Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:3][C:4]([C@@H:6]1[C@H:10]2[O:11]C(C)(C)[O:13][C@H:9]2[C@H:8]([N:16]2[CH:24]=[N:23][C:22]3[C:17]2=[N:18][C:19]([C:40]([NH:42][CH2:43][CH2:44][NH:45][C:46]([NH:48][CH:49]2[CH2:54][CH2:53][N:52]([C:55]4[CH:60]=[CH:59][CH:58]=[CH:57][N:56]=4)[CH2:51][CH2:50]2)=[O:47])=[O:41])=[N:20][C:21]=3[NH:25][CH2:26][CH:27]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:7]1)=[O:5])[CH3:2].Cl.C(=O)(O)[O-].[Na+]>C(O)C>[C:28]1([CH:27]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:26][NH:25][C:21]2[N:20]=[C:19]([C:40]([NH:42][CH2:43][CH2:44][NH:45][C:46]([NH:48][CH:49]3[CH2:54][CH2:53][N:52]([C:55]4[CH:60]=[CH:59][CH:58]=[CH:57][N:56]=4)[CH2:51][CH2:50]3)=[O:47])=[O:41])[N:18]=[C:17]3[C:22]=2[N:23]=[CH:24][N:16]3[C@H:8]2[C@H:9]([OH:13])[C@H:10]([OH:11])[C@@H:6]([C:4]([NH:3][CH2:1][CH3:2])=[O:5])[O:7]2)[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(C(=O)NCCNC(=O)NC4CCN(c5ccccn5)CC4)nc32)[C@@H]2OC(C)(C)O[C@@H]21
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(C(=O)NCCNC(=O)NC4CCN(c5ccccn5)CC4)nc32)[C@H](O)[C@@H]1O
Temperature: 62.5 °C

Procedure:
To a solution of 9-{(3aR,4R,6S,6aS)-6-[(ethylamino)carbonyl]-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl}-6-[(2,2-diphenylethyl)amino]-N-{2-[({[1-(2-pyridinyl)-4-piperidinyl]amino}carbonyl)amino]ethyl}-9H-purine-2-carboxamide (Preparation 71) (20.9 g, 0.0255 moles) in absolute ethanol (200 ml) was added aqueous hydrochloric acid (76.5 ml of a 1M solution, 0.0765 moles) and the resultant solution was heated at 60-65° C. for 24 hours. The reaction mixture was allowed to cool to ambient temperature and saturated aqueous sodium bicarbonate solution (200 ml) was cautiously added. The resultant mixture was then concentrated in vacuo and the aqueous mixture was then extracted with ethyl acetate (200 ml) and then dichloromethane (200 ml). The extracts were dried over anhydrous magnesium sulphate which caused the deposition of a gum that was redissolved by the addition of dichloromethane (100 ml) and methanol (20 ml). The resultant violet solution was then concentrated in vacuo to give the crude product as a purple foam (20.86 g) that was purified by flash chromatography on silica gel (600 g) eluting with a gradient of 6% v/v methanol in dichloromethane changing to 8% v/v methanol in dichloromethane changing to 10% v/v methanol in dichloromethane changing to 15% v/v methanol in dichloromethane to give the title compound in several fractions of varying purity. The major fraction (11.4 g) was dissolved in dichloromethane (264 ml) and was filtered to remove insoluble matter To this solution was added diethyl ether (112 ml) and the resultant cloudy mixture was stirred at ambient temperature for 1 hour. The solids were then collected by filtration and were dried in vacuo. This material was then ground using a pestle and mortar and was dried further in vacuo at 50° to give the title compound (9.9 g) as a fine colourless powder.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH2:10])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:18](Cl)(=[O:22])/[CH:19]=[CH:20]/[CH3:21]>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][C:18](=[O:22])/[CH:19]=[CH:20]/[CH3:21])=[CH:4][CH:3]=1
Reactant: C/C=C/C(=O)Cl
Reactant: NCCc1ccc(F)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C/C=C/C(=O)NCCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 2-(4-fluorophenyl)ethylamine (13.25 mL, 100 mmol) and triethylamine (14.6 mL, 105 mmol) in dichloromethane (375 mL) was stirred on an ice bath. A solution of crotonyl chloride (10.65 mL, 100 mmol) in dichloromethane (25 mL) was added dropwise over 15 minutes. The cooling bath was removed and the solution was stirred at room temperature for 2 hours. It was then washed twice with 1.0 N aqueous hydrochloric acid, then twice with saturated aqueous sodium hydrogen carbonate. The organic phase was dried over sodium sulfate and concentrated under vacuum to provide a yellowish solid (20.78 g, quantitative). Recrystallization from toluene provided white needles (15.5 g, 75%), mp 121-123° C. 1H NMR (300 MHz, CDCl3) δ7.16 (m, 2H), 7.01 (t, J=9 Hz, 2H), 6.85 (dq, J=15, 7 Hz, 1H), 5.74 (dd, J=15, 1 Hz, 1H), 5.49 (bs, 1H), 3.56 (m, 2H), 2.83 (t, J=7 Hz, 2H), 1.85 (dd, J=7, 2 Hz, 3H). Mass spec (ES+) m/z 249.0 (M+H+acetonitrile+, 100%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH2:8][OH:9])[CH:7]=1.[H-].[Na+].[CH3:12]I.O>O1CCCC1>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH2:8][O:9][CH3:12])[CH:7]=1
Reactant: OCc1cncc(Br)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COCc1cncc(Br)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 65.8 %

Procedure:
Under a nitrogen atmosphere, a solution of 3-bromo-5-hydroxymethylpyridine (379 mg, 2.0 mmol) in dry tetrahydrofuran (10 mL) was treated at ambient temperature with sodium hydride (160 mg, 4.0 mmol, 60% dispersion in mineral oil). After stirring 5 min at ambient temperature, the opaque, yellow mixture was treated with methyl iodide (342 mg, 2.4 mmol). After stirring 2 h at ambient temperature, the mixture was added to cold water (30 mL) and extracted with diethyl ether (3×20 mL). The combined ether extracts were dried (Na2SO4), filtered, and concentrated by rotary evaporation to an orange oil (429 mg). Purification by column chromatography on silica gel, eluting with 15% (v/v) ethyl acetate in hexane afforded 266 mg (65.3%) of 3-bromo-5-methoxymethylpyridine as a colorless oil.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][N:14]([C:17]([C:19]2[N:20]=[C:21]([CH3:24])[NH:22][CH:23]=2)=[O:18])[CH2:13][CH2:12]1)([CH3:4])([CH3:3])[CH3:2].Br[CH2:26][C:27]([O:29][CH3:30])=[O:28].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:12][CH2:13][N:14]([C:17]([C:19]2[N:20]=[C:21]([CH3:24])[N:22]([CH2:26][C:27]([O:29][CH3:30])=[O:28])[CH:23]=2)=[O:18])[CH2:15][CH2:16]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1nc(C(=O)N2CCN(c3ccccc3C(C)(C)C)CC2)c[nH]1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)Cn1cc(C(=O)N2CCN(c3ccccc3C(C)(C)C)CC2)nc1C
Temperature: 50 °C
Reaction time: 16 h
Yield: 41 %

Procedure:
A mixture of 1-(2-tert-butylphenyl)-4-[(2-methyl-1H-imidazol-4-yl)carbonyl]piperazine (0.50 g, 1.53 mmol), methyl bromoacetate (0.28 g, 1.84 mmol) and potassium carbonate (0.63 g, 4.6 mmol) in N,N-dimethylformamide (5 mL) was stirred at 50° C. for 16 h. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by NH-silica gel column chromatography (hexane/ethyl acetate 50:50). The residue was washed with hexane-ethyl acetate and purified by silica gel column chromatography (hexane/ethyl acetate 50:50 to 0/100 then ethyl acetate/methanol 100/0 to 90/10) to give the title compound (0.25 g, 40%) as a white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH2:11])(=[O:10])=[O:9].[C:12]([C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1)([OH:14])=[O:13].C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>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.C(OCC)C>[NH2:11][S:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:18]1[CH:19]=[CH:20][C:15]([C:12]([OH:14])=[O:13])=[CH:16][CH:17]=1)(=[O:10])=[O:9]
Reactant: O=C(O)c1ccc(B(O)O)cc1
Reactant: NS(=O)(=O)c1ccccc1Br
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: [Na+]
Solvent: CCOCC
Solvent: Cc1ccccc1
Solvent: O
Product: NS(=O)(=O)c1ccccc1-c1ccc(C(=O)O)cc1
Temperature: 25 °C
Yield: 57.4 %

Procedure:
2-Bromobenzenesulfonamide (800 mg) and 4-carboxyphenylboronic acid (563 mg) were suspended in a mixed solvent of toluene (5 ml) and water (5 ml). Tetrakis(triphenylphosphine)palladium (392 mg) and anhydrous sodium carbonate (1.08 g) were successively added to the suspension, and the mixture was heated under reflux overnight. After the reaction mixture was cooled to room temperature, diethyl ether and water were added to conduct liquid separation. The resultant organic layer was extracted twice with water. The resultant water layers were all combined, and 12N hydrochloric acid was added to this solution to acidify it. The solution was concentrated to about 20 ml under reduced pressure. Colorless powder deposited was collected by filtration and dried under reduced pressure to obtain the title compound (539 mg).
Reaction SMILES: Br[C:2](Br)=[CH:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[C:6]([O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH:5]=1.[Li]CCCC>C1COCC1>[CH2:11]([O:10][C:7]1[CH:8]=[CH:9][C:4]([C:3]#[CH:2])=[CH:5][C:6]=1[O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCCCCCCCOc1ccc(C=C(Br)Br)cc1OCCCCCCCCCCCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C#Cc1ccc(OCCCCCCCCCCCC)c(OCCCCCCCCCCCC)c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 65.1 %

Procedure:
4-(2,2-Dibromo-vinyl)-1,2-bis-dodecyloxy-benzene (JYC-II-003-A) (9.0 g, 14.3 mmol) in 150 mL of dry THF was cooled down to −78° C. under Ar atmosphere. nBuLi (11.4 mL of 2.5 M solution in hexanes, 28.5 mmol) was added dropwise to the mixture and the resulting mixture was stirred at −78° C. for 1 h. The reaction mixture was allowed to warm up to room temperature and stirred at room temperature for additional 2 h. The reaction was quenched with a saturated NH4Cl aqueous solution and extracted with diethyl ether. The organic layer was dried over anhydrous MgSO4. The solvent was removed under reduced pressure. (The reaction did not go to completion and the product has very similar Rf value to that of the starting material.) The crude mixture was re-dissolved in dry THF and nBuLi (11.4 mL of 2.5 M solution in hexanes, 28.5 mmol) was added dropwise to the mixture. The mixture was stirred at room temperature for 2 h. The workup procedure was repeated. The product was further purified by column chromatography (silica gel, hexanes, then hexanes:dichloromethane=50:1 (v/v)) to give a white solid (4.38 g, 65.2%). 1H NMR (300 MHz, CDCl3, δ): 7.04 (dd, J=8.2 Hz, J=1.9 Hz, 1H), 6.97 (d, J=1.9 Hz, 1H), 6.77 (d, J=8.2 Hz, 1H), 3.97 (t, J=6.6 Hz, 2H), 3.95 (t, J=6.6 Hz, 2H), 2.96 (s, 1H), 1.74-1.84 (m, 4H), 1.20-1.50 (m, 36H), 0.87 (t, J=6.6 Hz, 6H). 13C{1H} NMR (75 MHz, CDCl3, δ): 149.87, 148.45, 125.36, 116.91, 113.93, 112.91, 83.92, 75.39, 69.18, 69.05, 32.00, 29.78, 29.73, 29.70, 29.48, 29.45, 29.22, 26.08, 22.78, 14.22. HRMS-EI (m/z): [M]+ calcd for C32H54O2, 470.4124; found, 470.4113. Anal. Calcd for C32H54O2,: C, 81.64; H, 11.56. Found: C, 81.36; H, 11.70.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:14]3[C:9](=[CH:10][N:11]=[CH:12][CH:13]=3)[C:8](=[O:15])[N:7]([CH3:16])[C:6]=2[CH:17]=1.C1C=C(Cl)C=C(C(OO)=[O:26])C=1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:14]3[C:9](=[CH:10][N+:11]([O-:26])=[CH:12][CH:13]=3)[C:8](=[O:15])[N:7]([CH3:16])[C:6]=2[CH:17]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cn1c(=O)c2cnccc2c2ccc(Cl)cc21
Solvent: ClCCl
Product: Cn1c(=O)c2c[n+]([O-])ccc2c2ccc(Cl)cc21
Temperature: 0 °C
Reaction time: 4 h
Yield: 93.9 %

Procedure:
To the stirred solution of 8-chloro-6-methylbenzo[c][2,7]naphthyridin-5(6H)-one (1.0 g, 4.09 mmol), prepared as described in Example 2, Part C, in DCM (20 mL) cooled to 0° C. was added m-CPBA (1.763 g, 10.22 mmol). The reaction mixture was then warmed to ambient temperature and stirred for 4 h. Reaction mixture was then diluted with dichloromethane (100 mL) and washed with saturated sodium bicarbonate solution (200 mL), brine solution (50 mL). The organics were then dried over sodium sulphate, filtered and concentrate to afford 8-chloro-6-methyl-5-oxo-5,6-dihydrobenzo[c][2,7]naphthyridine 3-oxide (1.0 g, 3.84 mmol, 94% crude yield) as a yellow solid. The material was carried on without further purification. LC/MS (ESI) m/e 261.0, [(M+H)+, calcd for C13H10ClN2O2, 261.0]; LC/MS retention time (method C): tR=1.65 min.
Reaction SMILES: O1CCCC1.[BH4-].[Na+].[C:8]([O:12][C:13](=[O:31])[NH:14][CH:15]([C:26]1[O:27][CH:28]=[CH:29][N:30]=1)S(C1C=CC(C)=CC=1)(=O)=O)([CH3:11])([CH3:10])[CH3:9].[Cl-].[NH4+]>O>[C:8]([O:12][C:13](=[O:31])[NH:14][CH2:15][C:26]1[O:27][CH:28]=[CH:29][N:30]=1)([CH3:11])([CH3:9])[CH3:10]
Reactant: Cc1ccc(S(=O)(=O)C(NC(=O)OC(C)(C)C)c2ncco2)cc1
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCc1ncco1
Yield: 53.6 %

Procedure:
To 4 mL of tetrahydrofuran was added 51.4 mg of sodium borohydride, and added with 240 mg of [oxazole-2-yl-(toluene-4-sulfonyl)-methyl]-carbamic acid tert-butyl ester obtained by Production example 769 over 13 minutes at room temperature under stirring. Thereafter, the solution was stirred for another 2 hours and 30 minutes under room temperature, added with saturated aqueous ammonium chloride under ice cooling, and stirred for another 30 minutes under ice cooling. Thereafter, water was added, extracted twice with diethyl ether and dried over anhydrous magnesium sulfate. The solvent was evaporated, followed by purification and separation by silica gel column chromatography, to afford 72.3 mg of the title compound as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:22]([O:24]CC)=O)=[N:4][N:5]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[Cl:21])[C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1.[NH2:27][NH2:28]>C(O)C>[Cl:1][C:2]1[C:3]([C:22]([NH:27][NH2:28])=[O:24])=[N:4][N:5]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[Cl:21])[C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1
Reactant: CCOC(=O)c1nn(-c2ccc(Cl)cc2Cl)c(-c2ccc(Cl)cc2)c1Cl
Reactant: NN
Solvent: CCO
Product: NNC(=O)c1nn(-c2ccc(Cl)cc2Cl)c(-c2ccc(Cl)cc2)c1Cl
Temperature: 100 °C

Procedure:
A solution of ethyl 4-chloro-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-1H-pyrazole-3-carboxylate (3.1 g, 7.2 mmol) in ethyl alcohol (30 ml) was added hydrazine (5 ml, 64% solution in water) in one portion. The reaction mixture was refluxed 100° C. for 6 hours, and then cooled down to room temperature. After volatile solvent was removed in reduced pressure, the residue was purified with silica gel column (5% methanol in methylene chloride) to obtained title compound (3 g, quantitatively) as slightly yellow solid.
Reaction SMILES: [C:1]1([C:11]([OH:13])=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[I-].[CH2:48]([N+:52]1[N:56]=[C:55]([CH3:57])[S:54][C:53]=1[CH3:58])[CH2:49][CH2:50][CH3:51]>>[CH2:48]([N:52]1[N:56]=[C:55]([CH3:57])[S:54]/[C:53]/1=[CH:58]\[C:11]([C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1)=[O:13])[CH2:49][CH2:50][CH3:51]
Reactant: CCCC[n+]1nc(C)sc1C
Reactant: O=C(O)c1cccc2ccccc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Product: CCCCN1N=C(C)S/C1=C\C(=O)c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 20 mL vial 1-naphthoic acid (0.9 mL of 0.2 M in DMA, 1.10 equiv) was added followed by the addition of HATU (76 mg in 0.7 mL of DMA, 0.2 mmol, 1.20 equiv.), DIEA (51 mg in 0.7 mL of DMA, 0.4 mmol, 2.40 equiv.), and finally 3-butyl-2,5-dimethyl-1,3,4-thiadiazol-3-ium iodide (49 mg in 0.7 mL of DMA, 0.17 mmol, 1 equiv.). The mixture was shaken overnight at room temperature and then concentrated in vacuo. The resulting residue was taken up in 1:1 DMSO/MeOH and purified by reverse phase HPLC using a method analogous to that described in Example 53 to provide the title compound. 1H NMR (500 MHz, DMSO-d6/D2O) δ ppm 0.87-0.93 (m, 3 H) 1.27-1.35 (m, 2 H) 1.69-1.78 (m, 2 H) 2.51 (s, 3 H) 4.16-4.20 (m, 2 H) 6.40 (s, 1 H) 7.49-7.59 (m, 3 H) 7.73-7.78 (m, 1 H) 7.94-8.01 (m, 2 H) 8.37-8.43 (m, 1 H); MS (ESI) m/z 325 (M+H)+.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:20]=[CH:21][CH:22]=2)[O:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]([NH:18][NH2:19])=[S:17])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:23]([N:25]=[C:26]=[O:27])[CH3:24]>>[CH2:23]([NH:25][C:26]([NH:19][NH:18][C:16]([NH:15][CH2:14][CH2:13][CH2:12][O:11][C:10]1[CH:20]=[CH:21][CH:22]=[C:8]([CH2:7][N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH:9]=1)=[S:17])=[O:27])[CH3:24]
Reactant: NNC(=S)NCCCOc1cccc(CN2CCCCC2)c1
Reactant: CCN=C=O
Product: CCNC(=O)NNC(=S)NCCCOc1cccc(CN2CCCCC2)c1

Procedure:
The compound is prepared by a method analogous to that of Example 9 from N-[3-[3-(1-piperidinylmethyl)phenoxy]propyl]-hydrazine carbothioamide and ethyl isocyanate. The analytical values are summarized in Table I.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[CH:19]=[CH:18][C:14]([C:15]([NH2:17])=[O:16])=[CH:13][CH:12]=3)=[CH:9][N:8](S(C3C=CC(C)=CC=3)(=O)=O)[C:5]2=[N:6][CH:7]=1.[C:30]([O:34][C:35]([N:37]1[CH2:42][CH2:41][N:40]([C:43](=[O:59])[C:44]2[CH:49]=[CH:48][C:47](B3OC(C)(C)C(C)(C)O3)=[CH:46][CH:45]=2)[CH2:39][CH2:38]1)=[O:36])([CH3:33])([CH3:32])[CH3:31].C([O-])([O-])=O.[Na+].[Na+]>CC#N.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>[C:30]([O:34][C:35]([N:37]1[CH2:42][CH2:41][N:40]([C:43](=[O:59])[C:44]2[CH:45]=[CH:46][C:47]([C:2]3[CH:3]=[C:4]4[C:10]([C:11]5[CH:12]=[CH:13][C:14]([C:15](=[O:16])[NH2:17])=[CH:18][CH:19]=5)=[CH:9][NH:8][C:5]4=[N:6][CH:7]=3)=[CH:48][CH:49]=2)[CH2:39][CH2:38]1)=[O:36])([CH3:33])([CH3:31])[CH3:32]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ccc(C(N)=O)cc3)c3cc(Br)cnc32)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc(-c3cnc4[nH]cc(-c5ccc(C(N)=O)cc5)c4c3)cc2)CC1
Yield: 46 %

Procedure:
4-[5-Bromo-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-benzamide (Intermediate CA, 200 mg, 0.425 mmol), 4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoyl]-piperazine-1-carboxylic acid tert-butyl ester (212 mmg, 0.51 mmol) and dichlorobis(triphenylphosphine)palladium (II) (15 mg, 0.021 mmol) were combined in CH3CN (5 ml) and 1 M Na2CO3 (5 ml) and reacted in a microwave reactor at 150° C. for 10 min. The mixture was filtered, water was added, extracted with EtOAc and purified by silica gel chromatography using 0-8% MeOH:DCM. The title compound was obtained in 46% yield (102 mg). 1H NMR (DMSO-d6, 300 MHz): δ 12.2 (bs, 1H), 8.63 (d, J=1.1 Hz, 1H), 8.54 (d, J=1.1 Hz, 1H), 8.08 (s, 1H), 7.98 (bs, 1H), 7.96 (d, J=5.1 Hz, 2H), 7.89 (m, 4H), 7.54 (d, J=4.9 Hz, 2H), 7.32 (bs, 1H), 3.6 (bs, 2H), 3.4 (bs), 1.41 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=2[F:15])[N:5]=[C:4]([C:16]([O:18][CH3:19])=[O:17])[CH:3]=1.[I:20](O)(=O)(=O)=O.II.S([O-])([O-])=O.[Na+].[Na+]>CO.ClCCl>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=2[F:15])[N:5]=[C:4]([C:16]([O:18][CH3:19])=[O:17])[C:3]=1[I:20]
Reactant: COC(=O)c1cc(N)nc(-c2ccc(Cl)cc2F)n1
Reactant: [O-][I+3]([O-])([O-])O
Agent: II
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: COC(=O)c1nc(-c2ccc(Cl)cc2F)nc(N)c1I
Yield: 38.9 %

Procedure:
Methyl 6-amino-2-(4-chloro-2-fluorophenyl)pyrimidine-4-carboxylate (6.17 g, 21.91 mmol, see US 20090088322 for preparation) was diluted with methanol (100 ml). Periodic acid (2.10 g, 9.21 mmol) and iodine (5.26 g, 20.72 mmol) were added and the reaction was heated at reflux overnight. The cooled reaction mixture was diluted with dichloromethane and poured into a 1N solution of sodium sulfite. The aqueous phase was extracted with dichloromethane. The combined organic phases were washed with 1N sodium sulfite, washed with saturated sodium chloride, dried over magnesium sulfate, filtered, and concentrated onto celite. Purification by flash chromatography (SiO2, 30% EtOAc:Hex) provided the title compound (1.46 g, 16% yield) as a white solid: 1H NMR (400 MHz, DMSO-d6) d 3.89 (s, 3H), 7.34-7.46 (m, 1H), 7.53 (dd, J=10.7, 2.0 Hz, 1H), 7.89 (t, J=8.4 Hz, 1H); 19F NMR (376 MHz, DMSO-d6) d −110.23; ESIMS m/z 408 ([M+H]+), 406 ([M−H]−).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.[Cl:15][C:16]1[CH:24]=[C:23]([S:25]([CH3:28])(=[O:27])=[O:26])[CH:22]=[CH:21][C:17]=1[C:18](O)=[O:19]>>[Cl:15][C:16]1[CH:24]=[C:23]([S:25]([CH3:28])(=[O:27])=[O:26])[CH:22]=[CH:21][C:17]=1[C:18]([NH:6][C:5]1[CH:7]=[CH:8][C:2]([Cl:1])=[C:3]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[CH:4]=1)=[O:19]
Reactant: Nc1ccc(Cl)c(-c2ccccn2)c1
Reactant: CS(=O)(=O)c1ccc(C(=O)O)c(Cl)c1
Product: CS(=O)(=O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1

Procedure:
Procedure G was used to couple 4-chloro-3-(pyridin-2-yl)aniline (50 mg) and 2-chloro-4-methylsulfonylbenzoic acid to produce 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonyl)benzamide. MS (Q1) 421.0 (M)+. The product was then dissolved in 1 N HCl solution followed by freebasing with 0.5 N NaOH solution (pH to 11). The resulting precipitate was filtered and vacuum-dry.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[N+:10]([O-])=O.[H][H]>CO.[Pd]>[NH2:10][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:2]=1[NH2:1])[C:6]#[N:7]
Reactant: N#Cc1ccc(N)c([N+](=O)[O-])c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: N#Cc1ccc(N)c(N)c1
Yield: 90.1 %

Procedure:
A solution of 4-amino-3-nitrobenzonitrile (20 mmol) in MeOH (300 mL) in the presence of 5% of Pd/C (1 g) was treated with hydrogen at room temperature for 16 hours. The reaction mixture was filtered and concentrated to give 3,4-diaminobenzonitrile (2.4 g, 90% of yield), which was directly treated with formic acid (20 mL) under reflux for 4 hours. After removal of the excess formic acid, the residue was dissolved in EtOAc, washed with 10% sodium bicarbonate and brine, and dried over MgSO4. Concentration gave 5-cyanobenzimidazole (2.2 g, 85%). 1H NMR (CD3OD) δ8.39 (s, 1H), 8.05 (s, 1H), 7.76 (d, J=8.4 Hz, 1H), 7.59 (dd, J=8.4 Hz, J=1.1 Hz, 1H); MS: 144 (M+H)+.
Reaction SMILES: O=[C:2]1[CH2:6][S:5][CH2:4][CH:3]1[C:7]([O:9][CH3:10])=[O:8].[ClH:11].[NH2:12]O>C(#N)C>[ClH:11].[NH2:12][C:2]1[C:3]([C:7]([O:9][CH3:10])=[O:8])=[CH:4][S:5][CH:6]=1
Reactant: COC(=O)C1CSCC1=O
Reactant: NO
Agent: Cl
Solvent: CC#N
Product: COC(=O)c1cscc1N
Yield: 62.3 %

Procedure:
A mixture of 4-oxo-3-methoxycarbonyltetrahydrothiophene (6.5 g, 40.62 mmol), hydroxylamine hydrochloride (2.84 g, 40.62 mmol) and acetonitrile (30 mL) was stirred under reflux for 1 h. The mixture was then cooled and the solid which separated was filtered off and washed with dry ether to afford the title compound (4.9 g, 62%), mp 192-196° C.