Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[CH2:6][O:7][C:8]([C:10]1[CH:11]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[Cl:28])[C:12]([C:18]([O:20][CH3:21])=[O:19])=[C:13]([CH3:17])[NH:14][C:15]=1[CH3:16])=[O:9].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>C(Cl)Cl>[O:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[CH2:6][O:7][C:8]([C:10]1[C:11]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[Cl:28])=[C:12]([C:18]([O:20][CH3:21])=[O:19])[C:13]([CH3:17])=[N:14][C:15]=1[CH3:16])=[O:9]
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OCC2CCCO2)C1c1ccccc1Cl
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: COC(=O)c1c(C)nc(C)c(C(=O)OCC2CCCO2)c1-c1ccccc1Cl
Temperature: 25 °C
Reaction time: 5 h
Yield: 66 %

Procedure:
A mixture of 8 g (0.02 mol) of 4-(2-chlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid 3-methyl ester 5-(tetrahydrofuran-2-ylmethyl) ester, obtained according A) and 71 g (0.059 mol) of pyridinium chlorochromate adsorbed on alumina, was suspended in 200 ml of CH2Cl2, and the whole mixture was stirred at room temperature for 5 hours. The remaining solid was eliminated by filtration, and the liquid was washed with water (3×250 ml), dried over anh. Na2SO4, and concentrated at reduced pressure, to dryness. The product was obtained as an oil, which was purified by column chromatography (Silicagel, n-hexane:EtAcO, 8:2) with a yield of 66%,
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][CH:3]1[NH:12]C(=O)C.[ClH:16]>>[ClH:16].[NH2:12][CH:3]1[CH2:4][CH2:5][C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]1=[O:1]
Reactant: CC(=O)NC1CCc2ccccc2C1=O
Agent: Cl
Product: NC1CCc2ccccc2C1=O
Temperature: 100 °C
Reaction time: 5 h
Yield: 100 %

Procedure:
N-(1-oxo-1,2,3,4-tetrahydronaphthalen-2-yl)-acetamide (16.5 g, 81 mmol) was added to 3N aqueous hydrochloric acid (270 ml) and stirred at 100° C. for 5 hours. After removal of the solvent, the precipitate was filtered, washed with ethanol, and dried to give 2-amino-3,4-dihydro-2H-naphthalen-1-one hydrochloride (16.0 g, 81 mmol, 100%) as white crystals.
Reaction SMILES: [F:1][C:2]1[C:3]([OH:13])=[C:4]([CH:9]=[CH:10][C:11]=1[CH3:12])[C:5]([O:7][CH3:8])=[O:6].[Br:14]Br.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(O)(=O)C>[Br:14][C:10]1[C:11]([CH3:12])=[C:2]([F:1])[C:3]([OH:13])=[C:4]([CH:9]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1ccc(C)c(F)c1O
Reactant: BrBr
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC(=O)O
Product: COC(=O)c1cc(Br)c(C)c(F)c1O
Reaction time: 2 h

Procedure:
To a solution of methyl 3-fluoro-2-hydroxy-4-methylbenzoate (6.40 g) in acetic acid (120 mL) was added bromine (1.87 mL) at room temperature, and the mixture was stirred at the same temperature for 2 hr. To the reaction mixture was added 10% aqueous sodium thiosulfate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give a mixture (7.99 g) of the title compound and the raw material (about 2:1). The obtained product was used in the next step without an additional purification.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][CH:8]1[CH2:13][N:12]2[N:14]=[C:15]([CH2:17][O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:16]=[C:11]2[C:10](=O)[NH:9]1>C1COCC1.CCOC(C)=O>[CH3:7][CH:8]1[CH2:13][N:12]2[N:14]=[C:15]([CH2:17][O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:16]=[C:11]2[CH2:10][NH:9]1
Reactant: CC1Cn2nc(COc3ccccc3)cc2C(=O)N1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC1Cn2nc(COc3ccccc3)cc2CN1
Temperature: 25 °C
Reaction time: 60 h
Yield: 95.3 %

Procedure:
A 1M solution of lithium aluminum hydride in THF (2.14 mL, 2.14 mmol) was added dropwise to a stirred solution of rac-6-methyl-2-phenoxymethyl-6,7-dihydro-5H-pyrazolo[1,5-a]pyrazin-4-one (0.5 g, 1.94 mmol) in THF (12 mL) under N2 at 0° C. The reaction mixture was stirred at room temperature for 2.5 days and diluted with AcOEt. Na2SO4.10H2O was added at 0° C. and the mixture stirred for 15 minutes at 0° C., filtered through a pad of diatomaceous earth and then washed with additional AcOEt. The solvents were evaporated in vacuo to yield rac-6-methyl-2-phenoxymethyl-4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyrazine (0.45 g, 84% yield) as an oil that crystallized upon standing, and that was used in the next step without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[C:9](O)[CH:8]=2)([O-:3])=[O:2].[H-].[Na+].[OH-].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>C(N(CC)CC)C.CS(C)=O.O1CCCC1.N1C=CC=CC=1.ClCCl.C1(C)C=CC=CC=1.C1C=CC=CC=1.CN(C)C=O>[N+:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cnc2cc(O)ccc2c1
Agent: O=C([O-])[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=[N+]([O-])c1cnc2ccccc2c1

Procedure:
The 3-nitro-7-hydroxyquinoline of the formula (a) is reacted with a halogenated compound of the formula (b) in an inert solvent such as dimethylformamide (DMF), benzene, toluene, dichloromethane, pyridine, tetrahydrofuran (THF), or dimethylsulfoxide (DMSO) in the presence of a base such as sodium hydride, sodium alkoxide, triethylamine, sodium hydroxide, or sodium carbonate, to give the 3-nitroquinoline derivative of the formula (c).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH3:9])[C:5]([N+:10]([O-])=O)=[CH:4][CH:3]=1.[Sn](Cl)Cl.[OH-].[Na+].C(OCC)(=O)C>Cl>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH3:9])[C:5]([NH2:10])=[CH:4][CH:3]=1
Reactant: CNc1nc(Cl)ccc1[N+](=O)[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CNc1nc(Cl)ccc1N
Temperature: 25 °C

Procedure:
6-Chloro-N-methyl-3-nitropyridin-2-amine (1-1, 10.5 g, 56 mmol) and tin(II) chloride dehydrate (50.5 g, 224 mmol) were suspended in concentrated HCl (80 mL) and refluxed overnight. The solution was cooled to room temperature and then added very slowly to a NaOH/ethyl acetate solution at −78° C., until the solution had a slightly basic pH. The suspension was washed with sodium bicarbonate, brine, dried over sodium sulfate, filtered, and concentrated to produce 6-chloro-N2-methylpyridine-2,3-diamine (1-2) as a black solid. HRMS (M+H)+: observed=158.0487, calculated=158.0480.
Reaction SMILES: Br[C:2]1[C:3]([N+:13]([O-:15])=[O:14])=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)[CH:7]=[O:8].C(=O)([O-])[O-].[Na+].[Na+].[CH:22]1(B(O)O)[CH2:24][CH2:23]1>C1(C)C=CC=CC=1.O.CCOC(C)=O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH:22]1([C:2]2[C:3]([N+:13]([O-:15])=[O:14])=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=2)[CH:7]=[O:8])[CH2:24][CH2:23]1
Reactant: OB(O)C1CC1
Reactant: O=Cc1cc(Br)c([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: O=Cc1cc(C2CC2)c([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 77.7 %

Procedure:
To a stirred solution of (iii) (3 g, 10.9 mmol) in toluene (75 mL) was added a solution of sodium carbonate (2.29 g, 21.8 mmol) in water (15 mL). The mixture was sparged with nitrogen for 10 min whereupon cyclopropyl boronic acid (1.4 g, 16.4 mmol) and tetrakis(triphenylphosphine) palladium(0) (0.25 g, 0.22 mmol) were added and the reaction mixture was heated at reflux and progress monitored by TLC. After heating for 6 h the reaction was then cooled to RT and diluted with EtOAc (100 mL). The organic layer was separated and concentrated in vacuo. Purification of the residue by column chromatography on silica gel to gave (iv) (2 g, 78%).
Reaction SMILES: C(NCC)C.CC(O)(C)C.Br[CH2:12][C:13]([C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1)=[O:14].[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([C:31](=[O:33])[CH3:32])=[CH:27][C:26]=1[N+:34]([O-:36])=[O:35].OS(O)(=O)=O>C1C=CC=CC=1.[Cl-].[Zn+2].[Cl-]>[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([C:31](=[O:33])[CH2:32][CH2:12][C:13]([C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)=[O:14])=[CH:27][C:26]=1[N+:34]([O-:36])=[O:35]
Reactant: O=C(CBr)c1ccc([N+](=O)[O-])cc1
Reactant: CC(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Agent: O=S(=O)(O)O
Agent: [Cl-]
Agent: [Zn+2]
Solvent: c1ccccc1
Solvent: CCNCC
Solvent: CC(C)(C)O
Product: O=C(CCC(=O)c1ccc(Cl)c([N+](=O)[O-])c1)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of zinc chloride (39.1 g, 287 mmol) in benzene (215 mL) was added diethylamine (22.24 mL, 215 mmol) and 2-methylpropan-2-ol (20.57 mL, 215 mmol). The resulting mixture was stirred at rt for 2 h, and 2-bromo-1-(4-nitrophenyl)ethanone (35.0 g, 143 mmol) and 1-(4-chloro-3-nitrophenyl)ethanone (42.9 g, 215 mmol) were added in one portion. The resulting mixture was stirred at rt overnight. Added 5% aq. H2SO4 (50 mL) and stirred vigorously to induce precipitation. The resulting solid was collected by filtration and washed successively with benzene, water, methanol, and CH2Cl2. The solid was dried in vacuo to give the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[C:15](=[C:16]3[CH2:21][CH2:20][N:19](C(OCC)=O)[CH2:18][CH2:17]3)[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:9]3[CH2:8][CH2:7][C:6]=2[CH:27]=1.[OH-].[K+]>C(O)C.O.[Cl-].[Na+].O>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[C:15](=[C:16]3[CH2:17][CH2:18][NH:19][CH2:20][CH2:21]3)[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:9]3[CH2:8][CH2:7][C:6]=2[CH:27]=1
Reactant: CCOC(=O)N1CCC(=C2c3ccc(F)cc3CCc3cccnc32)CC1
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Fc1ccc2c(c1)CCc1cccnc1C2=C1CCNCC1
Yield: 95.9 %

Procedure:
A solution of 8-fluoro-6,11-dihydro-11-(1- ethoxycarbonyl-4-piperidylidene)-5H-benzo[5,6]cyclohepta[1,2-b]pyridine (3.6 g, 0.0098 mole) and potassium hydroxide (4.5 g, 0.094 mole) in 50 mL of ethanol:water (1:1) is heated at reflux for 66 hours. The reaction mixture is diluted with brine and the product is extracted into ethyl acetate. The solution is concentrated to a residual solid which is washed with acetone/ethvl acetate to yield 2.76 g (0.0094 mole) of 8- fluoro-11-(4-piperidylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:14]2[N:15]=[C:16]([NH:19][CH:20]([CH3:22])[CH3:21])[S:17][CH:18]=2)[CH:3]=1.C(C1N=C(C2C=C(O[CH:42]3[CH2:60][CH:59]4[N:44]([C:45](=[O:65])[CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH:52]=[CH:53][CH:54]5[C:56]([C:62]([OH:64])=[O:63])([NH:57][C:58]4=[O:61])[CH2:55]5)[CH2:43]3)C3C(=CC(OC)=CC=3)N=2)SC=1)(C)C>>[CH:20]([NH:19][C:16]1[S:17][CH:18]=[C:14]([C:4]2[CH:3]=[C:2]([O:1][CH:42]3[CH2:60][CH:59]4[N:44]([C:45](=[O:65])[CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH:52]=[CH:53][CH:54]5[C:56]([C:62]([OH:64])=[O:63])([NH:57][C:58]4=[O:61])[CH2:55]5)[CH2:43]3)[C:11]3[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=3)[N:5]=2)[N:15]=1)([CH3:22])[CH3:21]
Reactant: COc1ccc2c(O)cc(-c3csc(NC(C)C)n3)nc2c1
Reactant: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)O)CC5C=CCCCCCCC(=O)N4C3)cc(-c3nc(C(C)C)cs3)nc2c1
Product: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)O)CC5C=CCCCCCCC(=O)N4C3)cc(-c3csc(NC(C)C)n3)nc2c1

Procedure:
The title compound was prepared from 4-hydroxy-2-[2-(isopropylamino)thiazol-4-yl]-7-methoxyquinoline and intermediate 7 following the procedure (Step F-H) reported for 18-[2-[4-(isopropyl)thiazol-2-yl]-7-methoxyquinolin-4-yloxy]-2,15-dioxo-3,16-diazatricyclo[14.3.0.04,6]nonadec-7-ene-4-carboxylic acid 10: m/z=648 (M+H)+. 1H NMR (CDCl3): 1.01-1.41 (m, 12H), 1.81-1.95 (m, 3H), 2.11-2.30 (m, 3H), 2.43 (m, 1H), 2.55 (m, 1H), 2.91 (m, 1H), 3.47 (m, 2H), 3.60 (m, 1H), 3.94 (s, 3H), 4.27 (M, 1H), 4.78 (d, J=8.0 Hz, 1H), 5.52-5.70 (m, 3H), 7.10 (d, 1H, J=8.6 Hz), 7.32 (s, 1H), 7.45-7.52 (m, 2H), 7.96 (d, 1H, J=8.6 Hz), 9.5 (s, 1H).
Reaction SMILES: [C:1]1(=[O:8])[NH:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1(C)C=CC=CC=1.S(=[N:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][CH:20]=1)=O>N1C=CC=CC=1>[NH2:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([N:7]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]2=[O:8])=[O:24])=[CH:21][CH:20]=1
Reactant: O=C1CCCCCN1
Reactant: O=S=Nc1ccc(C(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: Nc1ccc(C(=O)N2CCCCCC2=O)cc1
Temperature: 0 °C
Yield: 68 %

Procedure:
A 3-liter three-necked flask was charged with 144 g (1.27 moles) of ε-caprolactam, 2 L of toluene, and 1 L of pyridine. The mixture was stirred at 0° C. under nitrogen, to which was then added 256.5 g (1.27 moles) of p-sulfinylaminobenzoyl chloride. The mixture was slowly stirred until the temperature reached room temperature and then reacted for 14 hours. A deposited pyridine hydrochloride was filtered off, and the filtrate was washed twice with a 5% sodium hydrogencarbonate aqueous solution. A white residue obtained by distilling off the solvent of the organic phase was recrystallized twice from ethyl acetate to obtain N-(p-aminobenzoyl)caprolactam in a percent yield of 68%.
Reaction SMILES: CON(C)[C:4]([C:6]1[CH:11]=[CH:10][N:9]=[C:8]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH:7]=1)=[O:5].[CH3:21][Mg+].[Br-]>C1COCC1>[C:4]([C:6]1[CH:11]=[CH:10][N:9]=[C:8]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:16])([CH3:17])[CH3:18])[CH:7]=1)(=[O:5])[CH3:21]
Reactant: CON(C)C(=O)c1ccnc(NC(=O)OC(C)(C)C)c1
Reactant: C[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Product: CC(=O)c1ccnc(NC(=O)OC(C)(C)C)c1
Temperature: 25 °C

Procedure:
To a solution of tert-butyl 4{[methoxy(methyl)amino]carbonyl}pyridin-2-ylcarbamate (16-2, 224 mg, 0.8 mmole) in dry THF (5 mL) was added MeMgBr (0.6 mL, 3 M in Et2O, 1.75 mmole) at −20° C. After 30 minutes the mixture was warmed to RT. After 30 minutes additional MeMgBr (0.3 mL) was added. After 1 hr the mixture was quenched with saturated NH4Cl and extracted with EtOAc (3×). The combined organic layers were dried (MgSO4), filtered, and concentrated to give the titled compound as an off-white solid which was sufficiently pure for use in the next step. 1H-NMR (500 MHz, (CDCl3) δ8.44 (s, 1H), 8.40 (d, 1H, J=5.13 Hz), 8.02 (bs, 1H), 7.41 (d, 1H, J=5.13 Hz), 2.64 (s, 3H), 1.56 (s, 9H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]([OH:18])=O)[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH:19]([CH3:21])[CH3:20].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C1COCC1.O>[CH3:20][N:19]([CH3:21])[C:16]([CH:13]1[CH2:12][CH2:11][N:10]([C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)[CH2:15][CH2:14]1)=[O:18]
Reactant: CNC
Reactant: O=C(O)C1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CN(C)C(=O)C1CCN(c2ccc([N+](=O)[O-])cc2)CC1

Procedure:
A solution of 1-(4-nitrophenyl)piperidine-4-carboxylic acid, (CH3)2NH (2.37 g, 29.06 mmol), HATU (11.05 g, 29.06 mmol) and DIPEA (7.51 g, 58.12 mmol) in 30 mL of THF, was stirred at room temperature overnight. The mixture was added to 20 mL of water, extracted with EA, washed with water and brine, dried over Na2SO4. The volatiles were removed in vacuo to give 4.2 g of N,N-dimethyl-1-(4-nitrophenyl)piperidine-4-carboxamide. MS (m/z)=278 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:24]=[C:5]2[C:6]([NH:10][CH2:11][C:12]3[C:13]([N:18]([CH3:23])[S:19]([CH3:22])(=[O:21])=[O:20])=[N:14][CH:15]=[CH:16][CH:17]=3)=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[N:25]1([CH2:30][CH2:31][O:32][C:33]2[CH:38]=[CH:37][C:36]([NH2:39])=[CH:35][CH:34]=2)[CH2:29][CH2:28][CH2:27][CH2:26]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[CH3:23][N:18]([C:13]1[C:12]([CH2:11][NH:10][C:6]2[C:5]3[N:4]([N:3]=[C:2]([NH:39][C:36]4[CH:37]=[CH:38][C:33]([O:32][CH2:31][CH2:30][N:25]5[CH2:29][CH2:28][CH2:27][CH2:26]5)=[CH:34][CH:35]=4)[N:24]=3)[CH:9]=[CH:8][CH:7]=2)=[CH:17][CH:16]=[CH:15][N:14]=1)[S:19]([CH3:22])(=[O:21])=[O:20]
Reactant: CN(c1ncccc1CNc1cccn2nc(Cl)nc12)S(C)(=O)=O
Reactant: Nc1ccc(OCCN2CCCC2)cc1
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CN(c1ncccc1CNc1cccn2nc(Nc3ccc(OCCN4CCCC4)cc3)nc12)S(C)(=O)=O

Procedure:
N-Methyl-N-[3-({2-[4-(2-pyrrolidin-1-yl-ethoxy)-phenylamino]-[1,2,4]triazolo[1,5-a]pyridin-8-ylamino}-methyl)-pyridin-2-yl]-methanesulfonamide was prepared from N-{3-[(2-chloro-[1,2,4]triazolo[1,5-a]pyridin-8-ylamino)-methyl]-pyridin-2-yl}-N-methyl-methanesulfonamide and 4-(2-pyrrolidin-1-yl-ethoxy)-phenylamine (51.0 mg, 0.247 mmol)(prepared as described in J. Med. Chem., 2006, 49, 4451-4454) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (25.0 mg, 0.0457 mmol) as the ligand in a manner analogous to Example 2d. Product isolated as a tan foam (0.021 g, 19%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.42-8.39 (m, 1H), 7.85 (d, J=7.6 z, 1H), 7.80 (d, J=6.6 Hz, 1H), 7.48 (d, J=8.9 Hz, 2H), 7.30-7.25 (m, 1H), 6.92 (d, J=9.0 Hz, 2H), 6.64 (t, J=7.4 Hz, 1H), 6.52 (s, 1H), 6.29 (d, J=7.8 Hz, 1H), 5.27 (t, J=6.2, 1H), 4.77 (d, J=6.4 Hz, 2H), 4.10 (t, J=6.0 Hz, 2H), 3.32 (s, 3H), 3.09 (s, 3H), 2.90 (t, J=6.0 Hz, 2H), 2.68-2.58 (m, 4H), 1.86-1.76 (m, 4H). MS=537 (MH)+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:10]([OH:12])=O)[CH:3]=[CH:2]1.[CH3:13][N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1>CN(C)C=O>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:10]([N:17]2[CH2:18][CH2:19][N:14]([CH3:13])[CH2:15][CH2:16]2)=[O:12])[CH:3]=[CH:2]1
Reactant: CN1CCNCC1
Reactant: O=C(O)c1cccc2cc[nH]c12
Solvent: CN(C)C=O
Product: CN1CCN(C(=O)c2cccc3cc[nH]c23)CC1
Reaction time: 1 h
Yield: 48 %

Procedure:
Indole-7-carboxylic acid (3.20 g, 0.020 mole) was dissolved in 30 ml of dimethylformamide (DMF) and chilled with an ice-water bath. N,N'-Carbonyldiimidazole was added (3.3 g, 0.020 mole) and the reaction mixture was stirred for 1 hour in the cold. At the end of this time N-methylpiperazine was added (2.5 g, 0.025 mole) and the reaction was allowed to come to room temperature overnight (about 16 hours). The DMF was removed under reduced pressure and the residue was passed over a column of basic alumina (50% methanol-ether) to remove residual imidazole.Recrystallization of the product from CH2Cl2 -pentane gave 2.35 g (48%) of 1-(1H-indole-7-ylcarbonyl)-4-methylpiperazine, m.p. 176°-178° C.
Reaction SMILES: C([NH:4][C:5]1([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)[CH2:10][CH2:9][N:8](C(OCC)=O)[CH2:7][C:6]1([CH3:17])[CH3:16])(=O)C.[OH-].[Na+].O>C(O)C>[Cl:24][C:21]1[CH:22]=[CH:23][C:18]([C:5]2([NH2:4])[CH2:10][CH2:9][NH:8][CH2:7][C:6]2([CH3:16])[CH3:17])=[CH:19][CH:20]=1
Reactant: CCOC(=O)N1CCC(NC(C)=O)(c2ccc(Cl)cc2)C(C)(C)C1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC1(C)CNCCC1(N)c1ccc(Cl)cc1
Yield: 92.7 %

Procedure:
A solution of ethyl 4-acetamido-4-(4-chlorophenyl)-3,3-dimethylpiperidine-1-carboxylate (2.04 g, 5.78 mmol) in ethanol (25 mL) was treated with 5 N NaOH (aq) (23.13 mL, 116 mmol), and the mixture was heated at reflux for two days. During the reflux, a colorless, soapy solid predipitated. Water was added until a clear solution was observed. The ethanol was removed under reduced pressure, and the aqueous mixture was extracted 4× with ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated in-vacuo to yield the title compound (1.28 g, 5.36 mmol, 93% yield) as a colorless powder. MS (ESI+)=239, (M+H)+.
Reaction SMILES: BrN1C(=[O:7])CCC1=O.[Cl:9][C:10]1[CH:11]=[C:12]([S:17][CH2:18][CH2:19][CH2:20][CH2:21][O:22][C:23]2[CH:24]=[CH:25][C:26]3[NH:31][C:30](=[O:32])[O:29][C:28]([CH3:34])([CH3:33])[C:27]=3[CH:35]=2)[CH:13]=[CH:14][C:15]=1[Cl:16].O>CO>[Cl:9][C:10]1[CH:11]=[C:12]([S:17]([CH2:18][CH2:19][CH2:20][CH2:21][O:22][C:23]2[CH:24]=[CH:25][C:26]3[NH:31][C:30](=[O:32])[O:29][C:28]([CH3:33])([CH3:34])[C:27]=3[CH:35]=2)=[O:7])[CH:13]=[CH:14][C:15]=1[Cl:16]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC1(C)OC(=O)Nc2ccc(OCCCCSc3ccc(Cl)c(Cl)c3)cc21
Solvent: CO
Solvent: O
Product: CC1(C)OC(=O)Nc2ccc(OCCCCS(=O)c3ccc(Cl)c(Cl)c3)cc21

Procedure:
One gram (0.0056 mol) of N-bromosuccinimide is gradually added to a solution of 2.13 gm (0.005 mol) of 6-[4-(3,4-dichlorophenylmercapto)-butoxy]-4,4-dimethyl-4H-3,1-benzoxazin-2-one in 50 ml of methanol, under stirring. After reaction for 24 hours, 500 ml of water at 80° C. is added, and the precipitate is subjected to suction filtration after stirring for two hours. By recrystallization from isopropanol/diisopropylether, crystals are obtained, melting point: 136°-139° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:9]([NH:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[N+:23]([O-])=O)[S:8][C:7]=2[CH:26]=1.[H][H]>[C].[Pd].C(OCC)(=O)C>[NH2:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[NH:16][C:9]1[S:8][C:7]2[CH:26]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=2[C:10]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)c1c(Nc2ccccc2[N+](=O)[O-])sc2cc(OC)ccc12
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(Nc2ccccc2N)sc2cc(OC)ccc12

Procedure:
In the same manner as in Starting Material Synthesis Example 19 and using ethyl 6-methoxy-2-(2-nitroanilino)benzo[b]thiophene-3-carboxylate, ethyl acetate, 10% palladium-carbon and hydrogen (60 atm kg/cm2), ethyl 2-(2-aminoanilino)-6-methoxybenzo[b]thiophene-3-carboxylate is obtained.
Reaction SMILES: Cl.[CH3:2][C:3]1([NH2:6])[CH2:5][CH2:4]1.[CH3:7][S:8](Cl)(=[O:10])=[O:9]>N1C=CC=CC=1.C(OCC)(=O)C>[CH3:2][C:3]1([NH:6][S:8]([CH3:7])(=[O:10])=[O:9])[CH2:5][CH2:4]1
Reactant: CS(=O)(=O)Cl
Reactant: CC1(N)CC1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC1(NS(C)(=O)=O)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 78.2 %

Procedure:
To a stirred solution of 1-methylcyclopropan-1-amine hydrochloride (0.100 g, 0.9 mmol) in pyridine (1 mL) was added methanesulfonyl chloride (0.108 mL, 1.4 mmol). The reaction mixture was stirred at room temperature for 16 hrs. The mixture was diluted with ethyl acetate and washed with 2 N aqueous hydrochloric acid, saturated aqueous sodium bicarbonate, saturated aqueous sodium chloride, dried (anhydrous sodium sulfate), filtered, and concentrated to afford the product as a yellow oil (0.105 g, 76%). 1H NMR (300 MHz, CDCl3) δ 4.68 (br s, 1H), 3.02 (s, 3H), 1.50 (s, 3H), 1.02-0.94 (m, 2H), 0.71-0.64 (m, 2H).
Reaction SMILES: C(SCCCC)CCC.[H-].[Na+].C(S)CCC.C[O:18][C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[CH:25]=[C:24]([C:29](=[O:37])[CH2:30][CH2:31][CH2:32][CH2:33][C:34]([OH:36])=[O:35])[CH:23]=[CH:22]2.C(SC)CCC>CN(C=O)C.O>[OH:18][C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[CH:25]=[C:24]([C:29](=[O:37])[CH2:30][CH2:31][CH2:32][CH2:33][C:34]([OH:36])=[O:35])[CH:23]=[CH:22]2
Reactant: COc1ccc2cc(C(=O)CCCCC(=O)O)ccc2c1
Agent: CCCCSC
Agent: [H-]
Agent: [Na+]
Solvent: CCCCS
Solvent: CCCCSCCCC
Solvent: O
Product: O=C(O)CCCCC(=O)c1ccc2cc(O)ccc2c1
Reaction time: 0.08 h
Yield: 7.9 %

Procedure:
Butyl sulfide was generated by placing NaH (2.57 g, 0.11 mol) in a 500 ml round bottom flask, adding butanethiol (5.14 ml, 0.48 mol) and stirring for 5 minutes. DMF (200 mls) was added and the reaction heated at reflux. Slowly, 6-(6-methoxy-2-naphthyl)-6-oxo-hexanoic acid (Example 5) (7.2 g, 0.25 mol) in DMF (100 ml) was added to the reaction and heated at reflux for 1 hour. The methyl butyl sulfide and DMF were vacuum distilled (7 torr, 28° C.) to leave a bright yellow powder that was dissolved in water and precipitated with 5% HCl. The precipitate was filtered, dissolved in ethyl acetate (1800 ml), dried (Na2SO4), filtered and evaporated to give a yellow solid that was recrystallized (ethyl acetate) to give the title compound (5.38 grams, 79% yield), mp 191°-193° C.; MS, m/e 272 (M+).