Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH2:3][N:4]=[CH:5][C:6]2([CH3:20])[CH:17]([CH3:18])[CH:15]3[CH2:16][C:10]4=[C:11]([N:14]3[CH3:19])[CH2:12][CH2:13][C:7]2=[C:8]4[CH:9]=1.C(O)(=O)C.C([BH3-])#N.[Na+].[OH-].[Na+]>O>[Cl:1][C:2]1[CH2:3][NH:4][CH2:5][C:6]2([CH3:20])[CH:17]([CH3:18])[CH:15]3[CH2:16][C:10]4=[C:11]([N:14]3[CH3:19])[CH2:12][CH2:13][C:7]2=[C:8]4[CH:9]=1
Reactant: CC1C2CC3=C(CCC4=C3C=C(Cl)CN=CC41C)N2C
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: CC1C2CC3=C(CCC4=C3C=C(Cl)CNCC41C)N2C
Reaction time: 6.75 h
Yield: 68.9 %

Procedure:
To a stirred solution of 1.50 g of 10-chloro-1,2,3,4,5,6-hexahydro-3,6,12-trimethyl-2,6-methano-9H-pyrrolo[3,2-h][3]benzazocine and 14 ml of acetic acid, cooled to 15° C. under nitrogen, was added, 1.00 g of sodium cyanoborohydride, with stirring. The reaction mixture was stirred an additional 6.75 hr and water was added. The solution was made basic (pH 12) with 50% aqueous sodium hydroxide solution. The mixture was extracted with ether and the combined organic layers were washed with brine, dried over anhydrous potassium carbonate and filtered. The filtrate was concentrated. The residue was dissolved in 15 ml acetic acid and, as above, treated with 1.63 g of sodium cyanoborohydride for 5 hr. The residue was purified by flash column chromatography (silica gel, 2% triethylamine/0-10% methanol/ether) to afford 1.04 g (69%) of product. Recrystallization from ether-dichloromethane afforded the analytical sample, mp 168°-170° C.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[N:5][CH:6]=[C:7]([CH2:9][CH3:10])[CH:8]=1.[CH3:11][C:12]1[N:17]=[C:16]([SH:18])[N:15]=[C:14]([OH:19])[CH:13]=1.C(N(CC)CC)C.CCOCC>C(O)C>[CH2:9]([C:7]1[CH:8]=[C:3]([CH2:2][S:18][C:16]2[N:15]=[C:14]([OH:19])[CH:13]=[C:12]([CH3:11])[N:17]=2)[CH:4]=[N:5][CH:6]=1)[CH3:10]
Reactant: CCc1cncc(CBr)c1
Reactant: Cc1cc(O)nc(S)n1
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CCc1cncc(CSc2nc(C)cc(O)n2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 3-(bromomethyl)-5-ethylpyridine (4.82 g, 24.08 mmol), 6-methyl-2-sulfanylpyrimidin-4-ol (2.22 g, 15.65 mmol) in anhydrous ethanol (100 mL) at 0° C. was added triethylamine (9.74 g, 13.41 mL, 96.35 mmol). The reaction mixture was allowed to stir at room temperature overnight. The solvent was evaporated to provide a crude residue. Ether was added to precipitate the triethylamine hydrobromide salt. The solid was filtered and was washed with ether several times. The solvent was evaporated to provide a crude residue, which was purified by combiflash using 0-10% MeOH:dichloromethane. 2-{[(5-ethylpyridin-3-yl)methyl]sulfanyl}-6-methylpyrimidin-4-ol was obtained as a white solid (2.83 g, 45% yield); 1H NMR (400 MHz, DMSO-d6): δ 1.14 (t, 3H), 2.21 (s, 3H), 2.61 (q, 2H), 4.35 (s, 2H), 6.00 (bs, 1H), 7.69 (s, 1H), 8.31 (s, 1H), 8.45 (s, 1H); M+261.5.
Reaction SMILES: [CH2:1]([C:3]1[N:4]=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)[NH:6][CH:7]=1)[CH3:2].[Br:15]Br.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[Br:15][C:7]1[NH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)=[N:4][C:3]=1[CH2:1][CH3:2]
Reactant: BrBr
Reactant: CCc1c[nH]c(-c2ccc(F)cc2)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCc1nc(-c2ccc(F)cc2)[nH]c1Br
Temperature: 25 °C
Reaction time: 3 h
Yield: 74.4 %

Procedure:
To a suspension of 4-ethyl-2-(4-fluorophenyl)imidazole (4.90 g) in chloroform (100 ml) was added bromine (4.53 g), and the mixture was stirred at room temperature for 3 hours. To the reaction mixture was added a saturated aqueous sodium hydrogen carbonate solution, and the organic layer was collected. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The resulting residue was crystallized from chloroform to obtain 5-bromo-4-ethyl-2-(4-fluorophenyl)-imidazole (5.16 g) as colorless crystal. 53 mg of the product was treated with 4N hydrogen chloride-dioxane solution to obtain 5-bromo-4-ethyl-2-(4-fluorophenyl)imidazole (60 mg) as colorless crystal.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]([CH2:19][CH2:20][CH2:21][C:22]([O-:24])=O)[CH2:5][N:6]2[CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].[Li+].C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[O:24]=[C:22]1[NH:1][C:2]2[C:3]3[CH:4]([CH2:5][N:6]([CH2:11][C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13])[C:7]=3[CH:8]=[CH:9][CH:10]=2)[CH2:19][CH2:20][CH2:21]1
Reactant: CC(C)(C)OC(=O)CN1CC(CCCC(=O)[O-])c2c(N)cccc21
Agent: On1nnc2cccnc21
Agent: [Li+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CN1CC2CCCC(=O)Nc3cccc1c32

Procedure:
A mixture of lithium 4-[4-amino-1-(2-tert-butoxy-2-oxoethyl)-2,3-dihydro-1H-indol-3-yl]butanoate from Step E (900 mg, 2.69 mmol), EDC (1.29 g, 6.73 mmol), HOAT (916 mg, 6.73 mmol), and N,N-diisopropylethylamine (0.94 mL, 5.38 mmol) was stirred in DMF (10 mL) at ambient temperature for 4 h, then concentrated under reduced pressure. The residue was partitioned between saturated aqueous NaHCO3 (5 mL) and EtOAc (50 mL). The organic layer was washed with H2O (5 mL), then 10% aqueous citric acid (5 mL), then dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc—80:20 to 0:100, to give the racemic product. The enantiomers were resolved by HPLC, utilizing a Chiralpak AS column and eluting with CH3CN:MeOH—25:75. The first major peak to elute was tert-butyl (6-oxo-2a,3,4,5,6,7-hexahydroazocino[4,3,2-cd]indol-1(2H)-yl)acetate, enantiomer A, the title compound, and the second major peak to elute was tert-butyl (6-oxo-2a,3,4,5,6,7-hexahydroazocino[4,3,2-cd]indol-1(2H)-yl)acetate, enantiomer B. MS: m/z=317 (M+1).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][N:11]3[C:7](=[N:8][C:9]([C:15]([NH2:17])=[O:16])=[CH:10]3)[C:6]=2[CH:18]=1.[C:19]([O:23][C:24]([N:26]1[CH:31]2[CH2:32][CH2:33][CH:27]1[CH2:28][C:29]([C:35]#[CH:36])([OH:34])[CH2:30]2)=[O:25])([CH3:22])([CH3:21])[CH3:20]>C(#N)C.C(N(CC)CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[C:15]([C:9]1[N:8]=[C:7]2[C:6]3[CH:18]=[C:2]([C:36]#[C:35][C:29]4([OH:34])[CH2:30][CH:31]5[N:26]([C:24]([O:23][C:19]([CH3:21])([CH3:20])[CH3:22])=[O:25])[CH:27]([CH2:33][CH2:32]5)[CH2:28]4)[CH:3]=[CH:4][C:5]=3[O:14][CH2:13][CH2:12][N:11]2[CH:10]=1)(=[O:16])[NH2:17]
Reactant: C#CC1(O)CC2CCC(C1)N2C(=O)OC(C)(C)C
Reactant: NC(=O)c1cn2c(n1)-c1cc(Br)ccc1OCC2
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1C2CCC1CC(O)(C#Cc1ccc3c(c1)-c1nc(C(N)=O)cn1CCO3)C2
Yield: 104.5 %

Procedure:
This compound was prepared according to a procedure similar to that described in Procedure E. In a solution of 9-Bromo-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene-2-carboxylic acid amide (300 mg, 1.0 mmol) in acetonitrile (6 mL) and triethylamine (3 mL) were added Pd(PPh3)2Cl2 (70 mg, 0.1 mmol), 3-Ethynyl-3-hydroxy-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (0.5 g, 2 mmol) and CuI (19 mg, 0.1 mmol). Then the solution was bubbled N2 for 5 min and microwaved for 2 h at 120° C. under nitrogen. The reaction mixture was filtered and the filtrate was purified by column (EtOAc/hexanes 2:1) to afford crude product (0.5 g, 99%). LCMS=479.2 [M+H]+.
Reaction SMILES: [NH2:1][CH:2]1[C:8]([CH3:10])([CH3:9])[S:7][C:6]2[CH:11]=[CH:12][CH:13]=[CH:14][C:5]=2[N:4]([CH2:15][C:16]([N:18]([CH:27]([CH3:29])[CH3:28])[C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)=[O:17])[C:3]1=[O:30].[F:31][C:32]1[CH:33]=[C:34]([N:38]=[C:39]=[O:40])[CH:35]=[CH:36][CH:37]=1>C(Cl)Cl>[F:31][C:32]1[CH:33]=[C:34]([NH:38][C:39](=[O:40])[NH:1][CH:2]2[C:8]([CH3:9])([CH3:10])[S:7][C:6]3[CH:11]=[CH:12][CH:13]=[CH:14][C:5]=3[N:4]([CH2:15][C:16]([N:18]([CH:27]([CH3:28])[CH3:29])[C:19]3[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=3)=[O:17])[C:3]2=[O:30])[CH:35]=[CH:36][CH:37]=1
Reactant: COc1ccc(N(C(=O)CN2C(=O)C(N)C(C)(C)Sc3ccccc32)C(C)C)cc1
Reactant: O=C=Nc1cccc(F)c1
Solvent: ClCCl
Product: COc1ccc(N(C(=O)CN2C(=O)C(NC(=O)Nc3cccc(F)c3)C(C)(C)Sc3ccccc32)C(C)C)cc1

Procedure:
Similarly to Example 22, to 2-(3-amino-2,2-dimethyl-4-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazepin-5-yl)-N-isopropyl-N-(4-methoxy-phenyl)-acetamide, intermediate 34 G (300 mg, 0.70 mmol) in DCM (2 mL) was added m-fluorophenyl isocyanate (0.80 mL, 0.70 mmol) to give the crude titled compound (225 mg, 57%). A sample (75 mg) was purified by RP-HPLC (40-60%, over 30 min) to give the titled product (47 mg). tR =20.9 min (40-60%, over 30 min); 1HNMR (300 MHz, d6-DMSO) d 0.96 (d, J=6.2 Hz, 3H), 1.21 (s, 6H), 3.59 (d, J=16.2 Hz, 1H), 3.76 (s, 3H), 4.26 (d, J=7.8, 1H), 4.55 (d, J=16.2, 1H), 4.80 (m, 1H), 6.74 (m, 1H), 7.19 (m, 3H), 7.20 (m, 2H), 7.32 (m, 1H), 7.49 (m, 1H), 7.60 (m, 2H), 9.03 (s, 1H); MS(FAB) m/z 565.1 (MH+).
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=1[O:19][CH3:20])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9]C)=O.[C:21]1([C:27]2[CH:28]=[N:29][CH:30]=[C:31]([CH:34]=2)[CH:32]=O)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH3:20][O:19][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]([O:17][CH3:18])[C:11]=1[CH:2]1[N:1]([CH2:32][C:31]2[CH:30]=[N:29][CH:28]=[C:27]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:34]=2)[C:7](=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: COC(=O)CCCCC(N)c1c(OC)cccc1OC
Reactant: O=Cc1cncc(-c2ccccc2)c1
Product: COc1cccc(OC)c1C1CCCCC(=O)N1Cc1cncc(-c2ccccc2)c1

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 6-amino-6-(2,6-dimethoxyphenyl)hexanoate with 5-phenylnicotinaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions I): tR=1.26 min.; [M+H]+: 417.20 g/mol.
Reaction SMILES: [NH:1]1[CH:8]=[CH:7][C:5](=[O:6])[NH:4][C:2]1=[O:3].CN(CCN(C)C)C.[F:17][C:18]([F:29])([F:28])[C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][CH:24]=1>CO.CN(C)C=O.O.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[F:17][C:18]([F:29])([F:28])[C:19]1[CH:24]=[C:23]([N:1]2[CH:8]=[CH:7][C:5](=[O:6])[NH:4][C:2]2=[O:3])[CH:22]=[CH:21][CH:20]=1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: O=c1cc[nH]c(=O)[nH]1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: CN(C)CCN(C)C
Solvent: O
Solvent: CN(C)C=O
Solvent: CO
Product: O=c1ccn(-c2cccc(C(F)(F)F)c2)c(=O)[nH]1
Temperature: 25 °C
Yield: 4.8 %

Procedure:
To a solution of uracil (8.9 g), copper(II) acetate (9.6 g), N,N,N,N-tetramethylethylenediamine (10.2 ml) in methanol/dimethy formamide/water (500/100/100 ml) was added 3-trifluoromethylphenyl boronic acid (10.0 g) and the resulting mixture was stirred at room temperature for twelve hours. The reaction mixture was concentrated under reduced pressure so as to remove methanol and thereto was added water (100 ml). The resulting mixture was extracted with ethyl acetate (100 ml×3) and the organic layer was washed with water (100 ml×2) and saturated saline (50 ml), dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to afford 1-(3-trifluoromethylphenyl)pyrimidin-2,4(1H,3H)-dione (650.0 mg).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][NH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:17]1([C:23]2[N:24]=[C:25]([C:34]3[CH:35]([CH2:40][C:41]4[CH:42]=[C:43]([S:47](Cl)(=[O:49])=[O:48])[CH:44]=[CH:45][CH:46]=4)[CH2:36][CH2:37][CH2:38][CH:39]=3)[O:26][C:27]=2[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(Cl)Cl.CCOC(C)=O>[C:17]1([C:23]2[N:24]=[C:25]([C:34]3[CH:35]([CH2:40][C:41]4[CH:42]=[C:43]([S:47]([NH:9][CH2:8][CH2:7][C:1]5[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=5)(=[O:49])=[O:48])[CH:44]=[CH:45][CH:46]=4)[CH2:36][CH2:37][CH2:38][CH:39]=3)[O:26][C:27]=2[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=S(=O)(Cl)c1cccc(CC2CCCC=C2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Reactant: NCCc1ccccc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S(=O)(NCCc1ccccc1)c1cccc(CC2CCCC=C2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 21.5 %

Procedure:
To a solution of 2-phenylethylamine (0.082 ml, 0.65 mmol) and triethylamine (0.097 ml, 0.70 mmol) in methylene chloride (3 ml) was added a solution of crude 3-{[2-(4,5-diphenyloxazol-2-yl)-2-cyclohexen-1-yl]methyl}benzenesulfonyl chloride (213 mg, 0.44 mmol) in methylene chloride (3 ml) at 5° C. After stirring at room temperature for 1 hour, the reaction mixture was diluted with EtOAc, washed with 1N hydrochloric acid, water, saturated sodium hydrogencarbonate solution, water and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by silica gel column chromatography (hexane:EtOAc, 5:1-3:1 elution) to give 3-{[2-(4,5-diphenyloxazol-2-yl)-2-cyclohexen-1-yl]methyl}-N-(phenethyl)benzenesulfonamide (54.3 mg, 22%).
Reaction SMILES: [C:1]([OH:7])(=O)[CH2:2][C:3]([OH:5])=[O:4].[CH2:8]([K])[CH3:9].[Mg+2].[Cl-].[Cl-].[CH3:14][O:15][C:16]([N:18]1[CH2:23][CH2:22][CH:21](C(O)=O)[CH2:20][CH:19]1[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=1)=[O:17].C(N1C=CN=C1)(N1C=CN=C1)=O>C1COCC1>[CH2:8]([O:5][C:3](=[O:4])[CH2:2][C:1]([C@@H:21]1[CH2:22][CH2:23][N:18]([C:16]([O:15][CH3:14])=[O:17])[C@@H:19]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([C:34]([F:36])([F:35])[F:37])=[CH:30][CH:29]=2)[CH2:20]1)=[O:7])[CH3:9]
Reactant: CC[K]
Reactant: COC(=O)N1CCC(C(=O)O)CC1Cc1ccc(C(F)(F)F)cc1
Reactant: O=C(O)CC(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Cl-]
Agent: [Mg+2]
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)[C@@H]1CCN(C(=O)OC)[C@@H](Cc2ccc(C(F)(F)F)cc2)C1
Temperature: 50 °C
Reaction time: 4 h
Yield: 43 %

Procedure:
Ethyl potassium malonate (1.065 g, 6.26 mmol) and MgCl2 (0.496 g, 5.21 mmol) were added to dry THF (50 mL). The reaction mixture was stirred vigorously for 4 h at 50° C. (flask 1). 1-(Methoxycarbonyl)-2-(4-(trifluoromethyl)benzyl)piperidine-4-carboxylic acid (1.8 g, 5.21 mmol) (reference compound 47) and carbonyldiimidazole (1.268 g, 7.82 mmol) were added to dry THF (50 ml) at 5° C. (flask 2). The contents of flask 2 was added to flask 1 and the resulting suspension was stirred at room temperature overnight. THF was evaporated and the reaction mixture was partitioned between water and diethyl ether. The organic phase was isolated, dried with Na2SO4, filtered through celite and the solvent was evaporated. Chromatography using the Biotage equipment. Gradient eluation using ethylacetate-heptane, started 15-85 and ended 40-60. Trans-methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(4-(trifluoromethyl)benzyl)piperidine-1-carboxylate (0.93 g, 42.9%) was isolated. 1H NMR (600 MHz, cdcl3) δ 1.20-1.29 (m, 3H), 1.46-1.99 (m, 4H), 2.74-3.04 (m, 4H), 3.34-3.70 (m, 5H), 4.01-4.32 (m, 3H), 4.60 (d, 1H), 7.22-7.38 (m, 2H), 7.51-7.56 (m, 2H). MS m/z 416 (M+H)+
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[C:11]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=1)([CH2:16][CH3:17])/[CH:12]=[CH:13]/[C:14]#[N:15].CN1CCOCC1.[CH3:32][S:33](Cl)(=[O:35])=[O:34]>C(Cl)Cl>[Cl:24][C:21]1[CH:20]=[CH:19][C:18]([C:11]([N:6]2[C:7]3[C:3](=[C:2]([NH:1][S:33]([CH3:32])(=[O:35])=[O:34])[CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:5]2)([CH2:16][CH3:17])/[CH:12]=[CH:13]/[C:14]#[N:15])=[CH:23][CH:22]=1
Reactant: CCC(/C=C/C#N)(c1ccc(Cl)cc1)n1ccc2c(N)cccc21
Reactant: CS(=O)(=O)Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CCC(/C=C/C#N)(c1ccc(Cl)cc1)n1ccc2c(NS(C)(=O)=O)cccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of compound from step B (123 mg, 0.367 mmol) and NMM (74 mg, 0.734 mmol) in DCM (15 mL) was added methanesulfonyl chloride (62 mg, 0.550 mmol) dropwise. Then the mixture was stirred at room temperature overnight. The reaction was quenched with saturated ammonium chloride solution, and extracted with ethyl acetate (20 mL). The organic layer was washed with brine, dried over sodium sulfate, filtered and evaporated. The residue was purified by silica gel chromatography eluting with PE/EA (10/1 to 3/1, v/v) to afford the title compound as a white solid. LC/MS m/z=436.1 [M+Na]+.
Reaction SMILES: [N+]([C:4]1C=[C:6]2[CH:12]=[C:11]([C:13]([OH:15])=O)[NH:10][C:7]2=[N:8][CH:9]=1)([O-])=O.[CH3:16][N:17]([CH3:20])[CH:18]=O>>[NH:10]1[CH2:7][CH2:6][O:15][CH2:13][CH2:11]1.[CH3:16][N:17]([CH3:20])[CH2:18][CH2:4][CH2:9][N:8]=[C:7]=[N:10][CH2:11][CH3:12]
Reactant: O=C(O)c1cc2cc([N+](=O)[O-])cnc2[nH]1
Reactant: CN(C)C=O
Product: C1COCCN1
Product: CCN=C=NCCCN(C)C

Procedure:
A flask is charged successively with 600 mg (2.90 mmol) of the 5-nitro-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid formed during the preceding stage, 10 mL of dimethylformamide (distilled on calcium hydride), 0.5 mL (5.80 mmol) of morpholine and 1.11 g (5.80 mmol) of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (EDCl) hydrochloride under argon atmosphere. The solution is stirred at room temperature for 18 hours. The solvent is then evaporated under reduced pressure and the raw product is purified directly by silica gel chromatography (ethyl acetate/methanol eluent). 313 mg of a white solid is recovered (39%).
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:18]3[C:19]([NH2:23])=[N:20][CH:21]=[CH:22][C:17]=3[O:16][N:15]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I:24]N1C(=O)CCC1=O>CN(C)C=O>[I:24][C:22]1[C:17]2[O:16][N:15]=[C:14]([C:11]3[CH:10]=[CH:9][C:8]([O:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[CH:13][CH:12]=3)[C:18]=2[C:19]([NH2:23])=[N:20][CH:21]=1
Reactant: O=C1CCC(=O)N1I
Reactant: Nc1nccc2onc(-c3ccc(Oc4ccccc4)cc3)c12
Solvent: CN(C)C=O
Product: Nc1ncc(I)c2onc(-c3ccc(Oc4ccccc4)cc3)c12
Yield: 64.7 %

Procedure:
3-(4-Phenoxyphenyl)isoxazolo[4,5-c]pyridin-4-amine (0. 11 g, 0.36 mmol) and N-iodosuccinimide (0.098 g, 0.43 mmol) in N,N-dimethylformamide (1.5 mL) was stirred at ambient temperature for 30 minutes. The mixture was applied to a silica gel column and eluted with dichloromethane/ethyl acetate (8:2) to provide the title compound (100 mg): 1H NMR (DMSO-d6, 400 MHz) δ 8.26 (s, 1H), 7.71 (d, 2H), 7.46 (t, 2H), 7.15-7.25 (m, 5H), 6.45 (bs, 2H);
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:13])[CH:9]=[C:10]([CH3:12])[NH2:11])=[CH:4][CH:3]=1.BrC1C=CC([C:21](=O)[CH2:22][C:23](=[O:25])C)=CC=1.[OH-].[NH4+]>CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:9]2[CH:21]=[CH:22][C:23](=[O:25])[NH:11][C:10]=2[CH3:12])=[O:13])=[CH:6][CH:7]=1
Reactant: CC(=O)CC(=O)c1ccc(Br)cc1
Reactant: CC(N)=CC(=O)c1ccc(Br)cc1
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Product: Cc1[nH]c(=O)ccc1C(=O)c1ccc(Br)cc1
Reaction time: 8 h

Procedure:
The intermediate 3-(4-bromophenyl)-1-methyl-3-oxo-1-propenamine, m.p. 126°-128° C., 56.8 g, was prepared following the procedure described in Example A-2 using 83 g of 1-(4-bromophenyl)-1,3-butanedione, 750 ml of methanol and 100 ml of concentrated aqueous ammonium hydroxide solution. The solid residue after stripping the reaction mixture to dryness on a rotary evaporator was treated with 500 ml of boiling n-hexane, the mixture allowed to stand at room temperature overnight, and, the product collected and dried at room temperature.
Reaction SMILES: [OH:1][CH:2](CC#N)[CH2:3][C:4]#[N:5].CC[O:11][C:12]([CH3:14])=[O:13].Cl>N#N>[OH:1][C@H:2]([CH2:3][C:4]#[N:5])[CH2:14][C:12]([OH:11])=[O:13]
Reactant: N#CCC(O)CC#N
Reactant: CCOC(C)=O
Agent: Cl
Agent: N#N
Product: N#CC[C@@H](O)CC(=O)O
Reaction time: 22 h

Procedure:
3-hydroxyglutaronitrile (1 g, 9 mmol) was suspended in 37.5 mL of N2 (g) sparged, room temperature, 100 mM sodium phosphate buffer at pH 7. To this 240 mM solution of HGN was added 150 mg of cell lysate normalized for protein content. As assessed by PAGE, the nitrilase content was established to be 20% of the total protein. Therefore effectively, 30 mg of nitrilase is used in this reaction. The reaction was agitated at 100 rpm. Reaction progress was monitored by TLC (1:1 EtOAc:Hexanes, Rf=0.32, nitrile; Rf=0.0, acid) and GC. After 22 h, the reaction was filtered through a 10,000 MW cutoff filter and then concentrated in vacuo. The concentrated hydrolysis solution was acidified with 1M HCl and the product was continuously extracted with MTBE (30 mL). The acid product (R)-3-hydroxy-4-cyanobutyric acid was isolated as a yellow oil (1.15 g, 98% yield). 1H NMR (d6-DMSO, 500 MHz) δ 12.32 (s, 1H), 5.52 (s, 1H), 4.10 (m, 1H), 2.70 (dd, 1H, J=16.8, 4.1 Hz), 2.61 (dd, 1H, J=16.9, 6.3 Hz), 2.44 (dd, 1H, J=15.4, 5.3 Hz), 2.37 (dd, 1H, J=15.6, 7.8 Hz). 13C NMR (DMSO, 298K, 125 MHz) δ 171.9, 118.7, 63.4, 41.2, 25.2 MS calc'd for [C5H7NO3]: 129.0. found: 130.0 [M+H+], (ESI+). ee=95% [HPLC]. Based on the isolated yield a productivity of 40 g g−1 d−1 is calculated.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](O)[CH2:9][CH2:10][N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)=[CH:4][CH:3]=1.[Cl:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:21]2[CH:22]=[CH:23][C:18]([Cl:17])=[CH:19][CH:20]=2)[CH2:9][CH2:10][N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)=[CH:4][CH:3]=1
Reactant: OC(CCn1ccnc1)c1ccc(Br)cc1
Reactant: Clc1ccccc1
Product: Clc1ccc(C(CCn2ccnc2)c2ccc(Br)cc2)cc1
Yield: 67 %

Procedure:
Chlorobenzene (5 ml) was reacted with 1-(4-Bromo-phenyl)-3-imidazol-1-yl-propan-1-ol (0.41 mg, 1.46 mmol) following the procedure set out in Example 42B to give the title compound (0.37 g, 67% yield). LC/MS: (PS-A2) Rt 2.40 [M+H]+ 375.16, 377.17.
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].[C:11]1([CH:17]([N:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)[C:18]([O:20][C@@H:21]2[CH:26]3[CH2:27][CH2:28][N:23]([CH2:24][CH2:25]3)[CH2:22]2)=[O:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>CCOC(C)=O>[Br-:1].[O:4]=[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:2][N+:23]12[CH2:24][CH2:25][CH:26]([CH2:27][CH2:28]1)[C@@H:21]([O:20][C:18](=[O:19])[CH:17]([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[N:29]1[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]1)[CH2:22]2
Reactant: O=C(CBr)c1ccccc1
Reactant: O=C(O[C@H]1CN2CCC1CC2)C(c1ccccc1)N1CCCCC1
Solvent: CCOC(C)=O
Product: O=C(C[N+]12CCC(CC1)[C@@H](OC(=O)C(c1ccccc1)N1CCCCC1)C2)c1ccccc1
Product: [Br-]
Temperature: 25 °C
Reaction time: 3 h
Yield: 79003.7 %

Procedure:
2-Bromo-1-phenylethanone (91.0 mg, 0.46 mmol) was added to a solution of (R)-quinuclidin-3-yl 2-phenyl-2-(piperidin-1-yl)acetate (150 mg, 0.46 mmol) in EtOAc (10 ml). The mixture was stirred at room temperature for 3 hours. The precipitate was collected by suction filtration to obtain (3R)-1-(2-oxo-2-phenylethyl)-3-(2-phenyl-2-(piperidin-1-yl)acetoxy)-1-azoniabicyclo[2.2.2]octane bromide (191.7 g, 80% yield) as a white solid.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:20][CH2:19][C@@:18]2([CH3:21])[C@H:4]([CH2:5][CH2:6][C@@H:7]3[C:17]2=[CH:16][CH2:15][C@@:14]2([CH3:22])[C@H:8]3[CH2:9][CH2:10]/[C:11]/2=[CH:12]/[CH3:13])[CH2:3]1.C(N(CC)CC)C.[C:30](OC(=O)C)(=[O:32])[CH3:31]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:30]([O:1][C@@H:2]1[CH2:20][CH2:19][C@@:18]2([CH3:21])[C@H:4]([CH2:5][CH2:6][C@@H:7]3[C:17]2=[CH:16][CH2:15][C@@:14]2([CH3:22])[C@H:8]3[CH2:9][CH2:10]/[C:11]/2=[CH:12]/[CH3:13])[CH2:3]1)(=[O:32])[CH3:31]
Reactant: CC(=O)OC(C)=O
Reactant: C/C=C1/CC[C@H]2[C@@H]3CC[C@@H]4C[C@H](O)CC[C@]4(C)C3=CC[C@]12C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C/C=C1/CC[C@H]2[C@@H]3CC[C@@H]4C[C@H](OC(C)=O)CC[C@]4(C)C3=CC[C@]12C
Temperature: 25 °C
Reaction time: 2 h
Yield: 102 %

Procedure:
Compound 1.5 (19.0 g, 63 mmol) was dissolved in CH2Cl2 (380 mL). Triethylamine (17.6 mL, 126.6 mmol), DMAP (0.772 g, 6 mmol) and acetic anhydride (8.98 mL, 94 mmol) were added sequentially at 25° C. under a nitrogen atmosphere. The resulting solution was stirred for 2 h at 25° C., at which point the reaction was determined by TLC to be complete. The reaction was quenched by the addition of ice-water (100 mL) and the phases were separated. The aqueous layer was extracted three times with DCM (3×150 mL). The organic fractions were combined and washed with saturated brine solution (100 mL), dried over anhydrous Na2SO4 (50 g), and filtered. The filtrate was concentrated under vacuum to afford compound 1.6a (22.0 g, 95% yield) as an off-white solid.