Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[N:8]=[CH:9][N:10]([C:18]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li]CCCC.[CH2:42]([O:44][C:45]1[CH:46]=[C:47]([O:62][CH:63]([CH3:65])[CH3:64])[C:48]([F:61])=[C:49]([CH:60]=1)/[CH:50]=[N:51]/[C:52]1[CH:59]=[CH:58][C:55]([C:56]#[N:57])=[CH:54][CH:53]=1)[CH3:43]>C1COCC1>[C:1]1([C:7]2[N:8]=[C:9]([N:51]([CH2:50][C:49]3[CH:60]=[C:45]([O:44][CH2:42][CH3:43])[CH:46]=[C:47]([O:62][CH:63]([CH3:65])[CH3:64])[C:48]=3[F:61])[C:52]3[CH:59]=[CH:58][C:55]([C:56]#[N:57])=[CH:54][CH:53]=3)[N:10]([C:18]([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc(-c2ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c2-c2ccccc2)cc1
Reactant: CCOc1cc(/C=N/c2ccc(C#N)cc2)c(F)c(OC(C)C)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOc1cc(CN(c2ccc(C#N)cc2)c2nc(-c3ccccc3)c(-c3ccccc3)n2C(c2ccccc2)(c2ccccc2)c2ccccc2)c(F)c(OC(C)C)c1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 56.3 %

Procedure:
To a solution of Intermediate 19.1 (100 mg, 0.216 mmol) in 3 mL THF at 0° C., was added BuLi (1.4 M in THF, 170 μL, 0.238 mmol). The mixture was stirred at 0° C. for 20 min, then a solution of Intermediate 7.3 (70.5 mg, 0.216 mmol) in 0.5 mL THF was added dropwise. The mixture was stirred at rt for 30 min, then was quenched with sat. NH4Cl. The mixture was diluted with EtOAc, washed with H2O and brine, dried (Na2SO4) and concentrated. The crude product was purified by flash chromatography (0 to 30% EtOAc/hexanes gradient) to afford 96 mg of Intermediate 19.2 as a white solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[C:4]([Cl:9])[N:3]=1.CC1(C)C(C)(C)OB([C:18]2[CH:19]=[N:20][N:21]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[CH:22]=2)O1.C([O-])([O-])=O.[K+].[K+].O>O1CCOCC1.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>[Cl:9][C:4]1[N:3]=[C:2]([C:18]2[CH:19]=[N:20][N:21]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[CH:22]=2)[N:7]=[C:6]([NH2:8])[CH:5]=1
Reactant: CC1(C)OB(c2cnn(COCC[Si](C)(C)C)c2)OC1(C)C
Reactant: Nc1cc(Cl)nc(Cl)n1
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: C1COCCO1
Product: C[Si](C)(C)CCOCn1cc(-c2nc(N)cc(Cl)n2)cn1
Temperature: 50 °C
Yield: 25.1 %

Procedure:
A flask was charged with 2,6-dichloropyrimidin-4-amine (10.0 g, 61.0 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (Preparation E; 29.7 g, 91.5 mmol), and K2CO3 (25.3 g, 183 mmol) in dioxane (40 mL) before 300 mL of dioxane and 11 mL of water were added to the reaction mixture. The reaction mixture was then purged with argon for 30 minutes before tetrakis(triphenylphosphine)palladium (0) (3.52 g, 3.05 mmol) was added in one portion to the reaction which was then purged with argon for another 30 minutes. The reaction mixture was then sealed and heated at 50° C. overnight. The reaction mixture was cooled to ambient temperature and partitioned between ethyl acetate (300 mL) and aqueous saturated sodium bicarbonate (300 mL). The aqueous layer was then extracted with ethyl acetate twice more and separated. The organic layers were combined, dried over MgSO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography eluting with 20-100% ethyl acetate in hexanes to afford 6-chloro-2-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)pyrimidin-4-amine (5.00 g, 15.3 mmol, 25.2% yield). MS (apci) m/z=326.1 (M+H). Structure and regioisomer confirmed by observed nOe.
Reaction SMILES: [F:1][C:2]1[CH:21]=[C:20]([I:22])[CH:19]=[CH:18][C:3]=1[NH:4][C:5]1[C:6]([C:13]([O:15]CC)=[O:14])=[CH:7][N:8]([CH3:12])[C:9](=[O:11])[CH:10]=1.[OH-].[Na+]>CCO.Cl>[F:1][C:2]1[CH:21]=[C:20]([I:22])[CH:19]=[CH:18][C:3]=1[NH:4][C:5]1[C:6]([C:13]([OH:15])=[O:14])=[CH:7][N:8]([CH3:12])[C:9](=[O:11])[CH:10]=1
Reactant: CCOC(=O)c1cn(C)c(=O)cc1Nc1ccc(I)cc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cn1cc(C(=O)O)c(Nc2ccc(I)cc2F)cc1=O
Temperature: 25 °C
Reaction time: 15 h
Yield: 100 %

Procedure:
Ethyl 4-(2-fluoro-4-iodoanilino)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxylate (140 mg, 0.34 mmol) was suspended in EtOH (10 mL), to which was added 1 M NaOH (10 mL). This mixture was stirred at R.T. for 15 h., then diluted with 1 M HCl (50 mL) and the resulting precipitate extracted into EtOAc (2×50 mL). The combined EtOAc fractions were dried (Na2SO4) and the solvent removed under reduced pressure to afford 4-(2-fluoro-4-iodoanilino)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxylic acid as a white solid (132 mg, 100%), m.p. (acetone/MeOH) 254-257° C. 1H NMR [(CD3)2SO, 400 MHz] δ 13.30 (v br s, 1H), 9.66 (s, 1H), 8.52 (s, 1H), 7.76 (dd, J=10.1, 1.9 Hz, 1H), 7.59 (ddd, J=8.4, 1.7, 0.8 Hz, 1H), 7.31 (t, J=8.5 Hz, 1H), 5.49 (d, J=0.7 Hz, 1H), 3.41 (s, 3H). Anal. Calcd for C13H10FIN2O3: C, 40.2; H, 2.6; N, 7.2. Found: C, 40.5; H, 2.3; N, 7.3.
Reaction SMILES: [O:1]1CCO[CH:2]1[CH2:6][N:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:17]([O:19][CH3:20])=[O:18])=[CH:9][C:8]1=[O:21].C(=O)([O-])O.[Na+]>FC(F)(F)C(O)=O>[O:21]=[C:8]1[CH:9]=[C:10]([C:17]([O:19][CH3:20])=[O:18])[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:7]1[CH2:6][CH:2]=[O:1]
Reactant: COC(=O)c1cc(=O)n(CC2OCCO2)c2ccccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1cc(=O)n(CC=O)c2ccccc12
Temperature: 25 °C
Reaction time: 11.5 h

Procedure:
0.10 mg of methyl 1-(1,3-dioxolan-2-ylmethyl)-1,2-dihydro-2-oxoquinoline-4-carboxylate was dissolved in 3 mL of 67% aqueous trifluoroacetic acid solution, and stirred at room temperature for 11.5 hours. After the reaction mixture was alkalized by adding aqueous saturated sodium hydrogen carbonate solution, it was extracted with ethyl acetate. The organic layer was washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to give methyl 2-oxo-1-(2-oxoethyl)-1,2-dihydroquinoline-4-carboxylate as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:10])[CH3:9])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].S(=O)(=O)(O)O.[CH3:19]COC(C)=O.O>CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([O:10][CH3:19])[CH3:9])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: CCOC(C)=O
Reactant: CC(O)c1ccc(F)c([N+](=O)[O-])c1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CO
Product: COC(C)c1ccc(F)c([N+](=O)[O-])c1
Temperature: 150 °C
Yield: 71 %

Procedure:
1-(4-fluoro-3-nitrophenyl)ethanol (870 g, 4.7 mmol) was dissolved in MeOH (10 ml) and concentrated sulfuric acid (2.5 ml, 47 mmol) was added carefully. The reaction mixture was heated at 150° C. using microwave (Biotage Initiator) for 5 minutes. After cooling to room temperature, the reaction mixture was poured into EtOAc/water. The organic layer was washed with brine, dried over MgSO4 and evaporated. The resulting material was purified by flash chromatography on silica eluting with 0% to 50% EtOAc/Hexane to afford the title compound (664 mg, yield: 71%). 1H-NMR (400 MHz, CDCl3) δ 1.45 (d, 3H) 3.27 (s, 3H) 4.36 (q, 1H) 7.28-7.32 (m, 1H) 7.56-7.63 (m, 1H) 7.98-8.04 (m, 1H)
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([S:12]([OH:15])(=[O:14])=[O:13])=[CH:4][C:3]=1[N:16]=[N:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1.N1C=CC=CC=1.[C:30](Cl)(=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(N(CC)CC)C>CC(C)=O>[C:30]([O:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([S:12]([OH:15])(=[O:13])=[O:14])=[CH:4][C:3]=1[N:16]=[N:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1)(=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: O=S(=O)(O)c1cc(N=Nc2ccccn2)c(O)c2ccccc12
Reactant: O=C(Cl)c1ccccc1
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: O=C(Oc1c(N=Nc2ccccn2)cc(S(=O)(=O)O)c2ccccc12)c1ccccc1

Procedure:
4-Hydroxy-3-(2-pyridylazo)-1-naphthalenesulfonic acid (110 g) was added to pyridine (350 ml) followed by benzoyl chloride (250 ml). Triethylamine (100 ml) was added slowly and the reaction mixture got warm. After 1 hour the mixture was diluted with five times its volume of acetone and filtered. The product was washed with acetone and allowed to suck dry. It was dissolved in water (minimum volume) and neutralized with hydrochloric acid. After filtration, the product was washed with acetone and ether. Yield 120 g (83 percent).
Reaction SMILES: C1(COC2C(C3[N:16]([CH2:17][C:18]4[CH:23]=[CH:22][C:21](CCC(O)=O)=[CH:20][CH:19]=4)[C:15]4[CH:29]=[C:30]([F:34])[C:31]([F:33])=[CH:32][C:14]=4[N:13]=3)=CC=CN=2)CC1.[C:35]([C:37]1[CH:53]=[CH:52][C:40]([O:41][CH2:42]C2C=CC=CC=2C(Cl)=O)=[CH:39][C:38]=1[F:54])#[N:36].FC1C=C(N)C(N)=CC=1F>>[F:33][C:31]1[C:30]([F:34])=[CH:29][C:15]2[NH:16][C:17]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:23]=3[CH2:42][O:41][C:40]3[CH:52]=[CH:53][C:37]([C:35]#[N:36])=[C:38]([F:54])[CH:39]=3)=[N:13][C:14]=2[CH:32]=1
Reactant: O=C(O)CCc1ccc(Cn2c(-c3cccnc3OCC3CC3)nc3cc(F)c(F)cc32)cc1
Reactant: N#Cc1ccc(OCc2ccccc2C(=O)Cl)cc1F
Agent: Nc1cc(F)c(F)cc1N
Product: N#Cc1ccc(OCc2ccccc2-c2nc3cc(F)c(F)cc3[nH]2)cc1F

Procedure:
The title compound was prepared in analogy to Example 40, intermediate b, from 2-(4-cyano-3-fluoro-phenoxymethyl)-benzoyl chloride and 4,5-difluoro-benzene-1,2-diamine (CAS Reg. No. 76179-40-3). Light yellow solid (15%). MS (Turbo Spray): m/z=380.2 (M+H).
Reaction SMILES: S([O-])([O-])(=O)=O.[Ca+2].[CH3:7][C:8]([C:12]1[CH:20]=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][CH:13]=1)([CH3:11])[CH2:9][OH:10].[C:21](=O)(O)[O-].[Na+].CI>CN(C)C(=O)C>[CH3:21][O:17][C:16](=[O:18])[C:15]1[CH:14]=[CH:13][C:12]([C:8]([CH3:7])([CH3:11])[CH2:9][OH:10])=[CH:20][CH:19]=1
Reactant: CC(C)(CO)c1ccc(C(=O)O)cc1
Reactant: O=C([O-])O
Agent: O=S(=O)([O-])[O-]
Agent: [Ca+2]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: CI
Product: COC(=O)c1ccc(C(C)(C)CO)cc1
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 99 %

Procedure:
The following reagents were placed in a flask equipped with a magnetic stirrer, oil bath and reflux condenser protected with a guard tube containing anhydrous calcium sulfate ("Drierite"): p-(1,1-dimethyl-2-hydroxyethyl)benzoic acid, 20 g, 0.103 mole; sodium bicarbonate, 9.4 g, 0.112 mole; N,N-dimethylacetamide, 100 mL; and methyl iodide, 28.4 g, 0.2 mole. The mixture was heated at 80° C. for 2.5 hours, cooled to room temperature and filtered to remove any unreacted hydroxyacid. The clear solution was then poured into 600 mL water and stirred for 10 minutes. 50 mL of 5% aqueous sodium bicarbonate was added and the resultant solution extracted 3 times with 120 mL portions of ether. The ether layers were combined, washed with dilute aqueous bicarbonate, dilute aqueous sodium thiosulfate and finally water, and dried over anhydrous potassium carbonate. The ether solution was evaporated to give a colorless liquid which crystallized upon standing at room temperature. Yield 99%. The compound was purified by distillation, bp 135°- 140° C. at 0.3 to 0.5 mm Hg, (0.04 to 0.667 kPa) followed by recrystallization from ether/pentane (1/4 vol.) at -20° C., mp 44°-45° C. Elemental analysis, IR and NMR spectra were all consistent with the proposed structure.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[N:3]=1.[C:9]([CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]1)#[N:10].C[Si]([N-][Si](C)(C)C)(C)C.[K+]>C1(C)C=CC=CC=1.[Cl-].[Na+].O>[C:9]([C:11]1([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[N:3]=2)[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]1)#[N:10]
Reactant: CC(C)(C)OC(=O)N1CCC(C#N)CC1
Reactant: Cc1cccc(F)n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1cccc(C2(C#N)CCN(C(=O)OC(C)(C)C)CC2)n1

Procedure:
To a solution of 2-fluoro-6-methylpyridine (6.67 g, 60 mmole) in toluene (40 mL) was added tert-butyl 4-cyanopiperidine-1-carboxylate (I-1) (4.22 g, 20 mmole) and 0.5M solution of KHMDS (48 mL, 24 mmole). The reaction mixture was stirred 2h min at rt ° C. After this time, LCMS indicated that the reaction was completion. The reaction mixture was poured into brine (150 mL) and extracted with EtOAc (3×150 mL). The combined organic extracts were washed with brine (2×100 mL), dried over MgSO4, filtered and concentrated to afford the desired product tert-butyl 4-cyano4-(6-methylpyridin-2-yl)piperidine-1-carboxylate (II-2) as a yellow-brown solid. Analytical LCMS: single peak (214 nm), 3.241 min. This product was used in next step reaction without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:13]([CH2:14]O)=[C:12]([CH:16]([CH3:18])[CH3:17])[O:11][N:10]=1.P(Br)(Br)[Br:20]>C1COCC1.CCOC(C)=O>[Br:20][CH2:14][C:13]1[C:9]([C:3]2[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=2[Cl:8])=[N:10][O:11][C:12]=1[CH:16]([CH3:18])[CH3:17]
Reactant: CC(C)c1onc(-c2c(Cl)cccc2Cl)c1CO
Reactant: BrP(Br)Br
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)c1onc(-c2c(Cl)cccc2Cl)c1CBr

Procedure:
To a solution of [3-(2,6-dichloro-phenyl)-5-isopropyl-isoxazol-4-yl]-methanol (1.14 g, 4 mmol) in THF (20 mL) is added PBr3 (0.76 mL, 8 mmol). The reaction mixture is stirred at reflux for 30 minutes. The reaction mixture is diluted with EtOAc and is washed with 0.2 N HCl. The organic layer is separated, dried (MgSO4), filtered, and concentrated to give the title compound as an oil.
Reaction SMILES: C(O[C:4]([C:6]1[C:7]([OH:35])=[C:8]2[C:27]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[F:34])=[N:26][S:25][C:9]2=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:14][CH:13]=2)[N:11]=1)=[O:5])C.[NH2:36][CH2:37][C:38]([OH:40])=[O:39]>>[F:34][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=1[C:27]1[C:8]2[C:9](=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([O:18][C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)=[CH:14][CH:13]=3)[N:11]=[C:6]([C:4]([NH:36][CH2:37][C:38]([OH:40])=[O:39])=[O:5])[C:7]=2[OH:35])[S:25][N:26]=1
Reactant: CCOC(=O)c1nc(-c2ccc(Oc3ccccc3)cc2)c2snc(-c3ccccc3F)c2c1O
Reactant: NCC(=O)O
Product: O=C(O)CNC(=O)c1nc(-c2ccc(Oc3ccccc3)cc2)c2snc(-c3ccccc3F)c2c1O

Procedure:
The title compound was synthesized in analogy Example 1 from 3-(2-fluoro-phenyl)-4-hydroxy-7-(4-phenoxy-phenyl)-isothiazolo[5,4-c]pyridine-5-carboxylic acid ethyl ester and glycine: MS (m/z) 516.1 (M+1).
Reaction SMILES: C[O:2][C:3](=[O:19])[C:4]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]=2)=[CH:9][CH:8]=1)([CH3:6])[CH3:5].[OH-].[Na+]>C(O)C>[C:13]1([C:10]2[CH:9]=[CH:8][C:7]([C:4]([CH3:6])([CH3:5])[C:3]([OH:19])=[O:2])=[CH:12][CH:11]=2)[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]=1
Reactant: COC(=O)C(C)(C)c1ccc(C2=CCCCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C(=O)O)c1ccc(C2=CCCCC2)cc1

Procedure:
A solution of 11 g of α-[p-(1-cyclohexenyl)-phenyl]-isobutyric acid methyl ester in 100 ml of ethanol is mixed with 20 ml of 10N sodium hydroxide solution and heated for 2 hours to 60°-70° C. This batch is evaporated in vacuo, the residue dissolved in water, washed with ether and the aqueous phase rendered alkaline with 2N hydrochloric acid. Extraction with ether is effected, the ethereal extractes are washed with water, dried over sodium sulphate and evaporated. The solid residue, after recrystallization from ligroin, yields the α-[p-(1-cyclohexenyl)-phenyl]-isobutyric acid of the formula ##SPC19##
Reaction SMILES: CC1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC(C)=CC=2)C2C=CC(C)=CC=2)C2C=CC(C)=CC=2)=CC=1.[CH:51]([C:54]1[CH2:58][CH2:57][C:56](=[O:59])[CH:55]=1)([CH3:53])[CH3:52]>>[CH:51]([C@H:54]1[CH2:58][CH2:57][C:56](=[O:59])[CH2:55]1)([CH3:53])[CH3:52]
Reactant: CC(C)C1=CC(=O)CC1
Agent: Cc1ccc(P(c2ccc(C)cc2)c2ccc3ccccc3c2-c2c(P(c3ccc(C)cc3)c3ccc(C)cc3)ccc3ccccc23)cc1
Product: CC(C)[C@H]1CCC(=O)C1
Yield: 88 %

Procedure:
General procedure B using (S)-p-tol-BINAP and 3-isopropylcyclopentenone (0.11 g, 0.9 mmol) gave, after 3 d at 0° C. and Kugelrohr distillation (0.4 torr, 220° C.) followed by flash chromatography (10:1 pentane:diethyl ether), the title compound as a clear liquid (0.10 g, 89% yield). In addition to the desired product, starting material (0.011 g, 10%) was also isolated. Spectroscopic data for the title compound were consistent with previously reported data.16 [α]D25° C.−200° (c 1.6, CHCl3) (lit.16 [α]D25° C.−110° (c 1.0, CHCl3) for 60% ee). Chiral GC analysis (Chiraldex G-TA column) indicated that the title compound was obtained in 95% ee.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][CH:10]=2)[CH2:5][CH2:4]1)[CH3:2]>CO.[Pd]>[CH2:1]([N:3]1[CH2:4][CH2:5][N:6]([C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)[CH2:7][CH2:8]1)[CH3:2]
Reactant: CCN1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Agent: [Pd]
Solvent: CO
Product: CCN1CCN(c2ccc(N)cc2)CC1

Procedure:
The mixture containing 4-ethyl-1-(4-nitrophenyl)piperazine in methanol with catalytic amount of 10% Pd/C was hydrogenated to yield 4-(4-ethylpiperazinyl)phenylamine. MS: MH+=205.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:14][CH2:13][CH2:12][C@H:11]2[CH2:15][N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[O:9])=[C:4]([C:21]([F:24])([F:23])[F:22])[CH:3]=1.[N:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1>>[N:25]1[CH:30]=[CH:29][C:28]([C:7]2[CH:2]=[CH:3][C:4]([C:21]([F:24])([F:23])[F:22])=[C:5]([C:8]([N:10]3[CH2:14][CH2:13][CH2:12][C@H:11]3[CH2:15][N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)=[O:9])[CH:6]=2)=[CH:27][CH:26]=1
Reactant: OB(O)c1ccncc1
Reactant: O=C(c1ccc(Br)cc1C(F)(F)F)N1CCC[C@H]1CN1CCCC1
Product: O=C(c1cc(-c2ccncc2)ccc1C(F)(F)F)N1CCC[C@H]1CN1CCCC1

Procedure:
The title compound is prepared in a manner substantially analogous to Example 14 via Procedure F′ from (4-bromo-2-trifluoromethyl-phenyl)-(2-(S)-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone and pyridine-4-boronic acid. MS (FIA) 404 (MH+)
Reaction SMILES: Cl[CH2:2][O:3][CH2:4][CH3:5].[CH3:6][S:7][CH2:8][C:9]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=1)=[O:10].[OH-].[Na+].P([O-])(O)(O)=O.[K+]>ClCCl.[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1>[CH2:4]([O:3][CH2:2][N:11]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:19])([F:20])[F:21])[CH:13]=1)[C:9](=[O:10])[CH2:8][S:7][CH3:6])[CH3:5]
Reactant: CCOCCl
Reactant: CSCC(=O)Nc1cccc(C(F)(F)F)c1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: O=P([O-])(O)O
Agent: [Cl-]
Solvent: ClCCl
Product: CCOCN(C(=O)CSC)c1cccc(C(F)(F)F)c1
Yield: 102.3 %

Procedure:
Chloromethyl ethylether (18.1 g) was added dropwise, during 20 minutes, to a vigorously stirred mixture of crude product of Step 1 (21.8 g) dissolved in dichloromethane (50 ml), 52% aqueous sodium hydroxide (34 g) and benzyl triethylammonium chloride (0.2 g), with water-bath cooling to 20° C. After 30 minutes the mixture was treated with saturated aqueous potassium dihydrogen phosphate until pH 8, at 20° C., extracted with dichloromethane (5×100 ml), the extract dried over sodium sulphate, filtered and concentrated under reduced pressure to give the crude product as a yellow oil (27.5 g). 1H NMR (CDCl3): δ 1.23(3 H,t); 2.21(3 H,s); 3.0(2 H,s); 3.68(2 H,bq); 5.1(2H,s); 7.58(4 H,m).
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[N:23]1([CH2:28][CH2:29][CH2:30][NH2:31])[CH:27]=[N:26][CH:25]=[N:24]1>O>[I:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:31][CH2:30][CH2:29][CH2:28][N:23]2[CH:27]=[N:26][CH:25]=[N:24]2)=[O:8])=[CH:9][CH:10]=1
Reactant: NCCCn1cncn1
Reactant: O=C(O)c1ccc(I)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Product: O=C(NCCCn1cncn1)c1ccc(I)cc1
Reaction time: 3 h

Procedure:
A mixture of about 2.48 g of 4-iodobenzoic acid, about 1.62 g of 1,1'-carbonyldiimidazole and about 30 ml oftetrahydrofuran was stirred for about 3 hours, then about 1.3 ml of 1H-1,2,4-triazole-1-propanamine was added and stirring was continued overnight. The mixture was heated for about 2 hours, about 5 ml of water was added, heating was continued for an additional hour then the mixture was concentrated to a residue. Methylene chloride and about 10 ml of approximately 1N sodium hydroxide were added. The organic layer was separated, washed with water, dried and concentrated, giving about 2.7 g of the desired product as a white solid, mp 132°-134° C.
Reaction SMILES: [CH3:1][CH:2]1[CH2:11][C:10]2[N:9]=[N:8][C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=3)=[CH:6][C:5]=2[CH:4]([OH:22])[CH2:3]1.C(N=C=NCCCN(C)C)C.[C:34]([O:38][C:39]([NH:41][C@H:42]([C:44](O)=[O:45])[CH3:43])=[O:40])([CH3:37])([CH3:36])[CH3:35]>O1CCCC1.ClCCl>[C:34]([O:38][C:39]([NH:41][C@H:42]([C:44]([O:22][CH:4]1[CH2:3][CH:2]([CH3:1])[CH2:11][C:10]2[N:9]=[N:8][C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=3)=[CH:6][C:5]1=2)=[O:45])[CH3:43])=[O:40])([CH3:36])([CH3:37])[CH3:35]
Reactant: CC1Cc2nnc(-c3cccc(C(F)(F)F)c3)cc2C(O)C1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC1Cc2nnc(-c3cccc(C(F)(F)F)c3)cc2C(OC(=O)[C@H](C)NC(=O)OC(C)(C)C)C1
Temperature: 25 °C

Procedure:
7-Methyl-3-(3-trifluoromethylphenyl)-5,6,7,8-tetrahydrocinnolin-5-ol (10 mg, 0.03 mmol) obtained in Example 6 was dissolved in a mixed solvent of tetrahydrofuran and dichloromethane (0.5 mL. 0.5 mL), followed by adding N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide (9 mg, 0.045 mmol), N,N-dimethylaminopyridine (catalytic amount) and N-(tert-butoxycarbonyl)-L-alanine (9 mg, 0.045 mmol) and stirring at room temperature over night. After completion of the reaction, the reaction liquid was concentrated and thus obtained residue was purified using silica gel column chromatography (hexane/ethyl acetate=1/1) to obtain an objective compound.
Reaction SMILES: [CH3:1][C:2]([CH2:4][C:5]([O:7][C:8]([CH3:11])(C)C)=[O:6])=[O:3].[CH2:12](O)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]CC.C1(C)C=CC=CC=1>C(O)(C)(C)C>[C:5]([O:7][CH2:8][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])(=[O:6])[CH2:4][C:2]([CH3:1])=[O:3]
Reactant: CCCCCCCCO
Reactant: CC(=O)CC(=O)OC(C)(C)C
Solvent: CC(C)(C)O
Solvent: Cc1ccccc1
Product: CCCCCCCCOC(=O)CC(C)=O
Yield: 83.2 %

Procedure:
Another procedure involved heating the alcohol and tBAA, (or beta-ketoester) in solvent, in a round-bottom flask with magnetic stirrer, 5-plate Oldershaw column and still head for removal of the t-butanol co-product. For example: a solution of n-octanol (13 g, 0.1 mol), tBAA (16.6 g, 0.105 mol) and 50 mL toluene was heated at reflux until the theoretical amount of t-butyl alcohol was obtained (ca. 15 min. after reflux). The reaction mixture was subsequently concentrated and distilled to give 17.8 g (83.2%) octyl acetoacetate b.p. 95°-110° C. (1.0 mm Hg).