Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:21])[O:4][C:5]2[CH:18]=[C:17]([CH3:19])[C:16]([CH3:20])=[CH:15][C:6]=2[C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH3:14].[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]=[C:30]=[O:31])=[CH:25][CH:24]=1>O1CCCC1>[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:30]([NH:1][C:2]2[C:3](=[O:21])[O:4][C:5]3[CH:18]=[C:17]([CH3:19])[C:16]([CH3:20])=[CH:15][C:6]=3[C:7]=2[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH3:14])=[O:31])=[CH:25][CH:24]=1
Reactant: Cc1cc2oc(=O)c(N)c(-c3ccccc3C)c2cc1C
Reactant: O=C=Nc1ccc(Cl)cc1
Solvent: C1CCOC1
Product: Cc1cc2oc(=O)c(NC(=O)Nc3ccc(Cl)cc3)c(-c3ccccc3C)c2cc1C
Temperature: 25 °C
Reaction time: 72 h
Yield: 88.3 %

Procedure:
To a solution of 3-amino-6,7-dimethyl-4-(2-methylphenyl)-2H-1-benzopyran-2- one (279 mg) in tetrahydrofuran (4 ml) was added 4-chlorophenylisocyanate (184 mg). The mixture was stirred for 3 days at room temperature and distilled to remove the solvent. Ethyl ether was added to the residue to obtain crystals of N-(4-chlorophenyl)-N'-[6,7-dimethyl-4-(2-methylphenyl)-2-oxo-2-H-1-benzopyran-3-yl] urea (382 mg, 88.2%). Recrystallization from acetone gave colorless needles.
Reaction SMILES: C[O-].[Na+].CO.[CH3:6][C:7](=O)[CH2:8][CH2:9][C:10](=O)[CH2:11][CH2:12][CH3:13].[CH:16]1[CH2:20][CH:19]=[CH:18][CH:17]=1>>[CH3:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:11][CH2:12][CH3:13])=[C:16]2[C:17]=1[CH:18]=[CH:19][CH2:20]2
Reactant: CCCC(=O)CCC(C)=O
Reactant: C1=CCC=C1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCCc1ccc(C)c2c1CC=C2
Temperature: 25 °C
Reaction time: 3 h
Yield: 39.5 %

Procedure:
45 ml of a 30 percent strength solution of sodium methanolate in methanol (250 mmol) were initially introduced into the reaction vessel at 0° C., and a mixture of 14.2 g (100 mmol) of 2,5-octanedione and 9 ml (110 mmol) of cyclopentadiene was added in the course of 30 minutes. After the mixture had been stirred at room temperature for 3 hours, it was poured into 300 ml of ice-water and extracted with diethyl ether and the organic phase was dried over magnesium sulfate. The residue which remained after evaporation was chromatographed on silica gel. 6.8 g (39%) of the indene 2 could be isolated with hexane as the mobile phase.
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([CH:19]2[CH2:21][CH2:20]2)=[N:5][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)=[N:7][CH:8]=1.[CH2:22]([O:24][C:25](=[O:37])[CH2:26][N:27]1[C:35]2[C:30](=[CH:31][C:32]([OH:36])=[CH:33][CH:34]=2)[CH:29]=[CH:28]1)[CH3:23].C(=O)([O-])[O-].[Cs+].[Cs+]>>[CH2:22]([O:24][C:25](=[O:37])[CH2:26][N:27]1[C:35]2[C:30](=[CH:31][C:32]([O:36][CH2:2][C:3]3[C:4]([CH:19]4[CH2:21][CH2:20]4)=[N:5][C:6]([C:9]4[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=4)=[N:7][CH:8]=3)=[CH:33][CH:34]=2)[CH:29]=[CH:28]1)[CH3:23]
Reactant: FC(F)(F)c1ccc(-c2ncc(CCl)c(C3CC3)n2)cc1
Reactant: CCOC(=O)Cn1ccc2cc(O)ccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CCOC(=O)Cn1ccc2cc(OCc3cnc(-c4ccc(C(F)(F)F)cc4)nc3C3CC3)ccc21

Procedure:
In analogy to the procedure described in example 1 h], 5-chloromethyl-4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidine was reacted with (5-hydroxy-indol-1-yl)-acetic acid ethyl ester (example 1 c]) in the presence of cesium carbonate to give {5-[4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-ylmethoxy]-indol-1-yl}-acetic acid ethyl ester, which was subsequently treated with lithium hydroxide in analogy to the procedure described in example 1 i] to yield {5-[4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-ylmethoxy]-indol-1-yl}-acetic acid.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH2:7])=[CH:4][CH:3]=1.[CH2:10]=[CH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[CH:18]([O:20][CH2:21][CH3:22])=[CH2:19]>>[CH2:18]([O:20][CH2:21][CH2:22][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH2:7])=[CH:4][CH:3]=1)[CH3:19].[OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH2:7])=[CH:4][CH:3]=1.[CH2:10]=[CH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: C=COCC
Agent: C=Cc1ccc(O)cc1
Solvent: C=Cc1ccccc1
Product: C=Cc1ccc(OCCOCC)cc1

Procedure:
Using 15.0 g of poly(p-hydroxystyrene/styrene) obtained according to (2) above and 3.2 g of vinylethyl ether, the procedure of (3) of Preparation Example 1 was carried out for reaction and after-treatments to give 14.1 g of poly(p-1-ethoxyethoxystyrene/p-hydroxystyrene/styrene) as white powdery crystals. P-1-ethoxyethoxystyrene unit/p-hydroxystyrene unit/styrene unit molar ratio in the polymer≈32:60:8 (1H NMR). Mw≈18,000; Mw/Mn≈1.85 (GPC with polystyrene calibration).
Reaction SMILES: CO[C:3](=[O:23])[CH2:4][N:5]1[CH2:9][C:8]([OH:10])=[C:7]([C:11]2[CH2:15][N:14]([CH2:16][C:17]([O:19]C)=O)[C:13](=[O:21])[CH:12]=2)[C:6]1=[O:22].[NH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>>[OH:10][C:8]1[CH2:9][N:5]([CH2:4][C:3]([N:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)=[O:23])[C:6](=[O:22])[C:7]=1[C:11]1[CH2:15][N:14]([CH2:16][C:17]([N:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)=[O:19])[C:13](=[O:21])[CH:12]=1
Reactant: COC(=O)CN1CC(C2=C(O)CN(CC(=O)OC)C2=O)=CC1=O
Reactant: C1CCNCC1
Product: O=C1C=C(C2=C(O)CN(CC(=O)N3CCCCC3)C2=O)CN1CC(=O)N1CCCCC1

Procedure:
Analogously to the procedure described in Example 2, from 4.8 g (0.015 mol) of 1,1',5,5'-tetrahydro-4-hydroxy-2,2'-dioxo-[3,4'-bi-2H-pyrrole]-1,1'-diacetic acid dimethyl ester and 25 ml of piperidine there is obtained 1,1',5,5'-tetrahydro-4-hydroxy-2,2'-dioxo[3,4'-bi-2H-pyrrole]-1,1'-diacetic acid dipiperidide in the form of pale yellow microcrystals having a melting point of 150°-155° (decomposition).
Reaction SMILES: [CH:1]#[C:2][CH2:3][CH2:4][CH2:5][CH3:6].I[C:8]1[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=1[NH2:10]>C(N(CC)CC)C.[Cu](I)I>[C:1]([C:8]1[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=1[NH2:10])#[C:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: C#CCCCC
Reactant: Nc1ccccc1I
Agent: I[Cu]I
Solvent: CCN(CC)CC
Product: CCCCC#Cc1ccccc1N
Temperature: 25 °C
Reaction time: 15 h

Procedure:
32 mg of copper iodide, 140 mg of bistriphenyl phosphine palladium chloride and then 2.3 ml of 1-hexyne were added to a solution of 4.4 g of 2-iodo aniline in 100 ml of triethylamine. The mixture was stirred for 15 hours at ambient temperature, followed by evaporating to dryness and taking up in ether. The insoluble part was filtered off, washed with ether and the ethereal fractions were evaporated to dryness. The residue was chromatographed on silica (eluant: hexane--ethyl acetate (9-1)) to obtain 3.27 g of the desired product.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[C:4]([F:11])[C:3]=1[F:12].Br[C:14]1[CH:15]=[N:16][C:17]([NH2:20])=[N:18][CH:19]=1>ClC1C=CC(C2N=CC(N)=NC=2)=C(F)C=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:14]2[CH:15]=[N:16][C:17]([NH2:20])=[N:18][CH:19]=2)=[C:4]([F:11])[C:3]=1[F:12]
Reactant: OB(O)c1ccc(Br)c(F)c1F
Reactant: Nc1ncc(Br)cn1
Agent: Nc1cnc(-c2ccc(Cl)cc2F)cn1
Product: Nc1ncc(-c2ccc(Br)c(F)c2F)cn1

Procedure:
The title compound was prepared using analogous conditions to those described in 5-(4-chloro-2-fluorophenyl)pyrazin-2-amine using (4-bromo-2,3-difluorophenyl)boronic acid and 5-bromopyrimidin-2-amine. MS (ESI): mass calcd. for C10H6BrF2N3, 284.97; m/z found, 286.0 [M+H]+.
Reaction SMILES: I[C:2]1[N:3]=[C:4]([NH2:20])[C:5]2[N:6]=[CH:7][N:8]([C:18]=2[N:19]=1)[C@@H:9]1[O:17][C@H:14]([CH2:15][OH:16])[C@@H:12]([OH:13])[C@H:10]1[OH:11].C(NC(C)C)(C)C.[C:28]([CH2:30][CH2:31][CH2:32][CH2:33][C:34]#[CH:35])#[N:29]>CN(C)C=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:28]([CH2:30][CH2:31][CH2:32][CH2:33][C:34]#[C:35][C:2]1[N:3]=[C:4]([NH2:20])[C:5]2[N:6]=[CH:7][N:8]([C:18]=2[N:19]=1)[C@@H:9]1[O:17][C@H:14]([CH2:15][OH:16])[C@@H:12]([OH:13])[C@H:10]1[OH:11])#[N:29]
Reactant: Nc1nc(I)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Reactant: C#CCCCCC#N
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CC(C)NC(C)C
Product: N#CCCCCC#Cc1nc(N)c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2n1
Temperature: 50 °C
Reaction time: 24 h
Yield: 55 %

Procedure:
Under argon, to a solution of 2-iodoadenosine (420 mg, 1.07 mmol) and bis(triphenylphosphine)palladium dichloride (75 mg, 10 mol %) dissolved in N,N-dimethylformamide (10 mL), diisopropylamine (0.18 mL, 1.28 mmol, 1.2 eq.) and 6-cyano-1-hexyne (137 mg, 1.28 mmol, 1.2 eq.) were added, and, under ice-cooling conditions, cuprous iodide (10 mg, 5 mol %) was added thereto, followed by stirring at 50° C. for 24 hours. The reaction mixture was cooled to room temperature, and the solvent was removed under reduced pressure. The residue was purified by dry packed silica gel column chromatography (ethyl acetate:methanol=10:1), to thereby yield a compound of the present invention as a pale yellow powder (yield: 217 mg, percent yield: 55%).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[O:14][CH3:15])[CH2:10][NH:9][CH2:8][CH2:7]2.Br[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH:23]([S:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(N(C(C)C)C(C)C)C>C(#N)C>[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[O:14][CH3:15])[CH2:10][N:9]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH:23]([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[S:30][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[CH2:8][CH2:7]2
Reactant: BrCCCCCCC(Sc1ccccc1)c1ccccc1
Reactant: COc1cc2c(cc1OC)CNCC2
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2c(cc1OC)CN(CCCCCCC(Sc1ccccc1)c1ccccc1)CC2
Yield: 36.4 %

Procedure:
The free base from 4.60 g of 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride, 3.63 g of [(7-bromo-1-phenylheptyl)thio]benzene, 50 ml of acetonitrile and 2.61 ml of ethyl diisopropylamine is heated at reflux temperature for 29 hours. The solvent is evaporated over night and the residue is partitioned between chloroform and aqueous ammonium hydroxide. The organic layer is dried and concentrated in vacuo to give 5.81 g of crude product. The residue is purified by chromatography (silica gel: chloroform/methyl alcohol) to give 1.73 g of the desired product. Calcd for C30H37NO2S: C=75.75: H=7.84; N=2.94; S=6.74 Found C=75.40; H=7.56; N=2.74; S=6.96 MS(CI): m/z 476(M-H+).
Reaction SMILES: [OH-].[Na+].[C:3]([CH2:11][C:12]([O:14]CC)=[O:13])(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>O>[C:3]([CH2:11][C:12]([OH:14])=[O:13])(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CCOC(=O)CC(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)CC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.5 %

Procedure:
Sodium hydroxide (0.4 g) was dissolved in water (10 mL), and ethyl benzoylacetate (2.14 g: 90% pure, made by Aldrich) was added and this was agitated overnight at room temperature. The reaction product was washed with ether, then 10% dilute sulfuric acid (4.9 g) was added and the reaction product was extracted with ether. The ether extract was dried by adding excess anhydrous sodium sulfate, and the anhydrous sodium sulfate was removed by filtration. The ether was then removed with a rotary evaporator, yielding benzoylacetic acid (yield 1.05 g).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:27])=[C:4]([C:23]([F:26])=[CH:24][CH:25]=1)[O:5][C:6]1[CH2:10][N:9]([C@@H:11]([CH2:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[C:12]([OH:14])=O)[C:8](=[O:22])[CH:7]=1.[NH2:28][C:29]1[CH:33]=[CH:32][N:31]([CH2:34][C:35]([CH3:38])([OH:37])[CH3:36])[N:30]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[C:3]([F:27])=[C:4]([C:23]([F:26])=[CH:24][CH:25]=1)[O:5][C:6]1[CH2:10][N:9]([C@@H:11]([CH2:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[C:12]([NH:28][C:29]2[CH:33]=[CH:32][N:31]([CH2:34][C:35]([OH:37])([CH3:36])[CH3:38])[N:30]=2)=[O:14])[C:8](=[O:22])[CH:7]=1
Reactant: CC(C)(O)Cn1ccc(N)n1
Reactant: O=C(O)[C@H](CC1CCCCC1)N1CC(Oc2c(F)ccc(Cl)c2F)=CC1=O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(O)Cn1ccc(NC(=O)[C@H](CC2CCCCC2)N2CC(Oc3c(F)ccc(Cl)c3F)=CC2=O)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 33.6 %

Procedure:
A solution of (S)-2-[4-(3-chloro-2,6-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-3-cyclohexyl-propionic acid (143 mg, 0.36 mmol) in N,N-dimethylformamide (3 mL) was treated with 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (prepared in U.S. Pat. Appl. US2008021032 Example 80, 70 mg, 0.45 mmol), benzotriazol-1-yl-oxy-tris(dimethylamino)phosphonium hexafluorophosphate (350 mg, 0.79 mmol) and N,N-diisopropylethylamine (103 mg, 0.80 mmol). The reaction mixture was stirred for 4 h at 25° C., under nitrogen. The reaction mixture was diluted with ethyl acetate, washed with saturated ammonium chloride, water, a saturated sodium chloride solution and dried over sodium sulfate. The organic layer was concentrated, and the crude product was purified by ISCO flash chromatography (Teledyne Isco RediSep Flash Column 12 g, 0% to 100% ethyl acetate/hexanes) to afford (S)-2-[4-(3-chloro-2,6-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-3-cyclohexyl-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-propionamide (65 mg, 34%) as a light yellow solid: HR-ES-MS m/z calculated for C26H31ClF2N4O4 [M+H]+ 537.2075, observed 537.2071; 1H NMR (300 MHz, DMSO-d6) δ ppm 0.79-1.31 (m, 6H) 1.05 (s, 3H) 1.06 (s, 3H) 1.52-1.85 (m, 7H) 3.89 (s, 2H) 4.29 (d, J=18.7 Hz, 1H) 4.64 (d, J=18.7 Hz, 1H) 4.68 (s, 1H) 4.90 (dd, J=10.7, 5.0 Hz, 1H) 5.24 (s, 1H) 6.44 (d, J=2.2 Hz, 1H) 7.45 (td, J=9.6, 2.0 Hz, 1H) 7.54 (d, J=2.2 Hz, 1H) 7.67 (td, J=8.7, 5.3 Hz, 1H) 10.81 (s, 1H).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[F:7][C:8]1[CH:17]=[C:16]2[C:11]([CH:12]=[CH:13][C:14]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[N:15]2)=[CH:10][C:9]=1[C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=1.Cl[CH2:31][C:32]1[C:33]([C:40]2[C:45]([Cl:46])=[CH:44][CH:43]=[CH:42][C:41]=2[Cl:47])=[N:34][O:35][C:36]=1[CH:37]([CH3:39])[CH3:38].O>CN(C)C=O>[Cl:46][C:45]1[CH:44]=[CH:43][CH:42]=[C:41]([Cl:47])[C:40]=1[C:33]1[C:32]([CH2:31][O:29][C:26]2[CH:25]=[CH:24][C:23]([C:9]3[CH:10]=[C:11]4[C:16](=[CH:17][C:8]=3[F:7])[N:15]=[C:14]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:13]=[CH:12]4)=[CH:28][CH:27]=2)=[C:36]([CH:37]([CH3:39])[CH3:38])[O:35][N:34]=1
Reactant: CC(C)c1onc(-c2c(Cl)cccc2Cl)c1CCl
Reactant: CCOC(=O)c1ccc2cc(-c3ccc(O)cc3)c(F)cc2n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc2cc(-c3ccc(OCc4c(-c5c(Cl)cccc5Cl)noc4C(C)C)cc3)c(F)cc2n1
Reaction time: 68 h
Yield: 48.8 %

Procedure:
Cesium carbonate (62.6 mg, 192.2 μmol) was added to ethyl 7-fluoro-6-(4-hydroxyphenyl)-2-quinolinecarboxylate (54.4 mg, 174.7 μmol) and 4-(chloromethyl)-3-(2,6-dichlorophenyl)-5-(1-methylethyl)isoxazole (58.6 mg, 192.2 μmol) in N,N-dimethylformamide (1.7 mL) at room temperature. The resulting suspension was stirred for 68 hours, then water was added and the reaction mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, then filtered and concentrated. The residue was purified by silica gel chromatography eluting with 3:7 ethyl acetate:hexanes to give 49.4 mg (49%) of ethyl 6-[4-({[3-(2,6-dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-7-fluoro-2-quinolinecarboxylate as an oil. 1H NMR (400 MHz, d6-DMSO): δ 8.61 (d, J=9 Hz, 1H), 8.23 (d, J=9 Hz, 1H), 8.11 (d, J=9 Hz, 1H), 8.02 (d, J=12 Hz, 1H), 7.65-7.62 (m, 2H), 7.56 (d, J=7 Hz, 2H), 7.56-7.52 (m, 1H), 6.96 (d, J=9 Hz, 2H), 4.90 (s, 2H), 4.42 (q, J=7 Hz, 2H), 3.48 (septet, J=7 Hz, 1H), 1.38 (t, J=7 Hz, 3H), 1.34 (d, J=7 Hz, 6H). ESI-LCMS m/z 579 (M+H)+.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:7]=[C:6]([Cl:8])[S:5][C:4]=1[S:9]([NH2:12])(=[O:11])=[O:10].[CH2:13]([N:16]=[C:17]=S)[CH:14]=[CH2:15]>>[CH2:13]([NH:16][C:17]1[NH:2][C:3]2[CH:7]=[C:6]([Cl:8])[S:5][C:4]=2[S:9](=[O:10])(=[O:11])[N:12]=1)[CH:14]=[CH2:15]
Reactant: Nc1cc(Cl)sc1S(N)(=O)=O
Reactant: C=CCN=C=S
Agent: Cl
Product: C=CCNC1=NS(=O)(=O)c2sc(Cl)cc2N1

Procedure:
The title compound was prepared from 3-amino-5-chlorothiophene-2-sulfonamide hydrochloride and allyl isothiocyanate by a procedure analogous to the procedure described in example 3Bc-d; mp 217°-221° C.; 1H-NMR (DMSO-d6): δ 3.83 (distorted t, 2H), 5.08-5.27 (m, 2H), 5.75-5.99 (m, 1H), 7.07 (s, 1H), 7.49 (br. t, 1H), 11.1 (s, 1H).
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[C:8]([O:10][C:11]3[CH:45]=[C:44]([N:46]4[CH2:51][CH2:50][N:49]([CH2:52][C:53]5[CH2:58][CH2:57][C:56]([CH3:60])([CH3:59])[CH2:55][C:54]=5[C:61]5[CH:66]=[CH:65][C:64]([Cl:67])=[CH:63][CH:62]=5)[CH2:48][CH2:47]4)[CH:43]=[CH:42][C:12]=3[C:13]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][CH:26]4[CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][CH2:27]4)=[C:21]([N+:39]([O-:41])=[O:40])[CH:20]=3)(=[O:18])=[O:17])=[O:14])[CH:9]=[C:4]2[CH:3]=[CH:2]1.FC(F)(F)C(O)=O>ClCCl>[NH:1]1[C:5]2=[N:6][CH:7]=[C:8]([O:10][C:11]3[CH:45]=[C:44]([N:46]4[CH2:47][CH2:48][N:49]([CH2:52][C:53]5[CH2:58][CH2:57][C:56]([CH3:60])([CH3:59])[CH2:55][C:54]=5[C:61]5[CH:62]=[CH:63][C:64]([Cl:67])=[CH:65][CH:66]=5)[CH2:50][CH2:51]4)[CH:43]=[CH:42][C:12]=3[C:13]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][CH:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)=[C:21]([N+:39]([O-:41])=[O:40])[CH:20]=3)(=[O:18])=[O:17])=[O:14])[CH:9]=[C:4]2[CH:3]=[CH:2]1
Reactant: CC1(C)CCC(CN2CCN(c3ccc(C(=O)NS(=O)(=O)c4ccc(NC5CCN(C(=O)OC(C)(C)C)CC5)c([N+](=O)[O-])c4)c(Oc4cnc5[nH]ccc5c4)c3)CC2)=C(c2ccc(Cl)cc2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1(C)CCC(CN2CCN(c3ccc(C(=O)NS(=O)(=O)c4ccc(NC5CCNCC5)c([N+](=O)[O-])c4)c(Oc4cnc5[nH]ccc5c4)c3)CC2)=C(c2ccc(Cl)cc2)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of EXAMPLE 226A (902 mg) in dichloromethane (10 mL) was added trifluoroacetic acid (5 mL). The mixture was stirred at room temperature for 3 hours. The mixture was concentrated under vacuum and co-concentrated with dichloromethane twice to afford the crude product which was used in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]([CH3:20])([CH2:18][CH3:19])[CH2:3][CH2:4][C@H:5]([NH:9][C:10]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)=[O:11])[C:6]([OH:8])=O.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.[NH2:35][C:36]1([C:47]#[N:48])[CH2:41][CH2:40][N:39]([CH2:42][CH2:43][CH2:44][O:45][CH3:46])[CH2:38][CH2:37]1>ClCCl>[C:47]([C:36]1([NH:35][C:6]([C@@H:5]([NH:9][C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[O:11])[CH2:4][CH2:3][C:2]([CH3:1])([CH3:20])[CH2:18][CH3:19])=[O:8])[CH2:41][CH2:40][N:39]([CH2:42][CH2:43][CH2:44][O:45][CH3:46])[CH2:38][CH2:37]1)#[N:48]
Reactant: CCC(C)(C)CC[C@H](NC(=O)N1CCOCC1)C(=O)O
Reactant: COCCCN1CCC(N)(C#N)CC1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Product: CCC(C)(C)CC[C@H](NC(=O)N1CCOCC1)C(=O)NC1(C#N)CCN(CCCOC)CC1
Yield: 15.5 %

Procedure:
A solution of (S)-5,5-Dimethyl-2-[(morpholine-4-carbonyl)-amino]-heptanoic acid (4.70 g, 16.4 mmol) in dichloromethane (75 mL), cooled in an ice water bath, was treated with HOBT (2.45 g, 18.13 mmol), then EDC (3.47 g, 18.1 mmol). The reaction mixture was stirred with cooling for 35 min, then the ice bath was removed and a solution of 4-amino-(3-methoxy-propyl)-piperidine-4-carbonitrile (3.61 g, 18.3 mmol) in dichloromethane (25 mL) was added. The reaction mixture was stirred overnight, then concentrated on a rotary evaporator. The resulting residue was taken up in ethyl acetate (300 mL) and washed with saturated sodium bicarbonate solution (2×300 mL). The organic phase was then dried (magnesium sulfate) and concentrated to provide 8.1 grams of crude material. This material was further purified on a shimadzu reverse phase hplc using a gradient of acetonitrile in water (40 to 65% over 35 min flow rate 45 mL/min) to provide 1.18 g (25.8%) of the desired product as a white crunchy foam; m/z calculated for C24H43N5O4 465.6, found 466.6 (M+H)+
Reaction SMILES: [CH2:1]([O:5][CH:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=[O:16])[N:8]([CH2:17][CH:18]([CH3:20])[CH3:19])[C:7]1(/[CH:30]=[CH:31]/[C:32](O)=[O:33])[CH2:21][NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:2][CH2:3][CH3:4].Cl.C([N:38]=C=NCCCN(C)C)C.[NH4+].ON1C2C=CC=CC=2N=N1.O>CN(C)C=O>[CH2:1]([O:5][CH:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=[O:16])[N:8]([CH2:17][CH:18]([CH3:19])[CH3:20])[C:7]1(/[CH:30]=[CH:31]/[C:32]([NH2:38])=[O:33])[CH2:21][NH:22][C:23]([O:25][C:26]([CH3:27])([CH3:29])[CH3:28])=[O:24])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC1c2ccccc2C(=O)N(CC(C)C)C1(/C=C/C(=O)O)CNC(=O)OC(C)(C)C
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Agent: [NH4+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCOC1c2ccccc2C(=O)N(CC(C)C)C1(/C=C/C(N)=O)CNC(=O)OC(C)(C)C
Yield: 86.6 %

Procedure:
A solution of (E)-3-(4-butoxy-3-[[(tert-butoxycarbonyl)amino]methyl]-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl)-2-propenic acid (0.47 g, 1 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.38 g, 2 mmol) and 1-hydroxybenzotriazole ammonium salt (0.30 g, 2 mmol) in N,N-dimethylformamide (10 mL) was stirred at room temperature for 2 h. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained crystals were recrystallized from ethyl acetate-n-hexane to give (E)-3-(4-butoxy-3-[[(tert-butoxycarbonyl)amino]methyl]-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl)-2-propenamide (0.41 g, 87.2%) as crystals.
Reaction SMILES: [F:1][C:2]1[C:3]([CH3:11])=[C:4]([C@@H:8]([NH2:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.C([O:16][C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]1[CH:30]=[CH:29][C:28]([CH2:31][N:32]2[C:40]3[C:35](=[CH:36][C:37]([C:41](O)=[O:42])=[CH:38][CH:39]=3)[C:34]([CH3:44])=[C:33]2[CH3:45])=[CH:27][CH:26]=1)=[O:18])(C)(C)C>>[F:1][C:2]1[C:3]([CH3:11])=[C:4]([C@@H:8]([NH:10][C:41]([C:37]2[CH:36]=[C:35]3[C:40](=[CH:39][CH:38]=2)[N:32]([CH2:31][C:28]2[CH:27]=[CH:26][C:25]([C:20]4[C:19]([C:17]([OH:18])=[O:16])=[CH:24][CH:23]=[CH:22][CH:21]=4)=[CH:30][CH:29]=2)[C:33]([CH3:45])=[C:34]3[CH3:44])=[O:42])[CH3:9])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(F)cccc1[C@H](C)N
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)O)cc12
Product: Cc1c(F)cccc1[C@H](C)NC(=O)c1ccc2c(c1)c(C)c(C)n2Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
The title compound was prepared following the same general protocol as described in Step 8-9, Example 1, using the (S)-1-(3-fluoro-2-methylphenyl)ethanamine and the 1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid. ESI-MS (m/z): 535 [M+H]+.
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[I-].[K+].Cl[CH:11]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[S:14][CH2:13][CH2:12]1>CC(N(C)C)=O>[S:14]1[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH:11]([N:1]2[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)[CH2:12][CH2:13]1
Reactant: C1CNCCNC1
Reactant: ClC1CCSc2ccccc21
Agent: [I-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: c1ccc2c(c1)SCCC2N1CCCNCC1
Temperature: 60 °C
Yield: 75.9 %

Procedure:
A 100 ml 3-necked flask equipped with a condenser, addition funnel and magnetic stirring bar and under a nitrogen atmosphere was charged with a solution of homopiperazine (3.0 g; 30.5 mmol) in DMAC (35 ml). Potassium iodide (300 mg) was added followed by the addition of a solution of 4-chloro-3,4-dihydro-2H-benzothiopyran (1.15 g; 6.1 mmol) in DMAC (15 ml). This solution was then heated in an oil bath at 60° C. overnight. The reaction mixture was partitioned between water and ethyl acetate, washed with brine and dried with magnesium sulphate. Filtration and evaporation of solvent gave a yellow oil (1.15 g) which exhibited a satisfactory proton nmr spectrum (300 MHz, CDCl3). This material was used without further purification.