Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:8][CH2:9][CH:10]1[CH2:15][CH2:14][N:13]([C:16]2[N:20]([CH3:21])[N:19]=[CH:18][C:17]=2[NH:22][C:23]([C:25]2[N:26]=[C:27](Br)[S:28][C:29]=2[NH:30]C(=O)OC(C)(C)C)=[O:24])[CH2:12][CH2:11]1)=O)CCC.[F:39][C:40]1[CH:41]=[CH:42][C:43]([OH:49])=[C:44](B(O)O)[CH:45]=1>>[NH2:30][C:29]1[S:28][C:27]([C:42]2[CH:41]=[C:40]([F:39])[CH:45]=[CH:44][C:43]=2[OH:49])=[N:26][C:25]=1[C:23]([NH:22][C:17]1[CH:18]=[N:19][N:20]([CH3:21])[C:16]=1[N:13]1[CH2:12][CH2:11][CH:10]([CH2:9][NH2:8])[CH2:15][CH2:14]1)=[O:24]
Reactant: OB(O)c1cc(F)ccc1O
Reactant: CCCCOC(=O)NCC1CCN(c2c(NC(=O)c3nc(Br)sc3NC(=O)OC(C)(C)C)cnn2C)CC1
Product: Cn1ncc(NC(=O)c2nc(-c3cc(F)ccc3O)sc2N)c1N1CCC(CN)CC1
Yield: 20 %

Procedure:
Following the procedure for Example 278 starting with tert-butyl 4-(5-(4-(butyloxycarbonylaminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-ylcarbamoyl)-2-bromothiazol-5-ylcarbamate and 5-fluoro-2-hydroxyphenylboronic acid gave 297 as an off-white solid (18 mg, 20%). 1H NMR (400 MHz, d4-MeOD) δ 7.64 (dd, J=9.6, 3.1 Hz, 1H), 7.49 (s, 1H), 6.96 (td, J=4.8, 3.1 Hz, 1H), 6.90 (dd, J=9.6, 4.8 Hz, 1H), 3.74 (s, 3H), 3.27-3.12 (m, 4H), 2.66 (d, J=6.5 Hz, 2H), 1.86 (d, J=12.5 Hz, 2H), 1.69-1.42 (m, 1H), 1.45-1.36 (m, 2H). LCMS (ES+) m/z 446 (M+1).
Reaction SMILES: [CH3:1][C:2]1(C)S[C@@H]2[C@H](NC([C@H](N)C3C=CC=CC=3)=O)C(=O)N2[C@H:3]1[C:21]([OH:23])=[O:22].CC(S[C@@H]1[O:34][C@H](CO)[C@H](O)[C@H](O)[C@H]1O)C.[Si]([CH:44]=[N+:45]=[N-])(C)(C)C>CCOC(C)=O>[OH:34][C@H:2]([CH2:1][C:44]#[N:45])[CH2:3][C:21]([OH:23])=[O:22]
Reactant: CC(C)S[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: CC1(C)S[C@@H]2[C@H](NC(=O)[C@H](N)c3ccccc3)C(=O)N2[C@H]1C(=O)O
Solvent: CCOC(C)=O
Product: N#CC[C@@H](O)CC(=O)O
Reaction time: 18 h

Procedure:
Putative nitrilase up-mutants were assayed in triplicate. Each transformant was grown in 5 mL LB (100 μg/mL ampicillin), at 37° C., 220 rpm for 18 h. The overnight culture was diluted 2-fold and nitrilase expression induced at 37° C., 220 rpm with 0.1 mM IPTG for 6 h. Cells were harvested by centrifugation, washed in 100 mM pH 7 sodium phosphate buffer and then re-suspended in 1 mL of 100 mM HGN in 100 mM pH 7 sodium phosphate buffer. Reactions were allowed to proceed for at least 36 h at 22° C. with gentle agitation. Reaction progress was monitored by TLC (1:1 EtOAc:Hexanes, Rf=0.5, nitrile; Rf=0.0, acid). Cells and other debris were removed by centrifugation and the treated with one volume methanol prior to lyophilization. The lyophilizate was re-suspended in methanol and treated with TMS-diazomethane (10 equivalents, 2 M solution in hexanes) until gas evolution ceased and yellow color persisted in order to prepare the methyl ester for GC analysis. Selected nitrilase variants producing (R)-(−)-3-hydroxy-4-cyanobutyric acid of 95% ee or greater were then evaluated for performance at 2.25 M HGN.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[N:8]([CH3:11])[CH:9]=[CH:10][C:5]2=[CH:4][CH:3]=1.[Li]C(C)(C)C.CCCCC.[B:22](OC)([O:25]C)[O:23]C>C1COCC1.O>[Cl:1][C:2]1[N:7]=[C:6]2[C:5]([CH:10]=[C:9]([B:22]([OH:25])[OH:23])[N:8]2[CH3:11])=[CH:4][CH:3]=1
Reactant: COB(OC)OC
Reactant: Cn1ccc2ccc(Cl)nc21
Agent: [Li]C(C)(C)C
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCC
Product: Cn1c(B(O)O)cc2ccc(Cl)nc21
Temperature: -78 °C
Reaction time: 2 h
Yield: 163.1 %

Procedure:
To a solution of 6-chloro-1-methyl-1H-pyrrolo[2,3-b]pyridine (1.02 g, 6.12 mmol)) in THF (60 mL) at −78° C. was added 1.7 M t-BuLi in pentane (9.00 mL, 15.31 mmol) and the mixture was stirred at −78° C. for 2 h. Trimethyl borate (1.026 mL, 9.18 mmol) was added at −78° C. and the mixture was allowed to warm to room temperature, and stirred at room temperature overnight. Water (2 mL) was added and the mixture was concentrated in vacuo. The solid was subjected to high vacuum overnight to afford 2.1 g of 6-chloro-N-methyl-7-aza indole-2-boronic acid. ESI-MS: m/z 211.1 (M+H)+
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](Cl)=[N:7]2.[CH3:13][C:14]1[O:18][C:17]([CH2:19][NH2:20])=[CH:16][CH:15]=1.[F:21][C:22]1[CH:29]=[CH:28][C:25]([CH:26]=[CH2:27])=[CH:24][CH:23]=1>>[F:21][C:22]1[CH:29]=[CH:28][C:25](/[CH:26]=[CH:27]/[C:2]2[CH:11]=[CH:10][CH:9]=[C:8]3[C:3]=2[CH:4]=[CH:5][C:6]([NH:20][CH2:19][C:17]2[O:18][C:14]([CH3:13])=[CH:15][CH:16]=2)=[N:7]3)=[CH:24][CH:23]=1
Reactant: C=Cc1ccc(F)cc1
Reactant: Cc1ccc(CN)o1
Reactant: Clc1ccc2c(Br)cccc2n1
Product: Cc1ccc(CNc2ccc3c(/C=C/c4ccc(F)cc4)cccc3n2)o1

Procedure:
The title compound, MS: m/e=359.0 (M+H+), was prepared in accordance with the general method of example 2 from 5-bromo-2-chloroquinoline, 5-methyl-2-furanmethanamine and 4-fluorostyrene.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[C@@H:4]2[CH2:5][C:6]3[C:10]([C@H:3]12)=[C:9]([CH3:11])[S:8][C:7]=3[C:12](=[O:14])[CH3:13].[CH2:16]([C:18]1[CH:19]=[C:20]([CH:23]=[C:24]([CH2:27][CH3:28])[C:25]=1[OH:26])[CH:21]=O)[CH3:17].COC([C@@H](NC([C@@H](N)CC(O)=O)=O)CC1C=CC=CC=1)=O.Cl.Cl>C(O)C.C(O)(C)C.CC(=O)OCC>[CH2:16]([C:18]1[CH:19]=[C:20]([CH2:21][CH2:13][C:12]([C:7]2[S:8][C:9]([CH3:11])=[C:10]3[C:6]=2[CH2:5][C@H:4]2[C:2]([CH3:15])([CH3:1])[C@H:3]23)=[O:14])[CH:23]=[C:24]([CH2:27][CH3:28])[C:25]=1[OH:26])[CH3:17]
Reactant: CCc1cc(C=O)cc(CC)c1O
Reactant: CC(=O)c1sc(C)c2c1C[C@@H]1[C@H]2C1(C)C
Agent: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N)CC(=O)O
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: CCc1cc(CCC(=O)c2sc(C)c3c2C[C@@H]2[C@H]3C2(C)C)cc(CC)c1O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of (1aS,5aR)-1-(1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pen-talen-4-yl)-ethanone (890 mg, 4.04 mmol) and 3,5-diethyl-4-hydroxy-benzaldehyde (900 mg, 5.05 mmol, Lit: G. Trapani, A. Latrofa, M. Franco, C. Altomare, E. Sanna, M. Usal, G. Biggio, G. Liso J. Med. Chem. 41 (1998) 1846-1854; G. G. Ecke, J. P. Napolitano, A. H. Bilbey, A. J. Kolka, J. Org. Chem. 22 (1957) 639-642) in ethanol (7.5 mL) and 5 N HCl in isopropanol (2.5 mL) is stirred at rt for 72 h. The mixture is diluted with EA and is washed with water. The sovent of the organic layer is evaporated, the residue is dissolved in ethanol, treated with Pd/C (200 mg, 10% Pd) and stirred at rt for 18 h under 1.8 bar H2. The mixture is filtered, the filtrate is concentrated and the crude product is purified by CC on silica gel eluting with heptane:EA 8:2 to give 3-(3,5-diethyl-4-hydroxy-phenyl)-1-((1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalen-4-yl)-propan-1-one (1.05 g) as a yellow oil; LC-MS: tR=1.15 min, [M+1]+=383.25.
Reaction SMILES: [N+:1]([CH:4]1[C:13]23S[C:6]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)([C:7](=[O:18])[N:8]2[CH2:9][CH2:10][C:11]2[CH:17]=[CH:16][S:15][C:12]=23)[CH2:5]1)([O-])=O.C[O-].[Na+].[S-2].[Na+].[Na+]>CO>[NH2:1][C:4]1[CH:5]=[C:6]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:7](=[O:18])[N:8]2[C:13]=1[C:12]1[S:15][CH:16]=[CH:17][C:11]=1[CH2:10][CH2:9]2
Reactant: O=C1N2CCc3ccsc3C23SC1(c1ccccc1)CC3[N+](=O)[O-]
Agent: C[O-]
Agent: [Na+]
Agent: [S-2]
Solvent: CO
Product: Nc1cc(-c2ccccc2)c(=O)n2c1-c1sccc1CC2
Reaction time: 4 h

Procedure:
3.2 g of 4,5,9,10-tetrahydro-10-nitro-8-phenyl-8,10a-epithio-10aH-thieno[2,3-a]quinolizin-7(8H)-one was suspended in 300 ml of methanol. The suspension was treated while stirring with a solution of sodium methylate in methanol (prepared from 4.46 g of sodium and 5 ml of methanol) and subsequently with a solution of 14 g of sodium sulfide in 40 ml of methanol, whereby there results a dark solution which is held at 60° for 4 hours. After the methanol is removed by distillation in vacuo, the residue was taken up in water. The solution was extracted with chloroform and the organic phase was washed with saturated aqueous sodium chloride solution. The organic phase was dried over magnesium sulfate, evaporated in vacuo and the product was chromatographed on silica gel with toluene/acetone (9:1). There was obtained 10-amino-4,5-dihydro-8-phenyl-7H-thieno[2,3-a]quinolizin-7-one of m.p. 180.5°-181.5° (from toluene).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:15][CH2:16][C:17]2[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=2[F:24])[C:5]2[N:6]([C:8]([C:12](O)=[O:13])=[C:9]([CH3:11])[N:10]=2)[CH:7]=1.[NH2:25][C@H:26]([CH2:29][CH2:30][CH2:31][OH:32])[CH2:27][OH:28].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O.O>[Cl:1][C:2]1[CH:3]=[C:4]([O:15][CH2:16][C:17]2[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=2[F:24])[C:5]2[N:6]([C:8]([C:12]([NH:25][C@H:26]([CH2:29][CH2:30][CH2:31][OH:32])[CH2:27][OH:28])=[O:13])=[C:9]([CH3:11])[N:10]=2)[CH:7]=1
Reactant: Cc1nc2c(OCc3c(F)cccc3F)cc(Cl)cn2c1C(=O)O
Reactant: N[C@@H](CO)CCCO
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc2c(OCc3c(F)cccc3F)cc(Cl)cn2c1C(=O)N[C@@H](CO)CCCO
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Under argon, 70 mg (0.20 mmol) of 6-chloro-8-[(2,6-difluorobenzyl)oxy]-2-methylimidazo[1,2-a]-pyridine-3-carboxylic acid were dissolved in 0.63 ml of dry dimethylformamide, 33.1 mg (0.28 mmol, 1.4 equivalents) of (2R)-2-aminopentan-1,5-diol, 98 μl of diisopropylethylamine (0.60 mmol, 3 equivalents) and 98 mg of HATU (0.26 mmol, 1.3 equivalents) were added and the mixture was stirred at room temperature overnight. A little water was then added, and the mixture was purified directly by preparative HPLC (Method 10). This gave 31.4 mg of the target compound (35% of theory).
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([N:11]2[CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[C:20]([F:23])([F:22])[F:21])[C:12]2=[O:24])[C:8](O)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.[C:31]([O:35][C:36](=[O:45])[CH2:37][CH2:38][N:39]1[CH:43]=[CH:42][C:41]([NH2:44])=[N:40]1)([CH3:34])([CH3:33])[CH3:32].N1C(C)=CC=CC=1C>C(Cl)Cl.CN(C)C=O>[C:31]([O:35][C:36](=[O:45])[CH2:37][CH2:38][N:39]1[CH:43]=[CH:42][C:41]([NH:44][C:8](=[O:9])[C@@H:7]([N:11]2[CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[C:20]([F:22])([F:21])[F:23])[C:12]2=[O:24])[CH2:6][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)=[N:40]1)([CH3:34])([CH3:32])[CH3:33]
Reactant: O=C(O)[C@H](CC1CCCC1)N1Cc2c(cccc2C(F)(F)F)C1=O
Reactant: CC(C)(C)OC(=O)CCn1ccc(N)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: Cc1cccc(C)n1
Product: CC(C)(C)OC(=O)CCn1ccc(NC(=O)[C@H](CC2CCCC2)N2Cc3c(cccc3C(F)(F)F)C2=O)n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 93.5 %

Procedure:
A solution of (S)-3-cyclopentyl-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-propionic acid (prepared as in Example 1, 100 mg, 0.29 mmol,) in methylene chloride (4 mL) and N,N-dimethylformamide (4 drops) was treated with a solution of oxalyl chloride in methylene chloride (2.0 M, 150 μL, 0.30 mmol) and stirred for 15 min at room temperature. After this time, the reaction mixture was then concentrated in vacuo and the resulting residue was dissolved in methylene chloride (4 mL) and then added dropwise to a separate reaction flask containing a mixture of 3-(3-amino-pyrazol-1-yl)-propionic acid tert-butyl ester (prepared as in US 20080021032, Example 8, 92 mg, 0.44 mmol) and 2,6-lutidine (100 μL, 0.87 mmol) in methylene chloride (3 mL) at room temperature. The resulting reaction mixture was the stirred room temperature for 2 h. The reaction mixture was quenched by the addition of methanol and then diluted with methylene chloride and then washed with a 1 N aqueous hydrochloric acid solution. The organic layer was then dried over sodium sulfate, filtered and the filtrate was then concentrated in vacuo with silica gel (2.0 g). The silica gel with absorbed material was placed in a SIM and purified via Biotage flash column chromatography (40 S silica gel column, 25% ethyl acetate/hexanes) to afford 3-{3-[(S)-3-cyclopentyl-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-propionylamino]-pyrazol-1-yl}-propionic acid tert-butyl ester (145 mg, 94%) as a white foam: HR-ES(+) m/e calcd for C27H33N4O4F3 [M+H]+ 535.2527, observed 535.2526; 1H NMR (400 MHz, DMSO-d6) δ 10.91 (s, 1H), 8.01 (dd, J=7.67, 12.79 Hz, 2H), 7.71-7.82 (m, 1H), 7.56 (d, J=2.13 Hz, 1H), 6.39 (d, J=2.13 Hz, 1H), 4.96-5.14 (m, 2H), 4.71 (d, J=18.33 Hz, 1H), 4.19 (t, J=6.50 Hz, 2H), 2.72 (t, J=6.61 Hz, 2H), 0.77-2.09 (m, 20H).
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:5]1[N:10]=[CH:9][C:8]([OH:11])=[C:7]([O:12][CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[CH:6]=1)[CH3:4].[C:18]([O-:21])([OH:20])=O.[Na+].[C:23](Cl)(=[O:31])[O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.O>C(Cl)Cl>[CH:13]1([O:12][C:7]2[C:8]([O:11][C:18]([O:21][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[O:20])=[CH:9][N:10]=[C:5]([CH:3]([CH3:4])[CH2:2][NH:1][C:23](=[O:31])[O:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:6]=2)[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: O=C([O-])O
Reactant: CC(CN)c1cc(OC2CCCC2)c(O)cn1
Reactant: O=C(Cl)Oc1ccccc1
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CC(CNC(=O)Oc1ccccc1)c1cc(OC2CCCC2)c(OC(=O)Oc2ccccc2)cn1
Temperature: 2.5 °C
Yield: 103.2 %

Procedure:
A mixture of (±)-6-(2-amino-1-methylethyl)4-(cyclopentyloxy)-3-pyridinol (0.037 mol) and NaHCO3 (0.0814 mol) in CH2Cl2 (200 ml) was stirred at 0-5° C. A solution of phenyl carbonochloridate (0.074 mol) in CH2Cl2(50 ml) was added dropwise and the resulting reaction mixture was stirred for one hour at RT. The reaction mixture was poured out into water and the layers were separated. The aqueous phase was extracted twice with CH2Cl2. The combined organic layers were dried, filtered and the solvent evaporated, yielding 18.2 g (±)-phenyl [2-[4-(cyclopentyloxy)-5-[(phenoxycarbonyl) oxy]-2-pyridinyl]propyl]carbamate (interm. 1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[CH:11][C:12]([NH:15][C:16]([C:18]3[C:19](=[O:31])[N:20]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[N:21]([CH3:24])[C:22]=3[CH3:23])=[O:17])=[N:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.CCN(CC)CC.[C:39](Cl)(=O)[O:40]C1C=CC=CC=1.[NH:49]1[CH2:54][CH2:53][O:52][CH2:51][CH2:50]1>C1COCC1>[CH3:24][N:21]1[C:22]([CH3:23])=[C:18]([C:16]([NH:15][C:12]2[N:13]=[CH:14][C:9]([O:8][C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:1][C:39]([N:49]4[CH2:54][CH2:53][O:52][CH2:51][CH2:50]4)=[O:40])[CH:7]=3)=[CH:10][CH:11]=2)=[O:17])[C:19](=[O:31])[N:20]1[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: C1COCCN1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Cc1c(C(=O)Nc2ccc(Oc3ccnc(N)c3)cn2)c(=O)n(-c2ccccc2)n1C
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1c(C(=O)Nc2ccc(Oc3ccnc(NC(=O)N4CCOCC4)c3)cn2)c(=O)n(-c2ccccc2)n1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 18.4 %

Procedure:
To a suspension of N-(5-((2-aminopyridin-4-yl)oxy)pyridin-2-yl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (171 mg, 0.41 mmol) and Et3N (0.17 mL, 1.23 mmol) in THF (8.0 mL) was added phenyl carbonochloridate (0.15 mL, 1.23 mmol). The mixture was stirred at rt for 2 hours, then morpholine (0.21 mL, 2.46 mmol) was added. The reaction mixture was stirred rt for 24 hours and partitioned between aq NH4Cl (40 mL) and DCM (40 mL). The organic phase was separated and the aqueous phase was extracted with DCM (40 mL×3). The combined organic phases were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (MeOH/EtOAc (v/v)=1/50) and TLC (MeOH/EtOAc (v/v)=1/30) to give the title compound as a pale yellow solid (40 mg, 18%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][C:3]=1[F:17].[CH2:18]([O:20][C:21]1[CH:22]=[C:23]([CH:26]=[C:27]([N+:30]([O-:32])=[O:31])[C:28]=1[OH:29])[CH:24]=O)[CH3:19].[NH2:33][C:34]([NH2:36])=[O:35].Cl>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:36][C:34](=[O:35])[NH:33][CH:24]([C:23]3[CH:26]=[C:27]([N+:30]([O-:32])=[O:31])[C:28]([OH:29])=[C:21]([O:20][CH2:18][CH3:19])[CH:22]=3)[C:9]=2[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][C:3]=1[F:17]
Reactant: NC(N)=O
Reactant: O=C(Cc1ccccc1)c1ccc(Cl)c(F)c1
Reactant: CCOc1cc(C=O)cc([N+](=O)[O-])c1O
Agent: Cl
Solvent: CCO
Product: CCOc1cc(C2NC(=O)NC(c3ccc(Cl)c(F)c3)=C2c2ccccc2)cc([N+](=O)[O-])c1O
Yield: 9.3 %

Procedure:
To a solution of 1-(4-chloro-3-fluorophenyl)-2-phenylethanone (Intermediate 16) (100 mg, 0.40 mmol), 3-ethoxy-4-hydroxy-5-nitrobenzaldehyde (79.5 mg, 0.40 mmol), and urea (73.2 mg, 1.20 mmol) in 5 mL of ethanol was added 0.2 mL of concentrated HCl solution, and the mixture was refluxed for 2 days. After the solvent was removed under reduced pressure, the residue was purified by reverse-phase preparatory HPLC (26-53% acetonitrile+0.1% trifluoroacetic acid in water+0.1% trifluoroacetic acid, over 15 min.) to give Compound 43 (18 mg, yield 9.3%). 1H NMR (DMSO-d6 300 MHz) δ 10.29 (s, 1H), 8.83 (s, 1H), 7.57 (s, 1H), 7.44 (m, 2H), 7.28 (d, J=9.9 Hz, 1H), 7.13-6.86 (m, 4H), 5.26 (s, 1H), 4.04 (m, 2H), 1.32 (t, J=6.3 Hz, 3H); MS (ESI): m/z 483.9 [M+1]+.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][C:4]=1[C:13]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:14]=1[CH2:15][CH2:16][NH:17][CH2:18]2.[F:23][C:24]1[S:28][C:27]([NH:29][S:30](N2C=CN=C2)(=[O:32])=[O:31])=[N:26][CH:25]=1.C(N(CC)CC)C>C1COCC1.CCOC(C)=O>[Br:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][C:4]=1[C:13]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:14]=1[CH2:15][CH2:16][N:17]([S:30]([NH:29][C:27]1[S:28][C:24]([F:23])=[CH:25][N:26]=1)(=[O:32])=[O:31])[CH2:18]2
Reactant: FC(F)(F)c1ccc(Br)c(-c2cccc3c2CCNC3)c1
Reactant: O=S(=O)(Nc1ncc(F)s1)n1ccnc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=S(=O)(Nc1ncc(F)s1)N1CCc2c(cccc2-c2cc(C(F)(F)F)ccc2Br)C1
Yield: 38.1 %

Procedure:
A solution of 5-(2-bromo-5-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline hydrochloride (Intermediate T, 0.200 g, 0.509 mmol), N-(5-fluorothiazol-2-yl)-1H-imidazole-1-sulfonamide (Intermediate N, 0.506 g, 2.037 mmol), and triethylamine (1.420 ml, 10.19 mmol) in 3 mL THF was heated to 80° C. for 30 minutes. The reaction mixture was diluted with EtOAc and washed with 1N citric acid. The organics were dried over MgSO4 and concentrated. Purification of the resulting residue by silica gel column chromatography (0 to 100% EtOAc/heptane) gave 5-(2-bromo-5-(trifluoromethyl)phenyl)-N-(5-fluorothiazol-2-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide (0.104 g, 0.194 mmol).
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[CH2:7]/[N:8]=[CH:9]/[CH2:10][C:11]([CH3:15])([CH3:14])[CH:12]=[CH2:13])([CH3:4])([CH3:3])[CH3:2].[Cl:17][C:18]1[C:19]([F:36])=[C:20](/[CH:24]=[C:25](/[C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=2[F:35])\[C:26]#[N:27])[CH:21]=[CH:22][CH:23]=1.C(N(CC)CC)C>ClCCl>[C:1]([O:5][C:6]([CH:7]1[CH:24]([C:20]2[CH:21]=[CH:22][CH:23]=[C:18]([Cl:17])[C:19]=2[F:36])[C:25]([C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=2[F:35])([C:26]#[N:27])[CH:9]([CH2:10][C:11]([CH3:15])([CH3:14])[CH:12]=[CH2:13])[NH:8]1)=[O:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: N#C/C(=C\c1cccc(Cl)c1F)c1ccc(Cl)cc1F
Reactant: C=CC(C)(C)C/C=N/CC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CC(C)(C)CC1NC(C(=O)OC(C)(C)C)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Yield: 28.6 %

Procedure:
In a manner similar to the method described in Example 1c, [3,3-dimethyl-pent-4-en-(E)-ylideneamino]-acetic acid tert-butyl ester prepared in Example 80a (2.1 g, 9.3 mmol) was reacted with (Z)-3-(3-chloro-2-fluoro-phenyl)-2-(4-chloro-2-fluoro-phenyl)-acrylonitrile (2 g, 6.4 mmol) prepared in Example 52a, AgF (0.9 g, 7.1 mmol), and triethylamine (1.5 g, 15 mmol) in dichloromethane (150 mL) at room temperature for 18 h 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-but-3-enyl)-pyrrolidine-2-carboxylic acid tert-butyl ester as a white foam (0.98 g, 56%).
Reaction SMILES: [C:1]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=[O:13])[CH2:2][C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4].Br[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]Br.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.O>[C:2]1([C:1]([O:14][CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[O:13])([C:3]([O:5][CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[O:4])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: O=C(CC(=O)OCc1ccccc1)OCc1ccccc1
Reactant: BrCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: O=C(OCc1ccccc1)C1(C(=O)OCc2ccccc2)CCCCC1

Procedure:
A solution of dibenzyl malonate (40 g, 161 mmol), 1,5-dibromopentane (22 mL, 161 mmol) and potassium carbonate (56 g, 402 mmol) in 300 mL of DMSO was stirred for 48 h in an oil bath at 50° C. The mixture was diluted with water and extracted with ethyl acetate (2×). The combined organic portions were dried over magnesium sulfate and concentrated. Flash chromatography (400 g silica, 15/1 hexane/EtOAc) gave the desired product. 1H NMR (500 MHz, CDCl3) δ1.4-1.5 (m, 1H), 1.52-1.6 (m, 5H), 2.03-2.1 (m, 4H), 5.13 (s, 4H), 7.22-7.38 (m, 10H).
Reaction SMILES: Br[C:2]([Cl:29])([CH:11]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:12][O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].[CH2:30]([NH:37][CH:38]([CH3:40])[CH3:39])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(#N)C>CCOCC>[ClH:29].[CH2:30]([N:37]([CH:38]([CH3:40])[CH3:39])[C:2]([Cl:29])([CH:11]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:12][O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CC(C)NCc1ccccc1
Reactant: O=C(c1ccccc1)C(Cl)(Br)C(COCc1ccccc1)OCc1ccccc1
Solvent: CCOCC
Solvent: CC#N
Product: CC(C)N(Cc1ccccc1)C(Cl)(C(=O)c1ccccc1)C(COCc1ccccc1)OCc1ccccc1
Product: Cl

Procedure:
A solution of 9.5 g. (0.02 m.) of the above α-bromobutyrophenone and 6.0 g. (0.04 m.) of N-benzylisopropylamine in 60 ml. of acetonitrile is stirred at 25°C. for 1 hour. The mixture is diluted with ether and filtered to remove N-benzylisopropylamine hydrobromide. The filtrate is treated with ethereal hydrogen chloride to give α-(N-benzylisopropylamino)-2-chloro-3,4-dibenzyloxybutyrophenone hydrochloride.