Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5](Cl)=[O:6].[NH2:12][C:13]1[CH:32]=[CH:31][C:16]([O:17][C:18]2[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:20][CH:19]=2)=[CH:15][CH:14]=1.C(N(CC)CC)C.O>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5]([NH:12][C:13]1[CH:14]=[CH:15][C:16]([O:17][C:18]2[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:20][CH:19]=2)=[CH:31][CH:32]=1)=[O:6]
Reactant: CCOC(=O)CCc1ccc(Oc2ccc(N)cc2)cc1
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)CCc1ccc(Oc2ccc(NC(=O)c3ccc(Cl)c(Cl)c3)cc2)cc1
Reaction time: 1 h

Procedure:
A solution of 3,4-dichlorobenzoyl chloride (3.65 g, 17.4 mmol) was added dropwise under ice cooling to a solution of ethyl 3-[4-(4-aminophenoxy)phenyl]propionate (4.52 g, 15.9 mmol) and triethylamine (2.65 mL, 19.0 mmol) in THF (80 mL), and the resulting solution was stirred for 1 hour at the same temperature. Water was added to the reaction mixture, and extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated sodium bicarbonate solution and brine. The ethyl acetate layer was dried over anhydrous magnesium sulfate and evaporated. The residue was recrystallized from water-containing ethanol to thereby yield 6.67 g of the title compound.
Reaction SMILES: [CH3:1][C:2]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[N:12]([O-])=O.[Na+]>C(O)(=O)C.O>[N+:9]([C:8]1[CH:7]=[CH:6][CH:5]=[C:3]2[C:2]=1[CH:1]=[N:12][NH:4]2)([O-:11])=[O:10]
Reactant: O=N[O-]
Reactant: Cc1c(N)cccc1[N+](=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=[N+]([O-])c1cccc2[nH]ncc12
Temperature: 25 °C

Procedure:
2-Methyl-3-nitroaniline (20 g) in acetic acid (˜200 mL) was treated with NaNO2 (20 g) in water (50 mL) at 4° C. (mechanical stirring). The reaction mixture was allowed to warm to room temperature and stir overnight. The solvent was removed under reduced pressure. The residue was treated with water (700 mL) and the mixture was filtered. The solid was dried at 45° C. in a vacuum oven overnight to provide the title compound. 1H NMR (DMSO) δ 8.56 (s, 1H), 8.2-8.05 (dd, 2H), 7.6 (t, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[N:7][N:8]([CH:14]([Si](C)(C)C)C)[C:9]=1[C:10]([O:12][CH3:13])=[O:11])=[O:4].[F-].[K+]>CO.C(OCC)(=O)C.CCCCCC>[CH3:1][O:2][C:3]([C:5]1[N:6]=[N:7][N:8]([CH3:14])[C:9]=1[C:10]([O:12][CH3:13])=[O:11])=[O:4]
Reactant: COC(=O)c1nnn(C(C)[Si](C)(C)C)c1C(=O)OC
Agent: [F-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)c1nnn(C)c1C(=O)OC
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of 1-trimethylsilanylethyl-1H-[1,2,3]triazole-4,5-dicarboxylic acid dimethyl ester (10 g, 36.9 mmol) in methanol (100 mL) was added potassium fluoride (11.07 g, 184.5 mmol) at RT. The reaction mixture was stirred at RT for 6 h. After solvent removal in vacuo, the crude material was diluted with water (100 mL) and extracted with ethyl acetate (2×150 mL). The combined organic layer was washed with water (2×50 mL) and brine (50 mL), dried over anhydrous Na2SO4, filtered, and evaporated in vacuo. The product was obtained after purification by flash chromatography (using silica gel and 30% ethyl acetate/hexane) as white solid (4.3 g, 21.6 mmol, 58.5%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([C:23]([F:26])([F:25])[F:24])[CH:17]=1.C(N(CC)CC)C.ClC(Cl)(O[C:38](=[O:44])OC(Cl)(Cl)Cl)Cl.[CH3:46][C:47]1[S:51][C:50]([CH:52]([NH2:54])[CH3:53])=[N:49][CH:48]=1>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:38]([NH:54][CH:52]([C:50]2[S:51][C:47]([CH3:46])=[CH:48][N:49]=2)[CH3:53])=[O:44])=[C:18]([C:23]([F:25])([F:26])[F:24])[CH:17]=1
Reactant: Cc1cnc(C(C)N)s1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2nccc(Oc3ccc(N)c(C(F)(F)F)c3)c2cc1OC
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1cc2nccc(Oc3ccc(NC(=O)NC(C)c4ncc(C)s4)c(C(F)(F)F)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 27.4 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-(trifluoromethyl)aniline (30 mg) was dissolved in chloroform (1 ml) and triethylamine (0.1 ml) to prepare a solution. A solution of triphosgene (35 mg) in chloroform (0.2 ml) was then added to the solution, and the mixture was stirred at room temperature for one hr. Next, a solution of 1-(5-methyl-1,3-thiazol-2-yl)-1-ethylamine (35 mg) in chloroform (0.2 ml) was added thereto, and the mixture was stirred at room temperature for 10 hr. The stirred mixture was purified by chromatography on silica gel using chloroform/methanol for development to give the title compound (12 mg, yield 26%).
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:23])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH3:22])([C:14]([NH:16][CH2:17][CH2:18][CH2:19][CH2:20][OH:21])=[O:15])[CH2:6][CH2:5]2.[O:24]=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+]>>[OH:24][C:7]([CH3:22])([CH2:6][CH2:5][C:4]1[C:9](=[O:8])[C:10]([CH3:13])=[C:11]([CH3:12])[C:2](=[O:1])[C:3]=1[CH3:23])[C:14]([NH:16][CH2:17][CH2:18][CH2:19][CH2:20][OH:21])=[O:15]
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(C(=O)NCCCCO)O2
Reactant: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Product: CC1=C(C)C(=O)C(CCC(C)(O)C(=O)NCCCCO)=C(C)C1=O

Procedure:
Oxidation as described in protocol B, using 100 mg (0.311 mmol) of 6-hydroxy-N-(4-hydroxybutyl)-2,5,7,8-tetramethylchroman-2-carboxamide and 375 mg CAN (0.685 mmol) yielded 2-hydroxy-N-(4-hydroxybutyl)-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4[NH:19][CH:20]=[CH:21][C:15]=4[CH:14]3[CH3:22])=[O:12])[CH:10]=2)[CH:7]=1.[NH:23]1[CH:27]=[N:26][N:25]=[N:24]1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4[N:19]([C:27]5[NH:26][N:25]=[N:24][N:23]=5)[CH:20]=[CH:21][C:15]=4[CH:14]3[CH3:22])=[O:12])[CH:10]=2)[CH:7]=1
Reactant: CC1c2cc[nH]c2CCN1C(=O)c1cc2ncc(Br)cn2n1
Reactant: c1nnn[nH]1
Product: CC1c2ccn(-c3nnn[nH]3)c2CCN1C(=O)c1cc2ncc(Br)cn2n1

Procedure:
(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(4-methyl-1,4,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-5-yl)-methanone is reacted with 1H tetrazole under Buchwald reaction conditions to provide the title compound.
Reaction SMILES: ClC1C=CC([N:8]([C@H:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]([C:22](=[O:31])[C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=3)[C@@H:14]([CH3:32])[CH2:13]2)C(=O)C)=C(C)C=1.FC1C=CC(C(Cl)=O)=CC=1>>[CH3:30][O:29][C:26]1[CH:25]=[CH:24][C:23]([C:22]([N:15]2[C:16]3[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=3)[C@H:12]([NH2:8])[CH2:13][C@@H:14]2[CH3:32])=[O:31])=[CH:28][CH:27]=1
Reactant: COc1ccc(C(=O)N2c3ccccc3[C@H](N(C(C)=O)c3ccc(Cl)cc3C)C[C@@H]2C)cc1
Agent: O=C(Cl)c1ccc(F)cc1
Product: COc1ccc(C(=O)N2c3ccccc3[C@H](N)C[C@@H]2C)cc1

Procedure:
N-(4-chloro-2-methylphenyl)-N-[(2S,4R)-1-(4-methoxybenzoyl)-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl]acetamide was made following general procedure G, substituting 4-methoxybenzoyl chloride for 4-fluorobenzoyl chloride. The amine-aryl coupling was performed differently to what is described in procedure G. Therefore (2S,4R)-1-(4-methoxybenzoyl)-2-methyl-1,2,3,4-tetrahydroquinolin-4-amine (obtained from the hydrogenation step, 500 mg, 1.5 mmol, 1 equ.) was dissolved in ethylene glycol dimethyl ether (5 mL) in a Schlenk tube. To this solution was added sequentially 2-bromo-5-chlorotoluene (400 mg, 1.95 mmol, 1.3 equ.), cesium carbonate (684 mg, 2.10 mmol, 1.4 equ.), palladium acetate (40 mg, 0.06 mmol, 0.04 equ.) and 2-(Dicyclohexylphosphino)-2′,4′,6′-tri-1-propyl-1,1′-biphenyl (60 mg, 0.12 mmol, 0.08 equ.). The reaction mixture was flushed with nitrogen and heated to 90° C. in the Schlenk tube for 48 h. Reaction mixture was concentrated to leave a residue which was partitioned between water and ethyl acetate and extracted. The aqueous layer was separated and the organic layer was washed with brine, dried over magnesium sulfate, filtered and concentrated to give a black oil. The crude product was purified by silica gel chromatography (methylene chloride/methanol: 99/1) to provide (2S,4R)-N-(4-chloro-2-methylphenyl)-1-(4-methoxybenzoyl)-2-methyl-1,2,3,4-tetrahydroquinolin-4-amine (200 mg, 32%).
Reaction SMILES: [Br:1][CH2:2][C:3](Cl)=[O:4].[F:6][C:7]([F:23])([F:22])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.O>ClCCl>[Br:1][CH2:2][C:3]([N:19]1[CH2:18][CH2:17][N:16]([CH2:15][CH2:14][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[C:7]([F:22])([F:23])[F:6])[CH2:21][CH2:20]1)=[O:4]
Reactant: O=C(Cl)CBr
Reactant: FC(F)(F)c1ccccc1CCN1CCNCC1
Solvent: O
Solvent: ClCCl
Product: O=C(CBr)N1CCN(CCc2ccccc2C(F)(F)F)CC1
Reaction time: 0.75 h

Procedure:
Bromoacetyl chloride (0.125 mL) was added slowly to a chilled (5 ° C.) solution of 1-[2-[2-(trifluoromethyl)phenyl]ethyl]piperazine (0.774 g) in dichloromethane (20 mL) and the mixture was stirred in an ice bath for 45 minutes, then at room temperature for 18 hours. After the addition of water (20 mL), the organic layer was separated and washed in turn with 0.5N hydrochloric acid and sodium bicarbonate solution. The dried (MgSO4) extract was evaporated to give 0.5 g of 1-(2-bromo-1-oxoethyl)-4-[2-[2-(trifluoromethyl)phenyl]ethyl]piperazine.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:9](=[O:10])[O:8][CH2:7]2.[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[O:20][CH:21]=[C:22]([CH2:24][O:25][C:26]3[CH:27]=[C:28]([OH:32])[CH:29]=[CH:30][CH:31]=3)[N:23]=2)=[CH:15][CH:14]=1.C[O-].[Na+]>CN1C(=O)CCC1>[F:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]2[O:20][CH:21]=[C:22]([CH2:24][O:25][C:26]3[CH:27]=[C:28]([CH:29]=[CH:30][CH:31]=3)[O:32][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[C:6]([CH3:7])[C:11]=3[C:9]([OH:10])=[O:8])[N:23]=2)=[CH:17][CH:18]=1
Reactant: Cc1cccc2c1C(=O)OC2
Reactant: Oc1cccc(OCc2coc(-c3ccc(F)cc3)n2)c1
Agent: C[O-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: Cc1cccc(COc2cccc(OCc3coc(-c4ccc(F)cc4)n3)c2)c1C(=O)O
Temperature: 130 °C

Procedure:
1 g (6.8 mmol) of 7-methylphthalide and 2 g (7.0 mmol) of 3-[2-(4-fluorophenyl)oxazol-4 -ylmethoxy]phenol are dissolved in NMP. 3.9 ml of methanolic sodium methoxide (30% strength) are added, the methanol is distilled off, and the mixture is heated to 130° C. No formation of 2-{3-[2-(4-fluorophenyl)oxazol-4-ylmethoxy]phenoxymethyl}-6-methylbenzoic acid is observed. The 3-[2-(4-fluorophenyl)oxazol-4-ylmethoxy]phenol decomposes.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.C([Li])CCC.[Cl:11][C:12]1[CH:39]=[CH:38][C:15]([C:16]([C:18]2[CH:19]=[C:20]3[C:25](=[CH:26][CH:27]=2)[NH:24][C:23](=[O:28])[CH:22]=[C:21]3[CH2:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([Cl:37])[CH:32]=2)=[O:17])=[CH:14][CH:13]=1>C1COCC1.CN(P(N(C)C)(N(C)C)=O)C>[Cl:37][C:33]1[CH:32]=[C:31]([CH:36]=[CH:35][CH:34]=1)[CH2:30][CH2:29][C:21]1[C:20]2[C:25](=[CH:26][CH:27]=[C:18]([C:16]([C:15]3[CH:38]=[CH:39][C:12]([Cl:11])=[CH:13][CH:14]=3)([OH:17])[C:2]3[S:1][CH:5]=[CH:4][N:3]=3)[CH:19]=2)[NH:24][C:23](=[O:28])[CH:22]=1
Reactant: c1cscn1
Reactant: O=C(c1ccc(Cl)cc1)c1ccc2[nH]c(=O)cc(CCc3cccc(Cl)c3)c2c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: O=c1cc(CCc2cccc(Cl)c2)c2cc(C(O)(c3ccc(Cl)cc3)c3nccs3)ccc2[nH]1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of thiazole (201 mg, 2.368 mmol, 4.00 equip) in THF (10 mL) at −78° C. was added n-butyllithium (1.6 M in hexanes, 1.495 mL, 2.392 mmol, 4.04 equip) dropwise. After 30 minutes, a solution of 6-(4-chlorobenzoyl)-4-(3-chlorophenethyl)quinolin-2(1H)-one (250 mg, 0.592 mmol, 1 equip, prepared as described in ANGIBAUD, P. R., et al., PCT Publication WO2002/051835 A1, published 4 Jul. 2002) in HMPA (4 mL) was added dropwise and the reaction mixture was warmed to room temperature. The reaction was stirred overnight, then quenched with water and the resulting mixture extracted with dichloromethane (3×). The combined organic extracts were washed with brine, dried (Na2SO4), and concentrated. The residue was purified by MPLC using methanol-dichloromethane as the eluent to yield 4-(3-chlorophenethyl)-6-((4-chlorophenyl)(hydroxy)(thiazol-2-yl)methyl)quinolin-2(1H)-one as a tan solid.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][CH2:6][CH2:7][O:8][C@@H:9]([C:39]1[CH:44]=[CH:43][CH:42]=[C:41]([Cl:45])[CH:40]=1)[CH2:10][CH2:11][N:12]([CH2:36][CH2:37][CH3:38])[C:13](=[O:35])[NH:14][C@@H:15]([CH2:28][C@H:29]1[CH2:34][CH2:33][CH2:32][O:31][CH2:30]1)[CH2:16][N:17](C)[C:18](=O)OCC[Si](C)(C)C)=[O:4].C(O)(C(F)(F)F)=O.C(Cl)Cl>>[Cl:45][C:41]1[CH:40]=[C:39]([C@H:9]([O:8][CH2:7][CH2:6][NH:5][C:3](=[O:4])[O:2][CH3:1])[CH2:10][CH2:11][N:12]([CH2:36][CH2:37][CH3:38])[C:13](=[O:35])[NH:14][C@@H:15]([CH2:28][C@H:29]2[CH2:34][CH2:33][CH2:32][O:31][CH2:30]2)[CH2:16][NH:17][CH3:18])[CH:44]=[CH:43][CH:42]=1
Reactant: CCCN(CC[C@@H](OCCNC(=O)OC)c1cccc(Cl)c1)C(=O)N[C@@H](C[C@H]1CCCOC1)CN(C)C(=O)OCC[Si](C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCN(CC[C@@H](OCCNC(=O)OC)c1cccc(Cl)c1)C(=O)N[C@H](CNC)C[C@H]1CCCOC1
Yield: 105.6 %

Procedure:
2-(trimethylsilyl)ethyl (S)-2-(3-((R)-3-(2-(methoxycarbonylamino)ethoxy)-3-(3-chlorophenyl)propyl)-3-propylureido)-3-((R)-tetrahydro-2H-pyran-3-yl)propyl(methyl)carbamate (31 mg) was treated with (V/V) 20% TFA/CH2Cl2 (2 mL) for 1 hr. The excess reagent was evaporated and the crude material was purified via preparative HPLC to afford the desired product (25.7 mg). LC-MS (3 min) tR=1.36 m/z=527. 1H NMR (CD3OD) d 7.25-7.35 (m, 4H), 4.30 (t, 1H), 4.10 (m, 1H), 3.89 (dd, 1H), 3.83 (m, 1H), 3.63 (s, 3H), 3.36-3.42 (m, 4H), 3.27 (m, 3H), 3.05-3.17 (m, 3H), 2.97 (t, 1H), 2.71 (s, 3H), 1.82-1.92 (m, 3H), 0.91 (t, 3H).
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][CH:8]([N:11]3[C:16](=[O:17])[C:15]([CH2:18][C:19]4[CH:24]=[CH:23][C:22]([C:25]5[C:26]([C:31]#[N:32])=[CH:27][CH:28]=[CH:29][CH:30]=5)=[C:21]([F:33])[CH:20]=4)=[C:14]([CH2:34][CH2:35][CH3:36])[N:13]4[N:37]=[CH:38][CH:39]=[C:12]34)[CH2:7][CH2:6]2)[O:4]CC1.Cl.[OH-].[Na+]>O1CCCC1.C(OCC)(=O)C>[F:33][C:21]1[CH:20]=[C:19]([CH2:18][C:15]2[C:16](=[O:17])[N:11]([C@H:8]3[CH2:9][CH2:10][C@H:5]([OH:4])[CH2:6][CH2:7]3)[C:12]3[N:13]([N:37]=[CH:38][CH:39]=3)[C:14]=2[CH2:34][CH2:35][CH3:36])[CH:24]=[CH:23][C:22]=1[C:25]1[C:26]([C:31]#[N:32])=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)c(F)c2)c(=O)n(C2CCC3(CC2)OCCO3)c2ccnn12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)c(F)c2)c(=O)n([C@H]2CC[C@H](O)CC2)c2ccnn12
Temperature: 70 °C
Reaction time: 2 h

Procedure:
To a solution of 4′-{[4-(1,4-dioxaspiro[4.5]dec-8-yl)-5-oxo-7-propyl-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl]methyl}-2′-fluorobiphenyl-2-carbonitrile (4.3 g) in tetrahydrofuran (40 mL) was added 3M hydrochloric acid (40 mL), and the mixture was stirred at 70° C. for 2 hr. The mixture was allowed to cool, and diluted with ethyl acetate, and the mixture was neutralized with 8M aqueous sodium hydroxide solution. The mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was dissolved in ethanol (15 mL)-tetrahydrofuran (15 mL). Thereto was added sodium borohydride (0.25 g) at 0° C. After stirring for 2 hr, ethyl acetate and saturated aqueous ammonium chloride solution were added. The mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography to give the title compound as a pale-yellow amorphous solid (3.0 g, 91%).
Reaction SMILES: [N+:1]([CH:4]([CH3:6])[CH3:5])([O-:3])=[O:2].[C:7]([N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)(=[O:9])[CH3:8].[OH-].[Na+].[CH2:18]=O>>[CH3:5][C:4]([N+:1]([O-:3])=[O:2])([CH3:18])[CH2:6][N:13]1[CH2:14][CH2:15][N:10]([C:7](=[O:9])[CH3:8])[CH2:11][CH2:12]1
Reactant: CC(=O)N1CCNCC1
Reactant: CC(C)[N+](=O)[O-]
Reactant: C=O
Agent: [Na+]
Agent: [OH-]
Product: CC(=O)N1CCN(CC(C)(C)[N+](=O)[O-])CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred ice cold solution of 2-nitropropane (3.5 mL, 38.9 mmol) and N-acetylpiperazine (5.0 g, 1 equiv, 39.6 mmol) was added dropwise a premixed solution of sodium hydroxide (156 μL, 5 N, 2 mol %) and a 37% aqueous solution of formaldehyde (2.9 mL, 1 equiv, 38.9 mmol) over 15 minutes maintaining an internal temperature between 10-15° C. The flask was removed from the ice bath and stirred at room temperature for 1 h. The reaction was then heated at 50° C. for 1 h. The biphasic mixture was cooled to room temperature and poured into a separatory funnel and diluted with ethyl acetate (150 mL) and water (50 mL). The layers were separated and the organic layer was washed with water (2×50 mL) and brine (50 mL). The organic layer was dried over anhydrous MgSO4, filtered and concentrated to a yellow liquid (7.20 g, 81%). This material was used without further purification. 1H NMR (CDCl3, 400 MHz): δ 1.57 (s, 6H), 2.06 (s, 3H), 2.50-2.55 (dt, J=5.6, 4H), 2.85 (s, 2H), 3.37-3.40 (t, J=5.0, 2H), 3.54-3.40 (t, J=4.8, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([NH:13][CH3:14])[CH2:10][CH2:9][N:8]([O:11][CH3:12])[CH2:7][CH2:6]1)=[O:4].[CH3:15][C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=1[CH2:23][C:24](Cl)=[O:25].Cl>N1C=CC=CC=1.C(OCC)(=O)C>[CH3:1][O:2][C:3]([C:5]1([N:13]([C:24](=[O:25])[CH2:23][C:17]2[CH:18]=[C:19]([CH3:22])[CH:20]=[CH:21][C:16]=2[CH3:15])[CH3:14])[CH2:10][CH2:9][N:8]([O:11][CH3:12])[CH2:7][CH2:6]1)=[O:4]
Reactant: CNC1(C(=O)OC)CCN(OC)CC1
Reactant: Cc1ccc(C)c(CC(=O)Cl)c1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: COC(=O)C1(N(C)C(=O)Cc2cc(C)ccc2C)CCN(OC)CC1
Temperature: 0 °C
Reaction time: 6 h

Procedure:
To a solution of 1-methoxy-4-methylamino-piperidine-4-carboxylic acid methyl ester (200 mg, 0.99 mmol) in pyridine (5 ml) was added (2,5-dimethyl-phenyl)-acetyl chloride (240 mg, 1.31 mmol) dropwise at 0° C. The reaction mixture was stirred at 0° C. for one hour and at room temperature for 6 hours, poured on ice water, acidified to pH 7 with an aqueous 2N HCl solution and diluted with ethyl acetate (50 ml). The layers were separated, the aqueous phase extracted with ethyl acetate (3×25 ml), the combined organic phases washed with water (3×15 ml) and brine, dried over sodium sulfate and concentrated. The residue was purified by chromatography on silica gel (cyclohexane/ethyl acetate 2:1). Yield: 170 mg of 4-{[2-(2,5-dimethyl-phenyl)-acetyl]-methyl-amino}-1-methoxy-piperidine-4-carboxylic acid methyl ester (title compound P4.46) as a colorless gum.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:12]([O:19][C:20](=[O:30])[C@H:21]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[NH2:22])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.Br[CH:32]1[CH2:37][CH2:36][O:35][C:33]1=[O:34].C(N(CC)CC)C.O>CN(C)C=O>[CH2:12]([O:19][C:20](=[O:30])[C@H:21]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[NH:22][CH:32]1[CH2:37][CH2:36][O:35][C:33]1=[O:34])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C1OCCC1Br
Reactant: N[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: O=C1OCCC1N[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1
Temperature: 70 °C
Reaction time: 18 h
Yield: 25.8 %

Procedure:
Dissolved in 40 ml of dimethylformamide were 8.54 g of L-phenylalanine benzyl ester p-toluenesulfonate and 3.40 g of 2-bromo-γ-butyrolactone. After a dropwise addition of 4.04 g of triethylamine, the resultant mixture was heated and stirred at 70° C. for 18 hours. The reaction mixture was poured into chilled water, followed by extraction with ethyl acetate. The extract was washed successively with water, a 2% aqueous solution of sodium hydrogencarbonate, and water. After drying the extract over anhydrous sodium sulfate, it was distilled under reduced pressure. The residue was isolated and purified by chromatography on a silica gel column (toluene:ethyl acetate=20:1-5:1). From initial fractions of the column effluent, 1.75 g of N-(2-oxo-3-tetrahydrofuranyl)-L-phenylalanine benzyl ester (Isomer A) was obtained as a colorless oily substance.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][N:9]=[C:10]=[O:11].[Cl:12][C:13]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[C:15]([F:23])[C:14]=1[O:24][C:25]1[CH:29]=[C:28]([CH3:30])[NH:27][N:26]=1.Cl>C(OCC)(=O)C>[CH3:8][NH:9][C:10]([N:27]1[C:28]([CH3:30])=[CH:29][C:25]([O:24][C:14]2[C:15]([F:23])=[CH:16][C:17]([C:19]([F:22])([F:20])[F:21])=[CH:18][C:13]=2[Cl:12])=[N:26]1)=[O:11]
Reactant: Cc1cc(Oc2c(F)cc(C(F)(F)F)cc2Cl)n[nH]1
Reactant: CN=C=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CNC(=O)n1nc(Oc2c(F)cc(C(F)(F)F)cc2Cl)cc1C
Temperature: 25 °C
Reaction time: 4 h
Yield: 56.9 %

Procedure:
Triethylamine (0.13 g, 1.3 mmol) and methyl isocyanate (0.07 g, 1.2 mmol) were added to a solution of 3-(2-chloro-6-fluoro-4-trifluoromethylphenyloxy)-5-methylpyrazole (0.32 g, 1.1 mmol) in ethyl acetate (10 ml), and the mixture was stirred at room temperature for 4 hours. After completion of the reaction, the reaction mixture was poured into 2N hydrochloric acid and extracted with ethyl acetate (10 ml×3). An organic layer was washed with water, dried over anhydrous magnesium sulfate and filtered to remove a desiccant, and the solvent was distilled off from the filtrate under reduced pressure. The resultant crude product was purified with a silica gel column (ethyl acetate/hexane=1/10), to give a white solid of N-methyl-3-(2-chloro-6-fluoro-4-trifluoromethylphenyloxy)-5-methylpyrazole-1-carboxamide (0.22 g, yield: 56.9%). mp: 87-88° C.; 1H-NMR (CDCl3, TMS, ppm): δ 2.59 (s, 3H), 2.88 (d, J=5.0 Hz, 3H), 5.80 (s, 1H), 6.55-6.75 (m, 1H), 7.40 (dd, JHF=2.0 and 9.3 Hz, 1H), 7.56 (s, 1H).
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C@H:5]1[CH2:24][C@@:23]2([CH3:25])[C@@H:8]([CH2:9][CH2:10][C@@H:11]3[C@@H:22]2[C:21](=[O:26])[CH2:20][C@@:19]2([CH3:27])[C@H:12]3[CH2:13][CH2:14][C@@H:15]2[C:16](=[O:18])[CH3:17])[CH2:7][C@@H:6]1[OH:28].[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>>[OH:28][C@@H:6]1[C@@H:5]([O:4][CH2:3][CH2:2][N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)[CH2:24][C@@:23]2([CH3:25])[C@@H:8]([CH2:9][CH2:10][C@@H:11]3[C@@H:22]2[C:21](=[O:26])[CH2:20][C@@:19]2([CH3:27])[C@H:12]3[CH2:13][CH2:14][C@@H:15]2[C:16](=[O:18])[CH3:17])[CH2:7]1
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)[C@@H](OCCCl)C[C@]4(C)[C@H]3C(=O)C[C@]12C
Reactant: C1COCCN1
Product: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)[C@@H](OCCN5CCOCC5)C[C@]4(C)[C@H]3C(=O)C[C@]12C

Procedure:
2β(2'-Chloroethoxy)-3α-hydroxy-5α-pregnane-11,20-dione (100 mg.) was dissolved in morpholine (10 ml.) and the solution heated on a steam-bath for 24 hours, complete reaction occurring. The morpholine was evaporated off in vacuo and the orange oil obtained purified by preparative TLC in ethyl acetate to give the title compound (40 mg.) as a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:12]([CH2:18][C:19]#[CH:20])[N:13]3[CH:17]=[CH:16][CH:15]=[CH:14]3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[CH3:21][N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.[CH2:28]=O>O1CCOCC1.C(OCC)(=O)C.Cl[Cu]>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:12]([CH2:18][C:19]#[C:20][CH2:21][N:22]3[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]3)[N:13]3[CH:14]=[CH:15][CH:16]=[CH:17]3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: C=O
Reactant: CN1CCNCC1
Reactant: C#CCN(c1ccnc2cc(Cl)ccc12)n1cccc1
Agent: Cl[Cu]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CN1CCN(CC#CCN(c2ccnc3cc(Cl)ccc23)n2cccc2)CC1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
To a solution of 7-chloro-N-(2-propynyl)-N-(1H-pyrrol-1-yl)-4-quinolinamine (8.0 g) in 150 ml of 1,4-dioxane were added N-methylpiperazine (3.11 g), paraformaldehyde (4 g) and CuCl (0.2 g), and this mixture was heated to 80° C. and stirred for four hours. The mixture was cooled, diluted with ethyl acetate, washed with water and dried (sat NaCl, anhy. MgSO4).