Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([OH:19])=[O:18])=[CH:15][CH:14]=1)(=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].O[C:23]1[CH:44]=[CH:43][C:26]([C:27]([O:29][CH:30]([CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[C:31]([F:34])([F:33])[F:32])=[O:28])=[CH:25][CH:24]=1>O1CCCC1>[C:1]([O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([O:19][C:23]2[CH:24]=[CH:25][C:26]([C:27]([O:29][CH:30]([CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[C:31]([F:32])([F:33])[F:34])=[O:28])=[CH:43][CH:44]=2)=[O:18])=[CH:15][CH:14]=1)(=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCC(OC(=O)c1ccc(O)cc1)C(F)(F)F
Reactant: CCCCCCCCCC(=O)Oc1ccc(C(=O)O)cc1
Solvent: C1CCOC1
Product: CCCCCCCCCC(=O)Oc1ccc(C(=O)Oc2ccc(C(=O)OC(CCCCCCCC)C(F)(F)F)cc2)cc1

Procedure:
To a solution of the 4-n-decanoyloxybenzoic acid (0.4 g) obtained in (3) and the 1,1,1-trifluoro-2-decyl 4-hydroxybenzoate (0.4 g) obtained in (2) in tetrahydrofuran (about 30 ml) were added dicyclohexylcarbodiimide (0.32 g) and dimethylaminopyridine (0.01 g). The mixture was stirred at room temperature for about 20 hours and was distilled to remove the solvent. The residue was dissolved in dichloromethane and washed with water. The organic layer was dried over anhydrous magnesium sulfate and was distilled to remove the solvent. The residue was purified by silica-gel column chromatography (a developer : hexane/ethyl acetate=20/1) to obtain the titled compound (0.15 g). Phase transition temperatures (° C.) were observed under a polarization microscope using a hot stage as follows: ##STR53## where
Reaction SMILES: [Na].[C:2]([O:8][CH2:9][CH3:10])(=[O:7])[CH2:3][C:4]([CH3:6])=[O:5].[C:11](#[N:14])[CH:12]=[CH2:13]>CCO>[C:11]([CH2:12][CH2:13][CH:3]([C:4](=[O:5])[CH3:6])[C:2]([O:8][CH2:9][CH3:10])=[O:7])#[N:14]
Reactant: C=CC#N
Reactant: CCOC(=O)CC(C)=O
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(CCC#N)C(C)=O
Reaction time: 4 h

Procedure:
A solution of solid sodium metal (450 mg, 19.75 mmol) in EtOH at 30° C. was treated with ethyl acetoacetate (103 g, 790 mmol) maintaining temperature. Then acrylonitrile (41.9 g, 790 mmol) was added dropwise over 15 minutes. The reaction was capped and stirred for 4 hours. The solution was concentrated and the resulting solid was dissolved in 20 mL of water and 3 mL of acetic acid, and washed with 50 mL of DCM. The organic layer was dried over Na2SO4 and concentrated to an oil. Distillation was performed under reduced pressure (0.5 mm) with a bath temperature of 80° C. Fractions were collected and concentrated to provide A-1 as a colorless oil. Data for A-1: LC/MS: m/z (M+H)=183.87 found; 183.20 required
Reaction SMILES: [NH2:1][C@H:2]([CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:3][OH:4].C1CCC(N=C=NC2CCCCC2)CC1.C1C=CC2N(O)N=NC=2C=1.[CH:37]1[C:49]2[CH:48]([CH2:50][O:51][C:52]([NH:54][C@H:55]([C:60](O)=[O:61])[C@H:56]([CH2:58][CH3:59])[CH3:57])=[O:53])[C:47]3[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=3)[C:41]=2[CH:40]=[CH:39][CH:38]=1>CN(C=O)C>[C:52]([NH:54][C@H:55]([C:60]([NH:1][C@@H:2]([CH2:3][OH:4])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:61])[C@H:56]([CH2:58][CH3:59])[CH3:57])([O:51][CH2:50][CH:48]1[C:49]2[C:41](=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:42]2[C:47]1=[CH:46][CH:45]=[CH:44][CH:43]=2)=[O:53]
Reactant: N[C@@H](CO)Cc1ccccc1
Reactant: CC[C@H](C)[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC[C@H](C)[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)N[C@@H](CO)Cc1ccccc1
Temperature: 25 °C
Yield: 47.2 %

Procedure:
(R)(+)-2-amino-3-phenyl-1-propanol (427 mg, 2.83 mmol) dissolved in dry DMF (20 mL), stirred under nitrogen, to this stirred mixture at 25° C. DCC (699 mg, 3.39 mmol), HOBt (457 mg, 3.38 mmol) was added with constant stirring. After 10 minutes of stirring N-(9-fluorenylmethoxycarbonyl)-L-isoleucine (1.0 g, 2.83 mmol) was added to the above mixture and then stirred at 25° C. for 14 h. After 14 h white colored crystals precipitated out (DCU), which was filtered. The filterate was checked on TLC (2% MeOH: CH2Cl2) which showed formation of a new compound at higher Rf (0.6), LC/MS also showed molecular ion peak corresponding to the dipeptide 1a with other impurities peaks. The crude product was chromatographed on silica gel (Silica gel 60, 63-200μ) column and eluted with 2% MeOH: CH2Cl2 to give 650 mg of the dipeptide Fmoc-NH-L-Ile-D-Phe-CH2OH (1a) as a white solid. Checked on LC/MS which showed M++1 (487.4) and M++Na (509.2).
Reaction SMILES: [C:1]([C:5]1[CH:19]=[CH:18][C:8]([O:9][CH2:10][C:11]([O:13]C(C)(C)C)=[O:12])=[CH:7][C:6]=1[Cl:20])([CH3:4])([CH3:3])[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:1]([C:5]1[CH:19]=[CH:18][C:8]([O:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:7][C:6]=1[Cl:20])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)COc1ccc(C(C)(C)C)c(Cl)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)c1ccc(OCC(=O)O)cc1Cl
Temperature: 25 °C
Reaction time: 5 h
Yield: 99.9 %

Procedure:
To a suspension of potassium carbonate (994 mg, 7.2 mmol) and 4-tert-butyl-3-chlorophenol (440 mg, 2.4 mmol) in acetone (5 ml) was added t-butyl bromoacetate (370 mg, 1.9 mmol) was added and the mixture was refluxed at 60° C. for 14 hours. Filtrating of potassium carbonate, evaporation, and purification through silica gel column chromatography eluting with hexane/EtOAc (20:1 to 10:1) to furnish the tert-butyl (4-tert-butyl-3-chlorophenoxy)acetate (720 mg, 100%). The mixture of tert-butyl (4-tert-butyl-3-chlorophenoxy)acetate (720 mg, 2.4 mmol), TFA (2.0 ml), DCM (2.0 ml) was stirred for 5 hours at room temperature. After being concentrated in vacuo, the residue was triturated with hexane to furnish the title compound (582 mg, 100%) as a white solid. 1H NMR (300 MHz, CDCl3): δ 1.45 (9H, s), 4.67 (2H, s), 6.76 (1H, dd, J=2.6, 8.6 Hz), 6.96 (1H, d, J=2.6 Hz), 7.35 (1H, d, J=8.6 Hz).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([CH3:14])([CH3:13])[C:10](=[O:15])[C:9]=2[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:31][C:32]1[CH:41]=[CH:40][C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[N:33]=1>C(#N)C>[CH3:23][O:22][C:19]1[CH:18]=[CH:17][C:16]([C:9]2[C:10](=[O:15])[C:11]([CH3:13])([CH3:14])[O:12][C:8]=2[C:5]2[CH:4]=[CH:3][C:2]([O:1][CH2:31][C:32]3[CH:41]=[CH:40][C:39]4[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=4)[N:33]=3)=[CH:7][CH:6]=2)=[CH:21][CH:20]=1
Reactant: COc1ccc(C2=C(c3ccc(O)cc3)OC(C)(C)C2=O)cc1
Reactant: ClCc1ccc2ccccc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc(C2=C(c3ccc(OCc4ccc5ccccc5n4)cc3)OC(C)(C)C2=O)cc1
Temperature: 80 °C
Reaction time: 16 h
Yield: 0.1 %

Procedure:
To a stirred solution of 5-(4-hydroxyphenyl)-4-(4-methoxyphenyl)-2,2-dimethylfuran-3(2H)-one (600 mg, 1.93 mol) in acetonitrile (50 mL) was added K2CO3 (800 mg, 5.8 mol). 2-Chloromethyl quinoline (500 mg, 2.32 mol) was added dropwise under an inert atmosphere. The reaction mixture was stirred at 80° C. for 16 h and then partitioned between water and EtOAc (200 mL). The organic layer was separated, washed with water, dried over Na2SO4 and then concentrated in vacuo to obtain a residue. The residue was purified via silica gel column chromatography to afford 4-(4-methoxyphenyl)-2,2-dimethyl-5-(4-(quinolin-2-ylmethoxy)phenyl) furan-3(2H)-one (0.51 g, 58%) as a white solid. 1H NMR (500 MHz, d6-DMSO): δ 8.45 (d, J=7.2 Hz, 1H), 8.02-7.97 (m, 2H), 7.85-7.77 (m, 1H), 7.76-7.68 (m, 2H), 7.59-7.51 (m, 2H), 7.19-7.11 (m, 4H), 6.95 (d, J=7.4 Hz, 2H), 5.41 (s, 2H), 3.75 (s, 3H), 1.45 (s, 6H). MS: M+H: m/z=452.1. HPLC: 97%, (Condition-I).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:10])[CH:5]=[N:6][C:7]=1[O:8][CH3:9].[Cl:11][C:12]1[CH:13]=[C:14]([C:19]2[N:24]=[C:23]([CH3:25])[N:22]=[C:21]([NH:26][CH2:27][CH2:28][O:29][CH3:30])[N:20]=2)[C:15](F)=[N:16][CH:17]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[Cl:11][C:12]1[CH:13]=[C:14]([C:19]2[N:24]=[C:23]([CH3:25])[N:22]=[C:21]([NH:26][CH2:27][CH2:28][O:29][CH3:30])[N:20]=2)[C:15]([NH:10][C:4]2[CH:5]=[N:6][C:7]([O:8][CH3:9])=[C:2]([F:1])[CH:3]=2)=[N:16][CH:17]=1
Reactant: COc1ncc(N)cc1F
Reactant: COCCNc1nc(C)nc(-c2cc(Cl)cnc2F)n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COCCNc1nc(C)nc(-c2cc(Cl)cnc2Nc2cnc(OC)c(F)c2)n1
Reaction time: 0.08 h
Yield: 62.7 %

Procedure:
A mixture of 5-fluoro-6-methoxypyridin-3-amine (Anichem, N.J., USA, 100 mg, 0.704 mmol) and 4-(5-chloro-2-fluoropyridin-3-yl)-N-(2-methoxyethyl)-6-methyl-1,3,5-triazin-2-amine (130 mg, 0.437 mmol) in THF (5 mL) was cooled in an ice bath and LiHMDS (1.0 M, 1500 μL, 1.500 mmol) was added under nitrogen. After 5 min, the cooling bath was removed. After 10 min, the mixture was neutralized with HCl (5N, 0.3 mL) and then partitioned between EtOAc (20 mL) and water (10 mL). The organic layer was washed with water (5 mL). The combined aqueous layers were extracted with EtOAc (2×5 mL). The combined organic layers were dried over Na2SO4 and concentrated. The resulting solid was triturated with EtOAc (5 mL) and filtered. The yellow solid was rinsed with ether (2×3 mL) to give the desired product as a yellow powder (115 mg). LCMS (ES, pos.): calcd for C18H19ClFN7O2: 419.1. found: 420.2 (M+H)+. 1H NMR (400 MHz, d6-DMSO) mixture of rotamers δ 11.89, 11.67 (s, 1H); 8.73 (dd, J=6.75, 2.64 Hz, 1H); 8.14-8.58 (m, 4H); 3.94 (2s, 3H); 3.46-3.65 (m, 4H); 3.23, 3.29 (s, 3H); 2.46, 2.47 (s, 3H). 19F NMR (377 MHz, d6-DMSO) δ −139.65 (S); 139.26 (S).
Reaction SMILES: C(O[C:4]([C:6]1[S:10][C:9]([N:11]2[C:15]3[CH:16]=[C:17]([O:22][CH3:23])[C:18]([O:20][CH3:21])=[CH:19][C:14]=3[N:13]=[CH:12]2)=[N:8][C:7]=1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:5])C.[CH2:30]([NH2:32])[CH3:31]>CO>[CH2:30]([NH:32][C:4]([C:6]1[S:10][C:9]([N:11]2[C:15]3[CH:16]=[C:17]([O:22][CH3:23])[C:18]([O:20][CH3:21])=[CH:19][C:14]=3[N:13]=[CH:12]2)=[N:8][C:7]=1[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)=[O:5])[CH3:31]
Reactant: CCN
Reactant: CCOC(=O)c1sc(-n2cnc3cc(OC)c(OC)cc32)nc1-c1ccccc1
Solvent: CO
Product: CCNC(=O)c1sc(-n2cnc3cc(OC)c(OC)cc32)nc1-c1ccccc1

Procedure:
2-(5,6-Dimethoxy-benzoimidazol-1-yl)-4-phenyl-thiazole-5-carboxylic acid ethylamide was prepared from 2-(5,6-Dimethoxy-benzoimidazol-1-yl)-4-phenyl-thiazole-5-carboxylic acid ethyl ester (30 mg, 0.07 mmol) and ethylamine in methanol (2 molar) as described above in the general amide formation procedure. Product was isolated by preparative HPLC: 16 mg, 56%. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.81 (s, 1H); 8.53 (t, 1H); 7.88-7.69 (m, 3H); 7.55-7.44 (m, 3H); 7.40 (s, 1H); 3.88 (s, 3H); 3.85 (s, 3H); 3.25 (q, 2H); 1.08 (t, 3H). MS M/z 409 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([Cl:12])[C:6]=2C=O.C(=O)([O-])[O-].[Na+].[Na+].[Cl-].[OH:22][NH3+:23].O>C(O)C>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[C:6](=[N:23][OH:22])[CH:7]([Cl:12])[CH:8]=[CH:9][C:10]=2[CH:11]=1
Reactant: O=Cc1c(Cl)ccc2cc(Cl)cnc12
Reactant: [NH3+]O
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: ON=C1c2ncc(Cl)cc2C=CC1Cl
Yield: 101.1 %

Procedure:
22.6 g of 3,7-dichloroquinoline-8-carbaldehyde were dissolved in 300 parts of ethanol, 10.6 g of sodium carbonate and 6.9 g of hydroxylammonium chloride were added to this solution, and the suspension was refluxed for 1 hour. Thereafter, 1,000 g of water were added, and the precipitated solid was filtered off and dried to give 23 g (96% of theory) of 3,7-dichloro-8-hydroxyliminoquinoline of melting point 202° C.
Reaction SMILES: C([O:5][C:6](=[O:25])[CH:7]=[CH:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]=[CH:16][C:17](=[O:24])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:11][N:10]=1)(C)(C)C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[O:24]=[C:17]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[CH:16]=[CH:15][C:12]1[CH:13]=[CH:14][C:9]([CH:8]=[CH:7][C:6]([OH:25])=[O:5])=[N:10][CH:11]=1
Reactant: CC(C)(C)OC(=O)C=Cc1ccc(C=CC(=O)c2ccccc2)cn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)C=Cc1ccc(C=CC(=O)c2ccccc2)cn1
Temperature: 25 °C
Reaction time: 4 h
Yield: 155.5 %

Procedure:
3-[5-(3-oxo-3-phenyl-propenyl)-pyridin-2-yl]-acrylic acid tert-butyl ester (130 mg, 0.38 mmol) was dissolved in DCM (4 ml) and TFA (1 ml). The resulting solution was stirred for 4 h at room temperature and then the solvent was removed under vacuo. The resulting oil was crystallized from Et2O to give 165 mg of 3-[5-(3-oxo-3-phenyl-propenyl)-pyridin-2-yl]-acrylic acid as the trifluoroacetate salt.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][CH:7]=1.C(N(CC)CC)C.[C:21]1([CH3:31])[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1>CC#N>[CH3:31][C:21]1[CH:26]=[CH:25][C:24]([S:27]([O:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]2[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][CH:7]=2)(=[O:29])=[O:28])=[CH:23][CH:22]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: N#Cc1ccc(NCCCO)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OCCCNc2ccc(C#N)cc2)cc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 77.2 %

Procedure:
A cooled (0° C.) solution of 4-[(3-hydroxypropyl)amino]benzonitrile (see step (i) above; 17 g, 96.5 mmol) in dry MeCN (195 mL) was treated with triethylamine (9.8 g, 96.5 mmol) and then p-toluenesulfonyl chloride (20.2 g, 106 mmol). The mixture was stirred at 0° C. for 90 minutes before being concentrated in vacuo. Water (200 mL) was added to the residue, and the aqueous solution was extracted with DCM. The organic phase was dried (Na2SO4), filtered and concentrated in vacuo. The resulting residue was purified by crystallisation from iso-propanol to yield 24.6 g (77%) of the sub-title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[NH:14][CH3:15])=[C:4]([CH3:16])[CH:3]=1.CCN(C(C)C)C(C)C.[F:26][C:27]([F:42])([F:41])[C:28]1[CH:29]=[C:30]([CH:34]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:36]=1)[C:31](Cl)=[O:32]>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[N:14]([CH3:15])[C:31](=[O:32])[C:30]2[CH:29]=[C:28]([C:27]([F:42])([F:41])[F:26])[CH:36]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:34]=2)=[C:4]([CH3:16])[CH:3]=1
Reactant: CNc1cnccc1-c1ccc(F)cc1C
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(F)ccc1-c1ccncc1N(C)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reaction time: 16 h

Procedure:
To a solution of 4-(4-fluoro-2-methylphenyl)-N-methylpyridin-3-amine (47 mg, 0.22 mmol) and DIPEA (57 μL, 0.33 mmol) was added 3,5-bis(trifluoromethyl)benzoyl chloride (78 mg, 0.28 mmol, CAS RN 1271-19-8) in CH2Cl2 (2 mL). After stirring for 16 hours, the reaction mixture was loaded directly onto a silica gel column and elution with EtOAc gave the title compound as a waxy oil which solidified upon standing (56 mg, 56%). MS (ESI): m/z=457.0 [M+H]+.
Reaction SMILES: [Na].[OH:2][N:3]1[C:7](=[O:8])[C:6]2=[CH:9][CH:10]=[CH:11][CH:12]=[C:5]2[C:4]1=[O:13].Cl.[CH3:15][C:16]1[NH:20][CH:19]=[N:18][C:17]=1[CH2:21]Cl>C(O)C>[CH3:15][C:16]1[NH:20][CH:19]=[N:18][C:17]=1[CH2:21][O:2][N:3]1[C:4](=[O:13])[C:5]2=[CH:12][CH:11]=[CH:10][CH:9]=[C:6]2[C:7]1=[O:8]
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: Cc1[nH]cnc1CCl
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: Cc1[nH]cnc1CON1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Yield: 48.7 %

Procedure:
A mixture of 1 g of sodium and 80 ml of ethanol was cooled in an ice-bath and 7.12 g of N-hydroxyphthalimide was added thereto and the mixture was stirred at room temperature. The mixture was cooled in an ice-bath and 3.16 g of 5-methyl-4-chloromethylimidazole hydrochloride was added thereto. The resulting mixture was stirred for 2 hours. The solvent was distilled off and SSB was added to the residue and the mixture was extracted with chloroform. The extract was washed with SSC and dried with sodium sulfate and concentrated to dryness. The residue was washed with ether to give 2.37 g of N-((5-methylimidazole-4-yl)methoxy)phthalimide with mp 155°-156° C.
Reaction SMILES: [C:1]([O:6][CH2:7][CH3:8])(=[O:5])[CH:2]=[C:3]=[CH2:4].[O:9]1[CH:13]=[CH:12][CH:11]=[CH:10]1.Cl>[Cl-].[Zn+2].[Cl-].C1(C)C=CC=CC=1>[CH2:7]([O:6][C:1]([CH:2]1[C:3](=[CH2:4])[CH:10]2[O:9][CH:13]1[CH:12]=[CH:11]2)=[O:5])[CH3:8]
Reactant: C=C=CC(=O)OCC
Reactant: c1ccoc1
Agent: Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: Cc1ccccc1
Product: C=C1C2C=CC(O2)C1C(=O)OCC
Temperature: 0 °C
Reaction time: 8 h
Yield: 87.3 %

Procedure:
Ethyl 2,3-butadienoate (0.84 g, 7.5 mmol) and 2.52 g of furan (37 mmol) were combined in a flask under nitrogen and cooled to 0° C. Anhydrous zinc chloride (0.25 g, 1.8 mmol) was added, then the reaction mixture was warmed to room temperature and stirred overnight. NMR analysis indicated that the reaction was complete. Toluene and dilute HCl were added. A black lump of material separated. The toluene and water phases were decanted. The toluene phase was washed with water, filtered and rotovapped. Methylene chloride and aqueous HCl were added to the black solids which dissolved. The methylene chloride phase was washed with water, combined with the rotovapped toluene phase and stripped. A total of 1.18 g of a light brown liquid was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][N:4]([CH2:7][C:8]([CH3:11])([OH:10])[CH3:9])[N:3]=1.N1C(C)=CC=CC=1C.[Cl:20][C:21]1[CH:22]=[C:23]([CH:31]([CH2:35][C@H:36]2[CH2:40][CH2:39][C:38]([F:42])([F:41])[CH2:37]2)[C:32](Cl)=[O:33])[CH:24]=[CH:25][C:26]=1[S:27]([CH3:30])(=[O:29])=[O:28]>C(Cl)Cl>[Cl:20][C:21]1[CH:22]=[C:23]([CH:31]([CH2:35][C@H:36]2[CH2:40][CH2:39][C:38]([F:42])([F:41])[CH2:37]2)[C:32]([NH:1][C:2]2[CH:6]=[CH:5][N:4]([CH2:7][C:8]([OH:10])([CH3:11])[CH3:9])[N:3]=2)=[O:33])[CH:24]=[CH:25][C:26]=1[S:27]([CH3:30])(=[O:29])=[O:28]
Reactant: CS(=O)(=O)c1ccc(C(C[C@H]2CCC(F)(F)C2)C(=O)Cl)cc1Cl
Reactant: CC(C)(O)Cn1ccc(N)n1
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CC(C)(O)Cn1ccc(NC(=O)C(C[C@H]2CCC(F)(F)C2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
In a round bottom flask was placed 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (prepared as in Example 80, 56 mg, 0.36 mmol), 2,6-lutidine (54 μL, 0.49 mmol) and methylene chloride (10 mL) which was then cooled to 0° C. in an ice bath. To this solution was then added dropwise a solution of 2-(3-chloro-4-methanesulfonyl-phenyl)-3-((R)-3,3-difluoro-cyclopentyl)-propionyl chloride (˜0.16 M solution, 2 mL, 0.33 mmol). The reaction was then allowed to warm up to 25° C. and stirred for 16 h. After this time the reaction mixture was quenched with a saturated aqueous sodium bicarbonate solution (10 mL) and then diluted with methylene chloride (10 mL) transferred to a separatory funnel and the layers separated. The aqueous layer was then extracted methylene chloride (3×10 mL). The organics were combined and then washed with a 1 N aqueous hydrochloric acid solution (10 mL) and then dried over magnesium sulfate, filtered and concentrated in vacuo. Purification on an AnaLogix Intelliflash system (12 g column, 55% ethyl acetate/hexanes) afforded 2-(3-chloro-4-methanesulfonyl-phenyl)-3-((R)-3,3-difluoro-cyclopentyl)-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-propionamide (as a mixture of two diastereomers, 90 mg, 55%) as a white foam: ES-HRMS m/e calcd for C22H28N3O4SClF2 (M+H)+ 504.1530, observed 504.1526; 1H NMR (300 MHz, DMSO-d6) δ 1.03 (s, 3H, CH3), 1.04 (s, 3H, CH3), 1.42 (m, 1H, CH), 1.68-2.33 (m, 8H, 4×CH2), 3.34 (s, 3H, SO2CH3), 3.87 (s, 2H, NCH2), 3.90 (m, 1H, ArCHCO), 4.66 (s, 1H, OH), 6.45 (d, J=2.2 Hz, 1H, Ar), 7.52 (d, J=2.2 Hz, 1H, Ar), 7.60 (d, Jo=8.3 Hz, 1 H, Ar), 7.71 (s, 1H, Ar), 8.02 (d, Jo=8.3 Hz, 1H, Ar), 10.85 (s, 1H, NH).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:26])=[C:5]([C:23]([OH:25])=[O:24])[C@@H:6]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=2)[C:7]=1[C:8]([O:10][CH2:11][CH2:12][NH2:13])=[O:9].[C:27](OC(=O)C)(=[O:29])[CH3:28]>O>[C:27]([NH:13][CH2:12][CH2:11][O:10][C:8]([C:7]1[C@H:6]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=2)[C:5]([C:23]([OH:25])=[O:24])=[C:4]([CH3:26])[NH:3][C:2]=1[CH3:1])=[O:9])(=[O:29])[CH3:28]
Reactant: CC1=C(C(=O)O)[C@@H](c2cccc([N+](=O)[O-])c2)C(C(=O)OCCN)=C(C)N1
Reactant: CC(=O)OC(C)=O
Solvent: O
Product: CC(=O)NCCOC(=O)C1=C(C)NC(C)=C(C(=O)O)[C@H]1c1cccc([N+](=O)[O-])c1
Temperature: 25 °C

Procedure:
That is, 10 mg of the (4R)-1,4-dihydro-2,6-dimethyl3-(2-aminoethyl) oxycarbonyl-4-(3-nitrophenyl)pyridine-5-carboxylic acid obtained in Example 28 was dissolved in 2 ml of deionized water and 0.2 ml of acetic anhydride was added to the solution while stirring at room temperature. After stirring for continuous 30 minutes, the reaction mixture was extracted 3 times with 5 ml each of ethyl acetate and washed with 10 ml of saturated saline. The ethyl acetate layer was adsorbed on a preparatory TLC plate, developed with chloroform/methanol (7:1) to elute fractions showing UV absorption at Rf 0.22. The eluate was evaporated to dryness to obtain 3.7 mg of (4R)-3-(2-acetamidoethyl) oxycarbonyl-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl) pyridine-5-carboxylic acid. The optical purity of this substance was determined by HPLC(mobile phase: 0.35% isopropanol/0.1M phosphaste buffer solution (pH 4.4), flow rate: 0.8 ml/minute) using an otical resolution column: CHIRAL AGP (4 mm×100 mm) manufactured by Daicel Chemical Industries Ltd. As a result, it revealed that the optical purity of the 4R form was 100% and the retention time was 14.3 minutes.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH:13][C:14](=[O:22])[C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[CH:7]=[CH:8][C:9]=1[N+:10]([O-])=O)([O-])=O.[CH:23]1([NH:26][C:27]([C:29]2[CH:36]=[CH:35][C:32]([CH:33]=O)=[CH:31][CH:30]=2)=[O:28])[CH2:25][CH2:24]1>>[CH:23]1([NH:26][C:27](=[O:28])[C:29]2[CH:36]=[CH:35][C:32]([C:33]3[NH:10][C:9]4[CH:8]=[CH:7][C:6]([NH:13][C:14](=[O:22])[C:15]5[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=5)=[CH:5][C:4]=4[N:1]=3)=[CH:31][CH:30]=2)[CH2:24][CH2:25]1
Reactant: O=C(Nc1ccc([N+](=O)[O-])c([N+](=O)[O-])c1)c1ccc(F)cc1
Reactant: O=Cc1ccc(C(=O)NC2CC2)cc1
Product: O=C(Nc1ccc2[nH]c(-c3ccc(C(=O)NC4CC4)cc3)nc2c1)c1ccc(F)cc1

Procedure:
Compound 234 was prepared according to the procedure similar to that described in Scheme III from N-(3,4-dinitrophenyl)-4-fluorobenzamide and 4-cyclopropylaminocarbonylbenzaldehyde. [M+H]+ calcd for C24H19FN4O2: 415.16; found: 415.53.
Reaction SMILES: FC(F)(F)C(O)=O.[BH4-].[Na+].[Cl:10][C:11]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=1[CH:18](O)[C:19]1[C:20]2[CH:28]=[C:27]([C:29]([O:31][CH3:32])=[O:30])[CH:26]=[CH:25][C:21]=2[S:22][C:23]=1[CH3:24].[OH-].[Na+]>C(Cl)Cl>[Cl:10][C:11]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=1[CH2:18][C:19]1[C:20]2[CH:28]=[C:27]([C:29]([O:31][CH3:32])=[O:30])[CH:26]=[CH:25][C:21]=2[S:22][C:23]=1[CH3:24]
Reactant: COC(=O)c1ccc2sc(C)c(C(O)c3ccc(Cl)cc3Cl)c2c1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc2sc(C)c(Cc3ccc(Cl)cc3Cl)c2c1
Temperature: 25 °C
Reaction time: 1.17 h

Procedure:
Trifluoroacetic acid (30 ml) was cooled with ice, and sodium borohydride (537 mg, 14.2 mmol) was gradually added at 5-7° C. for 20 min under a nitrogen atmosphere. A solution of 3-((2,4-dichlorophenyl)hydroxymethyl)-5-(methoxycarbonyl)-2-methylbenzo[b]thiophene in methylene chloride was added dropwise for 50 min and the mixture was stirred at room temperature for 70 min. After the completion of the reaction, the reaction mixture was poured into ice water, and trifluoroacetic acid was neutralized with 25% aqueous solution of sodium hydroxide to make the solution alkaline. The solution was extracted with ethyl acetate, and the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The desiccant was filtered off, and the filtrate was concentrated under reduced pressure to give the objective compound (0.52 g) as colorless crystals.