Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[S:22][C:5]2=[N:6][C:7]([CH3:21])=[CH:8][C:9]([NH:10][S:11]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=3)(=[O:13])=[O:12])=[C:4]2[C:3]=1[CH3:23].CC1(C)C(C)(C)OB([C:32]2[CH:33]=[N:34][O:35][CH:36]=2)O1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:20][C:16]1[CH:15]=[C:14]([S:11]([NH:10][C:9]2[CH:8]=[C:7]([CH3:21])[N:6]=[C:5]3[S:22][C:2]([C:32]4[CH:33]=[N:34][O:35][CH:36]=4)=[C:3]([CH3:23])[C:4]=23)(=[O:13])=[O:12])[CH:19]=[CH:18][CH:17]=1
Reactant: CC1(C)OB(c2cnoc2)OC1(C)C
Reactant: Cc1cc(NS(=O)(=O)c2cccc(Cl)c2)c2c(C)c(Br)sc2n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc(NS(=O)(=O)c2cccc(Cl)c2)c2c(C)c(-c3cnoc3)sc2n1
Temperature: 100 °C
Yield: 6 %

Procedure:
To a solution of N-(2-bromo-3,6-dimethylthieno[2,3-b]pyridin-4-yl)-3-chlorobenzenesulfonamide (Example 77) (80 mg, 0.185 mmol) in 1,4-dioxane (2 mL) and water (1 mL) was added 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole (36.1 mg, 0.185 mmol), bis(triphenylphosphine)palladium(II) chloride (13.01 mg, 0.019 mmol), and potassium carbonate (90 mg, 0.649 mmol) and the reaction mixture heated at 100° C. using a microwave reactor for 1.5 h. The reaction mixture was then filtered through celite, washing with DCM (30 mL) and the filtrate evaporated to dryness. The resulting material was then purified by MDAP (acidic conditions), to afford the title compound (4.67 mg). LCMS (A) m/z: 420 [M+1]+, Rt 1.09 min (acidic).
Reaction SMILES: C([O:3][C:4](=[O:25])[CH:5]([C:13]1[CH:18]=[CH:17][C:16]([S:19]([CH:22]2[CH2:24][CH2:23]2)(=[O:21])=[O:20])=[CH:15][CH:14]=1)[O:6][CH:7]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1)C.[Li+].[OH-]>O1CCCC1>[CH:22]1([S:19]([C:16]2[CH:15]=[CH:14][C:13]([CH:5]([O:6][CH:7]3[CH2:8][CH2:9][O:10][CH2:11][CH2:12]3)[C:4]([OH:25])=[O:3])=[CH:18][CH:17]=2)(=[O:21])=[O:20])[CH2:24][CH2:23]1
Reactant: CCOC(=O)C(OC1CCOCC1)c1ccc(S(=O)(=O)C2CC2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)C(OC1CCOCC1)c1ccc(S(=O)(=O)C2CC2)cc1
Reaction time: 2 h

Procedure:
To a stirred solution of intermediate 2-[4-(Cyclopropanesulfonyl)phenyl]-2-(tetrahydro-pyran-4-yloxy)acetic acid ethyl ester (8.0 g, 21 mmol) in tetrahydrofuran (80 mL) was added a solution of LiOH (2.27 g in 40 mL of water, 54 mmol) at 25° C. and stirred for 2 h. Completion of reaction was confirmed by TLC. Organic solvent was removed under reduced pressure. The aqueous layer was acidified to pH 2-3 using 1 N HCl. White solid obtained was filtered through Buchner funnel dried under vacuum to afford pure product.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH:5]1[C:10]1([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][Si](C(C)(C)C)(C)C)[CH:20]=2)[C:15](=[O:16])[NH:14][C:13](=[O:17])[NH:12][C:11]1=[O:18].C(O)(=O)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH:5]1[C:10]1([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([OH:25])[CH:20]=2)[C:15](=[O:16])[NH:14][C:13](=[O:17])[NH:12][C:11]1=[O:18]
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc(C2(C3CNCCN3CCO)C(=O)NC(=O)NC2=O)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: O=C1NC(=O)C(c2cccc(O)c2)(C2CNCCN2CCO)C(=O)N1
Reaction time: 3 h

Procedure:
To a solution of 5-[N-(2-hydroxyethyl)piperazinyl]-5-[3-(tertbutyldimethylsilyloxy)phenyl]barbituric acid (170 mg) in 12 ml of tetrahydrofuran, kept at 0° C. and under nitrogen atmosphere, are added 333 μl of acetic acid and 0.69 ml of tetrabutylammonium fluoride. The mixture is stirred for 3 hours then the solvent is evaporated off and the residue is purified by silica gel chromatography (15 g; eluent: ethyl acetate/methanol 4:1), to give, after crystallization from methanol, 35 mg of the product, m.p. 219-221° C.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][NH:10][CH:11]2[CH2:14][C:15]([OH:17])=[O:16])=[CH:6][CH:5]=1)([O-:3])=[O:2].[OH-].[K+].Cl[C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22].Cl>O>[C:25]1([CH2:24][O:23][C:21]([N:10]2[CH2:9][CH2:8][C:7]3[C:12](=[CH:13][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=3)[CH:11]2[CH2:14][C:15]([OH:17])=[O:16])=[O:22])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=C(O)CC1NCCc2ccc([N+](=O)[O-])cc21
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: O=C(O)CC1c2cc([N+](=O)[O-])ccc2CCN1C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 7-nitro-1,2,3,4-tetrahydroisoquinoline-1-acetic acid (5.0 g, 21.0 mmols) [Example 6(a)] in water (250 ml) at 0° C. was added 2M potassium hydroxide solution (15 ml). To this cooled solution was added in portions benzyl chloroformate (5.0 ml, 35 mmol) and the reaction mixture was stirred at 0° C. for 0.5 h. The solution was acidified with dilute hydrochloric acid and the precipitate which formed was collected. The dried solid was triturated with ether (200 ml) to give, after filtration, the title compound as a tan solid (4.83 g, 62%), m.p. 159.5-62° C.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH:10]=[O:11])=[CH:2]1.[H-].[Na+].[CH:14]([Si:17](Cl)([CH:21]([CH3:23])[CH3:22])[CH:18]([CH3:20])[CH3:19])([CH3:16])[CH3:15].O>O1CCCC1>[CH:14]([Si:17]([CH:21]([CH3:23])[CH3:22])([CH:18]([CH3:20])[CH3:19])[N:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH:10]=[O:11])=[CH:2]1)([CH3:16])[CH3:15]
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: O=Cc1c[nH]c2ncccc12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)[Si](C(C)C)(C(C)C)n1cc(C=O)c2cccnc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 1H-Pyrrolo[2,3-b]pyridine-3-carbaldehyde (46, 4.05 g, 27.71 mmol) in tetrahydrofuran (30.0 mL) were added sodium hydride (60% in mineral oil, 1.5 g, 38 mmol) and triisopropylsilyl chloride (8.0 mL, 38 mmol) under an atmosphere of nitrogen. The reaction was stirred for 2 hours at room temperature. The reaction was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 10% ethyl acetate in hexane to give compound (47, 3.0 g, 36%).
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[CH2:11]([O:13][C:14]([C:16]1[CH:20]=[C:19]([CH2:21][CH2:22][CH2:23][OH:24])[NH:18][N:17]=1)=[O:15])[CH3:12].C(N(CC)CC)C>C(Cl)Cl.C1COCC1>[CH2:11]([O:13][C:14]([C:16]1[CH:20]=[C:19]([CH2:21][CH2:22][CH:23]=[O:24])[NH:18][N:17]=1)=[O:15])[CH3:12]
Reactant: CCOC(=O)c1cc(CCCO)[nH]n1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(CCC=O)[nH]n1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Dimethylsulfoxide (0.14 mL, 1.9 mmol) was slowly added to a solution of oxalyl chloride (0.137 mg, 1.08 mmol) in CH2Cl2 (1 mL) and THF (1 mL) at −78° C. After stirring for 5 minutes, the solution was added dropwise to a solution of 5-(3-hydroxy-propyl)-1H-pyrazole-3-carboxylic Acid ethyl ester (178 mg, 0.898 mmol) in THF (10 mL) at −78° C. The reaction was stirred for 0.5 h and triethylamine (0.64 mL) was added. The suspension was stirred for 40 minutes and was warmed to room temperature. The reaction was diluted with CH2Cl2:hexanes (1:4, 40 mL) and the mixture was washed with 10% aqueous sodium bisulfate (15 mL) followed by water (2×10 mL). The organic solution was dried over MgSO4, filtered, and concentrated to provide the title aldehyde. 1H NMR (400 MHz, CDCl3) δ 9.82 (s, 1H), 6.59 (s, 1H), 4.35 (q, 2H), 3.06 (m, 2H), 2.84 (t, 2H), 1.91 (m, 2H), 1.34 (t, 3H); MS 197 (M+1).
Reaction SMILES: [CH3:1][C:2]([CH3:33])([CH3:32])[C@@H:3]([NH:11][C:12]([C:14]1[C:22]2[C:17](=[N:18][CH:19]=[C:20](Br)[N:21]=2)[N:16]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[CH:15]=1)=[O:13])[C:4]([N:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:5].[CH2:34]([N:36]1[CH:40]=[C:39](B2OC(C)(C)C(C)(C)O2)[CH:38]=[N:37]1)[CH3:35].C([O-])([O-])=O.[K+].[K+]>COCCOC.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][C:2]([CH3:33])([CH3:32])[C@@H:3]([NH:11][C:12]([C:14]1[C:22]2[C:17](=[N:18][CH:19]=[C:20]([C:39]3[CH:38]=[N:37][N:36]([CH2:34][CH3:35])[CH:40]=3)[N:21]=2)[N:16]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[CH:15]=1)=[O:13])[C:4]([N:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:5]
Reactant: CC(C)(C)[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12)C(=O)N1CCCC1
Reactant: CCn1cc(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: [K+]
Solvent: COCCOC
Product: CCn1cc(-c2cnc3c(n2)c(C(=O)N[C@@H](C(=O)N2CCCC2)C(C)(C)C)cn3COCC[Si](C)(C)C)cn1
Temperature: 90 °C
Yield: 75.2 %

Procedure:
In a pressure tube 2-bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2,2-dimethyl-1-(pyrrolidine-1-carbonyl)-propyl]-amide (162 mg, 0.30 mmol) and 1-ethyl-1H-pyrazole-4-boronic acid pinacol ester (80 mg, 0.36 mmol) were dissolved in DME (3.0 mL). Aqueous K2CO3 (2.0 M, 0.45 mL, 0.90 mmol) and Pd(PPh3)4 (17 mg, 0.015 mmol) were added and the mixture degassed with a gentle stream of N2 for 15 min. The vial was then sealed and heated at 90° C. for 6 h. The reaction mixture was cooled to room temperature, quenched with H2O and extracted with EtOAc. The organic extracts were washed with brine, dried over MgSO4, and concentrated. The residue was purified by SiO2 chromatography (20-100% EtOAc/hexane) to afford 125 mg (75%) of 2-(1-ethyl-1H-pyrazol-4-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2,2-dimethyl-1-(pyrrolidine-1-carbonyl)-propyl]-amide as a light brown foam.
Reaction SMILES: [CH2:1]([N:5]1[C:14]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=2[CH:8]=[C:7]([C:15]([OH:17])=O)[C:6]1=[O:18])[CH2:2][CH2:3][CH3:4].S(Cl)(Cl)=O.[CH2:23]([NH2:31])[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.Cl>C1(C)C=CC=CC=1.CN(C=O)C>[CH2:23]([NH:31][C:15]([C:7]1[C:6](=[O:18])[N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:14]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=2[CH:8]=1)=[O:17])[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: NCCc1ccccc1
Reactant: CCCCn1c2c(cc(C(=O)O)c1=O)CCCC2
Agent: Cl
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: CCCCn1c2c(cc(C(=O)NCCc3ccccc3)c1=O)CCCC2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 74.7 %

Procedure:
1-Butyl-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxylic; acid (4-002-01) (100 mg, 0.38 mmol) was dissloved in toluene (10 mL), and to the reaction mixture were added thionyl chloride (83 μL, 1.14 mmol) and catalytic amount of DMF, and the reaction mixture was reacted at 75° C. for 30 min. The reaction mixture was evaporated under reduced pressure and the residue was dissolved in methylene chloride (5 mL). To the reaction mixture was added phenethylamine (143 μL, 1.14 mmol) and the reaction mixture was stirred at room temperature for 10 min. To the reaction mixture was added diluted hydrochloric acid (1 mol/L, 10 mL) and the reaction mixture was extracted with ethyl acetate (30 mL), washed with brine (10 mL), dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (toluene/ethyl acetate), followed by recrystallization from diethyl ether to give 1-butyl-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxylic acid phenethylamide (4-002) (100 mg, 74%) as white crystal.
Reaction SMILES: [Mg].Cl[CH:3]1[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1.[O:9]=[C:10]1[C:15]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]3[C:24]([C:29]#[N:30])=[CH:25][CH:26]=[CH:27][CH:28]=3)=[CH:19][CH:18]=2)=[C:14]([CH2:31][CH2:32][CH3:33])[N:13]2[N:34]=[CH:35][N:36]=[C:12]2[N:11]1[CH:37]1[CH2:42][CH2:41][C:40](=[O:43])[CH2:39][CH2:38]1.Cl>BrCCBr.O1CCCC1>[OH:43][C:40]1([CH:3]2[CH2:8][CH2:7][O:6][CH2:5][CH2:4]2)[CH2:41][CH2:42][CH:37]([N:11]2[C:10](=[O:9])[C:15]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([C:23]4[C:24]([C:29]#[N:30])=[CH:25][CH:26]=[CH:27][CH:28]=4)=[CH:19][CH:18]=3)=[C:14]([CH2:31][CH2:32][CH3:33])[N:13]3[N:34]=[CH:35][N:36]=[C:12]23)[CH2:38][CH2:39]1
Reactant: ClC1CCOCC1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCC(=O)CC2)c2ncnn12
Agent: Cl
Agent: [Mg]
Solvent: BrCCBr
Solvent: C1CCOC1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCC(O)(C3CCOCC3)CC2)c2ncnn12
Temperature: 50 °C
Reaction time: 4 h
Yield: 52.5 %

Procedure:
To a mixture of magnesium (0.10 g) and tetrahydrofuran (1 mL) were added 4-chlorotetrahydro-2H-pyran (0.050 g) and 1,2-dibromoethane (10 drops) under an argon atmosphere. The mixture was heated to initiate the reaction, a solution of 4-chlorotetrahydro-2H-pyran (0.46 g) in tetrahydrofuran (5 mL) was added dropwise at 50° C., and the mixture was stirred at 50° C. for 4 hr. The reaction mixture was cooled to 0° C., a solution of 4′-{[5-oxo-4-(4-oxocyclohexyl)-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (0.50 g) in tetrahydrofuran (5 mL) was added dropwise, and the mixture was stirred at room temperature for 18 hr. The reaction mixture was added to 1 M hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography and HPLC to give the title compound as a colorless solid (0.12 g, 20%).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].FC(F)(F)C(O)=O.[NH2:15][CH2:16][CH2:17][C:18]([NH:20][C:21]1[CH:22]=[CH:23][C:24]2[NH:25][C:26]3[N:42]=[C:30]([NH:31][C:32]4[CH:33]=[CH:34][CH:35]=[C:36]([CH:41]=4)[CH2:37][CH2:38][C:39]=1[CH:40]=2)[N:29]=[CH:28][C:27]=3[Cl:43])=[O:19].[C:44]1([N:50]=[C:51]=[O:52])[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH:50]([C:51]([NH:15][CH2:16][CH2:17][C:18]([NH:20][C:21]1[CH:22]=[CH:23][C:24]2[NH:25][C:26]3[N:42]=[C:30]([NH:31][C:32]4[CH:33]=[CH:34][CH:35]=[C:36]([CH:41]=4)[CH2:37][CH2:38][C:39]=1[CH:40]=2)[N:29]=[CH:28][C:27]=3[Cl:43])=[O:19])=[O:52])[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: NCCC(=O)Nc1ccc2cc1CCc1cccc(c1)Nc1ncc(Cl)c(n1)N2
Reactant: O=C=Nc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(CCNC(=O)Nc1ccccc1)Nc1ccc2cc1CCc1cccc(c1)Nc1ncc(Cl)c(n1)N2
Yield: 35 %

Procedure:
The desired compound was prepared according to the procedure of Example A9, step H using 3-amino-N-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]propanamide bis(trifluoroacetate) and phenyl isocyanate as starting materials in 35% yield. LCMS for C28H27ClN7O2 (M+H)+: m/z=528.2.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][N:8]=2)[CH:6]=1.O.O.[Sn](Cl)Cl>CO>[Cl:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[N:8]=[CH:9][C:10]([NH2:13])=[CH:11][CH:12]=2)[CH:6]=1
Reactant: O=[N+]([O-])c1ccc(-n2cnc(Cl)c2)nc1
Agent: Cl[Sn]Cl
Solvent: CO
Solvent: O
Product: Nc1ccc(-n2cnc(Cl)c2)nc1
Temperature: 90 °C
Reaction time: 16 h
Yield: 64.9 %

Procedure:
A vial was charged with 2-(4-chloro-1H-imidazol-1-yl)-5-nitropyridine (675 mg, 3.01 mmol), tin(II) chloride dihydrate (2.03 g, 9.02 mmol), and methanol (10 mL). The vial was sealed and heated to 90° C. and stirred for 16 hours. The reaction was cooled to room temperature and concentrated. The residue was taken up in water (20 mL) and neutralized with saturated aqueous sodium bicarbonate. The mixture was extracted with ethyl acetate (3×50 mL) and the combined organics were dried over sodium sulfate, filtered, and concentrated. Purification by flash column chromatography gave 6-(4-chloro-1H-imidazol-1-yl)pyridin-3-amine (380 mg, 65%) as a light yellow solid. 1H NMR (400 MHz, CD3OD, δ): 8.20 (d, J=1.6 Hz, 1H), 7.89 (d, J=2.4 Hz, 1H), 7.68 (d, J=1.6 Hz, 1H), 7.38 (d, J=8.8 Hz, 1H), 7.21 (dd, J=8.8, 2.8 Hz, 1H).
Reaction SMILES: [N:1]([CH2:4][CH2:5][C@H:6]([NH:17][C:18]([C:20]1[C:21]2[CH:28]=[N:27][N:26]([C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)[C:22]=2[CH:23]=[N:24][CH:25]=1)=[O:19])[C:7]1[CH:12]=[CH:11][N:10]=[C:9]([S:13]([CH3:16])(=[O:15])=[O:14])[CH:8]=1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O.C(#N)C>C1COCC1>[NH2:1][CH2:4][CH2:5][C@H:6]([NH:17][C:18]([C:20]1[C:21]2[CH:28]=[N:27][N:26]([C:29]3[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=3)[C:22]=2[CH:23]=[N:24][CH:25]=1)=[O:19])[C:7]1[CH:12]=[CH:11][N:10]=[C:9]([S:13]([CH3:16])(=[O:14])=[O:15])[CH:8]=1
Reactant: CS(=O)(=O)c1cc([C@H](CCN=[N+]=[N-])NC(=O)c2cncc3c2cnn3-c2ccc(F)cc2)ccn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: O
Solvent: C1CCOC1
Product: CS(=O)(=O)c1cc([C@H](CCN)NC(=O)c2cncc3c2cnn3-c2ccc(F)cc2)ccn1
Reaction time: 75 h

Procedure:
To a room temperature solution of 1-(4-fluorophenyl)-1H-pyrazolo[3,4-c]pyridine-4-carboxylic acid [(S)-3-azido-1-(2-methanesulfonyl-pyridin-4-yl)-propyl]amide (86 mg, 0.17 mmol) in THF (7 mL) was added triphenylphosphine (57 mg, 0.22 mmol) (gas evolved) followed by water (700 μL). After 75 hours, the mixture was concentrated acetonitrile was added and the solution was filtered through a 0.45 um nylon Acrodisc and purified by reversed-phase HPLC using a 20 minute gradient of 5-95% MeCN (0.1% TFA) in H2O (0.1% TFA) (flow rate=25 mL/minute). The desired fractions were lyophilized to afford the title compound as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[Cl:24])[CH2:5][N:6]([CH3:20])[C:7]([C:9]1[CH2:10][N:11]([CH2:16][CH2:17][NH:18][CH3:19])[C:12](=[O:15])[C:13]=1[OH:14])=[O:8].CCN(CC)CC.[CH3:32][S:33](Cl)(=[O:35])=[O:34]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[Cl:24])[CH2:5][N:6]([CH3:20])[C:7]([C:9]1[CH2:10][N:11]([CH2:16][CH2:17][N:18]([S:33]([CH3:32])(=[O:35])=[O:34])[CH3:19])[C:12](=[O:15])[C:13]=1[OH:14])=[O:8]
Reactant: CNCCN1CC(C(=O)N(C)Cc2ccc(Cl)c(Cl)c2)=C(O)C1=O
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(Cc1ccc(Cl)c(Cl)c1)C(=O)C1=C(O)C(=O)N(CCN(C)S(C)(=O)=O)C1
Reaction time: 1 h
Yield: 12.9 %

Procedure:
To a stirred solution of 4-hydroxy-1-(2-methylamino-ethyl)-5-oxo-2,5-dihydro-1H-pyrrole-3-carboxylic acid (3,4-dichloro-benzyl)-methyl-amide (Compound 15) (150 mg, 0.367 mmol) in CH2Cl2 (5 mL) was added Et3N (0.14 mL, 1.0 mmol) followed by methanesulfonyl chloride (38 μL, 0.5 mmol) at room temperature. After 1 h, the reaction mixture was concentrated and the resulting residue was dissolved in methanol and purified by preparative HPLC on a C18 column using water/methanol-(0.1% TFA) as eluent. The fractions containing the desired product were combined, concentrated and lyophilized to give the title compound as a white powder (21.3 mg, 13% yield). 1HNMR (500 MHz, CDCl3) δ: 7.42 (1H, d, J=8.2 Hz), 7.35 (1H, s), 7.11 (1H, d, J=8.2 Hz), 4.58 (2H, s), 4.29 (2H, s), 3.71 (2H, t, J=5.8 Hz), 3.38 (2H, t, J=5.8 Hz), 3.02 (3H, s), 2.89 (3H, s), 2.78 (3H, s). HRMS calcd for C17H22Cl2N3O5S (M+H): 450.0657. found: 450.0658.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([S:14]([C:16]2[CH:17]=[C:18]3[C:23](=[CH:24][C:25]=2[Cl:26])[C:22](=[O:27])[N:21](CC2C=CC(OC)=CC=2)[CH:20]=[CH:19]3)=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C>C(O)(C(F)(F)F)=O>[Cl:26][C:25]1[CH:24]=[C:23]2[C:18]([CH:19]=[CH:20][NH:21][C:22]2=[O:27])=[CH:17][C:16]=1[S:14]([CH:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1)=[O:15]
Reactant: COc1ccc(Cn2ccc3cc(S(=O)C4CCN(C(=O)OC(C)(C)C)CC4)c(Cl)cc3c2=O)cc1
Solvent: O=C(O)C(F)(F)F
Product: O=c1[nH]ccc2cc(S(=O)C3CCNCC3)c(Cl)cc12
Temperature: 150 °C
Yield: 55.1 %

Procedure:
180 mg 4-[7-Chloro-2-(4-methoxy-benzyl)-1-oxo-1,2-dihydro-isoquinoline-6-sulfinyl]-piperidine-1-carboxylic acid tert-butyl ester (289) were dissolved in 2 ml of TFA and heated in a microwave at 150° C. for 40 min in total. After evaporation the mixture was dissolved in 1 N HCl and extracted with dichloromethane and lyophilized. 58 mg of 7-Chloro-6-(piperidine-4-sulfinyl)-2H-isoquinolin-1-one could be obtained as the hydrochloride. Rt=0.78 min (Method B). Detected mass: 311.1/313.1 (M+H+).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:10]([C:11](=[O:13])[CH3:12])[C@@H:9]([CH3:14])[CH2:8][N:7]([C:15]([CH:17]3[CH2:19][CH2:18]3)=[O:16])[C:6]=2[N:20]=1.BrC1C=CC2N(C(=O)C)[C@@H](C)CNC=2N=1.C1(C(Cl)=O)CC1.BrC1C=C2C(=CC=1)N(C(=O)C)[C@@H](C)CN2C(C1CC1)=O.[C:62]1([OH:68])[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(OCC)(=O)C.[Cu]I.C(#N)C>[CH:17]1([C:15]([N:7]2[CH2:8][C@H:9]([CH3:14])[N:10]([C:11](=[O:13])[CH3:12])[C:5]3[CH:4]=[CH:3][C:2]([O:68][C:62]4[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=4)=[N:20][C:6]2=3)=[O:16])[CH2:19][CH2:18]1
Reactant: CC(=O)N1c2ccc(Br)nc2N(C(=O)C2CC2)C[C@@H]1C
Reactant: Oc1ccccc1
Agent: [Cu]I
Agent: CC(=O)N1c2ccc(Br)cc2N(C(=O)C2CC2)C[C@@H]1C
Agent: CC(=O)N1c2ccc(Br)nc2NC[C@@H]1C
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(=O)N1c2ccc(Oc3ccccc3)nc2N(C(=O)C2CC2)C[C@@H]1C
Temperature: 80 °C
Yield: 56 %

Procedure:
A 1.5 mL reaction vial was charged with (S)-1-(6-bromo-4-(cyclopropanecarbonyl)-2-methyl-3,4-dihydropyrido[2,3-b]pyrazine-1(2H)-yl)ethanone (synthesized from Intermediate 6 and cyclopropane carbonyl chloride according to the procedure used to prepare Intermediate 15, 6.76 mg, 0.02 mmol), phenol (3.76 mg, 0.040 mmol), copper (I) iodide (0.762 mg, 4.00 μmol), cesium carbonate (0.012 g, 0.036 mmol), and acetonitrile (250 μL). The reaction was heated on a heater shake at 80° C. for 18 hrs. The reaction was diluted with ethyl acetate and washed with 1 N aqueous sodium hydroxide solution. The aqueous layer was separated and washed with ethyl acetate and the combined organic layers were concentrated under a stream of nitrogen. The crude product was purified by mass triggered preparatory HPLC. The product-containing fractions were combined and concentrated in a Genevac to afford (S)-1-(4-(cyclopropanecarbonyl)-2-methyl-6-phenoxy-3,4-dihydropyrido[2,3-b]pyrazine-1 (2H)-yl)ethanone (0.0039 g, 56%). MS (ESI, pos. ion) m/z 352.
Reaction SMILES: [Na+].[C:2]1([CH3:11])[C:3]([S:8]([O-:10])=[O:9])=[CH:4][CH:5]=[CH:6][CH:7]=1.O.Cl>C(OC)(C)(C)C>[C:2]1([CH3:11])[C:3]([S:8]([OH:10])=[O:9])=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccccc1S(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: O
Product: Cc1ccccc1S(=O)O
Yield: 73.2 %

Procedure:
Toluenesulfinic acid sodium salt (150 g, 0.84 mol), H2O (500 mL), and t-butylmethyl ether (TBME) (250 mL) were vigorously stirred, and concd HCl (75 mL) was added dropwise. The resulting two phases were separated and the aqueous phase was extracted with TBME (100 mL). The TBME phases were dried (Na2SO4) and concentrated to near dryness and the white solid was combined with hexane (350 mL) and filtered and dried in vacuo to afford 96 g of toluenesulfinic acid.