Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:25]([OH:27])=O)[C:11]3[C:16]([CH:17]=[CH2:18])=[N:15][N:14]([CH:19]4[CH2:24][CH2:23][CH2:22][CH2:21][O:20]4)[C:12]=3[N:13]=2)=[CH:4][CH:3]=1.[C:28]([N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1)([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29].ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>O1CCCC1.CN(C)C(=O)C>[C:31]([O:30][C:28]([N:35]1[CH2:40][CH2:39][N:38]([C:25]([C:10]2[C:11]3[C:16]([CH:17]=[CH2:18])=[N:15][N:14]([CH:19]4[CH2:24][CH2:23][CH2:22][CH2:21][O:20]4)[C:12]=3[N:13]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=3)[CH:9]=2)=[O:27])[CH2:37][CH2:36]1)=[O:29])([CH3:34])([CH3:32])[CH3:33]
Reactant: C=Cc1nn(C2CCCCO2)c2nc(-c3ccc(O)cc3)cc(C(=O)O)c12
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CC(=O)N(C)C
Product: C=Cc1nn(C2CCCCO2)c2nc(-c3ccc(O)cc3)cc(C(=O)N3CCN(C(=O)OC(C)(C)C)CC3)c12
Reaction time: 2 h
Yield: 89.7 %

Procedure:
To a solution of 6-(4-hydroxy-phenyl)-1-(tetrahydro-pyran-2-yl)-3-vinyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (3.12 g, 6.62 mmol) in tetrahydrofuran (44 mL) were added 1-boc-piperazine (1.35 g, 7.28 mmol), 1-hydroxybenzotriazole (0.09 g, 0.66 mmol), and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (1.27 g, 6.62 mmol). After 2 hours, N,N-dimethylacetamide (3 ml), 1-boc-piperazine (0.24 g, 1.32 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.25 g, 1.32 mmol) were added to the reaction mixture. After 1 hour, tetrahydrofuran was evaporated under reduced pressure, water and dichloromethane were then added. The organic layer was washed with an aqueous 1M HCl solution, water, brine, dried (Na2SO4), filtered, concentrated under vacuum. The crude residue was purified on a silica gel column chromatography using a gradient of methanol (0-5%) in dichloromethane to yield the title compound as a yellow foam (3.17 g, 90%).
Reaction SMILES: [O:1]=[C:2]1[NH:11][C:10]2[C:9]3[CH2:12][N:13]([C:16]([CH:18]4[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19]4)=[O:17])[CH2:14][CH2:15][C:8]=3[CH:7]=[CH:6][C:5]=2[NH:4][C:3]1=[O:31]>FC(F)(F)C(O)=O>[NH:21]1[CH2:22][CH2:23][CH:18]([C:16]([N:13]2[CH2:14][CH2:15][C:8]3[CH:7]=[CH:6][C:5]4[NH:4][C:3](=[O:31])[C:2](=[O:1])[NH:11][C:10]=4[C:9]=3[CH2:12]2)=[O:17])[CH2:19][CH2:20]1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)N2CCc3ccc4[nH]c(=O)c(=O)[nH]c4c3C2)CC1
Solvent: O=C(O)C(F)(F)F
Product: O=C(C1CCNCC1)N1CCc2ccc3[nH]c(=O)c(=O)[nH]c3c2C1
Reaction time: 0.25 h
Yield: 101.5 %

Procedure:
A mixture of the N-Boc quinoxalinedione from Example 32 (18 mg, 0.042 mmol) in trifluoroacetic acid (1.5 mL) was stirred under a nitrogen atmosphere for 15 min. After concentrating to dryness, the residue was triturated with water, basified to pH 8 and filtered. The filtrate was evaporated to give a beige solid (14 mg, 99% yield).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:17]([OH:19])=O)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20]1([NH2:27])[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[NH2:26].CCN(C(C)C)C(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[CH2:1]([O:8][C:9]([N:11]1[CH2:12][CH2:13][CH:14]([C:17](=[O:19])[NH:26][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[NH2:27])[CH2:15][CH2:16]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)C1CCN(C(=O)OCc2ccccc2)CC1
Reactant: Nc1ccccc1N
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Nc1ccccc1NC(=O)C1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 212.9 %

Procedure:
A mixture of 3.5 g of piperidine-1,4-dicarboxylic acid monobenzyl ester, 1.5 g of phenylendiamine, 2.3 mL of DIPEA and 6.9 g of PyBOP in 40 mL of DCM was stirred overnight at rt. The reaction was quenched with H2O, extracted with DCM, dried over MgSO4 and concentrated in vacuo to obtain 10 g of the desired compound as crude brown solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)[N:5]=[C:4]([CH3:15])[N:3]=1.[H-].[Na+].[N:18]1([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][OH:29])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>C1CCCCC1>[F:14][C:11]1[CH:12]=[CH:13][C:8]([C:6]2[CH:7]=[C:2]([O:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][N:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[N:3]=[C:4]([CH3:15])[N:5]=2)=[CH:9][CH:10]=1
Reactant: Cc1nc(Cl)cc(-c2ccc(F)cc2)n1
Reactant: OCCCCCN1CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCCCC1
Product: Cc1nc(OCCCCCN2CCCCC2)cc(-c2ccc(F)cc2)n1

Procedure:
13.8 kg of 4-chloro-6-(4-fluorophenyl)-2-methylpyrimidine, 4.8 kg of 60% sodium hydride, 130 kg of cyclohexane and 10.6 kg of 5-piperidino-1-pentanol were stirred under reflux for 4 hours.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[C:9]([O:10][CH3:11])=[N:8][CH:7]=[C:6]2[NH:12][CH:13]=[CH:14][C:5]=12.Cl[CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21]>C1COCC1>[Br:3][C:4]1[C:9]([O:10][CH3:11])=[N:8][CH:7]=[C:6]2[N:12]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[CH:13]=[CH:14][C:5]=12
Reactant: C[Si](C)(C)CCOCCl
Reactant: COc1ncc2[nH]ccc2c1Br
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ncc2c(ccn2COCC[Si](C)(C)C)c1Br
Temperature: 23 °C

Procedure:
To a suspension of NaH (0.238 g, 5.95 mmol, 1.3 eq, 60%) in THF at 0° C. was added a solution of 4-Bromo-5-methoxy-1H-pyrrolo[2,3-c]pyridine (1.05 g, 4.62 mmol) in THF and the solution stirred until no effervescence was observed (approx. 5 minutes). To the reaction mixture was added (2-Chloromethoxy-ethyl)-trimethyl-silane (1.00 mL, 5.64 mmol, 1.2 eq) and the solution was warmed to 23° C. and stirred for 16 hr. The reaction was quenched using sat'd NaHCO3 (aq) and most of the THF removed under reduced pressure. The aqueous layer was partitioned between EtOAc (100 mL), the organic layer washed with water, brine, dried, and concentrated. The crude reaction was purified using chromatography eluting with 20% EtOAc/Heptane giving 4-Bromo-5-methoxy-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrrolo[2,3-c]pyridine beige crystalline product (0.950 g, 2.53 mmol, 55%). MS ESI m/z 359.2 (M+2H)+. 1NMR (400 MHz, CDCl3) δ 8.46 (d, J=0.6 Hz 1H), 8.36 (s, 1H), 7.39 (d, J=3.2 Hz, 1H), 6.54 (dd, J=3.2 Hz, 0.6 Hz, 1H), 5.51 (s, 2H), 4.14 (s, 3H), 3.51 (m, 2H), 0.94 (m, 2H), 0.00 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:24]2([C:30]([O:32]CC)=[O:31])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[CH:5]=[C:6]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].O.[OH-].[Li+]>CO.C1COCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:24]2([C:30]([OH:32])=[O:31])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]2)[CH:5]=[C:6]([C:14]2[CH:15]=[CH:16][C:17]([C:20]([F:21])([F:22])[F:23])=[CH:18][CH:19]=2)[C:7]=1[O:8][CH2:9][C:10]([F:12])([F:13])[F:11]
Reactant: CCOC(=O)C1(c2cc(Cl)c(OCC(F)(F)F)c(-c3ccc(C(F)(F)F)cc3)c2)CCCCC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)C1(c2cc(Cl)c(OCC(F)(F)F)c(-c3ccc(C(F)(F)F)cc3)c2)CCCCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 72.2 %

Procedure:
A mixture of ethyl 1-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-cyclohexanecarboxylate (0.37 g, 0.72 mmol) and lithium hydroxide monohydrate (0.174 g, 7.28 mmol) in a MeOH/THF/Water solvent mixture (10 ml/10 ml/10 ml) was stirred for 3 h at room temperature. After completion of reaction volatiles were removed under reduced pressure. The residue was diluted with water, acidified with 5% HCl solution and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with water, dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was purified by Flash Column Chromatography to give 1-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-cyclohexane carboxylic acid (0.25 g) as a white solid. 1H-NMR (CDCl3, 400 MHz): 7.72 (d, 2H); 7.65 (d, 2H), 7.55 (s, 1H); 7.34 (s, 1H); 3.98 (q, 2H); 2.48 (dd, 2H); 1.52-1.81 (m, 6H); 1.33 (m, 2H).
Reaction SMILES: [H-].[Na+].[O:3]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[O:6][CH2:5][CH:4]1[CH2:13][C:14]1[NH:15][CH:16]=[CH:17][N:18]=1.[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O>CN(C)C=O>[CH2:19]([N:18]1[CH:17]=[CH:16][N:15]=[C:14]1[CH2:13][CH:4]1[O:3][C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[O:6][CH2:5]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: c1ccc2c(c1)OCC(Cc1ncc[nH]1)O2
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: c1ccc(Cn2ccnc2CC2COc3ccccc3O2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (3.0 g of 50% dispersion in oil) was added to a solution of 2-(1,4-benzodioxan-2-ylmethyl)-imidazole (5.2 g) in dimethylformamide (50 ml) and the resulting mixture was stirred for 30 minutes. The solution was cooled in an ice bath and benzyl bromide (3 ml) was added. After warming to room temperature the mixture was poured into water (250 ml) and extracted with ethyl acetate (3×100 ml). The ethyl acetate extracts were combined, washed with water (3×100 ml), dried over sodium sulfate, and evaporated. The residue was dissolved in methanolic hydrochloric acid and ether was added until an oil came out of solution. The oil was crystallized from isopropanol-ether to give the title compound (2.10 g) as a white powder, m.p. 105°-107° C.
Reaction SMILES: ON1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2N=N1.C(N=C=NC(C)C)(C)C.C[N:21](C)[CH:22]=[O:23]>>[C:22]([NH2:21])(=[O:23])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CN(C)C=O
Reactant: On1nnc2ccccc21
Agent: CC(C)N=C=NC(C)C
Product: NC(=O)c1ccccc1
Yield: 98 %

Procedure:
Rink amide resin (1.786 g; 1.00 mmol) is deprotected as described previously. The deprotected resin is shaken in a solution prepared from 4d (745 mg; 2.00 mmol), 1-hydroxybenzotriazole (810 mg, 6.00 mmol), N,N′-diisopropyl carbodiimide (1.010 g, 8.00 mmol) and dimethylformamide (100 mL) overnight at room temperature. The resin is washed thoroughly with several portions of dimethylformamide, then methanol, and finally dichloromethane. The washing continues until the latest filtrate is free of fluorescence. Solvents are evaporated under reduced pressure at room temperature. An aliquot of product (7a) is cleaved from the solid support (200 mg) by treatment of the resin with a 2:1 mixture of dichloromethane and triluoroacetic acid (10 mL) for 10 min. The solution is collected by vacuum filtration. The resin is further extracted with three portions of dichloromethane, followed by two portions of dimethylformamide. Removal of the solvents under reduced pressure and drying overnight in a desiccator provides 34.0 mg (98%) of 7a: mp 267-269° C.; homogeneous by thin layer chromatography: Rf=0.68; dichloromethane: methanol=9:1); 1H-NMR (DMSO-d6): 3.92 (s, 3H, OCH3); 7.43 (ddd, 1H); 7.61 (ddd, 1H); 7.95-8.00 (m, 3H); 8.13-8.16 (m, 4H); 8.23-8.25 (m, 3H); CONH2 broad (not assignable); 13C-NMR (DMSO-d6): 51.9 (COOCH3); 121.2; 121.6; 122.6; 123.0; 127.3; 127.9; 129.0; 129.4; 129.7; 132.5; 136.8; 139.9; 141.4; 144.4; 165.9 (CONH2); 167.03 (COOCH3).
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][C:5](=[CH:8][C:9]2[CH:10]=[C:11]([CH:23]=[CH:24][CH:25]=2)[O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][N:14]=2)[CH2:4][CH2:3]1.[CH3:26][C:27]1[CH:28]=[C:29]([NH:33][C:34](=O)[O:35]C2C=CC=CC=2)[CH:30]=[N:31][CH:32]=1.NC1C=NC=C(C)C=1.C(N(C(C)C)CC)(C)C>CS(C)=O>[CH3:26][C:27]1[CH:28]=[C:29]([NH:33][C:34]([N:2]2[CH2:7][CH2:6][C:5](=[CH:8][C:9]3[CH:25]=[CH:24][CH:23]=[C:11]([O:12][C:13]4[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:20])[F:21])=[CH:15][N:14]=4)[CH:10]=3)[CH2:4][CH2:3]2)=[O:35])[CH:30]=[N:31][CH:32]=1
Reactant: Cc1cncc(NC(=O)Oc2ccccc2)c1
Reactant: FC(F)(F)c1ccc(Oc2cccc(C=C3CCNCC3)c2)nc1
Agent: Cc1cncc(N)c1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: Cc1cncc(NC(=O)N2CCC(=Cc3cccc(Oc4ccc(C(F)(F)F)cn4)c3)CC2)c1
Temperature: 60 °C
Reaction time: 4 h
Yield: 64 %

Procedure:
A solution of 2-(3-piperidin-4-ylidenemethyl-phenoxy)-5-trifluoromethyl-pyridine hydrochloride (0.371 g, 1.00 mmol) (from Example 1, Step 5) and phenyl 5-methylpyridin-3-ylcarbamate (0.274 g, 1.2 mmol, prepared according to the procedure described in Synthesis, 1997, 1189-1194 from 3-amino-5-methylpyridine) in DMSO (2.5 mL) was treated with diisopropylethylamine (0.155 g, 1.2 mmol) and the mixture was heated to 60° C. After 4 h, the reaction mixture was partitioned between water and ethyl acetate. The organic layer was separated and the aqueous layer was extracted again with ethyl acetate. The organic layers were combined and were washed with brine and dried over sodium sulfate, filtered and concentrated to form a residue. The residue was purified by silica gel chromatography (10% of the 1N NH3 in MeOH, in dichloromethane) to afford the title compound as a white foam (300 mg, 64%). MS (APCI 10V) AP+ 458.16; 1H NMR (400 MHz, DMSO) δ ppm 2.34 (t, J=5.46 Hz, 2H) 2.46 (t, J=5.46 Hz, 2H) 3.29 (s, 3H) 3.46 (t, J=5.46 Hz, 2H) 3.54 (t, J=5.46 Hz, 2H) 6.38 (s, 1H) 7.03 (m, 2H) 7.13 (d, J=7.80 Hz, 1H) 7.21 (d, J=8.58 Hz, 1H) 7.4 (dd, J=7.8 Hz, 2 Hz, 1H) 7.70 (s, 1H) 7.96 (d, J=2 Hz, 1H) 8.20 (dd, J=8.8 Hz, 2.5 Hz, 1H) 8.41 (d, J=2.2 Hz, 1H) 8.55 (s, 1H) 8.64 (s, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:29]=[CH:28][C:5]2[C:6](=[O:27])/[C:7](=[CH:9]/[C:10]3[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[N:12]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[N:11]=3)/[O:8][C:4]=2[C:3]=1[CH2:30][N:31]1[CH2:36][CH2:35][N:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:33][CH2:32]1.C(=O)([O-])[O-].[K+].[K+].[O:50]1[CH2:54][CH2:53]OC1=O.O>CN(C=O)C>[OH:50][CH2:54][CH2:53][O:1][C:2]1[CH:29]=[CH:28][C:5]2[C:6](=[O:27])/[C:7](=[CH:9]/[C:10]3[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[N:12]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:25])([CH3:26])[CH3:24])[N:11]=3)/[O:8][C:4]=2[C:3]=1[CH2:30][N:31]1[CH2:36][CH2:35][N:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:33][CH2:32]1
Reactant: O=C1OCCO1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2c(O)ccc3c2O/C(=C\c2nn(COCC[Si](C)(C)C)c4ccccc24)C3=O)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(Cc2c(OCCO)ccc3c2O/C(=C\c2nn(COCC[Si](C)(C)C)c4ccccc24)C3=O)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 74.1 %

Procedure:
A solution of tert-butyl (Z)-4-({6-hydroxy-3-oxo-2-[(N-{[2-(trimethylsilyl)ethoxy]methyl}-1H-indazol-3-yl)methylene]-2,3-dihydrobenzofuran-7-yl}methyl)piperazine-1-carboxylate (0.416 g, 0.686 mmol) obtained in Step 2 in DMF (6 mL) was added with potassium carbonate (1.42 g, 10.3 mmol), and the mixture was stirred at room temperature for 10 minutes. The reaction mixture was added with 1,3-dioxolan-2-one (0.725 g, 8.23 mmol), and the mixture was stirred at 100° C. for 5 hours. The reaction mixture was cooled to room temperature, and then added with water (60 mL), and the mixture was vigorously stirred at room temperature for 30 minutes. The precipitated solid was collected by filtration to obtain tert-butyl (Z)-4-{[6-(2-hydroxyethoxy)-3-oxo-2-[(N-{[2-(trimethylsilyl)ethoxy]methyl}-1H-indazol-3-yl)methylene]-2,3-dihydrobenzofuran-7-yl]methyl}piperazine-1-carboxylate (0.331 g, 74%).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]2[C:8]3[C:16]([C:17]4[C:18]([CH3:36])=[C:19]([NH:23][CH2:24][C:25]5[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][C:26]=5[C:27](O)=[O:28])[CH:20]=[CH:21][CH:22]=4)=[N:15][N:14]=[C:13]([C:37](=[O:39])[NH2:38])[C:9]=3[NH:10][C:11]=2[CH:12]=1)(=[O:3])[CH3:2].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CN1CCOCC1>CN(C=O)C.C(OCC)(=O)C>[C:1]([C:4]1[CH:5]=[CH:6][C:7]2[C:8]3[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([N:23]5[CH2:24][C:25]6[C:26](=[CH:30][C:31]([O:34][CH3:35])=[CH:32][CH:33]=6)[C:27]5=[O:28])[C:18]=4[CH3:36])=[N:15][N:14]=[C:13]([C:37]([NH2:38])=[O:39])[C:9]=3[NH:10][C:11]=2[CH:12]=1)(=[O:3])[CH3:2]
Reactant: COc1ccc(CNc2cccc(-c3nnc(C(N)=O)c4[nH]c5cc(C(C)=O)ccc5c34)c2C)c(C(=O)O)c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)C(=O)N(c1cccc(-c3nnc(C(N)=O)c4[nH]c5cc(C(C)=O)ccc5c34)c1C)C2
Yield: 11 %

Procedure:
A mixture of 2-((3-(7-acetyl-4-carbamoyl-5H-pyridazino[4,5-b]indol-1-yl)-2-methylphenylamino)methyl)-5-methoxybenzoic acid (0.336 g, the crude product from previous step), BOP (0.852 g, 1.925 mmol), and N-methylmorpholine (0.635 mL, 5.78 mmol) in DMF (4 mL) was stirred at 45° C. for 1 hr. The mixture was diluted with ethyl acetate (100 mL), washed with water (2×25 mL) and brine (25 mL), and dried over anhydrous MgSO4. After solvent was removed under vacuum, the residue were divided into 4 portions and purified by reverse phase HPLC. The correct fractions were combined and concentrated under vacuum, basified with saturated NaHCO3 solution, and extracted with ethyl acetate (3×35 mL). The combined extract was washed with brine (30 mL) and dried over anhydrous MgSO4. Removal of solvent under vacuum provided the desired product (40 mg, 0.077 mmol, 11% yield over 3 steps) as a yellow solid. LCMS (M+H)+=506.29. 1H NMR (500 MHz, DMSO-d6) δ: 12.67 (s, 1H), 8.83 (s, 1H), 8.52 (s, 1H), 8.09 (s, 1H), 7.83 (dd, J1=8.5 Hz, J2=1.5 Hz, 1H), 7.77 (dd, J1=7.8 Hz, J2=1.1 Hz, 1H), 7.63-7.60 (m, 2H), 7.55 (d, J=6.4 Hz, 1H), 7.47 (d, J=8.3 Hz, 1H), 7.33 (d, J=2.5 Hz, 1H), 7.27 (dd, J1=8.3 Hz, J2=2.5 Hz, 1H), 5.02 (d, J=17.2 Hz, 1H), 4.91 (d, J=17.2 Hz, 1H), 3.86 (s, 3H), 2.68 (s, 3H), 1.89 (s, 3H).
Reaction SMILES: [F:1][C:2]([F:42])([F:41])[C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][CH:12]([O:15][C:16]3[CH:40]=[CH:39][C:19]4[N:20]=[C:21]([C:23]([NH:25][CH:26]5[CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][CH2:27]5)=[O:24])[S:22][C:18]=4[CH:17]=3)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.Cl>O1CCOCC1>[NH:29]1[CH2:30][CH2:31][CH:26]([NH:25][C:23]([C:21]2[S:22][C:18]3[CH:17]=[C:16]([O:15][CH:12]4[CH2:11][CH2:10][N:9]([C:6]5[CH:5]=[CH:4][C:3]([C:2]([F:42])([F:1])[F:41])=[CH:8][CH:7]=5)[CH2:14][CH2:13]4)[CH:40]=[CH:39][C:19]=3[N:20]=2)=[O:24])[CH2:27][CH2:28]1
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)c2nc3ccc(OC4CCN(c5ccc(C(F)(F)F)cc5)CC4)cc3s2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(NC1CCNCC1)c1nc2ccc(OC3CCN(c4ccc(C(F)(F)F)cc4)CC3)cc2s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 110.1 %

Procedure:
A mixture of tert-butyl 4-(6-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)benzo[d]thiazole-2-carboxamido)piperidine-1-carboxylate (compound 8) (0.16 g, 0.27 mmol) and 4N hydrochloric acid in dioxane (2 mL) was stirred at room temperature for 1 h. The reaction mixture was concentrated and washed with diethyl ether (2×3 mL) and then dried under reduced pressure to afford N-(piperidin-4-yl)-6-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)benzo[d]thiazole-2-carboxamide as a off-white solid (0.15 g, 99%). 1H NMR (CD3OD, 300 MHz) 7.83 (m, 5H), 7.48 (s, 1H), 7.23 (m, 1H), 4.93 (m, 1H), 4.22 (m, 1H), 3.90 (m, 3H), 3.35 (m, 2H), 3.17 (m, 2H), 2.23 (m, 8H), 1.98 (m, 2H) ppm; MS (ES) 489.1 (M+1).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[C:7]([CH2:10][NH:11][CH3:12])[CH:8]=[CH:9][C:2]1=2.Cl.[O:14]=[C:15]1[NH:24][C:23]2[N:22]=[CH:21][C:20]([CH:25]=[CH:26][C:27]([OH:29])=O)=[CH:19][C:18]=2[CH2:17][CH2:16]1.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C.Cl>CN(C=O)C.O>[S:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[C:7]([CH2:10][N:11]([CH3:12])[C:27](=[O:29])/[CH:26]=[CH:25]/[C:20]3[CH:21]=[N:22][C:23]4[NH:24][C:15](=[O:14])[CH2:16][CH2:17][C:18]=4[CH:19]=3)[CH:8]=[CH:9][C:2]1=2
Reactant: O=C(O)C=Cc1cnc2c(c1)CCC(=O)N2
Reactant: CNCc1ccc2sccc2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CN(Cc1ccc2sccc2c1)C(=O)/C=C/c1cnc2c(c1)CCC(=O)N2
Temperature: 40 °C
Reaction time: 8 h
Yield: 77.5 %

Procedure:
To a solution of benzo[b]thiophen-5-yl-N-methylmethanamine (260 mg, 1.47 mmol), 3-(7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-3-yl)-acrylic acid hydrochloride (377 mg, 1.48 mmol), HOBt (200 mg, 1.48 mmol) and DIPEA (1.05 mL, 6.03 mmol) in anhydrous DMF (24 mL) was added EDC hydrochloride (284 mg, 1.48 mmol). The mixture was stirred overnight at 40° C. Water (50 mL) was added and the solution was stirred for 1 h. The reaction mixture was extracted with ethyl acetate (3×80 mL). Combined organic layers were washed with water (50 mL) and brine (50 mL) and concentrated to give an orange solid which was purified by column chromatography (silica gel, 5% MeOH/CH2Cl2) to afford (E)-N-(benzo[b]thiophen-5-ylmethyl)-N-methyl-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide (430 mg, 78%) as a pink solid and a mixture of amide rotomers: 1H NMR (400 MHz, DMSO-d6) δ 10.67-10.64 (m, 1H), 8.37-8.33 (m, 1H), 8.08-8.05 (m, 1H), 8.00-7.95 (m, 1H), 7.75-7.71 (m, 2H), 7.56-7.52 (m, 1H), 7.45-7.43 (m, 1H), 7.37-7.22 (m, 2H), 4.93-4.73 (m, 2H), 3.12-2.86 (m, 5H), 2.54-2.51 (m, 2H); ESI MS m/z 378 [C21H19N3O2S+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:24])=[C:6]([N:8]([CH2:20][CH:21]([CH3:23])[CH3:22])[S:9]([C:12]2[CH:17]=[CH:16][C:15]([CH:18]=[CH2:19])=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH:7]=1.ClC1C=C(C=CC=1)C(OO)=[O:30]>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:24])=[C:6]([N:8]([CH2:20][CH:21]([CH3:22])[CH3:23])[S:9]([C:12]2[CH:17]=[CH:16][C:15]([CH:18]3[CH2:19][O:30]3)=[CH:14][CH:13]=2)(=[O:10])=[O:11])[CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=Cc1ccc(S(=O)(=O)N(CC(C)C)c2cc(Cl)ccc2F)cc1
Solvent: ClCCl
Product: CC(C)CN(c1cc(Cl)ccc1F)S(=O)(=O)c1ccc(C2CO2)cc1
Reaction time: 6 h
Yield: 58.5 %

Procedure:
To a stirred solution of N-(5-chloro-2-fluorophenyl)-N-isobutyl-4-vinylbenzenesulfonamide (824 mg, 2.240 mmol) in dichloromethane (DCM) at 0° C. was added meta-chloroperoxybenzoic acid (mCPBA) (1546 mg, 8.96 mmol) and the reaction mixture stirred for 6 hours from 0° C. to 25° C. The reaction was then washed with water (5 mL), sodium hydroxide solution (2M, 5 mL) and brine (5 mL), then evaporated in vacuo to give the required product (503 mg). LCMS [LCMS2] Rt 1.34 min, m/z (ES+) 384 (M+H).
Reaction SMILES: [Br:1]Br.[Cl:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:7]2[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.S(=O)(O)[O-].[Na+]>C(O)(=O)C>[Br:1][C:12]1[CH:11]=[C:10]2[C:6]([C:7]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:8]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[NH:9]2)=[CH:5][C:4]=1[Cl:3]
Reactant: CCOC(=O)c1[nH]c2ccc(Cl)cc2c1-c1ccccc1
Reactant: BrBr
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: CCOC(=O)c1[nH]c2cc(Br)c(Cl)cc2c1-c1ccccc1
Reaction time: 8 h

Procedure:
All 11 ml (33 g.) of bromine to a mixture of ethyl 5-chloro-3-phenylindole-2-carboxylate (30 g.) in 100 ml of acetic acid at 10- 20°. Stir overnight and then add a solution of sodium bisulfite. Filter and wash the precipitate with water. Stir the solid with methanol and filter to yield the title compound. Recrystallization from methanol yields the analytical sample; m.p. 205°-206°C.