Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[CH2:10][C:9]2[NH:8][N:7]=[C:6]([C:11]3[NH:12][C:13]4[C:18]([CH:19]=3)=[CH:17][CH:16]=[C:15]([NH:20][CH3:21])[CH:14]=4)[C:5]=2[CH2:4][CH2:3]1.[O:23]=[C:24]1[CH2:29][O:28][CH2:27][CH2:26][N:25]1[CH2:30][C:31]([OH:33])=O.Cl.C(N=C=NCCCN(C)C)C>N1C=CC=CC=1>[CH3:1][C:2]1([CH3:22])[CH2:10][C:9]2[NH:8][N:7]=[C:6]([C:11]3[NH:12][C:13]4[C:18]([CH:19]=3)=[CH:17][CH:16]=[C:15]([N:20]([CH3:21])[C:31](=[O:33])[CH2:30][N:25]3[CH2:26][CH2:27][O:28][CH2:29][C:24]3=[O:23])[CH:14]=4)[C:5]=2[CH2:4][CH2:3]1
Reactant: O=C(O)CN1CCOCC1=O
Reactant: CNc1ccc2cc(-c3n[nH]c4c3CCC(C)(C)C4)[nH]c2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: c1ccncc1
Product: CN(C(=O)CN1CCOCC1=O)c1ccc2cc(-c3n[nH]c4c3CCC(C)(C)C4)[nH]c2c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 67 %

Procedure:
Under an argon atmosphere, to a solution of N-[2-(6,6-dimethyl-4,5,6,7-tetrahydro-1H-indazol-3-yl)-1H-indol-6-yl]-N-methylamine obtained in Example 4, Step 1 (40 mg, 0.14 mmol) and (3-oxomorpholin-4-yl)acetic acid obtained in Reference Example 4 (76 mg, 0.48 mmol) in pyridine (1.3 ml) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (91 mg, 0.48 mmol) at room temperature, and the mixture was stirred at room temperature for 12 hr. Then, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in methanol (1.2 ml), 2 N aqueous sodium hydroxide solution (1.0 ml) was added, and the mixture was stirred at room temperature for 45 min. Then, to the reaction mixture were added water and ethyl acetate, and the organic layer was separated. The aqueous layer was extracted twice with ethyl acetate, and the combined organic layers were washed successively with water and saturated brine, and dried over sodium sulfate. Sodium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography to give the title compound (40 mg, yield 67%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([OH:16])[C:11]([C:17]([O:19][CH3:20])=[O:18])=[N:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].C([O-])([O-])=O.[K+].[K+].CS(O[CH:32]1[CH2:37][CH2:36][N:35]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:34][CH2:33]1)(=O)=O.CCOC(C)=O>CN(C=O)C.O>[C:41]([O:40][C:38]([N:35]1[CH2:36][CH2:37][CH:32]([O:16][C:12]2[C:11]([C:17]([O:19][CH3:20])=[O:18])=[N:10][N:9]([C:4]3[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=3)[C:14](=[O:15])[CH:13]=2)[CH2:33][CH2:34]1)=[O:39])([CH3:44])([CH3:42])[CH3:43]
Reactant: COC(=O)c1nn(-c2ccc(Cl)c(Cl)c2)c(=O)cc1O
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1nn(-c2ccc(Cl)c(Cl)c2)c(=O)cc1OC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 95 °C
Yield: 14.4 %

Procedure:
To a mixture of methyl 1-(3,4-dichlorophenyl)-4-hydroxy-6-oxo-1,6-dihydropyridazine-3-carboxylate (315 mg, 1.0 mmol) in DMF (3 mL) at room temperature under argon was added K2CO3 (415 mg, 3.0 mmol) and tert-butyl 4-(methylsulfonyloxy)piperidine-1-carboxylate (419 mg, 1.5 mmol). The reaction mixture was heated at 95° C. overnight. EtOAc (20 mL) and water (20 mL) were added to the reaction mixture. Layers were separated. Organic layer were washed with water (15 mL), and brine (15 mL). Organic phase was dried (MgSO4), filtered and concentrated. The crude product was dissolved in a small amount of DCM (˜2 ml) and loaded onto a 40 g ISCO silica gel column which was eluted with a 20 min gradient from 20% to 100% EtOAc/Hexanes. 72 mg (14.2%) of methyl 4-(1-(tert-butoxycarbonyl)piperidin-4-yloxy)-1-(3,4-dichlorophenyl)-6-oxo-1,6-dihydropyridazine-3-carboxylate was obtained as a gum. 1H NMR (400 MHz, CDCl3) δ ppm 1.40-1.50 (m, 9H) 1.68-1.82 (m, 1H) 1.92 (d, J=3.08 Hz, 3H) 3.23-3.45 (m, 2H) 3.49-3.59 (m, 1H) 3.59-3.73 (m, 1H) 3.82-4.03 (m, 3H) 4.48-5.43 (m, 1H) 6.12-6.38 (m, 1H) 7.38-7.64 (m, 2H) 7.75 (dd, J=7.91, 2.20 Hz, 1H). MS (ESI) 442 (M+H-tBu).
Reaction SMILES: Br[C:2]1[CH:20]=[CH:19][C:5]2[N:6]([CH2:14][CH2:15][N:16]([CH3:18])[CH3:17])[C:7]([CH2:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[N:8][C:4]=2[CH:3]=1.[SH:21][CH2:22][CH:23]1[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]1.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.C(N(CC)C(C)C)(C)C>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:17][N:16]([CH3:18])[CH2:15][CH2:14][N:6]1[C:5]2[CH:19]=[CH:20][C:2]([S:21][CH2:22][CH:23]3[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]3)=[CH:3][C:4]=2[N:8]=[C:7]1[CH2:9][C:10]([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)(C)OC(=O)N1CCC(CS)CC1
Reactant: CN(C)CCn1c(CC(C)(C)C)nc2cc(Br)ccc21
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CN(C)CCn1c(CC(C)(C)C)nc2cc(SCC3CCN(C(=O)OC(C)(C)C)CC3)ccc21
Temperature: 130 °C
Reaction time: 18 h

Procedure:
A mixture of 2-(5-bromo-2-neopentyl-1H-benzo[d]imidazol-1-yl)-N,N-dimethylethanamine (prepared in STEP A of Example 1, 1.41 g, 4.15 mmol), tert-butyl 4-(mercaptomethyl)piperidine-1-carboxylate (prepared in STEP B of Example 5, 1.20 g, 5.19 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (120 mg, 0.208 mmol), tris(dibenzylideneacetone)dipalladium(0) (95.2 mg, 0.104 mmol) and N,N-diisopropylethylamine (1.09 mL, 6.23 mmol) in 1,4-dioxane (8.5 mL) was stirred at 130° C. for 18 h. The mixture was filtered through a celite and the filtrate was concentrated in vacuo. The residue (2.40 g) was used for the next step without purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([S:9](Cl)(=[O:11])=[O:10])=[C:4]([Cl:13])[CH:3]=1.[NH2:14][C:15]1[C:16]([CH3:21])=[N:17][O:18][C:19]=1[CH3:20]>N1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([S:9]([NH:14][C:15]2[C:16]([CH3:21])=[N:17][O:18][C:19]=2[CH3:20])(=[O:11])=[O:10])=[C:4]([Cl:13])[CH:3]=1
Reactant: Cc1noc(C)c1N
Reactant: O=S(=O)(Cl)c1c(Cl)cc(Br)cc1Cl
Solvent: c1ccncc1
Product: Cc1noc(C)c1NS(=O)(=O)c1c(Cl)cc(Br)cc1Cl
Yield: 48.7 %

Procedure:
Prepared from 4-bromo-2,6-dichlorobenzenesulfonyl chloride (1.00 g, 3.19 mmol) and 4-amino-3,5-dimethylisoxazole (0.346 g, 3.1 mmol) in pyridine (6 ml) according to the method of intermediate 1, to give the title compound as a tan solid (606 mg, 1.51 mmol, 49%). δH (CDCl3, 300K) 7.70 (2H, s), 6.66 (1H, s), 2.23 (3H, s), 2.05 (3H, s). m/z (ES+, 70V) 400.9 (MH+).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)[S:5][C:4]=1[C:14]([O:16]C)=[O:15].C[O-].[Na+].CO.Cl>O>[CH3:1][NH:2][C:3]1[CH:7]=[C:6]([C:8]2[CH:9]=[CH:10][N:11]=[CH:12][CH:13]=2)[S:5][C:4]=1[C:14]([OH:16])=[O:15]
Reactant: CNc1cc(-c2ccncc2)sc1C(=O)OC
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CNc1cc(-c2ccncc2)sc1C(=O)O
Yield: 67.9 %

Procedure:
A mixture of methyl 3-(methylamino)-5-(pyridin-4-yl)thiophene-2-carboxylate (0.533 g, 2.15 mmol), sodium methoxide (0.348 g, 6.45 mmol), methanol (8.0 mL) and water (2.0 mL) was heated at reflux for 4 h. The mixture was cooled in an ice-bath and conc. HCl (0.533 mL, 6.45 mmol) was added to adjust the pH to 4. The resultant yellow precipitate was collected by filtration and washed with water and methanol to afford the title compound (0.342 g, 68%) as a yellow solid:
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:19]=[CH:18][C:7]([CH2:8][N:9]2[CH2:13][CH2:12][NH:11][C:10]2=[N:14][N+:15]([O-:17])=[O:16])=[CH:6][N:5]=1.I[CH2:21][CH2:22][CH2:23]I>CN(C=O)C>[Cl:3][C:4]1[CH:19]=[CH:18][C:7]([CH2:8][N:9]2[CH2:13][CH2:12][N:11]([CH2:21][CH2:22][CH2:23][N:11]3[CH2:12][CH2:13][N:9]([CH2:8][C:7]4[CH:18]=[CH:19][C:4]([Cl:3])=[N:5][CH:6]=4)[C:10]3=[N:14][N+:15]([O-:17])=[O:16])[C:10]2=[N:14][N+:15]([O-:17])=[O:16])=[CH:6][N:5]=1
Reactant: O=[N+]([O-])N=C1NCCN1Cc1ccc(Cl)nc1
Reactant: ICCCI
Agent: O=[N+]([O-])/N=C1\NCCN1Cc1ccc(Cl)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])N=C1N(CCCN2CCN(Cc3ccc(Cl)nc3)C2=N[N+](=O)[O-])CCN1Cc1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Sodium hydride (60% oil dispersion, 0.17 g, 4.25 mmol) was suspended in 10 ml of DMF. 1-(6-Chloronicotinyl)-2-nitroiminoimidazolidine (1.03 g, 4 mmol), which is commonly referred to as imidacloprid), was added to this suspension. This mixture was then stirred for 1 hour at room temperature. A solution of 1,3-diiodopropane (0.58 g, 2 mmol) in DMF (10 ml) was then added dropwise to this reaction mixture over the course of 30 minutes while cooling with ice. Following completion of dropping, the reaction mixture was stirred at room temperature for 4 hours.
Reaction SMILES: C([O:3][C:4](=[O:20])[C@@H:5]([O:18][CH3:19])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]([OH:17])=O)=[CH:9][CH:8]=1)C.[CH2:21]([NH:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[CH:26]=1)[CH3:22].C(O[C@@H](CC1C=CC(O[C@@H](C(=O)NCCC2C=CC(OC3C=CC=CC=3)=CC=2)C)=CC=1)C(O)=O)C>>[CH2:21]([N:23]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[CH:26]=1)[C:15]([CH2:14][O:13][C:10]1[CH:9]=[CH:8][C:7]([CH2:6][C@H:5]([O:18][CH3:19])[C:4]([OH:3])=[O:20])=[CH:12][CH:11]=1)=[O:17])[CH3:22]
Reactant: CCOC(=O)[C@H](Cc1ccc(OCC(=O)O)cc1)OC
Reactant: CCNCc1cccc(C)c1
Agent: CCO[C@@H](Cc1ccc(O[C@H](C)C(=O)NCCc2ccc(Oc3ccccc3)cc2)cc1)C(=O)O
Product: CCN(Cc1cccc(C)c1)C(=O)COc1ccc(C[C@H](OC)C(=O)O)cc1

Procedure:
The title compound was prepared from (2S)-3-(4-carboxymethoxy-phenyl)-2-methoxy-propionic acid ethyl ester (PREPARATION 3, step 2) and ethyl-(3-methyl-benzyl)-amine via the same procedure used for the preparation of (2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionic acid (Example 1, step 3) to produce a colorless oil. MS (ES) for C22H27NO5 [M+H]+: 386.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[N:10][C:9]2[C:8](=O)[N:7]=[CH:6][NH:5][C:4]=2[CH:3]=1.CCN(C(C)C)C(C)C.P(Cl)(Cl)([Cl:24])=O>C1(C)C=CC=CC=1>[Cl:24][C:8]1[C:9]2[N:10]=[CH:11][C:2]([Cl:1])=[CH:3][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: O=c1nc[nH]c2cc(Cl)cnc12
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: Clc1cnc2c(Cl)ncnc2c1
Temperature: 25 °C

Procedure:
To a mixture of 7-chloropyrido[3,2-d]pyrimidin-4(1H)-one (250 mg, 1.377 mmol) in toluene (12 mL) were added DIPEA (0.73 mL, 4.20 mmol) and phosphorus oxychloride (0.391 mL, 4.27 mmol), and the reaction was stirred at reflux for 1 hour. After cooling to RT, the reaction mixture was concentrated to provide the title compound. LC/MS (ESI+) m/z=200 (M+H).
Reaction SMILES: ClC(Cl)(Cl)C(Cl)(Cl)Cl.[F:9][C:10]1[CH:11]=[CH:12][C:13]([NH:16][NH:17][C:18](=O)[C:19]2[C:24]([Cl:25])=[CH:23][CH:22]=[CH:21][C:20]=2[Cl:26])=[N:14][CH:15]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>C1COCC1>[Cl:26][C:20]1[CH:21]=[CH:22][CH:23]=[C:24]([Cl:25])[C:19]=1[C:18]1[N:14]2[CH:15]=[C:10]([F:9])[CH:11]=[CH:12][C:13]2=[N:16][N:17]=1
Reactant: O=C(NNc1ccc(F)cn1)c1c(Cl)cccc1Cl
Agent: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Fc1ccc2nnc(-c3c(Cl)cccc3Cl)n2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 92.8 %

Procedure:
Hexachloroethane (2.60 g, 11.0 mmol) was added portionwise over 5 min at RT to a stirred mixture of Intermediate 26b (1.65 g, 5.50 mmol), triphenylphosphine (2.88 g, 11.0 mmol), and triethylamine (3.06 mL, 22.0 mmol) in THF (50 mL). The reaction mixture was stirred at RT for 18 h and then allowed to stand at RT for 72 h. The resulting suspension was filtered and the filtrate was concentrated in vacuo and purified by FCC using SCX-2 cartridge. The cartridge was washed with MeOH, and the product was eluted with 2M NH3 in MeOH to give the title compound (1.44 g, 93%) as a beige solid. LCMS (Method 3): Rt 3.08 min, m/z 282, 284 [MH+].
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH2:6]([O:13][C:14]1[CH:38]=[CH:37][C:36]([O:39][CH2:40][CH2:41][N:42]2[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]2)=[CH:35][C:15]=1[C:16]([NH:18][C:19]1[CH:28]=[C:27]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:26]=[CH:25][C:20]=1[C:21]([O:23][CH3:24])=[O:22])=[O:17])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C(Cl)Cl.N1C=CC=CC=1>[CH2:6]([O:13][C:14]1[CH:38]=[CH:37][C:36]([O:39][CH2:40][CH2:41][N:42]2[CH2:47][CH2:46][N:45]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:44][CH2:43]2)=[CH:35][C:15]=1[C:16]([NH:18][C:19]1[CH:28]=[C:27]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:26]=[CH:25][C:20]=1[C:21]([O:23][CH3:24])=[O:22])=[O:17])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(OCCN2CCNCC2)ccc1OCc1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(OCCN2CCN(S(C)(=O)=O)CC2)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Under ice-cooling, methanesulfonyl chloride (0.018 mL) was added to a solution mixture of methyl 2-(2-(benzyloxy)-5-(2-(piperazin-1-yl)ethoxy)benzamido)-4-phenylbenzoate (0.11 g) in methylene chloride (2.2 mL) and pyridine (0.024 mL), followed by stirring at room temperature for 1 hour. Pyridine (0.016 mL) and methanesulfonyl chloride (9.0 μL) were sequentially added to the reaction mixture, followed by stirring at room temperature for 1 hour and 30 minutes. The solvent was evaporated under reduced pressure, and a saturated aqueous solution of sodium bicarbonate and ethyl acetate were added to the residue. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 50-0% hexane/ethyl acetate] to obtain 0.085 g of methyl 2-(2-(benzyloxy)-5-(2-(4-(methylsulfonyl)piperazin-1-yl)ethoxy)benzamido)-4-phenylbenzoate as a white solid.
Reaction SMILES: [CH2:1]([C:3]1[CH:7]=[C:6]([NH:8][C:9](=[O:17])OC2C=CC=CC=2)[N:5]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:4]=1)[CH3:2].[CH3:24][O:25][C:26]1[CH:27]=[C:28]2[C:33](=[CH:34][C:35]=1[O:36][CH3:37])[N:32]=[CH:31][N:30]=[C:29]2[S:38][C:39]1[CH:40]=[C:41]([CH:43]=[CH:44][CH:45]=1)[NH2:42]>CS(C)=O.C(OCC)(=O)C>[CH3:24][O:25][C:26]1[CH:27]=[C:28]2[C:33](=[CH:34][C:35]=1[O:36][CH3:37])[N:32]=[CH:31][N:30]=[C:29]2[S:38][C:39]1[CH:40]=[C:41]([NH:42][C:9]([NH:8][C:6]2[N:5]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:4]=[C:3]([CH2:1][CH3:2])[CH:7]=2)=[O:17])[CH:43]=[CH:44][CH:45]=1
Reactant: CCc1cc(NC(=O)Oc2ccccc2)n(-c2ccccc2)n1
Reactant: COc1cc2ncnc(Sc3cccc(N)c3)c2cc1OC
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCc1cc(NC(=O)Nc2cccc(Sc3ncnc4cc(OC)c(OC)cc34)c2)n(-c2ccccc2)n1
Temperature: 70 °C
Yield: 34.2 %

Procedure:
A stirred mixture of phenyl 3-ethyl-1-phenyl-1H-pyrazol-5-ylcarbamate (prepared as described in Example 352A Step 3) (0.15 g, 0.50 mmol) and 3-(6,7-dimethoxyquinazolin-4-ylthio)aniline (prepared as described in Example 115B) (0.16 g, 0.50 mmol) in DMSO (2 mL) was heated at 70° C. for 15 h. After cooling to rt, the reaction mixture was diluted with ethyl acetate (50 mL) and washed with water (2×20 mL). The organic layer was separated, dried over magnesium sulfate, and concentrated under reduced pressure to afford an oil which was recrystallized from diethyl ether. Further purification via preparative silica gel thin-layer chromatography (eluting with a mixture of 8% methanol in dichloromethane containing 0.5% ammonia) afforded 1-(3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl)-3-(3-ethyl-1-phenyl-1H-pyrazol-5-yl)urea (90 mg, 35%) as a colorless solid. 1H NMR (400 MHz, DMSO-d6) δ 9.38 (s, 1H), 8.67 (s, 1H), 8.61 (s, 1H), 7.77 (s, 1H), 7.17-7.53 (m, 10H), 6.30 (s, 1H), 3.98 (s, 6H), 2.56 (m, 2H), 1.19 (m, 3H); LC-MS (ESI) m/z 527 (M+H)+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[CH:10]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:11][C:12]([NH:14][CH3:15])=O)[CH:3]=[CH:2]1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[CH:10]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:11][CH2:12][NH:14][CH3:15])[CH:3]=[CH:2]1
Reactant: CNC(=O)CC(c1ccccc1)c1cccc2cc[nH]c12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CNCCC(c1ccccc1)c1cccc2cc[nH]c12
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 64.9 %

Procedure:
To a stirring solution of 3-(1H-indol-7-yl)-N-methyl-3-phenyl-propionamide XIX (296 mg, 1.06 mmol) in THF (8 ml) was added a suspension of LiAlH4 (165 mg, 4.24 mmol) in THF (6 ml) at room temperature. The mixture was refluxed for 5 hours, cooled to room temperature, and quenched by slow addition of freshly ground Na2SO4.10H2O (4 g). The resulting mixture was stirred at room temperature for 45 minutes, and the solid was filtered and washed with EtOAc. The filtrate was concentrated and purified via flash chromatography (DCM/MeOH) affording [3-(1H-Indol-7-yl)-3-phenyl-propyl]-methyl-amine XX (182 mg, 65% yield). The free amine (100 mg) was dissolved in Et2O (15 ml) and cooled to 0° C. To the resulting solution was was added HCl (1 M in Et2O, 568 μl ), and the precipitate was filtered and dried in vacuo to afford the hydrochloride salt. (62 mg, 36% yield). MS (M+H)=265.
Reaction SMILES: [N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[NH:3][C:2]=1[C:10]1[CH:11]=[CH:12][C:13]([O:17][CH3:18])=[C:14]([NH2:16])[CH:15]=1.[S:19]1[CH:23]=[CH:22][CH:21]=[C:20]1[S:24](Cl)(=[O:26])=[O:25].O>N1C=CC=CC=1>[N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[NH:3][C:2]=1[C:10]1[CH:11]=[CH:12][C:13]([O:17][CH3:18])=[C:14]([NH:16][S:24]([C:20]2[S:19][CH:23]=[CH:22][CH:21]=2)(=[O:26])=[O:25])[CH:15]=1
Reactant: O=S(=O)(Cl)c1cccs1
Reactant: COc1ccc(-c2nc3cccnc3[nH]2)cc1N
Solvent: O
Solvent: c1ccncc1
Product: COc1ccc(-c2nc3cccnc3[nH]2)cc1NS(=O)(=O)c1cccs1
Reaction time: 8 h
Yield: 19.7 %

Procedure:
5-(3H-Imidazo[4,5-b]pyridin-2-yl)-2-methoxy-phenylamine (0.5 g, 2.1 mmol prepared as described above in Chemical Example 1) was dissolved in 15 mL pyridine at room temperature. Solid thiophene 2-sulfonyl chloride (0.38 g, 2.1 mmol) was added and the resulting blood red solution was stirred overnight The reaction mixture was poured into 250 mL water, stirred for 30 minutes, and filtered to give a pink solid. The solid was recrystallized from ethyl acetate after treatment with decolorizing charcoal to give 0.16 g of thiophene-2-sulfonic acid [5-(3H-imidazo[4,5-b]pyridin-2-yl)-2-methoxy-phenyl]-amide as an off-white solid; mp 252-254° C. 1H-NMR (DMSO-d6): δ 13.26 (d, 1H), 9.85 (bs, 1H), 8.27 (m, 2H), 8.02 (m, 2H), 7.87 (d, 1H), 7.43 (d, 1H), 7.16 (m, 3H), 3.59 (s, 3H) ppm. Anal. (C17H14N4O3S2) C,H,N values were within 0.4% of theoretical values.
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:30](=[O:38])[NH:31][S:32]([CH:35]4[CH2:37][CH2:36]4)(=[O:34])=[O:33])=[CH:12][C:13]=3[N:14]3[CH2:20][C:19]([C:21]([OH:23])=O)=[CH:18][C:17]4[CH:24]=[C:25]([O:28][CH3:29])[CH:26]=[CH:27][C:16]=4[C:15]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N:39]1([CH2:46][CH2:47][CH2:48][N:49]2[CH2:54][CH2:53][O:52][CH2:51][CH2:50]2)[CH2:45][CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CO>[CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:30]([NH:31][S:32]([CH:35]4[CH2:36][CH2:37]4)(=[O:34])=[O:33])=[O:38])=[CH:12][C:13]=3[N:14]3[CH2:20][C:19]([C:21]([N:42]4[CH2:43][CH2:44][CH2:45][N:39]([CH2:46][CH2:47][CH2:48][N:49]5[CH2:50][CH2:51][O:52][CH2:53][CH2:54]5)[CH2:40][CH2:41]4)=[O:23])=[CH:18][C:17]4[CH:24]=[C:25]([O:28][CH3:29])[CH:26]=[CH:27][C:16]=4[C:15]=23)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: C1CNCCN(CCCN2CCOCC2)C1
Reactant: COc1ccc2c(c1)C=C(C(=O)O)Cn1c-2c(C2CCCCC2)c2ccc(C(=O)NS(=O)(=O)C3CC3)cc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CO
Product: COc1ccc2c(c1)C=C(C(=O)N1CCCN(CCCN3CCOCC3)CC1)Cn1c-2c(C2CCCCC2)c2ccc(C(=O)NS(=O)(=O)C3CC3)cc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 72.6 %

Procedure:
To a stirring solution of 13-cyclohexyl-10-((cyclopropylsulfonyl)carbamoyl)-3-methoxy-7H-indolo[2,1-a][2]benzazepine-6-carboxylic acid (33 mg, 0.062 mmol) and 4-(3-(1,4-diazepan-1-yl)propyl)morpholine (36 mg, 0.158 mmol) in DMF (0.5 ml) and TEA (50 μl, 0.359 mmol) was added HATU (35 mg, 0.092 mmol). The reaction mixture was stirred at room temperature under nitrogen for 4 h. The crude reaction mixture was diluted with MeOH (˜1 mL), filtered and purified by preparative HPLC (H2O/CH3CN with 10 mM NH4OAc) to yield 13-cyclohexyl-N-(cyclopropylsulfonyl)-3-methoxy-6-((4-(3-(4-morpholinyl)propyl)-1,4-diazepan-1-yl)carbonyl)-7H-indolo[2,1-a][2]benzazepine-10-carboxamide (35.1 mg, 0.045 mmol, 72.6% yield) as a yellow solid. 1HNMR (300 MHz, CD3OD) δ 0.91-2.34 (m, 20H), 2.49-3.49 (m, 15H), 3.81-3.96 (m, 7H), 4.03-4.23 (m, 1H), 4.30-4.48 (m, 1H), 5.05-5.23 (m, 1H), 6.90 (s, 1H) 7.04 (d, J=2.6 Hz, 1H), 7.13 (dd, J=8.4, 2.6 Hz, 1H), 7.53 (d, J=8.4 Hz, 1H), 7.42-7.88 (m, 2H), 8.24 (s, 1H). LCMS: m/e 744 (M+H)+, ret time 2.88 min, column B, 4 minute gradient.
Reaction SMILES: [CH3:1][N:2]([CH3:50])[C:3](=[O:49])[CH2:4][C@@H:5]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([S:21]([NH:24][C:25]([C:27]2[CH:32]=[CH:31][C:30]([C:33]3[CH:38]=[CH:37][C:36]([CH2:39][CH2:40][C:41](O)=[O:42])=[CH:35][C:34]=3[O:44][CH3:45])=[CH:29][CH:28]=2)=[O:26])(=[O:23])=[O:22])=[CH:17][C:16]=1[N+:46]([O-:48])=[O:47])[CH2:6][S:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH2:51]([NH2:56])[C:52]([CH3:55])([CH3:54])[CH3:53].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C)C(=O)C.ClC(Cl)C>[CH3:45][O:44][C:34]1[CH:35]=[C:36]([CH2:39][CH2:40][C:41]([NH:56][CH2:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:42])[CH:37]=[CH:38][C:33]=1[C:30]1[CH:29]=[CH:28][C:27]([C:25]([NH:24][S:21]([C:18]2[CH:19]=[CH:20][C:15]([NH:14][C@@H:5]([CH2:6][S:7][C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH2:4][C:3]([N:2]([CH3:50])[CH3:1])=[O:49])=[C:16]([N+:46]([O-:48])=[O:47])[CH:17]=2)(=[O:23])=[O:22])=[O:26])=[CH:32][CH:31]=1
Reactant: COc1cc(CCC(=O)O)ccc1-c1ccc(C(=O)NS(=O)(=O)c2ccc(N[C@@H](CSc3ccccc3)CC(=O)N(C)C)c([N+](=O)[O-])c2)cc1
Reactant: CC(C)(C)CN
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CC(=O)N(C)C
Solvent: CC(Cl)Cl
Product: COc1cc(CCC(=O)NCC(C)(C)C)ccc1-c1ccc(C(=O)NS(=O)(=O)c2ccc(N[C@@H](CSc3ccccc3)CC(=O)N(C)C)c([N+](=O)[O-])c2)cc1

Procedure:
A solution of Example 126C (50 mg, 0.069 mmol), neopentylamine (21 mg, 0.20 mmol), EDCI (20 mg, 0.104 mmol), and HOBT (15 mg, 0.104 mmol) in N,N-dimethylacetamide (1 mL) and dichloroethane (0.5 mL) at room temperature was stirred for 16 hours. The mixture was concentrated, dissolved in 1:1 DMSO/methanol (1.0 mL) and purified by reverse phase preparative HPLC (using a C-18 column and a solvent system increasing in gradient from 20 to 95% acetonitrile/water containing 0.1% TFA) to provide the desired product. MS (ESI(−)) m/e 788 (M−H)−; 1H NMR (300 MHz, DMSO-d6) δ8.89 (br d, 1H), 8.57 (d, 1H), 7.90 (d, 2H), 7.85 (dd, 1H), 7.70(br t, 1H), 7.58 (d, 2H), 7.30-7.12 (m, 7H), 7.00 (d, 1H), 6.90 (dd, 1H), 4.45 (m, 1H), 3.75 (s, 3H), 3.42 (t, 2H), 2.90 (s, 3H), 2.79 (s, 3H), 3.00-2.70 (m, 8H), 0.80 (s, 9H).
Reaction SMILES: [CH3:1][C:2]([N:11]1[CH:15]=[C:14]([N+:16]([O-])=O)[N:13]=[CH:12]1)([CH3:10])[CH2:3][NH:4][CH2:5][C:6]([CH3:9])([CH3:8])[CH3:7].[F:19][C:20]1[CH:21]=[C:22]([CH2:27][C:28]([NH:30][C@@H:31]([C:35]2[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=2)[C:32](O)=[O:33])=[O:29])[CH:23]=[C:24]([F:26])[CH:25]=1>>[F:26][C:24]1[CH:23]=[C:22]([CH2:27][C:28]([NH:30][CH:31]([C:35]2[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=2)[C:32]([NH:16][C:14]2[N:13]=[CH:12][N:11]([C:2]([CH3:10])([CH3:1])[CH2:3][NH:4][CH2:5][C:6]([CH3:9])([CH3:8])[CH3:7])[CH:15]=2)=[O:33])=[O:29])[CH:21]=[C:20]([F:19])[CH:25]=1
Reactant: O=C(Cc1cc(F)cc(F)c1)N[C@H](C(=O)O)c1cccnc1
Reactant: CC(C)(C)CNCC(C)(C)n1cnc([N+](=O)[O-])c1
Product: CC(C)(C)CNCC(C)(C)n1cnc(NC(=O)C(NC(=O)Cc2cc(F)cc(F)c2)c2cccnc2)c1

Procedure:
2-methyl-N-neopentyl-2-(4-nitro-1H-imidazol-1-yl)propan-1-amine (U.S. Ser. No. 11/078,898 filed Mar. 11, 2005) was reduced and coupled with (S)-2-(2-(3,5-difluorophenyl)acetamido)-2-(pyridin-3-yl)acetic acid to afford the title compound: MS 513 m/z (M+1).