Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC1C=CC(C[O:8][C:9]2[C:10]([C:18]3[CH:23]=[CH:22][C:21]([N:24]4[CH2:29][CH2:28][CH2:27][CH2:26][C:25]4=[O:30])=[CH:20][CH:19]=3)=[N:11][N:12]([CH3:17])[C:13]=2[C:14](O)=O)=CC=1.[NH2:33][C:34]1[CH:35]=[C:36]([CH:39]=[CH:40][C:41]=1[NH2:42])[C:37]#[N:38].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C)C=O.C(OCC)(=O)C>[OH:8][C:9]1[C:10]([C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH2:29][CH2:28][CH2:27][CH2:26][C:25]3=[O:30])=[CH:20][CH:19]=2)=[N:11][N:12]([CH3:17])[C:13]=1[C:14]1[NH:42][C:41]2[CH:40]=[CH:39][C:36]([C:37]#[N:38])=[CH:35][C:34]=2[N:33]=1
Reactant: N#Cc1ccc(N)c(N)c1
Reactant: COc1ccc(COc2c(-c3ccc(N4CCCCC4=O)cc3)nn(C)c2C(=O)O)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cn1nc(-c2ccc(N3CCCCC3=O)cc2)c(O)c1-c1nc2cc(C#N)ccc2[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-(4-methoxybenzyloxy)-1-methyl-3-(4-(2-oxopiperidin-1-yl)phenyl)-1H-pyrazole-5-carboxylic acid T-22 (180 mg, 0.42 mmol) in N,N-dimethylformamide (4 mL) were added 3,4-diaminobenzonitrile (66 mg, 0.5 mmol), HATU (204 mg, 0.54 mmol) and diisopropylethylamine (0.22 mL, 1.3 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate. The organic layer was washed with water and saturated brine. The organic layer was dried over sodium sulfate. Solvent was evaporated under reduced pressure. The residue was purified by flash chromatography. To the purified fraction (155 mg, 0.28 mmol) was added acetic acid (4 mL). The reaction mixture was heated in a microwave reactor at 150° C. for 55 minutes. Solvent was evaporated under reduced pressure. To the residue was added trifluoroacetic acid (4 mL). The reaction mixture was heated in a microwave reactor at 120° C. for 30 minutes. Solvent was evaporated under reduced pressure. The crude product was purified by flash chromatography to afford the desired 2-(4-hydroxy-1-methyl-3-(4-(2-oxopiperidin-1-yl)phenyl)-1H-pyrazol-5-yl)-1H-benzo[d]imidazole-5-carbonitrile T-23 (110 mg, 0.27 mmol).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11](O)[CH3:12].P(Br)(Br)[Br:15]>C1(C)C=CC=CC=1>[Br:15][CH:11]([C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1)[CH3:12]
Reactant: BrP(Br)Br
Reactant: CC(O)c1ccc2ccccc2c1
Solvent: Cc1ccccc1
Product: CC(Br)c1ccc2ccccc2c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
1-(Naphthalen-2-yl)ethanol (2.0 g, 11.6 mmol) was dissolved in toluene (30 mL). The solution was cooled to 0° C. PBr3 (1.09 mL, 11.6 mmol) was added dropwise over 15 min. The reaction mixture was then brought up to room temperature and stirred for 1 h. The mixture was washed with K2CO3 solution and extracted with EtOAc (3×30 mL). The EtOAc layer was washed with brine and dried (MgSO4). The solvent was evaporated off in-vacuo to give crude 2-(1-bromoethyl)naphthalene. This intermediate was used in the following step.
Reaction SMILES: [CH3:1][N:2]1[CH2:8][CH2:7][CH:6]([OH:9])[C:5]2[CH:10]=[CH:11][O:12][C:4]=2[CH2:3]1.[Br:13][C:14]1[CH:15]=[C:16](F)[CH:17]=[CH:18][C:19]=1[Br:20]>>[Br:13][C:14]1[CH:15]=[C:16]([O:9][CH:6]2[CH2:7][CH2:8][N:2]([CH3:1])[CH2:3][C:4]3[O:12][CH:11]=[CH:10][C:5]2=3)[CH:17]=[CH:18][C:19]=1[Br:20]
Reactant: CN1CCC(O)c2ccoc2C1
Reactant: Fc1ccc(Br)c(Br)c1
Product: CN1CCC(Oc2ccc(Br)c(Br)c2)c2ccoc2C1

Procedure:
The same method as in Example 1 was conducted using 7-methyl-5,6,7,8-tetrahydro-4H-furo[2,3-c]azepin-4-ol (Reference Example 19) instead of 6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (Reference Example 6) and was conducted using 3,4-dibromo-1-fluorobenzene instead of 1-fluoronaphthalene to give the objective compound.
Reaction SMILES: FC(F)(F)S([O-])(=O)=O.[Dy+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O.[C:26]1([O:32][CH3:33])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[CH2:34]([CH:36]([CH2:40][CH3:41])[C:37](O)=[O:38])[CH3:35].O>C1(C)C=CC=CC=1>[CH3:33][O:32][C:26]1[CH:31]=[CH:30][C:29]([C:37](=[O:38])[CH:36]([CH2:40][CH3:41])[CH2:34][CH3:35])=[CH:28][CH:27]=1
Reactant: CCC(CC)C(=O)O
Reactant: COc1ccccc1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Dy+3]
Solvent: O
Solvent: Cc1ccccc1
Product: CCC(CC)C(=O)c1ccc(OC)cc1
Reaction time: 48 h
Yield: 43.7 %

Procedure:
Dysprosium (III) trifluoromethanesulfonate (3.66 g as a wet solid), anisole (1.08 g) and 2-ethylbutanoic acid (1.16 g) were refluxed together in 125 mL toluene with azeotropic removal of the lower water layer (Dean-Stark apparatus). After 48 hours, the mixture was cooled and extracted with 3×25 mL water, then by 2×25 mL saturated sodium bicarbonate solution. The organic layer was dried using anhydrous sodium sulfate, filtered, then concentrated down in vacuo to give para-methoxy-2-ethylbutyrophenone (0.90 g, 44% yield) as an amber-colored oil, which was practically pure by 1H NMR analysis. Removal of water from the three water extracts recovered 3.54 g as a damp, off-white solid.
Reaction SMILES: [C:1]([O:5][SiH:6]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9])([CH3:4])([CH3:3])[CH3:2].[CH2:17]=[CH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C1C2NC3C(=CC=CC=3)SC=2C=CC=1>C1(C)C(C)=CC=CC=1>[C:8]([O:7][Si:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH:17]=[CH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([CH3:11])([CH3:10])[CH3:9]
Reactant: CC(C)(C)O[SiH](OC(C)(C)C)OC(C)(C)C
Reactant: C=Cc1ccccc1
Agent: c1ccc2c(c1)Nc1ccccc1S2
Solvent: Cc1ccccc1C
Product: CC(C)(C)O[Si](C=Cc1ccccc1)(OC(C)(C)C)OC(C)(C)C
Temperature: 175 °C
Yield: 90 %

Procedure:
Into a 45 cc Parr bomb was added 2.5 g (0.02 mol) tritertbutoxysilane, 4.2 g (0.04 mol) styrene, 1.0 g xylene, 30 mg phenothiazine and 2000 ppm Ru3CO12 (20 mg). The reaction was heated in a fluidized sand bath at 175° C. for 5 hours. A single product 1-tritertbutoxysilyl-2-phenylethylene was formed in greater than 90% yield.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[CH2:14][C@H:13]3[C@H:11]([CH2:12]3)[C@H:10]2[CH2:15][NH2:16])=[O:8])[N:6]=1.[Cl:24][C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=1)[C:28](O)=[O:29]>>[NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[CH2:14][C@H:13]3[C@H:11]([CH2:12]3)[C@H:10]2[CH2:15][NH:16][C:28](=[O:29])[C:27]2[CH:31]=[CH:32][CH:33]=[C:25]([Cl:24])[CH:26]=2)=[O:8])[N:6]=1
Reactant: NC[C@@H]1[C@H]2C[C@H]2CN1C(=O)c1nc(N)sc1-c1cccc(F)c1
Reactant: O=C(O)c1cccc(Cl)c1
Product: Nc1nc(C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2cccc(Cl)c2)c(-c2cccc(F)c2)s1

Procedure:
prepared by reaction of [2-Amino-5-(3-fluoro-phenyl)-thiazol-4-yl]-((1S,2S,5R)-2-aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-methanone with 3-Chloro-benzoic acid.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:3]=1[O:4][CH2:5][CH2:6]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:33].N#N>C(Cl)Cl.CCOC(C)=O>[Br:33][CH2:6][CH2:5][O:4][C:3]1[CH:8]=[CH:9][C:10]([F:12])=[CH:11][C:2]=1[F:1]
Reactant: BrC(Br)(Br)Br
Reactant: OCCOc1ccc(F)cc1F
Agent: N#N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Fc1ccc(OCCBr)c(F)c1
Reaction time: 0.5 h

Procedure:
To a cool solution 2-(2,4-difluoro-phenoxy)-ethanol (0.48 g, 2.77 mmol.) in CH2Cl2 (15 ml), triphenyl phosphine (1.3 g, 5 mmol)) was added. Carbon tetrabromide (1.65 g, 5 mmol.) in CH2Cl2 (3 ml) was added to the solution dropwise under N2. The solution was stirred for 30 minutes. EtOAc was added, then the solvent was evaporated under reduced pressure.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1)=[O:2].Cl[C:13]1[N:18]=[CH:17][C:16]([Cl:19])=[CH:15][N:14]=1>C1(C)C=CC=CC=1.C(O)C>[Cl:19][C:16]1[CH:15]=[N:14][C:13]([C:6]2[CH:7]=[CH:8][C:3]([CH:1]=[O:2])=[CH:4][CH:5]=2)=[N:18][CH:17]=1
Reactant: O=Cc1ccc(B(O)O)cc1
Reactant: Clc1cnc(Cl)nc1
Solvent: CCO
Solvent: Cc1ccccc1
Product: O=Cc1ccc(-c2ncc(Cl)cn2)cc1
Temperature: 60 °C
Reaction time: 1.5 h

Procedure:
Palladium dichloro-bis(triphenylphosphine) (3.5 g) was added to a stirred solution of 4-formylbenzene boronic acid (32.5 g), 2,5-dichloro-pyrimidine (30 g) in toluene (1000 ml) and ethanol (100 ml) under an argon atmosphere. The solution was purged with argon and aqueous sodium carbonate (2N) (200 ml) was added. The reaction mixture was stirred at 60° C. for 90 minutes, cooled to ambient temperature, diluted with ethyl acetate, and washed successively with aqueous sodium hydrogen carbonate (saturated), water and brine. The combined organic extracts were treated with charcoal, dried over sodium sulfate, filtered through Hyflo® and concentrated in vacuo. The residue was triturated with diethyl ether (100 ml), the solid isolated by filtration and dried under high vacuum to give 4-(5-chloro-pyrimidin-2-yl)-benzaldehyde as a white solid. M.p. 186° C. 1H NMR (400 MHz, DMSO) 8.10 (d, 2H), 8.55 (d, 2H), 9.1 (s, 2H).
Reaction SMILES: C(OC([N:11]1[C@H:23]([CH2:24][C:25]([OH:27])=[O:26])[CH2:22][C:21]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:14][C:13]=2[CH2:12]1)=O)C1C=CC=CC=1.[ClH:28]>C(O)C.[H][H].[Pd]>[ClH:28].[CH2:12]1[C:13]2[NH:14][C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:21]=2[CH2:22][C@@H:23]([CH2:24][C:25]([OH:27])=[O:26])[NH:11]1
Reactant: [H][H]
Reactant: O=C(O)C[C@@H]1Cc2c([nH]c3ccccc23)CN1C(=O)OCc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: O=C(O)C[C@@H]1Cc2c([nH]c3ccccc23)CN1
Yield: 72 %

Procedure:
0.55 g of (3S)-2-benzyloxycarbonyl-1,2,3,4-tetrahydro-β-carboline-3-acetic acid is dissolved in 12 ml of 80% aqueous ethanol. 0.5 g of 10% Pd-C and 3 ml of 10% HCl are added to the solution. The mixture is subjected to catalytic reduction in hydrogen gas under atmospheric pressure at room temperature. The catalyst is filtered off, and washed with ethanol. The filtrate and the washings are combined, and evaporated to remove the solvent. The residue is recrystallized from ethyl acetate. 290 mg of (3S)-1,2,3,4-tetrahydro-β-carboline-3-acetic acid hydrochloride are obtained as pale yellow needles. Yield: 72%
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH2:12](Br)[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.CC[O-].[Na+].[Na]>C(O)C>[CH2:12]([CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:1]([O:9][CH2:10][CH3:11])=[O:8])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: BrCCc1ccccc1
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(CCc1ccccc1)C(=O)OCC

Procedure:
45 g of diethyl malonate and 30 g of phenethyl bromide were mixed and added dropwise, cooling in ice, to a solution of sodium ethylate prepared from 6.5 g of sodium and 130 ml of absolute ethanol. The mixture was then boiled under reflux for 6 hours and allowed to cool down overnight. The major part of the ethanol was removed in vacuo, the residue was taken up in water, extracted with ether, this was dried over Na2SO4, evaporated and distilled.
Reaction SMILES: C(N)=O.[NH2:4][CH2:5][CH2:6][C:7]1[CH:31]=[CH:30][C:10]([NH:11][CH:12]2[CH2:17][CH2:16][N:15]([C:18]([NH:20][CH2:21][C:22]3[CH:27]=[C:26]([F:28])[CH:25]=[C:24]([F:29])[CH:23]=3)=[O:19])[CH2:14][CH2:13]2)=[CH:9][CH:8]=1.C([Si]([O:49][C:50]1[CH:55]=[CH:54][C:53]([O:56][CH2:57][CH:58]2[CH2:60][O:59]2)=[CH:52][CH:51]=1)(C1C=CC=CC=1)C1C=CC=CC=1)(C)(C)C>C(Cl)(Cl)Cl.CO>[F:29][C:24]1[CH:23]=[C:22]([CH:27]=[C:26]([F:28])[CH:25]=1)[CH2:21][NH:20][C:18]([N:15]1[CH2:16][CH2:17][CH:12]([NH:11][C:10]2[CH:9]=[CH:8][C:7]([CH2:6][CH2:5][NH:4][CH2:60][C@H:58]([OH:59])[CH2:57][O:56][C:53]3[CH:54]=[CH:55][C:50]([OH:49])=[CH:51][CH:52]=3)=[CH:31][CH:30]=2)[CH2:13][CH2:14]1)=[O:19]
Reactant: CC(C)(C)[Si](Oc1ccc(OCC2CO2)cc1)(c1ccccc1)c1ccccc1
Reactant: NCCc1ccc(NC2CCN(C(=O)NCc3cc(F)cc(F)c3)CC2)cc1
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: NC=O
Product: O=C(NCc1cc(F)cc(F)c1)N1CCC(Nc2ccc(CCNC[C@H](O)COc3ccc(O)cc3)cc2)CC1
Yield: 29.4 %

Procedure:
4-[4-(2-Aminoethyl)anilino]-N-(3,5-difluorobenzyl)-1-piperidinecarboxamide formamide (0.33 g, 0.76 mmol) was reacted with tert-butyl-(4-oxiranylmethoxy-phenoxy)-diphenyl-silane (0.276 g, 0.68 mmol) according to Procedure G (eluant: 20:1 chloroform-methanol) to give the title compound (0.165 g, 0.20 mmol).
Reaction SMILES: [NH2:1][CH:2]([C:7]([F:10])([F:9])[F:8])[CH2:3][C:4]([OH:6])=[O:5].[ClH:11].[CH3:12]O>>[ClH:11].[NH2:1][CH:2]([C:7]([F:10])([F:9])[F:8])[CH2:3][C:4]([O:6][CH3:12])=[O:5]
Reactant: NC(CC(=O)O)C(F)(F)F
Reactant: CO
Agent: Cl
Product: COC(=O)CC(N)C(F)(F)F

Procedure:
1.5 g of 3-amino-4,4,4-trifluorobutanoic acid (9.55 mmol, 1 equivalent) were initially charged in 18 ml of methanol which had been saturated with hydrogen chloride, and the mixture was stirred under reflux for 4 h. The reaction solution was then concentrated, evaporated repeatedly with dichloromethane and dried under reduced pressure. This gave 1.86 g (94% of theory) of the title compound.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:11]2[CH:16]=[CH:15][C:14]([S:17][CH3:18])=[CH:13][CH:12]=2)[OH:10])=[CH:5][CH:4]=1>C(Cl)Cl.O=[Mn]=O>[CH3:18][S:17][C:14]1[CH:13]=[CH:12][C:11]([C:9]([C:6]2[CH:7]=[CH:8][C:3]([S:2][CH3:1])=[CH:4][CH:5]=2)=[O:10])=[CH:16][CH:15]=1
Reactant: CSc1ccc(C(O)c2ccc(SC)cc2)cc1
Agent: O=[Mn]=O
Solvent: ClCCl
Product: CSc1ccc(C(=O)c2ccc(SC)cc2)cc1

Procedure:
A solution of bis-(4-methylsulfanyl-phenyl)-methanol from Step 1 (1.0 g, 3.6 mmol) and MnO2 (3 g, 35 mmol) in CH2Cl2 (30 mL) was stirred at 21° C. for 18 h. The resulting mixture was filtered through a pad of celite and concentrated. Purification by flash chromatography (eluting with hexane/ethyl acetate, 85:15) provided the bis-(4-methylsulfanyl-phenyl)-methanone compound.
Reaction SMILES: [Si]([O:8][CH:9]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:10][NH:11][CH:12]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[CH:14]=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.C(OCC)(=O)C>[CH3:29][O:28][C:25]1[CH:24]=[CH:23][C:22]([CH:12]([NH:11][CH2:10][CH:9]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[OH:8])[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[CH:14]=2)=[CH:27][CH:26]=1
Reactant: COc1ccc(C(NCC(O[Si](C)(C)C(C)(C)C)c2ccccc2)c2cccc([N+](=O)[O-])c2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc(C(NCC(O)c2ccccc2)c2cccc([N+](=O)[O-])c2)cc1
Yield: 85.7 %

Procedure:
A mixture of N-[2-(t-butyl-dimethylsilyloxy)-2-phenylethyl]-N-[(4-methoxyphenyl)-(3-nitrophenyl)methyl]amine (4.95 g) [prepared as described in step (a) above] and a solution of tetrabutylammonium fluoride in tetrahydrofuran (1M, 20 ml) was stirred at ambient temperature for 1 hour. The reaction mixture was diluted with ethyl acetate, and the ethyl acetate was washed with water and with an aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and then evaporated under reduced pressure. The residue was purified by chromatography through a silica gel column using a 3:1 by volume mixture of cyclohexane and ethyl acetate as the eluant, to afford the title compound (3.26 g) as a pale yellow oil.
Reaction SMILES: [CH2:1]([N:3]1[CH2:13][CH:12]2[O:14][CH:5]([C:6]3[C:11]2=[CH:10][C:9]([NH2:15])=[CH:8][CH:7]=3)[CH2:4]1)[CH3:2].Cl[C:17]1[N:22]=[C:21]([NH:23][C:24]2[CH:33]=[CH:32][CH:31]=[CH:30][C:25]=2[C:26]([NH:28][CH3:29])=[O:27])[C:20]([Cl:34])=[CH:19][N:18]=1.Cl>C(O)(C)C.C([O-])(O)=O.[Na+]>[Cl:34][C:20]1[C:21]([NH:23][C:24]2[CH:33]=[CH:32][CH:31]=[CH:30][C:25]=2[C:26]([NH:28][CH3:29])=[O:27])=[N:22][C:17]([NH:15][C:9]2[CH:10]=[C:11]3[C:6](=[CH:7][CH:8]=2)[CH:5]2[O:14][CH:12]3[CH2:13][N:3]([CH2:1][CH3:2])[CH2:4]2)=[N:18][CH:19]=1
Reactant: CCN1CC2OC(C1)c1cc(N)ccc12
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: CCN1CC2OC(C1)c1cc(Nc3ncc(Cl)c(Nc4ccccc4C(=O)NC)n3)ccc12
Temperature: 120 °C
Yield: 26.8 %

Procedure:
10-Ethyl-12-oxa-10-aza-tricyclo[6.3.1.0*2,7*]dodeca-2,4,6-trien-4-ylamine (100 mg, 0.49 mmol) and 2-(2,5-dichloro-pyrimidin-4-ylamino)-N-methyl-benzamide (200 mg, 0.67 mmol) were combined with 4 N HCl (0.14 mL, 0.56 mmol) in isopropanol (4 mL) and heated in a microwave at 120° C. for 20 min. The resulting mixture was diluted with saturated aqueous NaHCO3 (3 mL), extracted with CH2Cl2 (3×5 mL), dried over MgSO4, filtered, and concentrated. The remaining residue was purified with silica gel chromatography (0-10% MeOH in CH2Cl2) to obtain 2-[5-Chloro-2-(10-ethyl-12-oxa-10-aza-tricyclo[6.3.1.0*2,7*]dodeca-2,4,6-trien-4-ylamino)-pyrimidin-4-ylamino]-N-methyl-benzamide as a light yellow solid (61 mg, 27%). 1HNMR (400 MHz, DMSO-d6) δ 11.5 (s, 1H), 9.5 (s, 1H), 8.8-8.7 (m, 2H), 8.2 (s, 1H), 7.8 (d, 1H, J=8.1 Hz), 7.6 (s, 1H), 7.5 (appt t, 1H, J=8.1 Hz), 7.4 (d, 1H, J=7.8 Hz), 7.2-7.1 (m, 2H), 5.0 (m, 2H), 2.8 (d, 3H, J=4.3 Hz), 2.7 (m, 2H), 2.4 (m, 2H), 2.3 (q, 2H, J=7.2 Hz), 0.8 (t, 3H, J=7.2 Hz); MS (m/e) 465 (M+1); mp 122-126° C.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[O:3][C:4]1[CH:11]=[CH:10][C:7]([CH2:8]Br)=[CH:6][CH:5]=1.[NH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1>C1COCC1>[F:1][C:2]([F:13])([F:12])[O:3][C:4]1[CH:11]=[CH:10][C:7]([CH2:8][N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[CH:6][CH:5]=1
Reactant: FC(F)(F)Oc1ccc(CBr)cc1
Reactant: C1CNCCN1
Solvent: C1CCOC1
Product: FC(F)(F)Oc1ccc(CN2CCNCC2)cc1

Procedure:
Synthesized according to General Procedure A: 4-trifluoromethoxybenzyl bromide (4{17}, 5 g, 19.6 mmol, 1 equiv.), piperazine (10.1 g, 117.6 mmol, 6 equiv.), THF (42.8 mL). Purification with flash column chromatography on silica gel (4:1 EtOAc:MeOH) afforded 5{17} (4.75 g, 93%) as a yellow liquid. 1H-NMR (500 MHz, CDCl3): δ 7.28 (d, 2H, J=8.0 Hz), 7.08 (d, 2H, J=8.0 Hz), 3.40 (s, 2H), 2.81 (t, 4H, J=5.0 Hz), 2.33 (br s, 4H), 1.51 (br s, 1H). 13C-NMR (125 MHz, CDCl3): δ 148.0, 136.9, 130.1, 120.5, 120.3 (q, JC-F=255.5 Hz), 62.6, 54.3, 45.9. 19F-NMR (375 MHz, CDCl3): −58.4.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[OH:5][C:6]1[CH:21]=[CH:20][C:9]([O:10][C:11]2[CH:19]=[CH:18][C:14]([C:15]([OH:17])=[O:16])=[CH:13][CH:12]=2)=[CH:8][CH:7]=1>C(Cl)Cl>[C:1]([O:5][C:6]1[CH:21]=[CH:20][C:9]([O:10][C:11]2[CH:19]=[CH:18][C:14]([C:15]([OH:17])=[O:16])=[CH:13][CH:12]=2)=[CH:8][CH:7]=1)(=[O:3])[CH3:2]
Reactant: O=C(O)c1ccc(Oc2ccc(O)cc2)cc1
Reactant: CC(=O)Cl
Solvent: ClCCl
Product: CC(=O)Oc1ccc(Oc2ccc(C(=O)O)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 55.1 %

Procedure:
Acetylchloride (1.5 mL, 21 mmol) is added to a solution of 4-(4-hydroxyphenoxy)benzoic acid (2.3 g, 10 mmol) and TEA (2.9 mL, 21 mmol) in CH2Cl2 (50 mL). The reaction is stirred for 16 hours at room temperature. The reaction mixture is diluted with CH2Cl2 and washed three times with saturated NaHCO3. The organic layer is dried (MgSO4), filtered and concentrated in vacuo. The resulting material is dissolved in dioxane (6 mL). Aqueous LiOH (1N, 930 μL) is added, and the reaction is allowed to stir for one hour at room temperature. The reaction mixture is poured into CH2Cl2 and washed twice with KHSO4. The organic layer is dried (MgSO4), filtered and concentrated in vacuo to give 4-(4-acetoxyphenoxy)benzoic acid (1.5 g, 87%). 1H NMR (300 MHz, DMSO) δ 12.80, 7.96, 7.23-7.13, 7.04, 2.29.
Reaction SMILES: CN(C)[CH:3]=[O:4].[Br:6][C:7]1[CH:8]=[C:9]([C:13]2[CH:22]=[C:16]3[CH:17]=[CH:18][CH:19]=[C:20]([Cl:21])[N:15]3[N:14]=2)[CH:10]=[CH:11][CH:12]=1.P(Cl)(Cl)(Cl)=O.O>ClCCl>[Br:6][C:7]1[CH:8]=[C:9]([C:13]2[C:22]([CH:3]=[O:4])=[C:16]3[CH:17]=[CH:18][CH:19]=[C:20]([Cl:21])[N:15]3[N:14]=2)[CH:10]=[CH:11][CH:12]=1
Reactant: Clc1cccc2cc(-c3cccc(Br)c3)nn12
Reactant: CN(C)C=O
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Product: O=Cc1c(-c2cccc(Br)c2)nn2c(Cl)cccc12
Temperature: 25 °C
Yield: 96 %

Procedure:
A solution of N,N-Dimethylformamide (150 mL) and 2-(3-bromophenyl)-7-chloropyrazolo[1,5-a]pyridine (10.3 g, 33 mmol) was cooled to 0° C. and treated with phosphorous oxychloride (4.7 mL, 50 mmol). After the addition was complete, the mixture was warmed to room temperature and the resultant solution was stirred over the weekend. Water was added, followed by dichloromethane. The aqueous layer was extracted with dichloromethane. The combined organics were washed with brine, dried over magnesium sulfate, filtered and concentrated. The residue was washed with diethyl ether and hexanes to give 2-(3-bromophenyl)-7-chloropyrazolo[1,5-a]pyridine-3-carbaldehyde (10.6 g, 96%) as a fluffy white solid. 1H NMR (DMSO-d6): δ 10.09 (s, 1 H), 8.37 (d, 1 H), 8.11 (d, 1H), 7.95 (d, 1H), 7.80 (m, 2 H), 7.65 (d, 1 H), 7.55 (m, 1 H).
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][CH:5]([CH3:7])[CH3:6].C([O:12][C:13](=[O:34])[C:14]([S:17][C:18]1[S:19][CH:20]=[C:21]([CH2:23][CH2:24][NH:25][C:26]2[N:31]=[CH:30][C:29]([CH2:32][CH3:33])=[CH:28][N:27]=2)[N:22]=1)([CH3:16])[CH3:15])(C)(C)C.CC(C)CCCO.[BrH:42].C(O)(=O)C>C(OCC)C>[BrH:42].[CH2:32]([C:29]1[CH:28]=[N:27][C:26]([N:25]([CH2:2][CH2:3][CH2:4][CH:5]([CH3:7])[CH3:6])[CH2:24][CH2:23][C:21]2[N:22]=[C:18]([S:17][C:14]([CH3:15])([CH3:16])[C:13]([OH:34])=[O:12])[S:19][CH:20]=2)=[N:31][CH:30]=1)[CH3:33]
Reactant: CCc1cnc(NCCc2csc(SC(C)(C)C(=O)OC(C)(C)C)n2)nc1
Reactant: CC(C)CCCI
Agent: Br
Agent: CC(C)CCCO
Solvent: CC(=O)O
Solvent: CCOCC
Product: CCc1cnc(N(CCCC(C)C)CCc2csc(SC(C)(C)C(=O)O)n2)nc1

Procedure:
A compound obtained using 1-iodo-4-methylpentane, which is synthesized using 2-[(4-{2-[(5-ethylpyrimidin-2-yl)amino]ethyl}-1,3-thiazol-2-yl)thio]-2-methylpropionic acid tert-butyl ester synthesized in Example 265-1 and 4-methylpentanol as starting materials and in reference to non-patent reference [Tetrahedron, 38, 11461 (1998)], and by an operation similar to that of Example 326, was dissolved in diethyl ether, and reacted with 30% hydrobromic acid-acetic acid to give the title compound.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][C:5](=[O:7])[C:4]([CH2:8][C:9]([F:12])([F:11])[F:10])=[C:3]1[CH3:13].N1C=CN=C1.[C:19]([Si:23]([CH3:26])([CH3:25])Cl)([CH3:22])([CH3:21])[CH3:20].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C)C=O>[Si:23]([O:1][CH:2]1[CH2:6][C:5](=[O:7])[C:4]([CH2:8][C:9]([F:10])([F:11])[F:12])=[C:3]1[CH3:13])([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:26])[CH3:25]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC1=C(CC(F)(F)F)C(=O)CC1O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC1=C(CC(F)(F)F)C(=O)CC1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 12 h
Yield: 90 %

Procedure:
After 10 g of (RS)-4-hydroxy-3-methyl-2-(2,2,2-trifluoroethyl)cyclopent-2-en-1-one and 4.2 g of imidazole were dissolved in 100 ml of dry dimethylformamide, 8.54 g of t-butyldimethylchlorosilane was added to the solution at an ambient temperature. After stirring at an ambient temperature for 12 hours, the reaction solution was added to 5% aqueous citric acid under ice-water cooling, and extracted three times with diethyl ether. The combined organic layer was washed successively with a saturated sodium hydrogencarbonate solution and a saturated sodium chloride solution, and dried with anhydrous magnesium sulfate. After removal of the solvent under reduced pressure, the residue was subjected to silica gel column chromatography to yield 14.3 g of (RS)-4-t-butyldimethylsilyloxy-3-methyl-2-(2,2,2-trifluoroethyl)cyclopent-2-en-1-one. Yield 90% (Eluent: n-hexane/ethyl acetate=5/1 (v/v))