Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH3:32])[CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]([OH:31])([C:27]([F:30])([F:29])[F:28])[C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=3)[CH2:11][CH2:10]2)=[C:4]([F:33])[CH:3]=1.[N:34]1[CH:39]=[CH:38][C:37]([NH:40][C:41](=O)[O:42]C2C=CC=CC=2)=[CH:36][CH:35]=1.O1CCOCC1>O1CCCC1>[F:33][C:4]1[CH:3]=[C:2]([NH:1][C:41]([NH:40][C:37]2[CH:38]=[CH:39][N:34]=[CH:35][CH:36]=2)=[O:42])[CH:7]=[CH:6][C:5]=1[N:8]([CH:9]1[CH2:14][CH2:13][N:12]([CH2:15][C:16]2[CH:17]=[CH:18][C:19]([C:22]([OH:31])([C:23]([F:24])([F:25])[F:26])[C:27]([F:30])([F:28])[F:29])=[CH:20][CH:21]=2)[CH2:11][CH2:10]1)[CH3:32]
Reactant: O=C(Nc1ccncc1)Oc1ccccc1
Reactant: CN(c1ccc(N)cc1F)C1CCN(Cc2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2)CC1
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: CN(c1ccc(NC(=O)Nc2ccncc2)cc1F)C1CCN(Cc2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2)CC1
Yield: 67 %

Procedure:
2-(4-((4-((4-Amino-2-fluorophenyl)(methyl)amino)piperidin-1-yl)methyl)-phenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol (0.209 mmol, 100 mg) and phenyl pyridin-4-ylcarbamate (0.313 mmol, 67.0 mg) were combined in tetrahydrofuran (1 mL) and dioxane (1 mL) and heated to 80° C. overnight. The reaction mixture was concentrated under vacuum. The residue was purified by prep-HPLC (acidic conditions) and SCX chromatography to afford title compound (83.9 mg). MS (ESI) m/z 600.2 [M+H]+
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH2:18][C:17]2[C:12](=[N:13][C:14](S(C)(=O)=O)=[N:15][CH:16]=2)[N:11]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29][CH2:30][OH:31])[CH:24]=2)[C:10]1=[O:32].[NH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>>[NH:33]([C:14]1[N:13]=[C:12]2[N:11]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29][CH2:30][OH:31])[CH:24]=3)[C:10](=[O:32])[N:9]([C:3]3[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=3[Cl:1])[CH2:18][C:17]2=[CH:16][N:15]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: CS(=O)(=O)c1ncc2c(n1)N(c1cccc(CCO)c1)C(=O)N(c1ccc(Cl)cc1Cl)C2
Reactant: Nc1ccccc1
Product: O=C1N(c2ccc(Cl)cc2Cl)Cc2cnc(Nc3ccccc3)nc2N1c1cccc(CCO)c1
Temperature: 120 °C
Yield: 55 %

Procedure:
A mixture of 1.09 g (2.2 mmol) of 3-(2,4-dichlorophenyl)-3,4-dihydro-1-[3-(2-hydroxyethyl)phenyl]-7-methanesulfonyl-pyrimido[4,5-d]pyrimidin-2(1H)-one and aniline was heated at 120° C. for 1 hour. The reaction mixture was partitioned between dichloromethane (20 ml) and 2M hydrochloric acid (20 ml) and the dichloromethane layer separated, washed with saturated aqueous sodium bicarbonate (20 ml), dried over magnesium sulfate, filtered and evaporated. The crude material was purified by flash chromatography on silica gel, eluting with 5:1 ethyl acetate/hexane. Product containing fractions were combined and evaporated to give 630 mg (55%) of 7-anilino-3-(2,4-dichlorophenyl)-3,4-dihydro-1-[3-(2-hydroxyethyl)phenyl]pyrimido[4,5-d]pyrimidin-2(1H)-one as a white solid of melting point 213-217° C. [Mass spectrum (ESI) MH+ =506].
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](SCCC)=[N:19][C:18]4=[O:26])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:29]([F:32])([F:31])[F:30])[CH:3]=1.[NH:33]1[CH2:37][CH2:36][CH2:35][CH2:34]1>>[Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:33]5[CH2:37][CH2:36][CH2:35][CH2:34]5)=[N:19][C:18]4=[O:26])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:29]([F:32])([F:31])[F:30])[CH:3]=1
Reactant: CCCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Reactant: C1CCNC1
Product: O=C1N=C(N2CCCC2)SC1=Cc1ccc2c(cnn2Cc2ccc(Cl)cc2C(F)(F)F)c1

Procedure:
5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-pyrrolidin-1-yl-thiazol-4-one was prepared from 5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-propylsulfanyl-thiazol-4-one and pyrrolidine following General Procedure B.
Reaction SMILES: [C:1]([CH:3]([CH:7]1[C:11]([Cl:12])=[C:10](Cl)C(=O)O1)[C:4]([NH2:6])=[O:5])#[N:2].Cl.[CH3:16][S:17]([C:19]1[CH:20]=[C:21]([CH2:25][NH2:26])[CH:22]=[CH:23][CH:24]=1)=[O:18].C(N(CC)CC)C>CO>[ClH:12].[Cl:12][C:11]1[CH:7]=[C:3]([C:4]([NH2:6])=[O:5])[C:1](=[NH:2])[N:26]([CH2:25][C:21]2[CH:22]=[CH:23][CH:24]=[C:19]([S:17]([CH3:16])=[O:18])[CH:20]=2)[CH:10]=1
Reactant: CS(=O)c1cccc(CN)c1
Reactant: N#CC(C(N)=O)C1OC(=O)C(Cl)=C1Cl
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: CS(=O)c1cccc(Cn2cc(Cl)cc(C(N)=O)c2=N)c1
Temperature: 50 °C
Reaction time: 8 h
Yield: 35.2 %

Procedure:
To a suspension of 2-cyano-2-(3,4-dichloro-5-oxo-2,5-dihydrofuran-2-yl)acetamide (1.0 g) in methanol (10 ml) was added a solution of 1-[3-(methylsulfinyl)phenyl]methanamine hydrochloride (1.8 g) and triethylamine (2.4 ml) in methanol (5 ml) at room temperature, and the mixture was stirred overnight at 50° C. The reaction solvent was evaporated under reduced pressure, acetic acid (5 ml) was added, and the mixture was stirred at 50° C. for 2 hr. The solvent was evaporated under reduced pressure, the residue was partitioned with ethyl acetate, 1N aqueous sodium hydroxide solution and aqueous sodium bicarbonate, and the organic layer was dried over sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate:hexane=7:3→1:0). 4N Hydrochloride-ethyl acetate solution (1 ml) was added to the obtained yellow oil, and the precipitated crystals were collected by filtration, and recrystallized to give the title compound (270 mg).
Reaction SMILES: [CH3:1][C:2]([O:4][C:5]1[C:10]([C:11](Cl)=[O:12])=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].[NH2:14][C:15]1[S:16][C:17]([C:20]([F:23])([F:22])[F:21])=[N:18][N:19]=1>>[C:2]([O:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=1[C:11]([NH:14][C:15]1[S:16][C:17]([C:20]([F:23])([F:22])[F:21])=[N:18][N:19]=1)=[O:12])(=[O:3])[CH3:1]
Reactant: CC(=O)Oc1ccccc1C(=O)Cl
Reactant: Nc1nnc(C(F)(F)F)s1
Product: CC(=O)Oc1ccccc1C(=O)Nc1nnc(C(F)(F)F)s1
Yield: 51.1 %

Procedure:
Using O-acetylsalicyloyl chloride and 2-amino-5-(trifluoromethyl)-1,3,4-thiadiazole as the raw materials, the same operation as the Example 2(1) gave the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9].[BrH:11].BrBr.C(OCC)C>C(O)(=O)C>[BrH:11].[Br:11][CH2:9][C:8]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:2]=1[CH3:1])=[O:10]
Reactant: CC(=O)c1cnccc1C
Agent: Br
Agent: BrBr
Solvent: CCOCC
Solvent: CC(=O)O
Product: Cc1ccncc1C(=O)CBr
Temperature: 25 °C
Reaction time: 2 h
Yield: 84 %

Procedure:
300 mg (2.22 mmol) of 1-(4-methylpyrid-3-yl)ethanone are dissolved in 20 mL of glacial acetic acid. 730 μl (4.44 mmol) of hydrobromic acid and 126 μl (2.44 mmol) of bromine are added to the medium. The reaction mixture is placed under magnetic stirring at room temperature for 2 hours. Ethyl ether is added to the solution until a precipitate appears. The precipitate corresponding to 2-bromo-1-(4-methylpyrid-3-yl)ethanone hydrobromide is filtered off, washed with ethyl ether and dried. The 550 mg of product obtained have the following characteristics:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2([NH:20][C:21]([CH3:28])([CH3:27])[C:22]([N:24]([CH3:26])[CH3:25])=[O:23])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18][CH3:19].[CH3:29][O:30][C:31]1[CH:36]=[CH:35][C:34]([S:37](Cl)(=[O:39])=[O:38])=[C:33]([O:41][C:42]([F:45])([F:44])[F:43])[CH:32]=1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:37]([C:34]1[CH:35]=[CH:36][C:31]([O:30][CH3:29])=[CH:32][C:33]=1[O:41][C:42]([F:43])([F:44])[F:45])(=[O:39])=[O:38])[C:6](=[O:11])[C:5]2([NH:20][C:21]([CH3:28])([CH3:27])[C:22]([N:24]([CH3:25])[CH3:26])=[O:23])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18][CH3:19]
Reactant: COc1ccccc1C1(NC(C)(C)C(=O)N(C)C)C(=O)Nc2ccc(Cl)cc21
Reactant: COc1ccc(S(=O)(=O)Cl)c(OC(F)(F)F)c1
Product: COc1ccc(S(=O)(=O)N2C(=O)C(NC(C)(C)C(=O)N(C)C)(c3ccccc3OC)c3cc(Cl)ccc32)c(OC(F)(F)F)c1
Yield: 45.6 %

Procedure:
With 0.51 g of the compound obtained in Step 255-4 and 378 mg of 4-methoxy-2-(trifluoromethoxy)benzene sulfonyl chloride as starting materials, 0.38 g of the title compound (colorless solid) was obtained by a similar procedure to Example 2.
Reaction SMILES: [C:1]([O:6][CH2:7][CH3:8])(=[O:5])[C:2]([CH3:4])=O.[C:9]([O:16][CH3:17])(=[O:15])[CH2:10][C:11]([O:13][CH3:14])=[O:12].CCOCC>C(OC(=O)C)(=O)C.[Cl-].[Cl-].[Zn+2]>[CH3:14][O:13][C:11](=[O:12])[C:10]([C:9]([O:16][CH3:17])=[O:15])=[C:2]([C:1]([O:6][CH2:7][CH3:8])=[O:5])[CH3:4]
Reactant: COC(=O)CC(=O)OC
Reactant: CCOC(=O)C(C)=O
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CC(=O)OC(C)=O
Solvent: CCOCC
Product: CCOC(=O)C(C)=C(C(=O)OC)C(=O)OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 68.9 %

Procedure:
A mixture of ZnCl2 (53 g, 388 mmol) in acetic anhydride (120 mL) was stirred at r.t. for 2 h. The resulting solution was decanted, and to this solution was added ethyl pyruvate (25 g, 215 mmol) and dimethyl malonate (25 mL, 215 mmol). The resulting mixture was heated at 100° C. for 1 h, then left standing at r.t. for 16 h. Ether (300 mL) was added and the mixture was washed with ice water (5×300 mL) and saturated NaHCO3 (2×300 mL). The organic layer was dried over MgSO4 and concentrated to give a dark brown oil, which was distilled under reduced pressure to give 34.1 g of the title compound as an orange oil. 1H NMR (CDCl3, 200 MHz): δ=4.26 (q, 2H, J=7.0 Hz), 3.82 (s, 3H), 3.79 (s, 3H), 2.22 (s, 3H), 1.32 (t, 3H, J=7.2 Hz).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[N:9]=2)[C:5]([Cl:15])=[CH:4][N:3]=1.[C@H:16]1([NH2:23])[CH2:21][CH2:20][C@H:19]([NH2:22])[CH2:18][CH2:17]1>CS(C)=O>[Cl:15][C:5]1[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[N:9]=2)=[N:7][C:2]([NH:22][C@H:19]2[CH2:20][CH2:21][C@H:16]([NH2:23])[CH2:17][CH2:18]2)=[N:3][CH:4]=1
Reactant: N[C@H]1CC[C@H](N)CC1
Reactant: Fc1cccc(-c2nc(Cl)ncc2Cl)n1
Solvent: CS(C)=O
Product: N[C@H]1CC[C@H](Nc2ncc(Cl)c(-c3cccc(F)n3)n2)CC1
Temperature: 75 °C
Reaction time: 2 h

Procedure:
A mixture of 2,5-dichloro-4-(6-fluoropyridin-2-yl)pyrimidine (37 mg, 0.152 mmol), DMSO (1.5 ml) and trans-cyclohexane-1,4-diamine (87 mg, 0.758 mmol)reaction mixture was stirred at about 75° C. for about 2 hours. The reaction mixture was cooled, filter and purified by prep LC, and then lyophilized to yield 39.5 mg of the title compound as a TFA salt. LCMS (m/z): 322.2 (MH+), retention time=0.59 min.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][C@H:10]2[CH2:15][CH2:14][CH2:13][CH2:12][N:11]2[CH2:16][CH:17]2[CH2:19][CH2:18]2)[C:5](=[O:20])[N:4]([CH2:21][C:22]([O:24]CC2C=CC=CC=2)=[O:23])[C:3]=1[CH3:32]>[OH-].[Pd+2].[OH-]>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][C@H:10]2[CH2:15][CH2:14][CH2:13][CH2:12][N:11]2[CH2:16][CH:17]2[CH2:18][CH2:19]2)[C:5](=[O:20])[N:4]([CH2:21][C:22]([OH:24])=[O:23])[C:3]=1[CH3:32]
Reactant: Cc1c(Cl)nc(NC[C@H]2CCCCN2CC2CC2)c(=O)n1CC(=O)OCc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Product: Cc1c(Cl)nc(NC[C@H]2CCCCN2CC2CC2)c(=O)n1CC(=O)O

Procedure:
The title compound was prepared by a similar method to preparation 44 from benzyl 2-[3-chloro-5-({[(2R)-1-(cyclopropylmethyl)piperidinyl]methyl}amino)-2-methyl-6-oxo-1(6H)-pyrazinyl]acetate [see preparation 71] and palladium hydroxide. To afford the product as a yellow foam, (100%).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[CH:11][C:12]2[N:16]=[N:15][N:14]([CH:17]([CH3:22])[C:18]([O:20][CH3:21])=[O:19])[C:13]=2[CH:23]=1)C1C=CC=CC=1.[H][H]>C(COC)OC.CO.[Pd]>[OH:8][C:9]1[CH:10]=[CH:11][C:12]2[N:16]=[N:15][N:14]([CH:17]([CH3:22])[C:18]([O:20][CH3:21])=[O:19])[C:13]=2[CH:23]=1
Reactant: [H][H]
Reactant: COC(=O)C(C)n1nnc2ccc(OCc3ccccc3)cc21
Agent: [Pd]
Solvent: CO
Solvent: COCCOC
Product: COC(=O)C(C)n1nnc2ccc(O)cc21

Procedure:
A solution of methyl 6-(benzyloxy)-α-methyl-1H-benzotriazole-1-acetate (31 g, 0.1 mole) in dimethoxyethane and methanol is shaken with 10% palladium on carbon catalyst (8 g, 50% water wet) under 24-33 psig of hydrogen in a Parr apparatus until approximately 0.1 mole of H2 is absorbed (21/2 hours). The reaction mixture is filtered and the filtrate is concentrated in vacuo to give the title compound as an off-white solid, 21.7 g, mp 132.5°-134.5° C., identified by NMR and elemental analyses.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:38])[NH:20][C:21]3[N:22]=[N:23][C:24]([C:27]4[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][C:28]=4[F:37])=[CH:25][CH:26]=3)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:39]([OH:41])=[O:40].C[O-].[Na+:44].CO>C1COCC1.CO>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:38])[NH:20][C:21]3[N:22]=[N:23][C:24]([C:27]4[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:34])[F:35])=[CH:29][C:28]=4[F:37])=[CH:25][CH:26]=3)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:39]([O-:41])=[O:40].[Na+:44]
Reactant: O=C(Nc1ccc(-c2ccc(C(F)(F)F)cc2F)nn1)c1ccc(Oc2cc3c(cc2Cl)C(C(=O)O)CCO3)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(Nc1ccc(-c2ccc(C(F)(F)F)cc2F)nn1)c1ccc(Oc2cc3c(cc2Cl)C(C(=O)[O-])CCO3)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96 %

Procedure:
To a solution of 6-chloro-7-(4-(6-(2-fluoro-4-(trifluoromethyl)phenyl)pyridazin-3-ylcarbamoyl)phenoxy)chroman-4-carboxylic acid (0.071 g, 0.12 mmol) in 1:1 THF/methanol (2 ml) was added a 0.5M solution of sodium methoxide in methanol (0.24 ml, 0.12 mmol), and the reaction was stirred at ambient temperature for 2 hours. The reaction was concentrated to yield the desired compound (0.071 g, 0.12 mmol, 96% yield). MS (apci) m/z=588.0 (M-Na+2H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=O.[NH2:8][CH2:9][C:10]1[NH:11][C:12](=[O:20])[C:13]2[CH2:19][O:18][CH2:17][CH2:16][C:14]=2[N:15]=1.C([BH3-])#N.C(O)(=O)C>C(O)C>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][NH:8][CH2:9][C:10]1[NH:11][C:12](=[O:20])[C:13]2[CH2:19][O:18][CH2:17][CH2:16][C:14]=2[N:15]=1
Reactant: O=Cc1cccs1
Reactant: NCc1nc2c(c(=O)[nH]1)COCC2
Agent: [BH3-]C#N
Solvent: CC(=O)O
Solvent: CCO
Product: O=c1[nH]c(CNCc2cccs2)nc2c1COCC2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 49.2 %

Procedure:
A mixture of thiophene-2-carbaldehyde (0.021 mL, 0.22 mmol), 2-aminomethyl-3,5,7,8-tetrahydro-pyrano[4,3-d]pyrimidin-4-one (40 mg, 0.22 mmol), and siliabond cyanoborohydride (240 mg, 0.24 mmol, 1 mmol/g) in ethanol (1 mL) was stirred at ambient temperature for 10 minutes. Acetic acid (0.013 mL, 0.22 mmol) was then added, and the mixture was stirred at ambient temperature for another 5 minutes. The reaction mixture was concentrated in vacuo and purified via flash column chromatography (ethyl acetate:hexane, 10:90 to 100:0, methanol: dichloromethane, 1:99 to 10:90) to provide the title compound (30 mg, 49% yield). m/z 278.1 (M+1), retention time=0.89 min.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([N:14]([CH3:16])[CH3:15])=[CH:10][CH:9]=2)[N:5]=[C:4]([C:17]([OH:19])=O)[CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:32][C:33]1[NH:37][N:36]=[N:35][N:34]=1>>[NH:34]1[C:33]([NH:32][C:17]([C:4]2[CH:3]=[C:2]([CH3:1])[CH:7]=[C:6]([C:8]3[CH:9]=[CH:10][C:11]([N:14]([CH3:15])[CH3:16])=[CH:12][CH:13]=3)[N:5]=2)=[O:19])=[N:37][N:36]=[N:35]1
Reactant: Cc1cc(C(=O)O)nc(-c2ccc(N(C)C)cc2)c1
Reactant: Nc1nnn[nH]1
Agent: O=C(n1ccnc1)n1ccnc1
Product: Cc1cc(C(=O)Nc2nnn[nH]2)nc(-c2ccc(N(C)C)cc2)c1
Yield: 19 %

Procedure:
In the same manner as described in Example 1-(1), 4-methyl-6-(4-dimethylaminophenyl)-2-pyridinecarboxylic acid (1.25 g), carbonyldiimidazole (1.38 g) and 5-aminotetrazole (0.47 g) are reacted to give N-(5-tetrazolyl)-4-methyl-6-(4-dimethylaminophenyl)-2-pyridinecarboxamide (0.3 g). M.P. 265°-269° C. (decomp.) (wetted from 255° C.) (recrystallized from dimethylformamide-ethanol)
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([C:24]2[C:25]([CH3:30])=[N:26][CH:27]=[CH:28][CH:29]=2)[N:5]2[C:10]3[CH:11]=[CH:12][N:13]([S:14]([C:17]4[CH:23]=[CH:22][C:20]([CH3:21])=[CH:19][CH:18]=4)(=[O:16])=[O:15])[C:9]=3[N:8]=[CH:7][C:6]=12.[OH2:31]>O1CCOCC1>[Br:1][C:2]1[N:3]=[C:4]([C:24]2[C:25]([CH:30]=[O:31])=[N:26][CH:27]=[CH:28][CH:29]=2)[N:5]2[C:10]3[CH:11]=[CH:12][N:13]([S:14]([C:17]4[CH:18]=[CH:19][C:20]([CH3:21])=[CH:22][CH:23]=4)(=[O:16])=[O:15])[C:9]=3[N:8]=[CH:7][C:6]=12
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c2ncc2c(Br)nc(-c4cccnc4C)n23)cc1
Reactant: O
Solvent: C1COCCO1
Product: Cc1ccc(S(=O)(=O)n2ccc3c2ncc2c(Br)nc(-c4cccnc4C=O)n23)cc1
Temperature: 105 °C
Yield: 69 %

Procedure:
The 3-bromo-1-(2-methylpyridin-3-yl)-6-tosyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazine (0.500 g, 1.03 mmol, prepared using J.1 from Example #2, Step B with 2-methylnicotinic acid, L.2 with POCl3 and AB) in 1,4-dioxane (20 mL) was treated with SeO2 (0.210 g, 1.89 mmol) then the mixture was heated at about 105° C. for about 1 h. The mixture was cooled to rt then water (0.6 mL) was added. The mixture was heated to reflux for about 3 days. The mixture was cooled to rt then concentrated in vacuo. The material was purified using a 10 g silica column eluting with EtOAc. The impure fractions were combined and concentrated then the material was purified using a 10 g silica column eluting with EtOAc. The materials were combined to give 3-(3-bromo-6-tosyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)picolinaldehyde (0.355 g, 69%): LC/MS (Table 2, Method b) Rt=3.53 min; MS m/z 480 (M+H)+.
Reaction SMILES: [C:1]([N:18]([CH2:23][C:24]([OH:26])=O)[CH2:19][C:20]([OH:22])=[O:21])([O:3][CH2:4][CH:5]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:2].FC(F)(F)C(OC(=O)C(F)(F)F)=O>C(OCC)(=O)C>[C:1]([N:18]1[CH2:23][C:24](=[O:26])[O:22][C:20](=[O:21])[CH2:19]1)([O:3][CH2:4][CH:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:12]2[C:17]1=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:2]
Reactant: O=C(O)CN(CC(=O)O)C(=O)OCC1c2ccccc2-c2ccccc21
Solvent: CCOC(C)=O
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: O=C1CN(C(=O)OCC2c3ccccc3-c3ccccc32)CC(=O)O1
Reaction time: 1 h

Procedure:
N-FMOC-Iminodiacetic acid (0.40 g, 1.13 mmol) was suspended in 30 ml ethyl acetate and treated with 1 ml of trifluoracetic anhydride. After stirring for one hour, most of the solvent was evaporated. Petroleum ether was added, followed by evaporation, resulting in a solid residue was dried in vacuo at room temperature. The yield was 0.37 g (97%) mp 180°-185° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([CH3:10])[CH:3]=1.[Mg].[C:12](Cl)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.Cl>O1CCCC1>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:19])=[CH:3][C:4]=1[CH3:10]
Reactant: COc1ccc(Br)cc1C
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Product: COc1ccc(C(=O)c2ccccc2)cc1C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 54.8 %

Procedure:
The corresponding Grignard reagent was prepared from 10 g of 4-bromo-2-methylanisole and 1.21 g of magnesium shavings in 30 ml of tetrahydrofuran and was added dropwise to a solution, pre-cooled to -72°, of 7 g of benzoyl chloride in 80 ml of tetrahydrofuran. In so doing, the temperature was held at below -65°. After the dropwise addition the mixture was stirred at 20° for 0.5 hour, whereupon it was hydrolyzed with 400 ml of ice-water. The solution, acidified with dilute hydrochloric acid, was extracted with ether and the organic phase was dried and evaporated. By chromatography of the residue on silica gel with hexane:ethyl acetate 7:3) there were obtained 6.17 g (55%) of 4-methoxy-3-methylbenzophenone as a yellowish oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[O:16][CH:15]([CH3:17])[C:14]([C:18]([O:20]CC)=[O:19])=[CH:13][C:12]=3[CH:23]=2)=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C.O1CCCC1>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[O:16][CH:15]([CH3:17])[C:14]([C:18]([OH:20])=[O:19])=[CH:13][C:12]=3[CH:23]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)C1=Cc2cc(-c3ccc(C)cc3)ccc2OC1C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)O)C(C)O3)cc1
Reaction time: 16 h
Yield: 78.8 %

Procedure:
To a solution of ethyl 6-(4-methylphenyl)-2-methyl-2H-1-benzopyran-3-carboxylate (3.0 g) in ethanol-tetrahydrofuran (30-30 ml) was added 1N sodium hydroxide (12 ml) at room temperature, and the mixture was stirred for 16 hours. Under reduced pressure, the solvent was evaporated and acidified with 1N hydrochloric acid. The mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated to give 6-(4-methylphenyl)-2-methyl-2H-1-benzopyran-3-carboxylic acid (2.15 g) as yellow crystals.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([SH:10])=[CH:6][CH:5]=1.[C:11]1([CH:17]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:18]2[CH2:23][C:20]3([O:22][CH2:21]3)[CH2:19]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.O>C1COCC1>[C:24]1([CH:17]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:18]2[CH2:23][C:20]([CH2:21][S:10][C:7]3[CH:8]=[CH:9][C:4]([F:3])=[CH:5][CH:6]=3)([OH:22])[CH2:19]2)[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: Fc1ccc(S)cc1
Reactant: c1ccc(C(c2ccccc2)N2CC3(CO3)C2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: OC1(CSc2ccc(F)cc2)CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 80 %

Procedure:
Sodium hydride (0.128 g of a 60% dispersion in mineral oil, 3.2 mmol) was added to a solution of 4-fluorobenzenethiol (0.29 mL, 2.7 mmol) in THF (10 mL). The resulting mixture was stirred at room temperature for 10 min and then cooled to 0° C. A solution of 5-(diphenylmethyl)-1-oxa-5-azaspiro[2.3]hexane [prepared by the method of J. L. Castro Pineiro et al. WO 97/42189] (0.68 g, 2.71 mmol) in THF (8 mL) was added and the resulting mixture stirred at −1° C. for 40 min then at room temperature overnight. The reaction mixture was poured into water (200 mL) and extracted with EtOAc (100 mL then 50 mL). The organic extracts were washed with saturated brine (100 mL), combined, dried (MgSO4) and concentrated. The residue was purified by flash silica chromatography, eluting with 25% EtOAc/isohexane, to give the title product as an oil (0.82 g, 80%). 1H NMR (400 MHz, CDCl3) δ 2.67 (1H, s), 2.94–2.96 (2H, m), 3.18–3.20 (2H, m), 3.43 (2H, s), 4.34 (1H, s), 6.96–7.02 (2H, m), 7.15–7.19 (2H, m), 7.23–7.26 (4H, m), 7.34–7.36 (4H, m), 7.41–7.46 (2H, m). (376 MHz, CDCl3) δF −115.2. m/z (ES+) 380 (M+H)+.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH:12]2[OH:24])=[CH:7][CH:6]=1)[CH:2]=[CH2:3].Cl[CH2:26][C:27]1[CH:36]=[CH:35][C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28]=1[O:37][CH2:38][CH2:39][O:40][CH3:41]>>[CH2:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH:12]2[O:24][CH2:26][C:27]2[CH:36]=[CH:35][C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:28]=2[O:37][CH2:38][CH2:39][O:40][CH3:41])=[CH:9][CH:10]=1)[CH:2]=[CH2:3]
Reactant: C=CCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2O)cc1
Reactant: COCCOc1c(CCl)ccc2ccccc12
Product: C=CCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCc2ccc3ccccc3c2OCCOC)cc1

Procedure:
In an analogous manner to that described in Example 1(g), by alkylating tert-butyl (3RS,4RS)-4-(4-allyloxy-phenyl)-3-hydroxy-piperidine-1-carboxylate [Example 86(b)] with 2-chloromethyl-1-(2-methoxy-ethoxy)-naphthalene [Example 122(h)] there was obtained tert-butyl (3RS,4RS)-4-(4-allyloxy-phenyl)-3-[1-(2-methoxy-ethoxy)-naphthalen-2-ylmethoxy]-piperidine-1-carboxylate, from which by cleavage of the allyl group by means of bis-(triphenylphosphine)-palladium(II) diacetate analogously to Example 152(e) there was obtained tert-butyl (3RS,4RS)-4-(4-hydroxy-phenyl)-3-[1-(2-methoxy-ethoxy)-naphthalen-2-ylmethoxy]-piperidine-1-carboxylate. Subsequent alkylation with 3-phenyl-isoxazol-5-ylmethyl methanesulphonate analogously to Example 44(e) gave tert-butyl (3RS,4RS)-3-[1-(2-methoxy-ethoxy)-naphthalen-2-ylmethoxy]-4-[4-(3-phenyl-isoxazol-5-ylmethoxy)-phenyl]-piperidine-1-carboxylate as a colourless solid; MS: 665 (M+H)+.