Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([SH:20])[NH:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.[H-].[Na+].I[C:24]1[S:25][CH:26]=[CH:27][CH:28]=1>CN(C)C=O>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([C:12]2[N:11]=[C:10]([S:20][C:24]3[S:25][CH:26]=[CH:27][CH:28]=3)[NH:9][C:8]=2[C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)=[CH:14][CH:15]=1
Reactant: Ic1cccs1
Reactant: Sc1nc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2)[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Clc1ccc(-c2nc(Sc3cccs3)[nH]c2-c2ccc(Cl)cc2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 86.9 %

Procedure:
6.43 g of 4,5-bis(4-chlorophenyl)-2-mercaptoimidazole is dissolved in 150 ml of absolute dimethylformamide and combined with 0.6 g of sodium hydride (80% strength in white oil). The mixture is agitated for another 30 minutes, and then 4.25 g of 2-iodothiophene in 30 ml of dimethylformamide is added dropwise thereto; the mixture is heated under reflux for 16 hours under argon. The solution is then poured into 600 ml of ice water, the product is extracted with ethyl acetate; the organic solution is dried over sodium sulfate and concentrated to dryness under vacuum. The residue is recrystallized from ether, yielding 7.02 g of 4,5-bis(4-chlorophenyl)-2-(2-thienylthio)imidazole, mp 219°.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[N:13]3[C:14]([CH2:17]Cl)=[N:15][N:16]=[C:12]3[CH2:11][N:10]=[C:9]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:8]=2[CH:25]=1)([O-:3])=[O:2].[I-].[K+].[CH2:28]([CH:31]=[CH:32][CH2:33][NH2:34])[CH2:29][CH3:30]>O1CCCC1>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[N:13]3[C:14]([CH2:17][NH:34][CH2:33][CH2:32][CH2:31][CH2:28][CH:29]=[CH2:30])=[N:15][N:16]=[C:12]3[CH2:11][N:10]=[C:9]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:8]=2[CH:25]=1)([O-:3])=[O:2]
Reactant: CCCC=CCN
Reactant: O=[N+]([O-])c1ccc2c(c1)C(c1ccccc1)=NCc1nnc(CCl)n1-2
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=CCCCCNCc1nnc2n1-c1ccc([N+](=O)[O-])cc1C(c1ccccc1)=NC2

Procedure:
In the manner given in Preparation 39, 8-nitro-1-(chloromethyl)-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine, potassium iodide and propylallylamine in tetrahydrofuran are reacted to give 8-nitro-1-[(allylpropylamino)methyl]-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine. Preparation 46 8-Fluoro-1-[(allylethylamino)methyl]-6-(o-fluorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine
Reaction SMILES: C[O:2][C:3](=[O:26])[CH2:4][C:5]1[CH:10]=[C:9]([Br:11])[C:8]([O:12][C:13]2[CH:18]=[C:17]([CH:19]([CH3:21])[CH3:20])[C:16]([O:22][CH3:23])=[C:15]([F:24])[CH:14]=2)=[C:7]([Br:25])[CH:6]=1.Cl>O1CCCC1.[OH-].[Li+]>[Br:11][C:9]1[CH:10]=[C:5]([CH2:4][C:3]([OH:26])=[O:2])[CH:6]=[C:7]([Br:25])[C:8]=1[O:12][C:13]1[CH:18]=[C:17]([CH:19]([CH3:20])[CH3:21])[C:16]([O:22][CH3:23])=[C:15]([F:24])[CH:14]=1
Reactant: COC(=O)Cc1cc(Br)c(Oc2cc(F)c(OC)c(C(C)C)c2)c(Br)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1c(F)cc(Oc2c(Br)cc(CC(=O)O)cc2Br)cc1C(C)C
Temperature: 25 °C
Yield: 105 %

Procedure:
To a solution of methyl[3,5-dibromo-4-(3-fluoro-5-isopropyl-4-methoxyphenoxy)phenyl]acetate (205 mg, 0.42 mmol) in tetrahydrofuran (30 mL), lithium hydroxide (30 mL, 1N) was added. The reaction mixture was stirred over night at room temperature, acidified with hydrochloric acid (1 N) and the aqueous and organic phase separated. The aqueous phase extracted with ethyl acetate. The combined organic phase was washed with water, dried over magnesium sulfate and concentrated in vacuo. The residue was purified on column (silica gel, chloroform/methanol/acetic acid 98:2:0.3) to give 210 mg (99%) of 3,5-dibromo-4-(3-fluoro-5-isopropyl-4-methoxyphenoxy)phenylacetic acid.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][CH:11]([C:14]([NH2:16])=[O:15])[CH2:10][CH2:9]1.[C:17]1(B(O)O)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[C:17]1([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][C:7]=2[N:8]2[CH2:13][CH2:12][CH:11]([C:14]([NH2:16])=[O:15])[CH2:10][CH2:9]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: NC(=O)C1CCN(c2ccncc2Br)CC1
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])O
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: NC(=O)C1CCN(c2ccncc2-c2ccccc2)CC1
Temperature: 170 °C
Yield: 25 %

Procedure:
To a mixture of 1-(3-bromopyridin-4-yl)piperidine-4-carboxamide E36 (20 mg, 0.070 mmol), phenylboronic acid (17 mg, 0.14 mmol) and tetrakis (triphenylphosphine)palladium(0) (8 mg, 10 mol %) in toluene (1.5 mL) was added a 0 potassium phosphate (45 mg, 0.21 mmol). The mixture was heated at 170° C. in a microwave reactor for 45 min, then poured into a saturated solution of sodium hydrogen carbonate (25 mL). The mixture was extracted with EtOAc (2×20 mL) and the combined organic extracts were washed with brine (25 mL), dried (MgSO4) and the solvent was removed under reduced pressure. The crude product was purified by flash column chromatography on silica gel (CH2Cl2, MeOH, 95:5) to furnish the title compound as a white solid (5 mg, 25%), LC-MS (ESI, 3.5 min) Rt 1.28 min, m/z 282 (100%, [M+H]+), m/z (ESI) C17H20N3O requires 282.1601 found [M+H]+ 282.1597.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([C:15]2[O:16][CH2:17][C@@H:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:19]=2)[CH:12]=[CH:13][CH:14]=1)C1C=CC=CC=1>C(OCC)(=O)C.[Pd]>[OH:8][C:9]1[CH:10]=[C:11]([C:15]2[O:16][CH2:17][C@@H:18]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:19]=2)[CH:12]=[CH:13][CH:14]=1
Reactant: c1ccc(COc2cccc(C3=N[C@H](c4ccccc4)CO3)c2)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Oc1cccc(C2=N[C@H](c3ccccc3)CO2)c1
Yield: 48.4 %

Procedure:
2-(3-Benzyloxyphenyl)-4,5-dihydro-4(R)-phenyloxazole (3 g, 8.9 mmol) was dissolved in ethyl acetate (15 ml) and hydrogenolyzed in the presence of 10% palladium-on-charcoal (300 mg). Recrystallization from ethyl acetate/n-hexane gave 4,5-dihydro-2-(3-hydroxyphenyl)-4(R)-phenyloxazole (1.03 g, 48% ) as colorless needles.
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:8]2[CH:9]=[C:10]([CH:18]=[C:19]([N:22]3[C:26]([CH3:27])=[CH:25][CH:24]=[C:23]3[CH3:28])[C:20]=2[CH3:21])[CH:11](O)CS(C)(=O)=O)[C:4]([CH3:7])=[CH:5][CH:6]=1.C[O-].[Na+].[NH:32]([CH2:39][CH2:40][C:41]#[N:42])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>CS(C)=O>[NH:32]([CH:39]=[C:40]([CH2:11][C:10]1[CH:18]=[C:19]([N:22]2[C:23]([CH3:28])=[CH:24][CH:25]=[C:26]2[CH3:27])[C:20]([CH3:21])=[C:8]([N:3]2[C:2]([CH3:1])=[CH:6][CH:5]=[C:4]2[CH3:7])[CH:9]=1)[C:41]#[N:42])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: N#CCCNc1ccccc1
Reactant: Cc1c(-n2c(C)ccc2C)cc(C(O)CS(C)(=O)=O)cc1-n1c(C)ccc1C
Agent: C[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: Cc1c(-n2c(C)ccc2C)cc(CC(C#N)=CNc2ccccc2)cc1-n1c(C)ccc1C

Procedure:
A mixture of 4.95 g. of 3,5-bis(2,5-dimethylpyrrol-1-yl)-4-methyl-α-[(methylsulfonyl)methyl]benzyl alcohol, 0.95 g. of sodium methylate and 2.16 g. of β-anilinopropionitrile in 13 ml. of dimethylsulfoxide was stirred with the exclusion of moisture for 5 hours at 50° C. The mixture was poured into 100 ml. of water, the precipitated oil extracted with ethyl acetate, the ethyl acetate solution dried over sodium sulfate and evaporated. By purification of the residue over aluminum oxide with ethyl acetate and recrystallization from ethyl acetate, there was obtained α-(anilinomethylene)-3,5-bis(2,5-dimethylpyrrol-1-yl)-4-methylhydrocinnamonitrile, having a melting point of 252° C.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=1[C:13](=[O:31])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30].[BH4-].[Na+].Cl>C(O)C>[OH:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=1[CH:13]([OH:31])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: CCCCCCCCCCCCCCCCCC(=O)c1cc(C(=O)OCC)ccc1O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCCCCCCCCCCCCCCCCC(O)c1cc(C(=O)OCC)ccc1O

Procedure:
The title compound of Example 1 (1.0 g) was dissolved in 20 ml of absolute ethanol, and 0.1 g NaBH4 was added with stirring under N2 atmosphere. The reaction mixture was stirred for two hours, added to 1N HCl, and the mixture concentrated to dryness under reduced pressure to give a crystalline mass. This solid was extracted into ethyl acetate, and the extractants combined and washed with water, then dried over sodium sulfate. The solvent was removed under reduced pressure to give the title compound, m.p. ca. 75° C. ##STR9##
Reaction SMILES: C(O[C:6]([C:8]1[N:13]=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:11]2[C:20]([CH2:23][N:24]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH:26]=[CH:25]3)=[N:21][S:22][C:10]=2[C:9]=1[OH:33])=[O:7])CCC.[NH2:34][CH2:35][C:36]([OH:38])=[O:37]>>[OH:33][C:9]1[C:10]2[S:22][N:21]=[C:20]([CH2:23][N:24]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH:26]=[CH:25]3)[C:11]=2[C:12]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[N:13][C:8]=1[C:6]([NH:34][CH2:35][C:36]([OH:38])=[O:37])=[O:7]
Reactant: NCC(=O)O
Reactant: CCCCOC(=O)c1nc(-c2ccccc2)c2c(Cn3ccc4ccccc43)nsc2c1O
Product: O=C(O)CNC(=O)c1nc(-c2ccccc2)c2c(Cn3ccc4ccccc43)nsc2c1O

Procedure:
The title compound was synthesized in analogy Example 1 from 7-hydroxy-3-indol-1-ylmethyl-4-phenyl-isothiazolo[4,5-c]pyridine-6-carboxylic acid butyl ester and glycine: MS (m/z) 459.1 (M+1).
Reaction SMILES: [C:1]1([N:7]([CH2:12][C:13]([OH:15])=[O:14])[CH2:8][C:9]([OH:11])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C)C=CC=CC=1.C(OC(=O)C)(=O)C>CCCCCC>[C:1]1([N:7]2[CH2:8][C:9](=[O:11])[O:15][C:13](=[O:14])[CH2:12]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)CN(CC(=O)O)c1ccccc1
Solvent: CC(=O)OC(C)=O
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: O=C1CN(c2ccccc2)CC(=O)O1
Temperature: 25 °C
Yield: 90.6 %

Procedure:
Into a 2-liter round-bottom flask was put 62.8 g of N-phenyliminodiacetic acid under nitrogen gas stream to dissolve with 500 ml of toluene. To the solution was added 32.0 g of acetic anhydride, and the mixture was refluxed by heating with stirring. After lapse of one our, the mixture was cooled to room temperature and 3 liters of hexane was added thereto with stirring to deposit. The deposit was collected by filtration to obtain 52.0 g of N-phenyliminodiacetic acid anhydride.
Reaction SMILES: [CH3:1][C:2](=[CH2:35])[CH2:3][CH:4]([CH2:12][CH2:13][C@H:14]1[CH2:19][CH2:18][CH2:17][C@@H:16]([O:20][CH2:21][C:22]2[N:23]=[C:24]([C:28]3[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=3)[O:25][C:26]=2[CH3:27])[CH2:15]1)[C:5]([O:7]C(C)(C)C)=[O:6]>C(OCC)(=O)C.[Pd]>[CH3:1][CH:2]([CH3:35])[CH2:3][CH:4]([CH2:12][CH2:13][C@H:14]1[CH2:19][CH2:18][CH2:17][C@@H:16]([O:20][CH2:21][C:22]2[N:23]=[C:24]([C:28]3[CH:29]=[CH:30][C:31]([CH3:34])=[CH:32][CH:33]=3)[O:25][C:26]=2[CH3:27])[CH2:15]1)[C:5]([OH:7])=[O:6]
Reactant: C=C(C)CC(CC[C@H]1CCC[C@@H](OCc2nc(-c3ccc(C)cc3)oc2C)C1)C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Cc1ccc(-c2nc(CO[C@@H]3CCC[C@H](CCC(CC(C)C)C(=O)O)C3)c(C)o2)cc1
Reaction time: 5 h

Procedure:
500 mg of tert-butyl 4-methyl-2-{2-[cis-3-(5-methyl-2-p-tolyloxazol-4-ylmethoxy)cyclohexyl]ethyl}pent-4-enoate are dissolved in 20 ml of ethyl acetate, and 50 mg of palladium (10% on activated carbon) are added. The mixture is stirred under an atmosphere of hydrogen (5 bar) for 5 hours. The catalyst is filtered off through Celite and the filtrate is concentrated under reduced pressure. The residue is dissolved in 20 ml of dichloromethane, and 10 ml of trifluoroacetic acid are added. The mixture is stirred at room temperature for 1 hour. 100 ml of toluene are added, and the solvents are then removed under reduced pressure. The residue is purified by RP-HPLC. This gives 100 mg of 4-methyl-2-{2-[cis-3-(5-methyl-2-p-tolyloxazol-4-ylmethoxy)cyclohexyl]ethyl}pentanoic acid as an oil. C26H37NO4 (427.59), MS(ESI): 428 (M+H+).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[CH3:7][CH:8]([CH3:24])[C:9]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[CH:13]=1)=[O:10].[Br:25][C:26]1[CH:31]=[CH:30][C:29]([C:32](=[O:37])[CH2:33][CH2:34][CH2:35]Cl)=[CH:28][CH:27]=1>>[Br:25][C:26]1[CH:27]=[CH:28][C:29]([C:32](=[O:37])[CH2:33][CH2:34][CH2:35][N:21]2[CH2:22][CH2:23][CH:18]([C:14]3[CH:13]=[C:12]([NH:11][C:9](=[O:10])[CH:8]([CH3:24])[CH3:7])[CH:17]=[CH:16][CH:15]=3)[CH2:19][CH2:20]2)=[CH:30][CH:31]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Reactant: O=C(CCCCl)c1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCC(=O)c3ccc(Br)cc3)CC2)c1

Procedure:
Prepared by Procedure K (KI) and Scheme E (K2CO3) using 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide and 1-(4-bromophenyl)-4-chloro-1-butanone: ESMS m/e: 471.3 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[CH2:19][CH2:18][C:5]2[N:6]([CH2:14][C:15](O)=[O:16])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.C1(N=C=NC2CCCCC2)CCCCC1.[C:35]([NH2:39])([CH3:38])([CH3:37])[CH3:36]>ClCCl.CN(C)C1C=CN=CC=1>[C:35]([NH:39][C:15](=[O:16])[CH2:14][N:6]1[C:7]2[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=2[C:4]2[CH2:3][N:2]([CH3:1])[CH2:19][CH2:18][C:5]1=2)([CH3:38])([CH3:37])[CH3:36]
Reactant: CC(C)(C)N
Reactant: Cc1ccc2c(c1)c1c(n2CC(=O)O)CCN(C)C1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1ccc2c(c1)c1c(n2CC(=O)NC(C)(C)C)CCN(C)C1
Reaction time: 14 h
Yield: 14.5 %

Procedure:
To a solution of 2-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)acetic acid (200 mg, 0.77 mmol) in dichloromethane (20 ml) was added N,N′-dicyclohexylcarbodiimide (191 mg, 0.92 mmol) followed by the addition of 4-dimethylaminopyridine (113 mg, 0.93 mmol) and tert butylamine (67 mg, 0.93 mmol). The resulting mixture was stirred at 25 deg C. for 14 h. The solvent was removed in vacuo and purified by reverse-phase chromatography (C-18, 500 mm×50 mm, Mobile Phase A=0.05% TFA in water, B=0.05% TFA in acetonitrile, Gradient: 10% B to 80% B in 30 min, injection vol. 5 ml) to obtain 35 mg of N-tert-butyl-2-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)acetamide as trifluoroacetic acid salt. 1H NMR (DMSO-D2O) TFA SALT 7.21-7.20 (d, 2H), 7.0-6.95 (d, 1H), 4.60-4.50 (d, 2H), 3.75-3.65 (m, 2H), 3.50-3.38 (m, 2H), 3.10-3.0 (m, 2H), 2.90 (s, 3H), 2.30 (s, 3H), 1.20 (s, 9H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[C:9]([CH3:15])=[CH:8][C:7]([N+:16]([O-:18])=[O:17])=[C:6]([CH3:19])[C:5]2=1.I[CH2:21][CH3:22]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH2:21][CH3:22])[C:10]1[C:9]([CH3:15])=[CH:8][C:7]([N+:16]([O-:18])=[O:17])=[C:6]([CH3:19])[C:5]2=1
Reactant: Cc1cc([N+](=O)[O-])c(C)c2c1[nH]c1ccc(Br)cc12
Reactant: CCI
Product: CCn1c2ccc(Br)cc2c2c(C)c([N+](=O)[O-])cc(C)c21

Procedure:
6-bromo-1,4-dimethyl-3-nitro-9H-carbazole (prepared as described in Chem. Pharm. Bull 35(1), 425-428 (1987), (4.8 g, 0.015 mol) was reacted with iodoethane by working in a similar manner to Example 1a).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[N:9][C:10]3[C:15]([N:16]=2)=[CH:14][C:13]([C:17]([O:19]C)=[O:18])=[CH:12][CH:11]=3)[CH2:3]1.[OH-].[Na+].Cl>CO.O>[OH:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[N:9][C:10]3[C:15]([N:16]=2)=[CH:14][C:13]([C:17]([OH:19])=[O:18])=[CH:12][CH:11]=3)[CH2:3]1
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(N3CC[C@@H](O)C3)nc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc2nc(-c3ccccc3)c(N3CC[C@@H](O)C3)nc2c1
Reaction time: 0.1 h

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of (R)-methyl 3-(3-hydroxypyrrolidin-1-yl)-2-phenylquinoxaline-6-carboxylate (147.4 mg, 0.42 mmol, 1.00 equiv) in methanol (15 mL). This was followed by the dropwise addition of a solution of sodium hydroxide (84.5 mg, 2.11 mmol, 5.00 equiv) in water (2 mL) with stirring. The resulting solution was stirred overnight at 50° C. in an oil bath. The pH value of the solution was adjusted to 3-4 with 1N hydrogen chloride. The resulting mixture was concentrated under vacuum. The crude product (120 mg) was purified by Prep-HPLC with the following conditions (1#-Waters 2767-1): Column, SunFire Prep C18, 5 um, 19*100 mm; mobile phase, water with 0.05% TFA and CH3CN (20% CH3CN up to 50% in 6 min, up to 100% in 1 min, down to 20% in 1 min); Detector, UV 220 254 nm. This resulted in 35 mg (24%) of (R)-3-(3-hydroxypyrrolidin-1-yl)-2-phenylquinoxaline-6-carboxylic acid as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[CH:5]=[CH:6][CH:7]=1>C1COCC1.[Pd]>[Br:1][C:2]1[CH:3]=[C:4]([CH2:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=Cc2cccc(Br)c2)CC1
Agent: [Pd]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Cc2cccc(Br)c2)CC1
Yield: 94.4 %

Procedure:
To a solution of 1,1-dimethylethyl 4-[(3-bromophenyl)methylidene]-1-piperidinecarboxylate (201 mg, 0.571 mmol) in THF (1 mL) was applied onto H-Cube using 10% Pd/C at a flow rate of 1 mL/min and 1 atm H2. The mixture was concentrated to afford 0.1909 g (94%) of the title compound. LC-MS m/z 354 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](Cl)=[CH:5][CH:4]=1.[C:10]1([CH3:19])[CH:15]=[CH:14][CH:13]=[C:12]([C:16](=[O:18])[CH3:17])[CH:11]=1.P>C1(C)C=CC=CC=1.C(Cl)C=CC1C=CC=CC=1.[Pd]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:17][C:16]([C:12]2[CH:11]=[C:10]([CH3:19])[CH:15]=[CH:14][CH:13]=2)=[O:18])=[CH:5][CH:4]=1
Reactant: COc1ccc(Cl)cc1
Reactant: CC(=O)c1cccc(C)c1
Agent: [Pd]
Agent: ClCC=Cc1ccccc1
Agent: P
Solvent: Cc1ccccc1
Product: COc1ccc(CC(=O)c2cccc(C)c2)cc1
Yield: 73.4 %

Procedure:
This reaction is carried out in the same manner as the reaction in example 3. The difference is that, the reactants are p-methoxyphenyl chloride (141.7 mg, 1.0 mmol), 1-(m-tolyl)ethanone (336.2 mg, 2.5 mmol), palladium cinnamyl chloride (7.8 mg, 0.015 mmol), 2-Methoxy-6-(N-methyl-N-phenyl-amino)phenyldicyclohexyl)phosphine (18.4 mg, 0.045 mmol), K3PO43H2O (664.9 mg, 2.5 mmol) in 3 mL dry toluene at 110° C. for 23 h. 2-(4′-Methoxyphenyl)-1-(m-tolyl)-1-ethanone (176.4 mg) was obtained with a yield of 74% as solid. m.p.: 56.7-57.8° C. (n-hexane); 1H NMR (300 MHz, CDCl3) δ 7.82-7.75 (m, 2H, ArH), 7.36-7.27 (m, 2H, ArH), 7.20-7.10 (m, 2H, ArH), 6.88-6.79 (m, 2H, ArH), 4.18 (s, 2H, CH2), 3.73 (s, 3H, OCH3), 2.37 (s, 3H, ArCH3); 13C NMR (75 MHz, CDCl3) δ 198.0, 158.3, 138.2, 136.4, 133.7, 130.3, 128.9, 128.3, 126.4, 125.7, 113.9, 55.0, 44.4, 21.2; IR (KBr) v (cm−1) 3034, 2999, 2933, 2835, 1694, 1682, 1614, 1585, 1515, 1463, 1301, 1282, 1246, 1178, 1156, 1107, 1035, 1000; MS (70 eV, EI) m/z (%): 241 (M++1, 1.89), 240 (M+, 10.02), 119 (100); Anal. Calcd. for C16H16O2: C, 79.97; H, 6.71. Found: C, 79.71; H, 6.69.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[N:19]1[CH:23]=[CH:22][N:21]=[CH:20]1)[C:5]([C:7]1[C:12]([CH3:13])=[CH:11][C:10]([CH3:14])=[CH:9][C:8]=1[CH3:15])=[O:6].[BH4-].[Na+]>C(O)C.O>[CH3:13][C:12]1[CH:11]=[C:10]([CH3:14])[CH:9]=[C:8]([CH3:15])[C:7]=1[CH:5]([C:4]1[CH:16]=[CH:17][C:18]([N:19]2[CH:23]=[CH:22][N:21]=[CH:20]2)=[C:2]([Cl:1])[CH:3]=1)[OH:6]
Reactant: Cc1cc(C)c(C(=O)c2ccc(-n3ccnc3)c(Cl)c2)c(C)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1cc(C)c(C(O)c2ccc(-n3ccnc3)c(Cl)c2)c(C)c1
Temperature: 50 °C
Reaction time: 17 h
Yield: 89.2 %

Procedure:
In 100 ml of ethanol is dissolved 15.6 g of oily 3-chloro-4-(1-imidazolyl)-2',4',6'-trimethylbenzophenone obtained in the reference example 4. To the ethanol solution is added a solution of 1.8 g of sodium borohydride in 20 ml of water. After the whole solution is stirred at 50° C. for 17 hours, the reaction mixture is poured into ice-cold water and extracted with chloroform. The chloroform is distilled off and the residue is recrystallized from toluene to give 14 g of α-(2,4,6-trimethylphenyl)-3-chloro-4-(1-imidazolyl)benzenemethanol as white crystals, melting at 156°-157° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([CH3:12])[C:10]=1[OH:11])[C:5]([OH:7])=[O:6].[C:13](OC(=O)C)(=[O:15])[CH3:14].O>N1C=CC=CC=1>[C:13]([O:11][C:10]1[C:9]([CH3:12])=[CH:8][C:4]([C:5]([OH:7])=[O:6])=[CH:3][C:2]=1[CH3:1])(=[O:15])[CH3:14]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cc(C(=O)O)cc(C)c1O
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)Oc1c(C)cc(C(=O)O)cc1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 93.7 %

Procedure:
To a solution of 3,5-dimethyl-4-hydroxy-benzoic acid (3.0 g, 18.05 mmol) in pyridine (7 mL) was added acetic anhydride (2.05 mL, 21.66 mmol) and the reaction mixture was stirred at room temperature for 16 h. Water was added and the mixture was extracted with ethyl acetate, washed with water, brine and dried over anhydrous Na2SO4. The solvent was evaporated in vacuo to obtain 4-acetoxy-3,5-dimethyl-benzoic acid (3.52 g, 94%). To a solution of 4-acetoxy-3,5-dimethyl-benzoic acid (6.02 g, 28.91 mmol) in CH2Cl2 (80 mL), oxalyl chloride (5.04 mL, 57.83 mmol) was added slowly, followed by a drop of dimethyl formamide. The reaction mixture was stirred at room temperature for 2 h. The solvent was removed and acetic acid 4-chlorocarbonyl-2,6-dimethyl-phenyl ester was dried under vacuum (6.37 g, 97%). To a solution of N,N,N,N-tetramethyl guanidine (2.77 mL, 22.078 mmol) in CH3CN (50 mL), a solution of 6,8-dimethoxy-isochroman-1,3-dione (4.46 g, 20.07 mmol) in CH3CN (100 mL) was added slowly at <0° C. (bath temperature −20° C.) in 30 min. Then, Et3N was added in one portion, followed by a solution of acetic acid 4-chlorocarbonyl-2,6-dimethyl-phenyl ester (6.37 g, 28.1 mmol) in CH3CN (50 mL) and stirred for 30 min. at <0+ C. The reaction mixture was stirred at room temperature for 16 h, then heated to reflux for 3 h. After cooling to room temperature, the reaction mixture was quenched with 1 N HCl. The precipitated solid was filtered off to give a mixture of acetic acid 4-(6,8-dimethoxy-1,3-dioxo-isochroman-4-carbonyl)-2,6-dimethyl-phenyl ester and acetic acid 4-(6,8-dimethoxy-1-oxo-1H-isochromen-3-yl)-2,6-dimethyl-phenyl ester (6.0 g).
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[NH:15][C:14](=[O:16])[CH2:13][CH2:12]1.Br[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][C:26]([F:29])([F:28])[F:27])=[CH:21][CH:20]=1>>[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]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][C:26]([F:27])([F:28])[F:29])=[CH:21][CH:20]=2)[C:14](=[O:16])[CH2:13][CH2:12]1
Reactant: FC(F)(F)Oc1ccc(CBr)cc1
Reactant: COc1cccc(OC)c1C1CCC(=O)N1
Product: COc1cccc(OC)c1C1CCC(=O)N1Cc1ccc(OC(F)(F)F)cc1

Procedure:
Prepared according to the described general procedure 4 (GP4) by reaction of 5-(2,6-dimethoxyphenyl)pyrrolidin-2-one with commercially available 1-(bromomethyl)-4-(trifluoromethoxy)benzene. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions E): tR=0.80 min.; [M+H]+: 396.00 g/mol.