Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:9]([O:10][CH3:11])=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[O:12][CH3:13].[CH3:14][Mg]Br.[Cl-].[NH4+]>O1CCCC1.C(OCC)C>[Cl:1][C:2]1[C:9]([O:10][CH3:11])=[CH:8][C:5]([CH:6]([OH:7])[CH3:14])=[CH:4][C:3]=1[O:12][CH3:13]
Reactant: COc1cc(C=O)cc(OC)c1Cl
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1cc(C(C)O)cc(OC)c1Cl
Reaction time: 1 h

Procedure:
To a solution of 4-chloro-3,5-dimethoxybenzaldehyde (1.0 g) in tetrahydrofuran (20 mL) was added dropwise a 3M solution of methylmagnesium bromide in diethyl ether (1.83 mL) under ice-cooling, and the mixture was stirred at the same temperature for 1 hour. Then, thereto was added aqueous ammonium chloride solution under ice-cooling, and the mixture was extracted with ethyl acetate. The organic layer was sequentially washed with water and saturated saline, and then dried over magnesium sulfate and concentrated under reduced pressure to give a crude product of 1-(4-chloro-3,5-dimethoxyphenyl)ethanol [REx(22-2)] (1.23 g) as a colorless powder.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([C:23](OC)=[O:24])=[C:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:8]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[CH2:10][C:9]=12)=O.[H-].[H-].[H-].[H-].[Li+].[Al+3].[H-].[OH-].[Na+]>ClCCl.CCOCC.O>[OH:24][CH2:23][C:6]1[C:5]([CH2:3][OH:2])=[C:9]2[CH2:10][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=3[N:8]2[C:7]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COC(=O)c1c(C(=O)OC)c(-c2ccccc2)n2c1Cc1ccccc1-2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: ClCCl
Solvent: O
Solvent: CCOCC
Product: OCc1c(CO)c(-c2ccccc2)n2c1Cc1ccccc1-2
Reaction time: 0.25 h

Procedure:
A solution of 3-phenyl-8H-3a-aza-cyclopenta[a]indene-1,2-dicarboxylic acid dimethyl ester (2.08 g, 6 mmol) in anhydrous dichloromethane (35 mL) was added dropwise to a stirred suspension of LiAlH4 (0.568 g, 15 mmol) in anhydrous ether (50 mL) at 0° C. The mixture was stirred for 15 min after the addition was completed. The excess hydride was carefully decomposed by the slow, sequential addition of water (2 mL), 15% NaOH aqueous solution (2 mL), and water (4 mL). The solid inorganic salt was filtered and washed with dichloromethane. The combined filtrate and washings was concentrated in vacuo to dryness. The residue was triturated with ether, the solid product was collected by filtration, and dried to yield (2-hydroxymethyl-3-phenyl-8H-3a-azacyclopenta[a]inden-1-yl)methanol (DA-1011), 1.24 g (71%): mp 169-171° C.; 1H NMR (DMSO-d6) δ3.93 (2H, s, CH2), 4.27 and 4.55 (each 2H, d, J=4.8 Hz, 2×CH2), 4.68 and 4.80 (each 1H, t, J=4.8 Hz, exchangeable, 2×OH), 6.73-6.74 (1H, m, ArH), 7.03-7.05 (1H, m, ArH), 7.09-7.12 (1H, m, ArH), 7.44-7.55 (6H, m, 6×ArH). Anal. Calcd. for C19H17NO2.0.3H2O: C, 76.90; H, 5.98; N, 4.72. Found: C, 76.89; H, 6.02; N, 4.56.
Reaction SMILES: [CH3:1][C:2]1([CH3:30])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH:12]([CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])/[CH:13]=[CH:14]/[C:15]3[CH:24]=[CH:23][C:18]([C:19]([O:21]C)=[O:20])=[CH:17][CH:16]=3)[CH:10]=2)[S:5][CH2:4][CH2:3]1.O.[OH-].[Li+]>C1COCC1.O.CCOCC>[CH3:1][C:2]1([CH3:30])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH:12]([CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])/[CH:13]=[CH:14]/[C:15]3[CH:16]=[CH:17][C:18]([C:19]([OH:21])=[O:20])=[CH:23][CH:24]=3)[CH:10]=2)[S:5][CH2:4][CH2:3]1
Reactant: CCCCCC(/C=C/c1ccc(C(=O)OC)cc1)c1ccc2c(c1)C(C)(C)CCS2
Agent: [Li+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: CCCCCC(/C=C/c1ccc(C(=O)O)cc1)c1ccc2c(c1)C(C)(C)CCS2
Temperature: 25 °C
Reaction time: 4 h
Yield: 95.7 %

Procedure:
200 mg of (RS)-(E)-methyl 4-[3-(4,4-dimethyl-thiochroman-6-yl)-oct-1-enyl]-benzoate were dissolved in 10 ml THF/3 ml water/3 ml methanol and 200 mg of lithium hydroxide hydrate were added. The mixture was stirred at room temperature 4 hours. The mixture was diluted with 10 ml water and acidified to pH 2 with 1N hydrochloric. The resulting suspension was taken in 50 ml ether and the phases were separated. The aqueous phase was extracted with three portions of 25 ml ether. The combined extracts were dried over MgSO4. The solvent was removed in vacuo and the crude product was purified by flash chromatography (SiO2, 10% methanol/methylene chloride) followed by recrystalization from hexanes, yielding 185 mg of product as white solid. M.p. 146-146.5° C.
Reaction SMILES: [CH3:1]OCOC.[ClH:6].Cl.Cl.[CH3:9][O:10][C:11]1[CH:35]=[CH:34][C:14]([CH2:15][CH2:16][NH:17][C:18]([NH:20][C:21]([NH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[NH:22])=[NH:19])=[CH:13][CH:12]=1>C(O)CCC>[ClH:6].[CH2:24]([NH:23][C:21]1[NH:20][C:18]([NH:17][CH2:16][CH2:15][C:14]2[CH:13]=[CH:12][C:11]([O:10][CH3:9])=[CH:35][CH:34]=2)=[N:19][CH2:1][N:22]=1)[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: COCOC
Reactant: CCCCCCCCCCNC(=N)NC(=N)NCCc1ccc(OC)cc1
Agent: Cl
Solvent: CCCCO
Product: CCCCCCCCCCNC1=NCN=C(NCCc2ccc(OC)cc2)N1

Procedure:
200 ml of n-butanol, 6 ml (67.8 mmol) of methylal and 0.7 ml of concentrated hydrochloric acid were added to 2.5 g (5.6 mmol) of N1-(4-methoxyphenethyl)-N5-decyl-biguanide dihydrochloride, and the mixture was refluxed for 68 hours. The solvent was distilled of f under reduced pressure, and dissolved in 80% aqueous acetonitrile. The solvent was distilled off under reduced pressure to give a residue, which was purified by silica gel column chromatography (elution with a mixture of chloroform/methanol/acetic acid (8:0.7:0.7)) to obtain 0.7 g of a colorless resinous solid.
Reaction SMILES: C([BH-](C(CC)C)C(CC)C)(CC)C.[Li+].[C:15]([O:19][C:20]([NH:22][C@@:23]1([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:28][C:27](=[O:29])[C@@H:26]2[C@H:24]1[C@H:25]2[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[O:21])([CH3:18])([CH3:17])[CH3:16].C([O-])([O-])=O.[Na+].[Na+].OO>O1CCCC1.O>[C:15]([O:19][C:20]([NH:22][C@@:23]1([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:28][C@H:27]([OH:29])[C@@H:26]2[C@H:24]1[C@H:25]2[C:30]([O:32][C:33]([CH3:35])([CH3:34])[CH3:36])=[O:31])=[O:21])([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)(C)OC(=O)N[C@@]1(C(=O)OC(C)(C)C)CC(=O)[C@H]2[C@H](C(=O)OC(C)(C)C)[C@H]21
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: O=C([O-])[O-]
Agent: OO
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@]1(C(=O)OC(C)(C)C)C[C@H](O)[C@H]2[C@H](C(=O)OC(C)(C)C)[C@H]21
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.1 %

Procedure:
Add 1M lithium tri(sec-butyl)borohydride in tetrahydrofuran (2.67 L, 2.67 mol) dropwise to a solution of di-tert-butyl(1S,2S,5R,6R)-2-[(tert-butoxycarbonyl)amino]-4-oxobicyclo[3.1.0]hexane-2,6-dicarboxylate (1000 g, 2.43 mol) in dry tetrahydrofuran (10 L) at 0° C. under nitrogen. After 2 hours at 0° C., 2M Na2CO3 in water (850 g, 8.02 mol) is added at 0° C. over 2 hours followed by 35% aqueous hydrogen peroxide (740 mL, 8.99 mol) in water (3.3 L). After 40 minutes, the mixture is warmed to ambient temperature whereupon the organic phase is separated. The organic phase is diluted with methyl tert-butyl ether (3.5 L) and the layers are separated again. The aqueous phase is extracted with methyl tert-butyl ether (3.5 L). All the combined organic phases are washed successively with 1M aqueous Na2SO3 (2.67 L), water (2.67 L), and brine (2.67 L), dried over sodium sulfate, filtered and concentrated to a volume of 3 L. The precipitated solid is filtered and washed with heptane (1.3 L) to obtain the title compound (864.76 g). The mother liquors are concentrated to dryness and the residue is triturated with heptane (500 mL) and filtered to obtain additional title compound (130.64 g, total 995.4 g, yield 99%). MS (m/z): 436 (M+23).
Reaction SMILES: C[OH:2].O.[F:4][C:5]1[C:10]([O:11][CH2:12][CH2:13][O:14][CH3:15])=[CH:9][C:8]([O:16][CH3:17])=[CH:7][C:6]=1[CH:18]([NH:34][C:35]1[CH:40]=[CH:39][C:38]([C:41]2[N:45]=[C:44]([C:46](F)(F)F)[O:43][N:42]=2)=[CH:37][CH:36]=1)[C:19]1[NH:20][C:21](=[O:33])[N:22]([C:24]2[C:29]([N+:30]([O-])=O)=[CH:28][CH:27]=[CH:26][N:25]=2)[N:23]=1>[Fe].C(O)(=O)C>[C:44]([OH:2])(=[O:43])[CH3:46].[NH2:30][C:29]1[C:24]([N:22]2[C:21](=[O:33])[NH:20][C:19]([CH:18]([NH:34][C:35]3[CH:36]=[CH:37][C:38]([C:41]([NH2:45])=[NH:42])=[CH:39][CH:40]=3)[C:6]3[CH:7]=[C:8]([O:16][CH3:17])[CH:9]=[C:10]([O:11][CH2:12][CH2:13][O:14][CH3:15])[C:5]=3[F:4])=[N:23]2)=[N:25][CH:26]=[CH:27][CH:28]=1
Reactant: CO
Reactant: COCCOc1cc(OC)cc(C(Nc2ccc(-c3noc(C(F)(F)F)n3)cc2)c2nn(-c3ncccc3[N+](=O)[O-])c(=O)[nH]2)c1F
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Product: COCCOc1cc(OC)cc(C(Nc2ccc(C(=N)N)cc2)c2nn(-c3ncccc3N)c(=O)[nH]2)c1F
Temperature: 65 °C
Reaction time: 24 h

Procedure:
Iron powder (55 mg) was added to 4.5 ml of a methanol:water:acetic acid=1:1:1 mixed solvent solution containing 38 mg of 5-{[2-fluoro-5-methoxy-3-(2-methoxyethoxy)phenyl]-[4-(5-trifluoromethyl-[1,2,4]oxadiazol-3-yl)phenylamino]methyl}-2-(3-nitropyridin-2-yl)-2,4-dihydro-[1,2,4]triazol-3-one. The mixture was stirred at 65° C. for 24 hours under a nitrogen atmosphere. The reaction mixture was filtered and then purified by reverse-phase high performance liquid chromatography (acetonitrile-water, 0.1% acetic acid) to give the title compound (25 mg).
Reaction SMILES: CO[C:3]([C:5]1([NH:8][C:9](=[O:25])[O:10][CH2:11][CH:12]2[C:24]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:18]3[C:13]2=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:7][CH2:6]1)=[O:4].[H-].[H-].[H-].[H-].[Li+].[Al+3].O.[CH2:33]1[CH2:37]OC[CH2:34]1>>[OH:4][CH2:3][C:5]1([NH:8][C:9](=[O:25])[O:10][CH2:11][CH:12]2[C:24]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:18]3[C:13]2=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:7][CH2:6][CH2:37][CH2:33][CH2:34]1
Reactant: COC(=O)C1(NC(=O)OCC2c3ccccc3-c3ccccc32)CC1
Reactant: C1CCOC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Product: O=C(NC1(CO)CCCCC1)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 90 %

Procedure:
To a solution of (9H-fluoren-9-yl)methyl 1-(methoxycarbonyl)-cyclopropylcarbamate (15 g, 44.5 mmol) in THF (100 mL) at −5° C. was added LiAlH4 (1.0 g, 26.3 mmol) in portions. After stirring at room temperature for 3 h, water (10 mL) was added to quench the reaction. The mixture was filtered and the filtrate was extracted with EtOAc (3×100 mL). The organic extract was washed with brine, and dried over anhydrous Na2SO4. After filtration and concentration, the crude product was purified by column chromatography to give the title compound (12.3 g, 90%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([C:8]([C:10]2[CH:15]=[C:14]([O:16][CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[N:13]=[C:12]([F:22])[C:11]=2[O:23]COC)=[O:9])[CH:7]=1.B(Br)(Br)Br.[Cl-].[NH4+].C(=O)([O-])[O-].[Cs+].[Cs+]>C(Cl)Cl.C(#N)C.O>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[O:23][C:11]1[C:12]([F:22])=[N:13][C:14]([O:16][CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:15][C:10]=1[C:8]2=[O:9]
Reactant: COCOc1c(C(=O)c2cc(Br)ccc2F)cc(OCC(C)(C)C)nc1F
Agent: BrB(Br)Br
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Solvent: CC#N
Product: CC(C)(C)COc1cc2c(=O)c3cc(Br)ccc3oc2c(F)n1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 78.6 %

Procedure:
A solution of (5-bromo-2-fluorophenyl)(2-fluoro-3-(methoxymethoxy)-6-(neopentyloxy)pyridin-4-yl)methanone (1.89 g, 4.25 mmol) in DCM (20 mL) was cooled to −78° C. under nitrogen atmosphere. Boron tribromide (1.0M in CH2Cl2; 4.25 mL, 4.25 mmol) was added drop wise and the reaction mixture was stirred for 5 min at rt. Aqueous, saturated ammonium chloride solution was added, followed by water and DCM. The organic phase was separated and dried over magnesium sulfate. The solvent was removed under reduced pressure to afford a yellow solid, which was dissolved in ACN (20.00 mL). Cesium carbonate (1.386 g, 4.25 mmol) was added in one portion and the reaction mixture was allowed to stir for 5 min. Water was added and the remaining light-yellow solid was filtered off and dried to afford 7-bromo-1-fluoro-3-(neopentyloxy)-5H-chromeno[2,3-c]pyridin-5-one (1.27 g).
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][O:6][C@@H:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[O:4][CH2:3]1.[H-].[Na+].Cl[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1>C1C=CC=CC=1>[C:8]1([C@H:5]2[O:4][CH2:3][C@@H:2]([O:1][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)[CH2:7][O:6]2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: ClCc1ccccn1
Reactant: O[C@H]1CO[C@@H](c2ccccc2)OC1
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Product: c1ccc([C@H]2OC[C@@H](OCc3ccccn3)CO2)cc1
Temperature: 25 °C

Procedure:
A solution of cis-5-hydroxy-2-phenyl-1,3-dioxane in 300 ml of benzene was treated with 4.45 g of 54% sodium hydride and the mixture stirred at ambient temperature until gas evolution ceased. To this mixture was added a solution of 2-chloromethylpyridine (obtained by extracting with benzene a carefully neutralized solution of 18.04 g of 2-chloromethylpyridine hydrochloride in 50 ml of water, then drying the benzene extracts) and the mixture was heated under reflux for 19 hours. The mixture was filtered and the filtrate washed with water and dried over sodium sulfate. Removal of the benzene under reduced pressure gave yellow solid which on recrystallization from benzene-petroleum ether (65°-110°) gave 14.2 g of cis-2-phenyl-5-(2-pyridyl)methoxy-1,3 -dioxane, m.p. 95°-98°. The nmr spectrum was consistent with the assigned structure and indicated pure cis isomer.
Reaction SMILES: [O:1]1[CH:5]=[C:4]([NH:6]C(=O)OCC2C=CC(OC)=CC=2OC)[N:3]=[CH:2]1.[CH3:21][O:22][C:23]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][C:24]=1[C:33]1[C:42]2[C:37](=[CH:38][C:39]([S:43](OC3C(F)=C(F)C(F)=C(F)C=3F)(=[O:45])=[O:44])=[CH:40][CH:41]=2)[CH:36]=[CH:35][N:34]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O.CCOC(C)=O>[CH3:21][O:22][C:23]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][C:24]=1[C:33]1[C:42]2[C:37](=[CH:38][C:39]([S:43]([NH:6][C:4]3[N:3]=[CH:2][O:1][CH:5]=3)(=[O:44])=[O:45])=[CH:40][CH:41]=2)[CH:36]=[CH:35][N:34]=1
Reactant: COc1cc(C(F)(F)F)ccc1-c1nccc2cc(S(=O)(=O)Oc3c(F)c(F)c(F)c(F)c3F)ccc12
Reactant: COc1ccc(COC(=O)Nc2cocn2)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: COc1cc(C(F)(F)F)ccc1-c1nccc2cc(S(=O)(=O)Nc3cocn3)ccc12
Temperature: 25 °C
Reaction time: 10 h
Yield: 9.2 %

Procedure:
In a 5-mL round bottom flask under N2 were dissolved 2,4-dimethoxybenzyl oxazol-4-ylcarbamate (100 mg, 0.359 mmol), perfluorophenyl 1-(2-methoxy-4-(trifluoromethyl)phenyl)isoquinoline-6-sulfonate (182 mg, 0.395 mmol) (Intermediate LLL) and cesium carbonate (351 mg, 1.078 mmol) in 1 mL of DMSO, and then the mixture was stirred at rt for 10 h. The reaction mixture was diluted with AcOEt then neutralized with NH4Cl/Ice. The aqueous phase was extracted 3× with AcOEt then the organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The crude mixture was purified by MPLC (ISCO) with Hexanes:AcOEt 100:0 to 0:100 to afforded 1-(2-methoxy-4-(trifluoromethyl)phenyl)-N-(oxazol-4-yl)isoquinoline-6-sulfonamide (15 mg, 0.033 mmol, 9.29%) as a white solid. MS (ESI, positive ion) [M+1]+: 450.0.
Reaction SMILES: [CH3:1][CH:2]([CH3:20])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[N:9]=[N:10][C:11]([N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[CH:12][CH:13]=1)=[O:7].[O:21]1[C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=[N:22]1.C(N(CC)CC)C>ClCCl>[CH3:1][CH:2]([CH3:20])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[N:9]=[N:10][C:11]([N:14]2[CH2:19][CH2:18][N:17]([C:26]([C:25]3[O:21][N:22]=[CH:23][CH:24]=3)=[O:27])[CH2:16][CH2:15]2)=[CH:12][CH:13]=1)=[O:7]
Reactant: O=C(Cl)c1ccno1
Reactant: CC(C)CCNC(=O)c1ccc(N2CCNCC2)nn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)CCNC(=O)c1ccc(N2CCN(C(=O)c3ccno3)CC2)nn1

Procedure:
To a stirred solution of 6-piperazin-1-yl-pyridazine-3-carboxylic acid (3-methylbutyl)amide (277 mg, 1 mmol) in dichloromethane (15 mL) was added isoxazole-5-carbonyl chloride (1.0 mmol) as a dichloromethane solution in the presence of triethylamine (0.4 mL) at ambient temperature. After 1 hour the mixture was evaporated and the residue was subjected to column chromatography. Final product was isolated as a solid (0.107 g, yield 29%). 1H NMR (300 MHz, CDCl3) δ 8.34, 8.05, 7.83, 7.00, 6.86, 3.90-3.84, 3.51-3.45, 1.75-1.62, 1.53-1.46, 0.92. MS (ES+) m/z 373.3 (M+1).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([OH:8])=O.C(Cl)(=O)C(Cl)=O.[CH3:15][NH2:16]>C(Cl)Cl.CN(C=O)C.N1C=CC=C1C(Cl)=O.C(OCC)(=O)C>[CH3:15][NH:16][C:6]([C:2]1[NH:1][CH:5]=[CH:4][CH:3]=1)=[O:8]
Reactant: O=C(O)c1ccc[nH]1
Reactant: CN
Agent: O=C(Cl)C(=O)Cl
Agent: O=C(Cl)c1ccc[nH]1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CNC(=O)c1ccc[nH]1
Temperature: 25 °C

Procedure:
To a solution of 1H-pyrrole-2-carboxylic acid (1 g, 9 mmol) (Aldrich, Milwaukee, Wis.) in DCM (15 mL) was added oxalyl chloride (1.1 mL) and DMF (3 drops). The mixture was stirred at room temperature resulting in 1H-pyrrole-2-carbonyl chloride. Methylamine (30 mmol) was then added to the acid chloride and the mixture was stirred at room temperature. The reaction was diluted with ethyl acetate, washed with brine (2×), NaHCO3, dried and concentrated to give 1H-pyrrole-2-carboxylic acid methylamide.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]([N:8]1[C:17]2[C:12](=[CH:13][C:14](I)=[CH:15][CH:16]=2)[C:11](=[O:19])[C:10]([C:20]([N:22]2[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]2)=[O:21])=[CH:9]1)[CH2:5][O:6][CH3:7].[CH2:35]([NH:37][C:38]([NH:40][C:41]1[CH:46]=[C:45]([C:47]2[S:48][CH:49]=[C:50]([C:52]([F:55])([F:54])[F:53])[N:51]=2)[C:44](B2OC(C)(C)C(C)(C)O2)=[CH:43][N:42]=1)=[O:39])[CH3:36].C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O.O.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>[CH3:1][O:2][CH2:3][CH:4]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([C:44]3[CH:43]=[N:42][C:41]([NH:40][C:38](=[O:39])[NH:37][CH2:35][CH3:36])=[CH:46][C:45]=3[C:47]3[S:48][CH:49]=[C:50]([C:52]([F:55])([F:53])[F:54])[N:51]=3)=[CH:15][CH:16]=2)[C:11](=[O:19])[C:10]([C:20]([N:22]2[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]2)=[O:21])=[CH:9]1)[CH2:5][O:6][CH3:7]
Reactant: COCC(COC)n1cc(C(=O)N2CCN(C(=O)OC(C)(C)C)CC2)c(=O)c2cc(I)ccc21
Reactant: CCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(B2OC(C)(C)C(C)(C)O2)cn1
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: CN(C)C=O
Solvent: O
Product: CCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(-c2ccc3c(c2)c(=O)c(C(=O)N2CCN(C(=O)OC(C)(C)C)CC2)cn3C(COC)COC)cn1
Temperature: 25 °C
Yield: 49.4 %

Procedure:
A solution of tert-butyl 4-{[1-(1,3-dimethoxypropan-2-yl)-6-iodo-4-oxo-1,4-dihydroquinolin-3-yl]carbonyl}piperazine-1-carboxylate (Intermediate 79, 400 mg, 0.68 mmol) in dimethylformamide (15 mL) was purged argon gas, then tetrakis(triphenylphosphine)palladium (69.25 mg, 0.06 mmol) followed by 1-ethyl-3-{5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-[4-(trifluoromethyl)-1,3-thiazol-2-yl]pyridin-2-yl}urea (Intermediate 17, 360 mg, 0.82 mmol) was added. The mixture was stirred at room temperature and sodium carbonate (217 mg, 2.05 mmol) which was dissolved in minimum amount of water was added and the reaction mixture was heated to 95° C. for 3 h. After completion of the reaction, the reaction mixture was cooled to room temperature, filtered through celite, and the filtrate was poured into water (200 mL) and stirred for 30 min. The obtained solid was filtered and dried to give the crude compound. The crude was purified by column chromatography eluting with a gradient of 30% ethyl acetate/petroleum ether to 60% ethyl acetate/petroleum ether to afford 260 mg (49%) of tert-butyl 4-{[1-(1,3-dimethoxypropan-2-yl)-6-{6-[(ethylcarbamoyl)amino]-4-[4-(trifluoromethyl)-1,3-thiazol-2-yl]pyridin-3-yl}-4-oxo-1,4-dihydroquinolin-3-yl]carbonyl}piperazine-1-carboxylate.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]2[C:7]([CH:14]=[O:15])=[CH:8][NH:9][C:10]=2[CH:11]=[CH:12][CH:13]=1)=O.Cl.[NH2:17][OH:18].C([O-])(=O)C.[Na+]>CO>[CH3:1][O:2][C:3](=[N:17][OH:18])[C:5]1[C:6]2[C:7]([CH:14]=[O:15])=[CH:8][NH:9][C:10]=2[CH:11]=[CH:12][CH:13]=1
Reactant: COC(=O)c1cccc2[nH]cc(C=O)c12
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(=NO)c1cccc2[nH]cc(C=O)c12
Reaction time: 1 h

Procedure:
A mixture of 3-formyl-4-indolecarboxylic acid methyl ester (2.03 g), described in Example 1, 10 ml of a 5M aqueous solution of hydroxylamine hydrochloride, 10 ml of 5M aqueous sodium acetate and 20 ml of methanol is stirred at 45° - 55°C for 1 hour. The precipitate is collected and washed with cold water. Recrystallization from methanol-water gives the title compound, mp 178° - 179°C.
Reaction SMILES: [F:1][C:2]1([F:14])[CH2:7][CH2:6][CH:5]([N:8]2[CH2:12][CH2:11][CH2:10][C:9]2=[O:13])[CH2:4][CH2:3]1.[Li+].CC([N-]C(C)C)C.[Br:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30]Br)=[C:26]([Cl:32])[CH:25]=1>C1COCC1.CCCCCC>[Br:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][CH:10]2[CH2:11][CH2:12][N:8]([CH:5]3[CH2:4][CH2:3][C:2]([F:1])([F:14])[CH2:7][CH2:6]3)[C:9]2=[O:13])=[C:26]([Cl:32])[CH:25]=1
Reactant: Clc1cc(Br)ccc1CBr
Reactant: O=C1CCCN1C1CCC(F)(F)CC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C1C(Cc2ccc(Br)cc2Cl)CCN1C1CCC(F)(F)CC1
Reaction time: 8 h

Procedure:
To a solution of 1-(4,4-difluoro-cyclohexyl)-pyrrolidin-2-one (190 mg, 0.94 mmol) in 10 mL dry THF, add 1.04 mL of 1.5M LDA (1.5 eq.) in hexane dropwise at −78° C. Then, add 0.59 g of 4-bromo-1-bromomethyl-2-chloro-benzene (1.5 eq) at −78° C. Allow the resulting solution to stand at room temp for overnight. Quench the mixture with saturated aqueous NaCl and extract with Et2O. Wash the organic layer with water, then brine, and dry over Na2SO4, filter and concentrate. Purify the crude material by chromatography to afford the title compound: mass spectrum (m/z): 407 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:12][C:13](=[O:26])[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([C:22]([F:25])([F:24])[F:23])[CH:15]=2)=[CH:4][CH:5]=[C:6]2[C:11]=1[CH2:10][NH:9][CH2:8][CH2:7]2.Br[CH2:28][CH2:29][O:30][Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32]>CN(C)C=O>[Si:31]([O:30][CH2:29][CH2:28][N:9]1[CH2:8][CH2:7][C:6]2[C:11](=[C:2]([Cl:1])[C:3]([NH:12][C:13](=[O:26])[C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([C:22]([F:23])([F:24])[F:25])[CH:15]=3)=[CH:4][CH:5]=2)[CH2:10]1)([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32]
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Reactant: COc1ccc(C(=O)Nc2ccc3c(c2Cl)CNCC3)cc1C(F)(F)F
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)Nc2ccc3c(c2Cl)CN(CCO[Si](C)(C)C(C)(C)C)CC3)cc1C(F)(F)F
Temperature: 80 °C
Yield: 33.2 %

Procedure:
A mixture of N-(8-chloro-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-methoxy-3-trifluoromethylbenzamide (0.192 g) and 2-bromoethoxy-tert-butyldimethylsilane (0.24 g) were combined in dimethylformamide and warmed to 80° C. for 18 h. Solvent was removed at reduced pressure, the residue dissolved in dichloromethane and washed with saturated sodium hydrogen carbonate. The organic phase was dried (MgSO4) and solvent removed at reduced pressure. The residue was column chromatographed (silica gel, ammonia/methanol/dichloromethane mixtures as eluant) to give N-(2-(2-tert-butyldimethylsilyloxyethyl)-8-chloro-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-methoxy-3-trifluoromethylbenzamide (0.09 g)