Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@@H:12]1[C:16]([C:18]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([Br:27])[CH:25]=2)[NH:20][CH:19]=1)=O)=O)C1C=CC=CC=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1.C(OCC)(=O)C>[Br:27][C:24]1[CH:25]=[C:26]2[C:21](=[CH:22][CH:23]=1)[NH:20][CH:19]=[C:18]2[CH2:16][C@H:12]1[CH2:13][CH2:14][CH2:15][N:11]1[CH3:9]
Reactant: O=C(c1c[nH]c2ccc(Br)cc12)[C@H]1CCCN1C(=O)OCc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CN1CCC[C@@H]1Cc1c[nH]c2ccc(Br)cc12
Reaction time: 18 h
Yield: 71.5 %

Procedure:
A solution of (R)-3-(N-benzyloxycarbonyl-pyrrolidin-2-ylcarbonyl)-5-bromo-1H-indole (1.04 g) in dry tetrahydrofuran (20 mL) was added dropwise to a stirred suspension of lithium aluminium hydride (0.27 g) in dry tetrahydrofuran (15 mL) at room temperature under an atmosphere of dry nitrogen. The mixture was heated under reflux with stirring for 18 hours and then cooled. Additional lithium aluminium hydride (50 mg) was added and refluxing was continued for an additional 3 hours. The mixture was again cooled, lithium aluminium hydride (40 mg) was added, and refluxing was continued for a further 18 hours. The mixture was cooled and water (0.44 mL) was carefully added with stirring, followed by 20% aqueous sodium hydroxide (0.44 mL), followed by more water (1.33 mL). The mixture was diluted with ethyl acetate and filtered through Celite (trademark) filter aid. The filtrate was washed with water, brine and then dried (Na2SO4). Evaporation of the solvent gave an oil which was chromatographed on silica gel. Elution with dichloromethane/ethanol/concentrated aqueous ammonia (90:10:0.5) gave the title compound as a solid (0.51 g), m.p. 137°-140° C. (from dichloromethane/hexane); IR (KBr) 1620, 1595, 1570, 1480, 1450, 1435 cm-1 ; 1H NMR (DMSO-d6) δ11.05 (br s, 1H), 7.65 (br d, 1H), 7.31 (d, J=8.6 Hz, 1H), 7.21 (br d, 1H), 7.16 (dd, J=1.8 and 8.6 Hz, 1H), 3.03-2.94 (m, 2H), 2.47 (dd, J=9.2 and 14.0 Hz, 1H), 2.36-2.26 (m, 1H), 2.33 (s, 3H), 2.09 (dd, J=8.7 and 17.3 Hz, 1H), 1.73-1.38 (m, 4H); 13C NMR (DMSO-d6) δ134.8, 129.5, 124.7, 123.2, 120.7, 113.4, 112.1, 110.9, 66.1, 57.0, 40.5, 30.9, 29.1, 21.6; LRMS, m/z (relative intensity) 294 (M+ with 81Br, 1), 293 (2), 292 (M+ with 79Br, 1), 210 (14), 208 (15), 154 (8), 129 (42), 128 (19), 01 (26) 85 (57), 84 (100), 83 (30); [α]25D =+62° (methanol, c=0.10). Anal Calcd for C14H17N2Br. 0.25H2O: C, 56.48; H, 5.93; N, 9.41. Found: C, 56.65; H, 5.69; N,9.23.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:15]3[CH2:19][NH:18][C:17](=[O:20])[CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.Br[C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[C:25]#[N:26].P([O-])([O-])([O-])=O.[K+].[K+].[K+].[C@@H]1(N)CCCC[C@H]1N>CCOC(C)=O.[Cu]I.O1CCOCC1.CN(C=O)C>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:15]3[CH2:19][N:18]([C:22]4[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=4)[C:25]#[N:26])[C:17](=[O:20])[CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: N#Cc1cccc(Br)c1
Reactant: COc1ccc(C2CNC(=O)C2)cc1OC1CCCC1
Agent: [Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(C2CC(=O)N(c3cccc(C#N)c3)C2)cc1OC1CCCC1
Temperature: 110 °C
Yield: 96.2 %

Procedure:
A mixture of 4-(3-cyclopentyloxy-4-methoxyphenyl)-pyrrolidin-2-one (1.5 g, 5 mmol), 3-bromobenzonitrile (1.36 g, 7.5 mmol), potassium phosphate (1.9 g, 9.8 mmol), and 1,2-trans-cyclohexanediamine (60 μL) was created in a dry round bottom flask under nitrogen containing DMF (9 mL) and dioxane (9 mL). The mixture was stirred and CuI (100 mg) was added. The resulting reaction mixture was heated to 110° C. with stirring under N2 for 20 h, and then cooled to r.t. The mixture was diluted with EtOAc and then filtered. The filtrate was washed with saturated aqueous solutions of NH4Cl and brine, dried over MgSO4, and concentrated under reduced pressure. Chromatography on silica gel (EtOAc:hexane=1:3 to 1:1) gave 1.81 g of 3-[4-(3-cyclopentyloxy-4-methoxy-phenyl)-2-oxo-pyrrolidin-1-yl]benzonitrile. Yield: 90%.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([CH3:12])[CH:9]=[CH:8][C:3]=1[C:4]([NH:6][NH2:7])=[O:5].[N:13]#[C:14]Br.C([O-])(O)=O.[Na+]>O1CCOCC1.O>[CH3:1][C:2]1[CH:11]=[C:10]([CH3:12])[CH:9]=[CH:8][C:3]=1[C:4]1[O:5][C:14]([NH2:13])=[N:7][N:6]=1
Reactant: Cc1ccc(C(=O)NN)c(C)c1
Reactant: N#CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1ccc(-c2nnc(N)o2)c(C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.6 %

Procedure:
To a solution of 2,4-dimethylbenzohydrazide (example 16b) (2 g) in dry dioxane (12 mL) was added cyanic bromide (1.28 g, 12.2 mmol) followed by a solution of NaHCO3 (1.02 g, 12.2 mmol) in water (12 mL). The resulting mixture was stirred 2 hours at rt. The solution was concentrated to ½ volume on vacuum and diluted with water (20 mL). The resulting solid was collected and dried on vacuum to give 5-(2,4-Dimethylphenyl)-1,3,4-oxadiazol-2-amine (1.88 g, 82%) as a white solid. 1H NMR (300 MHz, dMSO): δ 2.29 (s, 3H), 2.52 (d, 3H), 7.13 (d, 1H), 7.16 (s, 3H), 7.54-7.56 (d, 1H); MS (M+H, 190).
Reaction SMILES: [C:1](=[O:34])([O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][O:30][N+:31]([O-:33])=[O:32])[O:2][CH2:3]/[C:4](/[C:14]1[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=1)=[C:5](/[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)\[CH2:6][OH:7].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=[O:37].O.OP(O)(O)=O.[O-]Cl=O.[Na+].CC(=CC)C>ClCCl.CCOC(C)=O>[CH3:23][S:20]([C:17]1[CH:18]=[CH:19][C:14](/[C:4](/[CH2:3][O:2][C:1]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][O:30][N+:31]([O-:33])=[O:32])=[O:34])=[C:5](\[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)/[C:6]([OH:37])=[O:7])=[CH:15][CH:16]=1)(=[O:21])=[O:22]
Reactant: CS(=O)(=O)c1ccc(/C(COC(=O)OCCCCCO[N+](=O)[O-])=C(/CO)c2ccccc2)cc1
Reactant: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: CC=C(C)C
Agent: O=P(O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(/C(COC(=O)OCCCCCO[N+](=O)[O-])=C(/C(=O)O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of (2Z)-4-hydroxy-2-[4-(methylsulfonyl)phenyl]-3-phenylbut-2-enyl 5-(nitrooxy)pentyl carbonate (1 eq, 0.2M) in dichloromethane was treated with Dess-Martin reagent (1.3 eq) for 1 h at rt. The reaction was quenched by 10 eq of water and stirred at rt for 1 h, filtered on a silica gel pad eluted with 60% EtOAc/hexanes and evaporated. The residue was dissolved in a 3:1 solvent mixture of tBuOH/CH2Cl2, and treated with 1 M H3PO4 (4 eq) and 1 M NaClO2 (2 eq) in the presence of an excess of 2-methyl-2-butene. The resulting mixture was stirred at rt for 30 min, diluted with EtOAc and the organic layer was separated, washed with brine, dried (Na2SO4), and evaporated to afford the crude acid used as such for next step.
Reaction SMILES: [C:1]([CH2:3][C:4]([O-:6])=[O:5])#[N:2].[CH2:7](O)[CH2:8][CH:9]([CH3:11])[CH3:10].S(=O)(=O)(O)O>>[C:1]([CH2:3][C:4]([O:6][CH2:7][CH2:8][CH:9]([CH3:11])[CH3:10])=[O:5])#[N:2]
Reactant: CC(C)CCO
Reactant: N#CCC(=O)[O-]
Agent: O=S(=O)(O)O
Product: CC(C)CCOC(=O)CC#N

Procedure:
Using the procedure of Example 1, cyanoacetate acid (85.5 g; 1.00 mol) and isoamyl alcohol (176 g; 2 mol) are reacted in the presence of sulfuric acid (0.49 g; 0.005 mol). Isoamyl cyanoacetate (bp 133/20 mm of Hg) is recovered as a clear liquid. The yield was 150 g (97% of theoretical) and its purity was >99% (GC assay).
Reaction SMILES: NC1C=CC(C2C=NN(CCCO)C=2)=CC=1C(N(CC)CC)=O.[F:24][C:25]([F:73])([CH2:71][OH:72])[CH2:26][N:27]1[CH:31]=[C:30]([C:32]2[N:37]=[C:36]([C:38](=[O:41])[NH:39][CH3:40])[C:35]([NH:42][C:43]3[C:48]([C:49]([F:52])([F:51])[F:50])=[CH:47][N:46]=[C:45]([NH:53][C:54]4[CH:68]=[CH:67][C:57]([CH2:58][P:59](=[O:66])([O:63]CC)[O:60][CH2:61][CH3:62])=[CH:56][C:55]=4[O:69][CH3:70])[N:44]=3)=[CH:34][CH:33]=2)[CH:29]=[N:28]1>>[F:73][C:25]([F:24])([CH2:71][OH:72])[CH2:26][N:27]1[CH:31]=[C:30]([C:32]2[N:37]=[C:36]([C:38](=[O:41])[NH:39][CH3:40])[C:35]([NH:42][C:43]3[C:48]([C:49]([F:52])([F:51])[F:50])=[CH:47][N:46]=[C:45]([NH:53][C:54]4[CH:68]=[CH:67][C:57]([CH2:58][P:59](=[O:63])([OH:66])[O:60][CH2:61][CH3:62])=[CH:56][C:55]=4[O:69][CH3:70])[N:44]=3)=[CH:34][CH:33]=2)[CH:29]=[N:28]1
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cnn(CC(F)(F)CO)c4)nc3C(=O)NC)n2)c(OC)c1)OCC
Agent: CCN(CC)C(=O)c1cc(-c2cnn(CCCO)c2)ccc1N
Product: CCOP(=O)(O)Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cnn(CC(F)(F)CO)c4)nc3C(=O)NC)n2)c(OC)c1
Yield: 93.4 %

Procedure:
Prepared analogously to Compound 3C using diethyl (4-{[4-({6-[1-(2,2-difluoro-3-hydroxypropyl)-1H-pyrazol-4-yl]-2-(methylcarbamoyl)pyridin-3-yl}amino)-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate (Compound 59B, 388 mg, 0.532 mmol) to afford 348 mg of the title compound (93%). 1H NMR (400 MHz, CD3OD) δ 8.96-9.11 (m, 2H), 8.56 (s, 1H), 8.31 (s, 2H), 7.74 (d, J=9.1 Hz, 1H), 7.10 (s, 1H), 6.94 (d, J=8.1 Hz, 1H), 4.66 (d, J=7.6 Hz, 2H), 3.88 (quin, J=6.9 Hz, 5H), 3.65-3.77 (m, 2H), 3.06 (s, 5H), 1.15 (t, J=6.9 Hz, 3H). MS (ESI): m/z=701.68 [M+H]+. UPLC: tR=1.27 min (UPLC-TOF: polar—2 min).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH2:12]Br)=[N:9]2)=[CH:4][CH:3]=1.[OH:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH:18]=[O:19].C([O-])([O-])=O.[K+].[K+].C(Cl)Cl>CC(C)=O>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH2:12][O:14][C:15]3[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=3)[CH:18]=[O:19])=[N:9]2)=[CH:4][CH:3]=1
Reactant: Clc1ccc2ccc(CBr)nc2c1
Reactant: O=Cc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: ClCCl
Product: O=Cc1cccc(OCc2ccc3ccc(Cl)cc3n2)c1

Procedure:
A suspension of 7-chloro-2-(bromomethyl)quinoline (50.5 g, 197 mmol, EP 233,763, Example 4, Step 1), 3-hydroxybenzaldehyde (22.9 g, 188 mmol) and K2CO3 (51.7 g, 375 mmol) in 600 mL of acetone was heated to reflux for 2 h. After cooling down, 200 mL of CH2Cl2 was added and the mixture was filtered through celite with acetone:CH2Cl2 3:1. The title product was purified by flash chromatography on silica with EtOAc:toluene 5:95 to yield 46.64 g, 83%. (Alternatively, the product may be purified by a swish in ether:hexane 7:1).
Reaction SMILES: [N+:1]1([O-:8])[C:2]([CH3:7])=[CH:3][CH:4]=[CH:5][CH:6]=1.C([O-])(C)(C)C.[K+].[C:15]1([CH3:23])[CH:20]=[CH:19][C:18]([CH:21]=O)=[CH:17][CH:16]=1>C(O)CCC.O>[C:15]1([CH3:23])[CH:20]=[CH:19][C:18]([CH:21]=[CH:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N+:1]=2[O-:8])=[CH:17][CH:16]=1
Reactant: Cc1ccc(C=O)cc1
Reactant: Cc1cccc[n+]1[O-]
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CCCCO
Product: Cc1ccc(C=Cc2cccc[n+]2[O-])cc1
Temperature: 25 °C
Yield: 54.9 %

Procedure:
To a refluxing solution of 2-picoline-1-oxide (10.9 g, 100 mmol), potassium tert.-butanolate ( 11.2 g, 100 mmol) in butanol (100 ml) was added portion-wise p-tolualdehyde (12.0 g, 100 mmol). Reflux was maintained for 90 min. Then the mixture was cooled to rt, diluted with H2O (100 ml) and extracted with CH2Cl2. The combined organic phases were dried with MgSO4, concentrated and chromatographed (SiO2 with CH2Cl2/MeOH=95:5) to provide the title compound (11.6 g, 55%) as a yellow solid material. MS: m/e=211 (M+).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][OH:8])[CH:2]=1.[F:9][C:10]([F:21])([F:20])[C:11]1[CH:16]=[CH:15][C:14]([N:17]=[C:18]=[O:19])=[CH:13][CH:12]=1>C1N2CCN(CC2)C1.C1C=CC=CC=1>[F:9][C:10]([F:20])([F:21])[C:11]1[CH:12]=[CH:13][C:14]([NH:17][C:18](=[O:19])[O:8][CH2:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[CH:15][CH:16]=1
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1
Reactant: OCc1cccnc1
Agent: C1CN2CCN1CC2
Solvent: c1ccccc1
Product: O=C(Nc1ccc(C(F)(F)F)cc1)OCc1cccnc1
Reaction time: 1 h
Yield: 93 %

Procedure:
To a solution of 2.5 g. (0.023 mole) of 3-pyridylcarbinol in 50 ml. of benzene containing 0.1 g. of Dabco catalyst (1,4-diazabicyclo [2,2,2] octane) was added, dropwise, a solution of 43 g. (0.023 mole) of p-trifluoromethyl-phenyl isocyanate in 50 ml. of benzene. A temperature rise from 23° to 35° was noted during the addition, and a white precipitate formed. After stirring for 1 hr., the mixture was filtered, and the solid product was air-dried. There was obtained 6.3 g. (93% of theory) of product; melting point 173° - 175° C. (decomposed). This is a 93% yield of 3-pyridylmethyl N-(4'-trifluoromethylphenyl)-carbamate.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH2:9][C:10]([OH:12])=O)[CH:6]=[CH:7][CH:8]=1)#[N:2].[C:13]1([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[Cl-].[Al+3].[Cl-].[Cl-].Cl>C(Cl)Cl>[CH2:19]([C:13]1[CH:14]=[CH:15][C:16]([C:10](=[O:12])[CH2:9][C:5]2[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=2)[C:1]#[N:2])=[CH:17][CH:18]=1)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCCCCCc1ccccc1
Reactant: N#Cc1cccc(CC(=O)O)c1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCCCCCCCc1ccc(C(=O)Cc2cccc(C#N)c2)cc1
Temperature: 0 °C
Yield: 31.2 %

Procedure:
The acid chloride prepared from 3-cyanophenylacetic acid (5 g) as described in Example 18 is added at once to 1-phenyloctane (5.9 g, 0.03 moles) in methylene chloride (20 ml). Anhydrous aluminium chloride (4.96 g, 0.037 moles) is added in 1 portion and the resulting mixture heated under reflux for 2 hours. The reaction mixture is cooled and poured into a mixture of ice water (200 ml) and concentrated hydrochloric acid (20 ml). The mixture is extracted with ether (3×50 ml) and the combined extracts dried over magnesium sulfate, filtered, and evaporated to dryness. The residue is chromatographed on silica gel (hexane: ether; 70:30) to yield 3-(4-n-octylphenacyl)benzonitrile (3.12 g, m.p. 59°-64° C). This nitrile is heated under reflux in a mixture of concentrated hydrochloric acid (30 g) and acetic acid (30 g) for 48 hours. The reaction mixture is diluted with water (60 ml) and extracted with ether (3×50 ml). The combined ether extracts are washed with water (50 ml) then dried over magnesium sulfate, filtered, and evaporated to dryness. The residue is recrystallized from heptane and again from aqueous ethanol to provide 3-(4-octyl-phenacyl)benzoic acid (1.5 g), m.p. 103°-110° C.
Reaction SMILES: C(OC([N:8]1[C@@H:12]([CH2:13][N:14]([C:17]2[CH:22]=[CH:21][C:20]([CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:19][CH:18]=2)[CH2:15][CH3:16])[CH2:11][O:10]C1(C)C)=O)(C)(C)C.Cl.O1CCOC[CH2:34]1>>[NH2:8][C@@H:12]([CH2:13][N:14]([C:17]1[CH:22]=[CH:21][C:20]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:19][CH:18]=1)[CH:15]([CH3:16])[CH3:34])[CH2:11][OH:10]
Reactant: CCN(C[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C)c1ccc(Cc2ccccc2)cc1
Reactant: C1COCCO1
Agent: Cl
Product: CC(C)N(C[C@H](N)CO)c1ccc(Cc2ccccc2)cc1
Reaction time: 16 h
Yield: 71 %

Procedure:
To a stirred solution of (S)-4-{[(4-benzyl-phenyl)-ethyl-amino]-methyl}-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (405 mg; prepared in analogy to example 1.a and 1.b starting from tert-butyl (R)-(+)-4-formyl-2,2-dimethyl-3-oxazolinecarboxylate and 4-benzylaniline) at r.t. in dioxane (5 ml) under an argon atmosphere was added HCl solution (4M in dioxane; 4.77 ml). The mixture was stirred overnight 16 h, then concentrated. The residue was taken up in CH2Cl2/MeOH 95:5 and 1N NaOH. The aqueous phase was back extracted with CH2Cl2/MeOH 95:5. The combined organics were washed with brine, dried over MgSO4, filtered and concentrated. The crude product was purified by column chromatography (Isolute® SPE flash NH2 column, aminopropyl-functionalized silica; gradient:CH2Cl2->CH2Cl2/MeOH 9:1) to give (S)-2-amino-3-[(4-benzyl-phenyl)-isopropyl-amino]-propan-1-ol (192 mg, 71%) as colorless amorphous solid. MS (ISP): 285.3 ([M+H]+)
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:8]2[CH:12]=[C:11]([C:13](N(OC)C)=[O:14])[NH:10][N:9]=2)[C:4]([CH3:7])=[CH:5][CH:6]=1.[CH3:19][Mg+].[Br-]>C1COCC1>[CH3:7][C:4]1[N:3]([C:8]2[CH:12]=[C:11]([C:13](=[O:14])[CH3:19])[NH:10][N:9]=2)[C:2]([CH3:1])=[CH:6][CH:5]=1
Reactant: CON(C)C(=O)c1cc(-n2c(C)ccc2C)n[nH]1
Reactant: C[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Product: CC(=O)c1cc(-n2c(C)ccc2C)n[nH]1
Temperature: 25 °C
Reaction time: 5 h
Yield: 88.6 %

Procedure:
A 250-mL round-bottomed flask equipped with a magnetic stirrer was charged with 150c (7.44 g, 1.0 eq., 30.0 mmol) and THF (100 mL). Under N2 protection, a solution of MeMgBr (3.0 Min ether) (25 mL, 2.5 eq., 75.0 mmol) was added at 0° C. The mixture was stirred at room temperature for 5 h and quenched with saturated NH4Cl solution (30 mL). The mixture was concentrated under reduced pressure and the residue was extracted with ethyl acetate (3×50 mL). The combined organic layer was evaporated under reduced pressure and the residue was purified by silica-gel column chromatography eluting with 4:1 petroleum ether/ethyl acetate to afford 150d as a white solid (5.40 g, 89%). MS-ESI: [M+H]+ 204.0. 1H NMR (500 MHz, CDCl3) δ 6.74 (s, 1H), 5.92 (s, 2H), 2.61 (s, 3H), 2.15 (s, 6H).
Reaction SMILES: [CH2:1]([C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1)[CH3:2].C1C(=O)N([Br:17])C(=O)C1>CN(C=O)C>[Br:17][C:5]1[CH:4]=[C:3]([CH2:1][CH3:2])[CH:9]=[CH:8][C:6]=1[NH2:7]
Reactant: CCc1ccc(N)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: CCc1ccc(N)c(Br)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 92.9 %

Procedure:
To 4-ethylaniline (1.76 g, 14.52 mmol) and NBS (2.58 g, 14.52 mmol) was added DMF (67 mL) and the reaction mixture was stirred at 0° C. for 10 min. The reaction mixture was purified by silica gel chromatography (0-50% ethyl acetate/hexanes) to provide 2-bromo-4-ethylaniline (2.7 g, 93% yield). LC/MS m/z 201.0 [M+H]+.
Reaction SMILES: [C:1]([OH:11])(=[O:10])[C@@H:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[OH:3].[C:12](#[N:21])[CH:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[OH:14].[C:22]([NH2:32])(=O)[CH:23]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[OH:24]>>[C:1]([OH:11])(=[O:10])[C@@H:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[OH:3].[C:12](#[N:21])[CH:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[OH:14].[C:22](#[N:32])[C@H:23]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[OH:24]
Reactant: NC(=O)C(O)c1ccccc1
Agent: N#CC(O)c1ccccc1
Agent: O=C(O)[C@H](O)c1ccccc1
Product: N#C[C@@H](O)c1ccccc1

Procedure:
Yamamoto et al. (1991) tested various isolates (wildtype strains) with respect to their ability to convert mandelonitrile into (R)-(−)-mandelic acid. A. faecalis strain ATCC 8750 was found to have the highest level of activity and enantioselectivity to produce (R)-(−)-mandelic acid from racemic mandelonitrile (Yamamoto et al., 1991). In particular, the (R)-(−)-mandelic acid made of mandelonitrile by resting cells was present in a 100% enantiomeric excess. A. faecalis ATCC 8750 has an (R)-enantioselective nitrilase and an amidase used to process mandelonitrile and mandelamide, respectively. As (R)-(−)-mandelic acid was produced from racemic mandelonitrile in a yield of 91%, whereas no (S)-mandelonitrile was left, the (S)-(−)-mandelonitrile remaining in the reaction is spontaneously racemised because of the chemical equilibrium of the (R)- and the (S)-isomer of mandelonitrile on the one hand and benzaldehyde/HCN on the other hand. Consequently, almost all the mandelonitrile is consumed and converted to (R)-(−)-mandelic acid. It is noted that, according to Yamamoto et al. (1991), the A. faecalis cells employed for production of (R)-mandelic acid require specifically optimized culture conditions.
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[C:4]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[CH:3]=1.[NH:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:25][CH2:24]1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1>[F:22][C:19]1[CH:20]=[CH:21][C:16]([NH:15][C:4]2[CH:3]=[C:2]([N:23]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[CH2:25][CH2:24]3)[CH:14]=[CH:13][C:5]=2[C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[CH:17][CH:18]=1
Reactant: CC(C)(C)OC(=O)c1ccc(Br)cc1Nc1ccc(F)cc1
Reactant: c1ccc2c(c1)CCN2
Agent: [Pd+2]
Agent: [Pd]
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)c1ccc(N2CCc3ccccc32)cc1Nc1ccc(F)cc1
Temperature: 25 °C

Procedure:
To toluene 3.0 mL solution of tert-butyl 4-bromo-2-(4-fluoroanilino)benzoate 0.10 g were added indoline 0.046 mL, cesium carbonate 0.18 g, tris(dibenzylideneacetone)dipalladium(0) 3.0 mg, 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl 7.0 mg and palladium acetate 1.0 mg, and it was heated and refluxed for 2 hours. Tris(dibenzylideneacetone)dipalladium(0) 3.0 mg, 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl 7.0 mg and palladium acetate 1.0 mg were added to it, and it was heated and refluxed for 3 hours. Tris(dibenzylideneacetone)dipalladium(0) 3.0 mg, 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl 7.0 mg and palladium acetate 1.0 mg were added to it, and it was heated and refluxed for 7 hours. After the reaction mixture was cooled to room temperature, and toluene and 10% citric acid aqueous solution were added to it. The organic layer was separated and collected, dried over anhydrous magnesium sulfate after sequential washing with 10% citric acid aqueous solution and saturated sodium chloride aqueous solution, and the solvent was removed under reduced pressure. The obtained residue was refined by silica gel column chromatography [Trikonex company, Flash Tube 2008, eluent; hexane:ethyl acetate=10:1] to give tert-butyl 2-(4-fluoroanilino)-4-(indolin-1-yl)benzoate.
Reaction SMILES: [C:1]([N:8]1[CH2:12][C@@H:11]([F:13])[CH2:10][C@H:9]1[C:14]([OH:16])=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[F-].[Na+].[F:19]C1(F)N(C)CCN1C>ClCCl>[C:1]([N:8]1[CH2:12][C@@H:11]([F:13])[CH2:10][C@H:9]1[C:14]([F:19])=[O:16])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CN1CCN(C)C1(F)F
Reactant: CC(C)(C)OC(=O)N1C[C@@H](F)C[C@H]1C(=O)O
Agent: [F-]
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C[C@@H](F)C[C@H]1C(=O)F
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 71.9 %

Procedure:
(2S,4S)—N-Boc-4-fluoropyrrolidine-2-carboxylic acid (1.17 g, 5 mmol) and sodium fluoride (0.63 g, 15 mmol) were put in a fluoropolymer (PFA) vessel, and 10 ml of dichloromethane was added into the vessel. The mixture was cooled with ice. A solution of 2,2-difluoro-1,3-dimethylimidazolidine (817 mg, 6 mmol) in 2 ml of dichloromethane was added slowly. After 5 minutes of addition, the ice bath was removed and the mixture warmed to room temperature. The reaction mixture was stirred for a total 20 min. 19F NMR analysis of the reaction mixture showed that (2S,4S)—N-Boc-4-fluoropyrrolidine-2-carbonyl fluoride (Id) was produced in 85% yield. The mixture was diluted with 10 ml of dichloromethane and washed with water. The organic layer was dried over anhydrous magnesium sulfate and filtered. Removal of solvent followed by washing with a small amount of water and then drying gave 846 mg (yield 72%) of (2S,4S)—N-Boc-4-fluoropyrrolidine-2-carbonyl fluoride (Id): Oil: 19F-NMR (CDCl3) (as a 6:4 mixture of two rotamers) δ 28.22 (s, 0.6 F, COF), 28.14 (s, 0.4 F, COF), −173.18 (m, 1 F, CF): 1H-NMR (CDCl3) 8 (as a mixture of two rotamers) 1.40 (s, 0.55×9H, t-Bu), 1.43 (s, 0.45×9H, t-Bu), 2.2-2.6 (m, 2H), 3.45-3.95 (m, 2H), 4.5-4.7 (m, 1H), 5.22 (br.d, J=51.9 Hz, 1H, CHF): 13C-NMR (CDCl3) 8 (as a mixture of two rotamers); 90.94 (d, J=177.0 Hz, 1H, CF), 92.02 (d, J=177.0 Hz, CF), 153.06 (s, CON), 153.82 (s, CON), 161.50 (d, J=372.1 Hz, COF), 161.66 (d, J=372.8 Hz, COF): High Resolution Mass/ESI-APCI method (solvent; methanol); (M-F+OCH3+Na)+ 270.1109 [calcd 270.1112 for (C11H18FNO4+Na)].