Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7](O)=[O:8].CN(C=O)C.S(Cl)([Cl:18])=O>>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([Cl:18])=[O:8]
Reactant: O=C(O)c1cncc(Br)c1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: O=C(Cl)c1cncc(Br)c1
Temperature: 25 °C

Procedure:
To a mixture of 5-bromonicotinic acid (10 g) in thionyl chloride (25 ml) was added anhydrous DMF (0.5 ml). The whole was heated to reflux for overnight. After cooled to RT, the excess thionyl chloride was removed under reduced pressure. A white solid 5 (11 g) was obtained, which was used for the next step without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[CH:11][C:12]([C:18]([OH:20])=O)=[C:13]([O:16][CH3:17])[CH:14]=2)[C@H:9]([N:21]([CH2:26][C:27]2[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[C:29]([C:37]([F:40])([F:39])[F:38])[CH:28]=2)[C:22]([O:24][CH3:25])=[O:23])[CH2:8][C@@H:7]1[CH3:41])=[O:5])[CH3:2].[CH3:42][N:43]([CH3:47])[CH2:44][CH2:45][NH2:46]>ClCCl.C(N(CC)CC)C>[CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[CH:11][C:12]([C:18](=[O:20])[NH:46][CH2:45][CH2:44][N:43]([CH3:47])[CH3:42])=[C:13]([O:16][CH3:17])[CH:14]=2)[C@H:9]([N:21]([CH2:26][C:27]2[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[C:29]([C:37]([F:38])([F:40])[F:39])[CH:28]=2)[C:22]([O:24][CH3:25])=[O:23])[CH2:8][C@@H:7]1[CH3:41])=[O:5])[CH3:2]
Reactant: CN(C)CCN
Reactant: CCOC(=O)N1c2cc(OC)c(C(=O)O)cc2[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C(=O)OC)C[C@@H]1C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)N1c2cc(OC)c(C(=O)NCCN(C)C)cc2[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C(=O)OC)C[C@@H]1C
Reaction time: 1.5 h

Procedure:
A mixture of cis-4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-7-methoxy-2-methyl-3,4-dihydro-2H-quinoline-1,6-dicarboxylic acid 1-ethyl ester (Example 60) (75 mg, 1.26 mmol) and 1.5 ml SOCK was heated at reflux for 1.5 h. The cooled solution was evaporated to dryness and the residue dried under high vacuum for 30 min. The residue was diluted with 0.75 ml dichloromethane, and triethylamine (0.021 ml) and N,N-dimethyl ethylenediamine (11 mg, 1.26 mmol) were added sequentially. After 1.5 h, the reaction mixture was concentrated and the residue was chromatographed (5% MeOH-dichloromethane) to afford the desired product (72 mg (86%). MS m/z 663 (M+ +1); 1H NMR (CDCl3) δ 3.75 (s, 3H), 7.22 (s, 1H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][N:15]2[CH:19]=[N:18][C:17]([C@:20]([CH:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)([OH:27])[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[N:16]2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.CCOCC>C(Cl)Cl>[CH:28]1([C@@:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:17]2[N:18]=[CH:19][N:15]([CH2:14][CH:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)[N:16]=2)[OH:27])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: CC(C)(C)OC(=O)N1CCC(Cn2cnc([C@](O)(c3ccccc3)C3CCCCC3)n2)CC1
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: O[C@](c1ccccc1)(c1ncn(CC2CCNCC2)n1)C1CCCCC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 92 %

Procedure:
Tert-butyl4-({3-[(R)-cyclohexyl(hydroxy)phenylmethyl]-1H-1,2,4-triazol-1-yl}methyl)piperidine-1-carboxylate (Preparation 3, 5.60 g, 12.3 mmol) was dissolved in DCM (31 ml) and 2M HCl in ether (31 ml, 60 mmol) added. After stirring at room temperature for 5 hours the solvent was removed in vacuo, and the residue partitioned between dichloromethane (200 ml) and saturated aqueous sodium bicarbonate solution (200 ml). The organic layer was separated, dried over magnesium sulphate, filtered and the solvent removed in vacuo to furnish the title compound as a white foam, in 92% yield, 4.03 g (contains 10% of other triazole regio-isomer).
Reaction SMILES: CO[C:3]([C:5]1[C:10](=[O:11])[N:9]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[N:8]2[CH:19]=[C:20]([Cl:22])[CH:21]=[C:7]2[C:6]=1[OH:23])=[O:4].[NH2:24][CH2:25][C:26]([O-:28])=[O:27].[Na+]>>[Cl:22][C:20]1[CH:21]=[C:7]2[C:6]([OH:23])=[C:5]([C:3]([NH:24][CH2:25][C:26]([OH:28])=[O:27])=[O:4])[C:10](=[O:11])[N:9]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)[N:8]2[CH:19]=1
Reactant: COC(=O)c1c(O)c2cc(Cl)cn2n(Cc2ccccn2)c1=O
Reactant: NCC(=O)[O-]
Agent: [Na+]
Product: O=C(O)CNC(=O)c1c(O)c2cc(Cl)cn2n(Cc2ccccn2)c1=O

Procedure:
Prepared according to the glycinolysis condition used in Example 1 step d) from 6-chloro-4-hydroxy-2-oxo-1-pyridin-2-ylmethyl-1,2-dihydro-pyrrolo[1,2-b]pyridazine-3-carboxylic acid methyl ester (1.0 eq.) and sodium glycinate (5 eq.). ESI (m/z): 377 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH3:11])[C:5](I)=[CH:4][N:3]=1.[CH3:13][N:14]([C@@H:22]([CH3:31])[C:23](=[O:30])[NH:24][CH2:25][CH2:26][CH2:27][C:28]#[CH:29])[C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18].[Cl-].[NH4+].C(OCC)(=O)C>CN(C)C=O.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.[Cu]I>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH3:11])[C:5]([C:29]#[C:28][CH2:27][CH2:26][CH2:25][NH:24][C:23](=[O:30])[C@@H:22]([N:14]([CH3:13])[C:15](=[O:21])[O:16][C:17]([CH3:18])([CH3:20])[CH3:19])[CH3:31])=[CH:4][N:3]=1
Reactant: C#CCCCNC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C
Reactant: CCCNc1nc(Cl)ncc1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCNc1nc(Cl)ncc1C#CCCCNC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 84.6 %

Procedure:
To a solution of 2-chloro-5-iodo-N-propylpyrimidin-4-amine (F1, 2.00 g) and (S)-tert-butyl methyl(1-oxo-1-(4-pentyn-1-ylamino)propan-2-yl)carbamate (U4, 2.16 g) in N,N-dimethylformamide (40 mL), triethylamine (4.67 mL), bis(triphenylphosphine)palladium(II) dichloride (0.47 g) and copper(I) iodide (0.26 g) were added at room temperature, and the mixture was stirred at the same temperature for 1.5 hours, and then further stirred at 45° C. for 0.5 hour. The reaction mixture was cooled to room temperature, and then saturated aqueous ammonium chloride and ethyl acetate were added to the reaction mixture. The organic layer was separated, washed with saturated aqueous sodium chloride, and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent, 80 to 30% hexane in ethyl acetate) to obtain (S)-tert-butyl (1-((5-(2-chloro-4-(propylamino)pyrimidin-5-yl)-4-pentyn-1-yl)amino)-1-oxopropan-2-yl)(methyl)carbamate (V1, 2.49 g) as pale yellow oil.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13]([C:15]([CH3:23])([CH3:22])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH:12]=[CH:11][C:10]=1[C@H:24]1[CH2:29][C@H:28]([CH3:30])[CH2:27][C:26](=[O:31])[CH2:25]1)C1C=CC=CC=1.[H][H]>[Pd].CO>[CH3:23][C:15]([C:13]1[CH:12]=[CH:11][C:10]([C@H:24]2[CH2:29][C@H:28]([CH3:30])[CH2:27][C:26](=[O:31])[CH2:25]2)=[C:9]([OH:8])[CH:14]=1)([CH3:22])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: [H][H]
Reactant: CCCCCCC(C)(C)c1ccc([C@@H]2CC(=O)C[C@@H](C)C2)c(OCc2ccccc2)c1
Agent: [Pd]
Solvent: CO
Product: CCCCCCC(C)(C)c1ccc([C@@H]2CC(=O)C[C@@H](C)C2)c(O)c1
Yield: 64.6 %

Procedure:
A mixture of trans-3-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-5-methylcyclohexanone (175 mg, 0.417 mmole) and 175 mg of 5% palladium on carbon-50% water in methanol (8 ml) was stirred under one atmosphere of hydrogen gas until hydrogen uptake ceased. The reaction mixture was filtered through diatomaceous earth and the filtrate evaporated under reduced pressure. Crystallization of the residue in pentane gave 89 mg (64%) of the title compound.
Reaction SMILES: [C:1]([N:9]1[CH2:14][CH2:13][N:12]([C:15](=[O:28])[C:16]([C:18]2[C:26]3[C:21](=[C:22](Cl)[N:23]=[CH:24][CH:25]=3)[NH:20][CH:19]=2)=[O:17])[CH:11]([CH3:29])[CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:30]1[O:38][C:37]2[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][C:32]=2[O:31]1>>[C:1]([N:9]1[CH2:14][CH2:13][N:12]([C:15](=[O:28])[C:16]([C:18]2[C:26]3[C:21](=[C:22]([C:35]4[CH:34]=[CH:33][C:32]5[O:31][CH2:30][O:38][C:37]=5[CH:36]=4)[N:23]=[CH:24][CH:25]=3)[NH:20][CH:19]=2)=[O:17])[CH:11]([CH3:29])[CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)c1ccc2c(c1)OCO2
Reactant: CC1CN(C(=O)c2ccccc2)CCN1C(=O)C(=O)c1c[nH]c2c(Cl)nccc12
Product: CC1CN(C(=O)c2ccccc2)CCN1C(=O)C(=O)c1c[nH]c2c(-c3ccc4c(c3)OCO4)nccc12

Procedure:
Example 5, was prepared according to the general method described above from 1-benzoyl-3-methyl-4-[(7-chloro-6-azaindol-3-yl)-oxoacetyl]piperazine and 3,4-methylenedioxyphenyl boronic acid, Precursor 14a-13, to provide 1-benzoyl-3-methyl-4-[(7-(3,4-methylenedioxyphenyl)-6-azaindol-3-yl)-oxoacetyl]piperazine. MS m/z: (M+H)+ Calc'd for C28H25N4O5: 497.18; found 497.03. HPLC retention time: 1.41 minutes (column B).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[C:10]3[C:16]([C:17]4[CH:18]=[N:19][N:20]([CH2:22][CH2:23][C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)[CH:21]=4)=[CH:15][N:14]([S:30]([C:33]4[CH:39]=[CH:38][C:36]([CH3:37])=[CH:35][CH:34]=4)(=[O:32])=[O:31])[C:11]3=[N:12][CH:13]=2)[CH:5]=[CH:4][C:3]=1[C:40]1[CH2:45][CH2:44][N:43]([C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[CH2:42][CH:41]=1>[N+](C1C=C(C=CC=1)CN1C=C(B2OC(C)(C)C(C)(C)O2)C=N1)([O-])=O.[OH-].[Pd+2].[OH-]>[F:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[C:10]3[C:16]([C:17]4[CH:18]=[N:19][N:20]([CH2:22][CH2:23][C:24]5[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=5)[CH:21]=4)=[CH:15][N:14]([S:30]([C:33]4[CH:39]=[CH:38][C:36]([CH3:37])=[CH:35][CH:34]=4)(=[O:31])=[O:32])[C:11]3=[N:12][CH:13]=2)[CH:5]=[CH:4][C:3]=1[CH:40]1[CH2:41][CH2:42][N:43]([C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[CH2:44][CH2:45]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(CCc4ccccc4)c3)c3cc(-c4ccc(C5=CCN(C(=O)OC(C)(C)C)CC5)c(F)c4)cnc32)cc1
Agent: [Pd+2]
Agent: CC1(C)OB(c2cnn(Cc3cccc([N+](=O)[O-])c3)c2)OC1(C)C
Agent: [OH-]
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(CCc4ccccc4)c3)c3cc(-c4ccc(C5CCN(C(=O)OC(C)(C)C)CC5)c(F)c4)cnc32)cc1
Yield: 74.2 %

Procedure:
Using similar reaction conditions as described in step-ii of example-82, tert-butyl 4-(2-fluoro-4-(3-(1-phenethyl-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate (190 mg, 0.264 mmol) was reduced with palladium hydroxide (100 mg) in ethyl acetate/ethanol 10/20 mL to afford 141 mg (74% yield) of the titled compound. MS: m/z=720.7 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([CH:6]=[N:7][OH:8])=[CH:4][CH:3]=1.[Cl:11]N1C(=O)CCC1=O>CN(C)C=O.C(OC)(C)(C)C>[OH:8][N:7]=[C:6]([Cl:11])[C:5]1[CH:9]=[CH:10][C:2]([CH3:1])=[CH:3][CH:4]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cc1ccc(C=NO)cc1
Solvent: COC(C)(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(C(Cl)=NO)cc1
Yield: 79.7 %

Procedure:
A solution of 4-methylbenzaldehyde oxime (2 g) and N-chlorosuccinimide (2.17 g) in dimethylformamide (20 mL) was stirred for one hour at 55° C. After the reaction solution was diluted with t-butylmethylether, the solution was washed with water and saturated brine. The organic layer was dried over-anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain N-hydroxy-4-methylbenzene carboximidoyl chloride (2 g). A solution of resultant N-hydroxy-4-methylbenzene carboximidoyl chloride and 1,3-dichloro-5-[1-(trifluoromethyl)-vinyl]benzene (5.3 g) in toluene (50 mL) was heated to reflux for 8 hours. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography to obtain [5-(3,5-dichlorophenyl) 3-(4-methylphenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole (5.0 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH3:9])=[C:7]([CH3:10])[C:6]([O:11][CH3:12])=[C:5]([CH3:13])[C:4]=1[CH:14]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:15][CH2:16][CH2:17][CH2:18][C:19]#[C:20][CH2:21][CH2:22][OH:23]>C(O)C.[C].[Pd]>[CH3:1][O:2][C:3]1[C:8]([CH3:9])=[C:7]([CH3:10])[C:6]([O:11][CH3:12])=[C:5]([CH3:13])[C:4]=1[CH:14]([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][OH:23]
Reactant: COc1c(C)c(C)c(OC)c(C(CCCCC#CCCO)c2ccccc2)c1C
Agent: [Pd]
Solvent: CCO
Product: COc1c(C)c(C)c(OC)c(C(CCCCCCCCO)c2ccccc2)c1C
Reaction time: 2 h
Yield: 98.9 %

Procedure:
5% Palladium-carbon (0.2 g) was added to a solution of 1.970 g (5.0 mmole) of 9-(2,5-dimethoxy-3,4,6-trimethylphenyl)-9-phenyl-3-nonyn -1-ol in ethanol (20 ml), and catalytic reduction was conducted at room temperature for 2 hours. The catalyst was filtered out, and the ethanol was distilled off under reduced pressure. The residue was chromatographed on a silica gel column to perform purification (elution with isopropyl ether) to thereby give 1.97 g (99%) of 9-(2,5-dimethoxy-3,4,6-trimethylphenyl)-9-phenylnonanol. Its typical physical properties and nuclear magnetic resonance spectrum data are shown in Table 14.
Reaction SMILES: Br[C:2]1[S:6][C:5]([CH:7]=[CH:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[F:12][C:13]([F:25])([F:24])[O:14][C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.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>[F:12][C:13]([F:24])([F:25])[O:14][C:15]1[CH:20]=[CH:19][C:18]([C:2]2[S:6][C:5]([CH:7]=[CH:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=2)=[CH:17][CH:16]=1
Reactant: O=C(O)C=Cc1ccc(Br)s1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
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: COCCOC
Product: O=C(O)C=Cc1ccc(-c2ccc(OC(F)(F)F)cc2)s1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
0.72 g (3.1 mmol) of 3-(5-bromo-thiophen-2-yl)-acrylic acid and 178.3 mg (0.2 mmol) of tetrakis(triphenylphosphine)palladium were dissolved in 50 ml of degassed DME and stirred at room temperature for 10 min. 0.954 g (4.6 mmol) of 4-trifluoromethoxy-phenylboronic acid and 3 ml of a 2 M aqueous sodium carbonate solution were added together with an additional 5 ml of degassed DME. The reaction mixture was heated to 95° C. for 4 h and then stirred at room temperature for 16 h. Solids were removed by filtration, and the filtrate was evaporated to dryness. The residue was dissolved in ethyl acetate and washed three times with a saturated sodium hydrogencarbonate solution and once with saturated sodium chloride solution. The organic phase was dried with sodium sulfate, filtered, and the solvent was removed under reduced pressure. Yield: 426 mg.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:13][CH:12]=2)=[O:10])=[CH:5][CH:4]=1.C[S-].[Na+]>CN(C)C=O>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]([C:11]2[CH:12]=[CH:13][C:14]([C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:15][CH:16]=2)=[O:10])=[CH:7][CH:8]=1
Reactant: COc1ccc(C(=O)c2ccc(C(C)(C)C)cc2)cc1
Agent: C[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc(C(=O)c2ccc(O)cc2)cc1
Yield: 97.2 %

Procedure:
4-t-Butylphenyl 4-methoxyphenyl ketone (862 mg) obtained in Example 29 was dissolved in N,N-dimethylformamide (35 ml), sodium thiomethoxide (562 mg) was added, and the admixture was refluxed for 3 hours under argon. The reaction mixture was partitioned between 10% aqueous phosphoric acid and ethyl acetate. The ethyl acetate layer was then dried with anhydrous magnesium sulfate and the solvent was removed by reduced-pressure distillation to obtain 794 mg of the title compound (yield: 97%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[C:12]([CH3:13])=[N:11][C:10]([CH3:14])=[N:9]2)[N:5]=[C:4]([CH3:15])[N:3]=1.[CH2:16]([Sn](CCCC)(CCCC)C=C)[CH2:17]CC>C1(C)C=CC=CC=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>[CH3:14][C:10]1[N:11]=[C:12]([CH3:13])[N:8]([C:6]2[CH:7]=[C:2]([CH:16]=[CH2:17])[N:3]=[C:4]([CH3:15])[N:5]=2)[N:9]=1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: Cc1nc(Cl)cc(-n2nc(C)nc2C)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=Cc1cc(-n2nc(C)nc2C)nc(C)n1

Procedure:
A slurry of 4-chloro-6-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-2-methylpyrimidine (2-2, 800 mg, 3.58 mmol, 1.0 eq.), tributyl(vinyl)tin (1.358 mL, 4.65 mmol, 1.3 eq.) and tetrakis(triphenylphosphine)palladium(0) (207 mg, 0.179 mmol, 0.050 eq.) in toluene (20 mL) was heated at 110° C. for 3 hours. Toluene was removed by roto-evaporation and the resulting residue was purified by silica gel column chromatography (0-100% ethyl acetate in hexanes) to afford 4-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-2-methyl-6-vinylpyrimidine (2-3) as a white solid. 1H NMR (500 MHz, CDCl3) δ 7.64 (s, 1H), 6.77 (m, 1H), 6.53 (d, 1H, J=17 Hz), 5.73 (d, 2H, J=11 Hz), 2.92 (s, 3H), 2.72 (s, 3H), 2.42 (s, 3H). LRMS m/z (M+H) 216.2 found, 216.1 required.
Reaction SMILES: O[C:2]1([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[O:15]CC(C)(C)N=3)=[C:10]([CH3:21])[CH:9]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.Cl.C(O)(=[O:25])C>>[C:2]1([C:8]2[CH:13]=[CH:12][C:11]([C:14]([OH:15])=[O:25])=[C:10]([CH3:21])[CH:9]=2)[CH2:3][CH2:4][CH2:5][CH2:6][CH:7]=1
Reactant: Cc1cc(C2(O)CCCCC2)ccc1C1=NC(C)(C)CO1
Reactant: CC(=O)O
Agent: Cl
Product: Cc1cc(C2=CCCCC2)ccc1C(=O)O

Procedure:
To a solution of 2-[4-(1-hydroxy-1-cyclohexyl)-2-methylphenyl]-4,4-dimethyl-2-oxazoline (4.29 g) in acetic acid (40 ml) is added a 10% hydrochloric acid (20 ml), and the mixture is refluxed for two days. The precipitated crystals are collected by filtration, washed with water, and dried to give 4-cyclohexenyl-2-methylbenzoic acid (2.61 g) as white powder.
Reaction SMILES: [CH2:1]([O:5][C@H:6]1[C@@H:11]([NH:12][C:13]([C:15]2[NH:16][C:17]([CH2:21][CH3:22])=[C:18]([Cl:20])[N:19]=2)=[O:14])[CH2:10][CH2:9][N:8]([C:23]2[S:24][C:25]([C:28]([O:30]CC)=[O:29])=[CH:26][N:27]=2)[CH2:7]1)[CH2:2][CH2:3][CH3:4].[OH-].[Li+].CO>C1COCC1>[CH2:1]([O:5][C@H:6]1[C@@H:11]([NH:12][C:13]([C:15]2[NH:16][C:17]([CH2:21][CH3:22])=[C:18]([Cl:20])[N:19]=2)=[O:14])[CH2:10][CH2:9][N:8]([C:23]2[S:24][C:25]([C:28]([OH:30])=[O:29])=[CH:26][N:27]=2)[CH2:7]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCO[C@@H]1CN(c2ncc(C(=O)OCC)s2)CC[C@@H]1NC(=O)c1nc(Cl)c(CC)[nH]1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCCCO[C@@H]1CN(c2ncc(C(=O)O)s2)CC[C@@H]1NC(=O)c1nc(Cl)c(CC)[nH]1
Yield: 82.2 %

Procedure:
The same operation as in Example (91d) was performed using ethyl cis(±)-2-(3-butoxy-4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}piperidin-1-yl)-1,3-thiazole-5-carboxylate obtained in Example (119f) (0.39 g, 0.8 mmol), 2 N lithium hydroxide (5 mL, 10 mmol), methanol (3 mL) and THF (3 mL), to obtain 0.30 g of the title compound as a colorless solid (82%).
Reaction SMILES: [CH2:1]([N:3]1[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH3:2].[I:16]I.OO.S(=O)(=O)(O)O>O.C(O)(=O)C.O>[I:16][C:7]1[CH:6]=[CH:5][C:4]2[N:3]([CH2:1][CH3:2])[C:15]3[C:10]([C:9]=2[CH:8]=1)=[CH:11][CH:12]=[CH:13][CH:14]=3
Reactant: CCn1c2ccccc2c2ccccc21
Reactant: II
Agent: O=S(=O)(O)O
Agent: OO
Solvent: O
Solvent: CC(=O)O
Product: CCn1c2ccccc2c2cc(I)ccc21
Temperature: 60 °C
Reaction time: 2 h
Yield: 126.9 %

Procedure:
Into 5.0 g (25.6 mmol) of 9-ethylcarbazole, 40 ml of a 9:1 acetic acid-water mixture, 3.3 g (13.0 mmol) of iodine, 2.5 g of a 30% hydrogen peroxide solution, and 1.8 g of 97% sulfuric acid were added, and the mixture was stirred at 60° C for 2 hours. After natural cooling, the mixture was diluted with water and then extracted with toluene. After the toluene layer was concentrated, the residual component was purified with a silica gel column. As a result, 5.3 g of 3-iodo-9-ethylcarbazole was obtained (corresponding to a 65% yield).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.CO[CH:11]1[CH2:15][CH2:14][CH:13](OC)O1.C(O)(=O)C>O>[F:1][C:2]1[CH:8]=[CH:7][C:5]([N:6]2[CH:11]=[CH:15][CH:14]=[CH:13]2)=[CH:4][CH:3]=1
Reactant: COC1CCC(OC)O1
Reactant: Nc1ccc(F)cc1
Solvent: CC(=O)O
Solvent: O
Product: Fc1ccc(-n2cccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 107.5 %

Procedure:
4-Fluoroaniline (100 g) and 2,5-dimethoxytetrahydrofuran (124.9 g) were added to acetic acid (500 ml) and the mixture was stirred at a refluxing temperature for 1 h. After cooling to room temperature, the reaction mixture was added to water (2.5 Liters) and the mixture was stirred further for 30 min. The precipitated crystals were recrystallized from a mixed solvent of methanol-acetone (ratio=2:1) to give 1-(4-fluorophenyl)pyrrole (156 g), melting point: 57–58° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:9]=[C:8]([OH:10])[N:7]([CH3:11])[N:6]=1)=[O:4].C(=O)([O-])[O-].[K+].[K+].Cl[CH:19]([F:21])[F:20].O>CN(C)C=O.C(OCC)(=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:9]=[C:8]([O:10][CH:19]([F:21])[F:20])[N:7]([CH3:11])[N:6]=1)=[O:4]
Reactant: FC(F)Cl
Reactant: COC(=O)c1cc(O)n(C)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(OC(F)F)n(C)n1
Temperature: 70 °C
Reaction time: 1.5 h

Procedure:
67.6 g (0.43 mol) 3-Methoxycarbonyl-5-hydroxy-1-methylpyrazole and 299.2 g (2.17 mol) potassium carbonate were dissolved in 1500 ml dimethylformamide and warmed to 70° C. At this temperature, chlorodifluoromethane was passed through for 2 hours and then stirred for 1.5 hours at 80° C. The reaction mixture was added to water and shaken 6 times with ethyl acetate. The combined organic phases were washed with saturated sodium chloride and dried over magnesium sulfate. The reaction solution was concentrated.
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][O:8][C:9]2=[O:10])=[CH:5][CH:4]=1.[OH-].[Ca+2].[OH-].[H][H]>CO.O1CCOCC1.[Pd]>[CH3:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][O:8][C:9]2=[O:10])=[CH:5][CH:4]=1
Reactant: O=C1OCc2ccc(CBr)cc21
Reactant: [H][H]
Agent: [Pd]
Agent: [Ca+2]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Product: Cc1ccc2c(c1)C(=O)OC2
Yield: 96 %

Procedure:
A total of 107 g (472 mmol) of 6-bromomethylphthalide was dissolved in 50 mL of methanol (dioxane was also used in different experiment). The solution was added to a parr bottle with 40 g (540 mmol) of calcium hydroxide and 2 g of 10% Pd/C. The suspension was hydrogenated at 40 psi until no more hydrogen uptake was recorded. All solids were filtered and filtrate was concentrated to a total of 67 g of brown solid in 96% yield. 1H NMR (CDCl3) (300 MHz) δ 2.53 (s, 3H), 5.30 (s, 2H), 7.49 (s 1H), 7.54 (d, 3JHCCH=7.9 Hz, 1H), 7.47 (d, 3JHCCH=7.9 Hz, 1H)
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[C:8]([O:10][C:11]2[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][CH:12]=2)[N:7]=[CH:6][N:5]=1)[CH3:2].[C:18]1([C@@H:24]2[CH2:26][C@H:25]2[N:27]=[C:28]=[O:29])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C1COCC1>[CH2:1]([NH:3][C:4]1[CH:9]=[C:8]([O:10][C:11]2[CH:17]=[CH:16][C:14]([NH:15][C:28]([NH:27][C@@H:25]3[CH2:26][C@H:24]3[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:29])=[CH:13][CH:12]=2)[N:7]=[CH:6][N:5]=1)[CH3:2]
Reactant: CCNc1cc(Oc2ccc(N)cc2)ncn1
Reactant: O=C=N[C@@H]1C[C@H]1c1ccccc1
Solvent: C1CCOC1
Product: CCNc1cc(Oc2ccc(NC(=O)N[C@@H]3C[C@H]3c3ccccc3)cc2)ncn1
Reaction time: 8 h

Procedure:
To a solution of 4-(4-ethylaminopyrimidin-6-yl-oxy)-aniline (Stage 89.1; 271 mg, 1.177 mmol) In THF (5 ml) under N2-atmosphere, trans-2-phenyl-cyclopropyl-isocyanate (188 mg, 1.18 mmol; Aldrich) Is added. Then the solution is stirred for 8 h, whereas a precipitate is formed. Filtration and washing with THF and ether yields the title compound: m.p.: 205-206° C.; 1H-NMR (DMSO-d6): 8.50 (s, HN), 8.11 (s, 1H), 7.42 (d, 2H), 7.27 (m, 3H), 7.15 (m, 3H), 7.01 (d, 2H), 6.67 (s, HN), 5.67 (s, 1H), 3.25 (m, 2H), 2.74 (m, 1H), 1.98 (m, 1H), 1.17 (m, 2H), 1.09 (t, 3H); Anal.: CHN.