Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7])[CH2:2][C:3]([OH:5])=O.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C1C=CC2N(O)N=NC=2C=1.[NH2:53][C@H:54]([C:67]([N:69]1[CH2:80][CH2:79][CH2:78][C@H:70]1[C:71]([O:73][C:74]([CH3:77])([CH3:76])[CH3:75])=[O:72])=[O:68])[CH2:55][CH2:56][CH2:57][CH2:58][NH:59][C:60]([O:62][C:63]([CH3:66])([CH3:65])[CH3:64])=[O:61]>CN(C=O)C.C(Cl)Cl>[NH:1]([C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7])[CH2:2][C:3]([NH:53][C@H:54]([C:67]([N:69]1[CH2:80][CH2:79][CH2:78][C@H:70]1[C:71]([O:73][C:74]([CH3:77])([CH3:76])[CH3:75])=[O:72])=[O:68])[CH2:55][CH2:56][CH2:57][CH2:58][NH:59][C:60]([O:62][C:63]([CH3:65])([CH3:66])[CH3:64])=[O:61])=[O:5]
Reactant: CC(C)(C)OC(=O)NCCCC[C@H](N)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCCC[C@H](NC(=O)CNC(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C
Yield: 70.1 %

Procedure:
C] Z-Gly-OH (0.762 g, 3.64 mmoles) was dissolved in 15 ml of DMF/methylene chloride (1:1 v/v) and sequentially added with BOP (1.61 go 3.64 mmoles), HOBT (0.491 g, 3.64 mmoles), TEA (1.01 ml, 7.28 mmoles) and H-Lys(Boc)-Pro-OtBu (1.119 g, 2.8 mmoles) dissolved in 15 ml of the same mixture. The reaction mixture was treated as described under A]. There were obtained 1.16 g of Z-Gly-Lys(Boc)-Pro-OtBu.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)=[C:9]([C:15]2[NH:19][N:18]=[N:17][N:16]=2)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.[CH3:27][C:28](=[CH2:30])[CH3:29].OS(O)(=O)=O.C([O-])(O)=O.[Na+]>C(OCC)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:20]2[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=2)=[C:9]([C:15]2[N:16]=[N:17][N:18]([C:28]([CH3:30])([CH3:29])[CH3:27])[N:19]=2)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:7]=1
Reactant: C=C(C)C
Reactant: CCOC(=O)C(=C(c1ccc(F)cc1)c1ccc(F)cc1)c1nnn[nH]1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCOCC
Product: CCOC(=O)C(=C(c1ccc(F)cc1)c1ccc(F)cc1)c1nnn(C(C)(C)C)n1
Temperature: -50 °C
Yield: 67.8 %

Procedure:
To a stired suspension of 10 mg of 10 g of ethyl 3,3-bis-(4-fluorophenyl)-2-(1H-tetrazol-5-yl)-2-propenoate in 250 mL dry diethyl ether cooled at -50° C. was slowly added 60 mL of liquid isobutylene (previously condensed from gaseous material in a dry ice-alcohol bath). With continued stirring and cooling, 50 mL of concentrated H2SO4 was added slowly and carefully. The mixture was then sealed in a stainless steel Parr container and stirred at -30° C. for 40 hours. After releasing the pressure, the mixture was added slowly and carefully to excess saturated NaHCO3 solution. The aqueous mixture was extracted with diethyl ether, dried over Na2SO4 and concentrated in vacuo to give 7.8 g (67.8%) of the title compound, m.p. 143-144° C.
Reaction SMILES: [C:1]1([C:7]2[N:12]=[CH:11][C:10]([C:13]3[N:14]=[N:15][NH:16][N:17]=3)=[CH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(O[CH:29]1[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31][CH2:30]1)(C1C=CC(C)=CC=1)(=O)=O.OC1CCN(C(OC(C)(C)C)=O)CC1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.C(OCC)(=O)C>[C:1]1([C:7]2[N:12]=[CH:11][C:10]([C:13]3[N:14]=[N:15][N:16]([CH:29]4[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31][CH2:30]4)[N:17]=3)=[CH:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(-c2ncc(-c3nn[nH]n3)cn2)cc1
Reactant: Cc1ccc(S(=O)(=O)OC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(n2nnc(-c3cnc(-c4ccccc4)nc3)n2)CC1
Temperature: 70 °C
Reaction time: 24 h

Procedure:
To a solution consisting of 2-phenyl-5-(2H-tetrazol-5-yl)pyrimidine (25 mg, 0.111 mmol) in DMF (2.0 mL) was added tert-butyl 4-(tosyloxy)piperidine-1-carboxylate (40 mg, 0.111 mmol), synthesized from tert-butyl 4-hydroxypiperidine-1-carboxylate (PCT International Application No. WO 2007/060026), and sodium carbonate (85 mg, 0.45 mmol). The suspension was vigorously stirred for 24 hours and an additional molar equivalent of tert-butyl 4-(tosyloxy)piperidine-1-carboxylate was added and the reaction was heated for another 24 hours at 70° C. After cooling to room temperature, the crude reaction mixture was diluted with ethyl acetate, washed sequentially with 1 M sodium carbonate, 5% citric acid, and brine. After solvent evaporation, the remaining crude solid was dissolved in a minimal amount of dichloromethane and purified by flash silica column chromatography. Elution through a 40-g Analogix® flash silica cartridge with 100% dichloromethane to 2% methanol in dichloromethane provided the title compound as an off-white solid. The solid was further purified by triturating with methanol to afford the title compound as a white solid (15 mg, 33% yield); Rf 0.37 with 95:2 v/v dichloromethane-methanol; melting point 178-180° C.; 1H-NMR (400 MHz; CDCl3) δ 9.47 (s, 2H), 8.52-8.49 (m, 2H), 7.52-7.50 (m, 3H), 4.96-4.95 (m, 2H), 4.23 (bs, 2H), 3.10-2.97 (m, 2H), 2.30-2.21 (m, 4H), 1.48 (s, 9H); MS (ESI+) m/z 408.2 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8]([Br:15])=[CH:9][CH:10]=3)[C:5](=[O:16])[C:4]=2[CH:3]=1>C(OCC)C>[C:11]1([C:12]2[CH:4]=[CH:3][CH:2]=[CH:14][CH:13]=2)[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=1[C:5]1([OH:16])[C:4]2[CH:3]=[C:2]([Br:1])[CH:14]=[CH:13][C:12]=2[C:11]2[C:6]1=[CH:7][C:8]([Br:15])=[CH:9][CH:10]=2
Reactant: O=C1c2cc(Br)ccc2-c2ccc(Br)cc21
Solvent: CCOCC
Product: OC1(c2ccccc2-c2ccccc2)c2cc(Br)ccc2-c2ccc(Br)cc21
Temperature: 50 °C
Yield: 198.7 %

Procedure:
15.2 g (45 mmol) of 2,7-dibromo-9-fluorenone was put in a 100 mL three-necked flask, and nitrogen substitution was conducted. 40 mL of diethyl ether was added. The Grignard reagent above was transferred into a dropping funnel by a cannula so as not to expose it to the atmosphere, and was added dropwise into the mixture. The mixture was refluxed at 50° C. After the reaction, the solution was washed with water. Then the aqueous layer was extracted with ethyl acetate and combined with the organic layer. The layers were washed with a saturated saline solution, then dried with magnesium sulfate. Filtration and concentration were carried out, and 22 g of 9-(biphenyl-2-yl)-2,7-dibromo-9-fluorenol was obtained as a white solid, in a yield of 90%.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=3)=[N:8][C:7]=2[CH:18]=1.[CH3:19][O:20][C:21](=[O:33])[CH2:22][C:23]1[C:24]2[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][C:25]=2[S:26][CH:27]=1>>[CH3:19][O:20][C:21](=[O:33])[CH2:22][C:23]1[C:24]2[CH:31]=[CH:30][C:29]([O:32][CH2:2][C:3]3[CH:4]=[CH:5][C:6]4[O:10][C:9]([C:11]5[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=5)=[N:8][C:7]=4[CH:18]=3)=[CH:28][C:25]=2[S:26][CH:27]=1
Reactant: Fc1cccc(-c2nc3cc(CCl)ccc3o2)c1
Reactant: COC(=O)Cc1csc2cc(O)ccc12
Product: COC(=O)Cc1csc2cc(OCc3ccc4oc(-c5cccc(F)c5)nc4c3)ccc12

Procedure:
Compound 69C and Compound 5C were reacted in a manner analogous to Compound 59A to give {6-[2-(3-Fluoro-phenyl)-benzooxazol-5-ylmethoxy]-benzo[b]thiophen-3-yl}-acetic acid methyl ester. This was reacted in a manner analogous to Compound 59 to give the title product. 400 MHz 1H NMR (DMSO-d6) δ ppm 3.7 (s, 2H) 5.3 (s, 2H) 7.1 (dd, J=8.8, 2.4 Hz, 1H) 7.3 (s, 1H) 7.5 (m, 1H) 7.5 (dd, J=8.3, 1.7 Hz, 1H) 7.6 (m, 3H) 7.8 (d, J=8.3 Hz, 1H) 7.9 (m, 2H) 8.0 (dt, J=8.1, 1.1 Hz, 1H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.CCN(C(C)C)C(C)C.[CH3:18][N:19]([CH3:24])[CH2:20][CH2:21][CH2:22][NH2:23].O>CC(O)C>[Cl:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:23][CH2:22][CH2:21][CH2:20][N:19]([CH3:24])[CH3:18])[CH:7]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: CN(C)CCCN
Solvent: O
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)CCCNc1cc(Cl)ncn1
Reaction time: 2 h
Yield: 79.9 %

Procedure:
To a solution of 4,6-dichloro-pyrimidine (1 g, 6.7 mmol) and DIPEA (1.03 g, 8 mmol) in iPrOH (20 mL) was added N,N-dimethyl-propane-1,3-diamine (714 g, 7 mmol) at room temperature. The resulting mixture was stirred for 2 hours. Water was added and the mixture was extracted with DCM. The combined extracts were washed with brine, dried over anhydrous Na2SO4, and concentrated to give the crude product, which was purified by flash chromatography on silica to obtain the title compound (1.15 g, yield: 80%). MS (ESI): 215 [M+H]+.
Reaction SMILES: CO.[OH:3][C:4]1([CH3:18])[CH2:9][CH:8]([OH:10])[CH2:7][C:6]([CH3:12])([CH3:11])[CH:5]1[CH:13]=[CH:14][C:15](=[O:17])[CH3:16].[BH4-].[Na+]>C(O)(=O)C>[OH:3][C:4]1([CH3:18])[CH2:9][CH:8]([OH:10])[CH2:7][C:6]([CH3:11])([CH3:12])[CH:5]1[CH:13]=[CH:14][CH:15]([OH:17])[CH3:16]
Reactant: CC(=O)C=CC1C(C)(C)CC(O)CC1(C)O
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(O)C=CC1C(C)(C)CC(O)CC1(C)O
Temperature: 25 °C
Reaction time: 5 h
Yield: 320.1 %

Procedure:
To 20 ml of a methanol solution containing 200 mg of 4-(2,4-dihydroxy-2,6,6-trimethylcyclohexyl)but-3-en-2-one was added 40 mg of sodium borohydride under ice-cooling, and the mixture was stirred at room temperature for 5 hours. After completion of the reaction, the reaction mixture was treated with acetic acid, and the solvent, etc. were removed by distillation under reduced pressure. Ethyl acetate was added to the residue, followed by washing with a saturated sodium chloride aqueous solution and then, with water. The organic layer was dried over magnesium sulfate, and the ethyl acetate was removed by distillation. The residue was purified by silica gel column chromatography to obtain 646 mg (yield: 73%) of 4-(2,4-dihydroxy-2,6,6-trimethylcyclohexyl)but-3-en-2-ol.
Reaction SMILES: [Br:1][Si](C)(C)C.[CH2:6]([O:8][C:9](=[O:18])[CH2:10][C:11]1[CH:12]=[N:13][C:14](Cl)=[N:15][CH:16]=1)[CH3:7].C(OCC)C.[OH-].[Na+]>C(#N)CC>[CH2:6]([O:8][C:9](=[O:18])[CH2:10][C:11]1[CH:12]=[N:13][C:14]([Br:1])=[N:15][CH:16]=1)[CH3:7]
Reactant: C[Si](C)(C)Br
Reactant: CCOC(=O)Cc1cnc(Cl)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCC#N
Solvent: CCOCC
Product: CCOC(=O)Cc1cnc(Br)nc1
Temperature: 101.5 °C
Yield: 90.6 %

Procedure:
Bromotrimethylsilane (1.7 mL, 12 mmol) was added to a solution of (2-chloro-pyrimidin-5-yl)acetic acid ethyl ester (Example 43-(2); 810 mg, 4.04 mmol) in propionitrile (4 mL), and the mixture was heated under reflux at an external temperature of 98 to 105° C. for nine hours. After cooling the reaction mixture to room temperature, diethyl ether was added to the reaction mixture, which was neutralized with a 2 N sodium hydroxide aqueous solution (6.3 mL). The reaction mixture was extracted with diethyl ether. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate=2/1) to give the title compound (897 mg, 91%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C@H:6]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-:24])=[O:23])[CH:17]=2)[C:7]([C:13](O)=[O:14])=[C:8]([CH3:12])[NH:9][C:10]=1[CH3:11])=[O:4].C(Cl)(=O)C(Cl)=O.[CH3:31][C:32]1([OH:45])[CH2:36][CH2:35][N:34]([CH:37]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH3:38])[CH2:33]1.CCN(C(C)C)C(C)C>ClCCl.CN(C=O)C>[CH3:12][C:8]1[NH:9][C:10]([CH3:11])=[C:5]([C:3]([O:2][CH3:1])=[O:4])[C@H:6]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-:24])=[O:23])[CH:17]=2)[C:7]=1[C:13]([O:45][C:32]1([CH3:31])[CH2:36][CH2:35][N:34]([CH:37]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH3:38])[CH2:33]1)=[O:14]
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)O)[C@H]1c1cccc([N+](=O)[O-])c1
Reactant: CC(c1ccccc1)N1CCC(C)(O)C1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OC2(C)CCN(C(C)c3ccccc3)C2)[C@H]1c1cccc([N+](=O)[O-])c1
Yield: 48 %

Procedure:
According to Example 15, (R)-5-methoxycarbonyl-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylic acid was synthesized. To a solution of (R)-5-methoxycarbonyl-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylic acid (2.9 g, 8.73 mmol) in dichloromethane was added 0.1 mL DMF. To the mixture was slowly added oxalyl chloride (2.2 g, 17.33 mmol) dropwisely in an ice bath. The reaction was conducted at 25° C. until the completion of reaction. The resulting mixture was evaporated under reduced pressure to remove oxalyl chloride. To the reaction flask were slowly added dichloromethane (20 mL), 3-methyl-1-phenylethylpyrrolidin-3-ol (1 g, 4.87 mmol) and DIPEA (1.56 g, 12.1 mmol) dropwisely under cooling in an ice bath respectively and successively. The reaction was conducted at 25° C. After the completion of reaction monitored by HPLC, the reaction solution was washed with water thrice. The organic phase was dried over sodium sulfate, and filtered by suction. The filtrate was evaporated to dryness, and purified by column chromatography (silica gel column, eluted with petroleum ether:ethyl acetate=78:1 (volumetric ratio)) to produce (4S)-3-(3-methyl-1-phenylethylpyrrolidin-3-yl) 5-methyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate (1.21 g) in a yield of 48%.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:25][C:26]1[CH:27]=[C:28]([NH:37][C:38]([C@@H:40]2[NH:49][CH2:48][CH2:47][C:46]3[N:45]=[C:44]([O:50][CH3:51])[CH:43]=[CH:42][C:41]2=3)=[O:39])[CH:29]=[C:30]2[C:34]=1[C:33]([CH3:36])([CH3:35])[CH2:32][CH2:31]2.CCN(C(C)C)C(C)C.[C@H:61]1([C:68](O)=[O:69])[CH2:64][C@H:63]([C:65]([OH:67])=[O:66])[CH2:62]1>CN(C=O)C.O.C(#N)C.O>[F:25][C:26]1[CH:27]=[C:28]([NH:37][C:38]([C@@H:40]2[N:49]([C:68]([C@H:61]3[CH2:64][C@H:63]([C:65]([OH:67])=[O:66])[CH2:62]3)=[O:69])[CH2:48][CH2:47][C:46]3[N:45]=[C:44]([O:50][CH3:51])[CH:43]=[CH:42][C:41]2=3)=[O:39])[CH:29]=[C:30]2[C:34]=1[C:33]([CH3:35])([CH3:36])[CH2:32][CH2:31]2
Reactant: COc1ccc2c(n1)CCN[C@H]2C(=O)Nc1cc(F)c2c(c1)CCC2(C)C
Reactant: O=C(O)[C@H]1C[C@H](C(=O)O)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2c(n1)CCN(C(=O)[C@H]1C[C@H](C(=O)O)C1)[C@H]2C(=O)Nc1cc(F)c2c(c1)CCC2(C)C

Procedure:
HATU (124 mg, 0.32 mmol) was added to a solution of (R)—N-(7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)-2-methoxy-5,6,7,8-tetrahydro-1,6-naphthyridine-5-carboxamide (100 mg, 0.27 mmol), DIEA (0.093 mL, 0.54 mmol) and the crude trans-cyclobutane-1,3-dicarboxylic acid (58.5 mg, 0.41 mmol) in DMF (2.0 mL) at room temperature, and the mixture was stirred at room temperature for 5 hr. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 20→90% ethyl acetate/hexane), and then preparative HPLC (C18, mobile phase: water/acetonitrile (containing 0.1% TFA)) to give the title compound (24.0 mg, 0.048 mmol, 17.89%) as a white solid.
Reaction SMILES: [Br-:1].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.[CH:55]1([C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][C:60]=2[OH:65])[CH2:58][CH2:57][CH2:56]1.S([O-])([O-])=O.[Na+].[Na+].CCOC(C)=O>C(Cl)Cl>[Br:1][C:63]1[CH:62]=[CH:61][C:60]([OH:65])=[C:59]([CH:55]2[CH2:56][CH2:57][CH2:58]2)[CH:64]=1
Reactant: Oc1ccccc1C1CCC1
Reactant: [Br-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Oc1ccc(Br)cc1C1CCC1
Reaction time: 8 h
Yield: 166.9 %

Procedure:
Tetra-n-butylammonium tribromide (4.72 g) was added to a solution of 2-cyclobutylphenol (1.21 g) in CH2Cl2 (24.2 mL) at room temperature, and the mixture was stirred at the same temperature overnight. After the reaction mixture was pour into a saturated aqueous sodium sulfite solution, extraction was performed on the mixture using EtOAc, and the extract was washed with water and saturated brine. The organic layer was dried over Na2SO4 and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Hex:EtOAc=100:0 to 84:16), whereby 4-bromo-2-cyclobutylphenol (1.85 g) was obtained as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH2:4][C:5]1[CH:10]=[CH:9][C:8](Cl)=[CH:7][C:6]=1[F:12].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH2:51]([C:53]([C:78]1[CH:83]=[CH:82][C:81](B2OC(C)(C)C(C)(C)O2)=[C:80]([CH3:93])[CH:79]=1)([C:56]1[CH:61]=[CH:60][C:59]([C:62]#[C:63][C:64]([O:73][CH2:74][O:75][CH3:76])([C:69]([F:72])([F:71])[F:70])[C:65]([F:68])([F:67])[F:66])=[C:58]([CH3:77])[CH:57]=1)[CH2:54][CH3:55])[CH3:52].C(=O)(O)[O-].[Na+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:13])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:81]2[CH:82]=[CH:83][C:78]([C:53]([CH2:54][CH3:55])([C:56]3[CH:61]=[CH:60][C:59]([C:62]#[C:63][C:64]([O:73][CH2:74][O:75][CH3:76])([C:69]([F:72])([F:71])[F:70])[C:65]([F:68])([F:67])[F:66])=[C:58]([CH3:77])[CH:57]=3)[CH2:51][CH3:52])=[CH:79][C:80]=2[CH3:93])=[CH:7][C:6]=1[F:12]
Reactant: COC(=O)Cc1ccc(Cl)cc1F
Reactant: CCC(CC)(c1ccc(C#CC(OCOC)(C(F)(F)F)C(F)(F)F)c(C)c1)c1ccc(B2OC(C)(C)C(C)(C)O2)c(C)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: Cc1ccccc1
Solvent: O
Product: CCC(CC)(c1ccc(C#CC(OCOC)(C(F)(F)F)C(F)(F)F)c(C)c1)c1ccc(-c2ccc(CC(=O)OC)c(F)c2)c(C)c1
Temperature: 100 °C
Reaction time: 1.5 h

Procedure:
(4-Chloro-2-fluoro-phenyl)acetic acid methyl ester (Example 40; 37.2 mg, 0.183 mmol), toluene (2.0 mL), palladium acetate (2.7 mg, 0.012 mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl (10.0 mg, 0.0244 mmol), potassium phosphate (78 mg, 0.3666 mmol) and water (0.200 mL) were added to 2-(4-{1-ethyl-1-[3-methyl-4-(4,4,4-trifluoro-3-methoxymethoxy-3-trifluoromethyl-1-butynyl)-phenyl]-propyl}-2-methyl-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (Example 25-(4); 75 mg, 0.122 mmol), and the mixture was stirred in a nitrogen atmosphere at 100° C. for 1.5 hours. The reaction solution was poured into a saturated aqueous sodium bicarbonate solution, and then the aqueous layer was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (17% ethyl acetate/hexane) to give the title compound containing (4-chloro-2-fluoro-phenyl)acetic acid methyl ester (41 mg, 52%).
Reaction SMILES: [F:1][C:2]([F:15])([CH:9]([F:14])[C:10]([F:13])([F:12])[F:11])[CH2:3][CH:4]([C:7]#[N:8])[C:5]#[N:6].FC(F)(F)S(O[CH2:22][C:23]([F:31])([F:30])[CH:24]([F:29])[C:25]([F:28])([F:27])[F:26])(=O)=O.C(=O)([O-])[O-].[K+].[K+].Cl>CC(C)=O>[F:1][C:2]([F:15])([CH:9]([F:14])[C:10]([F:12])([F:13])[F:11])[CH2:3][C:4]([CH2:22][C:23]([F:31])([F:30])[CH:24]([F:29])[C:25]([F:28])([F:27])[F:26])([C:7]#[N:8])[C:5]#[N:6]
Reactant: N#CC(C#N)CC(F)(F)C(F)C(F)(F)F
Reactant: O=S(=O)(OCC(F)(F)C(F)C(F)(F)F)C(F)(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: N#CC(C#N)(CC(F)(F)C(F)C(F)(F)F)CC(F)(F)C(F)C(F)(F)F
Temperature: 25 °C
Reaction time: 10 h
Yield: 1.5 %

Procedure:
In 50 ml of acetone, 2.0 g of 2-(2,2,3,4,4,4-hexafluorobutyl)malononitrile and 5.3 g of 2,2,3,4,4,4-hexafluorobutyl trifluoromethanesulfonate were dissolved, 1.9 g of potassium carbonate was added and the mixture was stirred at room temperature for 10 hours. Thereafter, dilute hydrochloric acid was added to the reaction mixture and the mixture was extracted with t-butyl methyl ether. The organic layer was washed successively with water, aqueous saturated sodium hydrogen carbonate and aqueous saturated sodium chloride, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.05 g of 2,2-bis(2,2,3,4,4,4-hexafluorobutyl)malononitrile (hereinafter, referred to as the present compound (95)).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11](CC2C=CC=CC=2)[CH2:10][CH:9]1[CH2:21][N:22]([CH3:24])[CH3:23])C1C=CC=CC=1>CCO.[Pd]>[CH3:23][N:22]([CH3:24])[CH2:21][CH:9]1[CH2:10][NH:11][CH2:12][CH2:13][NH:8]1
Reactant: CN(C)CC1CN(Cc2ccccc2)CCN1Cc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CN(C)CC1CNCCN1
Temperature: 130 °C

Procedure:
{[1,4-bisbenzylpiperazin-2-yl]methyl}dimethylamine (1 equivalent), was dissolved in EtOH and the solution was transferred to a stainless steel high pressure vessel equipped with a pressure gauge. 10% Pd/C was added (10 wt. %), and the vessel charged with H2. The reaction mixture was stirred at 130° C. and 200 psi of H2 overnight. The reaction mixture was cooled to room temperature, filtered over a pad of Celite, and then evaporated. The desired amine was obtained in quantitative yield as a pale yellow oil. GC/MS: 143 (10%, M+), Rt=14.3 minutes.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([C:16]2[CH:17]=[N:18][N:19]([CH3:21])[CH:20]=2)[NH:9][S@@](C(C)(C)C)=O)=[CH:4][C:3]=1[F:22].Cl.CO>>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([C:16]2[CH:17]=[N:18][N:19]([CH3:21])[CH:20]=2)[NH2:9])=[CH:4][C:3]=1[F:22]
Reactant: Cn1cc([C@@H](N[S@](=O)C(C)(C)C)c2ccc(Cl)c(F)c2)cn1
Agent: Cl
Solvent: CO
Product: Cn1cc([C@@H](N)c2ccc(Cl)c(F)c2)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 56 %

Procedure:
To a solution of 48 (2.9 g, 8.4 mmol) in MBTE (40 mL) was added 3N HCl/methanol (6.0 mL, 18 mmol). The mixture was stirred for 2 h at RT. The resulting solid was filtered and washed with MTBE to afford 650 mg (35%) of 50a. 1H NMR (500 MHz, CD3OD) δ 7.46-7.43 (m, 2H), 7.38 (s, 1H), 7.31 (dd, J=10.5, 2.0 Hz, 1H), 7.21 (dd, J=8.5, 1.5 Hz, 1H), 5.13 (s, 1H), 3.85 (s, 3H). LCMS (ESI) m/z: 240.0 [M+H]+.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.[F:33][C:34]([F:44])([F:43])[C:35]1[CH:42]=[CH:41][C:38]([CH2:39][NH2:40])=[CH:37][CH:36]=1.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C(=NC=CC=2)[N+]([O-])=N1)C.C(N(C(C)C)CC)(C)C>O.C(=O)(O)[O-].[Na+].CN(C)C=O>[CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:40][CH2:39][C:38]5[CH:37]=[CH:36][C:35]([C:34]([F:33])([F:43])[F:44])=[CH:42][CH:41]=5)=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reactant: NCc1ccc(C(F)(F)F)cc1
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ncccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COc1cc(C(=O)NCc2ccc(C(F)(F)F)cc2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reaction time: 18 h
Yield: 50.7 %

Procedure:
A mixture of 0.070 g (0.16 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoic acid (I-22), 0.027 g (0.19 mmole) of 4-trifluoromethyl-benzylamine, 0.071 g (0.19 mmole) of 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate, 0.136 mL (0.78 mmole) of diisopropylethyl amine and 2.0 mL of dimethylformamide was stirred for 18 hours. The mixture was diluted with 10 mL of water plus 2 mL of saturated aqueous sodium bicarbonate and then extracted 3 times with 10 mL of ethyl acetate. The combined extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with hexanes-ethyl acetate (gradient, 80:20-0:100) to give 0.049 g of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(4-trifluoromethyl-benzyl)-benzamide (I-36) as a white solid.