Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:3]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.Cl[C:17]1[NH:18][C:19]2[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=2[N:21]=1>CC(O)C>[CH3:1][C:2]1[C:3]([O:8][C:9]2[CH:10]=[CH:11][C:12]([NH:15][C:17]3[NH:21][C:20]4[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=4[N:18]=3)=[CH:13][CH:14]=2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Clc1nc2ccccc2[nH]1
Reactant: Cc1cccnc1Oc1ccc(N)cc1
Solvent: CC(C)O
Product: Cc1cccnc1Oc1ccc(Nc2nc3ccccc3[nH]2)cc1
Temperature: 170 °C

Procedure:
A mixture of 4-(3-methylpyridin-2-yloxy)benzenamine (1.00 g, 4.99 mmol) and 2-chlorobenzimidazole (0.860 g, 5.64 mmol) in 10 mL of iPrOH was heated at 170° C. for 30 min in the microwave. The reaction mixture was evaporated onto silica gel. Purification by flash chromatography (2M NH3 in MeOH:CH2Cl2) afforded N-(4-(3-methylpyridin-2-yloxy)phenyl)-1H-benzo[d]imidazol-2-amine as solid. MS (ESI, pos. ion) m/z: 317.1 (M+1). IC50 (uM) ++++.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]3[N:14]([CH2:29][C@H:30]4[CH2:35][CH2:34][C@H:33]([CH3:36])[CH2:32][CH2:31]4)[C:15]([N:17]4[CH2:22][CH2:21][O:20][CH2:19][C@H:18]4[C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[N:16][C:12]=3[CH:11]=[C:10]([NH2:37])[N:9]=2)[CH:5]=[N:6][CH:7]=1.[CH3:38][S:39](Cl)(=[O:41])=[O:40].CO.[Li+].[OH-]>ClCCl.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]3[N:14]([CH2:29][C@H:30]4[CH2:35][CH2:34][C@H:33]([CH3:36])[CH2:32][CH2:31]4)[C:15]([N:17]4[CH2:22][CH2:21][O:20][CH2:19][C@H:18]4[C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[N:16][C:12]=3[CH:11]=[C:10]([NH:37][S:39]([CH3:38])(=[O:41])=[O:40])[N:9]=2)[CH:5]=[N:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: C[C@H]1CC[C@H](Cn2c(N3CCOC[C@H]3c3ccccc3)nc3cc(N)nc(-c4cncc(Cl)c4)c32)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: CS(=O)(=O)Nc1cc2nc(N3CCOC[C@H]3c3ccccc3)n(C[C@H]3CC[C@H](C)CC3)c2c(-c2cncc(Cl)c2)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-[(3R)-3-phenylmorpholin-4-yl]-3H-imidazo[4,5-c]pyridin-6-amine (70 mg, 0.13 mmol) in dichloromethane (2.0 mL) was added TEA (27 mg, 0.27 mmol) at 0° C. followed by slow addition of methane sulfonyl chloride (15 mg, 0.13 mmol). The reaction was warmed slowly to room temperature and stirred for 2 h. The reaction was then diluted with CH2Cl2 (70 mL) and water (10 mL). The organic layer was separated, washed with saturated brine solution (2×20 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was dissolved in THF (1 mL), MeOH (1 mL), and H2O (0.5 mL), and then LiOH (20 mg, 0.48 mmol) was added. The reaction was stirred at room temperature for 1 h. The reaction was then concentrated under reduced pressure. The residue was purified by silica gel chromatography (90% EtOAc/petroleum ether). The isolated product was further purified by preparative HPLC (acetonitrile:water: 0.1% v/v trifluoroacetic acid modifier) to afford N-{4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-[(3R)-3-phenylmorpholin-4-yl]-3H-imidazo[4,5-c]pyridin-6-yl}methanesulfonamide (TFA salt). MS ES/APCI calc'd. for C30H36ClN6O3S [M+H]+ 595. found 595. 1H NMR (400 MHz, DMSO-d6): δ 10.26 (bs, 1H), 8.77 (d, J=2.0 Hz, 2H), 8.23 (t, J=2.0 Hz, 1H), 7.43 (d, J=7.2 Hz, 2H), 7.29-7.21 (m, 3H), 6.99 (s, 1H), 4.75 (t, J=5.2 Hz, 1H), 3.92-3.88 (m, 4H), 3.75-3.70 (m, 1H), 3.54-3.49 (m, 2H), 3.26 (s, 3H), 3.25-3.20 (m, 1H), 1.41-1.35 (m, 2H), 1.08-1.07 (m, 1H), 0.76-0.74 (m, 3H), 0.70 (d, J=6.8 Hz, 3H), 0.58-0.55 (m, 1H), 0.50-0.47 (m, 1H), 0.40-0.27 (m, 2H).
Reaction SMILES: [OH:1][C@H:2]1[CH2:22][C@@:21]2([CH3:23])[C@@H:13]([CH2:14][CH2:15][C@:16]2([OH:24])[C:17](=[O:20])[CH2:18][OH:19])[C@H:12]2[C@H:3]1[C@:4]1([CH3:27])[C:9]([C@@H:10]([CH3:25])[CH2:11]2)=[CH:8][C:7](=[O:26])[CH2:6][CH2:5]1.[CH3:28][O:29][CH2:30][C:31](Cl)=[O:32]>>[OH:1][C@H:2]1[CH2:22][C@@:21]2([CH3:23])[C@@H:13]([CH2:14][CH2:15][C@:16]2([OH:24])[C:17](=[O:20])[CH2:18][O:19][C:31](=[O:32])[CH2:30][O:29][CH3:28])[C@H:12]2[C@H:3]1[C@:4]1([CH3:27])[C:9]([C@@H:10]([CH3:25])[CH2:11]2)=[CH:8][C:7](=[O:26])[CH2:6][CH2:5]1
Reactant: COCC(=O)Cl
Reactant: C[C@H]1C[C@@H]2[C@H]([C@@H](O)C[C@@]3(C)[C@H]2CC[C@]3(O)C(=O)CO)[C@@]2(C)CCC(=O)C=C12
Product: COCC(=O)OCC(=O)[C@@]1(O)CC[C@H]2[C@@H]3C[C@H](C)C4=CC(=O)CC[C@]4(C)[C@H]3[C@@H](O)C[C@@]21C

Procedure:
1.5 g of 11β,17,21-trihydroxy-6α-methyl-4-pregnene-3,20-dione is reacted analogously to Example 1(a) with methoxyacetic acid chloride, worked up, and chromatographed, thus isolating 1.6 g of 11β,17-dihydroxy-21-methoxyacetoxy-6α-methyl-4-pregnene-3,20-dione.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[N:5][C:6]([CH3:13])=[CH:7][C:8]=2[CH3:12])[N:3]=1.[S:14]([O-:17])([O-:16])=[O:15].[Na+].[Na+].Cl>O>[OH:17][S:14]([C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[N:5][C:6]([CH3:13])=[CH:7][C:8]=2[CH3:12])[N:3]=1)(=[O:16])=[O:15]
Reactant: O=S([O-])[O-]
Reactant: Cc1cc(C)c2ccc(Cl)nc2n1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: Cc1cc(C)c2ccc(S(=O)(=O)O)nc2n1
Reaction time: 12 h
Yield: 64.6 %

Procedure:
9.6 g (50 mmol) of 2-chloro-5,7-dimethyl-1,8-naphthyridine prepared in accordance with Lit.8),9) is introduced into a solution of 8.2 g (65 mmol) of sodium sulfite in 40 ml of water which has been adjusted to a pH of 7-8 with dilute aqueous hydrochloric acid. The suspension which is obtained is heated for 12 hours under reflux. After cooling, solid residues are removed from the solution and the solution itself is acidified with aqueous hydrochloric acid (pH about 1). The acidified solution is left for 12 hours at 0° to 5° C., the product crystallizing out. There is obtained 7.7 g (65%) of the title compound; m.p.: >280° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([O:12]CC)=[O:11].[OH-].[K+].[CH3:17][C:18]1([O:21][CH2:20]1)[CH3:19].Cl>CS(C)=O.C(OCC)(=O)C.O>[OH:21][C:18]([CH3:20])([CH3:19])[CH2:17][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([OH:12])=[O:11]
Reactant: CCOC(=O)c1cc2ccccc2[nH]1
Reactant: CC1(C)CO1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(O)Cn1c(C(=O)O)cc2ccccc21
Reaction time: 0.5 h

Procedure:
To 760 mg of ethyl 2-indole carboxylate (4 mmol) dissolved in 8 ml dimethyl sulfoxide was added 290 mg of crushed potassium hydroxide (4.4 mmol). The mixture was stirred for approximately 30 minutes. 1.8 ml of isobutylene oxide was then added and the mixture was stirred at 50 C for 65 hours. The reaction was worked up by addition of water, 1M HCl to adjust the pH to 4-5, and ethyl acetate. The layers were separated and the ethyl acetate layer was washed with brine and dried over sodium sulfate. Evaporation gave 1-(2-hydroxy-2-methyl-propyl)-1H-indole-2-carboxylic acid (840 mg) as a solid (M−H=233) that was used directly in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([NH:6][C:7]2[CH:15]=[C:14]([C:16]([OH:18])=O)[C:13]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)=[CH:12][C:8]=2[C:9]([OH:11])=O)=[CH:4][CH:3]=1.O>CO>[CH:3]1[C:2]([Cl:1])=[CH:28][C:27]2[C:9]([C:8]3[C:7]([NH:6][C:5]=2[CH:4]=1)=[CH:15][C:14]1[C:16]([C:21]2[CH:22]=[C:23]([Cl:26])[CH:24]=[CH:25][C:20]=2[NH:19][C:13]=1[CH:12]=3)=[O:18])=[O:11]
Reactant: O=C(O)c1cc(Nc2ccc(Cl)cc2)c(C(=O)O)cc1Nc1ccc(Cl)cc1
Solvent: CO
Solvent: O
Product: O=c1c2cc(Cl)ccc2[nH]c2cc3c(=O)c4cc(Cl)ccc4[nH]c3cc12
Temperature: 150 °C
Yield: 102.4 %

Procedure:
To 200.0 g of polyphosphoric acid (118%) were added 30.0 g (71.7 mmol) of 2,5-bis(p-chloroanilino)terephthalic acid and 0.6 g of phthalimidomethylquinacridone. The stirred mixture was irradiated in the microwave oven for 2.0 minutes. The reaction mixture was cooled to 150° C. and drowned in 400 g of methanol with vigorous stirring. The resultant methanol suspension was maintained at reflux for one hour, cooled to 60° C., added to 800 g of water, and heated at 60° C. for 30 minutes. The solid component was collected by filtration and washed with 8.0 liters of water. The presscake was dried overnight in an oven at 60° C. to give 28.0 g of 2,9-dichloroquinacridone (C. I. Pigment Red 202).
Reaction SMILES: [N+:1](/[CH:4]=[CH:5]/[C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=1)([O-:3])=[O:2].[CH:16](=[O:20])[CH:17]([CH3:19])[CH3:18].CC(O)C.CCCCCC>C(Cl)(Cl)Cl>[CH3:18][C:17]([CH3:19])([C@H:5]([C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=1)[CH2:4][N+:1]([O-:3])=[O:2])[CH:16]=[O:20]
Reactant: CC(C)C=O
Reactant: O=[N+]([O-])/C=C/c1ccc2ccccc2c1
Solvent: CCCCCC
Solvent: CC(C)O
Solvent: ClC(Cl)Cl
Product: CC(C)(C=O)[C@@H](C[N+](=O)[O-])c1ccc2ccccc2c1

Procedure:
The title compound was prepared from (E)-2-(2-nitrovinyl)naphthalene and isobutyraldehyde according to General Procedure. The enantiomeric excess was determined by HPLC with Chiralpak AS-H column at 210 nm (2-propanol:hexane=10:90), 1 mL/min, tmajor=16.2 min, tminor=18.0 min, [α]D20=+1.7 (c=1.8, CHCl3)
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1([C:23]([OH:25])=[O:24])[C:12]2[C:7](=[CH:8][C:9]([C:15](=[O:22])[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[C:10]([O:13][CH3:14])[CH:11]=2)[CH2:6][CH2:5]1.[CH3:26]O>>[CH3:26][O:24][C:23]([C:4]1([CH3:3])[C:12]2[C:7](=[CH:8][C:9]([C:15](=[O:22])[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[C:10]([O:13][CH3:14])[CH:11]=2)[CH2:6][CH2:5]1)=[O:25]
Reactant: COc1cc2c(cc1C(=O)c1ccccc1)CCC2(C)C(=O)O
Reactant: CO
Agent: [Na+]
Agent: [OH-]
Product: COC(=O)C1(C)CCc2cc(C(=O)c3ccccc3)c(OC)cc21

Procedure:
Analogously to the description in Example 2, 0.4 g of 1-methyl-5-benzoyl-6-methoxy-indane-1-carboxylic acid methyl ester and 5 ml of 2 N sodium hydroxide solution in 15 ml of methanol give 1-methyl-5-benzoyl-6-methoxy-indane-1-carboxylic acid of melting point 135°-137° C (from ether-petroleum ether). The starting material can be obtained as follows:
Reaction SMILES: C(S([C:5]1[N:6]=[CH:7][C:8]2[CH:14]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:12]([C:21]3[CH:28]=[CH:27][C:24]([CH:25]=[O:26])=[CH:23][CH:22]=3)=[N:11][C:9]=2[N:10]=1)=O)C.[CH3:29][N:30]([CH3:39])[CH2:31][CH2:32][N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1>O1CCOCC1>[CH3:29][N:30]([CH3:39])[CH2:31][CH2:32][N:33]1[CH2:38][CH2:37][N:36]([C:5]2[N:6]=[CH:7][C:8]3[CH:14]=[C:13]([C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=4)[C:12]([C:21]4[CH:28]=[CH:27][C:24]([CH:25]=[O:26])=[CH:23][CH:22]=4)=[N:11][C:9]=3[N:10]=2)[CH2:35][CH2:34]1
Reactant: CN(C)CCN1CCNCC1
Reactant: CCS(=O)c1ncc2cc(-c3ccccc3)c(-c3ccc(C=O)cc3)nc2n1
Solvent: C1COCCO1
Product: CN(C)CCN1CCN(c2ncc3cc(-c4ccccc4)c(-c4ccc(C=O)cc4)nc3n2)CC1
Temperature: 150 °C

Procedure:
To a solution of 4-[2-(ethylsulfinyl)-6-phenylpyrido[2,3-d]pyrimidin-7-yl]benzaldehyde (6-4; 900 mg, 2.33 mmoles) in dioxane (1 mL) was added 1-(2-dimethylaminoethyl)-piperazine (66 mg, 2.33 mmoles) and heated to 150° C. in a microwave reactor for 30 min. The mixture was concentrated under reduced pressure and the residue was purified by silica gel chromatography (100% Hex. to 100% EtOAc) to give the title compound. LRMS m/z (M+H) Calcd: 467.2, found 467.6.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[N:15]=[CH:14][C:13]2[N:16]=[CH:17][N:18]([C:19]3[S:23][C:22]([C:24]([O:26][CH3:27])=[O:25])=[C:21]([OH:28])[CH:20]=3)[C:12]=2[CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[F:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[CH:36](O)[CH3:37].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>ClCCl>[Si:1]([O:8][CH2:9][C:10]1[N:15]=[CH:14][C:13]2[N:16]=[CH:17][N:18]([C:19]3[S:23][C:22]([C:24]([O:26][CH3:27])=[O:25])=[C:21]([O:28][CH:36]([C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=4[F:29])[CH3:37])[CH:20]=3)[C:12]=2[CH:11]=1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: COC(=O)c1sc(-n2cnc3cnc(CO[Si](C)(C)C(C)(C)C)cc32)cc1O
Reactant: CC(O)c1ccccc1F
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)c1sc(-n2cnc3cnc(CO[Si](C)(C)C(C)(C)C)cc32)cc1OC(C)c1ccccc1F

Procedure:
In a similar manner as described for example B31, 3.0 g of methyl 5-[6-({[tert-butyl(dimethyl)silyl]oxy}methyl)-1H-imidazo[4,5-c]pyridin-1-yl]-3-hydroxythiophene-2-carboxylate, 1.50 g of 1-(2-fluorophenyl)ethanol, 4.76 g of triphenylphosphine (polymer bound, ˜3 mmol/g) and 3.29 g of di-tert-butyl azodicarboxylate in 85 ml anhydrous dichloromethane yield the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C:16](=[O:33])[C:17]1[CH:22]=[CH:21][C:20]([C:23]2[C:28]([C:29]#[N:30])=[CH:27][C:26]([CH:31]=O)=[CH:25][N:24]=2)=[CH:19][CH:18]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:34]([NH2:36])[CH3:35].[BH4-].[Na+].C(=O)(O)[O-].[Na+]>C1COCC1.ClCCl.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-].O.CO>[C:29]([C:28]1[C:23]([C:20]2[CH:19]=[CH:18][C:17]([C:16]([NH:15][C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:33])=[CH:22][CH:21]=2)=[N:24][CH:25]=[C:26]([CH2:31][NH:36][CH2:34][CH3:35])[CH:27]=1)#[N:30]
Reactant: CCN
Reactant: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(-c2ncc(C=O)cc2C#N)cc1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: O=C([O-])O
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CCNCc1cnc(-c2ccc(C(=O)Nc3ccccc3NC(=O)OC(C)(C)C)cc2)c(C#N)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
N-(2-t-Butoxycarbonylaminophenyl)-4-(3-cyano-5-formylpyridin-2-yl)benzamide (0.80 g, 1.8 mmol; prepared as described in Method 15 below) and ethylamine (1.4 ml of a 1.0M solution in THF, 1.4 mmol) were dissolved in dichloromethane (15 ml). Titanium (IV) isopropoxide (1.55 g, 1.62 ml, 5.4 mmol) was added and the mixture stirred at ambient temperature for 1 hour. Sodium borohydride (342 mg) and methanol (3 ml) were then added and the mixture stirred for a further 30 minutes. Water (20 ml) then a saturated aqueous sodium bicarbonate solution (30 ml) was added and the product extracted with dichloromethane (3×30 ml). The organic residues were concentrated and the residue purified using flash column chromatography eluting with ethyl acetate, followed by 2M NH3/MeOH (3-5%) in ethyl acetate to give t-butyl {2-[(4-{3-cyano-5-[(ethylamino)methyl]pyridin-2-yl}benzoyl)amino]phenyl}carbamate (508 mg) as a white solid. This was dissolved in methanol (4 ml), a 4M solution of hydrogen chloride in 1,4-dioxan (10 ml, 40 mmol) was added and the solution then stirred at ambient temperature for 2 hours. The solvent was evaporated, methanol (5 ml) was added and the resulting solution was absorbed onto an SCX-2 column, which was washed with methanol (2 column volumes) and then eluted with a 2M solution of ammonia in methanol (2 column volumes) to give the product as a foam. This was re-precipitated by stirring in diethyl ether (20 ml) to give the title compound as a white solid (359 mg, 53%); NMR Spectrum: (DMSO-d6 373K) 1.08 (t, 3H), 2.62 (q, 2H), 3.67 (s, 2H), 4.73 (br s, 2H), 6.63 (m, 1H), 6.82 (m, 1H), 6.98 (m, 1H), 7.27 (m, 1H), 7.99 (d, 2H), 8.13 (d, 2H), 8.28 (d, 1H), 8.88 (d, 1H), 9.50 (br s, 1H); Mass Spectrum: M+H+ 372.
Reaction SMILES: [CH2:1]([OH:4])[CH:2]=[CH2:3].C([Zn]CC)C.CCCCCCC.O[C@H]([C@@H](O)C(OC(C)C)=O)C(OC(C)C)=O.Cl[C:34](=[N:42][OH:43])[C:35]1[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=1>C(Cl)(Cl)Cl.C(Cl)Cl.CO>[F:41][C:38]1[CH:39]=[CH:40][C:35]([C:34]2[CH2:3][C@H:2]([CH2:1][OH:4])[O:43][N:42]=2)=[CH:36][CH:37]=1
Reactant: ON=C(Cl)c1ccc(F)cc1
Reactant: C=CCO
Agent: CC(C)OC(=O)[C@H](O)[C@@H](O)C(=O)OC(C)C
Agent: CC[Zn]CC
Solvent: CO
Solvent: ClCCl
Solvent: CCCCCCC
Product: OC[C@H]1CC(c2ccc(F)cc2)=NO1
Reaction time: 0.25 h

Procedure:
To a cooled (0° C.) solution of allyl alcohol (1.0 ml, 14.7 mmol) in chloroform (15.0 ml) was added 1.0 M diethylzinc in heptane (15.0 ml, 15.0 mmol) and stirred for 15 min under an atmosphere of nitrogen. A solution of (2R,3R)-diisopropyl 2,3-dihydroxysuccinate (2.7 ml, 12.7 mmol) was added to above mixture and stirred for 2 hours. Then another portion of 1.0 M diethylzinc in heptane (15.0 ml, 15.0 mmol) was added at 0° C. A solution of α-chloro-4-fluorobenzaldoxime (2.8 g, 16.1 mmol) in chloroform (15 ml) was added to the reaction mixture. After 3 hours, the reaction was quenched with saturated NH4Cl4, and the mixture extracted with CHCl3 (3×50 ml). The combined organic phase was washed with brine, dried over Mg2SO4, filtered, and concentrated under reduced pressure to yield a crude solid. Chromatography (1:98 to 10:90 MeOH:CH2Cl2) over silica gel yielded ((R)-3-(4-fluorophenyl)-4,5-dihydroisoxazol-5-yl)methanol, a compound of formula (22) as a white solid (2.34 g, 12.0 mmol).
Reaction SMILES: [H-].[Na+].[OH:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1.I[CH3:18].O>CN(C=O)C>[CH3:18][O:3][N:4]1[CH2:5][CH2:6][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:8][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCN(O)CC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CON1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 36.2 %

Procedure:
A 57% oil dispersion containing 0.6 g (0.025 mole) NaH was added in one portion to a solution of 4.7 g (0.023 mole) 1-hydroxy-4-(1,1-dimethylethoxycarbonyl)piperazine in 100 ml DMF under a dry N2 atmosphere. The mixture was stirred for 2 hours at room temperature and then 6.5 g (0.046 mole) iodomethane was added over 1 minute. After stirring for an additional 15 minutes, the mixture was poured into 100 ml H2O, stirred briefly, and extracted thoroughly with low boiling (35°-65° C.) petroleum ether. The extracts were dried (MgSO4), filtered and evaporated in vacuo to give 1.8 g of an oil. The oil was dissolved in ethyl ether, washed with dilute aqueous HCl, dried (MgSO4), filtered, and evaporated in vacuo to yield 1.3 g yellow oil. Short path distillation (Kugelrohr) returned 0.8 g colorless distillate, b.p.* 55°-65° C./0.15 mm. Calc. for C10H 20 N2O3 (216.28): C, 55.53; H, 9.32; N, 12.95; O, 22.19. Found: C, 55.61; H, 9.13; N, 12.96; O, 22.33.
Reaction SMILES: CO[C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9]([OH:13])=[CH:10]2)=[CH:5][CH:4]=1>C1C2C(=CC=CC=2)C=CC=1O.C(Cl)(Cl)(Cl)Cl>[CH:4]1[CH:5]=[C:6]2[CH:7]=[CH:8][C:9]([OH:13])=[C:10]([C:10]3[C:11]4[C:6](=[CH:5][CH:4]=[CH:3][CH:12]=4)[CH:7]=[CH:8][C:9]=3[OH:13])[C:11]2=[CH:12][CH:3]=1
Reactant: COc1ccc2ccc(O)cc2c1
Agent: Oc1ccc2ccccc2c1
Solvent: ClC(Cl)(Cl)Cl
Product: Oc1ccc2ccccc2c1-c1c(O)ccc2ccccc12
Reaction time: 0.17 h
Yield: 95 %

Procedure:
A reaction flask described in example 9 was charged with a solution of catalyst 1c (12.2 mg, 0.02 mmol) in anhydrous CCl4 (1 mL). The solution was stirred for 10 min under an oxygen atmosphere and then treated with a solution of 7-methoxy-2-naphthol (35 mg, 0.2 mmol) in anhydrous CCl4 (1 mL) under 0° C. The reaction mixture was stirred at 0° C. until the reaction was complete (monitored by TLC). The crude mixture was concentrated under reduced pressure, and purified by column chromatography (Ethyl acetate/Petroleum ether=⅓) to give (R)-BINOL 3b, Yield 95%. [α]D25=−104.7 (c=0.35 in EtOAc), 1HNMR (300 MHz, CDCl3) δ (ppm) 7.88 (d, J=9.0 Hz, 2H, 2×HC (5)), 7.79 (d, J=9.0 Hz, 2H, 2×HC (4)), 7.22 (d, J=8.7 Hz, 2H, 2×HC (3)), 7.03 (dd, J=9.0 Hz, 2.4 Hz, 2H, 2×HC (6)), 6.49 (d, J=2.4 Hz, 2H, 2×HC (8)), 5.08 (s, 2H, 2×OH), 3.59 (s, 6H, 2×OCH3). e.e. 95%, and the configuration was R (Kromasil CHI-TBB column, Hexane/propan-2-ol=80: 20; flow rate 1 mL/min; S-isomer, tR 4.95 min and R-isomer, tR 5.32 min).
Reaction SMILES: [C:1]([O:10]CC)(=O)[C:2]([O:4][C:5]([CH3:8])([CH3:7])[CH3:6])=[O:3].[Li][C:14]#[C:15][CH:16]([CH3:18])[CH3:17].CC(C)C#C.C([Li])CCC.O=O.C(=O)=O>O1CCCC1.O>[CH3:17][CH:16]([CH3:18])[C:15]#[C:14][C:1](=[O:10])[C:2]([O:4][C:5]([CH3:6])([CH3:7])[CH3:8])=[O:3]
Reactant: CCOC(=O)C(=O)OC(C)(C)C
Reactant: [Li]C#CC(C)C
Agent: C#CC(C)C
Agent: O=C=O
Agent: O=O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)C#CC(=O)C(=O)OC(C)(C)C

Procedure:
Ethyl t-butyl oxalate ##EQU1## can be prepared by the method of Carpino [J. Amer. Chem. Soc. 82: 2725 (1960)], and 1-lithio-3-methylbut-1-yne ##EQU2## can be prepared by reacting commercially available 3-methylbut-1-yne and n-butyllithium under anhydrous conditions in an inert atmosphere (i.e., no H2O, O2, or CO2) at a temperature of from 0° to 5° C. Anhydrous tetrahydrofuran (THF) is the preferred solvent for the reactions of step (a).
Reaction SMILES: CC1(C)[O:6][C:5](=[O:7])[CH:4]([CH:8]([CH2:12][CH2:13][CH2:14][CH3:15])[C:9]([OH:11])=O)[O:3]1.[C:17]1([CH:23]2[CH2:27][CH2:26][CH2:25][NH:24]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[OH:3][C@@H:4]([C@H:8]([C:9]([N:24]1[CH2:25][CH2:26][CH2:27][CH:23]1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:11])[CH2:12][CH2:13][CH2:14][CH3:15])[C:5]([OH:6])=[O:7]
Reactant: CCCCC(C(=O)O)C1OC(C)(C)OC1=O
Reactant: c1ccc(C2CCCN2)cc1
Product: CCCC[C@@H](C(=O)N1CCCC1c1ccccc1)[C@H](O)C(=O)O

Procedure:
The title compound is prepared from 2-(2,2-dimethyl-4-oxo-1,3-dioxolan-5-yl)hexanoic acid A-5 and commercially available 2-phenyl-pyrrolidine B-5 according to General Procedure B.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[NH2:12][C:13]1[CH:14]=[C:15]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:16]=[CH:17][CH:18]=1>>[C:15]1([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:16]=[CH:17][CH:18]=[C:13]([NH:12][C:7](=[O:9])[C:6]2[CH:10]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[OH:11])[CH:14]=1
Reactant: O=C(O)c1cc(Cl)ccc1O
Reactant: Nc1cccc(-c2ccccc2)c1
Product: O=C(Nc1cccc(-c2ccccc2)c1)c1cc(Cl)ccc1O
Yield: 75.6 %

Procedure:
Using 5-chlorosalicylic acid and 3-aminobiphenyl as the raw materials, the same operation as the example 16 gave the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:9][C:8](=[O:10])[N:7]([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)[CH2:6]1)=[O:4].C(OC)(C)(C)C.[OH-].[Na+]>P([O-])([O-])([O-])=O.S([O-])([O-])(=O)=O.[Na+].[Na+].O>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C:8](=[O:10])[N:7]([C:11]2[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=2)[CH2:6]1)=[O:4]
Reactant: COC(=O)C1CC(=O)N(c2ccc(O)cc2)C1
Agent: O=P([O-])([O-])[O-]
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COC(C)(C)C
Product: COC(=O)[C@@H]1CC(=O)N(c2ccc(O)cc2)C1

Procedure:
A suspension of 2.51 g (10.6 mmol) of (RS)-1-(4-hydroxy-phenyl)-5-oxo-pyrrolidine-3-carboxylic acid methyl ester in 10 ml of phosphate buffer [c(KH2PO4)=0.05 mol/l], 25 ml of sodium sulfate solution [c(Na2SO4)=4 mol/l], 45 ml of deionised water, and 20 ml of tert-butylmethylether is adjusted to pH 6.0. Under moderate stirring, 51.3 mg of cholesterase from Candida cylindracea (Roche Applied Science, Industrial Products, Enzyme Projects, Sandhofer Str. 116, D-68305 Mannheim, Germany, order no. 10129046103) are added in solid form. By an automatic pH-Stat-System, the pH is kept constant at 6.0 by addition of sodium hydroxide solution [c(NaOH)=1.0 mol/l] at RT. The progress of the reaction is followed by the consumption of sodium hydroxide solution. After the addition of 5.21 ml of sodium hydroxide solution, the reaction is stopped by addition of dichloromethane. The organic layer is separated, then washed three times with water, thereafter, dried over sodium sulfate, and finally evaporated. The crude ester is a slightly rose oil which after trituration in tert-butylmethylether at RT is obtained as a white solid. The product is collected on a filter funnel and yields after drying under high vacuum at RT 1.11 g (44.3% of theory) of (R)-1-(4-hydroxy-phenyl)-5-oxo-pyrrolidine-3-carboxylic acid methyl ester; m.p.: 122.9° C.; optical integrity: 97.9% e.e.; [α]20D=−35.2 (c=1.162 g/100 ml CHCl3).