Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C:11]2[N:19]3[C:14]([CH:15]=[N:16][C:17]([NH:20][C:21]4[CH:26]=[CH:25][C:24]([C:27]5[CH2:28][CH2:29][N:30]([CH2:33][C:34]([NH2:36])=[O:35])[CH2:31][CH:32]=5)=[C:23]([C:37]([F:40])([F:39])[F:38])[CH:22]=4)=[N:18]3)=[CH:13][CH:12]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3].CS(C1C=C(C2N3C(C=N[C:57]([OH:60])=N3)=CC=2)C=CC=1)(=O)=O.NC1C=CC(C2CCN(CC(N)=O)CC=2)=C([C:78]([F:81])([F:80])[F:79])C=1>CS(C)=O>[CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C:11]2[N:19]3[C:14]([CH:15]=[N:16][C:17]([NH:20][C:21]4[CH:26]=[CH:25][C:24]([C:27]5[CH2:28][CH2:29][N:30]([CH2:33][C:34]([NH2:36])=[O:35])[CH2:31][CH:32]=5)=[C:23]([C:37]([F:39])([F:38])[F:40])[CH:22]=4)=[N:18]3)=[CH:13][CH:12]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:3])=[O:4].[C:57]([OH:60])([C:78]([F:81])([F:80])[F:79])=[O:3]
Reactant: CS(=O)(=O)c1cccc(-c2ccc3cnc(O)nn23)c1
Reactant: NC(=O)CN1CC=C(c2ccc(N)cc2C(F)(F)F)CC1
Agent: CS(=O)(=O)c1cccc(-c2ccc3cnc(Nc4ccc(C5=CCN(CC(N)=O)CC5)c(C(F)(F)F)c4)nn23)c1
Solvent: CS(C)=O
Product: O=C(O)C(F)(F)F
Yield: 72 %

Procedure:
2-(4-{4-[7-(3-Methanesulfonyl-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino]-2-trifluoromethyl-phenyl}-3,6-dihydro-2H pyridin-1-yl) acetamide. 7-(3-Methanesulfonyl-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-ol (46.1 mg, 0.159 mmol) and 2-[4-(4-Amino-2-trifluoromethyl-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-acetamide (0.0596 g, 0.199 mmol) were reacted in an analogous manner to Example 908D at 50° C. for 16 h. Concentrated reaction mixture, took up in DMSO, and purified by Gilson RP-HPLC. The fractions containing desired product were lyophilized to afford title compound as a TFA salt (65 mg, 72%). LCMS=570.9 (M+H), HPLC rt=2.435, purity=95% , 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 10.14 (bs, 1H), 9.60 (s, 1H), 9.11 (s, 1H), 8.56 (s, 1H), 8.49 (d J=7.8 Hz, 1H), 8.11 (d, J=8.8 Hz, 1H), 8.01 (s, 2H), 7.95 (d, J=7.9 Hz, 1H) 7.80-7.73 (m, 2H), 7.36-7.34 (m, 2H), 7.07 (d, J=4.7 Hz, 1H), 5.60 (s, 1H), 4.02 (s, 2H), 4.01-3.95 (m, 1H), 3.90-3.80 (m, 1H), 3.65-3.55 (m, 1H), 3.44-3.34 (m, 1H), 3.20 (s, 3H), 2.82-2.70 (m, 1H), 2.45-2.38 (m, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:12][CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])[CH3:2].Cl[C:14]1[NH:15][C:16]2[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=2[N:18]=1.CO.C(=O)(O)[O-].[Na+]>CO.ClCCl>[CH2:1]([O:3][C:4]([N:6]1[CH2:12][CH2:11][CH2:10][N:9]([C:14]2[NH:18][C:17]3[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=3[N:15]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCCNCC1
Reactant: Clc1nc2ccccc2[nH]1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CCOC(=O)N1CCCN(c2nc3ccccc3[nH]2)CC1
Temperature: 130 °C
Reaction time: 4 h

Procedure:
Combine 1-ethoxycarbonyl[1,4]diazepane (18.0 g, 104 mmol) and 2-chlorobenzimidazole (7.93 g, 52 mmol). Heat to 130° C. After 4 hours, cool to ambient temperature and add hot methanol to dissolve the reaction mixture. Add a saturated aqueous solution of sodium bicarbonate (150 mL) and concentrate in vacuo to remove most of the methanol. Combine the aqueous reaction mixture and 95/5 diethyl ether/ethyl acetate. Separate the aqueous layer and extract three times with dichloromethane. Combine the dichloromethane layers, dry over Na2SO4, filter, and evaporate in vacuo to give a residue. Triturate the residue with ethyl acetate (100 mL) to give a solid. Chromatograph on silica gel eluting with 10% methanol/dichloromethane/0.1% concentrated aqueous ammonia to give a residue. Triturate that residue with 9/1 diethyl ether/ethyl acetate to give a solid. Collect solid by filtration and dry in vacuo to give 1-ethoxycarbonyl-4-(1H-benzimidazol-2-yl)[1,4]diazepane: mp; 161-162° C.
Reaction SMILES: [NH:1]([C:47]([CH3:49])=[O:48])[C@H:2]([C:12]([NH:14][C@H:15]([C:27]([NH:29][C@H:30]([C:32]([NH:34][C@H:35]([C:37]([O:39]CC1C=CC=CC=1)=[O:38])[CH3:36])=[O:33])[CH3:31])=[O:28])[CH2:16][C:17](=[O:26])[O:18]CC1C=CC=CC=1)=[O:13])[CH2:3][O:4]CC1C=CC=CC=1.CO.O>CC(O)=O>[NH:1]([C:47]([CH3:49])=[O:48])[C@H:2]([C:12]([NH:14][C@H:15]([C:27]([NH:29][C@H:30]([C:32]([NH:34][C@H:35]([C:37]([OH:39])=[O:38])[CH3:36])=[O:33])[CH3:31])=[O:28])[CH2:16][C:17](=[O:18])[OH:26])=[O:13])[CH2:3][OH:4]
Reactant: CC(=O)N[C@@H](COCc1ccccc1)C(=O)N[C@@H](CC(=O)OCc1ccccc1)C(=O)N[C@@H](C)C(=O)N[C@@H](C)C(=O)OCc1ccccc1
Solvent: CC(=O)O
Solvent: CO
Solvent: O
Product: CC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](C)C(=O)N[C@@H](C)C(=O)O
Yield: 86.3 %

Procedure:
Ac-Ser(Bzl)-Asp(OBzl)-Ala-Ala-OBzl (0.6 g, 0.888 mmol) was hydrogenated in a Parr apparatus at 50 psi in the presence of 0.62 g catalyst (5% Pd on BaSO4) in a solvent mixture consisting of 35 ml MeOH, 15 ml H2O, and 1 ml HOAc for 4 hours. The catalyst was filtered off and the filtrate concentrated to a smaller volume and lyophilized to give 0.38 g crude material. Tlc showed two minor contaminants in addition to the major component. The compound was then purified on a Bio-Rad AGl × 2 column (3 × 24 cm) which was washed with 0.2M NaOH, H2O, 0.2 M HOAc, and equilibrated with pH 8.5 buffer of 0.025 M ammonium acetate. The sample was applied at this pH and the column eluted with 250 ml each of the following acetic acid solution in the order of: 0.25M, 0.5M, 1.0M, 1.5M, 2.0M, 2.5M, 3.0M, 3.5M, 4.0M, and 4.5M. The flow rate was adjusted to approximately 50 ml/hr and each 10 ml fraction was collected into an LKB fraction collector. The compound was located by spotting a 5 μl portion from each tube on silica gel tlc plate (Merck 60, F-254) and developed in the solvent system of n-BuOH:HOAc:EtOAc:H2O (1:1:1:1) and then stained with chlorine-tolidine reaction. The fractions containing the major component were pooled and lyophilized twice to give 310 mg (86.3%) of the desired product; [α]D25 =-77.01° (c 1, 10% HOAc).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]([NH:14][C@@H:15]1[CH2:19][NH:18][CH2:17][C@H:16]1[NH:20][C:21]([C:23]1[S:24][C:25]3[CH2:26][N:27]([CH3:32])[CH2:28][CH2:29][C:30]=3[N:31]=1)=[O:22])=[O:13])=[CH:6]2.C(=O)([O-])[O-].[K+].[K+].Br[CH2:40][C:41]([O:43][CH3:44])=[O:42]>CN(C)C=O.C(OCC)(=O)C>[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]([NH:14][C@H:15]1[C@H:16]([NH:20][C:21]([C:23]3[S:24][C:25]4[CH2:26][N:27]([CH3:32])[CH2:28][CH2:29][C:30]=4[N:31]=3)=[O:22])[CH2:17][N:18]([CH2:40][C:41]([O:43][CH3:44])=[O:42])[CH2:19]1)=[O:13])=[CH:6]2
Reactant: COC(=O)CBr
Reactant: CN1CCc2nc(C(=O)N[C@@H]3CNC[C@H]3NC(=O)c3cc4cc(Cl)ccc4[nH]3)sc2C1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)CN1C[C@@H](NC(=O)c2cc3cc(Cl)ccc3[nH]2)[C@H](NC(=O)c2nc3c(s2)CN(C)CC3)C1

Procedure:
The compound (230 mg) obtained in Example 95 and potassium carbonate (90 mg) were dissolved in N,N-dimethylformamide (4.6 ml), and the mixture was cooled with ice. Methyl bromoacetate (0.062 ml) was added, and the resultant mixture was stirred for 45 minutes. The reaction mixture was diluted with ethyl acetate, washed with water and saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resultant residue was purified by preparative thin-layer chromatography on silica gel (chloroform:methanol=10:1) and solidifier with methanol-water to obtain the title compound (190 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[CH:22]=[C:23]([CH:27]=[CH:28][CH:29]=4)[C:24](O)=[O:25])=[CH:17][C:11]=3[C:12]=2[C:13](=[O:16])[NH:14][CH3:15])=[CH:4][CH:3]=1.CCN=C=NCCCN(C)C.Cl.[C:42]1([S:48]([NH2:51])(=[O:50])=[O:49])[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1.ClCCCl>CN(C1C=CN=CC=1)C.CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[CH:29]=[CH:28][CH:27]=[C:23]([C:24](=[O:25])[NH:51][S:48]([C:42]5[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=5)(=[O:50])=[O:49])[CH:22]=4)=[CH:17][C:11]=3[C:12]=2[C:13]([NH:14][CH3:15])=[O:16])=[CH:4][CH:3]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cccc(C(=O)O)c3)cc12
Reactant: NS(=O)(=O)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cccc(C(=O)NS(=O)(=O)c4ccccc4)c3)cc12
Yield: 67.3 %

Procedure:
In a 1 dram vial with stir bar were combined 3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)benzoic acid (35 mg, 0.090 mmol), DMAP (33 mg, 0.27 mmol), EDC hydrochloride (26 mg, 0.14 mmol), and benzenesulfonamide (43 mg, 0.27 mmol). 1,2-Dichloroethane (1 mL) and DMF (0.3 mL) were added, the vial was capped, and the suspension was stirred at r.t. overnight, over which time the solids dissolved. The reaction was concentrated, filtered, purified by prep HPLC, and concentrated to give 32 mg (67% yield) of the title compound as a white powder. 1H NMR (500 MHz, DMSO-d6) δ ppm 12.78 (br. s., 1H) 8.52 (q, J=4.48 Hz, 1H) 8.24 (s, 1H) 7.97-8.06 (m, 4H) 7.90-7.97 (m, 2H) 7.85 (d, J=7.94 Hz, 1H) 7.74-7.81 (m, 2H) 7.66-7.73 (m, 1H) 7.63 (t, J=7.63 Hz, 2H) 7.58 (t, J=7.63 Hz, 1H) 7.40 (t, J=8.85 Hz, 2H) 2.87 (d, J=4.58 Hz, 3H). LC/MS was performed by using Shimadzu-VP instrument with UV detection at 220 nm and Waters Micromass. LC/MS method: solvent A=10% CH3CN/90% H2O/0.1% TFA, solvent B=90% CH3CN/10% H2O/0.1% TFA, start % B=0, final % B=100, gradient time=2 min, stop time=3 min, flow rate=4 ml/min, column: Sunfire C18 5 μm 4.6×50 mm; HPLC Rt=1.77 min, (ES+) m/z (MH+)=529. Analytical HPLC were performed using a Shimadzu-VP instrument with UV detection at 220 nm and 254 nm. Analytical HPLC method: solvent A=5% CH3OH/95% H2O/10 mM NH4HCO3, solvent B=95% CH3OH/5% H2O/10 mM NH4HCO3, start % B=10, final % B=100, gradient time=15 min, stop time=18 min, flow rate=1 ml/min. Column: Phenomenex Gemini C18, 4.6 mm, 3 μm, Rt=15.70 min, purity=100%; column: Waters Xbridge Phenyl 4.6×150 mm, 3.5 μm, Rt=14.90 min, purity=99%.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[H-].[Na+].Br[CH2:13][CH2:14][CH2:15][O:16][CH3:17]>>[CH3:17][O:16][CH2:15][CH2:14][CH2:13][N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: c1ccc2[nH]cnc2c1
Reactant: COCCCBr
Agent: [H-]
Agent: [Na+]
Product: COCCCn1cnc2ccccc21
Temperature: 0 °C
Yield: 75.7 %

Procedure:
1H-benzo[d]imidazole (12.7 mmoles, 1.5 g) was added to an oven dried 200 mL round-bottomed flask equipped for stirring under nitrogen. DMF (20 mL) was added and the solution was cooled to 0° C. with an ice bath. To this cooled solution was added NaH (60% in mineral oil, 13.3 mmoles, 533 mg) in two portions. The resultant solution was allowed to stir at 0° C. for 30 minutes under nitrogen. 1-bromo-3-methoxypropane (14.0 mmoles, 2.14 g) was added and the solution was allowed to warm to room temperature and stirred for 1 hr. The reaction solution was then poured into ice-water, extracted with ethyl acetate, and washed once with saturated aqueous sodium chloride. The organic layer was collected and subsequently dried with anhydrous Na2SO4 and filtered. This filtrate was collected, concentrated, and dried in-vacuo. This material was then purified by chromatography on silica gel (5-15% CH3OH/CH2Cl2) to afford 1-(3-methoxypropyl)-1H-benzo[d]imidazole (137A) as a clear oil (9.62 mmoles, 1.83 g, 76% yield). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.10 (dt, J=12.57, 6.22 Hz, 2H) 3.29 (t, J=5.68 Hz, 2H) 3.34 (s, 3H) 4.31 (t, J=6.69 Hz, 2H) 7.23-7.34 (m, 2H) 7.37-7.45 (m, 1H) 7.78-7.83 (m, 1H) 7.89 (s, 1H). ESI-MS: m/z 191.4 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([C:8]([C:13]#[N:14])=[CH:9][NH:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[K].[CH3:16]C(C)([O-])C.CI.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1.O>[CH3:16][N:10]1[C:11]2[C:7](=[CH:6][CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:12]=2)[C:8]([C:13]#[N:14])=[CH:9]1
Reactant: CC(C)(C)[O-]
Reactant: N#Cc1c[nH]c2cc([N+](=O)[O-])ccc12
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [K]
Solvent: O
Solvent: CI
Solvent: C1CCOC1
Product: Cn1cc(C#N)c2ccc([N+](=O)[O-])cc21
Reaction time: 0.5 h

Procedure:
1.6 g 6-nitro-1H-indole-3-carbonitrile are dissolved in 45 ml of tetrahydrofuran, combined with 1 g potassium-tert.-butoxide and stirred for 30 minutes. Then a solution of 560 μl methyl iodide in 5 ml of tetrahydrofuran is slowly added dropwise and the mixture is stirred for 5 hours. The solvents are eliminated in vacuo, water is added and the pH is adjusted to 4 by the addition of citric acid. The solid is suction filtered and washed with water and some cold methanol.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=1.C1C(=O)N([Br:16])C(=O)C1>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][Br:16])=[CH:4][N:3]=1
Reactant: Cc1ccc(Br)nc1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1ccc(Br)nc1

Procedure:
Synthesized from 2-bromo-5-methylpyridine (3.00 g, 17.40 mmol), NBS (3.41 g, 19.20 mmol) and DBPO (230 mg, 0.80 mmol) in carbon tetrachloride according to Method A. Yield: 2.56 g (59%); lachrymatory yellow needles; 1H NMR (CDCl3, 500 MHz): δH (ppm)=4.14 (s, 2H), 7.47 (d, J=8.2 Hz, 1H), 7.59 (d, J=8.2 Hz, 1H), 8.38 (s, 1H); MS (ESI): m/z=252.37 [M+H]+.
Reaction SMILES: C([N:8]1[C:13](=[O:14])[C:12]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)=[C:11]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)[C:10]([O:29]CC2C=CC=CC=2)=[N:9]1)C1C=CC=CC=1.C1(C)C=CC=CC=1>O>[Cl:28][C:25]1[CH:24]=[CH:23][C:22]([C:11]2[C:10](=[O:29])[NH:9][NH:8][C:13](=[O:14])[C:12]=2[C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)=[CH:27][CH:26]=1
Reactant: O=c1c(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2)c(OCc2ccccc2)nn1Cc1ccccc1
Solvent: Cc1ccccc1
Solvent: O
Product: O=c1[nH][nH]c(=O)c(-c2ccc(Cl)cc2)c1-c1ccc(Cl)cc1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
To a round bottom flask was added 2-benzyl-6-(benzyloxy)-4,5-bis(4-chlorophenyl)pyridazin-3(2H)-one (15.5 gm, 30.21 mmol), toluene (70 ml) and alumina chloride (10.08 gm, 75.54 mmol). The reaction was stirred at 90° C. for 2 h. After this time, the reaction was cooled to 0° C. and water (200 ml) was slowly added to the reaction. The solution was extracted with ethyl acetate (3 L). The organic layer was washed with water (200 ml) and saturated aqueous NaCl (200 ml). The organic layer was dried (MgSO4), filtered and concentrated. The title compound, 4,5-bis(4-chlorophenyl)-1,2-dihydropyridazine-3,6-dione, was obtained as a solid and used in the without further purification. MS (M+H)=330.9, 333.0.
Reaction SMILES: [CH2:1]([CH:3]1[C:16]2[C:11](=[CH:12][C:13]([CH3:17])=[CH:14][CH:15]=2)[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:4]1[S:18]([C:21]1[CH:26]=[CH:25][C:24]([O:27]C)=[CH:23][CH:22]=1)(=[O:20])=[O:19])[CH3:2].B(Cl)(Cl)Cl.ClCCl>[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:1]([CH:3]1[C:16]2[C:11](=[CH:12][C:13]([CH3:17])=[CH:14][CH:15]=2)[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:4]1[S:18]([C:21]1[CH:22]=[CH:23][C:24]([OH:27])=[CH:25][CH:26]=1)(=[O:20])=[O:19])[CH3:2]
Reactant: CCC1c2ccc(C)cc2-c2ccccc2N1S(=O)(=O)c1ccc(OC)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: ClB(Cl)Cl
Agent: [I-]
Solvent: ClCCl
Product: CCC1c2ccc(C)cc2-c2ccccc2N1S(=O)(=O)c1ccc(O)cc1
Yield: 35.7 %

Procedure:
The title compound was prepared from 6-ethyl-5-[(4-methoxyphenyl)sulfonyl]-9-methyl-5,6-dihydrophenanthridine (0.67 g, 1.7 mmol), tetrabutylammonium iodide (1.5 g, 4.1 mmol), and 1 M boron trichloride in dichloromethane (11.9 mL, 11.9 mmol) according to the procedure and in the same manner as described in Example 35, Step b. The crude product was purified by flash column chromatography on silica gel, eluting with a mixture of ethyl acetate-hexane (3:7 to 1:1 gradient), followed by trituration from a mixture of ethyl acetate-hexane, to yield 4-[(6-ethyl-9-methylphenanthridin-5(6H)-yl)sulfonyl]phenol as a homogeneous solid (0.23 g, 36%), m.p. 167-170° C.;
Reaction SMILES: Cl.[C:2](Cl)(=[O:9])[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.ClCCl.[N:21]1([C:27]2[CH:33]=[CH:32][CH:31]=[CH:30][C:28]=2[NH2:29])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>O>[N:21]1([C:27]2[CH:33]=[CH:32][CH:31]=[CH:30][C:28]=2[NH:29][C:2](=[O:9])[C:3]2[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=2)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: O=C(Cl)c1ccncc1
Reactant: Nc1ccccc1N1CCCCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: O=C(Nc1ccccc1N1CCCCC1)c1ccncc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Isonicotinoyl chloride hydrochloride (616 mg, 3.46 mmol, commercially available product) and triethylamine (800 μl, 5.73 mmol) were sequentially added at 0° C. to a dichloromethane (5 ml) solution of 2-(1-piperidinyl)aniline (203 mg, 1.15 mmol), obtained as described in Referential Example 18-2. The resulting mixture was warmed to room temperature and stirred for two hours. Water was added to the mixture, and the resulting mixture was extracted three times with ethyl acetate. The obtained organic layer was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (20 g, hexane/ethyl acetate=1/1). Thus, N-[2-(1-piperidinyl)phenyl]isonicotinamide (GIF-0349) (259 mg, 80.0%) was yielded as a colorless solid.
Reaction SMILES: [N:1]1([C:6]2[CH:13]=[CH:12][C:9]([CH:10]=O)=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.C([O-])(=O)C.[NH4+].[N+:19]([CH2:22][CH3:23])([O-:21])=[O:20]>>[N+:19]([CH:22]([CH3:23])[CH2:10][C:9]1[CH:12]=[CH:13][C:6]([N:1]2[CH:5]=[CH:4][CH:3]=[N:2]2)=[CH:7][CH:8]=1)([O-:21])=[O:20]
Reactant: O=Cc1ccc(-n2cccn2)cc1
Reactant: CC[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: CC(Cc1ccc(-n2cccn2)cc1)[N+](=O)[O-]

Procedure:
A mixture comprising 4-pyrazol-1-yl-benzaldehyde (7.0 g, 40.65 mmol), ammonium acetate (0.94 g, 12.19 mmol) and nitroethane (24 ml, 333.3 mmol) is stirred at reflux for 10 hours. The solvent is removed in vacuo and the resulting solid is dissolved in EtOAc and washed with water (3×50 ml). The organic portion is dried (MgSO4) and concentrated in vacuo to afford the title compound as an orange solid. [MH+ 230.1].
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:13]2[C:14]([CH3:20])=[N:15][C:16]([CH3:19])=[CH:17][CH:18]=2)[CH:5]=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[CH:8]=[CH:7]2.C>>[CH3:1][C:2]1[CH:3]=[C:4]([C:13]2[C:14]([CH3:20])=[N:15][C:16]([CH3:19])=[CH:17][CH:18]=2)[CH:5]=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[CH2:8][CH2:7]2
Reactant: Cc1ccc(-c2cc(C)c3[nH]c(=O)ccc3c2)c(C)n1
Product: Cc1ccc(-c2cc(C)c3c(c2)CCC(=O)N3)c(C)n1
Yield: 52.9 %

Procedure:
A solution of 8-methyl-6-[2,6-dimethylpyrid-3-yl]-2-(1H)-quinolone (0.30 g) was hydrogenated at 60° and 60 p.s.i. (4.13×105Pa) pressure over 10% palladised charcoal (0.10 g) for 48 hours. The cooled solution was then filtered through "Solkafloc" (Trademark for a cellulose-based filtering aid), evaporated to dryness in vacuo, and the residue chromatographed on silica (Merck "MK 60.9385") eluting with chloroform:methanol, 49:1. Combination and evaporation of appropriate fractions afforded a solid (0.16 g) which was recrystallised from ethyl acetate/methanol to give 8-methyl-6-[2,6-dimethylpyrid-3-yl]-3,4-dihydro-2-(1H)-quinoline, m.p. 255°-258° (0.110 g).
Reaction SMILES: C1(C2C=CC=CC=2)C=C[C:4]([S:7]([NH:10][C:11]([NH:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([N:22]3[C:26]4=[N:27][C:28]([CH3:32])=[CH:29][C:30]([CH3:31])=[C:25]4[N:24]=[C:23]3[CH2:33][CH3:34])=[CH:18][CH:17]=2)=[O:12])(=[O:9])=[O:8])=[CH:3]C=1.[S:41]1[C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=2C=C1S(N)(=O)=O>>[S:41]1[C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=2[CH:3]=[C:4]1[S:7]([NH:10][C:11]([NH:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[C:26]3=[N:27][C:28]([CH3:32])=[CH:29][C:30]([CH3:31])=[C:25]3[N:24]=[C:23]2[CH2:33][CH3:34])=[CH:18][CH:17]=1)=[O:12])(=[O:9])=[O:8]
Reactant: NS(=O)(=O)c1cc2ccccc2s1
Reactant: CCc1nc2c(C)cc(C)nc2n1-c1ccc(CCNC(=O)NS(=O)(=O)c2ccc(-c3ccccc3)cc2)cc1
Product: CCc1nc2c(C)cc(C)nc2n1-c1ccc(CCNC(=O)NS(=O)(=O)c2cc3ccccc3s2)cc1

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 18 from phenyl 2-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethylcarbamate (step 1 of Example 18) and 1-benzothiophene-2-sulfonamide (Chern, J.; Leu, Y.; et al. J. Med. Chem., 1997, 40, 2276.; Graham, S. L.; Shepard, K. L.; et al. J. Med. Chem., 1989, 32, 2548).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH:8]([S:17][C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=1)[C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[F:16].ClC1C=CC=C(C(OO)=[O:33])C=1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH:8]([S:17]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=1)=[O:33])[C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[F:16]
Reactant: Fc1ccc(F)c(C(Sc2ccc(Cl)cc2)c2ccncc2Cl)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: O=S(c1ccc(Cl)cc1)C(c1cc(F)ccc1F)c1ccncc1Cl
Reaction time: 3 h
Yield: 60.3 %

Procedure:
To a methylene chloride (10 ml) solution of the 3-chloro-4-[(4-chlorophenylthio)-(2,5-difluorophenyl)methyl]pyridine (75 mg, 0.20 mmol) obtained in Example 53 was added 3-chloroperbenzoic acid (33 mg, 0.20 mmol). Under ice cooling, the resulting mixture was stirred for 3 hours. After dilution with ether (80 ml), the diluted mixture was washed with water and brine and concentrated under reduced pressure. The residue thus obtained was purified by silica gel chromatography (hexane:ethyl acetate=3:1) to give the title compound (48 mg, 60%) as a diastereomer mixture (1:1).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.[NH2:15][C:16]1[CH:24]=[C:23]([S:25]([CH3:28])(=[O:27])=[O:26])[CH:22]=[CH:21][C:17]=1[C:18](O)=[O:19]>>[NH2:15][C:16]1[CH:24]=[C:23]([S:25]([CH3:28])(=[O:27])=[O:26])[CH:22]=[CH:21][C:17]=1[C:18]([NH:6][C:5]1[CH:7]=[CH:8][C:2]([Cl:1])=[C:3]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[CH:4]=1)=[O:19]
Reactant: Nc1ccc(Cl)c(-c2ccccn2)c1
Reactant: CS(=O)(=O)c1ccc(C(=O)O)c(N)c1
Product: CS(=O)(=O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(N)c1

Procedure:
2.2 g of methyl 4-(methylsulfonyl)-2-nitrobenzoate was reacted via Procedure C to afford methyl 2-amino-4-(methylsulfonyl)benzoate. 500 mg of methyl 2-amino-4-(methylsulfonyl)benzoate was hydrolyzed via Procedure M to give 2-amino-4-(methylsulfonyl)benzoic acid. 100 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 2-amino-4-(methylsulfonyl)benzoic acid via Procedure G. The product was purified on reverse phase HPLC to yield 2-amino-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonyl)benzamide. MS (Q1) 402.0 (M)+.
Reaction SMILES: C1(CNCC2C=C(C3C=C4C(=C(C(N)=O)C=3)NC=C4C3CCN(S(CC)(=O)=O)CC3)C=NC=2)CC1.[CH3:36][C:37]1([CH3:52])[C:41]([CH3:43])([CH3:42])[O:40][B:39]([C:44]2[CH:45]=[C:46]([CH:50]=O)[CH:47]=[N:48][CH:49]=2)[O:38]1.[CH3:53][O:54][CH2:55][CH2:56][CH2:57][NH2:58].[BH3-]C#N.[Na+]>>[CH3:53][O:54][CH2:55][CH2:56][CH2:57][NH:58][CH2:50][C:46]1[CH:47]=[N:48][CH:49]=[C:44]([B:39]2[O:38][C:37]([CH3:52])([CH3:36])[C:41]([CH3:43])([CH3:42])[O:40]2)[CH:45]=1
Reactant: COCCCN
Reactant: CC1(C)OB(c2cncc(C=O)c2)OC1(C)C
Agent: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cncc(CNCC5CC5)c4)cc23)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Product: COCCCNCc1cncc(B2OC(C)(C)C(C)(C)O2)c1
Yield: 55.7 %

Procedure:
Following the general procedure of 5-(5-{[(cyclopropylmethyl)amino]methyl}-3-pyridinyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide, 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinecarbaldehyde (30 mg, 0.129 mmol), [3-(methyloxy)propyl]amine (0.013 mL, 0.129 mmol), and NaCNBH3 (16 mg, 0.258 mmol) were reacted to give 22 mg of crude [3-(methyloxy)propyl]{[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinyl]methyl}amine. The crude [3-(methyloxy)propyl]{[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinyl]methyl}amine was then reacted with 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide (30 mg, 0.0723 mmol), potassium carbonate (60 mg, 0.434 mmol), and chloro-2-(dimethylaminomethyl)-ferrocen-1-yl-(dinorbornylphosphine)palladium(11) (4.4 mg, 0.00723 mmol) to give 31 mg of the title compound (83%).