Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:6][CH2:5]S[CH2:3][CH2:2]1.O[O:18][S:19]([O-:21])=O.[K+]>CO.O>[N:1]1([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:2][CH2:3][S:19](=[O:21])(=[O:18])[CH2:5][CH2:6]1
Reactant: O=C(OCc1ccccc1)N1CCSCC1
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: CO
Solvent: O
Product: O=C(OCc1ccccc1)N1CCS(=O)(=O)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 69.8 %

Procedure:
To a solution of benzyl 4-thiomorpholinecarboxylate (4.8 g) in methanol (30 mL) and H2O (20 mL) was added oxone (16.2 g) under ice water cooling and the mixture was stirred at ambient temperature for 2 hours. The solution was evaporated in vacuo and partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc. The combined organic layer was washed with water and brine, dried over MgSO4 and evaporated in vacuo. The residue was purified by silica gel column chromatography eluting with a mixture of hexane and EtOAc to give benzyl 4-thiomorpholinecarboxylate 1,1-dioxide as a colorless solid (3.8 g).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)N)#[N:2].[ClH:10].N([O-])=O.[Na+].[S:15](=[O:17])=[O:16]>O>[C:1]([C:3]1[CH:4]=[C:5]([S:15]([Cl:10])(=[O:17])=[O:16])[CH:7]=[CH:8][CH:9]=1)#[N:2]
Reactant: O=S=O
Reactant: N#Cc1cccc(N)c1
Reactant: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: N#Cc1cccc(S(=O)(=O)Cl)c1
Reaction time: 1 h

Procedure:
25.0 g (212 mmol) of 3-cyanoaniline was added to a mixed solution of 200 ml of water and 250 ml of concentrated hydrochloric acid and the mixture was stirred. An aqueous solution (80 ml) containing 15.5 g (223 mmol) of sodium nitrite was added dropwise into the mixture at −10° C. The reaction solution was added to a sulfur dioxide saturated acetic acid solution (solution prepared by saturating 250 ml of acetic acid with sulfur dioxide and then adding 2.1 g of cuprous chloride thereto) under ice-cooling with stirring. After one hour, the reaction solution was poured into 500 ml of ice-water and extracted with diethyl ether. The extract was successively washed with an aqueous saturated sodium bicarbonate, water and brine, and dried over magnesium sulfate. The solvent was evaporated, and to the residue was added a mixed solution of diethyl ether and hexane. The crystals were collected by filtration, to give 16.0 g of the title compound.
Reaction SMILES: B(F)(F)F.CCOCC.O[C:11]1([CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[O:15][C:14]2[CH:22]=[C:23]([O:26][CH3:27])[CH:24]=[CH:25][C:13]=2[CH2:12]1.C([SiH](CC)CC)C>C(Cl)Cl.C(O)C.[Pd]>[CH3:27][O:26][C:23]1[CH:24]=[CH:25][C:13]2[CH2:12][CH:11]([CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[O:15][C:14]=2[CH:22]=1
Reactant: CCOC(=O)CC1(O)Cc2ccc(OC)cc2Oc2ccccc21
Agent: [Pd]
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Solvent: CCO
Solvent: CCOCC
Solvent: ClCCl
Product: CCOC(=O)CC1Cc2ccc(OC)cc2Oc2ccccc21
Reaction time: 0.33 h
Yield: 85.9 %

Procedure:
Boron trifluoride etherate (0.48 mL, 3.9 mmole) was added to a solution of ethyl (±)-10,11-dihydro-10-hydroxy-3-methoxydibenzo[b,f]oxepine-10-acetate (690 mg, 1.95 mmole) and triethylsilane (0.62 mL, 3.9 mmole) in dry CH2Cl2 at 0° C. under argon. After 20 min, the reaction was quenched with 5% NaHCO3, and the mixture was extracted with CH2Cl2. Drying (MgSO4) and concentration gave a yellow oil. This was dissolved in absolute ethanol (20 mL) and 10% Pd/C (413 mg, 0.39 mmole) was added. The mixture was hydrogenated for 3 hr at 50 psi on a Parr hydrogenation apparatus. The catalyst was removed by filtration through celite®, and the filtrate was concentrated to afford the title compound (523 mg, 86%) as a clear oil. 1H NMR (300 MHz, CDCl3) δ7.18-6.58 (m, 7 H), 4.18-4.08 (m, 2 H), 3.80 (s, 3 H), 3.80-3.74(m, 1 H), 3.40-3.30 (dd, 1 H). 2.98-2.84 (dd, 1 H), 2.74-2.62 (dd, 1 H), 2.60-2.52(m, 1 H), 1.32-1.20 (t, 3 H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]([OH:19])=O)=[CH:14][CH:15]=2)[N:10]([CH:20]([CH3:22])[CH3:21])[N:9]=1.[CH3:23][C:24]1[N:28]=[C:27]([C@H:29]([NH2:31])[CH3:30])[O:26][N:25]=1.Cl.CN(C)CCCN=C=NCC.ON1C2N=CC=CC=2N=N1.CN1CCOCC1>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]([NH:31][C@@H:29]([C:27]3[O:26][N:25]=[C:24]([CH3:23])[N:28]=3)[CH3:30])=[O:19])=[CH:14][CH:15]=2)[N:10]([CH:20]([CH3:22])[CH3:21])[N:9]=1
Reactant: CC(C)n1nc(-c2ccccc2Cl)c2ccc(C(=O)O)cc21
Reactant: Cc1noc([C@@H](C)N)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: Cc1noc([C@@H](C)NC(=O)c2ccc3c(-c4ccccc4Cl)nn(C(C)C)c3c2)n1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 67.4 %

Procedure:
To a solution of 3-(2-chlorophenyl)-1-isopropyl-1H-indazole-6-carboxylic acid (13.3 mg, 42.0 μmol) in N,N-dimethylformamide (0.5 mL) were added hydrochloride salt of (1R)-1-(3-methyl-1,2,4-oxadiazol-5-yl)ethanamine (10.4 mg, 63.0 μmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (16.2 mg, 85.0 μmol), 1-hydroxy-7-azabenzotriazole (2.9 mg, 21.0 μmol) and N-methylmorpholine (18.6 μL, 0.17 mmol). The mixture was heated to 50° C. and stirred for 30 min. Purification by reverse phase HPLC (C-18, 95% water/acetonitrile→5% water/acetonitrile with 0.1% trifluoroacetic acid) gave the bistrifluoroacetate salt of the title compound (12 mg): HRMS [M+1] found=424.1530; 1H NMR (500 MHz, CDCl3): δ 8.12 (s, 1H); 7.75 (d, J=8.4 Hz, 1H); 7.63-7.59 (m, 1H); 7.57-7.53 (m, 1H); 7.49 (d, J=8.4 Hz, 1H); 7.39 (dd, J=5.9, 3.5 Hz, 2H); 6.84 (d, J=7.7 Hz, 1H); 5.68-5.61 (m, 1H); 5.03-4.95 (m, 1H); 2.42 (s, 3H); 1.74 (d, J=7.0 Hz, 3H); 1.67 (d, J=6.6 Hz, 6H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[O:17][CH2:16][CH2:15][C:14]([C:18]([NH:20][C:21]4[CH:26]=[CH:25][C:24]([CH2:27][S:28][C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)=[CH:23][CH:22]=4)=[O:19])=[CH:13][C:12]=3[CH:35]=2)=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:44])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[O:17][CH2:16][CH2:15][C:14]([C:18]([NH:20][C:21]4[CH:26]=[CH:25][C:24]([CH2:27][S:28]([C:29]5[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=5)=[O:44])=[CH:23][CH:22]=4)=[O:19])=[CH:13][C:12]=3[CH:35]=2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CSc4ccccc4)cc2)CCO3)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CS(=O)c4ccccc4)cc2)CCO3)cc1
Reaction time: 0.5 h
Yield: 106.4 %

Procedure:
To a solution of 7-(4-methylphenyl)-N-(4-(phenylthiomethyl)phenyl)-2,3-dihydro-1-benzoxepine-4-carboxamide (0.1 g) in dichloromethane (30 ml) was added 70% m-chloroperbenzoic acid (0.046 g) at the temperature ranging from -20 to -10° C., and the mixture was stirred for 30 minutes. To the mixture was added sodium thiosulfate solution, and the mixture was concentrated and extracted with ethyl acetate. The organic layer was washed with sodium hydrogen carbonate solution, water and saturated sodium chloride solution, and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated to give crude crystals, which were recrystallized from ethyl acetate-hexane to give 7-(4-methylphenyl)-N-(4-(phenylsulfinylmethyl)phenyl)-2,3-dihydro-1-benzoxepine-4-carboxamide (Compound 108) (0.11 g) as colorless crystals.
Reaction SMILES: Br([O-])(=O)=O.[Na+].[CH2:6]([OH:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.CC[O:16]CC>C(#N)C.O>[C:6]([OH:16])(=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CCOCC
Reactant: OCc1ccccc1
Agent: [Na+]
Agent: [O-][Br+2]([O-])[O-]
Solvent: CC#N
Solvent: O
Product: O=C(O)c1ccccc1
Temperature: 80 °C
Reaction time: 40 h
Yield: 90 %

Procedure:
A mixture of Ceiv catalyst from Example 47 (0.08 g), sodium bromate (0.3 g) and benzyl alcohol (0.216 g, 2 mmol) in acetonitrile:water (5:7, 12 ml) was stirred at 80° C. for 40 h under an atmosphere of nitrogen. On cooling ether (70 ml) was added and the catalyst was filtered off. The organic layer was separated and the aqueous phase was extracted with ether (2×50 ml). The combined organic extracts were washed with water (25 ml), dried with anhydrous magnesium sulphate and concentrated to give benzoic acid as a white solid (0.22 g, 90%). M.p. 120° C., lit. 120-122° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5]([O:8][CH2:9][CH:10]2[CH2:15][CH:14]3[N:16](C(OC(C)(C)C)=O)[CH:11]2[CH2:12][CH2:13]3)=[N:6][CH:7]=1.Cl>O1CCOCC1.CC(O)C>[F:1][C:2]1[CH:3]=[N:4][C:5]([O:8][CH2:9][CH:10]2[CH2:15][CH:14]3[NH:16][CH:11]2[CH2:12][CH2:13]3)=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1C2CCC1C(COc1ncc(F)cn1)C2
Agent: Cl
Solvent: CC(C)O
Solvent: C1COCCO1
Product: Fc1cnc(OCC2CC3CCC2N3)nc1
Temperature: 40 °C

Procedure:
To the title compound from step A (474 mg, 1.5 mmol) in 1,4-dioxane (1.5 mL) was added 6N HCl in iPrOH (1.5 mL). The reaction was heated to 40° C. for 1.5 h and concentrated to give the title compound that was used without further purification in subsequent steps. MS (ESI) mass calcd. for C11H14FN3O, 223.1; m/z found 224.0 [M+H]+.
Reaction SMILES: [Mg].[CH3:2][Si:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)(Cl)Cl.[CH2:12]1[CH2:16]O[CH2:14][CH2:13]1.C=CC=C>CCOCC.C(O)CO>[CH3:2][Si:3]1([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH2:14][CH:13]=[CH:12][CH2:16]1
Reactant: C1CCOC1
Reactant: C[Si](Cl)(Cl)c1ccccc1
Agent: C=CC=C
Agent: [Mg]
Solvent: CCOCC
Solvent: OCCO
Product: C[Si]1(c2ccccc2)CC=CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 42 %

Procedure:
In a 500 mL two neck rb flask equipped with a reflux condenser, a Teflon covered magnetic stirring bar and a rubber septum was placed active magnesium powder (9.6 g, 0.4 mol), methylphenyldichlorosilane (38.2 g, 0.2 mol) and THF (300 mL). The reflux condenser was connected to a refrigeration unit. Ethylene glycol cooled to -20° C. was circulated through the reflux condenser. 1,3-Butadiene (15.1 g, 0.28 mol) was condensed at -78° C. into a volumetric flask which was sealed with a rubber septum. The 1,3-butadiene was transferred into the reaction via a cannula. The reaction mixture was stirred at rt for 24 h. Ether (2×100 mL) was added. The organic solution was decanted from the magnesium chloride salts. These were transferred to a sintered glass funnel and were washed with ether (100 mL). The combined organic solution was washed with water (2×50 mL), dried over anhydrous magnesium sulfate, filtered and the volatile solvents removed by evaporation under reduced pressure. The residue was purified by distillation through a 10 cm vacuum jacketed Vigreux column. The expected compound, bp 105°-107° C., 5 mm Hg, 42% yield, was collected.
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH:2]=[CH2:3].[OH-].[Na+].[CH2:8]([CH:14]=CC(N)=O)[CH:9]=[CH:10]C(N)=O.O>C(OCC)(=O)C>[C:1]([O:5][CH2:14][CH2:8][CH2:9][CH3:10])(=[O:4])[CH:2]=[CH2:3].[C:1]([OH:5])(=[O:4])[C:2]([CH3:8])=[CH2:3]
Reactant: C=CC(=O)O
Reactant: NC(=O)C=CCC=CC(N)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: C=C(C)C(=O)O
Product: C=CC(=O)OCCCC

Procedure:
An aqueous monomer phase was formed containing 40 g acrylic acid, 36.2 g of 46% sodium hydroxide solution, 0.03 g methylenebisacrylamide and 73.8 g water. A continuous phase was formed of 500 g ethyl acetate and 20 g of a stabiliser of composition butyl acrylate/methacrylic acid (90/10 by weight), prepared in a similar manner to Example 1.
Reaction SMILES: [OH:1][C:2]1[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][N:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:3]=1.[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:18]([O:1][C:2]1[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][N:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:3]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CCOC(=O)c1cn(-c2ccccc2)nc1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(-c2ccccc2)nc1OCc1ccccc1
Temperature: 50 °C
Reaction time: 8 h
Yield: 77 %

Procedure:
A mixture of ethyl 3-hydroxy-1-phenyl-1H-pyrazole-4-carboxylate (7.76 g), benzyl bromide (3.97 mL), potassium carbonate (6.91 g) and N,N-dimethylformamide (75 mL) was stirred overnight at 50° C. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed successively with dilute hydrochloric acid and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give ethyl 3-benzyloxy-1-phenyl-1H-pyrazole-4-carboxylate (8.29 g, yield 77%) as colorless crystals from a fraction eluted with ethyl acetate-hexane (1:1, v/v). The crystals were recrystallized from ethyl acetate-hexane. melting point: 113-114° C.
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=[O:29])[C:5]2[N:6]=[CH:7][N:8]([CH2:11][O:12][CH2:13][CH2:14][O:15][C:16]([C:18]3([NH:21]C(OC(C)(C)C)=O)[CH2:20][CH2:19]3)=[O:17])[C:9]=2[N:10]=1.[F:30][C:31]([F:36])([F:35])[C:32]([OH:34])=[O:33]>C(Cl)Cl>[F:30][C:31]([F:36])([F:35])[C:32]([OH:34])=[O:33].[NH2:1][C:2]1[NH:3][C:4](=[O:29])[C:5]2[N:6]=[CH:7][N:8]([CH2:11][O:12][CH2:13][CH2:14][O:15][C:16]([C:18]3([NH2:21])[CH2:20][CH2:19]3)=[O:17])[C:9]=2[N:10]=1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)OCCOCn2cnc3c(=O)[nH]c(N)nc32)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1nc2c(ncn2COCCOC(=O)C2(N)CC2)c(=O)[nH]1
Temperature: 25 °C
Yield: 67.7 %

Procedure:
Suspend 1-tert-butoxycarbonylamino-cyclopropanecarboxylic acid 2-(2-amino-6-oxo-1,6-dihydro-purin-9-ylmethoxy)-ethyl ester (0.20 g, 0.49 mmol) in methylene chloride (2 mL) and stir at room temperature. Add trifluoroacetic acid (2 mL) dropwise and continue stirring. The suspension dissolves to give clear solution. Concentrate to dryness under vacuum. Triturate with ethyl acetate several times to isolate a white solid. Yield: 67.7% MS (ES+): 309.2 (M+1) MS (ES−): 307.2 (M−1)
Reaction SMILES: [O:1]=[C:2]([CH3:15])[CH2:3][C:4]([NH:6][CH2:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=[O:5].[N+:16]([C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH:22]=O)([O-:18])=[O:17].C(O)(=O)C.N1CCCCC1>C(O)(C)C>[N+:16]([C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH:22]=[C:3]([C:2](=[O:1])[CH3:15])[C:4]([NH:6][CH2:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=[O:5])([O-:18])=[O:17]
Reactant: CC(=O)CC(=O)NCC(=O)OC(C)(C)C
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Solvent: C1CCNCC1
Solvent: CC(=O)O
Solvent: CC(C)O
Product: CC(=O)C(=Cc1cccc([N+](=O)[O-])c1)C(=O)NCC(=O)OC(C)(C)C
Reaction time: 15 h

Procedure:
9.821 g (45.6 mmol) of t-butyl 2-[N-(3-oxobutanoyl)-amino]acetate and 6.891 g (45.6 mmol) of 3-nitrobenzaldehyde were suspended in 50 ml of isopropyl alcohol. With addition of 0.331 g (2.28 mmol) of piperidine acetate, the mixture was stirred for 15 hours. The above mixture was ice-cooled for one hour and the precipitated crystals were separated by filtration. The thus obtained crystals were washed with cooled isopropyl alcohol and dried under reduced pressure. The thus obtained crystals were recrystallized from acetonitrile, whereby 13.5 g (85%) of the captioned compound was obtianed.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:15][CH2:16][C:17]([CH3:20])([OH:19])[CH3:18])=[C:7]([N+:12]([O-])=O)[CH:8]=[N:9]2)=[N:4][CH:3]=1>[Pt].C(#N)C.CO>[NH2:12][C:7]1[CH:8]=[N:9][C:10]2[C:5]([C:6]=1[NH:15][CH2:16][C:17]([CH3:18])([OH:19])[CH3:20])=[N:4][CH:3]=[C:2]([Br:1])[CH:11]=2
Reactant: CC(C)(O)CNc1c([N+](=O)[O-])cnc2cc(Br)cnc12
Agent: [Pt]
Solvent: CO
Solvent: CC#N
Product: CC(C)(O)CNc1c(N)cnc2cc(Br)cnc12
Yield: 99.6 %

Procedure:
A Parr vessel was charged with 5% platinum on carbon (5.8 g) and a suspension of 1-[(7-bromo-3-nitro[1,5]naphthyridin-4-yl)amino]-2-methylpropan-2-ol (58.00 g) in acetonitrile (800 mL) and methanol (400 mL). The vessel was placed under hydrogen pressure (30 psi, 2.1×105 Pa) for 8 hours. The reaction mixture was filtered through a layer of CELITE filter aid. The filtrate was concentrated under reduced pressure to provide 52.70 g of 1-[(3-amino-7-bromo[1,5]naphthyridin-4-yl)amino]-2-methylpropan-2-ol as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([C:12](Cl)=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.ClC1C=C(C(O)=O)C2C(=CC=CC=2)N=1.[N-:29]=[N+:30]=[N-:31].[Na+].CC(C)=O>O1CCOCC1.O>[Cl:1][C:2]1[CH:11]=[C:10]([C:12]([N:29]=[N+:30]=[N-:31])=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: O=C(Cl)c1cc(Cl)nc2ccccc12
Reactant: [N-]=[N+]=[N-]
Agent: O=C(O)c1cc(Cl)nc2ccccc12
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: [N-]=[N+]=NC(=O)c1cc(Cl)nc2ccccc12
Reaction time: 16 h

Procedure:
2-Chloro-4-chlorocarbonylquinoline (0.5 g), prepared by standard methods from 2-chloroquinoline-4-carboxylic acid, was added to sodium azide in aqueous dioxan (2.1 ml 1:3) at 0° C. Acetone was then added and the mixture stirred for 16 h. Water (10 ml) was added, the precipitated solid collected by filtration and air dried to give 2-chloroquinoline-4-carbonyl azide (0.455 g). The azide (0.232 g) in toluene (10 ml) was warmed from room temperature to 75° C. and then heating continued for 1 h. After cooling to room temperature 6-amino-2-methylbenzoxazole (0.148 g) in dichloromethane (15 ml) containing 4-N,N-dimethylaminopyridine (20 mg) was added and the mixture stirred for 16 h. The precipitated solid was separated by filtration to give a solid (0.25 g). Column chromatography (silica gel, dichloromethane/methanol/ammonia mixtures) gave the title compound (0.072 g). 1H NMR δ: 5 2.60 (3H, s), 7.25 (1H, d, J=8.5 Hz), 7.61 (1H, d, J=8.5 Hz), 7.73 (1H, t, J=7.0 Hz), 7.84 (1H, t, J=6.7 Hz), 7.91 (1H, d, J=8.0 Hz), 8.05 (1H, s), 8.20 (1H, d, J=8.25 Hz), 8.28 (1H, s), 9.49 (1H, s), 9.61 (1H, s). m/z (API+): 353, 355(MH+).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:8]=[C:7]([NH2:9])[CH:6]=[CH:5][CH:4]=1.C1(C)C=CC=CC=1.CC1C=CC(S(O)(=O)=O)=CC=1.[C:28]1([C:34](=O)[CH2:35][CH2:36][C:37]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=O)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>CCO>[C:28]1([C:34]2[N:1]([CH2:2][C:3]3[N:8]=[C:7]([NH2:9])[CH:6]=[CH:5][CH:4]=3)[C:37]([C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=3)=[CH:36][CH:35]=2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=C(CCC(=O)c1ccccc1)c1ccccc1
Reactant: NCc1cccc(N)n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: CCO
Product: Nc1cccc(Cn2c(-c3ccccc3)ccc2-c2ccccc2)n1

Procedure:
6-(Aminomethyl)pyridin-2-amine (0.050 g, 0.4 mmol) was dissolved in EtOH (2 mL) and Toluene (10 mL) was added. To this mixture was added pTSA (5 mg) and 1,4-diphenyl-1,4-butanedione (0.124 g, 0.4 mmol). The solution was heated to reflux overnight. The solvent was removed and the residue was purified by flash chromatography (20:1 CHCl3: MeOH) to yield 6-[(2,5-diphenyl-1H-pyrrol-1-yl)methyl]pyridin-2-amine as a white solid. mp 143-144° C.; 1H NMR (500 MHz, DMSO-d6) δ: 5.06 (s, 2H), 5.50 (d, 1H, J=7.3 Hz), 5.82 (s, 2H), 6.16 (d, 1H, J=8.1 Hz), 6.34 (s, 2H), 7.18 (t, 1H, J=7.47 Hz), 7.28 (t, 2H, J=8.5 Hz), 7.36 (m, 4H), 7.40 (m, 4H); MS (ES) m/z 326.3.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[C:12]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:13]=1[CH:14]=[CH:15][C:16]([S:22]([NH:25][C:26]1[CH:31]=[CH:30][N:29]=[CH:28][N:27]=1)(=[O:24])=[O:23])=[CH:17]2.CC1(C)C(C)(C)OB([C:40]2[CH2:45][CH2:44][N:43]([C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[CH2:42][CH:41]=2)O1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C(C1C(C(C)(C)C)=C([Pd]Cl)C=CC=1NC)(C)(C)C.CCOC(C)=O>[N:29]1[CH:30]=[CH:31][C:26]([NH:25][S:22]([C:16]2[CH:17]=[C:18]3[C:13](=[CH:14][CH:15]=2)[C:12]([C:3]2[CH:4]=[CH:5][C:6]([C:8]([F:9])([F:10])[F:11])=[CH:7][C:2]=2[C:40]2[CH2:45][CH2:44][N:43]([C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[CH2:42][CH:41]=2)=[CH:21][CH:20]=[CH:19]3)(=[O:24])=[O:23])=[N:27][CH:28]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: O=S(=O)(Nc1ccncn1)c1ccc2c(-c3ccc(C(F)(F)F)cc3Cl)cccc2c1
Agent: CNc1ccc([Pd]Cl)c(C(C)(C)C)c1C(C)(C)C
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CC=C(c2cc(C(F)(F)F)ccc2-c2cccc3cc(S(=O)(=O)Nc4ccncn4)ccc23)CC1
Temperature: 110 °C
Yield: 46.1 %

Procedure:
A microwave vial was charged with 5-(2-chloro-4-(trifluoromethyl)phenyl)-N-(pyrimidin-4-yl)naphthalene-2-sulfonamide (Intermediate X) (82.5 mg, 0.178 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (110 mg, 0.356 mmol), potassium phosphate (113 mg, 0.534 mmol), and 1,1-bis[(di-t-butyl-p-methylaminophenyl]palladium(II) chloride (12.59 mg, 0.018 mmol). The vial was sealed, flushed with N2 and dioxane (1334 μl) and water (445 μl) was added. The mixture was sparged for 5 min with N2. The mixture was heated in a microwave at 110° C. for 4 h. The mixture was concentrated for purification by MPLC. The residue was taken up in minimal CH2Cl2 and absorbed onto a 5 g loading cartridge and passed through a silica gel column (12 g) using a 98:2 Heptane:EtOAc to 100% EtOAc (with 1% constant EtOH additive) gradient to afford tert-butyl 4-(2-(6-(N-(pyrimidin-4-yl)sulfamoyl)naphthalen-1-yl)-5-(trifluoromethyl)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate (50.0 mg, 0.082 mmol) as a light-yellow amorphous solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[O:9][CH3:10].[C:11]([Cu])#[N:12].[NH4+].[OH-]>CN1CCCC1=O>[F:8][C:5]1[CH:6]=[CH:7][C:2]([C:11]#[N:12])=[C:3]([O:9][CH3:10])[CH:4]=1
Reactant: N#C[Cu]
Reactant: COc1cc(F)ccc1Br
Agent: [NH4+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: COc1cc(F)ccc1C#N
Temperature: 180 °C
Reaction time: 5.5 h
Yield: 78.4 %

Procedure:
To a solution of intermediate 126, 1-bromo-4-fluoro-2-methoxybenzene (9.0 g) in N-methylpyrrolidone (100 mL, Sure Seal; Aldrich) was added CuCN (6.6 g, 73.7 mmol, 1.8 eq.; Aldrich), and the mixture stirred at 180° C. under anhydrous nitrogen for 5.5 hrs. After cooling, 14% aqueous NH4OH (330 mL) was added and stirring continued for 45 min at room temperature. The mixture was extracted with ether (100 mL×3), and the combined extracts washed sequentially with dilute aqueous NH4OH, dilute HCl and brine, then dried (MgSO4), and concentrated to provide the title compound (5.2 g, Yield 85% in 2 steps) as a white solid: 1H NMR (CDCl3, 500 MHz) δ ppm: 3.91 (3H, s, OMe), 6.69 (1H, dd, J=2.3 Hz, J=10.5 Hz, Ar—H), 6.72 (1H, dt, J=2.5 Hz, J=J=8.0 Hz, Ar—H), 7.55 (1H, dd; J=6.5 Hz, J=8.5 Hz, Ar—H); 13C NMR (CDCl3, 125.8 Hz) δ ppm: 56.49, 98.16, 100.06, 100.27, 108.31, 108.50, 115.83 135.37, 135.46, 163.25, 163.34 165.47, 167.50. An analytical sample was obtained by trituration with ether: Anal. calcd for C8H6FNO: C, 63.57; H, 4.00; N, 9.26; found: C, 63.36; H, 3.91; N, 9.16.
Reaction SMILES: [CH2:1]1[CH2:3][CH:2]1[NH:4][CH2:5][C:6]([C:8]1[N:9]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])[CH:10]=[CH:11][CH:12]=1)=[O:7].[BH4-].[Na+].CO.O>C(O)(C)C>[CH:2]1([NH:4][CH2:5][CH:6]([C:8]2[N:9]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[F:20])[CH:10]=[CH:11][CH:12]=2)[OH:7])[CH2:3][CH2:1]1
Reactant: O=C(CNC1CC1)c1cccn1Cc1ccccc1F
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Solvent: CO
Product: OC(CNC1CC1)c1cccn1Cc1ccccc1F
Temperature: 85 °C

Procedure:
A solution of 8.0 g of 2-(2-cyclopropylamino)acetyl-1-(o-fluorobenzyl)pyrrole, free base of a, in 100 ml of isopropyl alcohol is added to a suspension of 2.2 g sodium borohydride in 100 ml of isopropanol. The reaction mixture is refluxed at 85° C. for 4 hours, allowed to cool to ambient temperature and 50 ml of methanol introduced. The solvent is removed leaving a yellow semi-solid which is treated with water and then extracted into ether. The ether extract is washed with water, dried and filtered and the solvent removed leaving a pure yellow oil of 2-(cyclopropylamino)-1-[1-(o-fluorobenzyl)-2-pyrryl]ethanol. Infrared and nuclear magnetic resonance spectra confirm this structure.