Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([CH:11]([N:13]3[CH:17]=[N:16][CH:15]=[N:14]3)[CH3:12])[CH2:10][O:9]2)=[N:6][CH:7]=1.[NH:18]1[CH:22]=[N:21][CH:20]=[N:19]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[N:18]1([CH2:10][C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=2)([OH:9])[CH:11]([N:13]2[CH:17]=[N:16][CH:15]=[N:14]2)[CH3:12])[CH:22]=[N:21][CH:20]=[N:19]1
Reactant: CC(n1cncn1)C1(c2ccc(Cl)cn2)CO1
Reactant: c1nc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(n1cncn1)C(O)(Cn1cncn1)c1ccc(Cl)cn1
Reaction time: 3 h
Yield: 28.1 %

Procedure:
To a solution of 2-[5-chloropyrid-2-yl]-2-[1-(1H-1,2,4-triazol-1-yl)ethyl]oxirane (70 mg; 0.28 m.Mole) in dimethylformamide (5 ml) was added 1,2,4-triazole (39 mg; 0.56 m.Mole) and anhydrous potassium carbonate (39 mg; 0.28 m.Mole). Heating, with stirring, was carried out for three hours at 80°. The solvent was then evaporated, water (20 ml.) was added, and the mixture was extracted with methylene chloride (3×10 ml). The combined organic extracts were washed with water (3×5 ml), dried over anhydrous magnesium sulphate, and evaporated to an oil (100 mg). Purification was carried out using a flash column of Merck "Kieselgel 60" 230-400 mesh silica, eluting with methylene chloride containing gradually increasing amounts of methanol (from 1 to 5%). The appropriate fractions, on evaporation, gave the pure title compound, 25 mg; m.p. 156°-157° (28.1% yield).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:10](=[O:12])[O:9][C:8](=[O:13])[NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:16]I>CN(C)C=O>[Cl:1][C:2]1[C:11]2[C:10](=[O:12])[O:9][C:8](=[O:13])[N:7]([CH3:16])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=c1[nH]c2cccc(Cl)c2c(=O)o1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(=O)oc(=O)c2c(Cl)cccc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Under an atmosphere of nitrogen, 5-chloro-1H-benzo[d][1,3]oxazine-2,4-dione (10 g, 50.61 mmol, 1.00 equiv) was dissolved in N,N-dimethylformamide (100 ml) at about 5° C. Sodium hydride (2.8 g, 121.5 mmol, 2.4 equiv) and methyl iodide (5.7 ml, 2 equiv) were then added, and the resulting mixture was stirred at ambient temperature for about 16 hours. The mixture was purged with nitrogen for about 1 hour to give the title product as a yellow solid, which was used directly in the next step without any purification.
Reaction SMILES: [CH2:1]([O:3][C:4]([NH:6][C:7]1[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[C:8]=1[C:9]#[N:10])=[O:5])[CH3:2].Br[CH2:17][C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:19]>C(OCC)(=O)C>[NH2:10][C:9]1[C:8]2[C:7](=[CH:14][CH:13]=[CH:12][C:11]=2[F:15])[N:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[C:17]=1[C:18](=[O:19])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CCOC(=O)Nc1cccc(F)c1C#N
Reactant: O=C(CBr)c1ccccc1
Solvent: CCOC(C)=O
Product: CCOC(=O)n1c(C(=O)c2ccccc2)c(N)c2c(F)cccc21

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 1 from 2-(ethoxycarbonylamino)-6-fluorobenzonitrile (step 1) and 2-bromoacetophenone. tlc: Rf=0.3 (33% ethyl acetate in hexanes)
Reaction SMILES: O=O.[C:3]([NH:11][C:12](=[CH:17][N:18]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]([O:15][CH3:16])=[O:14])(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl-].[Rh]>[C:3]([NH:11][CH:12]([CH2:17][N:18]([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[C:13]([O:15][CH3:16])=[O:14])(=[O:10])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: COC(=O)C(=CN(c1ccccc1)c1ccccc1)NC(=O)c1ccccc1
Agent: [Rh]
Agent: O=O
Agent: [Cl-]
Product: COC(=O)C(CN(c1ccccc1)c1ccccc1)NC(=O)c1ccccc1
Reaction time: 20 h

Procedure:
With exclusion of oxygen, an autoclave was charged with 1 g (2.68 mmol) of methyl 2-benzoylamino-3-diphenylaminoacrylate and 40 mg (0.042 mmol) of tris(triphenylphosphine)rhodium(I) chloride. After purging with argon, 40 ml of oxygen-free methanol were added. The autoclave was sealed gas-tight and the solution was hydrogenated at RT for 20 hours (h). The autoclave was decompressed and purged with nitrogen. The solvent was evaporated off under reduced pressure and the residue was chromatographed through a column filled with silica gel 60 (eluent: 1:1 ethyl acetate/heptane). After the solvents had been evaporated off under reduced pressure, a white solid remained, which was utilized for the formulation of a method and as a system test for the determination of the enantiomeric purity by HPLC on chiral phase.
Reaction SMILES: C1C2C(COC([N:18]3[CH2:23][C@H:22]([NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][C@H:20]([C:32]([OH:34])=O)[CH2:19]3)=O)C3C(=CC=CC=3)C=2C=CC=1.C(N(C(C)C)C(C)C)C.CN1CCCC1=O.CN(C(ON1N=NC2C=CC(=CC1=2)Cl)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH:76]1([NH:79][CH2:80][C:81]2[CH:86]=[CH:85][CH:84]=[C:83]([Cl:87])[C:82]=2[Cl:88])[CH2:78][CH2:77]1.N1CCCCC1>C(Cl)Cl.CC#N>[C:28]([O:27][C:25](=[O:26])[NH:24][C@@H:22]1[CH2:21][C@H:20]([C:32](=[O:34])[N:79]([CH:76]2[CH2:77][CH2:78]2)[CH2:80][C:81]2[CH:86]=[CH:85][CH:84]=[C:83]([Cl:87])[C:82]=2[Cl:88])[CH2:19][NH:18][CH2:23]1)([CH3:29])([CH3:30])[CH3:31]
Reactant: Clc1cccc(CNC2CC2)c1Cl
Reactant: CC(C)(C)OC(=O)N[C@@H]1C[C@H](C(=O)O)CN(C(=O)OCC2c3ccccc3-c3ccccc32)C1
Agent: CN(C)C(On1nnc2ccc(Cl)cc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCNCC1
Product: CC(C)(C)OC(=O)N[C@H]1CNC[C@@H](C(=O)N(Cc2cccc(Cl)c2Cl)C2CC2)C1
Temperature: 0 °C
Reaction time: 14 h

Procedure:
To a stirred, ice-cooled mixture of (3S*,5R*)-5-tert-butoxycarbonylamino-piperidine-1,3-dicarboxylic acid 1-(9H-fluoren-9-ylmethyl) ester (300 mg, 0.643 mmol) in CH2Cl2 (7 mL) a 2M solution of N-ethyldiisopropylamine in 1-methyl-2-pyrrolidone (161 μl, 0.322 mmol) is added, followed by a solution of O-(1H-6-chlorobenzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HCTU) (292 mg, 0.707 mmol) in CH3CN (7 mL). After 15 min cyclopropyl-(2,3-dichloro-benzyl)-amine (139 mg, 0.643 mmol) is added. The mixture is stirred for 15 min at 0° C. and for 14 h at RT. After evaporation of the solvents in vacuo, the residue is diluted with CH2Cl2 and washed with a 10% aqueous K2CO3 solution, 2M HCl solution and brine. The organic layer is dried over Na2SO4, evaporated in vacuo and the residue purified by flash chromatography (SiO2, CH2Cl2/acetone 96:4). Part of the crude product (50 mg, 0.075 mmol) is dissolved in CH2Cl2 (1 mL), treated with piperidine (0.222 mL, 2.25 mmol) and stirred for 1 h at RT. After evaporation in vacuo, the residue is purified by preparative HPLC (YMC Pack Pro C18, 10-100% CH3CN+0.1% TFA/H2O+0.1% TFA, 20 min, flow 20 mL/min). The combined pure fractions are treated with solid K2CO3, CH3CN is removed in vacuo, and the residual aqueous phase is extracted twice with CH2Cl2. The combined organic layers are dried (Na2SO4) and evaporated to afford the title compound as a colourless foam. MS: 442.2/444.2 [M+H]+; tR (HPLC, Lichrospher RP8; 10-100% CH3CN+0.1% TFA/H2O+0.1% TFA for 5 min, then 100% CH3CN+0.1% TFA for 2.5 min, flow 1.5 ml/min): 5.08 min.
Reaction SMILES: Cl.[OH:2][C:3]1[C:8](=[O:9])[CH:7]=[CH:6][N:5]([CH3:10])[CH:4]=1.C[O:12][CH:13](O)[C:14]([F:17])([F:16])[F:15].Cl>[OH-].[Na+]>[OH:2][C:3]1[C:8](=[O:9])[CH:7]=[CH:6][N:5]([CH3:10])[C:4]=1[CH:13]([OH:12])[C:14]([F:17])([F:16])[F:15]
Reactant: COC(O)C(F)(F)F
Reactant: Cn1ccc(=O)c(O)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cn1ccc(=O)c(O)c1C(O)C(F)(F)F
Temperature: 95 °C
Yield: 34260.3 %

Procedure:
To a solution of 3-hydroxy-1-methylpyridin-4(1H)-one hydrochloride (100.0 g, 0.62 mol) dissolved in a solution of 6N NaOH (206.9 mL) at ice-water bath was added trifluoroacetaldehyde methyl hemiacetal (131.9 mL, 1.24 mmol). The resulting solution was heated to 95° C. for overnight. The reaction mixture was then cooled, and at ice-water bath the pH of the mixture was adjusted to about 5 using a 6N HCl solution. The precipitated solid was collected by filtration, and the solid was thoroughly washed with de-ionized water (100 mL×2), and then dried under vacuum at 43° C. for overnight to afford 3-hydroxy-1-methyl-2-(2,2,2-trifluoro-1-hydroxyethyl)pyridin-4(1H)-one (94.8 g) as a white solid. Yield=68% yield; 1H NMR (90 MHz, MeOD-D4) δ (ppm): 7.60 (d, J=7.1 Hz, 1H), 6.40 (d, J=7.2 Hz, 1H), 5.92 (q, J=8.2 Hz, 1H), 3.98 (s, 3H); MS m/z 224 [M+1], 158 (100%).
Reaction SMILES: CO[C:3]([C:5]1[C:14]([OH:15])=[C:13]2[C:8]([CH:9]=[CH:10][C:11](=[O:23])[N:12]2[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:7][N:6]=1)=[O:4].OC(C(F)(F)F)=O.[NH2:31][CH2:32][C:33]([CH3:38])([CH3:37])[C:34]([OH:36])=[O:35].C[O-].[Na+]>CCO.C([O-])(O)=O.[Na+]>[CH2:16]([N:12]1[C:13]2[C:8](=[CH:7][N:6]=[C:5]([C:3]([NH:31][CH2:32][C:33]([CH3:38])([CH3:37])[C:34]([OH:36])=[O:35])=[O:4])[C:14]=2[OH:15])[CH:9]=[CH:10][C:11]1=[O:23])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: COC(=O)c1ncc2ccc(=O)n(Cc3ccccc3)c2c1O
Reactant: CC(C)(CN)C(=O)O
Agent: C[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(CNC(=O)c1ncc2ccc(=O)n(Cc3ccccc3)c2c1O)C(=O)O
Temperature: 150 °C
Yield: 27.8 %

Procedure:
A mixture of 1-benzyl-8-hydroxy-2-oxo-1,2-dihydro-[1,6]naphthyridine-7-carboxylic acid methyl ester (19 mg, 0.061 mmol), 3-amino-2,2-dimethyl-propionic acid TFA salt (71 mg, 0.31 mmol) and NaOMe (33 mg, 0.61 mmol) in 2 mL of EtOH was heated at 150° C. in a microwave reactor for 6 h. Solvent was evaporated in vacuo, and the residue was partitioned between water and EtOAc. 1 M was added with vigorous stirring until pH about 1. The organic layer was dried over MgSO4 and concentrated in vacuo. The crude product was purified by silica gel chromatography (5-60% EtOAc/hexanes+2% AcOH). The product isolated was then dissolved in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH about 1 with 4 M HCl, and the resulting precipitate was collected by filtration and dried to give 6.7 mg of the title compound. MS: (+) m/z 396.30 (M+1).
Reaction SMILES: [CH2:1]([O:19][C@H:20]1[C@H:24]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]/[CH:34]=[CH:35]\[CH2:36]/[CH:37]=[CH:38]\[CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[CH2:23][N:22]([CH2:44][CH2:45][C:46]([O:48]CC)=[O:47])[CH2:21]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[OH-].[Na+].Cl>C(O)C>[CH2:26]([O:25][C@H:24]1[C@H:20]([O:19][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:21][N:22]([CH2:44][CH2:45][C:46]([OH:48])=[O:47])[CH2:23]1)[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]/[CH:34]=[CH:35]\[CH2:36]/[CH:37]=[CH:38]\[CH2:39][CH2:40][CH2:41][CH2:42][CH3:43]
Reactant: CCCCC/C=C\C/C=C\CCCCCCCCO[C@@H]1CN(CCC(=O)OCC)C[C@H]1OCCCCCCCC/C=C\C/C=C\CCCCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCC/C=C\C/C=C\CCCCCCCCO[C@@H]1CN(CCC(=O)O)C[C@H]1OCCCCCCCC/C=C\C/C=C\CCCCC
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.7 %

Procedure:
The ethyl 3-((3R,4R)-3,4-bis((9Z,12Z)-octadec-9,12-dienyloxy)pyrrolidin-1-yl)propanoate (180 mg, 0.257 mmol) obtained in Example 56 was dissolved in ethanol (2 mL). The solution was stirred at room temperature for 2 hours after adding a 2 mol/L sodium hydroxide aqueous solution (2 mL). The pH was brought to 4 by adding a 1 mol/L hydrochloric acid aqueous solution to the reaction solution, and the aqueous layer was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure after filtration to give 3-((3R,4R)-3,4-bis((9Z,12Z)-octadec-9,12-dienyloxy)pyrrolidin-1-yl)propanoic acid (148 mg, 85.8%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH:7][C:8]([C:10]2[C:18]3[C:17]4[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=4[O:15][C:14]=3[C:13]([O:23][CH2:24][CH:25]3[CH2:27][CH2:26]3)=[CH:12][CH:11]=2)=[O:9])=[CH:3][CH:2]=1.ClC1C=CC=C(C(OO)=[O:36])C=1>C(Cl)(Cl)Cl>[N:1]1[CH:2]=[CH:3][C:4]([NH+:7]([O-:36])[C:8]([C:10]2[C:18]3[C:17]4[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=4[O:15][C:14]=3[C:13]([O:23][CH2:24][CH:25]3[CH2:27][CH2:26]3)=[CH:12][CH:11]=2)=[O:9])=[CH:5][CH:6]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=C(Nc1ccncc1)c1ccc(OCC2CC2)c2oc3ccccc3c12
Solvent: ClC(Cl)Cl
Product: O=C(c1ccc(OCC2CC2)c2oc3ccccc3c12)[NH+]([O-])c1ccncc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 48 %

Procedure:
A suspension of N-(pyrid-4-yl)-4-cyclopropylmethoxy-dibenzo[b,d]furan-1-carboxamide (50 mg, 0.139 mmol) (example 28) and m-chloroperbenzoic acid (50-55%) (120 mg, 0.698 mmol) in chloroform (10 ml) was stirred at room temperature for 12-16 h. The reaction contents were washed with saturated sodium bicarbonate and water. The organic solvent was distilled of in vacuo and the residue was purified by column chromatography using 40% acetone-chloroform as the eluent to give 25 mg of N-(pyrid-4-yl)-4-cyclopropylmethoxy-dibenzo[b,d]furan-1-carboxamide-N1-oxide as white solid; mp: 266-268° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH:11]1[N:15]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=2)[C:14](=[O:28])[CH2:13][CH2:12]1.I[CH3:30]>>[CH3:10][O:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[C:4]=1[CH:11]1[N:15]([CH2:16][C:17]2[CH:18]=[CH:19][C:20]([O:23][C:24]([F:26])([F:25])[F:27])=[CH:21][CH:22]=2)[C:14](=[O:28])[CH:13]([CH3:30])[CH2:12]1
Reactant: CI
Reactant: COc1cccc(OC)c1C1CCC(=O)N1Cc1ccc(OC(F)(F)F)cc1
Product: COc1cccc(OC)c1C1CC(C)C(=O)N1Cc1ccc(OC(F)(F)F)cc1

Procedure:
Prepared according to the described general procedure 8 (GP8) by C-alkylation of 5-(2,6-dimethoxyphenyl)-1-(4-(trifluoromethoxy)benzyl)pyrrolidin-2-one with commercially available iodomethane. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions G): tR=1.03 min.; [M+H]+: 410.02 g/mol.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2.[F:24][C:25]1[C:26]([CH3:34])=[C:27]([CH:31]=[CH:32][CH:33]=1)[C:28](O)=[O:29]>>[F:24][C:25]1[C:26]([CH3:34])=[C:27]([CH:31]=[CH:32][CH:33]=1)[C:28]([NH:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2)=[O:29]
Reactant: Cc1c(F)cccc1C(=O)O
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CN)c1
Product: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2cccc(F)c2C)c1

Procedure:
prepared by reaction of ((1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-(2-methyl-5-m-tolyl-thiazol-4-yl)-methanone with 3-Fluoro-2-methyl-benzoic acid. LC-MS (basic): tR=0.92 min; [M+H]+=464.1.
Reaction SMILES: [C:1]([CH:6]1[CH2:11][C:10](O)([C:12]([O:14][CH3:15])=[O:13])[CH:9]=[CH:8][C:7]1=[O:17])(=[O:5])[CH2:2][CH2:3][CH3:4].B(F)(F)F.O(CC)CC>C1C=CC=CC=1>[C:1]([C:6]1[CH:11]=[C:10]([CH:9]=[CH:8][C:7]=1[OH:17])[C:12]([O:14][CH3:15])=[O:13])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)C1CC(O)(C(=O)OC)C=CC1=O
Agent: FB(F)F
Solvent: c1ccccc1
Solvent: CCOCC
Product: CCCC(=O)c1cc(C(=O)OC)ccc1O
Reaction time: 0.25 h

Procedure:
To a stirred solution of methyl 5-butyryl-1-hydroxy-4-oxocyclohex-2-ene-1-carboxylate in benzene was added BF3.O(Et)2 (1.3 mL, 10 mmol). The mixture was stirred for 0.25 h and then quenched with saturated sodium bicarbonate followed by extraction with dichloromethane. The organic layer was dried (sodium sulfate), filtered, and concentrated under reduced pressure to afford methyl 3-butyryl-4-hydroxybenzoate which was used without further purification or characterization.
Reaction SMILES: ClC1C=C(CCC(C2C=CC=CC=2)=O)C=CC=1.[Cl:18][C:19]1[CH:20]=[C:21]([CH2:25][CH2:26]/[C:27](/[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[CH:28]/[C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH:22]=[CH:23][CH:24]=1>>[Cl:18][C:19]1[CH:20]=[C:21]([CH2:25][CH2:26]/[C:27](/[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[CH:28]\[C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH:22]=[CH:23][CH:24]=1
Reactant: CCOC(=O)/C=C(/CCc1cccc(Cl)c1)c1ccccc1
Agent: O=C(CCc1cccc(Cl)c1)c1ccccc1
Product: CCOC(=O)/C=C(\CCc1cccc(Cl)c1)c1ccccc1

Procedure:
By a procedure similar to that of example 1.85.3, starting from 3-(3-chlorophenyl)-1-phenylpropan-1-one, (Z)-ethyl 5-(3-chloro-phenyl)-3-phenylpent-2-enoate and (E)-ethyl 5-(3-chlorophenyl)-3-phenylpent-2-enoate were obtained as colourless oils.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([O:13]C)=O)=[CH:8][CH:9]=2)[N:4]=[CH:3][CH:2]=1.[NH3:15]>CO>[N:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([NH2:15])=[O:13])=[CH:8][CH:9]=2)[N:4]=[CH:3][CH:2]=1
Reactant: COC(=O)c1ccc2nccnc2c1
Reactant: N
Solvent: CO
Product: NC(=O)c1ccc2nccnc2c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A suspension of methyl quinoxaline-6-carboxylate (2.00 g) in methanol (7.0 mL) and 28-30% ammonia (14 mL) was stirred in a sealed tube at room temperature for 16 h. The precipitated solid was filtered, washed with water and dried under high vacuum to give quinoxaline-6-carboxamide as a white powder. A portion of this material (0.10 g) was suspended in anhydrous dichloromethane and treated with oxalyl chloride (1.0 mL of a 2M solution in dichloromethane) under a nitrogen atmosphere. The mixture was heated at reflux for 16 h and concentrated under reduced pressure. The residue was dissolved in anhydrous tetrahydrofuran (1 mL) and added to an ice-cooled solution of 3-aminobiphenyl (0.98 g) in anhydrous tetrahydrofuran (1 mL). The mixture was stirred at room temperature for 2 h. The solvent was evaporated and the residue taken up in methanol and filtered to give N-{[(3-phenylphenyl)-amino]carbonyl}quinoxalin-6-ylcarboxamide as a white powder.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH2:14][N:15]2[C:19]([CH2:20][CH2:21]O)=[CH:18][N:17]=[CH:16]2)=[CH:4][CH:3]=1.S(Cl)([Cl:25])=O>C(Cl)Cl>[Cl:25][CH2:21][CH2:20][C:19]1[N:15]([CH2:14][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH:16]=[N:17][CH:18]=1
Reactant: OCCc1cncn1Cc1ccccc1-c1ccc(F)cc1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: Fc1ccc(-c2ccccc2Cn2cncc2CCCl)cc1

Procedure:
To a solution of 2-[3-(4′-fluorobiphenyl-2-ylmethyl)-3H-imidazol-4-yl]ethanol (0.341 g, 1.15 mmol) in CH2Cl2 (10 mL) is added, thionyl chloride (0.11 mL, 1.50 mmol) at 0° C. The mixture is then heated to reflux for 3 h before the solvent is removed and the residue dried under reduced pressure to give 5-(2-chloroethyl)-1-(4′-fluorobiphenyl-2-ylmethyl)-1H-imidazole. The residue is taken up in THF (60 mL). TMEDA (0.71 ml, 4.72 mmol) is added, followed by a hexane/THF solution of LDA (2.62 mL, 1.8 M) at −78° C. The resulting mixture is stirred at −78° C. for 5 h. The excess LDA is then quenched by the addition of saturated NH4Cl. The mixture is then diluted with CH2Cl2 and water. The organic layer is separated and washed with water, brine and dried over Na2SO4. After concentration, the residue is purified by flash chromatography (CH2Cl2/MeOH) to give 5-(4′-fluorobiphenyl-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazole. MS (ESI), m/z 279.1 (M+H). Resolution of the (R) and (S) enantiomers of the title compound is achieved by chiral HPLC using ChiralPak AD column and 13% IPA:hexane to give enantiomer A (tr=9.6 min) and enantiomer B=12.6 min). For enantiomer B: 1H NMR (400 MHz, CDCl3) (HCl salt) δ ppm 2.68-2.79 (m, 1H), 2.95-3.06 (m, 2H), 3.13-3.22 (m, 1H), 5.55 (app t, J=7.6 Hz, 1H), 6.96 (dd, J=7.6, 1.5 Hz, 1H), 7.13 (s, 1H), 7.18 (app t, J=8.6 Hz, 2H), 7.27-7.32 (m, 2H), 7.33-7.38 (m, 1H), 7.40-7.49 (m, 2H), 8.01 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([N:10]2[CH:14]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:13](=[O:19])[C:12]([CH3:21])([CH3:20])[C:11]2=[O:22])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].C([BH-](C(CC)C)C(CC)C)(CC)C.[Li+].C1COCC1>>[Cl:1][C:2]1[CH:9]=[C:8]([N:10]2[C@H:14]([CH2:15][CH:16]([CH3:17])[CH3:18])[C@H:13]([OH:19])[C:12]([CH3:20])([CH3:21])[C:11]2=[O:22])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: CC(C)CC1C(=O)C(C)(C)C(=O)N1c1ccc(C#N)c(Cl)c1
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)C[C@@H]1[C@H](O)C(C)(C)C(=O)N1c1ccc(C#N)c(Cl)c1

Procedure:
Using 2-chloro-4-(5-isobutyl-3,3-dimethyl-2,4-dioxopyrrolidin-1-yl)benzonitrile (620 mg) and lithium tri(sec-butyl)borohydride-THF solution (2.92 mL, 1 mol/L), and in the same manner as in Example 5, the title compound was obtained as a colorless solid (yield: 363 mg, 58%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[C:6]([NH2:8])=[O:7].C(Cl)(=O)[C:16](Cl)=[O:17]>C(Cl)CCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[C:6]([N:8]=[C:16]=[O:17])=[O:7]
Reactant: O=C(Cl)C(=O)Cl
Reactant: COc1cc(C(N)=O)ccc1[N+](=O)[O-]
Solvent: ClCCCl
Product: COc1cc(C(=O)N=C=O)ccc1[N+](=O)[O-]
Yield: 88.3 %

Procedure:
To a solution of 3-methoxy-4-nitrobenzamide (1.00 g, 5.10 mmol) in EDC (10 mL) was added oxalyl chloride (0.64 g, 6.12 mmol). The reaction mass was refluxed for 24 h. Excess of solvent was removed under vacuum to afford 1.0 g of desired product.
Reaction SMILES: N[C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.S(=O)(=O)(O)[OH:14].N([O-])=O.[Na+]>O>[OH:14][C@@H:2]([CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[C:10]([OH:12])=[O:11]
Reactant: O=S(=O)(O)O
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: O=C(O)[C@@H](O)Cc1ccccc1
Temperature: 0 °C
Reaction time: 20 h
Yield: 69.6 %

Procedure:
L-Phenylalanine (10.00 g, 60.5 mmol) was added to a dilution of 8.88 g (90.5 mmol) of concentrated sulfuric acid in 110 g of water and then, at an inside temperature of 0° C., a mixture of 10.45 g (151.5 mmol) of sodium nitrite and 20 g of water was added over 5 hours. After addition, the mixture was further stirred at 0° C. for 20 hours and, thereafter, the same work-up procedure as in Example 1 was followed. The combined extract (113.7 g) obtained contained 7.0 g of (2S)-2-hydroxy-3-phenylpropionic acid (yield 70%, optical purity 96.6% ee). The proton concentration (normality) in the reaction of this example was 1.7 mol/kg, the amount of the protonic acid was 3.0 equivalents (relative to L-phenylalanine) and the reaction temperature was 0° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH2:8].[C:9]1([C:11](=[CH:13][CH:14]=[CH:15][CH:16]=1)O)O>O>[CH:4]1[C:3]2[NH:8][C:11]3[C:9](=[CH:16][CH:15]=[CH:14][CH:13]=3)[NH:1][C:2]=2[CH:7]=[CH:6][CH:5]=1
Reactant: Oc1ccccc1O
Reactant: Nc1ccccc1N
Solvent: O
Product: c1ccc2c(c1)Nc1ccccc1N2
Temperature: 170 °C
Yield: 101.4 %

Procedure:
To a 12 L Morton flask is charged 702 g 1,2-diaminobenzene and 2.1 Kg catechol (3 equivalents based on 1,2-diaminobenzene). Heat is applied by a heating mantle, and at the end of 30 minutes, all materials are melted and the temperature has risen to 90° C. Over the next 40 minutes, the temperature is increased to ca. 170° C. The temperature is maintained in the range of 151° C. to 187° C. over a 4½ day period. The reaction mixture is cooled to 80° C. and 8 L deionized water added over 30 minutes. The mixture is allowed to cool to room temperature overnight, and a filter candle used to remove water. A further 8 L water is added and heated to 70° C., cooled to 40° C., and the water again removed. A further wash with 8 L water is again performed, with the wash temperature lowered only to 60° C. during removal of water. The product is filtered on a filter funnel and air dried for 30 minutes to yield ca. 1200 g of moist 5,10-dihydrophenazine containing approximately 20% water. Yield of dry 5,10-dihydrophenazine is 960 g (68% of theory, based on 1,2-diaminobenzene).