Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:16])[CH2:3][CH2:4][CH2:5][NH:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=1.[C:17](Cl)(=[O:19])[CH3:18]>>[C:17]([N:6]([C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=1)[CH2:5][CH2:4][CH2:3][N:2]([CH3:1])[CH3:16])(=[O:19])[CH3:18]
Reactant: CC(=O)Cl
Reactant: CN(C)CCCNc1ccc([N+](=O)[O-])cc1
Product: CC(=O)N(CCCN(C)C)c1ccc([N+](=O)[O-])cc1

Procedure:
Prepared from 4-(3-dimethylamino-propylamino)-nitrobenzene and acetylchloride
Reaction SMILES: [C:1]([O:5]C)(=O)[CH2:2][OH:3].[NH2:7][C:8]1[S:9][CH:10]=[C:11]([CH3:13])[N:12]=1>>[OH:3][CH2:2][C:1]([NH:7][C:8]1[S:9][CH:10]=[C:11]([CH3:13])[N:12]=1)=[O:5]
Reactant: Cc1csc(N)n1
Reactant: COC(=O)CO
Product: Cc1csc(NC(=O)CO)n1

Procedure:
The title compound was prepared in a manner similar to that described for Intermediate A3, starting from methyl glycolate and 2-amino-4-methylthiazole, 1H NMR (300 MHz, CDCl3) δ 10.11 (br s, 1H), 6.55 (s, 1H), 5.58 (br s, 1H), 4.36 (s, 2H), 2.34 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=3)[C:9]([CH2:18][C:19](O)=[O:20])=[C:8]2[CH3:22])=[CH:4][CH:3]=1.C([N:27](CC)CC)C.C(OC(Cl)=O)C(C)C>C1COCC1>[Br:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=3)[C:9]([CH2:18][C:19]([NH2:27])=[O:20])=[C:8]2[CH3:22])=[CH:4][CH:3]=1
Reactant: COc1ccc2c(c1)c(CC(=O)O)c(C)n2Cc1ccc(Br)cc1
Reactant: CCN(CC)CC
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Product: COc1ccc2c(c1)c(CC(N)=O)c(C)n2Cc1ccc(Br)cc1
Reaction time: 0.25 h
Yield: 80.2 %

Procedure:
To a solution of 1-(4-bromobenzyl)-5-methoxy-2-methylindole-3-acetic acid (8.5 g, 21.9 mmol) in 85 mL of THF at -10° C. was added triethylamine (3.8 mL, 27.4 mmol) and isobutylchloroformate (3.4 mL, 26.3 mmol). The reaction mixture was stirred for 15 min. then ammonia gas was bubbled through the solution for 5 min. A white precipitate formed whiCh was collected by vacuum filtration. The solid was washed with H2O then THF to give 6.8 g (80%) of the desired amide.
Reaction SMILES: C([O:4][CH2:5][CH2:6][CH2:7][CH:8]([O:14][N+:15]([O-:17])=[O:16])[CH2:9][O:10][N+:11]([O-:13])=[O:12])(=O)C.[OH-].[Na+]>CCO>[N+:15]([O:14][CH:8]([CH2:9][O:10][N+:11]([O-:13])=[O:12])[CH2:7][CH2:6][CH2:5][OH:4])([O-:17])=[O:16]
Reactant: CC(=O)OCCCC(CO[N+](=O)[O-])O[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=[N+]([O-])OCC(CCCO)O[N+](=O)[O-]
Reaction time: 1.5 h
Yield: 40.4 %

Procedure:
To a solution of 18.7 g of 4,5-bis(nitrooxy)pentyl acetate in 150 mL of EtOH at 25° C. was added 2.96 g of NaOH. The mixture was stirred for 90 min, quenched by addition of NaHCO3 sat., extracted with EtOAc, washed with brine and dried over sodium sulfate. Purification by flash chromatography afforded 6.3 g of the desired compound as an orange oil. 1H NMR (acetone-d6, 500 MHz): δ 5.56 (m, 1H), 5.01 (dd, 1H), 4.73 (dd, 1H), 3.68 (t, 1H), 3.60 (m, 2H), 1.93-1.86 (m, 2H), 1.69-1.64 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[C:13]([NH:22][S:23]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([N+:32]([O-])=O)[CH:27]=3)(=[O:25])=[O:24])=[N:14][C:15]3[C:20]([N:21]=2)=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[Sn](Cl)(Cl)(Cl)Cl>O.CC(N(C)C)=O>[NH2:32][C:28]1[CH:27]=[C:26]([S:23]([NH:22][C:13]2[C:12]([NH:11][C:5]3[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=3)=[N:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]=2)(=[O:24])=[O:25])[CH:31]=[CH:30][CH:29]=1
Reactant: COc1cc(Nc2nc3ccccc3nc2NS(=O)(=O)c2cccc([N+](=O)[O-])c2)cc(OC)c1
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: O
Solvent: CC(=O)N(C)C
Product: COc1cc(Nc2nc3ccccc3nc2NS(=O)(=O)c2cccc(N)c2)cc(OC)c1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
A flask was charged with N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)-3-nitro-benzenesulfonamide (3.4 g, 7.06 mmol), prepared using procedures similar to those in Example 14, tin chloride solvate (6.4 g, 28.2 mmol), and 30 mL of DMA. A few drops of water were added and the reaction mixture was stirred at 80° C. for 3 hours, after which time, solvent was removed on a rotary evaporator, and 50 mL of water and 10 mL of Methanol were added. The slurry was filtered, and the filtrate was washed with MeOH, water, and diethyl ether (20 mL of each), resulting in 3.25 g 3-amino-N-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2-yl)benzenesulfonamide. 1H NMR (400 MHz, DMSO) δ 12.2 (br s, 1H), 8.85 (s, 1H), 7.90 (br s, 1H), 7.50-7.60 (m, 1H), 7.3-7.4 (m, 4H), 7.2 (m, 3H), 6.74 (m, 1H), 6.24 (m, 1H), 5.56 (br s, 2H), 3.76 (s, 6H). MS (EI) m/z for C22H21N5O4S: 452.0 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]=[CH:10][C:11]1([C:14]2([S:17][CH2:18][CH2:19][CH3:20])[CH2:16][CH2:15]2)[CH2:13][O:12]1.[NH:21]1[CH:25]=[N:24][CH:23]=[N:22]1>CN(C)C=O.C(OCC)(=O)C.C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1/[CH:9]=[CH:10]/[C:11]([C:14]1([S:17][CH2:18][CH2:19][CH3:20])[CH2:16][CH2:15]1)([OH:12])[CH2:13][N:21]1[CH:25]=[N:24][CH:23]=[N:22]1
Reactant: CCCSC1(C2(C=Cc3ccc(Cl)cc3Cl)CO2)CC1
Reactant: c1nc[nH]n1
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCSC1(C(O)(/C=C/c2ccc(Cl)cc2Cl)Cn2cncn2)CC1
Temperature: 80 °C
Reaction time: 6 h
Yield: 25.3 %

Procedure:
A solution of 38.2 g (0.12 mol) of 2-(2,4-dichlorophenyl-ethenyl)-2-(1-propylmercaptocyclopropyl)-oxirane in 30 ml of dimethylformamide is added dropwise at 80° C. under a nitrogen atmosphere and with stirring to a mixture of 24 g (0.35 mol) of 1,2,4-triazole, 2.7 g (0.02 mol) of potassium tert.-butylate and 50 ml of dimethylformamide. The mixture is stirred for 6 hours at 80° C., then the solvent is stripped off under reduced pressure, and the residue is taken up in ethyl acetate/toluene, washed using water, dried over sodium sulphate and concentrated under reduced pressure. The residue remaining is chromatographed on silica gel using chloroform as eluant. In this manner, 12.1 g (26% of theory) of trans-4-(2,4-dichlorophenyl)-2-(1-propylmercaptocyclopropyl)-1-(1,2,4-triazol-1-yl)-but-3-en-2-ol are obtained in the form of an oily product.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([Br:11])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].C(Cl)(=O)C([Cl:15])=O>ClCCl>[CH3:1][C:2]1[CH:10]=[C:9]([Br:11])[CH:8]=[CH:7][C:3]=1[C:4]([Cl:15])=[O:5]
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1cc(Br)ccc1C(=O)O
Solvent: ClCCl
Product: Cc1cc(Br)ccc1C(=O)Cl

Procedure:
2-Methyl-4-bromobenzoic acid (26.8 g) was treated with oxalyl chloride (16.3 ml) in dry dichloromethane (250 ml) and the product was isolated by the method described in Example 1 (i) to give 2-methyl-4-bromobenzoyl chloride as an oil.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)[C:8]([O:11][CH2:12][CH2:13][CH2:14]Br)=[CH:9][CH:10]=1)=[O:4].[CH2:26]([N:33]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:35]([CH:42]=[N:43][OH:44])=[CH:34]1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.[OH-].[Na+]>>[CH2:26]([N:33]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:35](/[CH:42]=[N:43]/[O:44][CH2:14][CH2:13][CH2:12][O:11][C:8]2[C:7]([C:16]3[CH:17]=[CH:18][C:19]([C:22]([F:24])([F:23])[F:25])=[CH:20][CH:21]=3)=[CH:6][C:5]([C:3]([OH:2])=[O:4])=[CH:10][CH:9]=2)=[CH:34]1)[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: COC(=O)c1ccc(OCCCBr)c(-c2ccc(C(F)(F)F)cc2)c1
Reactant: ON=Cc1cn(Cc2ccccc2)c2ccccc12
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1ccc(OCCCO/N=C/c2cn(Cc3ccccc3)c3ccccc23)c(-c2ccc(C(F)(F)F)cc2)c1
Temperature: 25 °C
Yield: 9.9 %

Procedure:
To a solution of 6-(3-bromo-propoxy)-4′-trifluoromethyl-biphenyl-3-carboxylic acid methyl ester (0.30 g, 0.72 mmol) and 1-benzyl-1H-indole-3-carbaldehyde oxime (0.18 g, 0.72 mmol) in 10/5/3 tetrahydrofuran/ethanol/water (18 mL) was added 2.5 M sodium hydroxide solution (3 mL). This mixture was heated to reflux for 2.5 hours and then allowed to cool back to room temperature. The mixture was partitioned between ethyl acetate and water. The aqueous layer was acidified to approximately pH 1 using 1 N hydrochloric acid. The layers were then separated. The aqueous layer was extracted with one additional portion of ethyl acetate. The organics were combined, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography through silica gel using ethyl acetate/hexanes (20/80 with 1% formic acid) to give 6-[3-({[(1E)-(1-benzyl-1H-indol-3-yl)methylidene]amino }oxy)propoxy]-4′-(trifluoromethyl)-1,1′-biphenyl-3-carboxylic acid (0.041 g, 10%) as a white solid. mp=193-194° C. 1H NMR (400 MHz, DMSO-d6); δ 8.24 (s, 1H), 7.94 (d, 1H), 7.90-7.86 (m, 3H), 7.78-7.74 (m, 5H), 7.40 (d, 1H), 7.25-7.11 (m, 7H), 5.43 (s, 2H), 4.26 (t, 2H), 4.23 (t, 2H), 2.49 (m, 2H). Mass spec; (ES+) m/z 5.73.1 (ES−) m/z 571.5. Elemental analysis; Calculated for C33H27F3N2O4: C, 69.22; H, 4.75; N, 4.89. Found: C, 68.62; H, 4.93; N, 4.81.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:14]([F:17])([F:16])[F:15])=[C:7]2[C:12]=1[N:11]=[C:10](O)[N:9]=[CH:8]2.P(O[Cl:22])(=O)=O>>[Cl:22][C:10]1[N:9]=[CH:8][C:7]2[C:12](=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=2[C:14]([F:17])([F:16])[F:15])[N:11]=1
Reactant: O=P(=O)OCl
Reactant: COc1ccc(C(F)(F)F)c2cnc(O)nc12
Product: COc1ccc(C(F)(F)F)c2cnc(Cl)nc12
Temperature: 25 °C
Yield: 70 %

Procedure:
The crude 8-methoxy-5-(trifluoromethyl) quinazolin-2-ol was heated in neat phosphooxychloride (POCl3) at 110° C. for 2 h. The resulted mixture was cooled to room temperature and concentrated in vacuo to nearly dryness. Ice water was added and precipitate was filtered, washed and dried to provide 2-chloro-8-methoxy-5-(trifluoromethyl) quinazoline as a light pink solid in 70% yield. ES/MS m/z 263.0 (MH+).
Reaction SMILES: [F:1][CH:2]([F:6])[C:3](O)=[O:4].C(C1NC=CN=1)(C1NC=CN=1)=O.[NH2:19][C:20]1[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[N:24][CH:25]=1>C(Cl)Cl>[CH3:27][O:26][C:23]1[CH:22]=[CH:21][C:20]([NH:19][C:3](=[O:4])[CH:2]([F:6])[F:1])=[CH:25][N:24]=1
Reactant: O=C(O)C(F)F
Reactant: COc1ccc(N)cn1
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: ClCCl
Product: COc1ccc(NC(=O)C(F)F)cn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Difluoracetic acid was added to a mixture of carbonyl diimidazole (8.4 g, 0.052 mol) and methylene chloride (100 ml) under a nitrogen atmosphere. Gas was evolved and a new solid formed in the reaction. After stirring at room temperature for 30 minutes, 5-amino-2-methoxypyridine (5.7 ml, 0.052 mol) was added over a two-minute period. The reacion was slightly exothermic and was stirred further for another 30 minutes when it was washed with water (100 ml), 5% aqueous acetic acid (2×50 ml), 5% sodium bicarbonate (25 ml); dried over anhydrous magnesium sulfate; filtered; and evaporated in vacuo to give an oil. The oil was extracted with ether and the ether extract on dilution with pentane gave 3.7 g of crude product. This was extracted with ether and diluted with pentane to give 2.0 g of the title compound, m.p. 75°-78° C. The title product was identified by IR, NMR and MS analysis.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].C([O:11][C:12](=[O:25])[NH:13][C:14]1[C:19]([CH2:20][CH3:21])=[CH:18][C:17](Br)=[CH:16][C:15]=1[CH2:23][CH3:24])(C)(C)C.[Cl:26][C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1>O.CC(C)=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([C:17]2[CH:16]=[C:15]([CH2:23][CH3:24])[C:14]([NH:13][C:12](=[O:25])[OH:11])=[C:19]([CH2:20][CH3:21])[CH:18]=2)=[CH:29][CH:28]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: CCc1cc(Br)cc(CC)c1NC(=O)OC(C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: CC(C)=O
Solvent: O
Product: CCc1cc(-c2ccc(Cl)cc2)cc(CC)c1NC(=O)O
Temperature: 25 °C

Procedure:
A solution of cesium carbonate (89.12 g, 0.27 mol) in water (600 ml) is added to a degassed solution of (4-bromo-2,6-diethylphenyl)carbamic acid tert-butyl ester (30 g, 0.091 mol) and 4-chlorophenylboronic acid (21.54 g, 0.138 mol) in acetone (3000 ml), and the mixture is stirred at room temperature under an atmosphere of nitrogen. Palladium acetate (1.02 g, 0.004 mol) and 2-(dicyclohexylphosphino)-2′,4′,6′-tri-iso-propyl-1,1′-biphenyl (4.33 g, 0.009 mol) are added and the reaction mixture is stirred at room temperature for 12 hours. The mixture is filtered through diatomaceous earth, and the filtrate is evaporated under reduced pressure to remove most of the acetone. The remaining solution is extracted with ethyl acetate (3×300 ml). The organic extracts are combined and concentrated under reduced pressure to give (4′-chloro-3,5-diethylbiphen-4-yl)carbamic acid tent-butyl ester (22 g).
Reaction SMILES: [CH:1]1(B(O)O)[CH2:3][CH2:2]1.CN(C1C=CC=CN=1)C.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[N:26]1([C:32]2[N:33]=[C:34]([CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41])[NH:35][C:36](=[O:38])[CH:37]=2)[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1.Cl>C1(C)C=CC=CC=1.C([O-])(=O)C.[Cu+2].C([O-])(=O)C.ClCCl>[CH:1]1([N:35]2[C:36](=[O:38])[CH:37]=[C:32]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)[N:33]=[C:34]2[CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41])[CH2:3][CH2:2]1
Reactant: OB(O)C1CC1
Reactant: CCOC(=O)Cc1nc(N2CCOCC2)cc(=O)[nH]1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: CN(C)c1ccccn1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CCOC(=O)Cc1nc(N2CCOCC2)cc(=O)n1C1CC1
Temperature: 95 °C
Yield: 7.8 %

Procedure:
643 mg of cyclopropylboronic acid, 680 g of copper(II) acetate, 1.37 g of dimethylaminopyridine and, finally, 6.23 ml of a solution of sodium bis(trimethylsilyl)amide (0.6M in toluene) are added, using a dropping funnel, to a solution of 1 g of ethyl [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate, prepared in step 1d of example 1d, in 12 ml of toluene. The reaction mixture is heated at 95° C. for 16 and then cooled to ambient temperature. After the addition of 20 ml of an aqueous 1N hydrochloric acid solution and extraction with dichloromethane (3×50 ml), the organic phases are combined and then dried over magnesium sulfate, filtered through sintered glass, and concentrated under reduced pressure. The residue is purified by silica column chromatography, elution being carried out with a mixture of dichloromethane and methanol (98/02 then 95/05 V/V). 90 mg of ethyl (1-cyclopropyl-4-morpholin-4-yl-6-oxo-1,6-dihydropyrimidin-2-yl)acetate are obtained in the form of a yellow oil, used as it is in the next step.
Reaction SMILES: [C:1]([C:3]1[C:4]([NH:34][CH2:35][CH2:36][O:37][CH3:38])=[CH:5][C:6]([NH:9][C:10]([N:12]2[C:21]3[C:16](=[CH:17][C:18]([N:27]4[CH2:31][CH2:30][CH:29]([CH3:32])[C:28]4=[O:33])=[C:19]([CH:22](OC)[O:23]C)[N:20]=3)[CH2:15][CH2:14][CH2:13]2)=[O:11])=[N:7][CH:8]=1)#[N:2].Cl>C1COCC1.O>[C:1]([C:3]1[C:4]([NH:34][CH2:35][CH2:36][O:37][CH3:38])=[CH:5][C:6]([NH:9][C:10]([N:12]2[C:21]3[C:16](=[CH:17][C:18]([N:27]4[CH2:31][CH2:30][CH:29]([CH3:32])[C:28]4=[O:33])=[C:19]([CH:22]=[O:23])[N:20]=3)[CH2:15][CH2:14][CH2:13]2)=[O:11])=[N:7][CH:8]=1)#[N:2]
Reactant: COCCNc1cc(NC(=O)N2CCCc3cc(N4CCC(C)C4=O)c(C(OC)OC)nc32)ncc1C#N
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: COCCNc1cc(NC(=O)N2CCCc3cc(N4CCC(C)C4=O)c(C=O)nc32)ncc1C#N
Reaction time: 4 h

Procedure:
To a solution of (racemic) N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-7-(dimethoxymethyl)-6-(3-methyl-2-oxopyrrolidin-1-yl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide (intermediate 330, 63 mg, 0.120 mmol) in THF (0.9 ml) and water (0.3 mL) was added 37% aqueous HCl (0.1 mL, 3.29 mmol) at room temperature and the reaction mixture was stirred for 4 h. The reaction mixture was quenched by the addition of saturated aqueous Na2CO3 and diluted with DCM. Phases were separated and the water phase was extracted with DCM. The combined organic layers were dried using Na2SO4, filtered and solvents were concentrated. The crude product was precipitated from DCM and EtOAc, filtered and dried to yield the title compound as a yellow solid.
Reaction SMILES: [N:1]1([CH2:6][CH:7]2[C:16]3[C:11](=[C:12]([O:17][CH3:18])[CH:13]=[CH:14][CH:15]=3)[CH2:10][CH2:9][NH:8]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:19][C:20]1[CH:21]=[C:22]([CH2:27][C:28](O)=[O:29])[CH:23]=[CH:24][C:25]=1[Cl:26].C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[N:1]1([CH2:6][C:7]2([C:28](=[O:29])[CH2:27][C:22]3[CH:23]=[CH:24][C:25]([Cl:26])=[C:20]([Cl:19])[CH:21]=3)[C:16]3[C:11](=[C:12]([O:17][CH3:18])[CH:13]=[CH:14][CH:15]=3)[CH2:10][CH2:9][NH:8]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)Cc1ccc(Cl)c(Cl)c1
Reactant: COc1cccc2c1CCNC2CN1CCCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: COc1cccc2c1CCNC2(CN1CCCC1)C(=O)Cc1ccc(Cl)c(Cl)c1

Procedure:
Prepared as Ex. No. 1, from 1.2 g (4.88 mmoles) of 1-(pyrrolidin-1-yl)methyl-5-methoxy-1,2,3,4-tetrahydroisoquinoline, 1.1 g (5.37 mmoles) of 3,4-dichlorophenylacetic acid and 2.2 g (10.68 mmoles) of dicyclohexylcarbodiimide in 50 ml of dry methylene chloride.
Reaction SMILES: [BH4-].[Li+].C[O:4][C:5]([C@@H:7]1[C@@H:11]([O:12][CH3:13])[CH2:10][N:9]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:8]1)=O>C1COCC1>[C:17]([O:16][C:14]([N:9]1[CH2:10][C@H:11]([O:12][CH3:13])[C@@H:7]([CH2:5][OH:4])[CH2:8]1)=[O:15])([CH3:20])([CH3:19])[CH3:18]
Reactant: COC(=O)[C@H]1CN(C(=O)OC(C)(C)C)C[C@@H]1OC
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CO[C@H]1CN(C(=O)OC(C)(C)C)C[C@@H]1CO
Temperature: 60 °C
Yield: 91.9 %

Procedure:
Lithium borohydride (12.7 g, 4 eq) was added portionwise to a solution of (3S,4R)-4-methoxy-pyrrolidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester (35.81 g, 138.1 mmol) in THF (600 mL), then the reaction was heated to 60° C. for 4 hrs. The reaction was quenched with water at 0° C. and extracted with EtOAc. The organic layer was washed with sat. NaCl and dried over Na2SO4. The solvent was removed and the residue was purified through a plug of SiO2 (3:1 EtOAc/heptane) to yield the title compound as a clear oil (29.35 g, 92% yield). 1H NMR (400 MHz, chloroform-d) δ ppm 1.46 (s, 9H) 2.37-2.47 (m, 1H) 3.19 (dd, J=11.08, 5.29 Hz, 1H) 3.33 (d, J=4.03 Hz, 4H) 3.50-3.66 (m, 4H) 3.77-3.83 (m, 1H). m/z (APCI+) for product minus Boc (C6H13NO2) 132.2 (M+H)+. Specific Rotation: [a]D=+9.3 degrees (C=0.86, MeOH).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5].C(=O)([O-])[O-].[Na+].[Na+].C(N1[C:22](=[O:23])[C:21]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:20]2[C:19]1=[O:28])(OCC)=O>O>[CH:25]1[CH:24]=[C:21]2[C:22]([N:1]([CH2:2][CH2:3][C:4]([OH:6])=[O:5])[C:19](=[O:28])[C:20]2=[CH:27][CH:26]=1)=[O:23]
Reactant: NCCC(=O)O
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=C(O)CCN1C(=O)c2ccccc2C1=O
Reaction time: 1.5 h
Yield: 63.6 %

Procedure:
To a stirred mixture of β-alanine (4.45 g, 50.0 mmoL) and sodium carbonate (5.35 g, 50.5 mmoL) in 100 mL of water is added N-carbethoxyphthalimide (10.95 g, 50.0 mmoL). After 1.5 hour, the reaction slurry is filtered. The filtrate is stirred and the pH adjusted to 1-2 with 4N hydrochloric acid. After 15 minutes, the resulting slurry is filtered and the solid washed with water. The solid is dried in vacuo (60° C., <1 mm) to afford 6.96 g (64%) of N-phthaloyl-β-alanine, which can be alternatively named as 3-phthalimidopropionic acid, as a white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH3:26])=[C:6]([C@@:8]2([F:24])[C:16]3[C:11](=[CH:12][C:13]([C:17]([F:20])([F:19])[F:18])=[CH:14][CH:15]=3)[N:10]([CH2:21]Cl)[C:9]2=[O:23])[CH:7]=1.C(#N)C.[C:30]([OH:34])(=[O:33])[CH2:31][OH:32].C(=O)([O-])[O-].[Cs+].[Cs+]>C(OCC)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH3:26])=[C:6]([C@@:8]2([F:24])[C:16]3[C:11](=[CH:12][C:13]([C:17]([F:20])([F:19])[F:18])=[CH:14][CH:15]=3)[N:10]([CH2:21][O:34][C:30](=[O:33])[CH2:31][OH:32])[C:9]2=[O:23])[CH:7]=1
Reactant: O=C(O)CO
Reactant: COc1ccc(Cl)cc1[C@]1(F)C(=O)N(CCl)c2cc(C(F)(F)F)ccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: CCOCC
Product: COc1ccc(Cl)cc1[C@]1(F)C(=O)N(COC(=O)CO)c2cc(C(F)(F)F)ccc21
Temperature: 25 °C
Reaction time: 36 h
Yield: 57.5 %

Procedure:
To a 10 mL flask containing (S)-3-(5-chloro-2-methoxy-phenyl)-1-chloromethyl-3-fluoro-6-trifluoromethyl-1,3-dihydro-indol-2-one ((S)-V) (0.200 g, 0.489 mmol) was added 3 mL anhydrous acetonitrile, glycolic acid (0.045 g, 0.588 mmol) and cesium carbonate (0.079 g, 0.245 mmol). The reaction was stirred for 36 hours at room temperature, then the organic layer was diluted with 5 mL diethyl ether and the organic solution was decanted away from the solid cesium chloride. The solvent was evaporated in vacuo and the resulting white foam was purified by flash chromatography (silica gel 4:1 hexanes:acetone) producing the title compound (0.126 g, 58%) as a white powder. 1H NMR (CDCl3 400 MHz): δ=7.79 (s, 1H), 7.38-7.33 (m, 3H), 7.26 (d, 1H, J=7 Hz), 6.75 (d, 1H, J=7 Hz), 5.99 (d, 1H, J=12 Hz), 5.91 (d, 1H, J=12 Hz), 4.26 (s, 2H), 3.49 (s, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1[NH:12][C:13]([C:16](=[O:27])[NH:17][CH:18]2[CH2:23][CH2:22][N:21]([CH:24]([CH3:26])[CH3:25])[CH2:20][CH2:19]2)=[CH:14][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:35][C:36]1[CH:40]=[C:39]([C:41]2[S:42][C:43]([Cl:46])=[CH:44][CH:45]=2)[O:38][N:37]=1>CN(C=O)C>[CH2:1]([O:8][C:9]([C:11]1[N:12]([CH2:35][C:36]2[CH:40]=[C:39]([C:41]3[S:42][C:43]([Cl:46])=[CH:44][CH:45]=3)[O:38][N:37]=2)[C:13]([C:16](=[O:27])[NH:17][CH:18]2[CH2:23][CH2:22][N:21]([CH:24]([CH3:25])[CH3:26])[CH2:20][CH2:19]2)=[CH:14][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)N1CCC(NC(=O)c2ccc(C(=O)OCc3ccccc3)[nH]2)CC1
Reactant: Clc1ccc(-c2cc(CBr)no2)s1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)N1CCC(NC(=O)c2ccc(C(=O)OCc3ccccc3)n2Cc2cc(-c3ccc(Cl)s3)on2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 49.1 %

Procedure:
To a solution of 5-(1-isopropyl-piperidin-4-ylcarbamoyl)-1H-pyrrole-2-carboxylic acid benzyl ester (20 mg) in DMF (1 mL) was added Cs2CO3 μl mg). The mixture was stirred for 30 min at RT. 3-Bromomethyl-5-(5-chloro-thiophen-2-yl)-isoxazole (15 mg) was added and stirring was continued for 20 h at RT whereupon the mixture was filtered. The filtrate was directly subjected to preparative HPLC(CH3CN/H2O gradient+0.05% TFA). Pure 1-[5-(5-Chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-5-(1-isopropyl-piperidin-4-ylcarbamoyl)-1H-pyrrol e-2-carboxylic acid benzyl ester (15 mg) was obtained as its trifluoroacetate salt. MS (ESI+): m/e=567 [M+H]+, chloro pattern.
Reaction SMILES: [Br:1]N1C(=O)NC(=O)N(Br)C1=O.[F:12][C:13]1[C:18]([OH:19])=[C:17]([CH:20]=[O:21])[CH:16]=[CH:15][C:14]=1[C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>CN(C=O)C>[Br:1][C:15]1[C:14]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)=[C:13]([F:12])[C:18]([OH:19])=[C:17]([CH:20]=[O:21])[CH:16]=1
Reactant: O=Cc1ccc(-c2ccc(F)cc2)c(F)c1O
Reactant: O=c1[nH]c(=O)n(Br)c(=O)n1Br
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=Cc1cc(Br)c(-c2ccc(F)cc2)c(F)c1O
Reaction time: 3 h
Yield: 122.4 %

Procedure:
Dibromoisocyanuric acid (1.49 g) was added at room temperature to a DMF (50 mL) solution of 2,4′-difluoro-3-hydroxybiphenyl-4-carbaldehyde (2.02 g), and the mixture was stirred at the same temperature as above for 3 hours in a nitrogen atmosphere. A saturated aqueous solution of sodium thiosulfate was added to the reaction mixture at room temperature, followed by extraction with ethyl acetate. The obtained organic layer was washed with water and saturated saline in this order and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (1.99 g).