Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]2[CH2:6]S[CH2:8][C:4]=2[CH:3]=1.O[O:12][S:13]([O-:15])=O.[K+].S(=O)(O)[O-].[Na+].C([O-])(O)=O.[Na+]>CO>[Br:1][C:2]1[CH:10]=[CH:9][C:5]2[CH2:6][S:13](=[O:15])(=[O:12])[CH2:8][C:4]=2[CH:3]=1
Reactant: O=S([O-])OO
Reactant: Brc1ccc2c(c1)CSC2
Agent: O=C([O-])O
Agent: O=S([O-])O
Agent: [K+]
Solvent: CO
Product: O=S1(=O)Cc2ccc(Br)cc2C1
Temperature: 0 °C
Reaction time: 2 h
Yield: 65 %

Procedure:
Dissolve 5-bromo-1,3-dihydro-benzo[c]thiophene (1.25 g, 5.79 mmol) in methanol (25 mL) and add oxone (10.7 g, 17.4 mmol). Stir the reaction mixture for 2 hours at 0° C. and then add a 1M aqueous sodium bisulfite solution (100 mL). Stir the reaction mixture for 10 minutes and add saturated NaHCO3 solution (200 mL). Extract the aqueous layer with CH2Cl2 (3×100 mL). Combine the organic layers and dry with Na2SO4, filter, concentrate and purify by flash column chromatography (silica gel, 0-5% MeOH/CH2Cl2) to give 930 mg of 5-bromo-1,3-dihydro-benzo[c]thiophene 2,2-dioxide 65%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]=[CH:7][C:8](=O)[NH:9][C:10]=2[N:11]=1.O=P(Cl)(Cl)[Cl:15]>>[Cl:15][C:8]1[N:9]=[C:10]2[N:11]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]2=[N:6][CH:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1cnc2ccc(Cl)nc2[nH]1
Product: Clc1ccc2ncc(Cl)nc2n1
Temperature: 25 °C
Yield: 90 %

Procedure:
6-chloropyrido[3,2-b]pyrazin-3(4H)-one (E-27) (9 g, 49.8 mmol) was dissolved in POCl3 (100 mL) and the resulting mixture was stirred at reflux for 3 h. The reaction was complete based on TLC analysis. The mixture was cooled to RT and concentrated in vacuo to remove POCl3. The residue was poured into ice water (150 mL) and extracted with DCM (3×100 mL). The combined organic layers were washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo to give the desired product 3,6-dichloropyrido[2,3-b]pyrazine (E-28) (9 g, 90% yield) as a solid. ESI-MS m/z: 199.97 [M+H]+.
Reaction SMILES: [F:1][C:2]1[C:3]2[C:8]([C:9]3[CH:10]=[CH:11][C:12](Br)=[CH:13][C:14]=3[C:15]=1[F:16])=[CH:7][CH:6]=[C:5]([CH2:18][CH2:19][CH2:20][CH3:21])[CH:4]=2.[CH2:22]([O:32][C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]>[Pd]>[CH2:22]([O:32][C:33]1[CH:34]=[CH:35][C:36]([C:12]2[CH:11]=[CH:10][C:9]3[C:8]4[C:3](=[CH:4][C:5]([CH2:18][CH2:19][CH2:20][CH3:21])=[CH:6][CH:7]=4)[C:2]([F:1])=[C:15]([F:16])[C:14]=3[CH:13]=2)=[CH:37][CH:38]=1)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]
Reactant: CCCCc1ccc2c(c1)c(F)c(F)c1cc(Br)ccc12
Reactant: CCCCCCCCCCOc1ccc(B(O)O)cc1
Agent: [Pd]
Product: CCCCCCCCCCOc1ccc(-c2ccc3c(c2)c(F)c(F)c2cc(CCCC)ccc23)cc1

Procedure:
From 9,1 0-difluoro-2-bromo-7-butylphenanthrene and 4-decyloxyphenyl-boronic acid by means of palladium-catalyzed Suzuki coupling (in analogy to Acc. Chem. Res. 1982, 15, 178). The crude product is purified by column chromatography.
Reaction SMILES: COCN[C:5]([C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1)=[O:6].[C:13]1([O:21][CH3:22])[C:14](=[CH:17][CH:18]=[CH:19][CH:20]=1)[O:15][CH3:16]>>[CH3:16][O:15][C:14]1[C:13]([O:21][CH3:22])=[CH:20][CH:19]=[CH:18][C:17]=1[C:5]([C:7]1[CH:8]=[CH:9][N:10]=[CH:11][CH:12]=1)=[O:6]
Reactant: COc1ccccc1OC
Reactant: COCNC(=O)c1ccncc1
Product: COc1cccc(C(=O)c2ccncc2)c1OC

Procedure:
In Scheme H, step c, 4-[(methoxymethylamino)carbonyl]pyridine (19) is reacted with lithiated veratrole to give 4-(2,3-dimethoxybenzoyl)pyridine (12).
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH3:18])=[C:5]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[N:6]2[CH3:11].C([O-])([O-])=O.[K+].[K+].[CH3:25][O:26][C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1.ClCCl>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([C:2]2[CH:10]=[CH:9][CH:8]=[C:7]3[C:3]=2[C:4]([CH3:18])=[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:6]3[CH3:11])=[CH:29][CH:28]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: Cc1c(-c2ccccc2)n(C)c2cccc(Br)c12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: ClCCl
Product: COc1ccc(-c2cccc3c2c(C)c(-c2ccccc2)n3C)cc1

Procedure:
The desired product was prepared using a procedure similar to step 3 of example 3. Thus, 4-bromo-1,3-dimethyl-2-phenyl-1H-indole (1.182 g, 3.937 mmol) was reacted with aqueous 2M K2CO3 (3.9 ml), 4-methoxyphenylboronic acid (0.838 g, 5.512 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) complex with dichloromethane (1:1) (0.096 g, 0.118 mmol) in dioxane (39 ml) to give the product (1.253 g, 3.827 mmol, 97%) as a yellow, viscous oil. 1H NMR (DMSO-d6) δ 1.72 (s, 3H), 3.60 (s, 3H), 3.81 (s, 3H), 6.85 (dd, J=0.8, 7.0 Hz, 1H), 6.99 (d, J=8.7 Hz, 2H), 7.20 (t, J=7.3 Hz, 1H), 7.32 (d, J=8.7 Hz, 2H), 7.41-7.47 (m, 4H), 7.53 (t, J=7.6 Hz, 2H); [ESI(+)], m/z 328 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:19]([N+:20]([O-])=O)=[CH:18][C:6]2[CH2:7][CH2:8][N:9]([CH2:12][CH2:13][NH:14][C:15](=[O:17])[CH3:16])[CH2:10][CH2:11][C:5]=2[CH:4]=1>CO.[Pd]>[NH2:20][C:19]1[C:3]([O:2][CH3:1])=[CH:4][C:5]2[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][NH:14][C:15](=[O:17])[CH3:16])[CH2:8][CH2:7][C:6]=2[CH:18]=1
Reactant: COc1cc2c(cc1[N+](=O)[O-])CCN(CCNC(C)=O)CC2
Agent: [Pd]
Solvent: CO
Product: COc1cc2c(cc1N)CCN(CCNC(C)=O)CC2
Reaction time: 0.5 h
Yield: 108.2 %

Procedure:
To a solution of N-[2-(7-methoxy-8-nitro-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-ethyl]-acetamide (100 mg, 0.3 mmol) in methanol (20 mL) was added palladium 10% wt on Carbon (50% wet; 50 mg). The mixture was shaken in a Parr apparatus under an atmosphere of hydrogen (50 PSI) for 30 minutes. Filtration through Celite and evaporation of the solvent provided N-[2-(7-amino-8-methoxy-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-ethyl]-acetamide (90 mg, 100%) as a yellow oil, which was used without further purification. 1H-NMR (CDCl3) δ 6.59 (br s, 1H), 6.53 (s, 1H), 6.48 (s, 1H), 3.82 (s, 3H), 3.50-4.40 (br s, 2H), 3.40 (m, 2H), 2.65-2.93 (m, 10H), 2.02 (s, 3H); LC/MS (ESI+): 278.25 (M+H).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4]1.CN(C)/[CH:17]=[C:18](/[C:24](=[O:33])[C:25]1[CH:30]=[C:29]([I:31])[CH:28]=[CH:27][C:26]=1F)\[C:19]([O:21][CH2:22][CH3:23])=[O:20].C(=O)([O-])[O-].[K+].[K+]>O>[C:11]([O:10][C:8]([N:5]1[CH2:6][CH2:7][C@H:3]([CH2:2][N:1]2[C:26]3[C:25](=[CH:30][C:29]([I:31])=[CH:28][CH:27]=3)[C:24](=[O:33])[C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17]2)[CH2:4]1)=[O:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](CN)C1
Reactant: CCOC(=O)/C(=C\N(C)C)C(=O)c1cc(I)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCOC(=O)c1cn(C[C@H]2CCN(C(=O)OC(C)(C)C)C2)c2ccc(I)cc2c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(R)-3-(Aminomethyl)-1-N-Boc-pyrrolidine (994 mg, 4.86 mmol) was added to the stock solution of (Z)-ethyl 3-(dimethylamino)-2-(3-iodobenzoyl)acrylate (Intermediate 24, 0.34M, 13 mL, 4.42 mmol). The reaction mixture was stirred at room temperature overnight. The solvent was removed in vacuo and the residue was dried in a vacuum oven for 1.5 h. The resulting residue was then dissolved in dimethylformamide (8 mL) and potassium carbonate powder (670 mg, 4.86 mmol) was added. The reaction mixture was heated at 60° C. for overnight then cooled to room temperature. Water (50 mL) was added and the suspension was extracted with ethyl acetate (3×50 mL). The organic layers were dried over sodium sulfate, and the solvent was removed in vacuo to give quantitative (R)-ethyl 1-((1-(tert-butoxycarbonyl)pyrrolidin-3-yl)methyl)-6-iodo-4-oxo-1,4-dihydroquinoline-3-carboxylate as a brown sticky solid.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:15](=[O:17])[NH:14][C:13](=[O:18])[N:12]([CH3:19])[C:11]=2[N:10]=[C:9]1[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[C:23]([O:26][CH:27]([CH3:33])[CH2:28][CH2:29][CH2:30][CH2:31][Cl:32])(=[O:25])[CH3:24]>CS(C)=O>[C:23]([O:26][CH:27]([CH3:33])[CH2:28][CH2:29][CH2:30][CH2:31][Cl:32])(=[O:25])[CH3:24].[C:23]([O:26][C@H:27]([CH3:33])[CH2:28][CH2:29][CH2:30][CH2:31][N:14]1[C:15](=[O:17])[C:16]2[N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:9]([CH3:20])=[N:10][C:11]=2[N:12]([CH3:19])[C:13]1=[O:18])(=[O:25])[CH3:24]
Reactant: Cc1nc2c(c(=O)[nH]c(=O)n2C)n1Cc1ccccc1
Agent: CC(=O)OC(C)CCCCCl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(=O)O[C@H](C)CCCCn1c(=O)c2c(nc(C)n2Cc2ccccc2)n(C)c1=O
Temperature: 75 °C
Reaction time: 0.5 h
Yield: 154.8 %

Procedure:
7-Benzyl-3,8-dimethylxanthine (500 mg, 1.85 mmol) was added to a suspension of sodium hydride (50.5 mg) in anhydrous dimethylsulfoxide (20 ml). After stirring for 30 minutes, (R) 5-acetoxy-1-chlorohexane (357 mg) was added and the mixture was warmed to 70-80° C. for 12 hours. The (R) 5-acetoxy-1-chlorohexane was prepared according to methods described in U.S. Pat. No. 5,629,423 issued to Klein, J. P., Leigh, A. J., Michnick, J., Kumar, A. M., Underiner, G. E., on May 13, 1997. After cooling to room temperature, the reaction wash quenched by the addition of water (50 ml) and extracted with ethyl acetate (3×75 ml). The combined extracts were washed with water (2×50 ml), washed with saturated aqueous sodium chloride solution (50 ml), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate to give (R)-1-(5-acetoxyhexyl)-7-benzyl-3,8-dimethylxanthine (638 mg).
Reaction SMILES: C(OC([N:8]([CH2:35][C:36]1[CH:45]=[CH:44][C:39]2[O:40][CH2:41][CH2:42][O:43][C:38]=2[CH:37]=1)[CH:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][N:17]2[C:26]3[C:21](=[C:22]([O:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH:23]=[CH:24][CH:25]=3)[CH:20]=[CH:19][C:18]2=[O:34])[CH2:11][CH2:10]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)(Cl)Cl>[O:40]1[C:39]2[CH:44]=[CH:45][C:36]([CH2:35][NH:8][CH:9]3[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][N:17]4[C:26]5[C:21](=[C:22]([O:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH:23]=[CH:24][CH:25]=5)[CH:20]=[CH:19][C:18]4=[O:34])[CH2:13][CH2:14]3)=[CH:37][C:38]=2[O:43][CH2:42][CH2:41]1
Reactant: CCOC(=O)COc1cccc2c1ccc(=O)n2CCN1CCC(N(Cc2ccc3c(c2)OCCO3)C(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: CCOC(=O)COc1cccc2c1ccc(=O)n2CCN1CCC(NCc2ccc3c(c2)OCCO3)CC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 68.9 %

Procedure:
To 2 mL of a chloroform solution containing 83 mg of ethyl (1-(2-(4-((tert-butoxycarbonyl)(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)piperidin-1-yl)ethyl)-2-oxo-1,2-dihydroquinolin-5-yloxy)acetate, 2 mL of trifluoroacetic acid was added and stirred at room temperature for 6 hours. After the solvent was removed under reduced pressure and the residue was alkalized by aqueous saturated sodium hydrogen carbonate solution, it was extracted with ethyl acetate. The organic layer was washed sequentially with water and aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to give 48 mg of ethyl (1-(2-(4-((2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)piperidin-1-yl)ethyl)-2-oxo-1,2-dihydroquinolin-5-yloxy)acetate as a white solid.
Reaction SMILES: CON(C)[C:4](=[O:24])[CH:5]([N:13]1[C:17]2=[N:18][CH:19]=[CH:20][C:21]([O:22][CH3:23])=[C:16]2[CH:15]=[N:14]1)[CH2:6][CH:7]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1.[CH:26]([Mg]Br)=[CH2:27].Cl>O1CCCC1>[CH3:23][O:22][C:21]1[CH:20]=[CH:19][N:18]=[C:17]2[N:13]([CH:5]([CH2:6][CH:7]3[CH2:8][CH2:9][O:10][CH2:11][CH2:12]3)[C:4](=[O:24])[CH:26]=[CH2:27])[N:14]=[CH:15][C:16]=12
Reactant: C=C[Mg]Br
Reactant: COc1ccnc2c1cnn2C(CC1CCOCC1)C(=O)N(C)OC
Agent: Cl
Solvent: C1CCOC1
Product: C=CC(=O)C(CC1CCOCC1)n1ncc2c(OC)ccnc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 53 %

Procedure:
To a solution of N-methoxy-2-(4-methoxy-1H-pyrazolo[3,4-b]pyridin-1-yl)-N-methyl-3-(tetrahydro-2H-pyran-4-yl)propanamide (0.37 g) in dry tetrahydrofuran (15 mL) was slowly added vinylmagnesium bromide (1.0M tetrahydrofuran solution: 7.8 mL) at 0° C., and the mixture was stirred at 0° C. for 1 hr. To the reaction mixture was added again vinylmagnesium bromide (1.0M tetrahydrofuran solution: 2.6 mL) at 0° C., and the mixture was stirred for 1 hr under ice-cooling. The reaction solution was poured into an ice-cooled 6M hydrochloric acid, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography to give the title compound (0.178 g, yield 53%) as a pale-pink oil from the fraction eluted with ethyl acetate-hexane (6:4, volume ratio). MS: 316 (MH+).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:11]([OH:13])=O)[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.ClC(OCC(C)C)=O.[N+:29](=[CH2:31])=[N-:30]>O1CCCC1.CCOCC>[N+:29](=[CH:31][C:11](=[O:13])[C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH3:10])=[N-:30]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: C=[N+]=[N-]
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Solvent: CCOCC
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)C=[N+]=[N-]
Temperature: 25 °C
Reaction time: 0.23 h

Procedure:
To a vigorously stirred solution of [(t-butyloxy)carbonyl]-L-alanine (15.14 g, 80 mmol) and N-methylmorpholine (8.80 ml, 80 mmol) in 80 ml of dry tetrahydrofuran at -15° C. under argon was added a solution of isobutyl chloroformate (10.37 ml, 80 mmol) in 10 ml tetrahydrofuran, maintaining the reaction temperature below -12° C. After the addition was complete, the reaction mixture was stirred for 14 minutes and then diluted with 250 ml of anhydrous ether (prechilled to -20° C.) and quickly filtered. Approximately one-fourth of the filtrate was transferred to a separatory funnel (the remainder kept chilled) and added rapidly to a gently stirred, chilled (0° C.) solution of diazomethane (160 mmol, generated from 23.54 g of N-methyl-N'-nitro-N-nitrosoguanidine). Additional chilled portions were transferred to the separatory funnel until the entire solution had been added (over approximately 10 minutes). The resulting solution was stirred for 2 hours, warming gradually to room temperature, then purged with nitrogen for 1 hour, washed with chilled half-saturated sodium bicarbonate (2×100 ml) and water (3×50 ml), dried (sodium sulfate) and evaporated to a yellow semi-crystalline residue. Two recrystallizations from ethyl acetate-petroleum ether yielded yellow plates, 10.29 g, melting point 99°-102° C., plus an additional crop of 1.33 g, melting point 97.5°-101° C. A portion was recrystallized once more giving the analytical sample, melting point 102°-103° C.
Reaction SMILES: ClC1C=C(C=CC=1[N+]([O-])=O)C[P:6](=[O:13])([O:10][CH2:11][CH3:12])[O:7][CH2:8][CH3:9].Cl[CH2:21][C:22]1[CH:23]=[C:24]([O:32][CH3:33])[C:25]([N+:29]([O-:31])=[O:30])=[C:26]([F:28])[CH:27]=1>>[F:28][C:26]1[CH:27]=[C:22]([CH:23]=[C:24]([O:32][CH3:33])[C:25]=1[N+:29]([O-:31])=[O:30])[CH2:21][P:6](=[O:13])([O:10][CH2:11][CH3:12])[O:7][CH2:8][CH3:9]
Reactant: COc1cc(CCl)cc(F)c1[N+](=O)[O-]
Reactant: CCOP(=O)(Cc1ccc([N+](=O)[O-])c(Cl)c1)OCC
Product: CCOP(=O)(Cc1cc(F)c([N+](=O)[O-])c(OC)c1)OCC

Procedure:
The title compound was prepared using the procedure from Compound 104C (Diethyl (3-chloro-4-nitrobenzyl)phosphonate) with 5-(chloromethyl)-1-fluoro-3-methoxy-2-nitrobenzene (Compound 146C). 1H NMR (CDCl3, 400 MHz): δ=1.31 (t, J=7.07 Hz, 6 H), 3.11-3.18 (m, 2 H), 3.94 (s, 3 H), 4.07-4.13 (m, 4 H), 6.77 (dt, J=9.79, 1.93 Hz, 1 H), 6.82 (s, 1 H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:17]=[C:16]([NH:18][CH:19]2[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]2)[CH:15]=[C:14]2[C:9]=1[CH:10]=[CH:11][C:12](=[O:40])[N:13]2[C:32]1[C:37]([Cl:38])=[CH:36][CH:35]=[CH:34][C:33]=1[Cl:39].ClC1C=CC=CC=1C1N=C(NC2CCN(C(C)C)CC2)C=C2C=1C=CC(=O)N2C1C(Cl)=CC=CC=1Cl>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:17]=[C:16]([NH:18][CH:19]2[CH2:20][CH2:21][NH:22][CH2:23][CH2:24]2)[CH:15]=[C:14]2[C:9]=1[CH:10]=[CH:11][C:12](=[O:40])[N:13]2[C:32]1[C:33]([Cl:39])=[CH:34][CH:35]=[CH:36][C:37]=1[Cl:38]
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2cc3c(ccc(=O)n3-c3c(Cl)cccc3Cl)c(-c3ccccc3Cl)n2)CC1
Agent: CC(C)N1CCC(Nc2cc3c(ccc(=O)n3-c3c(Cl)cccc3Cl)c(-c3ccccc3Cl)n2)CC1
Product: O=c1ccc2c(-c3ccccc3Cl)nc(NC3CCNCC3)cc2n1-c1c(Cl)cccc1Cl

Procedure:
The title compound was prepared from tert-butyl 4-{[5-(2-chlorophenyl)-1-(2,6-dichlorophenyl)-2-oxo-1,2-dihydro-1,6-naphthyridin-7-yl]amino}piperidine-1-carboxylate by a procedure analogous to that described in EXAMPLE HHH2, Step C. Mass spectrum (ESI) 501 (M+1). Step C: 5-(2-Chlorophenyl)-1-(2,6-dichlorophenyl)-7-[(1-isopropylpiperidin-4-yl)amino]-1,6-naphthyridin-2(1H)-one
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[O:17][CH3:18])=[CH:9][N:8]([S:19]([C:22]3[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=3)(=[O:21])=[O:20])[C:5]2=[N:6][CH:7]=1.[NH:29]1[CH:33]=[CH:32][C:31](B(O)O)=[N:30]1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O.C(OCC)(=O)C>[CH3:18][O:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([C:33]3[CH:32]=[CH:31][NH:30][N:29]=3)[CH:3]=2)[N:8]([S:19]([C:22]2[CH:23]=[CH:24][C:25]([CH3:28])=[CH:26][CH:27]=2)(=[O:21])=[O:20])[CH:9]=1
Reactant: OB(O)c1cc[nH]n1
Reactant: COc1ccccc1-c1cn(S(=O)(=O)c2ccc(C)cc2)c2ncc(Br)cc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccccc1-c1cn(S(=O)(=O)c2ccc(C)cc2)c2ncc(-c3cc[nH]n3)cc12
Temperature: 165 °C
Yield: 80.1 %

Procedure:
5-Bromo-3-(2-methoxy-phenyl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine (200 mg, 0.438 mmol), commercial 1H-pyrazole-3-boronic acid (73.6 mg, 0.637 mmol) and 1,1′-bis(diphenylphosphino)ferrocenepalladium(II)-dichloride dichloromethane adduct (17.8 mg, 0.022 mmol) were combined in dimethylformamide (1.4 mL) and 2 M saturated sodium carbonate (657 μL) under nitrogen. The mixture was heated to 165° C. in the microwave for 900 s. The mixture was diluted with ethyl acetate and the aqueous layer was removed. After drying over sodium sulfate, the crude material was purified by silica gel chromatography to afford 3-(2-methoxy-phenyl)-5-(1H-pyrazol-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine (156 mg, 80.2%). %). MS: m/z 445 (M+H+).
Reaction SMILES: CI.[C:3](=O)([O-])[O-].[K+].[K+].[F:9][C:10]([F:27])([F:26])[C:11]1[C:16]([C:17]([O:19][CH3:20])=[O:18])=[C:15]([OH:21])[CH:14]=[C:13]([C:22]([F:25])([F:24])[F:23])[N:12]=1>CC(C)=O>[CH3:3][O:21][C:15]1[CH:14]=[C:13]([C:22]([F:25])([F:24])[F:23])[N:12]=[C:11]([C:10]([F:26])([F:9])[F:27])[C:16]=1[C:17]([O:19][CH3:20])=[O:18]
Reactant: COC(=O)c1c(O)cc(C(F)(F)F)nc1C(F)(F)F
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COC(=O)c1c(OC)cc(C(F)(F)F)nc1C(F)(F)F

Procedure:
A mixture of methyl iodide (32.3 ml, 0.519 mol), potassium carbonate (14.4 g, 0.104 mol), and product of Step 2 (25.0 g, 0.086, 5 mol) in acetone (100 ml) was refluxed for 18 hours and concentrated. The residue was dissolved in ether and washed with water. The ether layer was worked up as usual. The crude product, a yellow solid (27.25 g), was recrystallized (chloroform petroleum ether) to afford white rods (22.95 g), yield--88%; mp 101°-103° C.
Reaction SMILES: [C:1]([N:9]1[CH2:14][CH2:13][C:12]2([CH2:19][C:18](=O)[C:17]3[CH:21]=[C:22]([O:25][CH3:26])[CH:23]=[CH:24][C:16]=3[O:15]2)[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].C1(C)C=CC(S(O)(=O)=O)=CC=1>[Pd]>[C:1]([N:9]1[CH2:14][CH2:13][C:12]2([CH2:19][CH2:18][C:17]3[CH:21]=[C:22]([O:25][CH3:26])[CH:23]=[CH:24][C:16]=3[O:15]2)[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc2c(c1)C(=O)CC1(CCN(C(=O)c3ccccc3)CC1)O2
Agent: [Pd]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [BH4-]
Product: COc1ccc2c(c1)CCC1(CCN(C(=O)c3ccccc3)CC1)O2
Yield: 54 %

Procedure:
Following the procedures as described in Example 435, 1'-benzoyl-3,4-dihydro-6-methoxyspiro[(2H)-1-benzopyran-2,4'-piperidine]-4-one was reduced with sodium borohydride, dehydrated with p-toluenesulfonic acid and hydrogenated with palladium on carbon (5%) under hydrogen (50 psi) to give the piperidine as a foam (54%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:10].[CH2:17]([O:21][C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1)[CH2:18][CH2:19][CH3:20]>>[C:9]([C:3]1[CH:4]=[C:5]([Cl:8])[CH:6]=[CH:7][C:2]=1[NH:1][S:28]([C:25]1[CH:24]=[CH:23][C:22]([O:21][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:27][CH:26]=1)(=[O:30])=[O:29])(=[O:10])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CCCCOc1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccccc1
Product: CCCCOc1ccc(S(=O)(=O)Nc2ccc(Cl)cc2C(=O)c2ccccc2)cc1

Procedure:
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using 115 mg of (2-amino-5-chloro-phenyl)-phenyl-methanone and 124 mg of 4-butoxy-benzenesulfonyl chloride. 1H-NMR (400 MHz, CDCl3): δ 0.98 (t, 3H, J=7.6 Hz), 1.45 (m, 2H), 1.72 (m, 2H), 3.79 (t, 2H, J=6.6 Hz), 6.66 (d, 2H, J=8.8 Hz), 7.31 (d, 1H, J=2.8 Hz), 7.35–7.42 (m, 4H), 7.47 (dd, 1H, J=8.8 Hz, 2.8 Hz), 7.53–7.60 (m, 3H), 7.75 (d, 1H, J=8.8 Hz), 9.62 (s, 1H). MS: m/z 444.9 (M++1).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:18][C:19]([NH:21][C@@H:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C@H:25]([O:32][C:33]3[CH:34]=[CH:35][C:36]4[N:37]([C:39]([N:42]5[CH2:47][CH2:46][CH2:45][CH2:44][C@@H:43]5[CH3:48])=[N:40][N:41]=4)[CH:38]=3)[CH2:24][CH2:23]2)=[O:20])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]=O)=[CH:12][CH:11]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:49][N:50]1[CH2:56][CH2:55][CH2:54][NH:53][CH2:52][CH2:51]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>C(Cl)Cl>[C:1]([C:5]1[CH:6]=[C:7]([NH:18][C:19]([NH:21][C@@H:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C@H:25]([O:32][C:33]3[CH:34]=[CH:35][C:36]4[N:37]([C:39]([N:42]5[CH2:47][CH2:46][CH2:45][CH2:44][C@@H:43]5[CH3:48])=[N:40][N:41]=4)[CH:38]=3)[CH2:24][CH2:23]2)=[O:20])[N:8]([C:10]2[CH:11]=[CH:12][C:13]([CH2:16][N:53]3[CH2:54][CH2:55][CH2:56][N:50]([CH3:49])[CH2:51][CH2:52]3)=[CH:14][CH:15]=2)[N:9]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: C[C@H]1CCCCN1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4ccc(C=O)cc4)c4ccccc43)cn12
Reactant: CN1CCCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: C[C@H]1CCCCN1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4ccc(CN5CCCN(C)CC5)cc4)c4ccccc43)cn12
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.8 %

Procedure:
To an orange solution of Intermediate 176b (0.188 mmol) and N-methyl homopiperazine (43 mg, 0.38 mmol) in DCM (3 mL) was added sodium triacetoxyborohydride (60 mg, 0.28 mmol) and the mixture stirred at RT for 1 h. Water (3 mL) was added and the mixture shaken. The aqueous was extracted with DCM (3 mL) then the combined organics passed through a hydrophobic frit and concentrated in vacuo to leave a brown gum. Flash chromatography (silica 12 g, 7-11% [2M NH3 in MeOH] in DCM) gave the title compound as a yellow solid (102 mg, 73%). LCMS (Method 3): Rt 2.84 min, m/z 745 [MH+]. 1H NMR (300 MHz, CDCl3): 0.91 (3H, d, J=6.2 Hz), 1.34 (9H, s), 1.40-1.55 (2H, m), 1.62-1.99 (7H, m), 2.15-2.02-2.14 (2H, m), 2.21-2.30 (1H, m), 2.33 (3H, s), 2.55-2.69 (8H, m), 2.90 (1H, ddd, J=12.1, 9.3, 4.1), 3.04 (1H, dt, J=12.1, 4.2 Hz), 3.23-3.32 (1H, m), 3.58 (2H, s), 5.09 (1H, td, J=8.9, 5.2 Hz), 5.19 (1H, t, J=3.9 Hz), 6.04 (1H, br d, J=8.6 Hz), 6.33 (1H, s), 6.94 (1H, dd, J=9.9, 2.1 Hz), 7.22 (1H, br s), 7.25-7.39 (7H, m), 7.43 (1H, d, J=2.2 Hz), 7.47 (2H, m).