Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16][NH2:17])=[CH:14][CH:13]=1.C(N(CC)CC)C>C(Cl)Cl>[Cl:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16][NH:17][C:8](=[O:9])[CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:14][CH:13]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: NCc1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Cc1ccccc1)NCc1ccc(Cl)cc1

Procedure:
A mixture of (4.0 g, 25.9 mmol) of phenylacetyl chloride, 3.15 mL (25.9 mmol) of 4-chlorobenzylamine and 5.1 mL of triethylamine in 120 mL of methylene chloride was prepared at 0° C. and then heated to reflux under a nitrogen atmosphere for 18 hours. The solvent was evaporated and the residue was treated with 2 mL of 4-chlorobenzylamine and 3 mL of triethylamine and reheated to reflux overnight. After cooling, the mixture was suspended in 100 mL of methylene chloride, washed with 0.5 N hydrochloric acid, 0.5 N sodium hydroxide and saturated aqueous sodium chloride, followed by drying with magnesium sulfate (MgSO4). The solvent was removed in vacuo to give a white solid which was recrystallized from ethyl acetate:hexane to provide N-(4-chlorobenzyl)-phenylacetamide as a white crystalline solid, 4.15 g (62%).
Reaction SMILES: [F:1][C:2]1[CH:14]=[C:12]2[C:13]3[N:8]([CH:9]=[C:10]([C:16]([OH:18])=[O:17])[C:11]2=[O:15])[CH:7]([CH3:19])[CH2:6][CH2:5][C:4]=3[C:3]=1Br.[NH:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1.CN(C)P(=O)(N(C)C)N(C)C>C(OCC)(=O)C>[F:1][C:2]1[CH:14]=[C:12]2[C:13]3[N:8]([CH:9]=[C:10]([C:16]([OH:18])=[O:17])[C:11]2=[O:15])[CH:7]([CH3:19])[CH2:6][CH2:5][C:4]=3[C:3]=1[N:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1
Reactant: CC1CCc2c(Br)c(F)cc3c(=O)c(C(=O)O)cn1c23
Reactant: C1COCCN1
Solvent: CCOC(C)=O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CC1CCc2c(N3CCOCC3)c(F)cc3c(=O)c(C(=O)O)cn1c23
Reaction time: 7 h
Yield: 39.3 %

Procedure:
In a 200 ml stainless steel autoclave were placed 10 g of 9-fluoro-8-bromo-5-methyl-6,7-dihydro-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid, 12.8 g of morpholine and 80 ml of hexamethylphosphoric triamide and the mixture was reacted at 160° C. on an oil bath. After 7 hours, the temperature of the autoclave was lowered to room temperature and disappearance of the starting materials was confirmed by thin layer chromatography. Then, the reaction mixture was transferred from the autoclave to a 300 ml Erlenmeyer flask to which ethyl acetate was added and the resulting mixture was allowed to stand for 1 day. The crystals which formed were collected by filtration and recrystallized from dimethylformamide to give 4 g of 9-fluoro-8-morpholino-5-methyl-6,7-dihydro-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid. m.p. 279°-280° C., white rhombic crystals.
Reaction SMILES: NC1C(OC)=CC2C(=O)N(C)CCCC=2C=1.[NH2:17][C:18]1[C:23]2[C:24](=[O:30])[N:25]([CH3:29])[CH2:26][CH2:27][CH2:28][C:22]=2[CH:21]=[CH:20][C:19]=1[O:31][CH3:32].Cl.COCCO.Cl[C:40]1[N:45]=[C:44]([NH:46][C:47]2[CH:56]=[CH:55][CH:54]=[CH:53][C:48]=2[C:49]([NH:51][CH3:52])=[O:50])[C:43]([Cl:57])=[CH:42][N:41]=1>O1CCOCC1>[Cl:57][C:43]1[C:44]([NH:46][C:47]2[CH:56]=[CH:55][CH:54]=[CH:53][C:48]=2[C:49]([NH:51][CH3:52])=[O:50])=[N:45][C:40]([NH:17][C:18]2[C:23]3[C:24](=[O:30])[N:25]([CH3:29])[CH2:26][CH2:27][CH2:28][C:22]=3[CH:21]=[CH:20][C:19]=2[O:31][CH3:32])=[N:41][CH:42]=1
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: COc1ccc2c(c1N)C(=O)N(C)CCC2
Agent: COc1cc2c(cc1N)CCCN(C)C2=O
Agent: Cl
Solvent: C1COCCO1
Solvent: COCCO
Product: CNC(=O)c1ccccc1Nc1nc(Nc2c(OC)ccc3c2C(=O)N(C)CCC3)ncc1Cl
Temperature: 110 °C
Reaction time: 0.5 h
Yield: 21 %

Procedure:
7-Amino-8-methoxy-2-methyl-2,3,4,5-tetrahydro-benzo[c]azepin-1-one (110 mg, 0.50 mmol) and 9-Amino-8-methoxy-2-methyl-2,3,4,5-tetrahydro-benzo[c]azepin-1-one (prepared following the procedure of 7c) were added as an unseparated mixture with 4 M of Hydrogen chloride in 1,4-Dioxane (300 uL), 2-Methoxyethanol (10 mL, 100 mmol), and 2-(2,5-Dichloro-pyrimidin-4-ylamino)-N-methyl-benzamide (2 eq) charged into Radley tube. Heat 110° C. for about 3 hours, cooled to room temperature. Solid precipitated out and was filtered. This material was dissolved in dichloromethane/MeOH and treated with 3 eq. of MP-carbonate, stirred 30 min, filtered and concentrated to give 2-[5-Chloro-2-(8-methoxy-2-methyl-1-oxo-2,3,4,5-tetrahydro-1H-benzo[c]azepin-9-ylamino)-pyrimidin-4-ylamino]-N-methyl-benzamide as an orange solid (51 mgs, 21%). Melting point: 185-187° C. 1H-NMR (DMSO, 400 MHz): 8.67 (broad m, 1H), 8.67 (s, 1H), 8.47 (broad s, 1H), 8.00 (d, J=7.0 Hz, 1H), 7.47-7.43 (m, 1H), 708-7.03 (m, 2H), 6.82 (d, J=7.8 Hz, 1H), 3.81 (s, 3H), 3.17-3.07 (m, 2H), 2.85 (s, 3H), 2.69-2.65 (m, 2H) 2.50 (s, 3H), 1.78-1.71 (m, 2H); LC/MS: 481.37 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:15])[CH2:9][CH2:10][CH2:11][C:12]([OH:14])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1N=CN(C(N2C=NC=C2)=O)C=1.[Br-:28].[NH2:29][CH2:30][CH2:31][CH2:32][CH2:33][P+:34]([C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>CN(C)C=O.C(Cl)Cl>[Br-:28].[CH3:15][N:8]([C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:9][CH2:10][CH2:11][C:12](=[O:14])[NH:29][CH2:30][CH2:31][CH2:32][CH2:33][P+:34]([C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)([C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: NCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CN(CCCC(=O)O)C(=O)OC(C)(C)C
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Br-]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CN(CCCC(=O)NCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 105.9 %

Procedure:
4-[(tert-butoxycarbonyl)(methyl)amino]butanoic acid (J. Organic Chemistry, 1985, 50, 1302-1304, 349 mg, 1.61 mol) was dissolved in N,N-dimethylformamide (3.5 mL) and treated with N,N-carbonyldiimidazole (273 mg, 1.69 mmol). The mixture was stirred at room temperature for 30 minutes. (4-Aminobutyl)(triphenyl)phosphonium bromide (929 mg, 1.40 mmol) was added, and the reaction was stirred overnight at room temperature. The reaction mixture was diluted with methylene chloride and washed with 5% aqueous lithium chloride (3 times), 1N aqueous hydrogen chloride, and saturated sodium bicarbonate. The organic solution was dried over anhydrous sodium sulfate, filtered, and concentrated to give the title compound (0.91 g, 92%, 83% pure) as a white foam. Sample was used crude in next step.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[F:17])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:6].[Cl:18][C:19]1[CH:20]=[C:21]([N:26]=[C:27]=[S:28])[CH:22]=[C:23]([Cl:25])[CH:24]=1>>[Cl:18][C:19]1[CH:20]=[C:21]([NH:26][C:27](=[S:28])[NH:1][C:2]2[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=2[F:17])[C:5]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:6])[CH:22]=[C:23]([Cl:25])[CH:24]=1
Reactant: Nc1cc(C(=O)Nc2ccccc2)ccc1F
Reactant: S=C=Nc1cc(Cl)cc(Cl)c1
Product: O=C(Nc1ccccc1)c1ccc(F)c(NC(=S)Nc2cc(Cl)cc(Cl)c2)c1
Yield: 49.6 %

Procedure:
Prepared according to the procedure described for Example 60 using 3-amino-4-fluoro-N-phenyl-benzamide from Example 9 (0.481 g, 2.09 mmol) and 3,5-dichlorophenyl isothiocyanate (0.427 g, 2.09 mmol). Filtration afforded the product (0.45 g) in two crops; m.p. 173-175° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[C:11]([C:14](Cl)=[O:15])[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[NH2:17][C:18]1[CH:19]=[CH:20][C:21]([N:26]2[CH2:31][CH2:30][CH:29]([O:32][CH2:33][O:34][CH3:35])[CH2:28][CH2:27]2)=[C:22]([CH:25]=1)[C:23]#[N:24]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[C:11]([C:14]([NH:17][C:18]3[CH:19]=[CH:20][C:21]([N:26]4[CH2:31][CH2:30][CH:29]([O:32][CH2:33][O:34][CH3:35])[CH2:28][CH2:27]4)=[C:22]([C:23]#[N:24])[CH:25]=3)=[O:15])[CH:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: COCOC1CCN(c2ccc(N)cc2C#N)CC1
Reactant: Cc1c(C(=O)Cl)cnn1-c1ccc(Cl)cc1
Product: COCOC1CCN(c2ccc(NC(=O)c3cnn(-c4ccc(Cl)cc4)c3C)cc2C#N)CC1
Yield: 28.5 %

Procedure:
By the reaction and treatment in the same manner as in Example 150 using 1-(4-chlorophenyl)-5-methylpyrazole-4-carboxylic chloride (0.62 g) and 5-amino-2-(4-methoxymethoxypiperidin-1-yl) benzonitrile (0.63 g), the title compound (0.33 g) was obtained, melting point: 186–188° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:3][CH2:2]1.[CH3:22][N:23]1[C:27]([CH3:28])=[CH:26][C:25]([C:29](Cl)=[O:30])=[N:24]1>>[CH3:22][N:23]1[C:27]([CH3:28])=[CH:26][C:25]([C:29]([N:1]2[CH2:2][CH2:3][C:4]3([O:11][C:10]4[C:12]5[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=4[S:8][CH2:7]3)=[CH:16][CH:15]=[CH:14][CH:13]=5)[CH2:5][CH2:6]2)=[O:30])=[N:24]1
Reactant: O=C1C(=O)c2ccccc2C2=C1SCC1(CCNCC1)O2
Reactant: Cc1cc(C(=O)Cl)nn1C
Product: Cc1cc(C(=O)N2CCC3(CC2)CSC2=C(O3)c3ccccc3C(=O)C2=O)nn1C

Procedure:
Compound 45 was synthesized using spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, 1,5-dimethyl-1H-pyrazole-3-carbonyl chloride and conditions outlined in procedure N. M.p.=184-185° C.; 300 MHz 1H NMR (DMSO-d6) δ 8.04 (d, 1H), 7.80 (m, 1H), 7.65 (m, 1H), 7.46 (m, 1H), 6.42 (s, 1H), 3.80 (s, 3H), 3.47 (m, 2H), 2.98 (s, 2H), 2.26 (s, 3H), 2.18 (m, 2H), 1.90 (m 2H), 1.62 (brs, 2H); LCMS: 424 [M+H].
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH2:13][NH:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:19][CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C2C(=CC=CC=2)C(=O)NC=1.S(Cl)([Cl:34])=O>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([Cl:34])=[N:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:19][CH3:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc2c(cc1OCc1ccccc1)N=CNC2
Reactant: O=S(Cl)Cl
Agent: O=c1[nH]cnc2ccccc12
Solvent: CN(C)C=O
Product: COc1cc2c(Cl)ncnc2cc1OCc1ccccc1

Procedure:
After repetition of the reaction so described, a mixture of 7-benzyloxy-6-methoxy-3,4-dihydroquinazolin-3,4-dihydroquinazolin-4-one (20.3 g), thionyl chloride (440 ml) and DMF (1.75 ml) was heated to reflux for 4 hours. The thionyl chloride was evaporated under vacuum and the residue was azeotroped with toluene three times to give 7-benzyloxy-4-chloro-6-methoxyquinazoline.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@@H:12]1[CH2:16][C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23](Br)[CH:24]=2)[NH:19][CH:18]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:27]([S:29]([CH2:32][CH3:33])(=[O:31])=[O:30])=[CH2:28].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(#N)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@@H:12]1[CH2:16][C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([CH:28]=[CH:27][S:29]([CH2:32][CH3:33])(=[O:31])=[O:30])[CH:24]=2)[NH:19][CH:18]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OCc1ccccc1)N1CCC[C@@H]1Cc1c[nH]c2ccc(Br)cc12
Reactant: C=CS(=O)(=O)CC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCS(=O)(=O)C=Cc1ccc2[nH]cc(C[C@H]3CCCN3C(=O)OCc3ccccc3)c2c1
Yield: 72.2 %

Procedure:
A stirred mixture of 3-(N-benzyloxycarbonyl-2(R)-pyrrolidinylmethyl)-5-bromo-1H-indole (Preparation 2; 0.43 g, 1.04 mmol), ethyl vinyl sulphone (0.17 g, 1.4 mmol), tri-o-tolylphosphine (91 mg), palladium(II) acetate (16 mg), triethylamine (0.31 ml) and acetonitrile (4 ml), under nitrogen, was heated under reflux for 18 hours, allowed to cool, then evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with a dichloromethane to dichloromethane:ethanol (99:1) gradient, to afford the title compound as a foam (0.34 g). Rf 0.80 (SS 2). [α]D25 -50° (c=0.1, CH3OH). Found: C,65.16; H,6.17; N,5.97. C25H28N2O4S; 0.125 CH2Cl2 requires C,65.15; H,6.15; N,6.05%. δ(CDCl3)--mixture of rotamers: 1.42(3H,t), 1.70-1.88(4H,m), 2.78(1H,m), 3.05-3.48(5H,m), 4.20(1H,m), 5.16-5.28(2H, br q), 5.30(0.25H,s,CH2Cl2), 6.64-7.82(1H,m), 6.96 and 7.05(1H, 2×s), 7.30-7.45(7H,m), 7.55-7.80 and 8.00(2H, m and s), 8.32(1H,br s).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]2[CH:6]=[C:7]3[C:11](=[CH:12][CH:13]=2)[N:10]([S:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]4[O:27][CH:26]=[N:25][CH:24]=4)=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH:9]=[CH:8]3)[CH2:2]1.[ClH:28].FC(F)O[C:32]1[CH:37]=CC(S(N2C3C(=CC(C4CN(CCC)C4)=CC=3)C=C2)(=O)=O)=C[CH:33]=1>>[ClH:28].[O:27]1[C:23]([C:20]2[CH:19]=[CH:18][C:17]([S:14]([N:10]3[C:11]4[C:7](=[CH:6][C:5]([CH:3]5[CH2:2][N:1]([CH2:33][CH2:32][CH3:37])[CH2:4]5)=[CH:13][CH:12]=4)[CH:8]=[CH:9]3)(=[O:16])=[O:15])=[CH:22][CH:21]=2)=[CH:24][N:25]=[CH:26]1
Reactant: CCCN1CC(c2ccc3c(ccn3S(=O)(=O)c3ccc(OC(F)F)cc3)c2)C1
Reactant: O=S(=O)(c1ccc(-c2cnco2)cc1)n1ccc2cc(C3CNC3)ccc21
Agent: Cl
Product: CCCN1CC(c2ccc3c(ccn3S(=O)(=O)c3ccc(-c4cnco4)cc3)c2)C1

Procedure:
This compound was prepared from 5-azetidin-3-yl-1-(4-oxazol-5-yl-benzensulfonyl)-1H-indole by the method outlined for compound 4. ESI-MS [m/z]: 422.15 [M+H]+. 1H-NMR (500 MHz, d6-DMSO): δ=10.75 (bs, 1H), 8.55 (s, 1H), 8.1 (d, 2H), 7.9 (m, 5H), 7.7 (s, 1H), 7.4 (m, 1H), 6.85 (d, 1H), 4.4 (m, 2H), 4.25 (m, 1H), 4.1 (m, 2H), 3.15 (m, 2H), 1.55 (m, 2H), 0.95 ppm (t, 3H).
Reaction SMILES: [CH2:1]([N:4]([CH2:11][CH2:12][CH3:13])[CH2:5][CH2:6][C:7]([O:9]C)=O)[CH2:2][CH3:3].C[O-].[Na+].[CH2:17]([CH2:19][NH2:20])[OH:18]>C1C2NC3C(=CC=CC=3)SC=2C=CC=1>[OH:18][CH2:17][CH2:19][NH:20][C:7](=[O:9])[CH2:6][CH2:5][N:4]([CH2:1][CH2:2][CH3:3])[CH2:11][CH2:12][CH3:13]
Reactant: NCCO
Reactant: CCCN(CCC)CCC(=O)OC
Agent: C[O-]
Agent: [Na+]
Agent: c1ccc2c(c1)Nc1ccccc1S2
Product: CCCN(CCC)CCC(=O)NCCO
Yield: 99.6 %

Procedure:
To 746 g of methyl beta-dipropylaminopropionate which was prepared in the same manner as in Example 4 were added 15.4 g of 28% methanolic solution of sodium methoxide, then 293 g (4.8 moles) of ethanolamine were added dropwise thereinto and the mixture was made to react at 70° C. for one hour. After completion of the reaction, the mixture was neutralized, desalted, 0.3 g of phenothiazine were added thereto and the low-boiling-point substances were removed by distillation to give 858 grams of N-hydroxyethyl-beta-dipropylaminopropionamide. The purity as checked by gas chromatography was 98% and the yield was 97.3%.
Reaction SMILES: [F:1][C:2]1[C:9]([OH:10])=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[H-].[Na+].FC(F)(F)S(O[CH2:19][C:20]([F:23])([F:22])[F:21])(=O)=O.O>CN(C=O)C.[Cl-].[Na+].O>[F:1][C:2]1[C:9]([O:10][CH2:19][C:20]([F:23])([F:22])[F:21])=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: N#Cc1cccc(O)c1F
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1cccc(OCC(F)(F)F)c1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81.4 %

Procedure:
A stirred solution of 2-fluoro-3-hydroxybenzonitrile (800 mg, 5.83 mmol) in DMF (10 mL) at 0° C. was treated portionwise with NaH (280 mg, 7.00 mmol) (60% oil dispersion). The reaction mixture was then stirred for 0.5 h and 2,2,2-trifluoroethyl trifluoromethanesulfonate (1490 mg, 6.42 mmol) was added. The reaction was allowed to warm to rt overnight with stirring. The reaction mixture was then treated with water (40 mL) and brine (5 mL) and extracted with ethyl acetate (˜50 mL). The organic extract was washed with water, dried over anhydrous Na2SO4, filtered and conc. in vacuo to afford a residue which was purified via silica gel chromatography (10% to 30% ethyl acetate/hexanes) to yield the title compound as a white solid (1040 mg, 81%). 1H NMR (400 MHz, MeOD) δ ppm 7.56 (td, 1 H), 7.47-7.38 (m, 1 H), 7.38-7.24 (m, 1 H), 4.73 (q, 2 H); m/z 220.
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[CH2:11][CH:10]=[C:9]([C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)[C:8]2[CH:7]=[C:6]([C:17]([O:19]C)=[O:18])[CH:5]=[CH:4][C:3]1=2.[OH-].[Na+]>CCO.C1COCC1>[CH3:1][C:2]1([CH3:21])[CH2:11][CH:10]=[C:9]([C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)[C:8]2[CH:7]=[C:6]([C:17]([OH:19])=[O:18])[CH:5]=[CH:4][C:3]1=2
Reactant: COC(=O)c1ccc2c(c1)C(c1cccs1)=CCC2(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CC1(C)CC=C(c2cccs2)c2cc(C(=O)O)ccc21
Temperature: 35 °C

Procedure:
To a solution of methyl 5,5-dimethyl-5,6-dihydro-8-(2-thienyl)-2-naphthalenecarboxylate (Compound E5, 430.0 mg, 1.44 mmol) in 3.0 mL of EtOH and 3.0 mL THF was added NaOH (240.0 mg, 6.00 mmol; 3.0 mL of a 2N aqueous solution). The resulting solution was warmed to 35° C. for 6 h, cooled to room temperature and quenched with 1M HCl. The mixture was extracted with EtOAc and the combined organic layers washed with H2O and saturated aqueous Naa before being dried over MgSO4. Removal of the solvents under reduced pressure afforded the title compound as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][CH:9]2[C:28](O)=[O:29])[CH:5]=[CH:6][CH:7]=1.[NH2:32][C:33]1[CH:38]=[CH:37][C:36]([C:39](=[O:42])[CH2:40][Br:41])=[CH:35][CH:34]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[Br:41][CH2:40][C:39]([C:36]1[CH:37]=[CH:38][C:33]([NH:32][C:28]([CH:9]2[CH:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:31])[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:25])[CH3:26])[NH:10]2)=[O:29])=[CH:34][CH:35]=1)=[O:42]
Reactant: Nc1ccc(C(=O)CBr)cc1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)CC1NC(C(=O)Nc2ccc(C(=O)CBr)cc2)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Yield: 7.2 %

Procedure:
In a manner similar to the method described in Examples 1e, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (0.35 g, 0.75 mmol) was reacted with 1-(4-amino-phenyl)-2-bromo-ethanone (Astatech) (0.17 g, 0.9 mmol), HATU (0.5 g, 1.3 mmol) and iPr2NEt (0.33 mL, 2.6 mmol) in CH2Cl2 at room temperature to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid [4-(2-bromo-acetyl)-phenyl]-amide as a white solid (36 mg, 7%).
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[C@@H:4]([C:5]2[CH:6]=[N:7][C:8]([C:11]([CH3:14])([CH3:13])[CH3:12])=[N:9][CH:10]=2)[C@@H:3]1[C:15]([OH:17])=[O:16].[O:19]([C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH2:29]Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:1][C:2]1([CH3:18])[C@@H:4]([C:5]2[CH:6]=[N:7][C:8]([C:11]([CH3:12])([CH3:13])[CH3:14])=[N:9][CH:10]=2)[C@@H:3]1[C:15]([O:17][CH2:29][C:28]1[CH:31]=[CH:32][CH:33]=[C:26]([O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:27]=1)=[O:16]
Reactant: BrCc1cccc(Oc2ccccc2)c1
Reactant: CC(C)(C)c1ncc([C@H]2[C@H](C(=O)O)C2(C)C)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)(C)c1ncc([C@H]2[C@H](C(=O)OCc3cccc(Oc4ccccc4)c3)C2(C)C)cn1
Reaction time: 16 h
Yield: 92.3 %

Procedure:
A mixture of trans-2,2-dimethyl-3-[2-(2-methylprop-2-yl) pyrimidin-5-yl]cyclopropane carboxylic acid (500 mg), 3-phenoxybenzylbromide 552 mg), anhydrous potassium carbonate (304 mg) and acetone (10 cm3) was heated at the reflux temperature for 2 hours with stirring after which it was kept at the ambient temperature for 16 hours. After removing the solid precipitate by filtration the filtrate was concentrated by evaporation under reduced pressure. The residual oil was subjected to high performance liquid chromatography (Gilson) using a silica column and, as eluent, a mixture of dichloromethane (100 parts by volume) and ethyl acetate (2 parts by volume). The product, 3-phenoxybenzyl trans-2,2-dimethyl-3-[2-(2-methylprop-2-yl)-pyrimidin-5-yl]cyclopropane carboxylate (800 mg) was obtained as an oil and identification was confirmed by n.m.r. and infra red spectroscopy.
Reaction SMILES: [CH2:1]1[C:6]2[S:7][C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[C:5]=2[CH2:4][CH2:3][NH:2]1.C([O-])([O-])=O.[Na+].[Na+].Cl[CH2:21][CH2:22][CH2:23][C:24]#[N:25]>C(#N)C.CC1C=CC=CC=1>[CH2:1]1[C:6]2[S:7][C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[C:5]=2[CH2:4][CH2:3][N:2]1[CH2:21][CH2:22][CH2:23][C:24]#[N:25]
Reactant: N#CCCCCl
Reactant: c1ccc2c3c(sc2c1)CNCC3
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: Cc1ccccc1
Product: N#CCCCN1CCc2c(sc3ccccc23)C1
Yield: 101.4 %

Procedure:
A mixture of 1,2,3,4-tetrahydro-[1]benzothieno[2,3-c]pyridine (0.02 mol), Na2CO3 (5 g), KI (0.1 g) and 4-chlorobutanenitrile (0.025 mol) in acetonitrile (50 ml) and methylbenzene (150 ml) was stirred and refluxed overnight, then cooled, filtered and the filtrate was evaporated. The residue (oil) was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH 98/2). The pure fractions were collected and the solvent was evaporated, yielding 5.2 g of 3,4-dihydrobenzothieno[2,3-c]-pyridine-2(1H)-butanenitrile (interm. 6).
Reaction SMILES: [CH:1]([N:4]([S:17]([C:20]1[S:21][CH:22]=[CH:23][CH:24]=1)(=[O:19])=[O:18])[C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:13]=1[NH:12][C:11]([C:14](=[S:16])[NH2:15])=[CH:10]2)([CH3:3])[CH3:2].Br[CH:26]([CH:29]=O)[CH:27]=[O:28].CN(C)C(=O)C>O>[OH:28][CH2:27][C:26]1[S:16][C:14]([C:11]2[NH:12][C:13]3[C:9]([CH:10]=2)=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]([CH:1]([CH3:3])[CH3:2])[S:17]([C:20]2[S:21][CH:22]=[CH:23][CH:24]=2)(=[O:18])=[O:19])=[N:15][CH:29]=1
Reactant: O=CC(Br)C=O
Reactant: CC(C)N(c1cccc2cc(C(N)=S)[nH]c12)S(=O)(=O)c1cccs1
Solvent: O
Solvent: CC(=O)N(C)C
Product: CC(C)N(c1cccc2cc(-c3ncc(CO)s3)[nH]c12)S(=O)(=O)c1cccs1
Temperature: 90 °C
Reaction time: 2 h
Yield: 88.2 %

Procedure:
A mixture of 7-[isopropyl(2-thienylsulfonyl)amino]-1H-indole-2-carbothioamide (123 mg), bromomalonaldehyde (103 mg) and N,N-dimethylacetamide (3 mL) was stirred at 90° C. for 2 hr. To the reaction mixture was added water, and the obtained solid was washed with water, and then with hexane. To a mixture of the solid, tetrahydrofuran (5 mL) and methanol (5 mL) was added sodium borohydride (15 mg), and the mixture was stirred at room temperature for 14 hr. The reaction mixture was concentrated under reduced pressure, and ethyl acetate was added to the residue. The mixture was washed with aqueous sodium bicarbonate and saturated brine, and the ethyl acetate layer was dried over magnesium sulfate, and filtrated. The filtrate was concentrated. The residue was subjected to silica gel column chromatography, and eluted with a mixture of ethyl acetate-hexane (2:1) to give the title compound (124 mg, yield 88%) as crystals. melting point 209° C.