Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:5]1[C:13](=[O:14])[NH:12][C:11]2[C:6]1=[N:7][C:8]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][Si](C(C)C)(C(C)C)C(C)C)[CH:20]=1)=[N:9][C:10]=2[C:15]([O:17]C)=O)[CH:2]([CH3:4])[CH3:3].[NH2:36]C1C(C(OC)=O)=NC(C2C=CC=C(O[Si](C(C)C)(C(C)C)C(C)C)C=2)=NC=1NC1C2C(=CC=CC=2)CC1>ClCCl>[OH:25][C:21]1[CH:20]=[C:19]([C:8]2[N:7]=[C:6]3[C:11]([NH:12][C:13](=[O:14])[N:5]3[CH2:1][CH:2]([CH3:3])[CH3:4])=[C:10]([C:15]([NH2:36])=[O:17])[N:9]=2)[CH:24]=[CH:23][CH:22]=1
Reactant: COC(=O)c1nc(-c2cccc(O[Si](C(C)C)(C(C)C)C(C)C)c2)nc(NC2CCc3ccccc32)c1N
Reactant: COC(=O)c1nc(-c2cccc(O[Si](C(C)C)(C(C)C)C(C)C)c2)nc2c1[nH]c(=O)n2CC(C)C
Solvent: ClCCl
Product: CC(C)Cn1c(=O)[nH]c2c(C(N)=O)nc(-c3cccc(O)c3)nc21
Yield: 85 %

Procedure:
Methyl 9-isobutyl-8-oxo-2-(3-(triisopropylsilyloxy)phenyl)-8,9-dihydro-7H-purine-6-carboxylate. Methyl 5-amino-6-(2,3-dihydro-1H-inden-1-ylamino)-2-(3-(triisopropylsilyloxy)phenyl)pyrimidine-4-carboxylate (0.300 g, 0.635 mmol) and 1,1′-1,1′-carbonyldiimidazole (0.411 g, 2.54 mmol) in dichloromethane (25 mL) were reacted according to General Procedure F. The solution was condensed under reduced pressure and partitioned between water and ethyl acetate (3×). Organic fractions were combined and dried over magnesium sulfate, filtered and solvent removed under reduced pressure. The crude solid was diluted with methanol (15 mL) and sonicated. The resulting precipitate was filtered to afford the title compound (0.185 g, 85%). MS (ESI) m/z 268.2 [M+1]+.
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:12](Br)=[CH:11][C:3]=1[C:4]([N:6]([CH2:9][CH3:10])[CH2:7][CH3:8])=[O:5].CC1(C)C(C)(C)OB([C:24]2[CH:25]=[N:26][N:27]([CH2:29][CH2:30][CH2:31][OH:32])[CH:28]=2)O1.ClCCl.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1.O>>[NH2:1][C:2]1[CH:14]=[CH:13][C:12]([C:24]2[CH:25]=[N:26][N:27]([CH2:29][CH2:30][CH2:31][OH:32])[CH:28]=2)=[CH:11][C:3]=1[C:4]([N:6]([CH2:9][CH3:10])[CH2:7][CH3:8])=[O:5]
Reactant: CCN(CC)C(=O)c1cc(Br)ccc1N
Reactant: CC1(C)OB(c2cnn(CCCO)c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Solvent: ClCCl
Product: CCN(CC)C(=O)c1cc(-c2cnn(CCCO)c2)ccc1N
Yield: 51.9 %

Procedure:
A suspension of 2-amino-5-bromo-N,N-diethylbenzamide (Compound 3D, 326 mg, 1.20 mmol), 3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]propan-1-ol (Compound 3E, 0.33 g, 1.32 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (1:1) (106.8 mg, 0.13 mmol) and potassium carbonate (0.50 g, 3.64 mmol) in 1,4-dioxane (4 mL, 50 mmol) to H2O (1 mL, 60 mmol) was evacuated and charged with argon (3×). The sample was irradiated in a microwave reactor for 30 min at 100° C. The crude product was concentrated in vacuo to a solid and purified using a Teledyne ISCO Combiflash® Rf system [0→5% MeOH in DCM] to yield the desired product (197 mg, 52%). 1H NMR (400 MHz, CD3OD) δ 7.86 (d, J=0.51 Hz, 1H), 7.71 (d, J=0.76 Hz, 1H), 7.36 (dd, J=2.02, 8.34 Hz, 1H), 7.22 (d, J=2.02 Hz, 1H), 6.81 (d, J=8.34 Hz, 1H), 4.24 (t, J=6.82 Hz, 2H), 3.33-3.60 (m, 6H), 2.05 (quin, J=6.57 Hz, 2H), 1.04-1.35 (m, 6H). MS (ESI): m/z 317.59 [M+H]+. UPLC: tR=0.74 min (UPLC-SQD: analytical—2 min).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]#[N:17].Cl.N1C=CC=CC=1.[NH2:25][C:26]1[C:27]([CH3:35])=[C:28]([CH:32]=[CH:33][CH:34]=1)[C:29]([OH:31])=[O:30]>C(OCCO)C>[C:16]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:2]=1[NH:25][C:26]1[C:27]([CH3:35])=[C:28]([CH:32]=[CH:33][CH:34]=1)[C:29]([OH:31])=[O:30])=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][CH3:15])[CH:7]=2)#[N:17]
Reactant: COc1cc2ncc(C#N)c(Cl)c2cc1OC
Reactant: Cc1c(N)cccc1C(=O)O
Agent: Cl
Solvent: CCOCCO
Solvent: c1ccncc1
Product: COc1cc2ncc(C#N)c(Nc3cccc(C(=O)O)c3C)c2cc1OC
Yield: 24.7 %

Procedure:
Using an analogous procedure to that described in EXAMPLE 367, 248.7 mg (1 mmol) of 4-chloro-6,7-dimethoxy-3-quinolinecarbonitrile in 12 mL of 2-ethoxyethanol and in the presence of 115.6 mg (1 mmol) of pyridine hydrochloride was reacted with 196.5 mg (1.3 mmol) of 3-amino-2-methylbenzoicacid to give 89.6 mg (24.7%) of the product as a gray solid, m.p. 242-245° C., mass (electrospray, m/e): M+H 364.0.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]([C:6]([F:10])([F:9])[CH2:7][CH3:8])=[CH:4][F:5].[FH:13]>>[F:1][C:2]([F:11])([F:12])[CH:3]([C:6]([F:9])([F:10])[CH2:7][CH3:8])[CH:4]([F:13])[F:5]
Reactant: F
Reactant: CCC(F)(F)C(=CF)C(F)(F)F
Product: CCC(F)(F)C(C(F)F)C(F)(F)F

Procedure:
As another example, 2-difluoromethyl-1,1,1,3,3-pentafluoro-2-pentanol may be prepared by fluorinating commercially available 3-pentanone to form 3,3-difluoropentane which may then be dehydrogenated to form 3,3-difluoro-1-pentene. CF3 may then be reacted with the 3,3-difluoro-1-pentene to form 2-trifluoromethyl-1,3,3-trifluoropentane which may then be dehydrogenated to form 2-trifluoromethyl-1,3,3-trifluoro-1-pentene. The 2-trifluoromethyl-1,3,3-trifluoro-1-pentene may then be reacted with hydrogen fluoride to form 2-trifluoromethyl-1,1,3,3-tetrafluoropentane which may then be dehydrogenated to form 2-trifluoromethyl-1,1,3,3-tetrafluoro-1-pentene which may then be reacted with sulfuric acid and then water to form 2-difluoromethyl-1,1,1,3,3-pentafluoro-2-pentanol.
Reaction SMILES: [C:1]([C:3]1[C:4]([CH3:29])=[C:5]([C:10](=[O:28])[CH2:11][N:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH:13]2[CH2:25][CH2:26][OH:27])[CH:6]=[CH:7][C:8]=1[F:9])#[N:2].[BH4-].[Na+]>CCO>[C:1]([C:3]1[C:4]([CH3:29])=[C:5]([CH:10]([OH:28])[CH2:11][N:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:23])([CH3:24])[CH3:22])=[O:19])[CH2:14][CH:13]2[CH2:25][CH2:26][OH:27])[CH:6]=[CH:7][C:8]=1[F:9])#[N:2]
Reactant: Cc1c(C(=O)CN2CCN(C(=O)OC(C)(C)C)CC2CCO)ccc(F)c1C#N
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: Cc1c(C(O)CN2CCN(C(=O)OC(C)(C)C)CC2CCO)ccc(F)c1C#N
Reaction time: 3 h

Procedure:
tert-Butyl 4-(2-(3-cyano-4-fluoro-2-methylphenyl)-2-oxoethyl)-3-(2-hydroxyethyl)piperazine-1-carboxylate (3.81 g, 9.40 mmol) and dissolved in EtOH (60 mL) then NaBH4 (1.42 g, 37.6 mmol) was added and the mixture was stirred for 3 h. The ethanol was evaporated and brine was added then extracted with ethyl acetate twice. The organic layer was dried over sodium sulfate, filtered and concentrated. The crude product was purified by MPLC chromatography using a 330 g ISCO Redi-sep column with 5% MeOH/DCM solvent system to yield tert-butyl 4-(2-(3-cyano-4-fluoro-2-methylphenyl)-2-hydroxyethyl)-3-(2-hydroxyethyl)piperazine-1-carboxylate: LC-MS (IE, m/z): 408 [M+1]+;
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:19]([O-:21])=[O:20].[CH3:22][N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.C([O-])([O-])=O.[K+].[K+]>CC#N>[Cl:18][C:14]1[CH:13]=[C:12]([NH:11][S:8]([C:5]2[CH:6]=[CH:7][C:2]([N:26]3[CH2:27][CH2:28][N:23]([CH3:22])[CH2:24][CH2:25]3)=[C:3]([N+:19]([O-:21])=[O:20])[CH:4]=2)(=[O:10])=[O:9])[CH:17]=[CH:16][CH:15]=1
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)Nc2cccc(Cl)c2)ccc1Cl
Reactant: CN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CN1CCN(c2ccc(S(=O)(=O)Nc3cccc(Cl)c3)cc2[N+](=O)[O-])CC1
Yield: 78.6 %

Procedure:
A mixture of 4-chloro-3-nitrobenzenesulfonylchloride (1 g, 3.9 mmol), 3-chloroaniline (0.5 mL, 4.7 mmol) and pyridine (1.6 mL) in CH2Cl2 (2 mL) was stirred at room temperature. The reaction was quenched with NaHCO3 (sat aq solution, 30 mL×3). The organic phase was separated, dried (MgSO4), and filtered. The volatiles were evaporated and the residue was purified by column chromatography (SiO2, pentane:EtOAc, 4:1) to give 4-chloro-N-(3-chlorophenyl)-3-nitrobenzenesulfonamide; MS (posESI) m/z=349.2 (M+H+). 1H NMR (CDCl3) δ 7.00-7.40 (m, 3H), 7.60-7.90 (m, 3H), 8.70 (bs, 1H). 4-Chloro-N-(3-chlorophenyl)-3-nitrobenzenesulfonamide (0.45 g, 1.3 mmol), N-methylpiperazine (0.191 mL, 1.73 mmol) and K2CO3 (359 mg, 2.6 mmol) in CH3CN (2.5 mL) as the filtrated was concentrated to give a residue which was purified by column (SiO2, CHCl3:MeOH: NH3 9:1:0.4%) to give 420 mg of N-(3-chlorophenyl)-4-(4-methyl-1-piperazinyl)-3-nitrobenzenesulfonamide (85%). Purity >95% according to HPLC analysis. The compound was dissolved in THF (1 mL) and ethanol (5 mL) was added. The solution was treated with Raney-Ni (50 mg) and hydrazine monohydrate (0.05 mL) overnight. The Raney-Ni was filtered (celite pad), the volatiles were evaporated and the residue was purified by column chromatography (SiO2, CHCl3:MeOH: NH3 9:1:0.4%). The product was isolated as hydrochloride salt by treatment with HCl gas in diethyl ether to yield 170 mg of final product (32%).
Reaction SMILES: [F:1][CH:2]([F:34])[O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[N:12]=[N:13][C:14]([CH2:17][CH2:18][C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[N:24](C3CCCCO3)[N:23]=[CH:22]4)=[CH:15][CH:16]=2)=[CH:6][CH:5]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:24]1[C:25]2[C:21](=[CH:20][C:19]([CH2:18][CH2:17][C:14]3[N:13]=[N:12][C:11]([NH:10][C:7]4[CH:8]=[CH:9][C:4]([O:3][CH:2]([F:34])[F:1])=[CH:5][CH:6]=4)=[CH:16][CH:15]=3)=[CH:27][CH:26]=2)[CH:22]=[N:23]1
Reactant: FC(F)Oc1ccc(Nc2ccc(CCc3ccc4c(cnn4C4CCCCO4)c3)nn2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: FC(F)Oc1ccc(Nc2ccc(CCc3ccc4[nH]ncc4c3)nn2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of N-(4-(difluoromethoxy)phenyl)-6-(2-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)ethyl)pyridazin-3-amine (0.12 g, 0.258 mmol) in DCM (10 mL) was added TFA (1 mL, 12.98 mmol) and the reaction mixture was stirred at room temperature for 3 h. The reaction mixture was concentrated and washed with diethyl ether. The crude product was purified by preparative LCMS on a Waters Xbridge C18 column (19×150 mm, 5 μm) using 0-100% mobile phase B (95:5 Methanol:water with 10 mM NH4OAc) in mobile phase A (5:95 Methanol:water with 10 mM NH4OAc) to give 6-(2-(1H-indazol-5-yl)ethyl)-N-(4-(difluoromethoxy)phenyl)pyridazin-3-amine. 1H-NMR (300 MHz, DMSO-d6) δ ppm 3.07-3.14 (m, 4H) 6.28 (s, 1H) 7.00-7.37 (m, 6H) 7.46 (s, 1H) 7.56 (s, 1H) 7.78 (s, 3H) 7.97 (s, 1H) 9.19 (s, 1H) 12.93 (br. s., 1H).
Reaction SMILES: [C:1]1([S:7]([NH:10][C@@H:11]([CH2:19][CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30][CH2:31][C:32]3[N:33]=[CH:34][N:35]([CH3:37])[CH:36]=3)=[CH:24][CH:23]=2)[C:12]([O:14]C(C)(C)C)=[O:13])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl>CCOC(C)=O>[C:1]1([S:7]([NH:10][C@@H:11]([CH2:19][CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30][CH2:31][C:32]3[N:33]=[CH:34][N:35]([CH3:37])[CH:36]=3)=[CH:24][CH:23]=2)[C:12]([OH:14])=[O:13])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cn1cnc(CCCOc2ccc(CCC[C@H](NS(=O)(=O)c3ccccc3)C(=O)OC(C)(C)C)cc2)c1
Agent: Cl
Solvent: CCOC(C)=O
Product: Cn1cnc(CCCOc2ccc(CCC[C@H](NS(=O)(=O)c3ccccc3)C(=O)O)cc2)c1
Temperature: 0 °C

Procedure:
A solution of 35-9 (0.055 g, 0.127 mmol) in EtOAc (1 mL) was cooled to -78° C., and saturated with HCl gas. The reaction was warmed to 0° C. for 1/2 hr, then concentrated and the residue chromatographed (20:1:1 EtOH/NH4OH/H2O) to give 35-10 as a white solid.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[O:7][N:6]=[C:5]([CH2:8][CH3:9])[N:4]=1.CO[CH:12](OC)[N:13]([CH3:15])[CH3:14]>>[CH3:12][N:13]([CH3:15])[CH:14]=[N:1][C:2]([C:3]1[O:7][N:6]=[C:5]([CH2:8][CH3:9])[N:4]=1)=[CH:12][N:13]([CH3:15])[CH3:14]
Reactant: COC(OC)N(C)C
Reactant: CCc1noc(CN)n1
Product: CCc1noc(C(=CN(C)C)N=CN(C)C)n1
Temperature: 80 °C
Yield: 72 %

Procedure:
A mixture of 11.5 g of 5-aminomethyl-3-ethyl-1,2,4-oxadiazole and 24 ml of dimethylformamide dimethylacetal is heated to 80° C. for 7 hours; during this process, 10 ml of thus-formed methanol is removed by distillation. After adding another 12 ml of DMF-acetal, the mixture is refluxed for 3 hours, then subjected to fractional distillation. The fraction passing over at 155°-160° C. and 0.03 torr, 1,4-bis(di- methylamino)-3-(3-ethyl-1,2,4-oxadiazol-5-yl)-2-aza1,3-butadiene is obtained in a yield of 72% of theory; nD20 1.5908.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]1[CH:6]=[C:7]([CH:44]=[CH:45][CH:46]=1)[CH2:8][N:9]1[C:13]2=[N:14][CH:15]=[N:16][C:17]([N:18]3[CH2:23][CH2:22][N:21]([C:24](=[O:43])[C:25]4[CH:30]=[CH:29][C:28]([N:31]([C:37](=[O:42])[CH2:38][CH2:39][NH:40][CH3:41])[CH2:32][CH2:33][N:34]([CH3:36])[CH3:35])=[CH:27][CH:26]=4)[CH2:20][CH2:19]3)=[C:12]2[CH:11]=[N:10]1)[CH3:3].[Cl:47][C:48]([O:50][CH2:51][CH3:52])=[O:49].C(N(CC)CC)C>C(Cl)Cl.C(=O)([O-])O.[Na+]>[ClH:47].[CH2:2]([O:4][C:5]1[CH:6]=[C:7]([CH:44]=[CH:45][CH:46]=1)[CH2:8][N:9]1[C:13]2=[N:14][CH:15]=[N:16][C:17]([N:18]3[CH2:23][CH2:22][N:21]([C:24](=[O:43])[C:25]4[CH:26]=[CH:27][C:28]([N:31]([C:37](=[O:42])[CH2:38][CH2:39][N:40]([CH3:41])[C:48]([O:50][CH2:51][CH3:52])=[O:49])[CH2:32][CH2:33][N:34]([CH3:36])[CH3:35])=[CH:29][CH:30]=4)[CH2:20][CH2:19]3)=[C:12]2[CH:11]=[N:10]1)[CH3:3]
Reactant: CCOc1cccc(Cn2ncc3c(N4CCN(C(=O)c5ccc(N(CCN(C)C)C(=O)CCNC)cc5)CC4)ncnc32)c1
Reactant: CCOC(=O)Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)N(C)CCC(=O)N(CCN(C)C)c1ccc(C(=O)N2CCN(c3ncnc4c3cnn4Cc3cccc(OCC)c3)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 30 %

Procedure:
To a solution of the compound obtained in Example 725 (50 mg) in methylene chloride (3 mL) is added ethyl chloroformate (10 μL) and triethylamine (22 μL) and the mixture is stirred at room temperature overnight. The reaction mixture is diluted with a saturated sodium hydrogencarbonate solution and the mixture is extracted with chloroform. The organic layer is evaporated to remove solvent and the residue is purified by column chromatography on silica gel (solvent; chloroform/methanol=10:1), and the resultant product is treated in the same manner as described in Example 4 (3) to give 1-(3-ethoxybenzyl)-4-[4-[4-[N-[3-[N-methyl-N-(ethoxycarbonyl)amino]-propionyl)-N-[2-(dimethylamino)ethyl]amino]benzoyl]piperazin-1-yl]-1H-pyrazolo-[3,4-d]pyrimidine hydrochloride (17 mg, yield; 30%) as an amorphous powder. MS (APCI) m/z: 686 [M+H]+
Reaction SMILES: [CH2:1]([O:4][C:5]1([CH3:36])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[N:17]=[C:18]([CH2:20][N:21]=[N+:22]=[N-:23])[CH:19]=[C:15]3[N:14]=[C:13]([CH3:24])[C:12]=2[C@H:25]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:7][CH2:6]1)[CH:2]=[CH2:3].[CH2:37]([O:40][C:41]1([C:47]#[CH:48])[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]1)[CH:38]=[CH2:39].O=C1O[C@H]([C@H](CO)O)C([O-])=C1O.[Na+]>CO>[CH2:1]([O:4][C:5]1([CH3:36])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[N:17]=[C:18]([CH2:20][N:21]4[CH:48]=[C:47]([C:41]5([O:40][CH2:37][CH:38]=[CH2:39])[CH2:42][CH2:43][CH2:44][CH2:45][CH2:46]5)[N:23]=[N:22]4)[CH:19]=[C:15]3[N:14]=[C:13]([CH3:24])[C:12]=2[C@H:25]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:7][CH2:6]1)[CH:2]=[CH2:3]
Reactant: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OCC)c(C)nc3cc(CN=[N+]=[N-])nn23)CC1
Reactant: C#CC1(OCC=C)CCCCC1
Agent: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Agent: [Na+]
Solvent: CO
Product: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OCC)c(C)nc3cc(Cn4cc(C5(OCC=C)CCCCC5)nn4)nn23)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 35.8 %

Procedure:
A mixture of (S)-ethyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(azidomethyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (0.06 g, 0.120 mmol), 1-(allyloxy)-1-ethynylcyclohexane (0.039 g, 0.240 mmol), Cu(II)SO4.5H2O (3.00 mg, 0.012 mmol) and (+)-sodium L-ascorbate (0.024 g, 0.120 mmol) in MeOH (2 mL) was stirred for 16 h at rt. Then, purified by prep-HPLC to afford (S)-ethyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-((4-(1-(allyloxy)cyclohexyl)-1H-1,2,3-triazol-1-yl)methyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (0.0287 g, 0.043 mmol, 36.0% yield) as pale yellow paste. 1H NMR (500 MHz, CDCl3) δ 7.56 (s, 1H), 6.41 (s, 1H), 5.99-6.08 (m, 1H), 5.90 (br. s., 1H), 5.82 (tdd, J=5.3, 10.5, 17.2 Hz, 1H), 5.73 (s, 2H), 5.47 (d, J=16.4 Hz, 1H), 5.17-5.23 (m, 2H), 5.01-5.06 (m, 1H), 4.12-4.28 (m, 2H), 4.00-4.03 (m, 2H), 3.74 (td, J=1.5, 5.4 Hz, 2H), 2.61 (s, 3H), 1.90-2.06 (m, 6H), 1.67-1.75 (m, 4H), 1.54-1.61 (m, 1H), 1.44-1.52 (m, 2H), 1.35 (s, 3H), 1.23-1.25 (m, 12H). LCMS (M+H)=664.7.
Reaction SMILES: Cl.[Cl:2]C1C(Cl)=C(C)NC=1C(NC1CCNCC1)=O.[Br:19][C:20]1[CH:21]=[C:22]([C:26]([NH:28][CH:29]2[CH2:34][CH2:33][N:32](C(OC(C)(C)C)=O)[CH2:31][CH2:30]2)=[O:27])[NH:23][C:24]=1[CH3:25]>>[ClH:2].[Br:19][C:20]1[CH:21]=[C:22]([C:26]([NH:28][CH:29]2[CH2:30][CH2:31][NH:32][CH2:33][CH2:34]2)=[O:27])[NH:23][C:24]=1[CH3:25]
Reactant: Cc1[nH]c(C(=O)NC2CCNCC2)c(Cl)c1Cl
Reactant: Cc1[nH]c(C(=O)NC2CCN(C(=O)OC(C)(C)C)CC2)cc1Br
Agent: Cl
Product: Cc1[nH]c(C(=O)NC2CCNCC2)cc1Br

Procedure:
Title compound was synthesized by an analogous method to Intermediate 1, starting from tert-butyl 4-{[(4-bromo-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}piperidine-1-carboxylate (Intermediate 52).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([C:16](=[O:22])[CH2:17]C(OC)=O)[CH:8]=[C:9]([N:11]2[CH:15]=[CH:14][CH:13]=[CH:12]2)[CH:10]=1)=[O:4].CO.S(=O)(=O)(O)O.C(OCC)(=O)C>O>[C:16]([C:7]1[CH:6]=[C:5]([CH:10]=[C:9]([N:11]2[CH:15]=[CH:14][CH:13]=[CH:12]2)[CH:8]=1)[C:3]([O:2][CH3:1])=[O:4])(=[O:22])[CH3:17]
Reactant: COC(=O)CC(=O)c1cc(C(=O)OC)cc(-n2cccc2)c1
Agent: O=S(=O)(O)O
Solvent: CO
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(C(C)=O)cc(-n2cccc2)c1
Temperature: 25 °C
Yield: 24.9 %

Procedure:
A solution of methyl 3-[3-methoxycarbonyl-5-(pyrrol-1-yl)phenyl]-3-oxopropionate (0.1 g) in a mixture of water (1 ml), methanol (3 ml) and concentrated sulfuric acid (40 mg) was refluxed for 16 hours. After being cooled to room temperature, the reaction mixture was poured into a mixture of ethyl acetate (50 ml) and water (50 ml). The organic layer was successively washed with a saturated aqueous sodium hydrogencarbonate solution and brine, dried over magnesium sulfate and evaporated in vacuo to afford methyl 3-acetyl-5-(pyrrol-1-yl)benzoate (20.1 mg).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[C:5]1[CH:17]=[C:16]([CH:18]([OH:23])[C:19]([F:22])([F:21])[F:20])[CH:15]=[C:7]([C:8]([N:10]([CH3:14])[CH2:11][CH2:12][CH3:13])=[O:9])[CH:6]=1)[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl>[CH2:1]([O:3][C:4](=[O:24])[C:5]1[CH:17]=[C:16]([C:18](=[O:23])[C:19]([F:22])([F:21])[F:20])[CH:15]=[C:7]([C:8]([N:10]([CH3:14])[CH2:11][CH2:12][CH3:13])=[O:9])[CH:6]=1)[CH3:2]
Reactant: CCCN(C)C(=O)c1cc(C(=O)OCC)cc(C(O)C(F)(F)F)c1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CCCN(C)C(=O)c1cc(C(=O)OCC)cc(C(=O)C(F)(F)F)c1
Yield: 53.1 %

Procedure:
Treat a solution of N-methyl-N-propyl-5-(2,2,2-trifluoro-1-hydroxyethyl)-isophthalamic acid ethyl ester (1.8 mmol) in dichloromethane (20 mL) with Dess-Martin reagent at room temperature for 2 h. Quench with 10% aqueous sodium sulfite and extract with ethyl acetate (100 mL). Wash the organic layer with 10% aqueous sodium sulfite, saturated aqueous sodium chloride, dry (magnesium sulfate), concentrate and purify (silica gel chromatography, eluting with 60:40 ethyl acetate:hexanes) to give the title compound (330 mg) which is contaminated with recovered N-methyl-N-propyl-5-(2,2,2-trifluoro-1-hydroxyethyl)-isophthalamic acid ethyl ester in a ratio of about 4:1).
Reaction SMILES: C([O:8][C:9](=[O:22])[C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)=[CH:12][CH:11]=1)C1C=CC=CC=1.Cl[C:24]1[CH:40]=[CH:39][C:27]([C:28]([NH:30][C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([O:37][CH3:38])[CH:32]=2)=[O:29])=[CH:26][N:25]=1.C1(NC(C2C=CC(N3CCN(C4C=CC(C(O)=O)=CC=4)CC3)=NC=2)=O)C=CC=CC=1>>[CH3:38][O:37][C:33]1[CH:32]=[C:31]([NH:30][C:28]([C:27]2[CH:39]=[CH:40][C:24]([N:19]3[CH2:18][CH2:17][N:16]([C:13]4[CH:12]=[CH:11][C:10]([C:9]([OH:8])=[O:22])=[CH:15][CH:14]=4)[CH2:21][CH2:20]3)=[N:25][CH:26]=2)=[O:29])[CH:36]=[CH:35][CH:34]=1
Reactant: O=C(OCc1ccccc1)c1ccc(N2CCNCC2)cc1
Reactant: COc1cccc(NC(=O)c2ccc(Cl)nc2)c1
Agent: O=C(O)c1ccc(N2CCN(c3ccc(C(=O)Nc4ccccc4)cn3)CC2)cc1
Product: COc1cccc(NC(=O)c2ccc(N3CCN(c4ccc(C(=O)O)cc4)CC3)nc2)c1

Procedure:
4-{4-[5-(3-Methoxy-phenylcarbamoyl)-pyridin-2-yl]-piperazin-1-yl}-benzoic acid was prepared from 4-piperazin-1-yl-benzoic acid benzyl ester and 6-chloro-N-(3-methoxy-phenyl)-nicotinamide with a method similar to the one described in the synthesis of 4-[4-(5-phenylcarbamoyl-pyridin-2-yl)-piperazin-1-yl]-benzoic acid above. HRMS m/z calcd for C24H24N4O4 [M+H]+: 433.1871. Found: 433.1868.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:9]([CH2:10]O)=[C:8]([C:12]([F:15])([F:14])[F:13])[N:7]=[CH:6][N:5]=1)[CH3:2].P(Br)(Br)[Br:17].CO.O>C(OCC)C>[Br:17][CH2:10][C:9]1[C:4]([O:3][CH2:1][CH3:2])=[N:5][CH:6]=[N:7][C:8]=1[C:12]([F:15])([F:14])[F:13]
Reactant: BrP(Br)Br
Reactant: CCOc1ncnc(C(F)(F)F)c1CO
Solvent: O
Solvent: CO
Solvent: CCOCC
Product: CCOc1ncnc(C(F)(F)F)c1CBr
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 3.77 g (17.0 mmoles) of (4-ethoxy-6-trifluoromethylpyrimidin-5-yl)-methanol dissolved in 50 ml of diethyl ether was cooled to 0° C. Thereto was added 2.0 g (7.2 mmoles) of phosphorus tribromide. The mixture was stirred at room temperature for 1 hour. The resulting salt was dissolved using methanol. The resulting mixture was stirred for 1 hour to give rise to a reaction. The reaction mixture was poured into water, followed by extraction with diethyl ether. The resulting organic layer was washed with an aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein, to obtain crude 5-bromomethyl-4-ethoxy-6-trifluoromethylpyrimidine.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:21]3[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=3)[C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][C:10]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:9][CH:8]=3.[CH3:28][O:29][C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1.C1(C)C=CC=CC=1>C(O)C>[C:15]1([C:10]2[CH:9]=[CH:8][C:7]3[N:6]([C:21]4[CH:22]=[CH:23][C:24]([CH3:27])=[CH:25][CH:26]=4)[C:5]4[C:13]([C:12]=3[CH:11]=2)=[CH:14][C:2]([C:33]2[CH:34]=[CH:35][C:30]([O:29][CH3:28])=[CH:31][CH:32]=2)=[CH:3][CH:4]=4)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: Cc1ccc(-n2c3ccc(Br)cc3c3cc(-c4ccccc4)ccc32)cc1
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1ccc(-c2ccc3c(c2)c2cc(-c4ccccc4)ccc2n3-c2ccc(C)cc2)cc1
Yield: 67.4 %

Procedure:
The 3-bromo-6-phenyl-N-(4-methylphenyl)carbazole (3.20 g) and 4-methoxyphenylboronic acid (1.65 g) were added to a solvent mixture of toluene (30 mL) and ethanol (8 mL), followed by bubbling with nitrogen. Then, tetrakistriphenylphosphine palladium (150 mg) and 21.2% aqueous sodium carbonate solution (7.80 g) were added to the mixture, and the resultant mixture was refluxed under nitrogen flow for 3 hours. The mixture was diluted with toluene. The toluene layer was washed with water and dried and the toluene was evaporated. The residue was treated through silica gel column chromatography (eluent: toluene), to thereby obtain 2.30 g of 3-phenyl-6-(4-methoxyphenyl)-N-(4-methylphenyl)carbazole as colorless powder.