Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][N:5]=[CH:4]1.Br[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]Br>>[CH2:9]([N:3]1[CH:7]=[CH:6][N:5]=[CH:4]1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][N:3]1[CH:7]=[CH:6][N:5]=[CH:4]1
Reactant: c1c[nH]cn1
Reactant: BrCCCCCCCCBr
Agent: [H-]
Agent: [Na+]
Product: c1cn(CCCCCCCCn2ccnc2)cn1
Temperature: 40 °C

Procedure:
Sodium hydride (11.0 g of 60 wt % dispersion in mineral oil, 276 mmol) was added to a 500-mL, 3-neck round bottom flask equipped with stir bar and reflux condenser under argon purge. Anhydrous tetrahydrofuran (300 mL) was vacuum-transferred into the reaction vessel. Imidazole (15.0 g, 221 mmol) was added to the stirred slurry. The reaction was heated to 40° C. and held there until H2 gas evolution had visibly ceased. After this time, 1,8-dibromooctane (20.4 mL, 111 mmol) was injected into the reaction mixture and the reaction heated at reflux (65° C.) under argon overnight. The reaction was allowed to cool to room temperature and the solids were filtered and washed with tetrahydrofuran. The product solution was concentrated by rotary evaporation and then dissolved in methanol (100 mL). Addition of methanol caused residual mineral oil to separate from the product. The methanol solution was washed with hexanes (3×100 mL), and concentrated by rotary evaporation. The product was dried under vacuum overnight to yield an off-white waxy solid. Yield: 21.5 g (85%).
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][C:5]1[CH:6]=[C:7]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:8]([CH:11]([F:13])[F:12])=[N:9][CH:10]=1.C(N(CC)CC)C.[C:26](Cl)(=[O:30])[CH:27]([CH3:29])[CH3:28]>C(Cl)Cl>[F:12][CH:11]([F:13])[C:8]1[C:7]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:6][C:5]([CH2:4][NH:3][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])=[CH:10][N:9]=1
Reactant: CCOC(=O)c1cc(CN)cnc1C(F)F
Reactant: CC(C)C(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)c1cc(CNC(=O)C(C)C)cnc1C(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.8 %

Procedure:
Cool a mixture of ethyl 5-(aminomethyl)-2-(difluoromethyl)pyridine-3-carboxylate dihydrochloride (29.8 g, 111.8 mmol, 1.0 equiv), DCM (510 mL), and triethylamine (59.2 mL, 424.6 mmol, 3.8 equiv) to 0° C., then add a solution of isobutyryl chloride (15.3 mL, 145.3 mmol, 1.3 equiv) in DCM (23 mL) drop wise over 20 min. Stir overnight while allowing the mixture to warm to room temperature. Remove the solid precipitate by filtration, and rinse the filter with EtOAc (500 mL). Concentrate the filtrate under reduced pressure; filter the concentrate to remove the solids; and rinse the solids with EtOAc. Concentrate the filtrate under reduced pressure to give a yellow oil. Subject this crude material to silica gel chromatography eluting with a gradient of 40-90% EtOAc/hexanes gradient, to give the title compound as a light yellow crystalline solid (25.8 g, 77% yield). ES/MS (m/z) 301 (M+1).
Reaction SMILES: [S:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[N:3]=[CH:2]1.CI.[BH4-].[Na+].[C:14](=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[CH3:14][N:6]1[CH2:7][CH2:8][C:9]2[S:1][CH:2]=[N:3][C:4]=2[CH2:5]1
Reactant: c1cc2scnc2cn1
Reactant: O=C([O-])[O-]
Agent: [BH4-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: O
Product: CN1CCc2scnc2C1
Temperature: 80 °C

Procedure:
In N,N-dimethylformamide (80 ml) was dissolved thiazolo[4,5-c]pyridine (700 mg), followed by the addition of methyl iodide (0.65 ml). The resulting mixture was stirred under heat at 80° C. for 4 hours. After concentration of the reaction mixture under reduced pressure, the residue was dissolved in water (100 ml). Sodium borohydride (583 mg) was added to the resulting solution, followed by stirring at room temperature for 1 hour. After the addition of a saturated aqueous solution of potassium carbonate, the resulting mixture was extracted with ether. The organic layer thus extracted was dried over anhydrous sodium sulfate and distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column (methylene chloride:methanol=25:1), whereby the title compound (596 mg) was obtained as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[C:7]([C:8]#[N:9])=[CH:6][C:5]([N:10]2[C:19]3[C:14](=[CH:15][C:16]([S:20](OC4C(F)=C(F)C(F)=C(F)C=4F)(=[O:22])=[O:21])=[CH:17][CH:18]=3)[CH:13]=[CH:12][C:11]2=[O:35])=[C:4]([O:36][CH3:37])[CH:3]=1.[O:38]1[CH:42]=[CH:41][C:40]([NH2:43])=[N:39]1.C1COCC1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>CCOC(C)=O>[Br:1][C:2]1[C:7]([C:8]#[N:9])=[CH:6][C:5]([N:10]2[C:19]3[C:14](=[CH:15][C:16]([S:20]([NH:43][C:40]4[CH:41]=[CH:42][O:38][N:39]=4)(=[O:21])=[O:22])=[CH:17][CH:18]=3)[CH:13]=[CH:12][C:11]2=[O:35])=[C:4]([O:36][CH3:37])[CH:3]=1
Reactant: COc1cc(Br)c(C#N)cc1-n1c(=O)ccc2cc(S(=O)(=O)Oc3c(F)c(F)c(F)c(F)c3F)ccc21
Reactant: Nc1ccon1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cc(Br)c(C#N)cc1-n1c(=O)ccc2cc(S(=O)(=O)Nc3ccon3)ccc21
Reaction time: 0.25 h
Yield: 67.1 %

Procedure:
A RBF was charged with perfluorophenyl 1-(4-bromo-5-cyano-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonate (330.64 mg, 0.550 mmol), isoxazol-3-amine (46.7 μl, 0.632 mmol) and THF (3666 μl) to give a clear solution. The flask was cooled in an ice-water bath for 10 min, then lithium bis(trimethylsilyl)amide (1M in THF) (1155 μl, 1.155 mmol) was added dropwise. After 15 min, the mixture was diluted with EtOAc and washed with 1N aq. HCl. The aq. layer was extracted with EtOAc (2×). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated. The residue was purified by chromatography (45-g Redi-Sep column, 25-g silica gel loading column, 0-5% MeOH/DCM) to give 1-(4-bromo-5-cyano-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (185 mg, 0.369 mmol, 67.1% yield) as a light-yellow solid. 1 H NMR (400 MHz, DMSO-d6) □=11.67 (br. s., 1 H), 8.73 (d, J=1.8 Hz, 1 H), 8.38 (d, J=2.2 Hz, 1 H), 8.27-8.21 (m, 1 H), 8.12-8.06 (m, 1 H), 7.90-7.78 (m, 2 H), 6.90 (d, J=9.0 Hz, 1 H), 6.85-6.76 (m, 1 H), 6.45 (d, J=1.8 Hz, 1 H), 3.81 (s, 3 H). m/z/(ESI) 501.0 (M+H)+.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[NH2:6][C:7]1[C:8]([N:33]2[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]2)=[CH:9][C:10]([O:31][CH3:32])=[C:11]([NH:13][C:14]2[N:19]=[C:18]([C:20]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[NH:22][CH:21]=3)[C:17]([C:29]#[N:30])=[CH:16][N:15]=2)[CH:12]=1.CCN(C(C)C)C(C)C>C1COCC1>[C:29]([C:17]1[C:18]([C:20]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[NH:22][CH:21]=2)=[N:19][C:14]([NH:13][C:11]2[C:10]([O:31][CH3:32])=[CH:9][C:8]([N:33]3[CH2:34][CH2:35][N:36]([CH3:39])[CH2:37][CH2:38]3)=[C:7]([NH:6][C:1](=[O:4])[CH:2]=[CH2:3])[CH:12]=2)=[N:15][CH:16]=1)#[N:30]
Reactant: C=CC(=O)Cl
Reactant: COc1cc(N2CCN(C)CC2)c(N)cc1Nc1ncc(C#N)c(-c2c[nH]c3ccccc23)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: C=CC(=O)Nc1cc(Nc2ncc(C#N)c(-c3c[nH]c4ccccc34)n2)c(OC)cc1N1CCN(C)CC1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 21.6 %

Procedure:
Acryloyl chloride (0.100 mL, 1M in THF, 0.1 mmol) was added dropwise to a fine slurry of 2-{[5-amino-2-methoxy-4-(4-methylpiperazin-1-yl)phenyl]amino}-4-(1H-indol-3-yl)pyrimidine-5-carbonitrile (Intermediate 99, 47 mg, 0.10 mmol) and DIPEA (0.027 mL, 0.16 mmol) in THF (2 mL) at −10° C. over a period of 2 minutes under N2. The mixture was then stirred at 0° C. for 10 minutes then allowed to warm to r.t. over 20 minutes. The mixture was then cooled again to −10° C. and further acryloyl chloride (0.06 mL, 1M in THF, 0.06 mmol) was added dropwise. The mixture was stirred at 0° C. for a further 10 minutes, then allowed to warm to r.t. over 20 minutes. The mixture was then concentrated in vacuo and the resulting reside was dissolved in CH2Cl2 (2 mL). This solution was washed with sat. NaHCO3 (1 mL), dried (MgSO4) and concentrated in vacuo. Purification by FCC, eluting with 1.5-7% 7N methanolic ammonia in CH2Cl2 gave a residue that was washed with CH3OH (0.1 mL) and dried in air to give the title compound (11 mg, 20%) as a cream crystalline solid; 1H NMR: 2.28 (3H, s), 2.54-2.65 (4H, m), 2.93 (4H, s), 3.75 (3H, s), 5.71 (1H, d), 6.18 (1H, d), 6.64 (1H, dd), 6.91 (2H, m), 7.18 (1H, s), 7.47 (1H, d), 8.02 (1H, s), 8.52 (1H, s), 8.67 (1H, s), 9.04 (1H, s), 9.40 (1H, s), 11.99 (1H, s); m/z: ES+ MH+ 509.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].F[C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([C:16]([F:19])([F:18])[F:17])[CH:9]=1.[NH2:20][C@H:21]1[CH2:26][CH2:25][C@H:24]([OH:27])[CH2:23][CH2:22]1>O.C(#N)C>[OH:27][C@H:24]1[CH2:25][CH2:26][C@H:21]([NH:20][C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([C:16]([F:19])([F:18])[F:17])[CH:9]=2)[CH2:22][CH2:23]1
Reactant: N[C@H]1CC[C@H](O)CC1
Reactant: N#Cc1ccc(F)cc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: N#Cc1ccc(N[C@H]2CC[C@H](O)CC2)cc1C(F)(F)F
Temperature: 80 °C

Procedure:
Potassium carbonate (304 mg, 2.2 mmol) was dissolved in a minimum amount of water. Next, 4-fluoro-2-trifluoromethylbenzonitrile (378 mg, 2.0 mmol) and trans-4-aminocyclohexanol (460 mg, 4.0 mmol) dissolved in acetonitrile (10 mL) were added. The resulting mixture was then heated at 80° C. for 3 days. After cooling at room temperature, the mixture was concentrated under vacuum, taken up in ethyl acetate (15 mL), washed with saturated aqueous ammonium chloride (2×10 mL), and washed with water (10 mL). The organic phase was collected and dried over sodium sulfate, filtered, and concentrated under vacuum. The desired product was isolated as a colorless solid (456 mg, 80% yield).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([C:12]2[NH:16][C:15](=[O:17])[N:14]([C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=3)[N:13]=2)[C:6]([CH:9]([F:11])[F:10])=[N:7][CH:8]=1.[C:28](Cl)(=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30]>C(Cl)Cl>[F:10][CH:9]([F:11])[C:6]1[N:7]=[CH:8][C:3]([CH2:2][NH:1][C:28](=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:4][C:5]=1[C:12]1[NH:16][C:15](=[O:17])[N:14]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:26])([F:25])[F:27])=[CH:20][CH:19]=2)[N:13]=1
Reactant: NCc1cnc(C(F)F)c(-c2nn(-c3ccc(C(F)(F)F)cc3)c(=O)[nH]2)c1
Reactant: CC(C)(C)C(=O)Cl
Solvent: ClCCl
Product: CC(C)(C)C(=O)NCc1cnc(C(F)F)c(-c2nn(-c3ccc(C(F)(F)F)cc3)c(=O)[nH]2)c1
Yield: 17.8 %

Procedure:
The title compound was prepared by following the procedure as described in Example-108 by using 3-(5-(aminomethyl)-2-(difluoromethyl)pyridin-3-yl)-1-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-5(4H)-one (0.50 g, 0.12 mmol), pivaloyl chloride (0.018 g, 0.14 mmol), TEA (0.038 g, 0.37 mmol) in DCM (10 mL) to afford 0.010 g of the desired product. 1H NMR (300 MHz, DMSO d6): δ 1.18 (s, 9H), 4.38 (s, 2H), 7.24-7.63 (m, 1H), 7.64 (d, J=8.4 Hz, 2H), 7.99 (s, 1H), 8.10 (d, J=8.4 Hz, 2H), 8.61 (s, 1H); MS (m/z): 470.25 (M+H)+.
Reaction SMILES: [SH:1][C:2]1[NH:3][C:4]2[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:5]=2[N:6]=1.Cl.Cl[CH2:14][C:15]1[CH:21]=[CH:20][C:19]([CH3:22])=[C:18]([CH3:23])[C:16]=1[NH2:17]>C(O)(C)C>[CH3:11][C:9]1[CH:8]=[CH:7][C:5]2[NH:6][C:2]([S:1][CH2:14][C:15]3[CH:21]=[CH:20][C:19]([CH3:22])=[C:18]([CH3:23])[C:16]=3[NH2:17])=[N:3][C:4]=2[CH:10]=1
Reactant: Cc1ccc(CCl)c(N)c1C
Reactant: Cc1ccc2nc(S)[nH]c2c1
Agent: Cl
Solvent: CC(C)O
Product: Cc1ccc2[nH]c(SCc3ccc(C)c(C)c3N)nc2c1

Procedure:
The title compound was prepared by the method of Example 1 using 207 mg of 2-mercapto-5-methylbenzimidazole instead of 2-mercaptobenzimidazole and 260 mg of 2-(chloromethyl)-5,6-dimethylaniline hydrochloride instead of 2-(chloromethyl)-N,N-dimethylaniline in isopropyl alcohol. The basic extraction used 10% sodium hydroxide instead of sodium carbonate. The dichloromethane extract was dried over sodium sulfate, filtered, and concentrated in vacuo to 274 mg of the title compound as a gum. The compound was used in subsequent reactions without further purification.
Reaction SMILES: [NH2:1][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4].[CH:7](=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[OH-].[Na+].Cl.N(CCO)(CCO)C[CH2:20][OH:21]>C(Cl)(Cl)Cl>[CH3:5][C:2]1([CH3:6])[NH:1][CH:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:20](=[O:21])[O:4][CH2:3]1
Reactant: CC(C)(N)CO
Reactant: O=Cc1ccccc1
Reactant: OCCN(CCO)CCO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: CC1(C)COC(=O)C(c2ccccc2)N1

Procedure:
In a manner analogous to that described in Example 1A hereinbefore, 2-amino-2-methyl-1-propanol, benzaldehyde and chloroform are reacted at ice bath temperature in the presence of a phase transfer catalyst and aqueous NaOH is added dropwise into the reaction vessel while the contents are being stirred. The sodium salt of the compound is recovered with an analogous workup, and warmed with a mineral acid to yield a compound which is a hydrochloride. When the hydrochloride is reacted with triethanolamine, the compound recovered is identified as being 5,5-dimethyl-3-phenyl-2-morpholone.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:4]=1[C:5]#[N:6].[Br:12]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OCC)C.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:12][CH2:11][C:9]1[CH:8]=[CH:7][C:4]([C:5]#[N:6])=[C:3]([O:2][CH3:1])[CH:10]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1cc(C)ccc1C#N
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: CCOCC
Solvent: ClC(Cl)(Cl)Cl
Product: COc1cc(CBr)ccc1C#N
Temperature: 25 °C
Yield: 68.3 %

Procedure:
To a solution of 2-methoxy-4-methylbenzonitrile (0.438 g, 2.98 mmol) in CCl4 (6 mL) was added recrystallized N-bromosuccinimide (0.544 g, 3.05 mmol) followed by benzoyl peroxide (47 mg, 0.19 mmol). The resultant mixture was heated to reflux for 45 minutes then cooled to room temperature. The mixture was diluted with diethyl ether (30 mL), filtered through filter paper, and the filtrate was concentrated. Purification of the crude material by column chromatography (6:1 hexanes-EtOAc) provided 0.46 g (68%) of 4-(bromomethyl)-2-methoxybenzonitrile as a white solid. 1H NMR (CDCl3) δ 3.96 (s, 3H), 4.45 (s, 2H), 6.99 (s, 1H), 7.03 (d, 1H, J=9 Hz), 7.53 (d, 1H, J=9 Hz).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[NH:12][C:13](=[O:26])[N:14]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([CH3:25])([CH3:24])[C:22]#[N:23])=[CH:17][CH:16]=4)[C:5]=3[C:4]=2[CH:3]=1.C(N(CC)CC)C.[Br:34][C:35]1[CH:36]=[C:37]([S:41](Cl)(=[O:43])=[O:42])[CH:38]=[CH:39][CH:40]=1.O>ClCCl>[Br:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([S:41]([C:37]4[CH:38]=[CH:39][CH:40]=[C:35]([Br:34])[CH:36]=4)(=[O:43])=[O:42])[C:13](=[O:26])[N:14]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([CH3:24])([CH3:25])[C:22]#[N:23])=[CH:17][CH:16]=4)[C:5]=3[C:4]=2[CH:3]=1
Reactant: CC(C)(C#N)c1ccc(-n2c(=O)[nH]c3cnc4ccc(Br)cc4c32)cc1
Reactant: O=S(=O)(Cl)c1cccc(Br)c1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C#N)c1ccc(-n2c(=O)n(S(=O)(=O)c3cccc(Br)c3)c3cnc4ccc(Br)cc4c32)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-(4-(8-bromo-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)phenyl)-2-methylpropanenitrile (Intermediate 1, 50 mg, 0.12 mmol) and triethylamine (24.4 mg, 0.24 mmol) in dichloromethane (6 ml) was added 3-bromobenzene-1-sulfonyl chloride (46 mg, 0.18 mmol) at 0° C. The reaction was stirred at RT for 3 hours. The reaction mixture was poured into cold water and organic layer was separated. The aqueous layer was extracted with dichloromethane. The combined organic layer was washed with brine dried over sodium sulfate and evaporated to dryness. The crude product was purified by column chromatography (silica gel, 2% acetone in chloroform) to obtain the title compound. Yield: 40 mg (52%); 1H NMR (DMSO-d6, 300 MHz): δ 9.444 (s, 1H), 8.352 (s, 1H), 8.208-8.234 (d, 1H, J=7.8 Hz), 8.050-8.074 (d, 1H, J=7.2 Hz), 7.985-8.015 (d, 1H, J=9 Hz), 7.821-7.849 (d, 2H, J=8.4 Hz), 7.776-7.7.782 (d, 1H, 1.8 Hz), 7.643-7.714 (m, 3H), 6.753-6.759 (d, 1H, J=2.1 Hz), 1.777 (s, 6H); MS: m/z 625 (M+).
Reaction SMILES: Br[C:2]1[C:3](=[O:17])[CH2:4][CH2:5][C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:9][CH:8]=1.C1C=CC([As](C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C[Sn](C)(C)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][N:40]=1>CN1C(=O)CCC1.CCOC(C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[N:40]1[CH:41]=[CH:42][CH:43]=[CH:44][C:39]=1[C:2]1[C:3](=[O:17])[CH2:4][CH2:5][C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:9][CH:8]=1
Reactant: C[Sn](C)(C)c1ccccn1
Reactant: CS(=O)(=O)c1ccc(C2=C(Br)C(=O)CC2)cc1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: c1ccc([As](c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CS(=O)(=O)c1ccc(C2=C(c3ccccn3)C(=O)CC2)cc1
Temperature: 100 °C
Yield: 19.6 %

Procedure:
To a degassed r.t. solution of 2-bromo-3-(4-(methylsulfonyl)phenyl)-2-cyclopenten-1-one (1.103 g, 3.5 mmol), Pd2 (dba)3 (0.064 g, 0.07 mmol), and AsPh3 (0.171 g, 0.56 mmol) in NMP (7.5 mL) was added a degassed NMP solution (10 mL) of 2-trimethylstannanyl pyridine (~7.0 mmol). The resulting mixture was heated to 100° C. for 16 hours. The mixture was then cooled to r.t., diluted with EtOAc, washed 3 times with 10% NH4OH and brine, dried over MgSO4, and concentrated to dryness. The residue was purified by flash chromatography (5% MeOM/EtOAc) to provide 0.215 g of the title compound.
Reaction SMILES: [H-].[Na+].Cl[CH2:4][O:5][CH2:6][CH2:7][Si:8]([CH3:11])([CH3:10])[CH3:9].[CH:12]1([C:18]([C:20]2[C:21]3[CH:28]=[CH:27][NH:26][C:22]=3[N:23]=[CH:24][N:25]=2)=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.C[SiH](C)C>CN(C)C=O.C1(C(C2C3C=CNC=3N=CN=2)=O)CCCCC1.O>[CH:12]1([C:18]([C:20]2[C:21]3[CH:28]=[CH:27][N:26]([CH2:4][O:5][CH2:6][CH2:7][Si:8]([CH3:11])([CH3:10])[CH3:9])[C:22]=3[N:23]=[CH:24][N:25]=2)=[O:19])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]1
Reactant: O=C(c1ncnc2[nH]ccc12)C1CCCCC1
Reactant: C[Si](C)(C)CCOCCl
Agent: C[SiH](C)C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1ccc2c(C(=O)C3CCCCC3)ncnc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 985.1 %

Procedure:
Cyclohexyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)methanone (50.0 mg, 0.218 mmol) in N,N-dimethylformamide (1 mL) was mixed with sodium hydride (60 wt % dispersion in mineral oil, 9.6 mg, 0.24 mmol) and [2-(chloromethoxy)ethyl]trimethylsilane (42.5 μL, 0.240 mmol) under cooling with ice and stirred for 30 minutes while the temperature was gradually raised to room temperature. Separately, cyclohexyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)methanone (500 mg, 2.18 mmol) in N,N-dimethylformamide (5 mL) was mixed with sodium hydride (60 wt % dispersion in mineral oil, 96 mg, 2.4 mmol) and (chloromethoxy)ethyl]trimethylsilane (425 μL, 2.40 mmol) under cooling with ice and stirred for 30 minutes while the temperature was gradually raised to room temperature. After addition of water, the reaction solution and the previously obtained reaction solution were extracted with ethyl acetate, respectively, and the organic layers were washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residues were combined and purified by silica gel column chromatography (hexane/ethyl acetate=5/1 (v/v)) to give the title compound as a pale yellow oil (850 mg, yield 99%).
Reaction SMILES: C12[NH:7][CH:6]1[CH2:5][CH2:4][CH2:3][CH2:2]2.[CH3:8][NH:9][CH3:10].[CH3:11]CO>[Pd]>[CH3:8][N:9]([CH3:11])[C@@H:10]1[CH2:2][CH2:3][CH2:4][CH2:5][C@H:6]1[NH2:7]
Reactant: C1CCC2NC2C1
Reactant: CCO
Reactant: CNC
Agent: [Pd]
Product: CN(C)[C@@H]1CCCC[C@H]1N
Reaction time: 19 h

Procedure:
A solution of the benzylamino compound is hydrogenated in two batches, each containing 30.5 g. (0.131 mole), 175 ml. EtOH, 3.4 g Pd-C and 56.5 g. (0.394 mole) of 70% HClO4, at initial pressure of 51.5 p.s.i. for 19 hours. The two reduced batches are combined, filtered through Celite, and evaporated in vacuo at 45°. The residue is cooled in ice, basified with 40% KOH to pH 11. The resulting thick suspension is extracted with ether (5 × 200 ml.), the ether extract dried (MgSO4) and evaporated through a 9" Vigreux. The residue is distilled at 13 mm to give 32.5 g. (87% yield), b.p. 77°-78.5°. ir and nmr are identical to those of the sample prepared by the reaction of 7-azabicyclo[4.1.0]heptane with dimethylamine (Procedure I, Part C).
Reaction SMILES: [CH3:1][N:2]1[C:7]2=[CH:8][N:9]([CH2:17][CH2:18][C:19]([O:21]C)=[O:20])[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[C:6]2[C:5](=[O:23])[N:4]([CH3:24])[C:3]1=[O:25].O.[Li+].[OH-]>C1COCC1.CCOC(C)=O>[CH3:1][N:2]1[C:7]2=[CH:8][N:9]([CH2:17][CH2:18][C:19]([OH:21])=[O:20])[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[C:6]2[C:5](=[O:23])[N:4]([CH3:24])[C:3]1=[O:25]
Reactant: COC(=O)CCn1cc2c(c1-c1ccccc1)c(=O)n(C)c(=O)n2C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cn1c(=O)c2c(-c3ccccc3)n(CCC(=O)O)cc2n(C)c1=O
Temperature: 50 °C

Procedure:
A mixture of methyl 3-(1,3-dimethyl-2,4-dioxo-5-phenyl-3,4-dihydro-1H-pyrrolo[3,4-d]pyrimidin-6(2H)-yl)propanoate (step 2) (3.24 g, 9.49 mmol) in THF (33.9 mL)/water (33.9 mL) and LiOH (2.273 g, 95 mmol) was heated to 50° C. for 1 hr. The reaction mixture was diluted with EtOAc (50 ml) and the layers separated. The organics were then washed with water (3×50 ml). The aqueous extracts were combined and the pH adjusted to approx. pH3 with 5M HCl. The resulting precipitate was isolated using suction filtration.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:25]([F:28])([F:27])[F:26])[O:13][N:12]=[C:11]([C:14]3[CH:23]=[CH:22][C:17]([C:18]([NH:20][OH:21])=[NH:19])=[C:16]([CH3:24])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[F:29][C:30]([F:36])([F:35])CC(Cl)=O.O.[CH3:38][CH2:39]OC(C)=O>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:25]([F:26])([F:28])[F:27])[O:13][N:12]=[C:11]([C:14]3[CH:23]=[CH:22][C:17]([C:18]4[N:19]=[C:38]([CH3:39])[O:21][N:20]=4)=[C:16]([CH2:24][C:30]([F:36])([F:35])[F:29])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: O=C(Cl)CC(F)(F)F
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=N)NO
Reactant: CCOC(C)=O
Solvent: c1ccncc1
Solvent: O
Product: Cc1nc(-c2ccc(C3=NOC(c4cc(Cl)cc(Cl)c4)(C(F)(F)F)C3)cc2CC(F)(F)F)no1
Temperature: 140 °C
Yield: 53 %

Procedure:
To a solution of 4-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-N-hydroxy-2-methyl-benzamidine (i.e product of Step 1, Example 8, 400 mg, 0.93 mmol) in pyridine (10 mL) was added 3,3,3-trifluoropropionic acid chloride (0.271 g, 1.85 mmol) via syringe and the mixture was stirred at reflux for 30 min and at 140° C. in a microwave oven for 1 h. Water and EtOAc were added after cooling and the aqueous layer was extracted with EtOAc. Combined organic layers were dried (Na2SO4) and concentrated in vacuum. The residue was purified by flash chromatography on silica gel and yielded the title compound (260 mg, 53%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][C:5](C=C)=[CH:4][N:3]=1.S([O-])([O-])=[O:12].[Na+].[Na+].CCO[C:20]([CH3:22])=[O:21]>O.C(O)(C)(C)C>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([C@H:20]([OH:21])[CH2:22][OH:12])=[CH:6][C:7]=1[F:8]
Reactant: CCOC(C)=O
Reactant: C=Cc1cnc(Cl)c(F)c1
Reactant: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)(C)O
Product: OC[C@@H](O)c1cnc(Cl)c(F)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 89 %

Procedure:
To a solution of 112 (5.00 g, 31.75 mmol) in water (162 mL) and tert-butanol (162 mL) cooled to 0° C. with an ice bath was added AD-mix a (54.6 g, Sigma-Aldrich) to form a reaction mixture. With the bath ice left in place, the reaction mixture was allowed to warm to a temperature of about 25° C. After 16 hrs, excess solid sodium sulfite (60 g) was added and the resulting slurry was allowed to stir at a temperature of about 25° C. for 30 min. The mixture was extracted twice with EtOAc. The organic portions were combined, washed with brine, dried (Na2SO4), and concentrated under reduced pressure. The resulting mixture was chromatographed on a silica gel column eluted with a gradient of from 50:50 EtOAc:hexanes to 100% EtOAc to provide 5.39 g of 113 as a white solid (89% yield). 1H NMR (CDCl3) δ: 2.16 (1H, t, J=5.60 Hz), 2.88 (1H, d, J=3.54 Hz), 3.66 (1H, m), 3.84 (1H, m), 4.91 (1H, m), 7.59 (1H, dd, J=1.61, 8.73 Hz), 8.29 (1H, d, J=1.88 Hz). LC/MS (M+1): m/z=192.