Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]([NH2:17])=[O:16])[CH2:10][CH2:9]2)[C:5]([CH2:18][O:19][C:20]2[CH:25]=[C:24]([CH:26]([CH3:28])[CH3:27])[CH:23]=[CH:22][C:21]=2[CH3:29])=[C:4]([CH3:30])[N:3]=1.[CH3:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([CH3:38])[C:33]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1>[CH3:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([CH3:38])[C:33]=1[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]([NH2:17])=[O:16])[CH2:10][CH2:9]2)[C:5]([CH2:18][O:19][C:20]2[CH:25]=[C:24]([CH:26]([CH3:28])[CH3:27])[CH:23]=[CH:22][C:21]=2[CH3:29])=[C:4]([CH3:30])[N:3]=1
Reactant: Cc1cccc(C)c1B(O)O
Reactant: Cc1ccc(C(C)C)cc1OCc1c(C)nc(Cl)nc1N1CCN(CC(N)=O)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Cc1ccc(C(C)C)cc1OCc1c(C)nc(-c2c(C)cccc2C)nc1N1CCN(CC(N)=O)CC1
Temperature: 100 °C
Reaction time: 18 h

Procedure:
A mixture of 2-{4-[2-chloro-5-(5-isopropyl-2-methyl-phenoxymethyl)-6-methyl-pyrimidin-4-yl]-piperazin-1-yl}-acetamide (20 mg, 0.05 mmol), 2,6-dimethylphenylboronic acid (21 mg, 0.14 mmol) and 2 M sodium carbonate (0.14 mL, 0.28 mmol) in dioxane (1 mL) is degassed with bubbling argon for 20 min. Pd(PPh3)4 (2.9 mg, 5 mol %) is added and the reaction mixture is heated at 100° C. under nitrogen with magnetic stirring. After 18 h, the reaction mixture is partitioned between EtOAc (10 mL) and water (2 mL), the organic layer is separated, washed with brine (2 mL), dried over sodium sulfate, filtered and evaporated at reduced pressure to obtain a dark oil. Purification on silica gel (3% MeOH/CH2Cl2/0.1% NH4OH) provides the title compound as a colorless film. LC/MS (Method 3), M+H=502.3, Rt=2.43 min.; 1H NMR (CDCl3) δ=7.07-7.19 (m, 4H), 6.82 (m, 2H), 5.44 (br s, 1H), 4.97 (s, 2H), 3.57 (br s, 4H), 3.02 (s, 2H), 2.91 (m, 1H), 2.62 (m, 4H) 2.56 (s, 3H), 2.22 (s, 3H), 2.16 (s, 6H), 1.28 (d, 6H).
Reaction SMILES: [C:1]([O:6][CH3:7])(=[O:5])[C:2]([CH3:4])=[CH2:3].[C:8]([O:12][CH3:13])(=[O:11])[CH:9]=[CH2:10]>>[C:1]([O:6][CH3:7])(=[O:5])[C:2]([CH3:4])=[CH2:3].[C:8]([O:12][CH2:13][CH3:1])(=[O:11])[CH:9]=[CH2:10]
Reactant: C=CC(=O)OC
Agent: C=C(C)C(=O)OC
Product: C=CC(=O)OCC

Procedure:
U.S. Pat. No. 5,286,801 teaches that the impact strength of an (meth)acrylic polymer, consisting of a copolymer containing 99% methyl methacrylate and 1% methyl acrylate, is improved by the use of a five stage core-shell particle in which the core, second shell and fourth shell are formed from a methyl methacrylate/ethyl acrylate copolymer containing 95.4 to 95.8% w/w methyl methacrylate, 3.9 to 4.6% w/w ethyl acrylate and 0 to 0.3% w/w allyl methacrylate; and the first and third shells are a n-butyl acrylate/styrene copolymer containing 80.4% w/w butyl acrylate, 17.6% w/w styrene and 2% w/w allyl methacrylate. The methyl methacrylate/ethyl acrylate copolymer representing 34.5% w/w of the total particle. Comparative examples relate to a three stage core-shell particle in which the core and second shell are formed from a methyl methacrylatelethyl acrylate copolymer containing 95.9 to 96% w/w methyl methacrylate, 4% w/w ethyl acrylate and 0 to 0.1% w/w allyl methacrylate; and the first shell is a n-butyl acrylate/styrene copolymer containing 80.4% w/w butyl acrylate, 17.6% w/w styrene and 2% w/w of allyl methacrylate. The methyl methacrylate/ethyl acrylate copolymer representing 35.5% w/w of the total particle. When blended at a level of 39% with an (meth)acrylic polymer, to give a n-butyl acrylate/styrene content of 25.5% w/w (using the five stage core-shell particles) and 25.2% w/w (using the three stage particles), the best five stage core-shell particles gave an unnotched Charpy Impact strength of 81 kJ.m−2 which represented an increase of 19% over that achieved by the comparative three stage core particles.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](Cl)=[N:6][CH:7]=1.Cl.[CH3:10][NH:11][CH3:12].C([O-])([O-])=O.[K+].[K+]>CCO>[Br:1][C:2]1[CH:3]=[N:4][C:5]([N:11]([CH3:12])[CH3:10])=[N:6][CH:7]=1
Reactant: CNC
Reactant: Clc1ncc(Br)cn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CN(C)c1ncc(Br)cn1
Temperature: 120 °C

Procedure:
A mixture of 5-bromo-2-chloropyrimidine (1 g, 5.18 mmol), dimethylamine hydrochloride (1.26 g, 15.6 mmol) and K2CO3 (2.16 g, 15.6 mmol) in EtOH (15 mL) was heated to 120° C. for 16 h. After cooling, the solvent was evaporated off and the residue was used for next step without further purification. LCMS (m/z): 202.1/203.1 [M+H]+/[M+2H]+
Reaction SMILES: [C:1]([C:3](=[N:15][O:16][CH:17]([CH3:19])[CH3:18])[C:4]([N:10]1[CH:14]=[N:13][CH:12]=[N:11]1)=[N:5][O:6][CH:7]([CH3:9])[CH3:8])#[N:2].C[Si]([N:24]=[N+:25]=[N-:26])(C)C.C([Sn](=O)CCCC)CCC>C1(C)C=CC=CC=1>[CH:7]([O:6][N:5]=[C:4]([N:10]1[CH:14]=[N:13][CH:12]=[N:11]1)[C:3](=[N:15][O:16][CH:17]([CH3:19])[CH3:18])[C:1]1[NH:26][N:25]=[N:24][N:2]=1)([CH3:9])[CH3:8]
Reactant: CC(C)ON=C(C#N)C(=NOC(C)C)n1cncn1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Product: CC(C)ON=C(C(=NOC(C)C)n1cncn1)c1nnn[nH]1
Temperature: 25 °C
Reaction time: 3 h
Yield: 49.6 %

Procedure:
To 5 ml of a toluene solution containing 0.40 g (1.51 mmol) of 1-(2-cyano-1,2-diisopropoxyiminoethyl)-1H-1,2,4-triazole were added 0.35 g (3.03 mmol) of trimethylsilylazide and 0.38 g (1.51 mmol) of di-n-butyltin oxide, followed by stirring for 3 hours under heating and refluxing. The reaction mixture was cooled to room temperature, followed by extraction with ethyl acetate. The extract solution was washed with an aqueous saturated sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (elutant:ethyl acetate/hexane=1/0). The crystal obtained was washed with isopropyl ether to obtain 0.23 g (yield: 47%) of a title compound.
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]([CH3:19])[C:3]1=[O:20].[F:21][C:22]1[CH:23]=[C:24]([CH:36]=[C:37]([F:39])[CH:38]=1)[CH2:25][NH:26][C:27](=[O:35])[CH:28]([CH:32]([CH3:34])[CH3:33])[C:29](O)=[O:30]>>[F:21][C:22]1[CH:23]=[C:24]([CH:36]=[C:37]([F:39])[CH:38]=1)[CH2:25][NH:26][C:27](=[O:35])[CH:28]([CH:32]([CH3:34])[CH3:33])[C:29]([NH:1][CH:2]1[C:3](=[O:20])[N:4]([CH3:19])[C:5]2[CH:18]=[CH:17][CH:16]=[CH:15][C:6]=2[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:8]1)=[O:30]
Reactant: CC(C)C(C(=O)O)C(=O)NCc1cc(F)cc(F)c1
Reactant: CN1C(=O)C(N)N=C(c2ccccc2)c2ccccc21
Product: CC(C)C(C(=O)NCc1cc(F)cc(F)c1)C(=O)NC1N=C(c2ccccc2)c2ccccc2N(C)C1=O

Procedure:
The title compound, MS: m/e=519.3 (M+H+), was prepared in analogy to example 16 from 3-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one and N-(3,5-difluoro-benzyl)-2-isopropyl-malonamic acid.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])C.[F:8][C:9]1[CH:30]=[CH:29][CH:28]=[CH:27][C:10]=1[CH:11]=[C:12]1[C:17](=[O:18])[C:16](=[CH:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[F:26])[CH2:15][NH:14][CH2:13]1>C(O)=O>[CH:1]([N:14]1[CH2:13][C:12](=[CH:11][C:10]2[CH:27]=[CH:28][CH:29]=[CH:30][C:9]=2[F:8])[C:17](=[O:18])[C:16](=[CH:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[F:26])[CH2:15]1)=[O:3]
Reactant: CC(=O)OC(C)=O
Reactant: O=C1C(=Cc2ccccc2F)CNCC1=Cc1ccccc1F
Solvent: O=CO
Product: O=CN1CC(=Cc2ccccc2F)C(=O)C(=Cc2ccccc2F)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 45 %

Procedure:
Compound 18 was synthesized by two methods. In the first method, acetic anhydride (3 ml) was added drop-wise to an ice-cold solution of compound 1 (300 mg, 0.96 mmol) in formic acid (6 ml), and the reaction mixture was stirred at room temperature for 16 h. The solvent was distilled-off under vacuum. The solid obtained was recrystallized from chloroform and hexanes to obtain 18 as a yellow solid (148 mg, 45% yield). In the second method, ammonium formate (121 mg, 1.92 mmol) was added to a solution of compound 1 (300 mg, 0.96 mmol) in dry acetonitrile. The mixture was refluxed for 24 h, before evaporating to dryness. The solid was recrystallized from methylene chloride and hexanes to obtain pure 18 as a yellow solid (190 mg, 57% yield). Rf (60:40 ethyl acetate:hexanes)=0.60. 1H NMR (400 MHz, CDCl3): δ 8.16 (s, 1H, CHO), 8.09, 8.06 (2s, 2H, C═CH), 7.60-7.22 (m, 8H, Ar—H), 4.87, 4.66 (2s, 4H). 13C NMR (100 MHz, CDCl3): δ 185.34, 162.14 (d, J=45.6), 160.95, 159.87 (d, J=45.9), 132.85, 132.19 (d, J=25.7), 131.12 (d, J=25.4), 130.78, 124.46 (d, J=3.1), 116.49 (d, J=22.1), 116.18 (d, J=22.3), 46.38 (d, J=5.4), 41.11 (d, J=5.2). ESI Mass calculated for C20H15F2NNaO2 (M+Na)+362.10. found 362.07.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH2:11])[CH2:9][CH3:10])=[C:4]([F:12])[CH:3]=1.C(O)C.N[C@H](C(O)=O)CC(O)=O>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH2:11])[CH2:9][CH3:10])=[C:4]([F:12])[CH:3]=1
Reactant: CCC(N)c1ccc(Cl)cc1F
Agent: N[C@@H](CC(=O)O)C(=O)O
Solvent: CCO
Solvent: O
Product: CC[C@@H](N)c1ccc(Cl)cc1F
Temperature: 72 °C
Reaction time: 8 h

Procedure:
Step 4—Three runs were carried out in parallel and combined in the work-up. A mixture of 1-(4-chloro-2-fluoro-phenyl)-propylamine (497.6 g, 2.65 mol, 1.0 eq) from Step 3, ethanol and water (3.1 L ethanol/1.3 L water) and L-aspartic acid (353 g, 2.65 mol, 1.0 eq) was heated to 72° C. (oil bath) for 1 hour and then allowed to cool to room temperature. The resulting precipitate was filtered off, washed with ethanol (2 L) and air dried to give a white solid (4381.6 g-contains solvent, dry weight estimated by 1H NMR at 2674.2 g), which was split into four. To each of the four portions was added a mixture of ethanol and water (11.9 L EtOH, 4.9 L H2O) and the resulting mixture was then stirred at room temperature overnight before isolating the solid by filtration, washing with ethanol, and drying the solid in a vacuum oven overnight at 40° C., to give (R)-1-(4-chloro-2-fluoro-phenyl)-propylamine as the aspartate salt, a white solid (1409.2 g). 1H NMR (400 MHz, DMSO-d6): 7.56 (1H, t), 7.34 (1H, dd), 7.29 (1H, dd), 4.03 (1H, t), 3.68 (1H, dd), 2.67 (1H, dd), 2.38 (1H, dd), 1.69-1.49 (2H, m), 0.80 (3H, t).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH3:5][C:6]1[N:10]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][N:12]=2)[N:9]=[CH:8][C:7]=1[C:21]([NH:23][C:24]1[CH:25]=[N:26][C:27]([C:31]2[CH2:32][CH2:33][NH:34][CH2:35][CH:36]=2)=[C:28]([CH3:30])[CH:29]=1)=[O:22].O>N1C=CC=CC=1>[C:1]([N:34]1[CH2:35][CH:36]=[C:31]([C:27]2[N:26]=[CH:25][C:24]([NH:23][C:21]([C:7]3[CH:8]=[N:9][N:10]([C:11]4[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][N:12]=4)[C:6]=3[CH3:5])=[O:22])=[CH:29][C:28]=2[CH3:30])[CH2:32][CH2:33]1)(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: Cc1cc(NC(=O)c2cnn(-c3ccc(C(F)(F)F)cn3)c2C)cnc1C1=CCNCC1
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)N1CC=C(c2ncc(NC(=O)c3cnn(-c4ccc(C(F)(F)F)cn4)c3C)cc2C)CC1
Temperature: 40 °C
Reaction time: 6 h

Procedure:
Acetyl chloride (50 μl) was added to a solution of 5-methyl-N-[5-methyl-6-(1,2,3,6-tetrahydropyridin-4-yl)pyridin-3-yl]-1-[5-(trifluoromethyl)pyridin-2-yl]-1H-pyrazole-4-carboxamide (300 mg) described in Reference Example 170 in pyridine (3.4 ml), stirred at 40° C. for six hours. Acetyl chloride (50 μl) was added and stirred for two hours, and then, Acetyl chloride (50 μl) was added and stirred for six hours. Water was added to the reaction solution and the precipitated solid was washed with ethanol and water to give the titled compound (283 mg) as a pale yellow solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[C:5]([C:9]#[N:10])=[C:4](Cl)[N:3]=1.[CH2:12]([NH:14][CH2:15][CH3:16])[CH3:13]>C(OCC)C>[Cl:8][C:6]1[C:5]([C:9]#[N:10])=[C:4]([N:14]([CH2:15][CH3:16])[CH2:12][CH3:13])[N:3]=[C:2]([N:14]([CH2:15][CH3:16])[CH2:12][CH3:13])[N:7]=1
Reactant: CCNCC
Reactant: N#Cc1c(Cl)nc(Cl)nc1Cl
Solvent: CCOCC
Product: CCN(CC)c1nc(Cl)c(C#N)c(N(CC)CC)n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of 6.3 grams of 2,4,6-trichloro-5-pyrimidinecarbonitrile in 150 ml of diethyl ether at 10° was added dropwise 8.8 grams of diethylamine in 150 ml of diethyl ether. Upon complete addition, the reaction mixture was allowed to warm to room temperature, where it was stirred for 16 hours. The reaction mixture was heated under reflux for 1 hour, then cooled to room temperature. The reaction mixture was washed with water, and the diethyl ether layer was separated. The aqueous layer was washed with diethyl ether. The ether layers were combined and dried over magnesium sulfate. The mixture was filtered, and the filtrate was evaporated under reduced pressure to a residue. The residue was recrystallized from petroleum ether to give crude 4-chloro-2,6-bis(diethylamino)-5-pyrimidinecarbonitrile. This crude material was dissolved in diethyl ether, and 4.4 grams of diethylamine was added.
Reaction SMILES: CS(O[CH:6]1[CH2:9][N:8]([C:10]2[S:11][CH:12]=[C:13]([C:15](=[O:35])[NH:16][C@H:17]3[CH2:21][CH2:20][N:19]([C:22]([O:24][CH2:25][C:26]4[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][CH:27]=4)=[O:23])[CH2:18]3)[N:14]=2)[CH2:7]1)(=O)=O.[C:36]([O-:39])(=[S:38])[CH3:37].[K+]>CN(C)C=O>[C:36]([S:38][CH:6]1[CH2:7][N:8]([C:10]2[S:11][CH:12]=[C:13]([C:15](=[O:35])[NH:16][C@H:17]3[CH2:21][CH2:20][N:19]([C:22]([O:24][CH2:25][C:26]4[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][CH:27]=4)=[O:23])[CH2:18]3)[N:14]=2)[CH2:9]1)(=[O:39])[CH3:37]
Reactant: CS(=O)(=O)OC1CN(c2nc(C(=O)N[C@H]3CCN(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)cs2)C1
Reactant: CC([O-])=S
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)SC1CN(c2nc(C(=O)N[C@H]3CCN(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)cs2)C1
Temperature: 80 °C
Reaction time: 5 h
Yield: 72.8 %

Procedure:
To a solution of 3-methanesulfonyloxy-1-{4-[(3S)-1-(p-nitrobenzyloxycarbonyl)-pyrrolidin-3-ylcarbamoyl]-1,3-thiazol-2-yl}azetidine (410 mg, 0.780 mmol) (obtained as described in Reference Example 52(7)) in dimethylformamide (21 ml) was added potassium thioacetate (534 mg, 4.68 mmol) at room temperature, and the reaction mixture was stirred in an oil bath (80° C.) for 5 hours. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and 10% aqueous sodium chloride solution. The organic layer was washed successively with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by chromatography on a silica gel column using n-hexane:ethyl acetate (1:2)→ethyl acetate as the eluant to afford 3-acetylthio-1-{4-[(3S)-1-(p-nitrobenzyloxycarbonyl)-pyrrolidin-3-ylcarbamoyl]-1,3-thiazol-2-yl}azetidine (287 mg, yield 73%) as a pale brown solid.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([CH:12]([CH3:14])[CH3:13])=[CH:8][C:7]=2[C:15]2[C:16]3[NH:23][C:22]([CH3:24])=[C:21]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:3][CH2:2]1.Cl[CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36]>>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([CH:12]([CH3:14])[CH3:13])=[CH:8][C:7]=2[C:15]2[C:16]3[N:23]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[C:22]([CH3:24])=[C:21]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:3][CH2:2]1
Reactant: C[Si](C)(C)CCOCCl
Reactant: CCOC(=O)c1c(C)[nH]c2c(-c3cc(C(C)C)ccc3OCC3CC3)ncnc12
Product: CCOC(=O)c1c(C)n(COCC[Si](C)(C)C)c2c(-c3cc(C(C)C)ccc3OCC3CC3)ncnc12

Procedure:
Starting from ethyl 4-[2-(cyclopropylmethoxy)-5-(propan-2-yl)phenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylate (example D.a15) and commercially available (2-chloromethoxy-ethyl)-trimethyl-silane the title compound is obtained as yellow viscous oil.
Reaction SMILES: Br[C:2]1[C:3]([F:17])=[C:4]([CH:14]=[CH:15][CH:16]=1)[CH2:5][O:6][Si:7]([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8].C([O:25][CH2:26][CH:27]1[CH2:30][NH:29][CH2:28]1)C1C=CC=CC=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC(C)([O-])C.[Na+]>[Pd].C1(/C=C/C(=O)/C=C/C2C=CC=CC=2)C=CC=CC=1.[C].[Pd].CCO.CCOC(C)=O.C1(C)C=CC=CC=1>[Si:7]([O:6][CH2:5][C:4]1[C:3]([F:17])=[C:2]([N:29]2[CH2:30][CH:27]([CH2:26][OH:25])[CH2:28]2)[CH:16]=[CH:15][CH:14]=1)([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8]
Reactant: c1ccc(COCC2CNC2)cc1
Reactant: CC(C)(C)[Si](C)(C)OCc1cccc(Br)c1F
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC(C)(C)[Si](C)(C)OCc1cccc(N2CC(CO)C2)c1F
Temperature: 90 °C
Reaction time: 3 h
Yield: 19.3 %

Procedure:
Under argon atmosphere, [(3-bromo-2-fluorobenzyl)oxy](tert-butyl)dimethylsilane (5.5 g), 3-[(benzyloxy)methyl]azetidine (2.5 g), and toluene (50 ml) were mixed, and (1E,4E)-1,5-diphenylpenta-1,4-dien-3-one palladium (3:2) (900 mg), BINAP (1.8 g), and sodium tert-butoxide (2.5 g) were added thereto, followed by stirring at 90° C. for 3 hours. The reaction mixture was cooled to room temperature, and EtOAc were added thereto, followed by filtering using Celite as a filtration adjuvant. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/EtOAc). The purified product thus obtained was mixed with EtOH (40 ml), and 10% palladium carbon (1 g) was added thereto, followed by stirring at room temperature overnight under hydrogen atmosphere of 1 atm and filtering using Celite as a filtration adjuvant. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CHCl3/MeOH) to obtain {1-[3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-fluorophenyl]azetidin-3-yl}methanol (885 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=3)[C:10]=2[CH:29]=[O:30])=[CH:5][CH:4]=1.[Si]([C:35]([F:38])([F:37])[F:36])(C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>O1CCCC1>[F:36][C:35]([F:38])([F:37])[CH:29]([C:10]1[N:11]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:26])([F:27])[F:28])[CH:20]=2)[C:12]2[C:17]([C:9]=1[C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2)[OH:30]
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: COc1ccc(-c2c(C=O)n(Cc3cccc(C(F)(F)F)c3)c3ccccc23)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COc1ccc(-c2c(C(O)C(F)(F)F)n(Cc3cccc(C(F)(F)F)c3)c3ccccc23)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 21 %

Procedure:
To a solution of 3-(4-methoxyphenyl)-1-{[3-(trifluoromethyl)phenyl]methyl}indole-2-carbaldehyde (Example 218, 200 mg, 0.49 mmol) in tetrahydrofuran (5 mL) was added a 0.5 M solution of TMSCF3 in tetrahydrofuran (4.9 mL, 2.4 mmol). The resulting solution was cooled to 0° C. and a 1.0 M solution of TBAF in tetrahydrofuran (0.10 mL, 0.10 mmol) was added. The mixture was stirred for 10 min at 0° C. and then let warm to RT and quenched by the addition of water. The resulting mixture was extracted with tetrahydrofuran, adsorbed onto silica, and purified by flash chromatography on silica in 4:1 hexane:ethyl acetate (v/v) to yield 49 mg (21%) of an orange solid. 1H NMR (300 MHz, DMSO-d6) δ 7.60-7.26 (m, 6H), 7.22-7.01 (m, 6H), 5.81 (s, 2H), 3.83 (s, 3H); mass spectroscopy gave MH+=480.2 (calc'd exact mass for C25H19F3NO2=479.13).
Reaction SMILES: [C:1]([N:6]1[CH2:11][CH2:10][C:9](=[O:12])[CH2:8][CH2:7]1)([O:3][CH2:4][CH3:5])=[O:2].[Br:13]Br>ClCCl>[C:1]([N:6]1[CH2:7][CH2:8][C:9](=[O:12])[CH:10]([Br:13])[CH2:11]1)([O:3][CH2:4][CH3:5])=[O:2]
Reactant: CCOC(=O)N1CCC(=O)CC1
Reactant: BrBr
Solvent: ClCCl
Product: CCOC(=O)N1CCC(=O)C(Br)C1

Procedure:
1-carbethoxy-4-piperidone 1 reacts with bromine in an inert solvent such as dichloromethane to give high yields of 1-carbethoxy-3-bromo-4-piperidone 2. The bromo compound 2 reacts with sodium methoxide in methanol to give 1-carbethoxy-3-hydroxy-4,4-dimethoxypiperidine 3, which in turn is alkylated to the corresponding 3-methoxy analog 4 with iodomethane in dimethylformamide in the presence of sodium hydride. The ketal 4 is hydrolyzed to 1-carbethoxy-3-methoxy-4-piperidone 5 by stirring in 1% sulfuric acid at room temperature. The amine 6 of cis-configuration is then readily obtained by reductive alkylation of 5 with benzylamine in the presence of hydrogen gas and 10% Pd/C with a small amount of thiophene. Further hydrogenolysis of the benzyl moiety with Pd/C and no thiophene gives the primary amine 7. Compound 7 in turn reacts with the commercially available 4-amino-5-chloro-2-methoxybenzoic acid in the presence of DCC and dimethyaminopyridine in dichloromethane to give the benzamide 8. Compound 8 is then hydrolyzed to the intermediate 9 with potassium hydroxide in ethanol/water.
Reaction SMILES: Cl.[NH2:2][C:3]1[N:32]=[C:6]2[N:7]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)[C:8]([CH3:21])=[C:9]([C:19]#[N:20])[C@@H:10]([C:11]3[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=3)[N:5]2[N:4]=1.[C:33]([O:36][CH2:37][C:38](Cl)=[O:39])(=[O:35])[CH3:34]>N1C=CC=CC=1>[C:33]([O:36][CH2:37][C:38]([NH:2][C:3]1[N:32]=[C:6]2[N:7]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:29])([F:31])[F:30])[CH:23]=3)[C:8]([CH3:21])=[C:9]([C:19]#[N:20])[C@@H:10]([C:11]3[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=3)[N:5]2[N:4]=1)=[O:39])(=[O:35])[CH3:34]
Reactant: CC(=O)OCC(=O)Cl
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2)n2nc(N)nc2N1c1cccc(C(F)(F)F)c1
Agent: Cl
Solvent: c1ccncc1
Product: CC(=O)OCC(=O)Nc1nc2n(n1)[C@H](c1ccc(C#N)cc1)C(C#N)=C(C)N2c1cccc(C(F)(F)F)c1
Reaction time: 12 h

Procedure:
Under an atmosphere of argon protective gas, (7R)-2-amino-7-(4-cyanophenyl)-5-methyl-4-[3-(trifluoromethyl)phenyl]-4,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidine-6-carbonitrile hydrochloride (30 mg, 66 μmol) was dissolved in abs. pyridine (1.5 ml). At room temperature, acetoxyacetyl chloride (37 mg, 262 μmol, 4 eq.) was added. After 12 h, analysis of the reaction by HPLC showed substantial conversion. The reaction mixture was concentrated under reduced pressure and purified by preparative HPLC (Gromsil C18 column, 30×250 mm; mobile phase: acetonitrile-water-0.1% TFA). After lyophilization, the product was obtained as a solid (19.6 mg, 57% of theory).
Reaction SMILES: C([O:8][CH2:9][C@H:10]1[O:15][CH2:14][C@H:13]([CH:16]2[CH2:21][CH2:20][CH:19]([CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:18][CH2:17]2)[CH2:12][O:11]1)C1C=CC=CC=1.[H][H]>C1COCC1.[Pd]>[CH2:22]([CH:19]1[CH2:18][CH2:17][CH:16]([C@@H:13]2[CH2:14][O:15][C@@H:10]([CH2:9][OH:8])[O:11][CH2:12]2)[CH2:21][CH2:20]1)[CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCCC1CCC([C@H]2CO[C@H](COCc3ccccc3)OC2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: CCCCCC1CCC([C@H]2CO[C@H](CO)OC2)CC1

Procedure:
A solution of 100 mmol of trans/trans-2-benzyloxymethyl-5-(4-pentylcyclohexyl)-1,3-dioxane is hydrogenated in 300 ml of THF with the addition of 2.0 g of 5% Pd/activated charcoal until the take-up of hydrogen is complete. trans/trans-[5-(4-pentylcyclohexyl)-1,3-dioxan-2-yl]methanol is obtained by conventional work-up.