Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([C:10]#[N:11])=[CH:6][CH:5]=1.C#C.[C:15]1(C)[CH:20]=CC=[CH:17][CH:16]=1>[CH-]1C=CC=C1.[CH-]1C=CC=C1.[Co+2]>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:17]=[CH:16][CH:15]=[CH:20][N:11]=2)=[CH:6][CH:5]=1
Reactant: Cc1ccccc1
Reactant: COC(=O)c1ccc(C#N)cc1
Agent: [Co+2]
Agent: C#C
Agent: c1cc[cH-]c1
Product: COC(=O)c1ccc(-c2ccccn2)cc1
Temperature: 180 °C
Reaction time: 12 h

Procedure:
In an autoclave, 24.0 g (150 mmol) of 4-cyanobenzoic acid methyl ester (Fluka, Buchs, Switzerland) in 150 ml of toluene are placed under an acetylene atmosphere, and 0.30 g (1.6 mmol) of cobaltocene (=dicyclopentadienylcobalt; Aldrich, Milwaukee/USA) is added. Then an acetylene pressure of 15 atm is applied, and the mixture is heated to 180° C. and stirred for 12 h. After cooling and release of the pressure, 9.5 g of active carbon are added to the black suspension; the mixture is diluted with 250 ml of toluene, stirred for 30 min, filtered and concentrated by evaporation. Crystallisation from warm ether by the addition of hexane yields the title compound: m.p. 96° C.; TLC (hexane/ethyl acetate 4:1): Rf =0.37; FAB MS (M+H)+ =214. Further product can be obtained by column chromatography (SiO2, hexane/ethyl acetate 19:1→4:1) of the mother liquor.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:20]=[CH:19][C:8]([O:9][C:10]2[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][CH:11]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].C1(OP(Cl)(OC2C=CC=CC=2)=O)C=CC=CC=1.[NH2:38][C@@H:39]1[CH:44]2[CH2:45][CH2:46][N:41]([CH2:42][CH2:43]2)[CH2:40]1.CO>C(Cl)Cl.CN(C=O)C>[N:41]12[CH2:46][CH2:45][CH:44]([CH2:43][CH2:42]1)[C@@H:39]([NH:38][C:14](=[O:16])[C:13]1[CH:12]=[CH:11][C:10]([O:9][C:8]3[CH:7]=[CH:6][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[CH:20][CH:19]=3)=[CH:18][CH:17]=1)[CH2:40]2
Reactant: N[C@H]1CN2CCC1CC2
Reactant: CC(=O)Nc1ccc(Oc2ccc(C(=O)O)cc2)cc1
Agent: O=P(Cl)(Oc1ccccc1)Oc1ccccc1
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CO
Product: CC(=O)Nc1ccc(Oc2ccc(C(=O)N[C@H]3CN4CCC3CC4)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 38.9 %

Procedure:
TEA (130 μL, 1.0 mmol) is added to a suspension of the product of Step D (250 mg, 0.9 mmol) in CH2Cl2 (9 mL). Diphenylchlorophosphate (190 μL, 0.9 mmol) is added and the resulting solution is stirred at room temperature for 30 minutes. This solution is added to a solution of (R)-3-aminoquinuclidine (110 mg, 0.88 mmol) in DMF (1 mL). The resulting solution is stirred overnight at room temperature. MeOH is added and the mixture is poured through a column of AG50W×2 ion exchange resin (H+ form). The resin is washed with MeOH and then the product is eluted with 5% TEA in MeOH. The eluent is evaporated to dryness. The product is crystallized from CH3CN to yield the desired product (130 mg, 39%). MS for C22H25N3O3 (ESI) (M+H)+ m/z 380.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:24]([F:27])([F:26])[F:25])[N:5]2[CH2:22][CH2:21][N:20]([CH3:23])[C:7]3([CH2:12][CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9][CH2:8]3)[C:6]=12.[ClH:28]>C(Cl)Cl.O1CCOCC1>[ClH:28].[ClH:28].[F:1][C:2]1[CH:3]=[C:4]([C:24]([F:26])([F:25])[F:27])[N:5]2[CH2:22][CH2:21][N:20]([CH3:23])[C:7]3([CH2:8][CH2:9][NH:10][CH2:11][CH2:12]3)[C:6]=12
Reactant: CN1CCn2c(C(F)(F)F)cc(F)c2C12CCN(C(=O)OC(C)(C)C)CC2
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CN1CCn2c(C(F)(F)F)cc(F)c2C12CCNCC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.5 %

Procedure:
To tert-butyl 8-fluoro-2-methyl-6-(trifluoromethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4′-piperidine]-1′-carboxylate (310 mg, 0.80 mmol) in CH2Cl2 (2 mL) was added a solution of HCl (2.0 mL of 4 M, 8.0 mmol) in 1,4-dioxane. The reaction mixture was allowed to stir at room temperature for 1 hour. The volatiles were removed under reduced pressure providing 8-fluoro-2-methyl-6-(trifluoromethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4′-piperidine]dihydrochloride (290 mg, 99%) as a pink solid. ESI-MS m/z calc. 291.1, found 292.3 (M+1)+; Retention time: 0.75 minutes (3 minute run).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH:8]=O)=[C:6]([NH2:10])[CH:5]=[CH:4][N:3]=1.[CH3:11][C:12]([C:14]([CH3:17])([CH3:16])[CH3:15])=O.N1CCCCC1.C(O)C>ClCCl>[C:14]([C:12]1[CH:11]=[CH:8][C:7]2[C:6](=[CH:5][CH:4]=[N:3][C:2]=2[Cl:1])[N:10]=1)([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(=O)C(C)(C)C
Reactant: Nc1ccnc(Cl)c1C=O
Solvent: CCO
Solvent: ClCCl
Solvent: C1CCNCC1
Product: CC(C)(C)c1ccc2c(Cl)nccc2n1

Procedure:
A mixture of 15.7 g (100 mmol) of 2-chloro-3-formyl-4-aminopyridine [338452-92-9], 37.6 ml (300 mmol) of tert-butyl methyl ketone, 1.0 ml (10 mmol) of piperidine and 100 ml of ethanol is heated under reflux for 60 h. After cooling, the reaction mixture is diluted with 500 ml of dichloromethane, washed five times with 500 ml of water each time, dried over magnesium sulfate, and the solvent is removed in vacuo. The residue is recrystallised from ethanol. Yield: 8.2 g (37 mmol), 37%. Purity: >95% according to 1H-NMR.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[N:13]=[C:12]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=2Br)[N:11]2[CH2:25][CH2:26][N:27]([CH:30]([CH3:32])[CH3:31])[C:28](=[O:29])[C:10]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:33][C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1.C(=O)([O-])[O-].[K+].[K+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1>O1CCOCC1>[CH2:1]([O:8][C:9]1[C:14](=[O:15])[N:13]=[C:12]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=2[C:37]2[CH:38]=[CH:39][C:34]([F:33])=[CH:35][CH:36]=2)[N:11]2[CH2:25][CH2:26][N:27]([CH:30]([CH3:32])[CH3:31])[C:28](=[O:29])[C:10]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)N1CCn2c(Cc3ccc(Cl)cc3Br)nc(=O)c(OCc3ccccc3)c2C1=O
Reactant: OB(O)c1ccc(F)cc1
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CC(C)N1CCn2c(Cc3ccc(Cl)cc3-c3ccc(F)cc3)nc(=O)c(OCc3ccccc3)c2C1=O
Temperature: 80 °C
Yield: 44.2 %

Procedure:
Into a sealed tube was placed a stirred solution of 9-benzyloxy-6-(2-bromo-4-chlorobenzyl)-2-isopropyl-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (380) (70 mg, 0.136 mmol) in dioxane (3 mL). 4-Fluorophenyl boronic acid (18.99 mg, 0.14 mmol) and a 1N solution of potassium carbonate [(56.244 mg, 0.407 mmol) in 0.82 mL water] were added at room temperature and the reaction mixture was purged for 30 min with argon. To the reaction Pd(triphenyl phosphine)4 (15.676 mg, 0.014 mmol) was added under argon, followed by 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (11.138 mg, 0.027 mmol). The reaction mixture was further degassed for another 10 min, then heated to 80° C. for 30 min (monitored by LC-MS). The reaction mixture was filtered through a pad of celite. The filtrate was diluted with water (5 mL) and extracted with ethyl acetate (2×20 mL). The combined extracts were dried and concentrated. The resulting crude product was purified by column chromatography (using amine bound silica gel) to get 9-benzyloxy-6-(5-chloro-4′-fluoro-biphenyl-2-ylmethyl)-2-isopropyl-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (385) (32 mg, 44.34%) as an off-white solid.
Reaction SMILES: [C:1]([CH2:3][C:4]([NH2:6])=[S:5])#[N:2].[CH3:7][C:8](=O)[CH2:9][C:10](=O)[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].C(N(CC)CC)C>CCO>[CH2:11]([C:10]1[CH:9]=[C:8]([CH3:7])[C:3]([C:1]#[N:2])=[C:4]([SH:5])[N:6]=1)[CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: N#CCC(N)=S
Reactant: CCCCCC(=O)CC(C)=O
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCCCCc1cc(C)c(C#N)c(S)n1
Temperature: 50 °C
Yield: 64.2 %

Procedure:
To a stirred solution of 2-cyanothioacetamide (1.4 g, 14 mmol) and 2,4-nonanedione (2.0 g, 13 mmol) in anhydrous EtOH (40 mL) was added triethylamine (0.5 mL) and the reaction was heated at 50° C. for 1 h and then was allowed to cool to room temperature. Filtration and washing of the precipitates with EtOH gave 6-pentyl-2-mercapto4-methyl-nicotinonitrile as a yellow solid (1.84 g, 62.1%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.[CH:42]1([CH2:45][N:46]2[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]2)[CH2:44][CH2:43]1>CN(C=O)C>[Br:1][C:2]1[CH:7]=[N:6][C:5]([C:8]([N:49]2[CH2:50][CH2:51][N:46]([CH2:45][CH:42]3[CH2:44][CH2:43]3)[CH2:47][CH2:48]2)=[O:10])=[N:4][CH:3]=1
Reactant: C1CN(CC2CC2)CCN1
Reactant: O=C(O)c1ncc(Br)cn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(c1ncc(Br)cn1)N1CCN(CC2CC2)CC1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 28.9 %

Procedure:
To 5-bromopyrimidine-2-carboxylic acid (100 mg, 0.49 mmol) and TBTU (158 mg, 0.49 mmol) in anhydrous DMF 94.4. mL) was added DIPEA (0.36M in CH2Cl2, 1.4 mL, 0.49 mmol) and the reaction mixture stirred at RT for 40 min. N-cyclopropylmethylpiperazine (83 mg, 0.59 mmol) in anhydrous DMF (1 mL) was added and the reaction stirred at RT for 18 h. The reaction mixture was passed through a Si—NH2 cartridge (5 g), eluting with DMF and MeOH. The eluents were combined, concentrated in vacuo and purified by reverse phase preparative HPLC-MS to obtain (5-bromo-pyrimidin-2-yl)-(4-cyclopropylmethyl-piperazin-1-yl)-methanone as a pale yellow solid (46 mg, 29%).
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([N:11]2[CH2:15][C:14]([O:16][C:17]3[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=3[F:24])=[CH:13][C:12]2=[O:25])[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[OH:27][C@@H:28]([CH2:58]O)[CH2:29][N:30]1[CH:34]=[CH:33][C:32]([NH:35]C(=O)[C@@H](N2CC(OC3C=CC=C(Cl)C=3Cl)=CC2=O)CC(C)C)=[N:31]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=C[C:70]=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O.C(OCC)(=O)C>[CH:1]1([CH2:6][C@H:7]([N:11]2[CH2:15][C:14]([O:16][C:17]3[C:18]([F:24])=[CH:19][CH:20]=[CH:21][C:22]=3[F:23])=[CH:13][C:12]2=[O:25])[C:8]([NH:35][C:32]2[CH:33]=[CH:34][N:30]([CH2:29][C:28]([OH:27])([CH3:58])[CH3:70])[N:31]=2)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC(C)C[C@@H](C(=O)Nc1ccn(C[C@@H](O)CO)n1)N1CC(Oc2cccc(Cl)c2Cl)=CC1=O
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Reactant: O=C(O)[C@H](CC1CCCC1)N1CC(Oc2c(F)cccc2F)=CC1=O
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(O)Cn1ccc(NC(=O)[C@H](CC2CCCC2)N2CC(Oc3c(F)cccc3F)=CC2=O)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 34.3 %

Procedure:
A solution of (S)-3-cyclopentyl-2-[4-(2,6-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-propionic acid (109 mg, 0.31 mmol) in N,N-dimethylformamide (4 mL) was treated with 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (prepared in U.S. Pat. Appl. US2008021032 Example 80, 62 mg, 0.40 mmol), benzotriazol-1-yl-oxy-tris(dimethylamino)phosphonium hexafluorophosphate (354 mg, 0.8 mmol) and N,N-diisopropylethylamine (103 mg, 0.8 mmol). The reaction mixture was stirred for 4 h at 25° C., under nitrogen. The reaction mixture was diluted with ethyl acetate, washed with saturated ammonium chloride, water, a saturated sodium chloride solution and dried over sodium sulfate. The organic layer was concentrated, and the crude product was purified by ISCO flash chromatography (Teledyne Isco RediSep Flash Column 12 g, 10% to 80% ethyl acetate/hexanes) to afford (S)-3-cyclopentyl-2-[4-(2,6-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-propionamide (52 mg, 34%): HR-ES-MS m/z calculated for C25H30F2N4O4 [M+H]+ 489.2308 observed 489.2308; 1H NMR (300 MHz, DMSO-d6) δ ppm 1.05 (br. s., 3H) 1.06 (br. s., 3H) 1.09-1.98 (m, 11H) 3.89 (s, 2H) 4.30 (d, J=18.7 Hz, 1H) 4.61 (d, J=18.7 Hz, 1H) 4.68 (s, 1H) 4.82 (dd, J=10.1, 4.4 Hz, 1H) 5.03 (s, 1H) 6.45 (d, J=2.1 Hz, 1H) 7.26-7.50 (m, 3H) 7.54 (d, J=2.1 Hz, 1H) 10.82 (s, 1H).
Reaction SMILES: [CH2:1]([C:3]1[C:4]([CH3:21])=[C:5]2[C:12](I)=[C:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[S:10][C:6]2=[N:7][C:8]=1[CH3:9])[CH3:2].C([O-])([O-])=O.[K+].[K+].[CH3:28][O:29][C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([C:3]1[C:4]([CH3:21])=[C:5]2[C:12]([C:33]3[CH:34]=[CH:35][C:30]([O:29][CH3:28])=[CH:31][CH:32]=3)=[C:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[S:10][C:6]2=[N:7][C:8]=1[CH3:9])[CH3:2]
Reactant: COc1ccc(B(O)O)cc1
Reactant: CCc1c(C)nc2sc(C(=O)OC(C)(C)C)c(I)c2c1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: CCc1c(C)nc2sc(C(=O)OC(C)(C)C)c(-c3ccc(OC)cc3)c2c1C
Temperature: 25 °C
Yield: 30.2 %

Procedure:
To a solution of compound tert-butyl 5-ethyl-3-iodo-4,6-dimethyl-thieno[2,3-b]pyridine-2-carboxylate (42 mg, 0.1 mmol) in 0.5 mL of DME/H2O (1/1) was added K2CO3 (41 mg, 0.3 mmol), Pd(PPh3)4 (12 mg, 0.01 mmol), p-methoxyphenyl boronic acid (18 mg, 0.12 mmol). The mixture was then heated to reflux for 16 h. After cooling to room temperature, the solvent was evaporated under reduced pressure. The residue was dissolved with ethyl acetate (2 mL), washed with water (2 mL×3), brine, dried over anhydrous Na2SO4 and evaporated under reduced pressure. The crude solid was purified by preparative HPLC to provide t-butyl 5-ethyl-3-(4-methoxy-phenyl)-4,6-dimethyl-thieno[2,3-b]pyridine-2-carboxylate (12 mg, 30%).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7](B(O)O)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].C(=O)([O-])O.[Na+].C1(C)C=CC=CC=1.[C:25]([NH:33][CH:34]1[CH:43]=[CH:42][CH:41]=[CH:40][C:35]1(Br)[C:36]([O:38]C)=[O:37])(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O.C(O)C>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:42]2[CH:41]=[CH:40][C:35]([C:36]([OH:38])=[O:37])=[C:34]([NH:33][C:25](=[O:32])[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:43]=2)=[CH:6][CH:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc(B(O)O)cc1
Reactant: COC(=O)C1(Br)C=CC=CC1NC(=O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC(=O)c1ccc(-c2ccc(C(=O)O)c(NC(=O)c3ccccc3)c2)cc1
Temperature: 160 °C
Reaction time: 0.08 h

Procedure:
51 mg of 4-acetylphenylboronic acid, 61 mg of sodium hydrogen carbonate and 12 mg of tetrakis(triphenylphosphine)palladium(0) were added to a mixed solution of 2.0 mL of toluene, 0.6 mL of ethanol and 0.4 mL of water containing 70 mg of methyl 2-(benzamido)-1-bromobenzoate, and stirred under pressure at 160° C. for 5 minutes. After the reaction mixture was cooled to room temperature, insoluble were removed by filtration, ethyl acetate and 0.5 mol/L hydrochloric acid were added and a solid substance was separated by filtration. The obtained solid substance was added to a mixed solution of 1.0 mL of 2.0 mol/L aqueous sodium hydroxide and 5.0 mL of ethanol and stirred at room temperature for 1 hour and 30 minutes. 0.6 mol/L hydrochloric acid and ethyl acetate were added to the reaction mixture. The organic layer was separated, and the solvent was evaporated under reduced pressure to obtain 50 mg of 4-(4-acetylphenyl)-2-(benzamido)benzoic acid as white solid.
Reaction SMILES: [C:1]([OH:20])(=[O:19])[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].[C:21]([OH:40])(=[O:39])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]/[CH:29]=[CH:30]\[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38]>>[O:39]=[C:10]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]([OH:20])=[O:19].[OH:19][CH:30]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][C:21]([OH:40])=[O:39]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)O
Reactant: CCCCC/C=C\C/C=C\CCCCCCCC(=O)O
Product: CCCCCCCCC(=O)CCCCCCCCC(=O)O
Product: CCCCCCCCC(O)CCCCCCCCC(=O)O

Procedure:
The procedure of Example 1, supra., is repeated except that the linoleic acid as used therein is replaced with an equal weight of oleic acid. The products, 10-ketostearic acid and 10-hydroxystearic acid, are obtained as follows:
Reaction SMILES: [F:1][C:2]1[C:3]([C:9]2[C:13]([Cl:14])=[C:12]([O:15][CH:16]([F:18])[F:17])[N:11]([CH3:19])[N:10]=2)=[N:4][CH:5]=[C:6](Cl)[CH:7]=1.Cl.O1CCOC[CH2:22]1>>[F:1][C:2]1[C:3]([C:9]2[C:13]([Cl:14])=[C:12]([O:15][CH:16]([F:18])[F:17])[N:11]([CH3:19])[N:10]=2)=[N:4][CH:5]=[C:6]([CH3:22])[CH:7]=1
Reactant: C1COCCO1
Reactant: Cn1nc(-c2ncc(Cl)cc2F)c(Cl)c1OC(F)F
Agent: Cl
Product: Cc1cnc(-c2nn(C)c(OC(F)F)c2Cl)c(F)c1
Temperature: 90 °C
Reaction time: 4 h

Procedure:
2.0 g of 3-(3-fluoro-5-chloro-2-pyridyl)-4-chloro-5-difluoromethoxy-1-methyl-[1H]-pyrazole (Example P15) are introduced into 6 ml of absolute dioxane. In order to remove the oxygen, gentle evacuation is carried out three times (water-jet pump) and the mixture is gassed with argon. 6.4 ml of a 2M solution of trimethylaiuminium in toluene and 0.10 g of tetrakistriphenylphosphinepalladium (Pd(PPh3)4) are added thereto. The mixture is heated to 90° C., with stirring, in an argon atmosphere. The next day the mixture is cooled to 22° C., a further 0.10 g of Pd(PPh3)4 and 6.4 ml of a 2M solution of trimethylaluminium in toluene are added and the mixture is stirred at 110° C. After 4 hours, TLC analysis of a worked-up sample shows that all the starting material has reacted. The reaction mixture is introduced carefully into cold, dilute hydrochloric acid and is then extracted with ethyl acetate. The combined organic phases are washed with brine, dried over sodium sulfate, filtered and concentrated by evaporation in vacuo. The crude product obtained is purified over a flash chromatography column (silica gel; eluant: n-hexane/ethyl acetate 1/1 (v/v)). 1.36 g of the desired compound are obtained in the form of a yellow oil, which slowly crystallises; melting point 41-42° C.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([CH:15]=1)=[CH:13][C:12]([O:16][CH3:17])=[CH:11][CH:10]=2)=O)C.[H-].C([Al+]CC(C)C)C(C)C.CO>C1(C)C=CC=CC=1.C(Cl)Cl.C1(C)C=CC=CC=1>[OH:3][CH2:4][C:6]1[CH:7]=[N:8][C:9]2[C:14]([CH:15]=1)=[CH:13][C:12]([O:16][CH3:17])=[CH:11][CH:10]=2
Reactant: CCOC(=O)c1cnc2ccc(OC)cc2c1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: CO
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COc1ccc2ncc(CO)cc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 0 %

Procedure:
To a suspension of 5.9 g (25 mol) of 3-ethoxycarbonyl-6-methoxyquinoline in 120 mL of 1:1 toluene/methylene chloride were added dropwise at -50° C., 36.7 mL (55 mmol) of diisobutylaluminium hydride as a 1.5M solution in toluene. The reaction mixture was gradually warmed to room temperature. To this mixture were added about 4 mL of methanol to quench excess reducing agent, and then water was added with vigorous stirring. After 30 minutes, 150 mL of ethyl acetate and anhydrous magnesium sulfate were added and the mixture was stirred for an additional 30 minutes. The solid was removed by filtration and washed thoroughly with ethyl acetate. The filtrate and washings were combined and evaporated in vacuo. The residue was chromatographed on silica gel, using first ethyl acetate and then 2% ethanol in ethyl acetate as eluents, to give 1.72 g (36.4%) of the title compound as a solid which melts at 92°-93° C. after crystallization from a mixture of benzene and isopropyl ether. TLC Rf =0.17 (ethyl acetate); NMR (CDCl3) δ 8.6 (1H, d), 7.9 (2H, m), 7.3 (1H, q), 6.95 (1H, d) 4.8 (2H, s), 3.85 (3H, s); IR (KBr) ν 3070, 1625, 1500, 1215 cm-1.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]Br)=[CH:6][CH:5]=1.[CH3:16][C:17]1[CH:22]=[CH:21][C:20]([S:23]([CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[O:24])=[CH:19][CH:18]=1.O>CS(C)=O>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH:25]([S:23]([C:20]2[CH:19]=[CH:18][C:17]([CH3:16])=[CH:22][CH:21]=2)=[O:24])[C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:6][CH:5]=1
Reactant: Clc1ccc(CCCCCBr)cc1
Reactant: CCOC(=O)CS(=O)c1ccc(C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)C(CCCCCc1ccc(Cl)cc1)S(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
First 1.64 g (37.6 mmol) of sodium hydride in 55% mineral oil suspension, and then 9.8 g (37.6 mmol) of 5-(4-chlorophenyl)pentyl bromide, are added to a solution of 8.5 g (37.6 mmol) of ethyl 4-methylphenylsulfinylacetate in 75 ml of dimethylsulfoxide. Then the mixture is stirred at room temperature for another 4 hours. Then it is poured into water, extracted with ether, the extracts are washed with water, dried and concentrated. The concentrate is chromatographed with a mixture of n-heptane and butanone (2:1) on silica gel. Yield: 8.0 g (52% of theory) of ethyl 7-(4-chlorophenyl)-2-[(4-methylphenyl)sulfinyl]heptanoate, a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[O:7])=[CH:4][C:3]=1[CH3:15].[O:16]=[C:17]([CH:19]=[C:20]([CH3:22])[CH3:21])[CH3:18].C([O-])(O)=O.[Na+]>>[CH3:21][C:20]([CH3:22])([CH2:19][C:17](=[O:16])[CH3:18])[CH:8]([C:6](=[O:7])[C:5]1[CH:13]=[CH:14][C:2]([F:1])=[C:3]([CH3:15])[CH:4]=1)[C:9]([O:11][CH3:12])=[O:10]
Reactant: CC(=O)C=C(C)C
Reactant: COC(=O)CC(=O)c1ccc(F)c(C)c1
Agent: O=C([O-])O
Agent: [Na+]
Product: COC(=O)C(C(=O)c1ccc(F)c(C)c1)C(C)(C)CC(C)=O
Reaction time: 120 h

Procedure:
A mixture of methyl 4-fluoro-3-methylbenzoylacetate (1a) (26.95g, 0.128 mol) and mesityl oxide (2) (19.3g, 0.192 mol) was kept at 0°-5° C. for 5 days, poured onto cold saturated NaHCO3 and extracted with ether. The combined extracts were washed with H2O and brine and dried (MgSO4). Removal of the volatiles in vacuo furnished 3a which was used without further purification.
Reaction SMILES: [Br:1]Br.[F:3][C:4]1[CH:15]=[CH:14][C:7]2[CH2:8][CH2:9][CH2:10][CH2:11][C:12](=[O:13])[C:6]=2[CH:5]=1.O>CCOCC>[F:3][C:4]1[CH:15]=[CH:14][C:7]2[CH2:8][CH2:9][CH2:10][CH:11]([Br:1])[C:12](=[O:13])[C:6]=2[CH:5]=1
Reactant: O=C1CCCCc2ccc(F)cc21
Reactant: BrBr
Solvent: CCOCC
Solvent: O
Product: O=C1c2cc(F)ccc2CCCC1Br
Reaction time: 1 h
Yield: 101.3 %

Procedure:
68.9 g of bromine are added dropwise to a solution of 73.1 g of 3-fluoro-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-one in 700 ml of ether under ice-cooling during 1 hour. After the mixture is stirred for 1 hour, the reaction mixture is poured into water and the mixture is extracted with ether. The ether layer is washed, dried and evaporated to remove the solvent to obtain 106.8 g of 3-fluoro-6-bromo-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-one as an oil.