Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@:3]12[CH2:11][CH2:10][C@@H:9]3[C:12]4[CH:13]=[CH:14][C:15]([O:20][CH3:21])=[CH:16][C:17]=4[CH2:18][CH2:19][C@H:8]3[C@@H:7]1[CH2:6][CH2:5][C@@H:4]2[O:22][CH2:23][CH2:24][OH:25])[CH3:2].N1C=CC=CC=1.[CH3:32][S:33](Cl)(=[O:35])=[O:34]>CO.O>[CH3:32][S:33]([OH:35])(=[O:20])=[O:34].[CH2:1]([C@:3]12[CH2:11][CH2:10][C@@H:9]3[C:12]4[CH:13]=[CH:14][C:15]([O:20][CH3:21])=[CH:16][C:17]=4[CH2:18][CH2:19][C@H:8]3[C@@H:7]1[CH2:6][CH2:5][C@@H:4]2[O:22][CH2:23][CH2:24][OH:25])[CH3:2]
Reactant: CS(=O)(=O)Cl
Agent: CC[C@]12CC[C@@H]3c4ccc(OC)cc4CC[C@H]3[C@@H]1CC[C@@H]2OCCO
Solvent: O
Solvent: CO
Solvent: c1ccncc1
Product: CS(=O)(=O)O
Reaction time: 2 h

Procedure:
Stir a cooled solution of 344 mg. of dl-13-ethyl-17β-(2-hydroxyethoxy)-3-methoxygona-1,3,5(10)-triene in 2 ml. of pyridine (acetone-dry ice bath) and add dropwise 0.14 ml. of methanesulfonyl chloride. After 2 hours bring reaction mixture to room temperature. Mix with ice and water and a few drops of methanol to obtain a crystalline precipitate. Recrystallize this to obtain dl-13-ethyl-17β-(2-hydroxyethoxy)-3-methoxygona-1,3,5(10)-triene methane sulfonate from methanol (310 mg); m.p. 104°.
Reaction SMILES: C([C:4]1([CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:9][CH2:8][CH2:7][CH2:6][C:5]1=[O:10])(=O)C.OO.S(=O)(=O)(O)[OH:21]>C(O)(C)(C)C>[CH2:16]([O:15][C:13]([CH2:12][CH2:11][C:4]1([C:5]([OH:10])=[O:21])[CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:14])[CH3:17]
Reactant: CCOC(=O)CCC1(C(C)=O)CCCCC1=O
Reactant: O=S(=O)(O)O
Agent: OO
Solvent: CC(C)(C)O
Product: CCOC(=O)CCC1(C(=O)O)CCCC1
Reaction time: 24 h

Procedure:
To a solution of 2-acetyl-2-[2-(ethoxycarbonyl)-ethyl]-cyclohexanone (see Preparation 4) (40 g, 0.16 mol) in tert-butanol (85 ml) was added, dropwise, a 30% aqueous solution of hydrogen peroxide (21.7 ml, 0.19 mol) and concentrated sulfuric acid (0.25 ml, 98% w/w) at room temperature. The mixture was further stirred for 24 hours, partitioned between dichloromethane (100 ml) and distilled water (100 ml) and the layers separated. The dichloromethane layer was washed with 5% aqueous sodium sulphite solution, dried over magnesium sulphate, filtered and concentrated under reduced pressure to give a yellow oil, (34.35 g). Purification of this material by chromatography on silica by eluting with ethyl acetate/hexane (1:2 changing to 1:1), followed by neat ethyl acetate in the latter stages, gave, after combination and evaporation of appropriate fractions, the title compound as a yellow oil, (22.96 g, 67%). RF. 0.28 (silica, ethyl acetate/hexane, 1:1). 1H-NMR (300 MHz, CDCl3):=1.31 (t, 3H), 1.47-1.62 (m, 2H), 1.62-1.82 (m, 4H), 1.92-2.08 (m, 2H), 2.10-2.27 (m, 2H), 2.32-2.46 (m, 2H), 4.19 (q, 2H) ppm. 13 C-NMR (75.5 MHz, CDCl3):=14.26, 25.15, 31.21, 33.56, 36.15, 53.21, 60.49, 173.38, 183.52 ppm.
Reaction SMILES: [C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1)([O:3][CH3:4])=[O:2].[CH3:13][C:14]1[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][C:15]=1[NH2:16]>C(O)C>[C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[N:16][C:15]2[CH:17]=[CH:18][CH:19]=[C:20]([Cl:21])[C:14]=2[CH3:13])=[CH:7][CH:6]=1)([O:3][CH3:4])=[O:2]
Reactant: Cc1c(N)cccc1Cl
Reactant: COC(=O)c1ccc(C=O)cc1
Solvent: CCO
Product: COC(=O)c1ccc(C=Nc2cccc(Cl)c2C)cc1
Reaction time: 0.25 h

Procedure:
p-carbomethoxybenzaldehye (0.20 moles) was treated with 2-methyl-3-chloroaniline (0.20 moles) with vigorous stirring in a 1 liter Erlenmeyer flask. After 15 mins., 33 cc of 95% ethanol was added and the reaction mixture was stirred vigorously for an additional 45 mins. The reaction mixture was left standing at room temperature for 10 min., then it was placed in an ice bath for 0.5 hours. The crystals which formed were collected, washed with 95% ethanol, and air dried. Recrystallization from 95% ethanol gave N-(p-carbomethoxybenzylidene)-2-methyl-3-chloroaniline.
Reaction SMILES: [C:1]12([CH2:11][NH:12][C:13](=[O:25])[C:14]3[CH:19]=[C:18]([CH2:20][CH2:21][CH:22]=O)[CH:17]=[N:16][C:15]=3[Cl:24])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[NH2:26][C@H:27]([CH3:30])[CH2:28][OH:29].C([BH3-])#N.[Na+]>CO.C(O)(=O)C>[C:1]12([CH2:11][NH:12][C:13](=[O:25])[C:14]3[CH:19]=[C:18]([CH2:20][CH2:21][CH2:22][NH:26][C@H:27]([CH3:30])[CH2:28][OH:29])[CH:17]=[N:16][C:15]=3[Cl:24])[CH2:2][CH:3]3[CH2:4][CH:5]([CH2:6][CH:7]([CH2:9]3)[CH2:8]1)[CH2:10]2
Reactant: C[C@@H](N)CO
Reactant: O=CCCc1cnc(Cl)c(C(=O)NCC23CC4CC(CC(C4)C2)C3)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: C[C@H](CO)NCCCc1cnc(Cl)c(C(=O)NCC23CC4CC(CC(C4)C2)C3)c1
Yield: 73 %

Procedure:
The titled compound was prepared from N-(1-adamantylmethyl)-2-chloro-5-(3-oxopropyl)nicotinamide (Example 3(ii)) (0.10 g), (R)-2-aminopropanol (0.046 g) and sodium cyanoborohydride (0.020 g) in methanol (3 ml) and acetic acid (0.1 ml) by the method of Example 3(iii). The product was purified by chromatography on silica gel eluting with 0.7M anhydrous ammonia in methanol:ethyl acetate (1:5) to afford the titled compound as an oil (0.085 g).
Reaction SMILES: Cl[C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[Cl:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16]Br)=[CH:14][C:13]=1[C:20]([F:23])([F:22])[F:21].[F:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][C:32]=1[F:33])[CH2:28][NH2:29]>>[Cl:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16][N:6]2[C:5]3[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=3[N:3]=[C:2]2[NH:29][CH2:28][C:27]2[CH:30]=[CH:31][C:32]([F:33])=[C:25]([F:24])[CH:26]=2)=[CH:14][C:13]=1[C:20]([F:23])([F:22])[F:21]
Reactant: NCc1ccc(F)c(F)c1
Reactant: Clc1nc2ccccc2[nH]1
Reactant: FC(F)(F)c1cc(CBr)ccc1Cl
Product: Fc1ccc(CNc2nc3ccccc3n2Cc2ccc(Cl)c(C(F)(F)F)c2)cc1F

Procedure:
The title compound was prepared by Procedure B in two steps from 2-chloro-benzimidazole, 4-chloro-3-trifluoromethylbenzyl bromide and 3,4-difluorobenzylamine. The product was isolated by preparative LCMS to give the title compound as the free base (off-white solid, mp 158-161° C.). MS(ES+) m/z 452 ([M+1]+, 100). 1NMR (DMSO-d6) δ 4.55 (s, 2H), 5.36 (s, 2H), 6.87-6.98 (m, 2H), 7.13-7.37 (m, 6H), 7.50-7.55 (m, 1H), 7.68-7.71 (m, 2H).
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2[C:5](=[C:7]3[N:39]=[C:38]4[N:40]=[C:31]([C:32]5[CH:33]=[CH:34][CH:35]=[CH:36][C:37]=54)[N:30]=[C:28]4[NH:29][C:21]([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:27]=54)=[N:20][C:18]4=[N:19][C:11]([C:12]5[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=54)=[N:10][C:9]=2[NH:8]3)[CH:6]=1.N=C1C2C(=CC=CC=2)C(=N)N1.C1C=C(C#N)C(C#N)=CC=1.[O-:62]CCC.[O-]CCC.[O-]CCC.[O-]CCC.[Ti+4:78]>CN1CCCC1=O>[CH:2]1[CH:3]=[C:4]2[C:9]3[N-:8][C:7]([C:5]2=[CH:6][CH:1]=1)=[N:39][C:38]1=[N:40][C:31]([C:32]2[C:37]1=[CH:36][CH:35]=[CH:34][CH:33]=2)=[N:30][C:28]1=[N:29][C:21]([C:22]2[C:27]1=[CH:26][CH:25]=[CH:24][CH:23]=2)=[N:20][C:18]1[N-:19][C:11](=[C:12]2[C:17]=1[CH:16]=[CH:15][CH:14]=[CH:13]2)[N:10]=3.[O-2:62].[Ti+4:78]
Reactant: CCC[O-]
Reactant: c1ccc2c(c1)-c1nc-2nc2[nH]c(nc3nc(nc4[nH]c(n1)c1ccccc41)-c1ccccc1-3)c1ccccc21
Agent: [Ti+4]
Agent: N#Cc1ccccc1C#N
Agent: N=C1NC(=N)c2ccccc21
Solvent: CN1CCCC1=O
Product: [O-2]
Product: c1ccc2c(c1)-c1nc3nc(nc4[n-]c(nc5[n-]c(nc-2n1)c1ccccc51)c1ccccc41)-c1ccccc1-3
Temperature: 198 °C

Procedure:
A Type I titanyl phthalocyanine was prepared as follows: To a 300 milliliter three-necked flask fitted with mechanical stirrer, condenser and thermometer maintained under an argon atmosphere was added 3.6 grams (0.025 mole) of 1,3-diiminoisoindoline, 9.6 grams (0.075 mole) of o-phthalonitrile, 75 milliliters (80 weight percent) of N-methylpyrrolidone and 7.11 grams (0.025 mole) of titanium tetrapropoxide (all obtained from Aldrich Chemical Company except phthalonitrile which was obtained from BASF). The resulting mixture (20 weight percent of solids) was stirred and warmed to reflux (about 198° C.) for 2 hours. The resultant black suspension was cooled to about 150° C. and then was filtered by suction through a 350 milliliter, M-porosity sintered glass funnel, which had been preheated with boiling dimethyl foramide (DMF). The solid Type I TiOPc product resulting was washed with two 150-milliliter portions of boiling DMF and the filtrate, initially black, became a light blue-green color. The solid was slurried in the funnel with 150 milliliters of boiling DMF and the suspension was filtered. The resulting solid was washed in the funnel with 150 milliliters of DMF at 25° C. and then with 50 milliliters of methanol. The resultant shiny purple solid was dried at 70° C. overnight to yield 10.9 grams (76 percent) of pigment, which was identified as Type I TiOPc on the basis of its X-ray powder diffraction trace. Elemental analysis of the product indicated C, 66.54; H, 2.60; N, 20.31; and Ash (TiO2), 13.76. TiOPc requires (theory): C, 66.67; H, 2.80; N, 19.44; and Ash, 13.86.
Reaction SMILES: C(N(C(C)C)C(C)C)C.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.[F:28][C:29]1[C:34]([O:35][CH3:36])=[CH:33][CH:32]=[CH:31][C:30]=1[C:37]1[CH:41]=[C:40]([CH2:42][CH2:43][C@@:44]([CH3:52])([S:48]([CH3:51])(=[O:50])=[O:49])[C:45](O)=[O:46])[O:39][N:38]=1.[O:53]1[CH2:58][CH2:57][CH2:56][CH2:55][CH:54]1[O:59][NH2:60]>CN(C1C=CN=CC=1)C.C(OCC)(=O)C.O>[F:28][C:29]1[C:34]([O:35][CH3:36])=[CH:33][CH:32]=[CH:31][C:30]=1[C:37]1[CH:41]=[C:40]([CH2:42][CH2:43][C@@:44]([CH3:52])([S:48]([CH3:51])(=[O:49])=[O:50])[C:45]([NH:60][O:59][CH:54]2[CH2:55][CH2:56][CH2:57][CH2:58][O:53]2)=[O:46])[O:39][N:38]=1
Reactant: COc1cccc(-c2cc(CC[C@](C)(C(=O)O)S(C)(=O)=O)on2)c1F
Reactant: NOC1CCCCO1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: COc1cccc(-c2cc(CC[C@](C)(C(=O)NOC3CCCCO3)S(C)(=O)=O)on2)c1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 44.4 %

Procedure:
N,N-Dimethy-4-aminopyridine (0.04 g, 0.3 mmol, 0.3 equiv), N-ethyl-N-isopropylpropan-2-amine (0.89 mL, 5.2 mmol, 4.5 equiv), T3P® (50% w/w solution in ethyl acetate, 2.7 mL, 4.5 mmol, 4.0 equiv), and (2R)-4-[3-(2-fluoro-3-methoxyphenyl)isoxazol-5-yl]-2-methyl-2-(methylsulfonyl)butanoic acid (0.42 g, 1.1 mmol, 1.0 equiv) were allowed to stir at room temperature for 30 min. A solution of O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (0.15 g, 1.2 mmol, 1.2 equiv) in ethyl acetate (12 mL) was added, and the reaction was allowed to stir overnight (18 h) at room temperature. Water (40 mL) was added, and the mixture was extracted with ethyl acetate (2×50 mL). The combined organic phases were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography (25 g silica gel column, 0-100% gradient ethyl acetate in hexanes) to provide (2R)-4-[3-(2-fluoro-3-methoxyphenyl)isoxazol-5-yl]-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide as a tan solid (0.23 g, 42%). MS (LCMS) m/z 469.1 (M−1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:18]=[N:17][CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:31][CH:32]1[CH2:37][CH2:36][CH2:35][CH:34]([OH:38])[CH:33]1[OH:39]>CS(C)=O>[OH:39][CH:33]1[CH:34]([OH:38])[CH2:35][CH2:36][CH2:37][CH:32]1[NH:31][C:12](=[O:14])[C:11]1[CH:15]=[CH:16][N:17]=[CH:18][C:10]=1[NH:9][C:3]1[CH:4]=[CH:5][C:6]([I:8])=[CH:7][C:2]=1[F:1]
Reactant: NC1CCCC(O)C1O
Reactant: O=C(O)c1ccncc1Nc1ccc(I)cc1F
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CS(C)=O
Product: O=C(NC1CCCC(O)C1O)c1ccncc1Nc1ccc(I)cc1F
Temperature: 25 °C
Reaction time: 12 h

Procedure:
3-(2-Fluoro-4-iodo-phenylamino)-isonicotinic acid (300 mg, 0.84 mmol.) and 1,1′-carbonylbis(1H-imidazole) (177 mg, 1.1 mmol) were suspended in DMSO (4 ml). The mixture was allowed to stir overnight (12 hr) at room temperature. 3-aminocyclohexane-1,2-diol (racemic 27/28) (110 mg, 0.84 mmol) was then added. The mixture was stirred for another 12 h at room temperature. The mixture was separated by preparative HPLC to afford two products, racemic amide (3) and racemic esters (4). LC/MS [Method A: rt: 6.01 min; m/z: 472 (M+1)]. Chiral HPLC [7.10 min, 13.12 min].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.Cl[C:16]1[N:25]=[C:24]2[C:19]([C:20](=[O:38])[C:21]([C:33]([O:35]CC)=[O:34])=[CH:22][N:23]2[C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)=[CH:18][C:17]=1[F:39]>C(O)C>[F:39][C:17]1[CH:18]=[C:19]2[C:24](=[N:25][C:16]=1[N:12]1[CH2:13][CH2:14][N:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[O:2][CH3:1])[CH2:10][CH2:11]1)[N:23]([C:26]1[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=1)[CH:22]=[C:21]([C:33]([OH:35])=[O:34])[C:20]2=[O:38]
Reactant: CCOC(=O)c1cn(-c2ccc(F)cc2)c2nc(Cl)c(F)cc2c1=O
Reactant: COc1ccccc1N1CCNCC1
Solvent: CCO
Product: COc1ccccc1N1CCN(c2nc3c(cc2F)c(=O)c(C(=O)O)cn3-c2ccc(F)cc2)CC1
Yield: 63.1 %

Procedure:
In 40 ml of ethanol was dissolved 0.81 g (0.0042 mole) of 1-(2-methoxyphenyl)piperazine, and to the solution was added gradually 1.02 g (0.0028 mole) of ethyl 7-chloro-6-fluoro-1-(4-fluorophenyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3carboxylate at 30° C. while stirring. After completion of the addition, the mixture was reacted at the same temperature for 4 hours. After the reaction mixture was cooled, crystals precipitated were collected by filtration and washed with ethanol. To the crystals were added 12 ml of a 6N hydrochloric acid aqueous solution, and the mixture was refluxed by heating for 6 hours. After cooling, the reaction mixture was adjusted to pH 8.5 with a 1N sodium hydroxide aqueous solution, and crystals precipitated were collected by filtration and applied to silica gel column chromatography (the eluent used was a mixture of chloroform:methanol=9.5:0.5) to obtain 0.87 g of the title compound as slightly yellow powder.
Reaction SMILES: [CH2:1]([N:5]1C[CH2:9][CH2:8][CH2:7][C:6]1=O)[CH:2]([CH3:4])[CH3:3].CS(O)(=O)=O.[C:17](=[O:20])([O-])[O-:18].[Na+].[Na+].[Br:23][C:24]1[CH:25]=[CH:26][C:27](F)=[C:28]([CH:31]=1)[CH:29]=[O:30].Cl>CS(C)=O.O>[Br:23][C:24]1[CH:25]=[CH:26][C:27]([N:5]([CH2:6][CH2:7][CH2:8][CH2:9][C:17]([OH:18])=[O:20])[CH2:1][CH:2]([CH3:4])[CH3:3])=[C:28]([CH:29]=[O:30])[CH:31]=1
Reactant: CC(C)CN1CCCCC1=O
Reactant: O=Cc1cc(Br)ccc1F
Reactant: O=C([O-])[O-]
Agent: CS(=O)(=O)O
Agent: Cl
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)CN(CCCCC(=O)O)c1ccc(Br)cc1C=O
Temperature: 110 °C
Reaction time: 6 h
Yield: 75.8 %

Procedure:
A mixture of 1-isobutyl-2-piperidone (8.8 g) and aqueous methanesulfonic acid solution (10.9 g/19 ml) was refluxed at 110° C. for 3 days. To the mixture which was previously cooled to room temperature, were added water (10 ml) and sodium carbonate (18.0 g) slowly. Then, after heating the mixture at 50° C. for 1 hour, DMSO (13 ml) was added. The resulting mixture was heated to 135° C., and then a solution of 5-bromo-2-fluorobenzaldehyde (11.5 g) in DMSO (15 ml) was added dropwise. After stirring at 135° C. for 6 hours, the mixture was cooled to 0° C., and the mixture was adjusted to pH 2.5 by using 6N hydrochloric acid. After ethyl acetate extraction, the organic layer was dried over magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1 to ethyl acetate) to obtain brown oil of 5-(4-bromo-2-formyl-N-isobutylanilino)pentanoic acid (15.3 g).
Reaction SMILES: Br[CH2:2][C:3]1[C:8]([C:9]([O:11]C)=O)=[CH:7][C:6]([N+:13]([O-:15])=[O:14])=[CH:5][CH:4]=1.[CH2:16]([O:23][C:24](=[O:40])[CH2:25][C@@H:26]([CH3:39])[NH:27][C:28](=[O:38])[CH2:29][NH:30]C(OC(C)(C)C)=O)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(CC)CC)C.Cl>C(#N)C>[CH2:16]([O:23][C:24](=[O:40])[CH2:25][C@@H:26]([CH3:39])[NH:27][C:28](=[O:38])[CH2:29][N:30]1[CH2:2][C:3]2[C:8](=[CH:7][C:6]([N+:13]([O-:15])=[O:14])=[CH:5][CH:4]=2)[C:9]1=[O:11])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1CBr
Reactant: C[C@H](CC(=O)OCc1ccccc1)NC(=O)CNC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: C[C@H](CC(=O)OCc1ccccc1)NC(=O)CN1Cc2ccc([N+](=O)[O-])cc2C1=O

Procedure:
Methyl 6-bromomethyl-3-nitrobenzoate (430 mg, 1.64 mmol), N-glycyl-3(R)-methyl-β-alanine benzyl ester hydrochloride 2-4 (611 mg, 2.13 mmol) and triethylamine (0.68 mL, 4.92 mmol) were stirred in acetonitrile (10 mL) for 16 hours. The solution was poured into 1N HCl and extracted with EtOAc (3×), washed with brine, dried (MgSO4) and evaporated. Purification by column chromatography eluting with EtOAc afforded 2-6 as a solid. Rf (silica; EtOAc)=0.45. ##STR60## N-{[6-Amino-2,3-dihydro-1(1H)-isoindolone-2-yl]acetyl}-3(R)-methyl-β-alanine (2-7)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=2[NH:18][C:19]([C:21]2[CH:26]=[CH:25][C:24]([S:27]([CH3:38])(=[N:29][C:30]([CH:32]3[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]3)=[O:31])=[O:28])=[CH:23][CH:22]=2)=[O:20])=[O:10])=[N:6][CH:7]=1.[C:39](Cl)(=[O:41])[CH3:40]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=2[NH:18][C:19]([C:21]2[CH:22]=[CH:23][C:24]([S:27]([CH3:38])(=[N:29][C:30]([CH:32]3[CH2:37][CH2:36][N:35]([C:39](=[O:41])[CH3:40])[CH2:34][CH2:33]3)=[O:31])=[O:28])=[CH:25][CH:26]=2)=[O:20])=[O:10])=[N:6][CH:7]=1
Reactant: CS(=O)(=NC(=O)C1CCNCC1)c1ccc(C(=O)Nc2ccc(Cl)cc2C(=O)Nc2ccc(Cl)cn2)cc1
Reactant: CC(=O)Cl
Product: CC(=O)N1CCC(C(=O)N=S(C)(=O)c2ccc(C(=O)Nc3ccc(Cl)cc3C(=O)Nc3ccc(Cl)cn3)cc2)CC1
Yield: 87 %

Procedure:
Product of Example 25 was acetylated using standard N-acetylating procedure with acetyl chloride to give titled compound in 87% yield.
Reaction SMILES: [Si]([O:8][C@H:9]([C@H:33]1[CH2:37][C@@H:36](OCCC)[CH2:35][N:34]1C(OC(C)(C)C)=O)[C@@H:10]([NH:20][C:21](=[O:32])[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([O:30]C)=O)[CH:23]=1)[CH2:11][C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[C:14]([F:19])[CH:13]=1)(C(C)(C)C)(C)C.CNC(=O)[C:52]1[CH:60]=[CH:59][CH:58]=[C:54](C(N)=O)[CH:53]=1.[Si](O[C@H:70]([C@H:93]1[CH2:97][C@@H](OCCC)CN1C(OC(C)(C)C)=O)[C@@H:71]([NH:81][C:82](=O)C1C=CC=C(C(=O)N)C=1)CC1C=C(F)C=C(F)C=1)(C(C)(C)C)(C)C>CO.[Pd]>[CH2:71]([N:81]([CH3:82])[C:28](=[O:30])[C:24]1[CH:25]=[CH:26][CH:27]=[C:22]([C:21]([NH:20][C@@H:10]([CH2:11][C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[C:14]([F:19])[CH:13]=2)[C@H:9]([OH:8])[C@H:33]2[CH2:37][CH:36]([C:52]3[CH:53]=[CH:54][CH:58]=[CH:59][CH:60]=3)[CH2:35][NH:34]2)=[O:32])[CH:23]=1)[CH2:70][CH2:93][CH3:97]
Reactant: CNC(=O)c1cccc(C(N)=O)c1
Reactant: CCCO[C@@H]1C[C@H]([C@@H](O[Si](C)(C)C(C)(C)C)[C@H](Cc2cc(F)cc(F)c2)NC(=O)c2cccc(C(N)=O)c2)N(C(=O)OC(C)(C)C)C1
Reactant: CCCO[C@@H]1C[C@H]([C@@H](O[Si](C)(C)C(C)(C)C)[C@H](Cc2cc(F)cc(F)c2)NC(=O)c2cccc(C(=O)OC)c2)N(C(=O)OC(C)(C)C)C1
Agent: [Pd]
Solvent: CO
Product: CCCCN(C)C(=O)c1cccc(C(=O)N[C@@H](Cc2cc(F)cc(F)c2)[C@H](O)[C@H]2CC(c3ccccc3)CN2)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Step 7 (B): Preparation of N1-butyl-N3-((1R,2S)-3-(3,5-difluorophenyl)-1-hydroxy-1(2R)-4-phenylpyrrolidin-2-yl)propan-2-yl)-N1-methylisophthalamide. To a solution of (R)-tert-butyl 2-((1S,2S)-1-(tert-butyldimethylsilyloxy)-2-(3-(carbamoyl)benzamido)-3-(3,5-difluorophenyl)propyl)-4-phenyl-2,3-dihydropyrrole-1-carboxylate (Step 7 (A), 15 mg) in MeOH (1 mL) was added a catalytic amount of Pd on activated charcoal (10 wt %, 10 mg). The reaction mixture was put on hydrogenator at 50 psi for 3 h. The mixture was then filtered and concentrated in vacuo. To the above residue were added dioxane (0.5 mL) and 2 drops of H2O and the mixture was stirred at rt for 2 h. Solvent was removed and the mixture was purified by reverse phase HPLC to give the title compound (9 mg): 1H NMR (CDCl3, 500 MHz) δ 0.77 (2H, m), 1.03 (2H, m), 1.14 (1H, dd, J=10, 15 Hz), 1.45 (1H, dd, J=5, 15 Hz), 1.54 (1H, m), 1.69 (1H, m), 2.33 (1H, m), 2.58 (1H, m), 2.89 (1H, m), 2.94 (1H, s), 3.09 (1H, s), 3.23-3.29 (2H, m), 3.44 (1H, dd, J=5, 15 Hz), 3.57 (2H, m), 3.74 (1H, m), 4.00 (1H, m), 4.17 (1H, m), 4.26 (1H, m), 6.74 (1H, t, J=10 Hz), 6.89 (2H, d, J=10 Hz), 7.31 (1H, m), 7.36-7.40 (4H, m), 7.53-7.56 (2H, m), 7.67 (1H, s), 7.76-7.78 (1H, m). MS (ESI) (M+H)+ 550.31.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][C:11]1[N:12]([CH2:22][C:23](O)=[O:24])[C:13]2[C:18]([C:19](=[O:21])[N:20]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2.[CH3:26][C:27]([N:33]1[CH2:38][CH2:37][CH:36]([NH:39][CH2:40][C:41]2[CH:46]=[CH:45][C:44]([C:47]3[CH:52]=[CH:51][C:50]([C:53]([F:56])([F:55])[F:54])=[CH:49][CH:48]=3)=[CH:43][CH:42]=2)[CH2:35][CH2:34]1)([CH3:32])[C:28]([O:30][CH3:31])=[O:29].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(#N)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][C:11]1[N:12]([CH2:22][C:23]([N:39]([CH2:40][C:41]2[CH:46]=[CH:45][C:44]([C:47]3[CH:48]=[CH:49][C:50]([C:53]([F:55])([F:56])[F:54])=[CH:51][CH:52]=3)=[CH:43][CH:42]=2)[CH:36]2[CH2:37][CH2:38][N:33]([C:27]([CH3:26])([CH3:32])[C:28]([O:30][CH3:31])=[O:29])[CH2:34][CH2:35]2)=[O:24])[C:13]2[C:18]([C:19](=[O:21])[N:20]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2
Reactant: COC(=O)C(C)(C)N1CCC(NCc2ccc(-c3ccc(C(F)(F)F)cc3)cc2)CC1
Reactant: O=C(O)Cn1c(CCc2ccc(F)cc2F)nc(=O)c2ccccc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C(C)(C)N1CCC(N(Cc2ccc(-c3ccc(C(F)(F)F)cc3)cc2)C(=O)Cn2c(CCc3ccc(F)cc3F)nc(=O)c3ccccc32)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 57 %

Procedure:
mixture of [2-[2-(2,4-difluorophenyl)ethyl]-4-oxo-1(4H)-quinazolinyl]acetic acid (Int. C3) (100 mg, 1 equiv), methyl 2-methyl-2-[4-({[4′-(trifluoromethyl)-4-biphenylyl]methyl}-amino)-1-piperidinyl]propanoate (Int. B1) (130 mg, 1.03 equiv), DIPEA (0.1 ml, 2 equiv), acetonitrile (2 ml) and HATU (130 mg, 1.4 equiv) was stirred at room temperature for 1 h, then evaporated and redissolved in acetonitrile. Purification by reverse phase HPLC (Preparative Method B) gave methyl 2-[4-({[2-[2-(2,4-difluorophenyl)ethyl]-4-oxo-1(4H)-quinazolinyl]acetyl}{[4′-(trifluoromethyl)-4-biphenylyl]methyl}amino)-1-piperidinyl]-2-methylpropanoate (126 mg).
Reaction SMILES: [S:1]1[C:5]([C:6]2[C:7](Cl)=[C:8]([CH:12]=[C:13]([N+:15]([O-:17])=[O:16])[CH:14]=2)[C:9](O)=[O:10])=[CH:4][C:3]2[CH:19]=[CH:20][CH:21]=[CH:22][C:2]1=2.[NH2:23][NH2:24]>C(O)(C)C>[S:1]1[C:5]([C:6]2[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[C:8]3[C:7]=2[NH:24][N:23]=[C:9]3[OH:10])=[CH:4][C:3]2[CH:19]=[CH:20][CH:21]=[CH:22][C:2]1=2
Reactant: O=C(O)c1cc([N+](=O)[O-])cc(-c2cc3ccccc3s2)c1Cl
Reactant: NN
Solvent: CC(C)O
Product: O=[N+]([O-])c1cc(-c2cc3ccccc3s2)c2[nH]nc(O)c2c1
Temperature: 90 °C

Procedure:
A mixture of 3-Benzo[b]thiophen-2-yl-2-chloro-5-nitro-benzoic acid (0.11 g, 0.33 mmol), hydrazine (0.35 mL) and isopropyl alcohol (3 mL) was heated to about 90° C. for about 1 hour. The mixture was cooled then the solvents were evaporated under reduced pressure. The residue was treated with 6N aqueous hydrochloric acid (5 mL) the mixture was extracted with ethyl acetate (3×30 mL). The organic extracts were combined then concentrated to give 7-Benzo[b]thiophen-2-yl-5-nitro-1H-indazol-3-ol RP-HPLC (Table 1, Method e) Rt 1.41 min; m/z: (M−H)− 310.24.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4](CC(=O)C)=[CH:3][CH:2]=1.F[C:12]1[CH:13]=C(C=[CH:18][C:19]=1[O:20]C)C=O.N1CCCCC1>C1(C)C=CC=CC=1>[N:1]1[CH:2]=[CH:3][CH:4]=[C:5]([CH2:18][C:19](=[O:20])[CH:12]=[CH2:13])[CH:6]=1
Reactant: COc1ccc(C=O)cc1F
Reactant: CC(=O)Cc1ccncc1
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Product: C=CC(=O)Cc1cccnc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 146.9 %

Procedure:
A solution of 4-pyridylacetone (1.0 g, 7.4 mmol), 3-fluoro-p-anisaldehyde (1.25 g, 8.1 mmol), and piperidine (0.13 g, 1.5 mmol) in toluene (50 ml) was heated to reflux. After 18 hours, the reaction was cooled to room temperature and the solvent was removed under reduced pressure. The crude product (3.0 g) was purified by column chromatography (silica gel, 65:35 ethyl acetate/hexane) to give 4-(3-fluoro-4-methoxy]phenyl)-3-pyridyl-3-butene-2-one as a pale yellow solid (1.60 g, 80%).