Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[N:8]1[CH:17]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[Cl:25])[CH:16]([C:26]([NH:28][O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:27])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]1=[O:37].[S:38](N)([NH2:41])(=[O:40])=[O:39]>C(COC)OC>[NH2:41][S:38]([NH:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[N:8]1[CH:17]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[Cl:25])[CH:16]([C:26]([NH:28][O:29][CH2:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)=[O:27])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]1=[O:37])(=[O:40])=[O:39]
Reactant: NC1CCCCC1N1C(=O)c2ccccc2C(C(=O)NOCc2ccccc2)C1c1ccc(Cl)cc1Cl
Reactant: NS(N)(=O)=O
Solvent: COCCOC
Product: NS(=O)(=O)NC1CCCCC1N1C(=O)c2ccccc2C(C(=O)NOCc2ccccc2)C1c1ccc(Cl)cc1Cl
Temperature: 80 °C
Reaction time: 48 h
Yield: 27 %

Procedure:
To a mixed liquid of 200 mg of (3RS,4RS)-2-[(1SR,2SR)-2-aminocyclohexyl]-N-(benzyloxy)-3-(2,4-dichlorophenyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide and 40 ml of dimethoxyethane was added 357 mg of sulfamide, followed by stirring at 80° C. for 2 days. The reaction solution was concentrated, added with chloroform, and then washed with water. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was then evaporated. The residue was purified by silica gel column chromatography (eluent: chloroform-methanol), crystallized from ethyl acetate, and collected by filtration to obtain 62 mg of (3RS,4RS)-2-{(1SR,2SR)-2-[(aminosulfonyl)amino]cyclohexyl}-N-(benzyloxy)-3-(2,4-dichlorophenyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide as a white crystal.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[C:3]=1[C:9]1[NH:28][C:12]2=[CH:13][C:14]3[C:15](=[O:27])[N:16]([CH2:22][CH2:23][N:24]([CH3:26])[CH3:25])[C:17](=[O:21])[C:18]=3[C:19]([CH3:20])=[C:11]2[N:10]=1.[F:29][C:30]1[CH:31]=[CH:32][C:33]([CH3:40])=[C:34]([CH2:36][CH:37]([NH2:39])[CH3:38])[CH:35]=1.CCN(C(C)C)C(C)C>C(O)CCC>[CH3:25][N:24]([CH3:26])[CH2:23][CH2:22][N:16]1[C:15](=[O:27])[C:14]2[CH:13]=[C:12]3[NH:28][C:9]([C:3]4[C:4](=[O:8])[NH:5][CH:6]=[CH:7][C:2]=4[NH:39][CH:37]([CH3:38])[CH2:36][C:34]4[CH:35]=[C:30]([F:29])[CH:31]=[CH:32][C:33]=4[CH3:40])=[N:10][C:11]3=[C:19]([CH3:20])[C:18]=2[C:17]1=[O:21]
Reactant: Cc1c2c(cc3[nH]c(-c4c(Cl)cc[nH]c4=O)nc13)C(=O)N(CCN(C)C)C2=O
Reactant: Cc1ccc(F)cc1CC(C)N
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(F)cc1CC(C)Nc1cc[nH]c(=O)c1-c1nc2c(C)c3c(cc2[nH]1)C(=O)N(CCN(C)C)C3=O
Yield: 55 %

Procedure:
A mixture of 2-(4-chloro-2-oxo-1,2-dihydropyridin-3-yl)-6-(2-(dimethylamino)ethyl)-4-methylimidazo[4,5-f]isoindole-5,7(1H,6H)-dione (0.48 g, 1.20 mmol), 1-(5-fluoro-2-methylphenyl)propan-2-amine (0.24 g, 1.44 mmol), Hunig's base (0.78 g, 6.00 mmol), and 10 mL of anhydrous 1-butanol was heated at reflux for 12-13 h under an argon atmosphere. Product was purified by a silica gel column using methylene chloride and methanol (9:1 v/v) as eluent to afford 0.35 g of the designed compound as yellow solid. 1H NMR (500 MHz, DMSO-d6) δ 13.36 (s, 1H, NH), 11.24 (d, J=6.0 Hz, 1H, NH), 11.02 (d, J=8.5 Hz, 1H, NH), 7.99 (s, 1H, ArH), 7.32 (t, J=6.5 Hz, 1H, ArH), 7.15-7.08 (m, 2H, ArH), 6.91-6.87 (m, 1H, ArH), 6.16 (d, J=7.5 Hz, 1H, ArH), 4.22-4.18 (m, 1H, CH), 3.73-3.71 (m, 2H, CH2), 2.97-2.96 (m, 2H, CH2), 2.86 (s, 3H, CH3), 2.72-2.68 (m, 2H, CH2), 2.36 (s, 6H, 2×CH3), 2.27 (s, 3H, CH3), 1.34 (d, J=6.5 Hz, 3H, CH3); Mass (ESI, negative) m/z 529.0 [M−H]−.
Reaction SMILES: [CH3:1][C@:2]12[C@@:19]3([CH3:20])[C@@H:10]([C@:11]4([CH3:32])[C@@H:16]([CH2:17][CH2:18]3)[C:15]([CH3:22])([CH3:21])[C:14]([C:23]3[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=3)=[CH:13][CH2:12]4)[CH2:9][CH2:8][C@@H:7]1[C@H:6]1[C@H:33]([C:36]([CH3:38])=[CH2:37])[CH2:34][CH2:35][C@:5]1([NH:39][CH2:40][CH2:41][NH:42]C1N=NC=CC=1)[CH2:4][CH2:3]2.Br[C:50]1[CH:55]=[CH:54][C:53]([S:56]([CH3:59])(=[O:58])=[O:57])=[CH:52][N:51]=1.C(O)(C(F)(F)F)=O>>[CH3:1][C@:2]12[C@@:19]3([CH3:20])[C@@H:10]([C@:11]4([CH3:32])[C@@H:16]([CH2:17][CH2:18]3)[C:15]([CH3:21])([CH3:22])[C:14]([C:23]3[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=3)=[CH:13][CH2:12]4)[CH2:9][CH2:8][C@@H:7]1[C@H:6]1[C@H:33]([C:36]([CH3:38])=[CH2:37])[CH2:34][CH2:35][C@:5]1([NH:39][CH2:40][CH2:41][NH:42][C:50]1[CH:55]=[CH:54][C:53]([S:56]([CH3:59])(=[O:58])=[O:57])=[CH:52][N:51]=1)[CH2:4][CH2:3]2
Reactant: CS(=O)(=O)c1ccc(Br)nc1
Reactant: C=C(C)[C@@H]1CC[C@]2(NCCNc3cccnn3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Solvent: O=C(O)C(F)(F)F
Product: C=C(C)[C@@H]1CC[C@]2(NCCNc3ccc(S(C)(=O)=O)cn3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Yield: 11.9 %

Procedure:
The title compound was prepared following a similar procedure as described for the synthesis of 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-3a-(2-(pyridazin-3-ylamino)ethylamino)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoic acid, except 2-bromo-5-(methylsulfonyl)pyridine (0.024 g, 0.100 mmol) was used in place of 3-chloropyridazine. Purification of the crude Step 2 mixture by reverse phase preparative HPLC using Prep HPLC Method 10 gave the title compound as an off-white solid (10.6 mg, 11.9% yield over 2 steps) bis TFA salt. LCMS: m/e 728.5 (M+H)+, 2.22 min (method 11). 1H NMR (500 MHz, 1:1 mixture of CDCl3 and MeOD, MeOD lock) δ ppm 8.61 (d, J=1.8 Hz, 1H), 7.95-7.87 (m, 3H), 7.19 (d, J=8.2 Hz, 2H), 6.80 (d, J=8.9 Hz, 1H), 5.29 (d, J=4.6 Hz, 1H), 4.90 (s, 1H), 4.82 (br. s., 1H), 3.96-3.85 (m, 1H), 3.85-3.71 (m, 1H), 3.42 (br. s., 1H), 3.37 (s, 3H), 3.27-3.18 (m, 1H), 3.10 (s, 3H), 2.70 (br. s., 1H), 2.14 (dd, J=17.2, 6.3 Hz, 1H), 2.10-1.95 (m, 5H), 1.91-1.77 (m, 3H), 1.74 (s, 3H), 1.71 (d, J=17.4 Hz, 2H), 1.65-1.47 (m, 6H), 1.47-1.34 (m, 3H), 1.34-1.11 (m, 6H), 1.06 (s, 3H), 1.00 (s, 3H), 0.94 (s, 6H), 0.93 (s, 3H).
Reaction SMILES: C(O[C:6](=[O:14])[NH:7][C:8]1[O:9][C:10]([CH3:13])=[CH:11][CH:12]=1)(C)(C)C.[CH3:15][C:16]1OC(C(O)=O)=C[CH:17]=1>>[C:6]([NH:7][C:8]1[O:9][C:10]([CH3:13])=[CH:11][CH:12]=1)(=[O:14])[CH:16]([CH3:17])[CH3:15]
Reactant: Cc1ccc(NC(=O)OC(C)(C)C)o1
Reactant: Cc1ccc(C(=O)O)o1
Product: Cc1ccc(NC(=O)C(C)C)o1

Procedure:
tert-Butyl-5-methyl-2-furylcarbamate, (mp 80° C., 24 g, 0.12 mole) prepared as in Example 1 from 5-methyl-2-furoic acid was reacted as in Example 2 to give 2-isobutanamido-5-methylfuran (13.4 g) mp 78° C. which was then reacted as in Example 4 to give the title compound. b.p. 94° C./0.3 mm.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:17]=[C:16]3[C:12]([C:13]([NH:18][C:19]([C:21]4[CH:25]=[CH:24][S:23][CH:22]=4)=[O:20])=[N:14][NH:15]3)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[F:33][C:34]1[CH:39]=[CH:38][C:37]([C:40]([F:43])([F:42])[F:41])=[CH:36][C:35]=1[N:44]=[C:45]=[O:46]>O1CCCC1>[S:23]1[CH:24]=[CH:25][C:21]([C:19]([NH:18][C:13]2[C:12]3[C:16](=[CH:17][C:9]([C:6]4[CH:5]=[CH:4][C:3]([NH:2][C:45]([NH:44][C:35]5[CH:36]=[C:37]([C:40]([F:41])([F:43])[F:42])[CH:38]=[CH:39][C:34]=5[F:33])=[O:46])=[CH:8][CH:7]=4)=[CH:10][CH:11]=3)[NH:15][N:14]=2)=[O:20])=[CH:22]1
Reactant: O=C=Nc1cc(C(F)(F)F)ccc1F
Reactant: Nc1ccc(-c2ccc3c(NC(=O)c4ccsc4)n[nH]c3c2)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(-c2ccc3c(NC(=O)c4ccsc4)n[nH]c3c2)cc1)Nc1cc(C(F)(F)F)ccc1F
Temperature: 24 °C
Reaction time: 3.5 h

Procedure:
A solution of 1.72 g of 6-(4-aminophenyl)-3-[(thiophen-3-yl)carbonylamino]-1H-indazole hydrochloride and 0.65 mL of triethylamine in 70 mL of tetrahydrofuran is admixed slowly under an argon atmosphere with 0.67 mL of 2-fluoro-5-trifluoromethylphenyl isocyanate. The reaction mixture is stirred at 24° C. for 3.5 hours and then concentrated under reduced pressure. The residue is purified by flash chromatography on a silica column (60; 35-70 μM), eluting with a dichloromethane/methanol (97/3 by volume) mixture, to give 0.4 g of 1-(4-{3-[(thiophen-3-yl)carbonylamino]-1H-indazol-6-yl}phenyl)-3-(2-fluoro-5-trifluoromethylphenyl)urea, whose characteristics are as follows:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([NH:14][C:15]([C@@H:17]2[CH2:23][CH2:22][C@@H:21]3[CH2:24][N:18]2[C:19](=[O:33])[N:20]3[O:25]CC2C=CC=CC=2)=[O:16])[C@H:10]([F:34])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.C(OCC)(=O)C.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([NH:14][C:15]([C@@H:17]2[CH2:23][CH2:22][C@@H:21]3[CH2:24][N:18]2[C:19](=[O:33])[N:20]3[OH:25])=[O:16])[C@H:10]([F:34])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](NC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)[C@H](F)C1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CC[C@H](NC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3O)[C@H](F)C1
Reaction time: 8 h

Procedure:
To a solution of the product of Step 1 (3.0175 g, 6.33 mmol) in methanol (80 mL) and ethyl acetate (20 mL), was added 10% palladium on carbon (0.73 g, 6.86 mmol) and the reaction mixture was stirred under an atmosphere of hydrogen (balloon) overnight. LC/MS analysis showed reaction was complete. The reaction mixture was filtered through a microfilter and the collected solid was washed well with methanol. The filtrate was concentrated under vacuum and azeotroped with toluene to afford the title compound as a yellow foam which was used directly in the next step without purification
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:14])([CH3:13])[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.O>CN(C)C=O>[C:1]([O:5][C:6]([NH:8][C:9]([CH3:14])([CH3:13])[C:10]([O:12][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC(C)(C)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-(tert-butoxycarbonylamino)-2-methylpropionic acid (4.06 g) in N,N-dimethylformamide (40 mL) were added potassium carbonate (4.15 g) and benzyl bromide (2.85 mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into water, and the resulting mixture was extracted with ethylacetate. The extract was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure. The residue (solid) was treated with n-hexane and collected by filtration. The crystals were dried under reduced pressure to give benzyl 2-(tert-butoxycarbonylamino)-2-methylpropionate (4.44 g). To the obtained benzyl 2-(tert-butoxycarbonylamino)-2-methylpropionate (4.44 g) was added 4 mol/L hydrochloric acid (1,4-dioxane solution, 15 mL), and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with diethyl ether, and the mixture was stirred for 1 hour. The insoluble material was collected by filtration, washed with diethyl ether and dried under reduced pressure to give the title compound (3.4 g).
Reaction SMILES: C[O:2][C:3](=[O:14])[CH2:4][C:5]1[CH:10]=[C:9]([Br:11])[C:8]([F:12])=[CH:7][C:6]=1[CH3:13].[OH-].[Na+]>CO>[Br:11][C:9]1[C:8]([F:12])=[CH:7][C:6]([CH3:13])=[C:5]([CH2:4][C:3]([OH:14])=[O:2])[CH:10]=1
Reactant: COC(=O)Cc1cc(Br)c(F)cc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cc(F)c(Br)cc1CC(=O)O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of (5-bromo-4-fluoro-2-methyl-phenyl)-acetic acid methyl ester (10.3 g) in methanol (50 ml) was added 1N aqueous sodium hydroxide (47.4 ml) and the reaction mixture was stirred at room temperature for 18 hours. The mixture was concentrated, the residue treated with 1N hydrochloric acid, the resulting precipitate filtered off, washed with ice-water and dried. Yield: 8.60 g of (5-bromo-4-fluoro-2-methyl-phenyl)-acetic acid as a solid, mp: 100-101° C.
Reaction SMILES: O[C:2]1([C:26]([F:29])([F:28])[F:27])[CH2:6][N:5]([C:7]2[CH:12]=[CH:11][C:10]([S:13][CH3:14])=[CH:9][CH:8]=2)[C:4]([C:15]2[S:19][C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:17][N:16]=2)=[N:3]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:14][S:13][C:10]1[CH:9]=[CH:8][C:7]([N:5]2[CH:6]=[C:2]([C:26]([F:28])([F:27])[F:29])[N:3]=[C:4]2[C:15]2[S:19][C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:17][N:16]=2)=[CH:12][CH:11]=1
Reactant: CSc1ccc(N2CC(O)(C(F)(F)F)N=C2c2nnc(-c3ccccc3)s2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CSc1ccc(-n2cc(C(F)(F)F)nc2-c2nnc(-c3ccccc3)s2)cc1

Procedure:
A mixture of 4-hydroxy-1-[4-(methylthio)phenyl]-2-[2-(phenyl)-1,3,4-thiadiazol-5-yl]-4-(trifluoromethyl)-4,5-dihydro-1H-imidazole (0.5 g, 1.15 mmol) and p-toluenesulfonic acid monohydrate (30 mg) in toluene (50 mL) was heated to reflux for 1 hour. After aqueous work up, 1-[4-(Methylthio)phenyl]-2-[2-(phenyl)-1,3,4-thiadiazol-5-yl]-4-(trifluoromethyl)-imidazole was isolated as a white solid.
Reaction SMILES: S([C:5]1C=CC(C)=C[CH:6]=1)(O)(=O)=O.[OH:12][CH2:13][C@@H:14]1[C@@H:20]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([Cl:28])[CH:22]=2)[CH2:19][C@H:18]2[N:29]([CH3:30])[C@@H:15]1[CH2:16][CH2:17]2.[O-]CC.[Na+]>C(O)C>[CH2:5]([O:12][CH2:13][C@@H:14]1[C@@H:20]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([Cl:28])[CH:22]=2)[CH2:19][C@H:18]2[N:29]([CH3:30])[C@@H:15]1[CH2:16][CH2:17]2)[CH3:6]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CN1[C@H]2CC[C@@H]1[C@H](CO)[C@@H](c1ccc(Cl)c(Cl)c1)C2
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC[C@@H]1[C@@H](c2ccc(Cl)c(Cl)c2)C[C@@H]2CC[C@H]1N2C
Yield: 96.9 %

Procedure:
(1R, 2R, 3S)-2-hydroxymethyl-3-(3,4-dichlorophenyl)tropane tosylate (2.5 g, 5.5 mmol) was dissolved in anhydrous ethanol (20 ml). Sodium ethoxide in ethanol (2.4 ml, 2.5M, 6 mmol) was added and the reaction mixture was refluxed for 72 hours. The solvent was evaporated off. The residue was stirred with water and ether and extracted three times with ether (3×50 ml) and dried over MgSO4. Evaporation of the solvent yields 1.75 g of the title compound. The product was purified by column chromatography on silica using EtOAc:Et3N (99:1). Yield 1.24 g.
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[CH:4][C:3]=1[C:12]1[C:21]2[N:20]=[CH:19][CH:18]=[N:17][C:16]=2[C:15]([C:22]([OH:24])=O)=[CH:14][CH:13]=1.Cl.[CH2:26]([N:28]1[CH2:33][CH2:32][N:31]([CH2:34][C:35]2[CH:36]=[CH:37][C:38]([NH2:41])=[N:39][CH:40]=2)[CH2:30][CH2:29]1)[CH3:27]>>[CH2:26]([N:28]1[CH2:29][CH2:30][N:31]([CH2:34][C:35]2[CH:36]=[CH:37][C:38]([NH:41][C:22]([C:15]3[C:16]4[N:17]=[CH:18][CH:19]=[N:20][C:21]=4[C:12]([C:3]4[CH:4]=[C:5]([O:10][CH3:11])[CH:6]=[C:7]([O:8][CH3:9])[C:2]=4[F:1])=[CH:13][CH:14]=3)=[O:24])=[N:39][CH:40]=2)[CH2:32][CH2:33]1)[CH3:27]
Reactant: CCN1CCN(Cc2ccc(N)nc2)CC1
Reactant: COc1cc(OC)c(F)c(-c2ccc(C(=O)O)c3nccnc23)c1
Agent: Cl
Product: CCN1CCN(Cc2ccc(NC(=O)c3ccc(-c4cc(OC)cc(OC)c4F)c4nccnc34)nc2)CC1
Temperature: 25 °C
Reaction time: 144 h

Procedure:
The title compound was prepared in analogy to the procedure described in Step 14.1 but using 8-(2-fluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid (Step 94.1), 5-(4-ethyl-piperazin-1-ylmethyl)-pyridin-2-ylamine hydrochloride (Step 26.1) and stirring the reaction mixture for 6 days at rt. The crude product was purified by silica gel column chromatography (DCM/MeOH/NH3aq, 94:5:1). Title compound: ESI-MS: 531.2 [M+H]+; tR=3.40 min (System 1); TLC: Rf=0.19 (DCM/MeOH/NH3aq, 94:5:1).
Reaction SMILES: [CH3:1][N:2]([CH3:15])[CH2:3][C:4]#[C:5][CH2:6][NH:7][C:8](=[O:14])/[CH:9]=[CH:10]\[C:11]([OH:13])=O>C(Cl)Cl>[CH3:1][N:2]([CH3:15])[CH2:3][C:4]#[C:5][CH2:6][N:7]1[C:8](=[O:14])[CH:9]=[CH:10][C:11]1=[O:13]
Reactant: CN(C)CC#CCNC(=O)/C=C\C(=O)O
Solvent: ClCCl
Product: CN(C)CC#CCN1C(=O)C=CC1=O
Yield: 51.6 %

Procedure:
A Kugelrohr oven apparatus is used to heat 1.25 g of product from Example 10 at 145°-180° C. (0.1 mm Hg) for 30 minutes. The distillate is dissolved in methylene chloride, dried over sodium sulfate, filtered and concentrated in vacuo to give 0.59 g of the product as a dark oil. The oil is redistilled at 130°-135° C. (0.05-0.075 mm Hg) to give 0.240 g of the desired product as a dark amber oil.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([S:7]([NH:10][C:11]([NH:13][C:14]2[CH:23]=[CH:22][C:17]([C:18]([O:20]C)=[O:19])=[CH:16][CH:15]=2)=[O:12])(=[O:9])=[O:8])=[CH:4][CH:3]=1.[Li+].[OH-]>CO.C(#N)C>[Cl:1][C:2]1[S:6][C:5]([S:7]([NH:10][C:11]([NH:13][C:14]2[CH:23]=[CH:22][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=2)=[O:12])(=[O:9])=[O:8])=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(NC(=O)NS(=O)(=O)c2ccc(Cl)s2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: CC#N
Product: O=C(Nc1ccc(C(=O)O)cc1)NS(=O)(=O)c1ccc(Cl)s1
Temperature: 25 °C
Reaction time: 21 h
Yield: 127.5 %

Procedure:
To a suspension of methyl 4-({[(5-chloro-2-thienyl)sulfonyl]amino}carbonylamino)benzoate (56 mg, 0.15 mmol) in methanol (1 mL) and acetonitrile (1 mL) was added 1N LiOH (0.16 mL, 0.16 mmol). The resulting solution was stirred at room temp for 21 hr, then an additional 0.32 mL 1N LiOH was added and the reaction was stirred at 40° C. for another 21 hr til complete. Concentration in vacuo gave crude 4-({[(5-chloro-2-thienyl)sulfonyl]amino}carbonylamino)benzoic acid (69 mg). ES-MS (M+H)+=361.
Reaction SMILES: CO[C:3](=[O:17])[C:4]([C:6]1[C:14]2[C:9](=[C:10]([C:15]#[N:16])[CH:11]=[CH:12][CH:13]=2)[NH:8][CH:7]=1)=O.[C:18]1([CH2:30][C:31]([NH2:33])=[O:32])[C:28]2=[C:29]3[C:24](=[CH:25][CH:26]=[CH:27]2)[CH2:23][CH2:22][CH2:21][N:20]3[CH:19]=1>>[C:18]1([C:30]2[C:31](=[O:32])[NH:33][C:3](=[O:17])[C:4]=2[C:6]2[C:14]3[C:9](=[C:10]([C:15]#[N:16])[CH:11]=[CH:12][CH:13]=3)[NH:8][CH:7]=2)[C:28]2=[C:29]3[C:24](=[CH:25][CH:26]=[CH:27]2)[CH2:23][CH2:22][CH2:21][N:20]3[CH:19]=1
Reactant: NC(=O)Cc1cn2c3c(cccc13)CCC2
Reactant: COC(=O)C(=O)c1c[nH]c2c(C#N)cccc12
Product: N#Cc1cccc2c(C3=C(c4cn5c6c(cccc46)CCC5)C(=O)NC3=O)c[nH]c12

Procedure:
Beginning with 7-cyanoindole-3-glyoxylic acid methyl ester and 2-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)acetamide, the title compound was prepared essentially as described in Example 1.
Reaction SMILES: I[CH2:2][C:3]1([CH3:19])[O:18][C:6]2=[C:7]([CH3:17])[C:8]3[CH2:9][C:10]([CH3:16])([CH3:15])[NH:11][C:12]=3[C:13]([CH3:14])=[C:5]2[CH2:4]1.Cl.[CH3:21][N:22]([CH:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1)[C:23]1[S:24][C:25]2[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=2[N:27]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C(=O)C>[CH3:21][N:22]([CH:32]1[CH2:37][CH2:36][N:35]([CH2:2][C:3]2([CH3:19])[O:18][C:6]3=[C:7]([CH3:17])[C:8]4[CH2:9][C:10]([CH3:16])([CH3:15])[NH:11][C:12]=4[C:13]([CH3:14])=[C:5]3[CH2:4]2)[CH2:34][CH2:33]1)[C:23]1[S:24][C:25]2[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=2[N:27]=1
Reactant: CN(c1nc2ccccc2s1)C1CCNCC1
Reactant: Cc1c2c(c(C)c3c1NC(C)(C)C3)OC(C)(CI)C2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: Cc1c2c(c(C)c3c1NC(C)(C)C3)OC(C)(CN1CCC(N(C)c3nc4ccccc4s3)CC1)C2
Temperature: 180 °C
Reaction time: 4.5 h
Yield: 47.1 %

Procedure:
A suspension of 3,5,6,7-tetrahydro-2-(iodomethyl)-2,4,6,6,8-pentamethyl-2H-furo[2,3-f]indole (372 mg, 1.00 mmol), N-methyl-N-(4-piperidinyl)-1,3-benzothiazole-2-amine hydrochloride (427 mg, 1.50 mmol) and potassium carbonate (485 mg, 3.51 mmol) in N,N-dimethylacetamide (2 ml) was stirred for 4.5 hours at 180° C. under nitrogen atmosphere. Water was added to the reaction mixture and the mixture was extracted twice with ethyl acetate. The organic layers were combined, washed with water and saturated brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was subjected to basic silica gel column chromatography (hexane:ethyl acetate=5:1) and crystallized from ethyl acetate-hexane to obtain 231 mg of the title compound.
Reaction SMILES: [CH2:1]1[O:12][C:11]2[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH2:8])=[CH:4][C:3]=2[O:2]1.Cl[C:14]1[C:15]2[C:28]([CH3:29])=[C:27]([CH3:30])[S:26][C:16]=2[N:17]=[C:18]([C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[N:19]=1>>[N:22]1[CH:23]=[CH:24][CH:25]=[C:20]([C:18]2[N:19]=[C:14]([NH:8][CH2:7][CH2:6][C:5]3[CH:9]=[CH:10][C:11]4[O:12][CH2:1][O:2][C:3]=4[CH:4]=3)[C:15]3[C:28]([CH3:29])=[C:27]([CH3:30])[S:26][C:16]=3[N:17]=2)[CH:21]=1
Reactant: NCCc1ccc2c(c1)OCO2
Reactant: Cc1sc2nc(-c3cccnc3)nc(Cl)c2c1C
Product: Cc1sc2nc(-c3cccnc3)nc(NCCc3ccc4c(c3)OCO4)c2c1C

Procedure:
With the procedure of Example 1, the reaction of 3,4-methylenedioxyphenethylamine with 4-chloro-2-(pyridin-3-yl)-5,6-dimethyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-3-yl)-4-(3,4-methylenedioxyphenethylamino)-5,6-dimethyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[F:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[O:35][C:19]3=[N:20][CH:21]=[C:22]([C:24]4[CH:25]=[C:26]([CH:31]=[CH:32][C:33]=4[CH3:34])[C:27]([O:29][CH3:30])=[O:28])[CH:23]=[C:18]3[CH:17]=2)=[CH:12][CH:11]=1>[Al].ClC(Cl)C.CCOC(C)=O>[Br:8][C:17]1[C:18]2[C:19](=[N:20][CH:21]=[C:22]([C:24]3[CH:25]=[C:26]([CH:31]=[CH:32][C:33]=3[CH3:34])[C:27]([O:29][CH3:30])=[O:28])[CH:23]=2)[O:35][C:16]=1[C:13]1[CH:12]=[CH:11][C:10]([F:9])=[CH:15][CH:14]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ccc(C)c(-c2cnc3oc(-c4ccc(F)cc4)cc3c2)c1
Agent: [Al]
Solvent: CCOC(C)=O
Solvent: CC(Cl)Cl
Product: COC(=O)c1ccc(C)c(-c2cnc3oc(-c4ccc(F)cc4)c(Br)c3c2)c1
Reaction time: 8 h

Procedure:
The reaction flask was wrapped in aluminum foil. NBS (175 mg, 0.983 mmol) was added to a stirring solution of methyl 3-(2-(4-fluorophenyl)furo[2,3-b]pyridin-5-yl)-4-methylbenzoate (289 mg, 0.800 mmol) in dichloroethane (8 mL) at room temperature. It was allowed to stir overnight. The mixture was diluted with EtOAc and quenched with 10% sodium metabisulfate and washed with sat NaCl. The organic phase was dried over Na2SO4, filtered and concentrated was purified on silica gel (Biotage, EtOAc/hexanes gradient, fraction collection at λ=254 nm) the expected product consistent by LCMS and NMR. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.41 (1H, d, J=2.01 Hz), 8.16-8.26 (2H, m), 8.06 (1H, d, J=2.26 Hz), 7.95 (1H, dd, J=8.03, 1.76 Hz), 7.87 (1H, d), 7.45-7.57 (3H, m), 3.86 (3H, s), 2.34 (3H, s). LC-MS retention time: 2.85 min; m/z (MH+): 440, 442. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters SunFire 5u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% acetonitrile/90% H2O/0.1% trifluoroacetic acid and solvent B was 10% H2O/90% acetonitrile/0.1% trifluoroacetic acid. MS data was determined using a Micromass Platform for LC in electrospray mode.