trifluoromethyl)benzoyl]-4-[4-(2-hydroxy-1-phenylethyl)-1-piperazinyl]-2-(phenylmethyl)piperidine (compound 61).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH2:20][N:21]2[CH2:26][CH2:25][O:24][CH2:23][C@@H:22]2[CH2:27][OH:28])[NH:12][C:11]([C:29]2[S:30][CH:31]=[CH:32][N:33]=2)=[N:10]1.C(OC([NH:41][C@@H:42]([CH2:46][CH3:47])[C:43](O)=[O:44])=O)(C)(C)C>>[NH2:41][C@@H:42]([CH2:46][CH3:47])[C:43]([O:28][CH2:27][C@@H:22]1[N:21]([CH2:20][C:13]2[NH:12][C:11]([C:29]3[S:30][CH:31]=[CH:32][N:33]=3)=[N:10][CH:9]([C:3]3[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=3[Br:1])[C:14]=2[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:26][CH2:25][O:24][CH2:23]1)=[O:44]
Reactant: CC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CCOC(=O)C1=C(CN2CCOC[C@@H]2CO)NC(c2nccs2)=NC1c1ccc(F)cc1Br
Product: CCOC(=O)C1=C(CN2CCOC[C@@H]2COC(=O)[C@@H](N)CC)NC(c2nccs2)=NC1c1ccc(F)cc1Br
Yield: 31.2 %

Procedure:
Ethyl 4-(2-bromo-4-fluorophenyl)-6-(((S)-3-(hydroxymethyl)morpholino)methyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (1 g, 1.9 mmol) was reacted with (S)-2-((tert-butoxycarbonyl)amino)butanoic acid (0.61 g, 3 mmol) according to the procedure as described in Example 49 to give the title compound as yellow oil (0.37 g, 31%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[CH3:9][C:10]([CH3:13])([O-])C.[K+].C1(Br)CC1.O>CS(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH:13]2[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: Sc1ccc(Br)cc1
Reactant: CC(C)(C)[O-]
Agent: BrC1CC1
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: Brc1ccc(SC2CC2)cc1
Temperature: 25 °C
Yield: 71.2 %

Procedure:
Dissolve 4-bromo-benzenethiol (2.00 g, 10.6 mmol) in dry DMSO (50 mL) under a nitrogen atmosphere. Add potassium tert-butoxide (1.30 g, 11.7 mmol) and stir until dissolved. Add cyclopropyl bromide (2.6 mL, 31.8 mmol) and heat the reaction to 80° C. for 2 days. Cool to room temperature and pour the reaction into water (500 mL). Extract the aqueous layer with Et2O (2×200 mL) and wash the combined organic layers with water (100 mL). Dry over sodium sulfate and concentrate in vacuo. Chromatograph the residue on a SiO2 column eluting the material with hexanes to give 1.73 g of 1-bromo-4-cyclopropylsulfanyl-benzene (72%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:12][C:13]([OH:15])=[O:14])[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].[CH3:16][OH:17]>S(=O)(=O)(O)O>[C:13]([O-:15])(=[O:14])[CH3:12].[CH3:16][O:17][C:13](=[O:14])[CH2:12][C:4]1[CH:5]=[CH:6][C:7]([C:8]([F:9])([F:10])[F:11])=[C:2]([F:1])[CH:3]=1
Reactant: CO
Reactant: O=C(O)Cc1ccc(C(F)(F)F)c(F)c1
Agent: O=S(=O)(O)O
Product: CC(=O)[O-]
Product: COC(=O)Cc1ccc(C(F)(F)F)c(F)c1
Temperature: 25 °C
Yield: 97 %

Procedure:
A solution of 3-fluoro-4-(trifluoromethyl)phenylacetic acid (2.50 g, 11.25 mmol) in methanol (25 mL) was treated with concentrated sulfuric acid (4 drops). The resulting reaction mixture was heated under reflux for 15 h. The reaction mixture was allowed to cool to 25° C. and then concentrated in vacuo to remove methanol. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 1/1 hexaneslethyl acetate) afforded (3-fluoro-4-trifluoromethyl-phenyl)-acetic acid methyl ester (2.58 g, 97%) as a colorless oil: EI-HRMS m/e calcd for C10H8F4O2 (M+) 236.0460, found 236.0457.
Reaction SMILES: [N+:1]([C:4]1[CH:15]=[CH:14][C:7]2[CH:8]=[C:9]([C:11]([OH:13])=O)[O:10][C:6]=2[CH:5]=1)([O-:3])=[O:2].CN(C(ON1N=[N:31][C:26]2[CH:27]=[CH:28][CH:29]=[N:30][C:25]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH:40](N(CC)C(C)C)(C)[CH3:41]>CN(C=O)C>[N:30]12[CH2:29][CH2:28][CH:27]([CH2:40][CH2:41]1)[C@@H:26]([NH:31][C:11]([C:9]1[O:10][C:6]3[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:15]=[CH:14][C:7]=3[CH:8]=1)=[O:13])[CH2:25]2
Reactant: O=C(O)c1cc2ccc([N+](=O)[O-])cc2o1
Reactant: CCN(C(C)C)C(C)C
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: O=C(N[C@H]1CN2CCC1CC2)c1cc2ccc([N+](=O)[O-])cc2o1
Reaction time: 1 h

Procedure:
1.3 g (5.02 mmol) of 6-nitro-1-benzofuran-2-carboxylic acid, 1.0 g (5.02 mmol) of R-aminoquinuclidine dihydrochloride, 2.29 g (6.02 mmol) of HATU, 2.34 g (18.07 mmol) of N,N-diisopropylethylamine and 10 ml of DMF are reacted by general method B. The mixture is concentrated in vacuo and extracted with 1 N sodium hydroxide solution and with ethyl acetate, the organic phase is dried over sodium sulfate and concentrated, and the residue is dissolved in methanol. Dowex 50WX2-200 ion exchanger resin is added, and within 1 h, the mixture is concentrated in a rotary evaporator. The resin is washed successively with methanol, DMF, methanol, THF, methanol, dichloromethane, methanol and 10% triethylamine in methanol. The product fraction is concentrated. 1.75 g (99% of theory) of the title compound are obtained.
Reaction SMILES: C([Li])[CH2:2][CH2:3][CH3:4].Br[C:7]1[CH:12]=[C:11]([CH3:13])[C:10]([Br:14])=[CH:9][C:8]=1[CH3:15].C(#N)C(C)C.Cl.[O:22]1CCC[CH2:23]1>CCCCCC.C(OCC)C>[Br:14][C:10]1[C:11]([CH3:13])=[CH:12][C:7]([C:23]([CH:3]([CH3:2])[CH3:4])=[O:22])=[C:8]([CH3:15])[CH:9]=1
Reactant: [Li]CCCC
Reactant: Cc1cc(Br)c(C)cc1Br
Reactant: C1CCOC1
Agent: CC(C)C#N
Agent: Cl
Solvent: CCCCCC
Solvent: CCOCC
Product: Cc1cc(C(=O)C(C)C)c(C)cc1Br
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
31.2 ml of (50 mmol) of a 1.6 molar n-butyl lithium solution in hexane are added dropwise to a solution of 13.5 g (50 mmol) of 2,5-dibromo-p-xylene in 100 ml of tetrahydrofuran cooled to −78° C., the mixture is stirred for 30 minutes and then combined with 4.5 ml of (50 mmol) of isobutyronitrile. The reaction mixture is allowed to come back slowly to ambient temperature, stirred for 1 hour, then combined with 50 ml of 2N HCl and 70 ml of diethyl ether and stirred for another 16 hours. The aqueous phase is separated off and extracted 2× with diethyl ether. The combined organic phases are dried with Na2SO4, evaporated down and the residue is purified by flash chromatography (silica gel; petroleum ether to petroleum ether/ethyl acetate=9:1).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[O:8][CH2:9][C:10](=[O:12])[NH:11][C:6]=2[N:5]=[C:4](/[CH:13]=C/C2C=CC=CC=2)[N:3]=1.[O:21]1CCOCC1>O.O=[Os](=O)(=O)=O>[Cl:1][C:2]1[N:3]=[C:4]([CH:13]=[O:21])[NH:5][C:6]2[C:7]=1[O:8][CH2:9][C:10](=[O:12])[N:11]=2
Reactant: C1COCCO1
Reactant: O=C1COc2c(Cl)nc(/C=C/c3ccccc3)nc2N1
Agent: O=[Os](=O)(=O)=O
Solvent: O
Product: O=CC1=NC(Cl)=C2OCC(=O)N=C2N1
Temperature: 25 °C
Reaction time: 5 h
Yield: 84 %

Procedure:
To a solution of 4-chloro-2-[(E)-2-phenylethenyl]-6H-pyrimido[5,4-b][1,4]oxazin-7(8H)-one (0.45 g, 1.16 mmol) in 1,4-dioxane (25 mL) and water (10 mL) was added NaIO4 (1.26 g, 4.4 mmol) along with a catalytic amount of OsO4 (0.36 mL, 4 wt. % in water). The resulting mixture was stirred at room temperature for 5 h. The solvent was evaporated under reduced pressure and the residue was extracted with 10% methanol in DCM (3×50 ml). The organic extracts were combined, dried over anhydrous MgSO4, filtered and concentrated under reduced pressure to give a solid which was purified by column chromatography (silica gel) with a 0-10% methanol in DCM gradient to give the desired product as light yellow solid (0.28 g, 84%).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([NH2:8])[CH2:4][CH2:3]1.Cl[C:10]1[N:11]([C:30](=[O:32])[CH3:31])[CH2:12][C:13]2[N:19]=[C:18]([Cl:20])[N:17]=[C:16]([NH:21][C:22]3[CH:27]=[CH:26][C:25]([F:28])=[C:24]([Cl:29])[CH:23]=3)[C:14]=2[N:15]=1.C1COCC1.C(N(CC)CC)C>O>[Cl:20][C:18]1[N:17]=[C:16]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[C:24]([Cl:29])[CH:23]=2)[C:14]2[N:15]=[C:10]([NH:8][CH:5]3[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]3)[N:11]([C:30](=[O:32])[CH3:31])[CH2:12][C:13]=2[N:19]=1
Reactant: CN1CCC(N)CC1
Reactant: CC(=O)N1Cc2nc(Cl)nc(Nc3ccc(F)c(Cl)c3)c2N=C1Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)N1Cc2nc(Cl)nc(Nc3ccc(F)c(Cl)c3)c2N=C1NC1CCN(C)CC1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
47.2 g (0.413 mol) of 1-methyl-4-aminopiperidine is added dropwise at ambient temperature to a mixture of 123.3 g (0.317 mol) of (3), 740 ml of THF and 61.7 ml (0.445 mol) of triethylamine. The mixture is stirred for 30 min at 50° C. It is left to cool to 40° C., 1480 ml of water are added and the mixture is then stirred for 90 minutes at 10° C. The product that crystallises out is filtered off, washed with 150 ml of water and dried in vacuo at 60° C. The product is dissolved in 1150 ml of ethyl acetate at boiling temperature. It is cooled to 10° C., filtered and the product that crystallises out is dried at 60° C. in vacuo. Yield: 128.9 g (87.2%).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:13][CH:12]2[CH:8]([CH:9]([CH3:18])[C:10]3[CH:16]=[C:15](Br)[S:14][C:11]=32)[CH2:7]1)=[O:5])[CH3:2].[CH3:19][Zn]C.C1(C)C=CC=CC=1>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:1]([O:3][C:4]([N:6]1[CH2:13][CH:12]2[CH:8]([CH:9]([CH3:18])[C:10]3[CH:16]=[C:15]([CH3:19])[S:14][C:11]=32)[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CC2c3sc(Br)cc3C(C)C2C1
Reactant: C[Zn]C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: CCOC(=O)N1CC2c3sc(C)cc3C(C)C2C1
Temperature: 22 °C
Yield: 95 %

Procedure:
A solution of the product from step j) (284 mg, 0.86 mmol) in dioxane (4.3 ml) was treated with Pd(dppf)2Cl2 (42 mg, 0.051 mmol) and a 2M solution of dimethylzinc in toluene (0.86 ml, 1.72 mmol) at 102° C. for 1 hour. The reaction was cooled to 22° C. and carefully quenched with sat. NH4Cl (3 ml). After the effervescence subsided, the reaction was extracted with EtOAc (3×50 ml). The combined organic layers were dried (MgSO4) passed through a plug of silica-gel eluting with 50:50 hexanes:EtOAc to provide the subtitle compound (216 mg, 95% over 3-steps). MS calculated for C14H19NO2S +H 266, observed 266.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:6]=[CH:7][CH:8]=1)=O.Cl.Cl.[NH2:16][C:17]1[CH:18]=[CH:19][C:20]([N:24]2[CH2:29][CH2:28][CH2:27][C@@H:26]([C:30]([N:32]3[CH2:36][CH2:35][CH2:34][CH2:33]3)=[O:31])[CH2:25]2)=[N:21][C:22]=1[NH2:23].S(S([O-])(=O)=O)([O-])(=O)=O.[Na+].[Na+].C(N(CC)CC)C>O.C(O)C>[N:32]1([C:30]([C@@H:26]2[CH2:27][CH2:28][CH2:29][N:24]([C:20]3[N:21]=[C:22]4[NH:23][C:1]([C:3]5[CH:4]=[C:5]([CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:6]=[CH:7][CH:8]=5)=[N:16][C:17]4=[CH:18][CH:19]=3)[CH2:25]2)=[O:31])[CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: COC(=O)Cc1cccc(C=O)c1
Reactant: Nc1ccc(N2CCC[C@@H](C(=O)N3CCCC3)C2)nc1N
Agent: Cl
Agent: O=S(=O)([O-])S(=O)(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCO
Product: COC(=O)Cc1cccc(-c2nc3ccc(N4CCC[C@@H](C(=O)N5CCCC5)C4)nc3[nH]2)c1
Temperature: 110 °C
Reaction time: 18 h

Procedure:
Into a vial was added methyl 2-(3-formylphenyl)acetate (98 mg, 0.55 mmol), (R)-(1-(6-amino-5-nitropyridin-2-yl)piperidin-3-yl)(pyrrolidin-1-yl)methanone (Intermediate 1, Step 3) (140 mg, 0.45 mmol) and ethanol (1.5 mL). Then sodium dithionate (388 mg, 2.23 mmol) and water (0.5 mL) were added to the mixture. The vial was sealed. The reaction mixture was heated to 110° C. for 18 h. The solution was cooled to room temperature. Triethylamine (0.15 mL, 1.1 mmol) was added and the solution was stirred at 100° C. for 18 h. A sample (0.8 mL) of the solution was removed and concentrated to dryness, and the resulting residue was purified via HPLC to afford the title compound. MS (ESI+) (M+H) 448.2; HPLC retention time 2.28 min (Method A).
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1.[CH:9]1([NH2:13])[CH2:12][CH2:11][CH2:10]1.C(=O)([O-])[O-].[K+].[K+].O>CC(N(C)C)=O>[Cl:8][C:4]1[N:3]=[C:2]([NH:13][CH:9]2[CH2:12][CH2:11][CH2:10]2)[CH:7]=[N:6][CH:5]=1
Reactant: NC1CCC1
Reactant: Clc1cncc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: Clc1cncc(NC2CCC2)n1
Yield: 80 %

Procedure:
A solution of 2,6-dichloropyrazine (4.47 g), cyclobutanamine (3.8 mL) and potassium carbonate (6.20 g) in DMA (30 mL) was stirred at 80° C. for 14 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (solvent gradient: 5-15% ethyl acetate/hexane) to give the title compound (4.42 g, 80%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3[N:10]([OH:17])[C:9]=2[C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.[N+](=[CH2:26])=[N-]>C(Cl)(Cl)Cl.CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3[N:10]([O:17][CH3:26])[C:9]=2[C:18]2[CH:19]=[CH:20][N:21]=[CH:22][CH:23]=2)=[CH:6][CH:7]=1
Reactant: C=[N+]=[N-]
Reactant: On1c(-c2ccncc2)c(-c2ccc(F)cc2)c2ncccc21
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COn1c(-c2ccncc2)c(-c2ccc(F)cc2)c2ncccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 3-(4-fluorophenyl)-1-hydroxy-2-(pyridin-4-yl)-1H-pyrrolo[3,2-b]pyridine (0.38 g, 1.25 mmol) in chloroform (8 ml) and methanol (2 ml) was added to a solution of diazomethane at 0° C. The reaction was warmed to room temperature and stirred overnight. The solvent was removed in vacuo and the residue was purified by flash column chromatography (50%-100% ethyl acetate/hexanes gradient) to 3-(4-fluorophenyl)-1-methoxy-2-(pyridin-4-yl)-1H-pyrrolo[3,2-b]pyridine as an off white solid (210 mg).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:15](=[O:17])[NH:14][C:13](=[O:18])[N:12]([CH3:19])[C:11]=2[N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[C:22]([O:25][C@H:26]([CH3:32])[CH2:27][CH2:28][CH2:29][CH2:30][Br:31])(=[O:24])[CH3:23]>CS(C)=O>[C:22]([O:25][C@H:26]([CH3:32])[CH2:27][CH2:28][CH2:29][CH2:30][Br:31])(=[O:24])[CH3:23].[C:22]([O:25][C@H:26]([CH3:32])[CH2:27][CH2:28][CH2:29][CH2:30][N:14]1[C:15](=[O:17])[C:16]2[N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:9]=[N:10][C:11]=2[N:12]([CH3:19])[C:13]1=[O:18])(=[O:24])[CH3:23]
Reactant: Cn1c(=O)[nH]c(=O)c2c1ncn2Cc1ccccc1
Agent: CC(=O)O[C@H](C)CCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(=O)O[C@H](C)CCCCn1c(=O)c2c(ncn2Cc2ccccc2)n(C)c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 144 %

Procedure:
To a stirring suspension of 7-benzyl-3-methylxanthine (11.1 g, 43.2 mmol) in dimethyl sulfoxide (100 ml) was added 95% sodium hydride (1.24 g, 52 mmol) in one portion. After stirring for 30 minutes, (R)-5-acetoxy-1-bromohexane (8.1 g, 45.3 mmol) was added neat. The (R)-5-Acetoxy-1-bromohexane was prepared according to methods described in U.S. Pat. No. 6,075,029 issued to Klein, J. P., Kumar, A. M., and Woodson, P on Jun. 13, 2000, which is incorporated herein by reference. After stirring at 80° C. for 16 hours and cooled to room temperature, the reaction was quenched by addition of water (350 ml) and extracted with ethyl acetate (5×50 ml). The combined extracts were washed with saturated aqueous sodium bicarbonate solution (50 ml), with saturated aqueous sodium chloride solution (50 ml) and dried over magnesium sulfate. Evaporation of the solvent under reduced pressure gave a residue which was purified by flash chromatography on silica gel eluting with ethyl acetate to give (R)-1-(5-acetoxyhexyl)-7-benzyl-3-methylxanthine (13.0 g, 76% yield).