Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Mg].[CH:12](=[O:14])[CH3:13].[NH4+].[Cl-]>C(OCC)C>[C:1]1([CH2:7][CH2:8][CH2:9][CH:12]([OH:14])[CH3:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC=O
Reactant: BrCCCc1ccccc1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Product: CC(O)CCCc1ccccc1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
In one portion, 3.6 ml (4.72 g, 23.7 mmol) of 3-phenylpropyl bromide are added to a suspension of 5.2 g (213 mmol) of magnesium in 30 ml of diethyl ether. A further 30 ml (39.3 g, 197 mmol) of 3-phenylpropyl bromide are added dropwise at such a rate that constant reflux is maintained. After the addition has ended, the mixture is diluted with 100 ml of diethyl ether and refluxed for 30 min. The mixture is diluted with a further 80 ml of diethyl ether and cooled to −78° C. A solution, of a temperature of 0° C., of 19 ml of acetaldehyde in 50 ml of ether is added dropwise, and the reaction mixture is stirred at −78° C. for 2 hours and warmed to room temperature. 50 ml of saturated NH4Cl solution are added and the organic phase is extracted with 1N HCl and saturated NaHCO3 solution and dried over Na2SO4. Removal of the solvent gives 33.4 g (95%) of a slightly yellow oil.
Reaction SMILES: [I:1]N1C(=O)CCC1=O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH3:21][O:22][C:23](=[O:45])[C:24]1[C:29]([NH:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[F:37])=[CH:28][N:27]=[CH:26][C:25]=1[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1[Cl:44]>>[CH3:21][O:22][C:23](=[O:45])[C:24]1[C:29]([NH:30][C:31]2[CH:36]=[CH:35][C:34]([I:1])=[CH:33][C:32]=2[F:37])=[CH:28][N:27]=[CH:26][C:25]=1[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1[Cl:44]
Reactant: O=C1CCC(=O)N1I
Reactant: COC(=O)c1c(Nc2ccccc2F)cncc1-c1ccccc1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: COC(=O)c1c(Nc2ccc(I)cc2F)cncc1-c1ccccc1Cl
Temperature: 60 °C
Reaction time: 8 h
Yield: 84.6 %

Procedure:
N-iodosuccinimide (236 mg, 1.05 mmol) and p-toluenesulfonic acid monohydrate (400 mg, 2.1 mmol) were added to a solution of 3-(2-chloro-phenyl)-5-(2-fluoro-phenylamino)-isonicotinic acid methyl ester (300 mg, 0.84 mmol), and stirred overnight at 60° C. The reaction mixture was quenched with Na2S2O3 (1 mL, 10% aqueous solution), diluted with CH2Cl2, and filtered through an Extrelut column. The column was washed with CH2Cl2, and the filtrate was concentrated. The crude product was purified via Biotage eluting with a gradient of 0 to 55% EtOAc in hexanes to afford the desired product (343 mg, 85%). LC-MS (M+H=483, obsd.=483).
Reaction SMILES: [H-].[K+].[C:3]1([CH:13]2[C:19](=[O:20])[C:18]3=[CH:21][CH:22]=[CH:23][N:17]3[C:16]3[CH:24]=[CH:25][CH:26]=[CH:27][C:15]=3[S:14]2)[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1.[C:28](Cl)(=[O:30])[CH3:29]>C1COCC1>[C:28]([O:20][C:19]1[C:18]2=[CH:21][CH:22]=[CH:23][N:17]2[C:16]2[CH:24]=[CH:25][CH:26]=[CH:27][C:15]=2[S:14][C:13]=1[C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1)(=[O:30])[CH3:29]
Reactant: O=C1c2cccn2-c2ccccc2SC1c1cccc2ccccc12
Reactant: CC(=O)Cl
Agent: [H-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(=O)OC1=C(c2cccc3ccccc23)Sc2ccccc2-n2cccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 86 %

Procedure:
To a suspension of potassium hydride (0.303 g, 2.64 mmol, 35% in oil) in anhydrous THF (5.0 mL) was added the (±)-6-(1-naphthyl)pyrrolo[2,1-d][1,5]benzothiazepin-7(6H)-one (0.9 g, 2.64 mmol) dissolved in anhydrous THF (7 mL). The reaction mixture was stirred at rt for 2 h, and then acetyl chloride (0.239 g, 3.04 mmol) was slowly added. After stirring for 12 h at rt, the solvent was removed in vacuo and the residue was dissolved in chloroform. The organic layer was washed with brine, dried and concentrated. The residue was chromatographed (dichloromethane and hexane 1:1) to give the PBOX-9 in 86% yield. IR (neat) 1762 cm−1; 1HNMR (CDCl3) δ 1.70 (s, 3 H) 6.45 (m, 1 H), 6.63 (m, 1 H), 7.19-7.55 (m, 10 H), 7.78-7.87 (m, 2 H).
Reaction SMILES: N1C=CC=CC=1.[CH2:7]([S:10][C:11]1[N:15]=[CH:14][NH:13][N:12]=1)[C:8]#[CH:9].[CH2:16]([N:18]([CH2:22][CH3:23])[C:19](Cl)=[O:20])[CH3:17]>O>[CH2:16]([N:18]([CH2:22][CH3:23])[C:19]([N:13]1[CH:14]=[N:15][C:11]([S:10][CH2:7][C:8]#[CH:9])=[N:12]1)=[O:20])[CH3:17]
Reactant: C#CCSc1nc[nH]n1
Reactant: CCN(CC)C(=O)Cl
Solvent: c1ccncc1
Solvent: O
Product: C#CCSc1ncn(C(=O)N(CC)CC)n1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To 31.5 ml of pyridine was added 5.56 g of 3-(2-propynylthio)-1H-1,2,4-triazole and then 6.3 ml of diethylcarbamyl chloride. The resulting mixture was stirred under nitrogen at ambient temperature for 3 days and was then poured into 350 ml of cold water with agitation. The precipitate was collected by filtration, washed with water air dried and then dried in oven to give 8.1 g of the title compound as a solid. m.p. 67°-69° C. NMR (CDCl3): 1.3 (t, 6H); 2,21 (t. 1H); 3.62 (m, 4H); 3.88 (d, 2H); 8.78 (s, 1H).
Reaction SMILES: [CH:1]1([NH:5][C:6]2[N:7]=[N:8][C:9]([C:12]#[CH:13])=[CH:10][CH:11]=2)[CH2:4][CH2:3][CH2:2]1.[Cl:14][C:15]1[CH:39]=[CH:38][C:18]([C:19]([NH:21][C:22]2[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[C:24]([N:32]3[CH:36]=[C:35]([CH3:37])[N:34]=[CH:33]3)[CH:23]=2)=[O:20])=[CH:17][C:16]=1I>>[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([C:19]([NH:21][C:22]2[CH:27]=[C:26]([C:28]([F:31])([F:29])[F:30])[CH:25]=[C:24]([N:32]3[CH:36]=[C:35]([CH3:37])[N:34]=[CH:33]3)[CH:23]=2)=[O:20])=[CH:38][C:39]=1[C:13]#[C:12][C:9]1[N:8]=[N:7][C:6]([NH:5][CH:1]2[CH2:4][CH2:3][CH2:2]2)=[CH:11][CH:10]=1
Reactant: Cc1cn(-c2cc(NC(=O)c3ccc(Cl)c(I)c3)cc(C(F)(F)F)c2)cn1
Reactant: C#Cc1ccc(NC2CCC2)nn1
Product: Cc1cn(-c2cc(NC(=O)c3ccc(Cl)c(C#Cc4ccc(NC5CCC5)nn4)c3)cc(C(F)(F)F)c2)cn1

Procedure:
The title compound was synthesized from N-cyclobutyl-6-ethynylpyridazin-3-amine and 4-chloro-3-iodo-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)benzamide in a manner similar to that described for in Example 1. The product was obtained as a pale yellow solid. Mp: 225-227° C.; 1H NMR (300 MHz, DMSO-d6) δ: 10.82 (1H, s), 8.35 (1H, d, J=2.1 Hz), 8.27 (1H, s), 8.13 (1H, s), 7.99-8.03 (1H, dd, J=2.1 and 8.1 Hz), 7.81-7.84 (1H, d, J=8.7 Hz), 7.76 (1H, s), 7.66-7.68 (2H, m), 7.46-7.49 (1H, d, J=9.0 Hz), 6.76-6.80 (1H, d, J=9.3 Hz), 4.40 (1H, m), 2.32-2.34 (2H, m), 2.17 (3H, brs), 1.87-1.97 (2H, m), 1.71-1.76 (2H, m). HRMS (ESI-TOF+): m/z [M+2H]+2 calcd for C28H24ClF3N6O: 276.0821. found: 276.0819.
Reaction SMILES: C1(C)C=CC([S:7](Cl)(=[O:9])=[O:8])=CC=1.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([CH:21]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)[OH:22])=[O:20])=[CH:15][CH:14]=1.C(C(C)=[O:33])C>>[C:16]1([CH3:19])[C:15]([S:7]([OH:9])(=[O:33])=[O:8])=[CH:14][CH:13]=[CH:18][CH:17]=1.[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]([CH:21]([C:23]2[CH:24]=[CH:25][C:26]([Cl:29])=[CH:27][CH:28]=2)[OH:22])=[O:20])=[CH:17][CH:18]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCC(C)=O
Agent: O=C(c1ccc(Cl)cc1)C(O)c1ccc(Cl)cc1
Product: Cc1ccccc1S(=O)(=O)O

Procedure:
In accordance with Example 2, p-toluenesulfonyl chloride is reacted with 4,4'-dichlorobenzoin in 200 ml of methyl ethyl ketone. The resultant sulfone melts at 129°-130° C.
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[C:7]([CH2:12][CH:13]=O)[CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][C:3]1=[O:15].[CH3:16][NH:17][C:18]([C:20]1[O:21][C:22]2[CH:28]=[CH:27][CH:26]=[C:25]([N:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)[C:23]=2[CH:24]=1)=[O:19].CO.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.O>[CH3:16][NH:17][C:18]([C:20]1[O:21][C:22]2[CH:28]=[CH:27][CH:26]=[C:25]([N:29]3[CH2:34][CH2:33][N:32]([CH2:13][CH2:12][C:7]4[CH:8]=[CH:9][CH:10]=[C:11]5[C:6]=4[CH2:5][CH2:4][C:3](=[O:15])[N:2]5[CH3:1])[CH2:31][CH2:30]3)[C:23]=2[CH:24]=1)=[O:19]
Reactant: CNC(=O)c1cc2c(N3CCNCC3)cccc2o1
Reactant: CN1C(=O)CCc2c(CC=O)cccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: CNC(=O)c1cc2c(N3CCN(CCc4cccc5c4CCC(=O)N5C)CC3)cccc2o1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
2-(1-Methyl-2-oxo-3,4-dihydroquinolin-5-yl)acetaldehyde (Example 1j, 0.50 g, 2.5 mmol) dissolved in dichloromethane (12 mL) was added to neat N-methyl-4-piperazin-1-yl-benzofuran-2-carboxamide (Example 1e, 0.542 g, 2.09 mmol). Methanol (2 mL) was added and the mixture was stirred at ambient temp for 20 min. Sodium triacetoxyborohydride (0.782 g, 3.69 mmol) was added and the mixture was stirred over the weekend. The mixture was diluted with dichloromethane and water. The organic phase was separated, dried over MgSO4, filtered, concentrated and purified by ISCO (0 to 8% 7 N ammonia/methanol in dichloromethane) to give of the title compound as a solid. Yield: 0.77 g, 70% 1H NMR (500 MHz, CDCl3) δ ppm 2.58-2.71 (m, 4H) 2.78 (br. s., 4H) 2.87-3.00 (m, 4H) 3.06 (d, 3H) 3.31 (br. s., 4H) 3.38 (s, 3H) 6.63 (d, 1H) 6.72 (d, 1H) 6.91 (d, 1H) 6.98 (d, 1H) 7.10 (d, 1H) 7.23 (t, 1H) 7.32 (t, 1H) 7.53 (s, 1H). MS m/z 447.2 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:9]([OH:18])([C:14]([F:17])([F:16])[F:15])[C:10]([F:13])([F:12])[F:11])[CH:5]=[CH:6][C:7]=1[CH3:8].C(N(CC)CC)C.[F:26][C:27](=[CH2:31])[C:28](Cl)=[O:29]>C(OCC)C>[F:26][C:27](=[CH2:31])[C:28]([O:18][C:9]([C:4]1[CH:5]=[CH:6][C:7]([CH3:8])=[C:2]([CH3:1])[CH:3]=1)([C:10]([F:11])([F:12])[F:13])[C:14]([F:17])([F:15])[F:16])=[O:29]
Reactant: Cc1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1C
Reactant: C=C(F)C(=O)Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: C=C(F)C(=O)OC(c1ccc(C)c(C)c1)(C(F)(F)F)C(F)(F)F
Temperature: 20 °C
Reaction time: 3.5 h
Yield: 51.4 %

Procedure:
A solution of 27.3 g (0.1 mol) Of 2-(3,4-dimethylphenyl)-hexafluoro-2-propanol and 10.1 g (0.1 mol) of triethylamine in 50 ml of dry diethyl ether was added dropwise with stirring at a temperature of 20° C. to a solution of 20 g (0.184 mol) of α-fluoroacryloyl chloride (obtained according to Example 4) in 50 ml of dry diethyl ether in the course of 35 minutes. The reaction mixture was then stirred at a temperature of 20° C. for a further 3.5 hours. The resulting solid was filtered off. The filtrate was distilled under reduced pressure after addition of 0.01 g of hydroquinone monomethyl ether. 17.7 g (51 percent of theory) of 2-(3,4-dimethylphenyl)-hexafluoro-2-propyl α-fluoroacrylate having a boiling point of 72° to 73° C. (under 0.4 mbar) were obtained.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][N:10]=[C:9]2[CH:15]=[O:16])[CH:2]([CH3:4])[CH3:3].[C:17](=O)([O-])[O-].[K+].[K+].CI.O>C(#N)C>[CH2:1]([O:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH3:17])[N:10]=[C:9]2[CH:15]=[O:16])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)COc1ccc2[nH]nc(C=O)c2c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: O
Solvent: CC#N
Product: CC(C)COc1ccc2c(c1)c(C=O)nn2C
Temperature: 25 °C
Reaction time: 8 h
Yield: 30.1 %

Procedure:
A mixture of 5-iso-butoxy-1H-indazole-3-carbaldehyde (110 mg, 0.50 mmol, 1.00 equiv), potassium carbonate (209 mg, 1.50 mmol, 2.98 equiv) and methyl iodide (107.5 mg, 0.76 mmol, 1.50 equiv) in acetonitrile (4 mL) was stirred at room temperature overnight. The resulting mixture was concentrated under vacuum and the residue was filtered through a silica gel column eluted with 2-5% of ethyl acetate in petroleum ether. The crude product (70 mg) was purified by Pre-HPLC with the following conditions (1#-Pre-HPLC-005(Waters)): Column, XBridge Shield RP18 OBD Column, 5 μm, 19×150 mm; mobile phase, water with 10 mmol NH4HCO3 and CH3CN (18% CH3CN up to 58% in 10 min, up to 95% in 1 min, down to 18% in 2 min); Detector, UV 254/220 nm to give 35 mg (30%) of 5-iso-butoxy-1-methyl-1H-indazole-3-carbaldehyde as a white solid. 1H NMR (400 MHz, CDCl3): δ 10.1 (s, 1H), 7.55 (d, J=2.0 Hz, 1H), 7.27 (d, J=8.8 Hz, 1H), 7.07 (dd, J=8.8 Hz, 2.0 Hz, 1H), 4.08 (s, 3H), 3.74 (d, J=6.8 Hz, 2H), 2.09-2.02 (m, 1H), 0.98 (d, J=6.8 Hz, 6H) ppm. LCMS (method D, ESI): RT=2.23 min, m/z=233.1 [M+H]+ and 15 mg (13%) of 5-iso-butoxy-2-methyl-2H-indazole-3-carbaldehyde as a white solid. 1H NMR (400 MHz, CDCl3): 10.12 (s, 1H), 7.62 (d, J=9.2 Hz, 1H), 7.17 (d, J=2.4 Hz, 1H), 7.07 (dd, J=9.2 Hz, 2.4 Hz, 1H), 4.38 (s, 3H), 3.73 (d, J=6.4 Hz, 2H), 2.10-2.05 (m, 1H), 0.99 (d, J=6.8 Hz, 6H) ppm. LCMS (method D, ESI): RT=2.24 min, m/z=233.1 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:27][CH2:26][CH2:25][C@H:8]3[S:9](=[O:24])(=[O:23])[C:10]([CH3:22])([CH3:21])[C:11]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[N:12][C@:7]3([CH3:28])[C:6]=2[CH:29]=1.[Cl:30][C:31]1[CH:32]=[C:33]([CH:40]=[CH2:41])[C:34]([C:37](O)=[O:38])=[N:35][CH:36]=1.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[Cl:30][C:31]1[CH:32]=[C:33]([CH:40]=[CH2:41])[C:34]([C:37]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[O:27][CH2:26][CH2:25][C@H:8]4[S:9](=[O:23])(=[O:24])[C:10]([CH3:22])([CH3:21])[C:11]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[N:12][C@:7]4([CH3:28])[C:6]=3[CH:29]=2)=[O:38])=[N:35][CH:36]=1
Reactant: CC(C)(C)OC(=O)NC1=N[C@]2(C)c3cc(N)ccc3OCC[C@H]2S(=O)(=O)C1(C)C
Reactant: C=Cc1cc(Cl)cnc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=Cc1cc(Cl)cnc1C(=O)Nc1ccc2c(c1)[C@@]1(C)N=C(NC(=O)OC(C)(C)C)C(C)(C)S(=O)(=O)[C@@H]1CCO2
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To a solution of tert-butyl ((4aR,11bR)-10-amino-3,3,11b-trimethyl-4,4-dioxido-4a,5,6,11b-tetrahydro-3H-benzo[6,7]oxepino[4,5-b][1,4]thiazin-2-yl)carbamate (0.080 g, 0.19 mmol) in DCM (2.0 ml) were added 5-chloro-3-vinylpicolinic acid (0.036 g, 0.20 mmol), triethylamine (0.053 ml, 0.38 mmol) and HATU (0.079 g, 0.21 mmol). The mixture was stirred at room temperature for 2 h. The reaction mixture was absorbed onto a plug of silica gel and purified by chromatography through a Redi-Sep pre-packed silica gel column (12 g), eluting with a gradient of 10% to 60% EtOAc in hexane, to provide tert-butyl ((4aR,11bR)-10-(5-chloro-3-vinylpicolinamido)-3,3,11b-trimethyl-4,4-dioxido-4a,5,6,11b-tetrahydro-3H-benzo[6,7]oxepino[4,5-b][1,4]thiazin-2-yl)carbamate (0.11 g, 0.19 mmol, 99% yield) as a white solid. m/z (ESI) 589.0 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][NH:7][C:8]([C:10]2[N:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16]([CH2:21][OH:22])=[CH:15][CH:14]=3)=[O:9])=[CH:4][CH:3]=1.[C:25]([O-])([O-])=O.[K+].[K+].IC.O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([CH2:21][OH:22])[CH:17]=3)[N:12]([CH3:25])[N:11]=2)=[O:9])=[CH:23][CH:24]=1
Reactant: O=C(NCc1ccc(Cl)cc1)c1nnc2ccc(CO)cc2c1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: O
Product: Cn1nc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CO)ccc21
Temperature: 25 °C
Yield: 35.2 %

Procedure:
A solution of N-(4-chlorobenzyl)-4-hydroxy-6-(hydroxymethyl)-3-cinnolinecarboxamide (Prep. 6, 0.12 g), K2CO3 (0.21 g) and iodomethane (26 μL) in 5 mL anhydrous DMF is heated at 90° C. for 1.5 h. The reaction is cooled to room temperature and poured into 50 mL water. The resulting solid is filtered and dried, then dissolved in CH2Cl2/MeOH and adsorbed onto silica. Purification by chromatography (eluent CH2Cl2 (1L), 0.5% MeOH/CH2Cl2 (2L), 1% MeOH/CH2Cl2 (1L), 1.5% MeOH/CH2Cl2 (1L), 2% MeOH/CH2Cl2 (1L), 2.5% MeOH/CH2Cl2 (3L), 3% MeOH/CH2Cl2 (1L), 4% MeOH/CH2Cl2 (1L), 6% MeOH/CH2Cl2 (1L), 8% MeOH/CH2Cl2 (1L)) affords the desired product as a white solid (0.044 g, 36%). Physical characteristics are as follows: m.p. 203-205° C.; 1H NMR (300 MHz, DMSO-d6) δ10.11, 8.23, 7.95, 7.92, 7.40, 5.54, 4.68, 4.56, 4.26; IR (drift) 3380, 1653, 1600, 1551, 1482, 1406, 1351, 1107, 1090, 1015, 813, 801, 727, 709, 659 cm−1; MS (FAB) m/z 358 (MH+), 511, 361, 360, 359, 358, 217, 127, 125, 123, 39; HRMS (FAB) calcd for C18H16ClN3O3+H1 358.0958, found 358.0961.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][C:26]4[S:30][CH2:29][N:28]([CH3:31])[CH:27]=4)[CH2:23][CH2:22][C:21]([C:32]([O:34]C)=[O:33])=[CH:20][C:19]=3[CH:36]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+].O.Cl>O1CCCC1.CO>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][C:26]4[S:30][CH2:29][N:28]([CH3:31])[CH:27]=4)[CH2:23][CH2:22][C:21]([C:32]([OH:34])=[O:33])=[CH:20][C:19]=3[CH:36]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3CC2=CN(C)CS2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3CC2=CN(C)CS2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 73.9 %

Procedure:
To a solution of methyl 7-(4-butoxyethoxyphenyl)-1-[(3-methylthiazol-5-yl)methyl]-2,3-dihydro-1-benzazepine-4-carboxylate (640 mg) in a mixture of tetrahydrofuran (39 ml) and methanol (39 ml) was added 1N sodium hydroxide solution (13 ml), and the mixture was stirred at room temperature for 1 day. Then, to the mixture was added water at 0° C., and 1N hydrochloric acid was further added to neutral, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with magnesium sulfate. The solvent was evaporated under reduced pressure, which was recrystallized from hexane-ethyl acetate to give 7-(4-butoxyethoxyphenyl)-1-[(3-methylthiazol-5-yl)methyl]-2,3-dihydro-1-benzazepine-4-carboxylic acid (460 mg) as yellow crystals.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)[CH:7]=[CH:6][C:5]=1[NH2:16])([O-:3])=[O:2].[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1>N1C=CC=CC=1.C(OCC)(=O)C>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([S:24]([NH:16][C:5]2[CH:6]=[CH:7][C:8]([C:10]3[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=3)=[CH:9][C:4]=2[N+:1]([O-:3])=[O:2])(=[O:26])=[O:25])=[CH:20][CH:19]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: Nc1ccc(-c2ccncc2)cc1[N+](=O)[O-]
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1cc(-c2ccncc2)ccc1NS(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 40 %

Procedure:
To a solution of 2-nitro-4-pyridin-4-ylphenylamine (1 mmol) in pyridine (3 mL), 4-chloro-benzenesulfonyl chloride (1.2 mmol) was added and the resulting mixture was stirred at room temperature for 24 h. The reaction mixture was diluted with ethyl acetate (20 mL). The contents were washed with brine (25 mL), dried over sodium sulfate and concentrated under vacuum. The residue obtained was purified by column chromatography eluting with hexanes/ethyl acetate (1:1) then ethyl acetate to give 156 mg of 4-chloro-N-(2-nitro-4-pyridin-4-ylphenyl)benzene sulfonamide.
Reaction SMILES: [OH:1][CH2:2][C:3]1[S:7][C:6]([CH:8]([C:18]([NH:20][C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[CH:27]=[N:26][CH:25]=[CH:24]3)=[O:19])[CH2:9][NH:10]C(=O)OC(C)(C)C)=[CH:5][CH:4]=1.[ClH:31].O1CCOCC1>C(Cl)Cl>[ClH:31].[ClH:31].[NH2:10][CH2:9][CH:8]([C:6]1[S:7][C:3]([CH2:2][OH:1])=[CH:4][CH:5]=1)[C:18]([NH:20][C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][CH:30]=1)[CH:27]=[N:26][CH:25]=[CH:24]2)=[O:19]
Reactant: CC(C)(C)OC(=O)NCC(C(=O)Nc1ccc2cnccc2c1)c1ccc(CO)s1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: NCC(C(=O)Nc1ccc2cnccc2c1)c1ccc(CO)s1
Reaction time: 4 h

Procedure:
To a solution of tert-butyl 2-(5-(hydroxymethyl)thiophen-2-yl)-3-(isoquinolin-6-ylamino)-3-oxopropylcarbamate (E238) in CH2Cl2 was added 4 N HCl-dioxane and the solution was stirred for 4 h. The solvents were evaporated to give 3-amino-2-(5-(hydroxymethyl)thiophen-2-yl)-N-(isoquinolin-6-yl)propanamide dihydrochloride (E239).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([N:13]([CH2:15][CH2:16][CH2:17][N:18]([CH3:20])[CH3:19])[CH3:14])=[O:12])[S:10][C:3]=12.[OH:21][C:22]1[CH:30]=[C:29]2[C:25]([C:26]([C:33]([NH:35][CH3:36])=[O:34])=[C:27]([CH3:32])[N:28]2[CH3:31])=[CH:24][CH:23]=1.C([O-])([O-])=O.[Cs+].[Cs+]>>[CH3:19][N:18]([CH3:20])[CH2:17][CH2:16][CH2:15][N:13]([CH3:14])[C:11]([C:9]1[S:10][C:3]2[C:4](=[N:5][CH:6]=[CH:7][C:2]=2[O:21][C:22]2[CH:30]=[C:29]3[C:25]([C:26]([C:33]([NH:35][CH3:36])=[O:34])=[C:27]([CH3:32])[N:28]3[CH3:31])=[CH:24][CH:23]=2)[CH:8]=1)=[O:12]
Reactant: CNC(=O)c1c(C)n(C)c2cc(O)ccc12
Reactant: CN(C)CCCN(C)C(=O)c1cc2nccc(Cl)c2s1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CNC(=O)c1c(C)n(C)c2cc(Oc3ccnc4cc(C(=O)N(C)CCCN(C)C)sc34)ccc12
Yield: 62 %

Procedure:
This material was prepared by the reaction of 7-chloro-N-[3-(dimethylamino)propyl]-N-methylthieno[3,2-b]pyridine-2-carboxamide 32a (0.095 g, 0.32 mmole) with 6-hydroxy-N,1,2-trimethyl-1H-indole-3-carboxamide (0.070 g, 0.32 mmole) 16e and Cs2CO3 (0.104 g, 0.32 mmole) in a manner as described previously for example 1 to give a white solid (0.098 g, 62%). 1H NMR (300 MHz, CD3OD) δ 8.53 (1H, d, J=5.3 Hz), 7.91 (2H, m), 7.38 (1H, s), 7.09 (1H, dd, J=2.1, 8.7 Hz), 6.81(1H, d, J=5.3 Hz), 3.73 (3H, s), 3.66 (2H, m), 3.28 (2H, m), 3.01 (3H, s), 2.68 (9H, m), 2.06 (2H, m), 1.94(3H, s); HRMS (MH+): Calcd: 494.2223. Found: 494.2226.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([OH:12])[C:9]2[C:4](=[CH:5][C:6]([O:15][CH3:16])=[C:7]([O:13][CH3:14])[CH:8]=2)[N:3]=1.COC1C=C2C(=CC=1OC)N=C(SC)C=C2O[C:34]1[CH:39]=[CH:38][C:37]([NH2:40])=[CH:36][C:35]=1[F:41]>>[NH2:40][C:37]1[CH:38]=[CH:39][C:34]([O:12][C:10]2[C:9]3[C:4](=[CH:5][C:6]([O:15][CH3:16])=[C:7]([O:13][CH3:14])[CH:8]=3)[N:3]=[C:2]([NH2:1])[CH:11]=2)=[C:35]([F:41])[CH:36]=1
Reactant: COc1cc2nc(N)cc(O)c2cc1OC
Reactant: COc1cc2nc(SC)cc(Oc3ccc(N)cc3F)c2cc1OC
Product: COc1cc2nc(N)cc(Oc3ccc(N)cc3F)c2cc1OC

Procedure:
4-(4-Amino-2-fluoro-phenoxy)-6,7-dimethoxy-quinolin-2-ylamine was synthesized from 2-amino-6,7-dimethoxy-quinolin-4-ol in a similar manner as 4-(6,7-dimethoxy-2-methylsulfanyl-quinolin-4-yloxy)-3-fluoro-phenylamine, and obtained as a white solid (4.0% yield). LCMS: m/z 330 (M+H)+.
Reaction SMILES: [CH2:1]([CH:3]([C:7](Cl)=[O:8])[C:4](Cl)=[O:5])[CH3:2].[CH3:10][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([NH2:18])[CH:13]=1.C([N:21](CC)CC)C>C(Cl)Cl>[CH2:1]([CH:3]([C:7]([NH2:21])=[O:8])[C:4]([NH:18][C:14]1[CH:15]=[CH:16][CH:17]=[C:12]([O:11][CH3:10])[CH:13]=1)=[O:5])[CH3:2]
Reactant: COc1cccc(N)c1
Reactant: CCN(CC)CC
Reactant: CCC(C(=O)Cl)C(=O)Cl
Solvent: ClCCl
Product: CCC(C(N)=O)C(=O)Nc1cccc(OC)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.2 %

Procedure:
To a stirred, cooled (0° C.) solution of 2.13 mL (0.017 mol) of ethyl malonyl chloride in 10 mL of methylene chloride under nitrogen was added dropwise a solution of 2.03 mL (0.017 mol) of m-anisidine in 10 mL of methylene chloride over a half-hour period. After the addition the reaction mixture was allowed to warm to room temperature and stir for 2 h. The reaction mixture was cooled to 0° C. and a solution of 2.36 mL (0.017 mol) of triethylamine in 10 mL of methylene chloride was added dropwise over 2 h. Additional methylene chloride was added to keep the slurry of salts stirring efficiently. After the addition the reaction mixture was kept cold by placing it in the freezer. After 12 h the reaction was allowed to warm to room temperature and was immediately washed with water three times to remove the salts. The organic layer was dried over magnesium sulfate and filtered. Removal of solvent gave a crude oil. Purification by flash-chromatography (silica gel, 25% ethyl acetate/hexane eluent) afforded 2.5 g (64% yield) of ethyl N-3-methoxyphenylmalonamide as a red oil.