Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C(=CC=CC=2)C=CC=1P(C1C=CC=CC=1)C1C=CC=CC=1.[O:47]1[CH2:52][CH2:51][CH:50]([NH2:53])[CH2:49][CH2:48]1.Cl[C:55]1[C:60]([CH3:61])=[C:59]([C:62]([O:64][CH3:65])=[O:63])[CH:58]=[CH:57][N:56]=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.C(Cl)Cl.O.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:61][C:60]1[C:55]([NH:53][CH:50]2[CH2:51][CH2:52][O:47][CH2:48][CH2:49]2)=[N:56][CH:57]=[CH:58][C:59]=1[C:62]([O:64][CH3:65])=[O:63]
Reactant: COC(=O)c1ccnc(Cl)c1C
Reactant: NC1CCOCC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Solvent: ClCCl
Product: COC(=O)c1ccnc(NC2CCOCC2)c1C
Temperature: 40 °C
Yield: 37.3 %

Procedure:
A nitrogen purged suspension of Pd(OAc)2 (77 mg, 0.34 mmol) and 1,1′-binaphthalene-2,2′-diylbis(diphenylphosphane) (430 mg, 0.69 mmol) in 1,4-dioxane (11 ml) was heated at 40° C. for 1 hour. Oxan-4-amine (237 μl, 2.3 mmol), a solution of methyl 2-chloro-3-methylpyridine-4-carboxylate (213 mg, 1.2 mmol) in degassed dioxane (2 ml) and Cs2CO3 (562 mg, 1.7 mmol) were then added and the red suspension was heated at 100° C. for 6 hours. After cooling to room temperature, the mixture was diluted with CH2Cl2 (30 ml) and water (20 ml). The layers were separated and the aqueous phase was extracted with CH2Cl2 (3×15 ml). The combined organic phases were washed with brine (25 ml), dried (MgSO4), filtered and concentrated in-vacuo. The crude residue was purified by column chromatography (25 g SNAP cartridge, Isolera, 0-28% ethyl acetate:heptanes) followed by prep-HPLC (MeCN/Water) to give the title compound (112 mg, 39%) as a white crystalline solid. LC-MS 100%, m/z=251.0; 1H NMR (500 MHz, MeOD) δ ppm 7.91 (d, J=5.20 Hz, 1H) 6.77 (d, J=5.36 Hz, 1H) 4.07-4.17 (m, 1H) 3.98 (dd, J=12.06, 1.81 Hz, 2H) 3.88 (s, 3H) 3.55 (td, J=11.78, 1.66 Hz, 2H) 2.22 (s, 3H) 1.97 (dd, J=12.69, 1.97 Hz, 2H) 1.62 (qd, J=12.03, 4.41 Hz, 2H). NH not observed.
Reaction SMILES: [CH2:1]([NH2:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].ClCCl.[CH3:11][O:12][C:13]([C:15]1[C@H:16]2[CH2:33][C@@H:32]3[O:34][C@:31]3([CH3:35])[C@@H:17]2[C@H:18]([O:21][C:22](OC2C=CC=CC=2)=[O:23])[O:19][CH:20]=1)=[O:14]>CCCCCC.C(OCC)(=O)C>[CH3:11][O:12][C:13]([C:15]1[C@H:16]2[CH2:33][C@@H:32]3[O:34][C@:31]3([CH3:35])[C@@H:17]2[C@H:18]([O:21][C:22](=[O:23])[NH:7][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[O:19][CH:20]=1)=[O:14]
Reactant: COC(=O)C1=CO[C@@H](OC(=O)Oc2ccccc2)[C@@H]2[C@@H]1C[C@@H]1O[C@]21C
Reactant: CCCCCCN
Solvent: ClCCl
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCCCCCNC(=O)O[C@@H]1OC=C(C(=O)OC)[C@H]2C[C@@H]3O[C@]3(C)[C@H]12
Temperature: 25 °C
Reaction time: 1 h
Yield: 35 %

Procedure:
0.11 ml of n-hexylamine were added to a dichloromethane solution containing 246 mg of (1S,4aS,6S,7R,7aR)-6,7-epoxy-1,4a,5,6,7,7a-hexahydro-7-methyl-1-(phenoxycarbonyloxy) cyclopenta [c] pyrane-4-carboxylic acid methylester described in Example 10 followed by stirring for 1 hour at room temperature. The reaction mixture was then extracted with dichloromethane. After washing the organic phase with brine, it was dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel chromatography to obtain a colorless powder from the hexane-ethyl acetate eluate in the form of (1S,4aS,6S,7R,7aR)-6,7-epoxy-1-(n-hexylcarbamoyloxy)-1,4a,5,6,7,7a-hexahydro-7-methylcyclopenta [c] pyrane-4-carboxylic acid methylester (87 mg, yield: 35%). The physicochemical properties of this compound are described in Table 7, Compound No. 33.
Reaction SMILES: [NH2:1][CH:2]([C:6]1[N:15]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:14](=[O:23])[C:13]2[C:8](=[N:9][CH:10]=[CH:11][N:12]=2)[N:7]=1)[CH:3]([CH3:5])[CH3:4].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[C:38]([O:42][C:43](=[O:49])[NH:44][CH2:45][CH2:46][CH:47]=O)([CH3:41])([CH3:40])[CH3:39]>ClCCl>[C:38]([O:42][C:43](=[O:49])[NH:44][CH2:45][CH2:46][CH2:47][NH:1][CH:2]([C:6]1[N:15]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:14](=[O:23])[C:13]2[C:8](=[N:9][CH:10]=[CH:11][N:12]=2)[N:7]=1)[CH:3]([CH3:5])[CH3:4])([CH3:41])([CH3:40])[CH3:39]
Reactant: CC(C)C(N)c1nc2nccnc2c(=O)n1Cc1ccccc1
Reactant: CC(C)(C)OC(=O)NCCC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)C(NCCCNC(=O)OC(C)(C)C)c1nc2nccnc2c(=O)n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 97.8 %

Procedure:
Formula 108 where R2 and R3 are H; R5 is Benzyl; R6 is Isopropyl; R6′ is H; R7 is 3-Boc-amino-propyl-; X and Y are —C═ and W and Z are —N═: To a solution of dichloromethane (100 mL), 2-(1-amino-2-methyl-propyl)-3-benzyl-3H-pteridin-4-one (780 mg, 2.52 mmol) and Na(OAc)3BH (1.07 g, 5.04 mmol) was added t-butyl-N-(3-oxopropyl)-carbamate (611 mg, 3.53 mmol) at room temperature. The reaction mixture was stirred at room temperature for 3 hours, diluted with 100 mL of dichloromethane, washed with saturated sodium bicarbonate, water and brine, and dried over sodium sulfate. Concentration of the organic phase yielded the desired Boc amino product of Formula 108, {3-[1-(3-benzyl-4-oxo-3,4-dihydro-pteridin-2-yl)-2-methyl-propylamino]-propyl}-carbamic acid tert-butyl ester (1.15 g, 98%). MS (Cl) M/E: 467.3.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)[N:12]=[C:11]([C:20]([N:22]3[CH2:26][CH2:25][S:24][CH2:23]3)=[O:21])[CH:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.ClC1C=CC=C(C(OO)=[O:35])C=1>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)[N:12]=[C:11]([C:20]([N:22]3[CH2:26][CH2:25][S:24](=[O:35])[CH2:23]3)=[O:21])[CH:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=C(c1cc(-c2cc(F)cc(Cl)c2)n(-c2cccnc2)n1)N1CCSC1
Solvent: ClCCl
Product: O=C(c1cc(-c2cc(F)cc(Cl)c2)n(-c2cccnc2)n1)N1CCS(=O)C1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
100 mg (0.26 mmol) of the compound of Example 5 is dissolved in 5 ml of dichloromethane, mixed with 63 mg (0.26 mmol, 70% purity) of meta-chloroperbenzoic acid, and stirred for 4 hours at room temperature. The reaction mixture is separated by means of preparative HPLC (mobile solvent: acetonitrile/water gradient). 97 mg (93% of theory) of the title compound is obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:26][CH2:25][N:11]2[C:12](=[O:24])[C:13]3[C:18]([C@@H:10]2[CH2:9]1)=[CH:17][C:16](Br)=[CH:15][C:14]=3[C:20]([F:23])([F:22])[F:21])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:27](/B(O)O)=[CH:28]/[CH3:29].C(=O)([O-])[O-].[K+].[K+].O>COCCOC.[Cl-].[Na+].O>[C:1]([O:5][C:6]([N:8]1[CH2:26][CH2:25][N:11]2[C:12](=[O:24])[C:13]3[C:18]([C@@H:10]2[CH2:9]1)=[CH:17][C:16](/[CH:27]=[CH:28]\[CH3:29])=[CH:15][C:14]=3[C:20]([F:23])([F:22])[F:21])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C/C=C\B(O)O
Reactant: CC(C)(C)OC(=O)N1CCN2C(=O)c3c(cc(Br)cc3C(F)(F)F)[C@@H]2C1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: C/C=C\c1cc2c(c(C(F)(F)F)c1)C(=O)N1CCN(C(=O)OC(C)(C)C)C[C@@H]21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 88.3 %

Procedure:
To a stirring degassed solution of N-(t-butoxycarbonyl)-(R)-1,3,4,10b-tetrahydro-9-bromo-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-one (54 mg, 0.12 mmol) in DME (1.2 μL) was added tertrakis(triphenylphosphine)palladium(0) (1.7 mg, 0.0015 mmol). After 15 min., cis-1-propenylboronic acid (31 mg, 0.37 mmol), potassium carbonate (17 mg, 0.12 mmol), and water (0.3 mL) were added. The reaction was heated to reflux for 3 h and then cooled to room temp. The reaction was diluted with brine and extracted with EtOAc (3×5 mL). The organic layers were combined, dried over Na2SO4, and conc. in vacuo to a yellow oil. The oil was purified by flash chromatography (silica gel, 0–50% EtOAc in hexanes) to give 42 mg of the desired product as a colorless oil. MS (ESI) 397 (M+H).
Reaction SMILES: N[C@H]1C2C(=CC=CC=2)C[C@H]1O.[Br:12][CH2:13][C:14]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[C:18]([N+:30]([O-:32])=[O:31])[CH:17]=1)=[O:15]>C1COCC1>[N+:30]([C:18]1[CH:17]=[C:16]([C@H:14]([OH:15])[CH2:13][Br:12])[CH:21]=[CH:20][C:19]=1[O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([O-:32])=[O:31]
Reactant: O=C(CBr)c1ccc(OCc2ccccc2)c([N+](=O)[O-])c1
Agent: N[C@H]1c2ccccc2C[C@H]1O
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cc([C@H](O)CBr)ccc1OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 94 %

Procedure:
A cold (5° C.) solution of (1S,2R)-1-amino-2-indanol (400 mg, 2.68 mmol) in THF (160 mL) was added dropwise to a cold (0° C.) solution of borane-diethylaniline complex (7.0 g, 43 mmol) in THF (20 mL). After complete addition, the resulting solution was stirred at (0° C.) for 30 min then 2-bromo-4′-benzyloxy-3′-nitroacetophenone (20.0 g, 57.1 mmol) was added in three portions over a 30 min period. The resulting solution was stirred at <5° C. for 1 h, quenched by dropwise addition of acetone (17 mL) then allowed to warm to ambient temperature overnight. The reaction mixture was concentrated in vacuo to a residue, which was dissolved in toluene (100 mL) and washed in succession with 10% H2SO4 (2×45 mL), H2O (2×45 mL) and sat. brine (1×40 mL). The organic layer was dried over MgSO4, clarified then concentrated in vacuo to a volume of ˜40 mL. Heptane (45 mL) was slowly added to give a thick slurry. The solid was collected on a filter and washed with heptane (2×5 mL). This material was dissolved in warm toluene (−50 mL), the solution was clarified then diluted with heptane (50 mL). The resulting mixture was stirred for 30 min, the solids were collected, washed with heptane (2×5 mL) then dried to constant weight in vacuo to give 18.9 g (94.0%) of the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[OH:11].C(=O)([O-])[O-].[Na+].[Na+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CC(C)=O>[CH2:18]([O:11][C:3]1[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[CH3:1])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: BrCc1ccccc1
Reactant: Cc1ccc([N+](=O)[O-])cc1O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Product: Cc1ccc([N+](=O)[O-])cc1OCc1ccccc1
Yield: 33.5 %

Procedure:
To a stirred suspension of 2-methyl-5-nitrophenol (2.0 g, 13 mmol) and sodium carbonate (1.94 g, 18.3 mmol) in acetone was added benzyl bromide (1.7 mL, 14 mmol). The mixture was heated to reflux for 24 h, cooled, filtered, and the solid washed with acetone. The filtrate and acetone washings were combined and concentrated in vacuo. Recrystallization from ether/hexanes gave 1.06 g (33%) of the title product as an off-white solid. MS-FD 243 m/e (M+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].C(=O)([O-])[O-].[K+].[K+].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Oc1ccccc1Br
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Brc1ccccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.5 %

Procedure:
To a mixture of 7.45 g (43.1 mmol, Aldrich) of 2-bromophenol, and 6.9 g (50 mmol) of anhydrous potassium carbonate in 25 mL dimethylformamide (DMF) (Burdick and Jackson) heated to 80° was added dropwise 7.37 g (43.1 mmol, Aldrich) of benzyl bromide over 10 minutes. The reaction mixture was stirred at 80° for 1 hour then cooled to room temperature, added to 100 mL of water and extracted with two 50 mL portions of 1:5 ethyl ether/hexane. The organic extracts were combined, washed with 50 mL of 1M aqueous NaOH solution, 50 mL of water, dried (magnesium sulfate) and concentrated in vacuo to afford 10.6 g (40.3 mmol, 94%) of title compound as a colorless liquid.
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[C:3]=1[C:4]([N:6]=[C:7]=[O:8])=[O:5].[F:14][C:15]1[C:21]([Cl:22])=[C:20]([F:23])[C:19]([Br:24])=[CH:18][C:16]=1[NH2:17]>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[C:3]=1[C:4]([NH:6][C:7]([NH:17][C:16]1[CH:18]=[C:19]([Br:24])[C:20]([F:23])=[C:21]([Cl:22])[C:15]=1[F:14])=[O:8])=[O:5]
Reactant: O=C=NC(=O)c1c(F)cccc1F
Reactant: Nc1cc(Br)c(F)c(Cl)c1F
Solvent: Cc1ccccc1
Product: O=C(NC(=O)c1c(F)cccc1F)Nc1cc(Br)c(F)c(Cl)c1F
Reaction time: 5 h

Procedure:
3.75 g of 2,6-difluorobenzoyl isocyanate are added dropwise at room temperature, with stirring, to 5 g of 2,4-difluoro-3-chloro-5-bromoaniline dissolved in 50 ml of dry toluene, and the mixture is stirred for a further 5 hours. Approximately 75% of the solvent is then removed in a rotary evaporator. The residue is diluted with hexane and the resulting precipitate is filtered off with suction, washed with hexane and dried in vacuo. The title compound of formula ##STR14## is obtained in the form of colourless crystals; m.p. 225°-227° C.
Reaction SMILES: ClC(Cl)(Cl)C[O:4][C:5]([NH:7][C:8]1[N:12]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[N:11]=[C:10]([C:20]([CH3:23])([CH3:22])[CH3:21])[CH:9]=1)=O.[NH2:26][C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:30]([CH:37]=[CH:38][C:39]2[CH:44]=[CH:43][N:42]=[CH:41][CH:40]=2)=[CH:29][CH:28]=1.C(N(C(C)C)CC)(C)C.CS(C)=O>C(OCC)(=O)C>[C:20]([C:10]1[CH:9]=[C:8]([NH:7][C:5]([NH:26][C:27]2[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:30]([CH:37]=[CH:38][C:39]3[CH:40]=[CH:41][N:42]=[CH:43][CH:44]=3)=[CH:29][CH:28]=2)=[O:4])[N:12]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[N:11]=1)([CH3:23])([CH3:21])[CH3:22]
Reactant: Nc1ccc(C=Cc2ccncc2)c2ccccc12
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)OCC(Cl)(Cl)Cl)cc1
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(C=Cc3ccncc3)c3ccccc23)cc1
Reaction time: 5 h

Procedure:
A solution of 5-(2,2,2-trichloroethoxycarbonyl)amino-3-t-butyl-1-p-tolyipyrazole (26 mmol), 1-amino-4-(2-pyridin-4-yl-ethenyl)naphthalene (26 mmol), diisopropylethylamine (3.2 g, 25 mmol) and DMSO (75 mL) is heated to 55-90° C. and held for 2-8 h. To this solution, ethyl acetate (100 mL) is added. The organic layer is washed with brine (4×50 mL), and dried over MgSO4. The solvent is removed under reduced pressure, and residue is crystallized from a suitable solvent such as acetonitrile (50 mL) at 0° C. The product is collected by filtration and recrystallized from a suitable solvent such as isopropanol and dried in vacuum to constant weight.
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[CH:21][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13]CC3C=CC=CC=3)[CH:8]=2)=[C:4]([F:23])[CH:3]=1.[H][H]>C(O)=O.CO.[OH-].[OH-].[Pd+2]>[NH2:1][C:2]1[CH:22]=[CH:21][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH2:13])[CH:8]=2)=[C:4]([F:23])[CH:3]=1
Reactant: [H][H]
Reactant: Nc1ccc(Oc2ccnc(NCc3ccccc3)c2)c(F)c1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: O=CO
Product: Nc1ccc(Oc2ccnc(N)c2)c(F)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 26 %

Procedure:
Palladium hydroxide on carbon (10%, 0.050 g) was added to a solution of 4-(4-amino-2-fluorophenoxy)-N-benzylpyridin-2-amine (0.245 g, 0.790 mmol, 1.0 eq) in 5% HCO2H-MeOH (10 mL) under a blanket of hydrogen (from a balloon) at room temperature. The reaction mixture was stirred at room temperature for 12 h, filtered through Celite® and the filtrate concentrated in vacuo. The residue was purified by reverse phase preparative HPLC (YMC ODS-A S10 30×500 mm., 10-90% aqueous MeOH with 0.1% TFA, 30 minute gradient) and the appropriate fractions were concentrated in vacuo. The concentrate was neutralized with saturated aqueous NaHCO3 solution and the mixture was extracted with CHCl3 (3×35 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated in vacuo to afford the title compound (0.045 g, 26%) as a solid. 1H NMR (CD3OD) δ 7.62-7.63 (m, 1H), 6.77-6.82 (m, 1H), 6.38-6.47 (m, 2H), 6.09-6.11 (m, 1H), 5.83-5.84 (m, 1H); MS(ESI+) m/z 220 (M+H)+; HRMS(ESI+) calcd.: 220.0886, found: 220.0877.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][CH2:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=[CH:10][CH:9]=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:1][S:2]([O:6][CH2:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=[CH:10][CH:9]=1)(=[O:4])=[O:3]
Reactant: OCc1ccnc2ccccc12
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCc1ccnc2ccccc12

Procedure:
A solution of methanesulfonyl chloride (4.84 ml) in 20 ml of methylene chloride is slowly added over 20 minutes to a solution of 8.29 g of 4-hydroxymethylquinoline and 11 ml of triethylamine in 200 ml of methylene chloride at 0°. After completion of the reaction at room temperature, the reaction mixture is partitioned between methylene chloride and saturated potassium carbonate solution. The organic layer is dried over sodium sulfate and evaporated to dryness to yield 4-(methanesulfonyloxymethyl)quinoline as an oil.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([C:20]3[C:21]([CH3:26])=[N:22][O:23][C:24]=3[CH3:25])([C:14]3[N:18]([CH3:19])[N:17]=[N:16][CH:15]=3)[OH:13])[CH:10]=2)[N:5]=[C:4]([O:27][CH3:28])[C:3]=1[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C[C:75]([N:77](C)C)=O>[C-]#N.[Zn+2].[C-]#N.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].[Zn]>[CH3:26][C:21]1[C:20]([C:12]([OH:13])([C:14]2[N:18]([CH3:19])[N:17]=[N:16][CH:15]=2)[C:9]2[CH:10]=[C:11]3[C:6](=[CH:7][CH:8]=2)[N:5]=[C:4]([O:27][CH3:28])[C:3]([CH2:29][C:30]2[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=2)=[C:2]3[C:75]#[N:77])=[C:24]([CH3:25])[O:23][N:22]=1
Reactant: CC(=O)N(C)C
Reactant: COc1nc2ccc(C(O)(c3c(C)noc3C)c3cnnn3C)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: COc1nc2ccc(C(O)(c3c(C)noc3C)c3cnnn3C)cc2c(C#N)c1Cc1ccc(C(F)(F)F)cc1
Temperature: 125 °C
Reaction time: 1 h

Procedure:
(4-Chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinolin-6-yl)(3,5-dimethylisoxazol-4-yl)(1-methyl-1H-1,2,3-triazol-5-yl)methanol (180 mg, 0.32 mmol, Example 93), zinc cyanide (77 mg, 0.66 mol), X-phos (45 mg, 0.94 mmol), Pd2(dba)3 (50 mg, 0.055 mmol) and zinc metal (3 mg, 0.19 mmol) were added to a large microwave vial. DMA (4 mL, sparged with argon for 35 minutes) was added and the vial was sealed and evacuated. The mixture was heated to 125° C. in a preheated aluminum heating mantle. After 1 hour, the mixture was allowed to cool to room temperature and then was filtered through a Celite® pad and rinsed with EtOAc-MeOH (10:1). The effluent was concentrated under reduced pressure and the crude material was chromatographed directly on silica gel (20% EtOAc-hexanes increasing to 50% EtOAc) to provide the title compound as an off white solid. 1H NMR (500 MHz, CDCl3) δ 8.17 (d, J=2.1 Hz, 1H), 7.87 (d, J=8.8 Hz, 1H), 7.53 (d, J=8.2 Hz, 2H), 7.46 (d, J=8.2 Hz, 2H), 7.40 (dd, J=8.8, 2.2 Hz, 1H), 6.92 (s, 1H), 5.38 (s, 1H), 4.43-4.29 (m, 2H), 4.12 (s, 3H), 4.01 (s, 3H), 1.95 (s, 3H), 1.82 (s, 3H); MS (ESI): mass calc. for Chemical Formula: C28H23F3N6O3; Exact Mass: 548.2. m/z found 549.0 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:16]3[C:11](=[C:12]([CH:17]=[C:18]4[S:22][C:21](=[S:23])[NH:20][C:19]4=[O:24])[CH:13]=[CH:14][CH:15]=3)[CH2:10][CH2:9][C:8]2=[O:25])=[CH:4][CH:3]=1.[OH-].[Na+].CC(=NO)C(C)=NO.[BH4-].[Na+].S([O-])(O)(=O)=O.[K+]>CN(C=O)C.C1COCC1.O.CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:16]3[C:11](=[C:12]([CH2:17][CH:18]4[S:22][C:21](=[S:23])[NH:20][C:19]4=[O:24])[CH:13]=[CH:14][CH:15]=3)[CH2:10][CH2:9][C:8]2=[O:25])=[CH:26][CH:27]=1
Reactant: O=C1NC(=S)SC1=Cc1cccc2c1CCC(=O)N2Cc1ccc(Br)cc1
Agent: CC(=NO)C(C)=NO
Agent: O=S(=O)([O-])O
Agent: [BH4-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C1NC(=S)SC1Cc1cccc2c1CCC(=O)N2Cc1ccc(Br)cc1
Reaction time: 0.5 h
Yield: 89 %

Procedure:
50 mg of 1-(4-bromobenzyl)-5-(4-oxo-2-thioxothiazolidine-5-ylidenemethyl)-3,4-dihydro-1H-quinolin-2-one was suspended in a mixed solvent of 0.15 ml of methanol, 0.1 ml of water, 0.08 ml of an aqueous 1 N-sodium hydroxide solution, and 0.1 ml of THF. 0.03 ml of a DMF (5 ml) solution of 42 mg of cobalt chloride 6-hydrate and 250 mg of dimethylglyoxime was further added to the suspension, and the mixture was heated to 30° C. to 40° C. An aqueous solution (0.1 ml) of 15 mg of sodium borohydride was added, followed by stirring for 30 minutes. A saturated aqueous potassium hydrogensulfate solution was added, the mixture was extracted with ethyl acetate, and the extract was washed with water. The extract was dried over anhydrous magnesium sulfate and concentrated. The residue was purified by preparative silica gel thin layer chromatography (ethyl acetate:n-hexane=1:1) to give 44.7 mg (89% yield) of 1-(4-bromobenzyl)-5-(4-oxo-2-thioxothiazolidin-5-ylmethyl)-3,4-dihydro-1H-quinolin-2-one as a colorless amorphous solid, and further recrystallized from ethyl acetate-diethyl ether, giving a white powder.
Reaction SMILES: [NH2:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][NH:7][S:8]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])(=[O:10])=[O:9])=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:27]1([O:33][C:34](Cl)=[O:35])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>O1CCCC1.C(#N)C>[C:27]1([O:33][C:34](=[O:35])[NH:1][C:2]2[CH:20]=[CH:19][C:5]([CH2:6][NH:7][S:8](=[O:10])(=[O:9])[NH:11][C:12]([O:13][C:14]([CH3:16])([CH3:17])[CH3:15])=[O:18])=[CH:4][CH:3]=2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CC(C)(C)OC(=O)NS(=O)(=O)NCc1ccc(N)cc1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: CC#N
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NS(=O)(=O)NCc1ccc(NC(=O)Oc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 49.1 %

Procedure:
tert-Butyl N-(4-aminobenzyl)sulfamoylcarbamate (86 mg, 0.285 mmol) was dissolved in a tetrahydrofuran/acetonitrile (1:1 mixture). Pyridine (0.03 mL, 0.342 mmol) was added, followed by addition of phenylchloroformate (0.04 mL, 0.3 mmol) at 0° C. The mixture was stirred at 0° C. for 30 min and further 30 min at room temperature. The reaction mixture was extracted with ethyl acetate and washed with brine. Drying over magnesium sulfate, evaporation of the ethyl acetate and purification by column chromatography gave the N-[4-[[(tert-butoxycarbonyl-sulfamoyl)amino]methyl]-phenyl]-carbamic acid phenyl ester (59 mg, 49%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21]Cl)[CH:16]=1.[CH2:24]([NH2:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[I-].[Na+]>C1COCC1>[CH2:24]([NH:31][CH2:21][C:17]1[CH:16]=[C:15]([CH:20]=[CH:19][CH:18]=1)[C:14]([NH:13][CH2:12][CH2:11][C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([Cl:1])[CH:3]=2)[NH:7][CH:6]=1)=[O:23])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1cccc(CCl)c1
Reactant: NCc1ccccc1
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1cccc(CNCc2ccccc2)c1
Yield: 58.2 %

Procedure:
3-((Benzylamino)methyl)-N-(2-(5-chloro-1H-indol-3-yl)ethyl)benzamide was prepared following Method C starting from N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3-(chloromethyl)benzamide (0.050 g; 0.144 mmol), benzylamine (0.055 mL; 0.5 mmol), and sodium iodide (0.015 g; 0.1 mmol) in THF (3 mL), under a microwave irradiation at 150° C. for 5 minutes. Flash chromatography on silica gel (eluent 2 to 10% methanol in dichloromethane) furnished 0.035 g (58%) of the title compound as a white solid.