Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:5](=[O:7])C)(=O)C.C(O)=O.[Cl:11][C:12]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=1[CH:19]1[S:25][C:24]([CH3:27])([CH3:26])[CH2:23][NH:22][C:21]2[N:28]([CH3:32])[N:29]=[C:30]([CH3:31])[C:20]1=2.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[Cl:11][C:12]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=1[CH:19]1[S:25][C:24]([CH3:27])([CH3:26])[CH2:23][N:22]([CH:5]=[O:7])[C:21]2[N:28]([CH3:32])[N:29]=[C:30]([CH3:31])[C:20]1=2
Reactant: CC(=O)OC(C)=O
Reactant: Cc1nn(C)c2c1C(c1ccc(Cl)cc1Cl)SC(C)(C)CN2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=CO
Solvent: CCOC(C)=O
Product: Cc1nn(C)c2c1C(c1ccc(Cl)cc1Cl)SC(C)(C)CN2C=O
Temperature: 50 °C
Reaction time: 24 h
Yield: 64.3 %

Procedure:
To acetic anhydride (5 mL, 53 mmol), was added formic acid (2.83 mL, 75 mmol). The resulting mixture was heated for about 15 min at about 50° C. To this mixture (after cooling to about 0° C.), was added 4-(2,4-dichlorophenyl)-1,3,6,6-tetramethyl-7,8-dihydro-4H-pyrazolo[3,4-e][1,4]thiazepine (50 mg, 0.14 mmol, Ex. D.4). The reaction mixture was stirred, for about 24 h, at rt. Subsequently, 5% aqueous sodium bicarbonate (25 mL) and ethyl acetate (50 mL) were added. The layers were separated and the organic layer was washed with water (25 mL), dried (MgSO4), filtered and concentrated in vacuo. The resulting residue was purified by column chromatography (SiO2, ethyl acetate), to afford 4-(2,4-dichlorophenyl)-1,3,6,6-tetramethyl-4,7-dihydropyrazolo[3,4-e][1,4]thiazepine-8-carbaldehyde (35 mg, 0.09 mmol, 65%), as a white solid. LC-MS (Table 1, Method a) Rt=4.53/4.71 min (rotamers), m/z 384 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 1.30 (3H, s) 1.49 (3 H, s) 1.65 (3 H, br s) 3.58-3.85 (2 H, br s) 3.73 (3 H, s) 5.48 (1 H, s) 7.11 (1 H, br s) 7.20 (1 H, br s) 7.44 (1 H, br s) 8.45 (1 H, s) (Major) 1H NMR (400 MHz, CDCl3) δ ppm 1.17 (3H, br s) 1.34 (3 H, br s) 1.93 (3 H, s) 3.41 (1 H, d, J=14.2 Hz) 3.69 (3 H, s) 3.76 (1 H, d, J=14.2 Hz) 5.54 (1 H, s) 7.12 (1 H, br s) 7.20 (1 H, br s) 7.39 (1 H, br s) 8.23 (1 H, br s) (Minor).
Reaction SMILES: [OH:1][C:2]([C:8]([F:11])([F:10])[F:9])([CH3:7])[C:3]([O:5][CH3:6])=[O:4].[Cl:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17]Cl)=[CH:15][CH:14]=1>>[Cl:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][O:1][C:2]([CH3:7])([C:8]([F:9])([F:10])[F:11])[C:3]([O:5][CH3:6])=[O:4])=[CH:15][CH:14]=1
Reactant: ClCc1ccc(Cl)cc1
Reactant: COC(=O)C(C)(O)C(F)(F)F
Product: COC(=O)C(C)(OCc1ccc(Cl)cc1)C(F)(F)F

Procedure:
In a similar manner, but starting from (±)-methyl 2-hydroxy-2-trifluoromethylpropionate (8.6 g.) and 4-chlorobenzyl chloride (8.05g.), there is obtained (±)-methyl 2-(4-chlorobenzyloxy)-3,3,3-trifluoro-2-methylpropionate as an oil (8.0g.), b.p. 92°-98° C. (0.1 mm.Hg.).
Reaction SMILES: Cl.[F:2][C:3]1[CH:18]=[CH:17][C:6]2[NH:7][C:8]3[S:9][C:10]([CH3:16])=[CH:11][C:12]=3[C:13]([NH2:15])=[N:14][C:5]=2[CH:4]=1.[CH3:19][O:20][CH2:21][CH2:22][CH2:23][C@H:24]1[CH2:29]N[CH2:27][CH2:26][NH:25]1>C1(C)C=CC=CC=1.CS(C)=O>[F:2][C:3]1[CH:18]=[CH:17][C:6]2[NH:7][C:8]3[S:9][C:10]([CH3:16])=[CH:11][C:12]=3[C:13]([N:15]3[CH2:27][CH2:26][NH:25][C@@H:24]([CH2:23][CH2:22][CH2:21][O:20][CH3:19])[CH2:29]3)=[N:14][C:5]=2[CH:4]=1
Reactant: Cc1cc2c(s1)Nc1ccc(F)cc1N=C2N
Reactant: COCCC[C@H]1CNCCN1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CS(C)=O
Product: COCCC[C@H]1CN(C2=Nc3cc(F)ccc3Nc3sc(C)cc32)CCN1
Temperature: 110 °C
Reaction time: 24 h
Yield: 86.3 %

Procedure:
Combine 7-fluoro-2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulen-10-ylamine hydrochloride (270 mg, 0.95 mmol), (S)-2-(3-methoxy-propyl)-piperazine (330 mg, 2 mmol) in a mixture of toluene and dimethylsulfoxide (1:2) and stir at 110° C. for 24 hours. Evaporate the mixture then purify by flash chromatography, eluting with a step gradient starting with dichloromethane going to 5% 2N ammonia-methanol in dichloromethane gives (S)-7-fluoro-10-[3-(3-methoxy-propyl)-piperazin-1-yl]-2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulene (320 mg, 0.82 mmol): mass spectrum (APCI): m/z=389.1 (M+1).
Reaction SMILES: C([O:5][C:6](=[O:24])[CH:7]([O:19][CH2:20][CH2:21][CH2:22][CH3:23])[NH:8][C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])CCC.CO.[Na].C(=O)([O-])[O-]>O.C(OCC)(=O)C>[CH2:12]([O:11][C:9]([NH:8][CH:7]([O:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:6]([OH:24])=[O:5])=[O:10])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CCCCOC(=O)C(NC(=O)OCc1ccccc1)OCCCC
Agent: O=C([O-])[O-]
Agent: [Na]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: CCCCOC(NC(=O)OCc1ccccc1)C(=O)O

Procedure:
A solution of 0.002 mol. of N-benzyloxycarbonyl-2-n-butoxyglycine n-butyl ester is stirred with 10 ml. of methanol and 10 ml. of 5% aqueous sodium bicarbonatesodium carbonate solution for 5 hours at 25°. The reaction mixture is then diluted with water and shaken with ethyl acetate. The layers are separated and the aqueous layer is acidified to pH 2.0 and extracted with ethyl acetate containing 10% ethanol. The extracts are dried (Na2SO4) and concentrated in vacuo to give the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH3:26])[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18]C)=[CH:14][CH:13]=2)=[O:11])=[CH:4][CH:3]=1.B(Br)(Br)Br.O.C([O-])(O)=O.[Na+]>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH3:26])[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)=[O:11])=[CH:4][CH:3]=1
Reactant: COc1ccc(C(=O)CC(c2ccc(Br)cc2)c2ccccc2C)cc1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: Cc1ccccc1C(CC(=O)c1ccc(O)cc1)c1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 10.2 %

Procedure:
A stirred solution of 3-(4-bromo-phenyl)-1-(4-methoxy-phenyl)-3-o-tolyl-propan-1-one (214 mg) in dichloromethane (5.1 ml) under argon was cooled to −78° C. A solution of BBr3 (2.09 ml, 1 M in dichloromethane) was added dropwise. The mixture was stirred at −78° C. for 45 min, at 0° C. for 4 h and at room temperature for 30 min. Since the reaction was not complete, the mixture was again cooled to −78° C. and a solution of BBr3 (1 ml, 1 M in dichloromethane) was added. The mixture was stirred at −78° C. for 30 min and at 0° C. for 4.5 h. Water and a saturated aqueous NaHCO3 solution were added and the mixture was extracted with dichloromethane. The organic phase was washed with water, dried using MgSO4, filtered and concentrated to dryness. The product was purified by chromatography (SiO2, cyclohexane/ethyl acetate 1:0 to 7:3) to give the title compound (21 mg) as a light brown solid, MS (ESI+): m/z=394.8 [M−H]−.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10]O)=[CH:5][CH:4]=1.[BrH:14]>C(O)(=O)C.S(=O)(=O)(O)O>[Br:14][CH2:10][CH2:9][C:6]1[CH:7]=[CH:8][C:3]([C:2]([F:13])([F:12])[F:1])=[CH:4][CH:5]=1
Reactant: Br
Reactant: OCCc1ccc(C(F)(F)F)cc1
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: FC(F)(F)c1ccc(CCBr)cc1

Procedure:
A mixture of step 2-(4-trifluoromethylphenyl)-ethanol (10 g, 0.053 mol, from step (iii) above), 86 ml (1.06 M) HBr in acetic acid and 10 ml sulfuric acid was stirred at 100° C. for 4 h. The reaction mixture was poured into ice and extracted with diethylether. The organic layer was washed with NaHCO3, water and dried over sodium sulfate. Solvent evaporation under reduced pressure followed by purification over silica gel using petroleum ether as eluent afforded 5 g of the title compound as a liquid.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=3[OH:22])[N:9]=2)[CH:5]=[CH:4][CH:3]=1.[OH:23][C:24]1[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][C:25]=1B(O)O>>[OH:22][C:15]1[CH:16]=[CH:17][C:18]([O:20][CH3:21])=[CH:19][C:14]=1[C:10]1[N:9]=[C:8]([C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([C:25]3[CH:26]=[C:27]([CH3:30])[CH:28]=[CH:29][C:24]=3[OH:23])[N:7]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: COc1ccc(O)c(-c2cccc(-c3cccc(Br)n3)n2)c1
Reactant: Cc1ccc(O)c(B(O)O)c1
Product: COc1ccc(O)c(-c2cccc(-c3cccc(-c4cc(C)ccc4O)n3)n2)c1
Yield: 50 %

Procedure:
6-(2-Hydroxy-5-methoxyphenyl)-6′-(2-hydroxy-5-methylphenyl)-2,2′-bipyridine was prepared from 6-bromo-6′-(2-hydroxy-5-methoxyphenyl)-2,2′-bipyridine and 2-hydroxy-5-methylphenylboronic acid in 50% yield using method F; δH [2H6]-DMSO 13.27,(1H, b), 12.64,(1H, b), 8.37,(1H, d), 8.33,(1H, d), 8.21,(2H, t), 8.14,(2H, d), 7.93,(1H, s), 7.64,(1H, s), 7.17,(1H, d), 7.00,(1H, d), 6.93,(1H, d), 6.89,(1H, d), 3.82,(3H, s), 2.34,(3H, s).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=O)[C:6]([O:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)=[C:5]2[C:21]([F:24])([F:23])[F:22].BrC1C=[C:28]2[C:33](=CC=1)[NH:32][C:31](=O)[C:30](OC1C=CC=CC=1)=C2O>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([N:32]([CH2:33][CH3:28])[CH2:31][CH3:30])[C:6]([O:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)=[C:5]2[C:21]([F:24])([F:23])[F:22]
Reactant: O=c1[nH]c2ccc(Br)cc2c(C(F)(F)F)c1Oc1ccc(Cl)cc1
Reactant: O=c1[nH]c2ccc(Br)cc2c(O)c1Oc1ccccc1
Product: CCN(CC)c1nc2ccc(Br)cc2c(C(F)(F)F)c1Oc1ccc(Cl)cc1
Temperature: 60 °C

Procedure:
The title compound was prepared using 6-bromo-2-chloro-3-(4-chlorophenoxy)-4-(trifluoromethyl)quinoline (Intermediate 7, step d) in place of 6-bromo-2,4-dichloro-3-phenoxyquinoline (Intermediate 5, step c) according to the procedure described in Intermediate 5, step d except the reaction mixture was heated at 60° C. under reflux condenser for 12 hours.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[F:22])=[CH:10][C:9]=1[NH2:23])([CH3:4])([CH3:3])[CH3:2].CC1(C)[O:31][C:30]([C:32]2[CH:33]=[C:34]([CH:37]=[CH:38][CH:39]=2)[C:35]#[N:36])=[CH:29][C:28](=O)[O:27]1>>[C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[F:22])=[CH:10][C:9]=1[NH:23][C:28](=[O:27])[CH2:29][C:30]([C:32]1[CH:39]=[CH:38][CH:37]=[C:34]([C:35]#[N:36])[CH:33]=1)=[O:31])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(C#Cc2ccccc2F)cc1N
Reactant: CC1(C)OC(=O)C=C(c2cccc(C#N)c2)O1
Product: CC(C)(C)OC(=O)Nc1ccc(C#Cc2ccccc2F)cc1NC(=O)CC(=O)c1cccc(C#N)c1
Yield: 57.5 %

Procedure:
Prepared from [2-amino-4-(2-fluoro-phenylethynyl)-phenyl]-carbamic acid tert.-butyl ester (Example G34) (163 mg, 0.5 mmol) and 3-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-benzonitrile (Example J4) (126 mg, 0.55 mmol) according to the general procedure K. Obtained as a brown solid (143 mg).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20](=[O:33])[NH:21][C:22]3[S:23][C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[N:25][N:26]=3)=[CH:16][CH:15]=1)[O:9][CH2:8][CH2:7][CH:6]2[C:34]([O:36]C)=[O:35])#[N:2].[OH-].[Na+].CO>C1COCC1.C(OCC)(=O)C.Cl>[C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][C:14]1[CH:15]=[CH:16][C:17]([C:20](=[O:33])[NH:21][C:22]3[S:23][C:24]([C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)=[N:25][N:26]=3)=[CH:18][CH:19]=1)[O:9][CH2:8][CH2:7][CH:6]2[C:34]([OH:36])=[O:35])#[N:2]
Reactant: COC(=O)C1CCOc2cc(Oc3ccc(C(=O)Nc4nnc(-c5ccccc5)s4)cc3)c(C#N)cc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: N#Cc1cc2c(cc1Oc1ccc(C(=O)Nc3nnc(-c4ccccc4)s3)cc1)OCCC2C(=O)O
Reaction time: 2 h
Yield: 60.6 %

Procedure:
Methyl 6-cyano-7-(4-(5-phenyl-1,3,4-thiadiazol-2-ylcarbamoyl)phenoxy)chroman-4-carboxylate (17 mg, 0.033 mmol) was diluted with THF (500 μL) followed by the addition of NaOH (166 μL, 0.17 mmol) and methanol (200 μL). After stirring for 2 hours, the reaction was diluted with ethyl acetate and 2N HCl. The layers were separated and the organic layer was dried over MgSO4, filtered and concentrated to yield 6-cyano-7-(4-(5-phenyl-1,3,4-thiadiazol-2-ylcarbamoyl)phenoxy)chroman-4-carboxylic acid (10 mg, 0.020 mmol, 60% yield). MS (APCI)=498.9 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]2.[O:13]1[CH2:18][CH2:17][CH:16]([CH2:19]O)[CH2:15][CH2:14]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[O:13]1[CH2:18][CH2:17][CH:16]([CH2:19][O:1][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]3)[CH2:15][CH2:14]1
Reactant: OCC1CCOCC1
Reactant: O=C1CCCc2cc(O)ccc21
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1CCCc2cc(OCC3CCOCC3)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.1 %

Procedure:
To a suspension of 6-hydroxy-1-tetralone (2.0 g, 12.4 mmol), tetrahydropyran-4-methanol (1.7 g, 14.8 mmol) and triphenylphosphine (6.5 g, 24.7 mmol) in THF (40 mL) was added DEAD (4.3 g, 24.7 mmol) at 0° C. The reaction was stirred at rt overnight. The solution was concentrated and purified by silica gel chromatography (PE:EtOAc=12:1) to give 3.2 g (100%) of the title compound as a yellow oil. [M+H] Calc'd for C16H20O3, 261. Found, 261.
Reaction SMILES: [NH2:1][C:2](=[O:40])[CH2:3][C:4]1[CH:39]=[CH:38][CH:37]=[CH:36][C:5]=1[CH2:6][CH2:7][C:8]1[C:13]([C:14]([F:17])([F:16])[F:15])=[CH:12][N:11]=[C:10]([NH:18][C:19]2[CH:20]=[C:21]3[C:26](=[CH:27][CH:28]=2)[CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][CH2:22]3)[N:9]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:25]1[C:26]2[C:21](=[CH:20][C:19]([NH:18][C:10]3[N:9]=[C:8]([CH2:7][CH2:6][C:5]4[CH:36]=[CH:37][CH:38]=[CH:39][C:4]=4[CH2:3][C:2]([NH2:1])=[O:40])[C:13]([C:14]([F:16])([F:17])[F:15])=[CH:12][N:11]=3)=[CH:28][CH:27]=2)[CH2:22][CH2:23][NH:24]1
Reactant: CC(C)(C)OC(=O)N1CCc2cc(Nc3ncc(C(F)(F)F)c(CCc4ccccc4CC(N)=O)n3)ccc2C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)Cc1ccccc1CCc1nc(Nc2ccc3c(c2)CCNC3)ncc1C(F)(F)F
Yield: 73.1 %

Procedure:
tert-Butyl 6-((4-(2-(2-amino-2-oxoethyl)phenethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3,4-dihydroisoquinoline-2(1H)-carboxylate (I82) (136 mg, 0.245 mmol), DCM (10 mL) and TFA (1 mL) were stirred together at room temperature. After three hours the solution was concentrated and the residue treated with 1M sodium hydroxide (25 mL). The resulting suspension was extracted with ethyl acetate (3×50 mL) and the combined organic extracts washed with brine (100 mL), dried and evaporated to give the title compound (21) (81.6 mg, 74% yield) as a white solid; 1H NMR (400 MHz, d6-DMSO) δ 10.06 (s, 1H), 8.65 (s, 1H), 7.51 (s, 1H), 7.48 (dd, J=8.3, 2.1 Hz, 1H), 7.42 (s, 1H), 7.26-7.21 (m, 1H), 7.19-7.13 (m, 3H), 6.96 (d, J=8.3 Hz, 1H), 6.90 (s, 1H), 3.81 (s, 2H), 3.49 (s, 2H), 3.17 (d, J=3.1 Hz, 1H), 3.14-3.06 (m, 2H), 3.05-2.97 (m, 2H), 2.94 (t, J=5.9 Hz, 2H), 2.67 (t, J=5.6 Hz, 2H).
Reaction SMILES: [CH2:1]([N:8]1[C@H:12]([C:13]([O:15][CH2:16][CH2:17][CH3:18])=[O:14])[C@H:11]([C:19]([O:21]CCC)=[O:20])[N:10]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:9]1=[O:32])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>P([O-])([O-])([O-])=O>[CH2:1]([N:8]1[C@@H:12]([C:13]([O:15][CH2:16][CH2:17][CH3:18])=[O:14])[C@@H:11]([C:19]([OH:21])=[O:20])[N:10]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:9]1=[O:32])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCOC(=O)[C@@H]1[C@H](C(=O)OCCC)N(Cc2ccccc2)C(=O)N1Cc1ccccc1
Agent: O=P([O-])([O-])[O-]
Product: CCCOC(=O)[C@H]1[C@@H](C(=O)O)N(Cc2ccccc2)C(=O)N1Cc1ccccc1
Yield: 90.7 %

Procedure:
A suspension of di-n-propyl cis-1,3-dibenzyl-2-oxoimidazolidine-4,5-dicarboxylate (200 mg) in 0.1m phosphate buffer (pH 8.0, 20 ml) was treated with Pig Liver Esterase (manufactured by Sigma Lab., 640 units, 4 mg) in a manner similar to that in Example 1 (1) to give (4S,5R)-1,3-dibenzyl-5-n-propoxycarbonyl-2-oxoimidazolidine-4-carboxylic acid (164 mg). M.P., 75°-90° C. [α]D20 =+2.1° (c=1, CHCl3).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH2:12]([OH:18])[CH2:13][CH2:14][CH2:15][C:16]#[CH:17]>ClCCl.C(N(CC)CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:11]=[C:2]([C:17]#[C:16][CH2:15][CH2:14][CH2:13][CH2:12][OH:18])[CH:3]=1
Reactant: Brc1cnc2ccccc2c1
Reactant: C#CCCCCO
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: OCCCCC#Cc1cnc2ccccc2c1
Yield: 88.7 %

Procedure:
6-(3-Quinolinyl)-5-hexyn-1-ol was prepared in the manner described above in Example 105 starting with 15.0 g of 3-bromoquinoline, 8.5 g of 5-hexyn-1-ol, 1.05 g of bis(triphenylphosphine)palladium dichloride and 0.10 g of cuprous iodide in 115 ml of dichloromethane and 28.5 ml of triethylamine. The crude product was chromatographed on a preparative high pressure liquid chromatograph eluting with 2.5% methanol-dichloromethane to give 14.4 g (89%) of 6-(3-quinolinyl)-5-hexyn-1-ol as a colorless oil. A portion was purified further on a silica thick layer plate eluting with 10% methanol-dichloromethane and solidified on drying, mp 47°-48° C.
Reaction SMILES: CN([CH2:4][C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:8]([OH:15])=[C:7]([CH3:16])[CH:6]=1)C.[CH2:17]=[CH:18][CH:19]=[CH2:20]>C1(C)C=CC=CC=1>[CH3:16][C:7]1[C:8](=[O:15])[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:10][C:5]2([CH2:20][CH2:19][CH:18]=[CH:17][CH2:4]2)[CH:6]=1
Reactant: C=CC=C
Reactant: Cc1cc(CN(C)C)cc(C(C)(C)C)c1O
Solvent: Cc1ccccc1
Product: CC1=CC2(C=C(C(C)(C)C)C1=O)CC=CCC2

Procedure:
Following the same general procedure as in Example I, 40 mmols of N,N-dimethyl-4-aminomethyl-2-methyl-6-t-butylphenol were reacted with 80 mmols of 1,3-butadiene in 81 g of toluene at about 207° C. for 10 hours. The uncorrected isolated yield of 2-methyl-4-t-butylspiro[5.5]undeca-1,4,8-trien-3-one was 83%.
Reaction SMILES: [O:1]=[C:2]1[C:6]2=[CH:7][NH:8][C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[C:5]2=[N:4][N:3]1[C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=[O:20])=[CH:17][CH:16]=1.[H-].[Na+].[CH3:26]I.O>CN(C=O)C>[CH3:26][N:8]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=2[C:5]2=[N:4][N:3]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=[O:20])=[CH:17][CH:16]=3)[C:2](=[O:1])[C:6]2=[CH:7]1
Reactant: O=C(O)c1ccc(-n2nc3c4ccccc4[nH]cc-3c2=O)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1cc2c(=O)n(-c3ccc(C(=O)O)cc3)nc-2c2ccccc21
Temperature: 25 °C
Yield: 35.2 %

Procedure:
A suspension of 4-(3-oxo-3,5-dihydro-pyrazolo[4,3-c]quinolin-2-yl)-benzoic acid (0.050 g, 0.16 mmol) in DMF (1 ml) was added in small portions to a suspension of NaH (55%) (0.017 g, 0.39 mmol) in DMF (0.5 ml) under N2. The reaction was stirred at room temperature. After 1 h MeI (0.053 g, 0.38 mmol) was added. After additional 24 h water was added and the solid material (mainly consisting of ester product) was removed by filtration. The filtrate was acidified with 2M HCl. The precipitate was collected, washed with water and dried to yield 4-(5-methyl-3-oxo-3,5-dihydro-pyrazolo[4,3-c]quinolin-2-yl)-benzoic acid (0.018 g). This material contained approx. 10% of ester product: 1H NMR (400 MHz, DMSO-d6) δ 8.89 (1H, s), 8.34 (2H, d), 8.29 (1H, d), 7.99 (2H, d), 7.85 (1H, d), 7.76 (1H, t), 7.62 (1H, t), 4.00 (3H, s); ESI MS m/z 320 (M+H+).
Reaction SMILES: Br[C:2]1[CH:15]=[C:14]([CH3:16])[C:5]([O:6][Si:7]([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8])=[C:4]([CH3:17])[CH:3]=1.[Cl-].[CH:19]1([Zn+])[CH2:21][CH2:20]1>C1COCC1.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>[C:10]([Si:7]([O:6][C:5]1[C:14]([CH3:16])=[CH:15][C:2]([CH:19]2[CH2:21][CH2:20]2)=[CH:3][C:4]=1[CH3:17])([CH3:9])[CH3:8])([CH3:13])([CH3:12])[CH3:11]
Reactant: Cc1cc(Br)cc(C)c1O[Si](C)(C)C(C)(C)C
Reactant: [Zn+]C1CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Solvent: C1CCOC1
Product: Cc1cc(C2CC2)cc(C)c1O[Si](C)(C)C(C)(C)C
Temperature: 80 °C
Yield: 63.1 %

Procedure:
To a suspension of (4-bromo-2,6-dimethylphenoxy) tert-butyldimethylsilane (668 mg, 2.12 mmol) and tetrakis(triphenylphosphine)palladium (122 mg, 0.11 mmol) in THF (20 mL) was added cyclopropyl zinc chloride (28.0 mL, 11.2 mmol). The mixture was heated at 80° C. for 24 h and cooled to room temperature. The reaction was passed through a short pad of SiO2 to remove the catalyst and the solution was concentrated to oil. The resulting oil was diluted in EtOAc (100 mL), washed with brine (100 mL), dried with Na2SO4, and concentrated to dryness. Silica gel chromatography (Hexanes:EtOAc=90:10) yielded 370 mg (63%) of tert-butyl(4-cyclopropyl-2,6-dimethylphenoxy)dimethylsilane. To tert-butyl(4-cyclopropyl-2,6-dimethylphenoxy)dimethylsilane (320 mg, 1.16 mmol) in THF (10 mL) was added a solution of tetrabutylammonium fluoride (5.0 mL, 1 M in THF, 5.0 mmol) and acetic acid (0.40 mL). The reaction was stirred at room temperature for 3 h and concentrated to dryness. Silica gel chromatography (Hexanes:EtOAc=85:15) yielded 175 mg (93%) of 4-cyclopropyl-2,6-dimethylphenol as a light yellow oil.
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]([F:24])([F:23])[F:22])[CH:15]=2)[N:8]=1)=O.[CH3:26][O:27][C:28](=[O:37])[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([NH:35]N)[CH:30]=1>>[CH3:26][O:27][C:28](=[O:37])[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([N:35]2[C:5]([C:7]3[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]([F:24])([F:23])[F:22])[CH:15]=4)[N:8]=3)=[CH:4][CH:3]=[N:2]2)[CH:30]=1
Reactant: COC(=O)c1cccc(NN)c1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(OC(F)(F)F)c2)ccc1=O
Product: COC(=O)c1cccc(-n2nccc2-c2nn(-c3cccc(OC(F)(F)F)c3)ccc2=O)c1

Procedure:
Reaction of 3-((E)-3-dimethylamino-acryloyl)-1-(3-trifluoromethoxy-phenyl)-1H-pyridazin-4-one (A-6) and 3-hydrazino-benzoic acid methyl ester according to example 43 gave the desired product. MS: M=456.9 (M+H)+