Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:25])[C:12]2[CH:13]=[C:14]([CH:20]=[CH:21][C:22]=2[O:23][CH3:24])[C:15]([O:17]CC)=[O:16])=[CH:6][CH:5]=1.[OH-].[K+].Cl>CO>[F:1][C:2]([F:26])([F:27])[O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:25])[C:12]2[CH:13]=[C:14]([CH:20]=[CH:21][C:22]=2[O:23][CH3:24])[C:15]([OH:17])=[O:16])=[CH:6][CH:5]=1
Reactant: CCOC(=O)c1ccc(OC)c(C(=O)Nc2ccc(OC(F)(F)F)cc2)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(C(=O)O)cc1C(=O)Nc1ccc(OC(F)(F)F)cc1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 101.5 %

Procedure:
Ethyl N-(4-trifluoromethoxyphenyl)-4-methoxy-isophthalamate (51 mg) obtained in step E was dissolved in 2 mL of methanol, and 0.8 mL of a 20% aqueous solution of potassium hydroxide was added. The resulting solution was stirred for 30 minutes at 80° C., and then cooled to room temperature. One M hydrochloric acid (3 mL) was used to adjust the solution to pH of about 3. Then, the resulting aqueous solution was extracted with ethyl acetate. The respective organic layers were combined, whereafter the combined organic layer was washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate. The anhydrous sodium sulfate was separated by filtration, and washed with ethyl acetate. The filtrate and the washings were combined, and ethyl acetate was distilled off under reduced pressure to obtain 48 mg (100%) of N-(4-trifluoromethoxyphenyl)-4-methoxyisophthalamic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:26])[N:19]([CH2:23][CH2:24]O)[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:29]([F:32])([F:31])[F:30])[CH:3]=1.[CH3:33][O:34][C:35]([N:37]1[CH2:41][CH2:40][NH:39][S:38]1(=[O:43])=[O:42])=[O:36]>>[Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:26])[N:19]([CH2:23][CH2:24][N:39]5[S:38](=[O:43])(=[O:42])[N:37]([C:35]([O:34][CH3:33])=[O:36])[CH2:41][CH2:40]5)[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:29]([F:32])([F:31])[F:30])[CH:3]=1
Reactant: COC(=O)N1CCNS1(=O)=O
Reactant: O=C1S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C(=O)N1CCO
Product: COC(=O)N1CCN(CCN2C(=O)S/C(=C\c3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)C2=O)S1(=O)=O

Procedure:
Methyl 5-{2-[(5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidin-3-yl]ethyl}-1,2,5-thiadiazolidine-2-carboxylate 1,1-dioxide was prepared from (5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylene)-3-(2-hydroxyethyl)thiazolidine-2,4-dione (from Example 340) and 1,1-dioxo-1λ6-[1,2,5]thiadiazolidine-2-carboxylic acid methyl ester following General Procedure C.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[NH:7][C:6](=[O:8])[CH2:5][CH2:4]1.Br[C:10]1[CH:15]=[CH:14][C:13]([C:16]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[C:29]([CH3:30])=[CH:28][C:27]([CH3:31])=[CH:26][N:25]=3)[CH2:20][CH2:19]2)=[O:17])=[C:12]([S:32]([CH3:35])(=[O:34])=[O:33])[CH:11]=1>>[CH3:30][C:29]1[C:24]([N:21]2[CH2:22][CH2:23][N:18]([C:16]([C:13]3[CH:14]=[CH:15][C:10]([N:7]4[C@@H:3]([CH2:2][OH:1])[CH2:4][CH2:5][C:6]4=[O:8])=[CH:11][C:12]=3[S:32]([CH3:35])(=[O:34])=[O:33])=[O:17])[CH2:19][CH2:20]2)=[N:25][CH:26]=[C:27]([CH3:31])[CH:28]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3S(C)(=O)=O)CC2)c(C)c1
Reactant: O=C1CC[C@H](CO)N1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4C(=O)CC[C@@H]4CO)cc3S(C)(=O)=O)CC2)c(C)c1
Yield: 42.5 %

Procedure:
Using (R)-5-hydroxymethylpyrrolidin-2-one (409 mg) and (4-bromo-2-methanesulfonylphenyl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (1.53 g) described in Preparation Example 112 and by the reaction and treatment in the same manner as in Example 1, (R)-1-{4-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]-3-methanesulfonylphenyl}-5-hydroxymethylpyrrolidin-2-one (700 mg) was obtained. Using the obtained (R)-1-{4-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]-3-methanesulfonylphenyl}-5-hydroxymethylpyrrolidin-2-one (700 mg) and methyl tosylate (0.21 mL) and by the reaction and treatment in the same manner as in Example 36, the title compound (319 mg) was obtained.
Reaction SMILES: C(Cl)(=O)C.[NH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[N:16]([CH2:17][CH:18]([CH3:20])[CH3:19])[C:15]([CH2:21][CH2:22][CH3:23])=[N:14][C:13]=1[C:24]#[N:25]>C(O)C>[CH3:19][CH:18]([CH3:20])[CH2:17][N:16]1[C:12]2[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=3[N:5]=[C:24]([NH2:25])[C:13]=2[N:14]=[C:15]1[CH2:21][CH2:22][CH3:23]
Reactant: CCCc1nc(C#N)c(-c2ccccc2N)n1CC(C)C
Solvent: CC(=O)Cl
Solvent: CCO
Product: CCCc1nc2c(N)nc3ccccc3c2n1CC(C)C
Temperature: 25 °C
Yield: 60 %

Procedure:
Under a nitrogen atmosphere, a solution of acetyl chloride (15 mmol) in anhydrous ethanol (50 mL) was stirred for 15 minutes and then added to 5-(2-aminophenyl)-1-(2-methylpropyl)-2-propyl-1H-imidazole-4-carbonitrile (2.75 g). The reaction was heated at reflux under nitrogen for 16 hours, allowed to cool to room temperature, and concentrated under reduced pressure. The residue was partitioned between 2M aqueous sodium carbonate and chloroform. The aqueous layer was separated and extracted twice with chloroform. The combined organic fractions were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product (2.81 g) was purified by automated flash chromatography (eluting with 0% to 20% CMA in chloroform) and then recrystallized from acetonitrile (50 mL). The crystals were dried overnight at 33 Pa and 98° C. to provide 1.65 g of 1-(2-methylpropyl)-2-propyl-1H-imidazo[4,5-c]quinolin-4-amine as white needles, mp 191-192° C.
Reaction SMILES: [Cl:1][C@H:2]1[C@H:6]([CH2:7][CH2:8][CH2:9][C:10]2[S:14][C:13]([C:15]([OH:17])=[O:16])=[CH:12][CH:11]=2)[C@@H:5]([CH2:18][CH2:19][C:20]2[CH:25]=[C:24]([Cl:26])[CH:23]=[C:22]([Cl:27])[CH:21]=2)[C@H:4]([OH:28])[CH2:3]1.C(=O)(O)[O-].[K+].Br.Br[CH2:36][CH2:37][N:38]([CH2:41][CH3:42])[CH2:39][CH3:40].C(#N)C>O.CCOC(C)=O>[Cl:1][C@H:2]1[C@H:6]([CH2:7][CH2:8][CH2:9][C:10]2[S:14][C:13]([C:15]([O:17][CH2:36][CH2:37][N:38]([CH2:41][CH3:42])[CH2:39][CH3:40])=[O:16])=[CH:12][CH:11]=2)[C@@H:5]([CH2:18][CH2:19][C:20]2[CH:25]=[C:24]([Cl:26])[CH:23]=[C:22]([Cl:27])[CH:21]=2)[C@H:4]([OH:28])[CH2:3]1
Reactant: CCN(CC)CCBr
Reactant: O=C(O)c1ccc(CCC[C@@H]2[C@@H](CCc3cc(Cl)cc(Cl)c3)[C@H](O)C[C@H]2Cl)s1
Agent: Br
Agent: O=C([O-])O
Agent: [K+]
Solvent: CC#N
Solvent: O
Solvent: CCOC(C)=O
Product: CCN(CC)CCOC(=O)c1ccc(CCC[C@@H]2[C@@H](CCc3cc(Cl)cc(Cl)c3)[C@H](O)C[C@H]2Cl)s1
Temperature: 65 °C
Reaction time: 48 h
Yield: 39.9 %

Procedure:
A mixture of 5-(3-((1R,2R,3R,5R)-5-chloro-2-(3,5-dichlorophenethyl)-3-hydroxycyclopentyl)propyl)thiophene-2-carboxylic acid (212 mg, 0.46 mmol), potassium bicarbonate (212 mg, 2.1 mmol), 2-bromo-N,N-diethylethanamine hydrobromide (132 mg, 0.51 mmol) and acetonitrile (1.5 mL) was heated at 65° C. After 2 d at 65° C., the mixture was cooled to room temperature and diluted with water (50 mL) and EtOAc (100 mL). The phases were separated and the aqueous phase was extracted with EtOAc (2×50 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated in vacuo. The crude residue was purified on 40 g silica (CH2Cl2→20% MeOH/CH2Cl2, gradient) to afford a mixture of the desired ester and the starting acid. Fractions containing the desired ester were combined and concentrated. The residue was taken up in EtOAc (100 mL) and washed with saturated aqueous NaHCO3 (50 mL). The aqueous phase was extracted with EtOAc (50 mL) and the combined organic phases were dried (Na2SO4), filtered and concentrated in vacuo. The crude residue was purified on 80 g silica (CH2Cl2→15% MeOH/CH2Cl2, gradient) to afford 103 mg (40%) of 2-(diethylamino)ethyl 5-(3-((1R,2R,3R,5R)-5-chloro-2-(3,5-dichlorophenethyl)-3-hydroxycyclopentyl)propyl)thiophene-2-carboxylate
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]#[CH:10])=[CH:5][CH:4]=1)#[CH:2].[CH2:11]([O:13][C:14](=[O:18])/[CH:15]=[CH:16]\I)[CH3:12]>>[CH2:11]([O:13][C:14](=[O:18])[CH:15]=[CH:16][C:2]#[C:1][C:3]1[CH:8]=[CH:7][C:6]([C:9]#[C:10][CH:16]=[CH:15][C:14]([O:13][CH2:11][CH3:12])=[O:18])=[CH:5][CH:4]=1)[CH3:12]
Reactant: CCOC(=O)/C=C\I
Reactant: C#Cc1ccc(C#C)cc1
Product: CCOC(=O)C=CC#Cc1ccc(C#CC=CC(=O)OCC)cc1

Procedure:
The general procedure was used to convert 1,4-Diethynyl-benzene and (Z)-ethyl-3-iodoacrylate to the title product in 12 hours. Purification by flash chromatography (10% ethyl acetate in hexane as the eluent) gave the analytically pure product as a light yellow solid (560 mg, 87% yield). 1H NMR (400 MHz, CDCl3) δ 7.50 (s, 4H), 6.37-6.34 (d, J=11.4, 2H), 6.17-6.14 (d, J=11.4, 2H), 4.28-4.23 (q, J=7.1, 4H), 1.34-1.30 (t, J=7.1, 6H). 13C NMR (100 MHz, CDCl3) δ 164.57, 131.88, 128.72, 123.31, 122.34, 100.27, 88.36, 60.39, 14.21. Anal. Calcd. for C20H18O4: C, 74.52; H, 5.63; Found C, 74.33; H, 5.71. m.p.: 73.0°-74.0° C.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[N:7]=[C:8]([CH3:12])[N:9]=[C:10](O)[C:5]=2[N:4]([CH2:13][CH3:14])[N:3]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:16]>P(Cl)(Cl)(Cl)=O>[Cl:16][C:10]1[C:5]2[N:4]([CH2:13][CH3:14])[N:3]=[C:2]([CH3:1])[C:6]=2[N:7]=[C:8]([CH3:12])[N:9]=1
Reactant: CCn1nc(C)c2nc(C)nc(O)c21
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: CCn1nc(C)c2nc(C)nc(Cl)c21
Yield: 85.8 %

Procedure:
A mixture of 16 g (0.083 mol) of 3,5-dimethyl-1-ethyl-7-hydroxy-1H-pyrazolo[4,3-d]pyrimidine and 18.5 g (0.087 mol) of phosphorus pentachloride in 120 ml of phosphorus oxychloride is stirred under reflux five hours. The solution is evaporated in vacuo. The residue is redissolved in ether and percolated over neutral alumina to yield 15 g of 7-chloro-3,5-dimethyl-1-ethyl-1H-pyrazolo[4,3-d]pyrimidine, a low-melting waxy solid (40°-50° C.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:10][C@@H:11]2[CH2:13][O:12]2)=[CH:5][C:4]=1[N+:14]([O-])=O.[NH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1.C(O)(C)C>C(O)C.[Pd]>[NH2:14][C:4]1[CH:5]=[C:6]([O:9][CH2:10][C@@H:11]([OH:12])[CH2:13][N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[CH:7]=[CH:8][C:3]=1[O:2][CH3:1]
Reactant: COc1ccc(OC[C@@H]2CO2)cc1[N+](=O)[O-]
Reactant: C1CCNC1
Agent: [Pd]
Solvent: CC(C)O
Solvent: CCO
Product: COc1ccc(OC[C@@H](O)CN2CCCC2)cc1N
Temperature: 140 °C
Reaction time: 8 h
Yield: 93.9 %

Procedure:
In a sealed tube were placed (2S)-2-({[4-(methyloxy)-3-nitrophenyl]oxy}methyl)oxirane (1.0 g, 4.4 mmol), pyrrolidine (3.2 g, 44 mmol), and isopropanol (20 mL). The mixture was heated under microwave to 140° C. for 10 min. Removal of the isopropanol afforded the crude product which was placed in ethanol (100 mL) with 10% palladium on carbon (0.5 g). The reation mixture was kept stirring under H2 at 60 psi overnight. Filtration removed the catalyst and concentration afforded (2S)-1-{[3-amino-4-(methyloxy)phenyl]oxy}-3-(1-pyrrolidinyl)-2-propanol (1.1 g, 95% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.67 (ddd, J=6.4, 3.5, 3.3 Hz, 4H), 2.47-2.50 (m, 1 H), 2.55 (d, J=1.8 Hz, 4 H), 2.64 (dd, J=12.3, 5.7 Hz, 1 H), 3.63-3.71 (m, 4 H), 3.75-3.82 (m, 1 H), 3.83-3.89 (m, 1 H), 4.70 (s, 2 H), 4.88 (s, 1 H), 6.03 (dd, J=8.4, 2.9 Hz, 1 H), 6.24 (d, J=2.9 Hz, 1 H), 6.63 (d, J=8.8 Hz, 1 H).
Reaction SMILES: [C:1]1([N:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][CH2:15][C:16]3[N:17]=[N:18][NH:19][CH:20]=3)=[C:9]([OH:21])[C:8]2=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:24].[Al].C(Cl)Cl>CO>[C:1]1([N:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][CH2:15][C:16]3[N:17]=[N:18][NH:19][CH:20]=3)=[C:9]([OH:21])[C:8]2=[S:24])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: O=c1c(O)c(CCCc2c[nH]nn2)ccn1-c1ccccc1
Agent: [Al]
Solvent: ClCCl
Solvent: CO
Product: Oc1c(CCCc2c[nH]nn2)ccn(-c2ccccc2)c1=S
Temperature: 175 °C
Yield: 121.9 %

Procedure:
159b (0.062 g, 0.21 mmol) was ground together with P4S10 (0.047 g, 0.105 mmol) in mortar and pestle to form grey powder. The powder was stirred under argon in a flask fitted with condenser and heated to 175° C. for 2 h. The reaction flask was covered with aluminum foil during reaction. After 2 h of reaction, flask was cooled down to room temperature. 25 mL of CH2Cl2:MeOH (10%) mixtures was added and stirred for 15 min. This reaction mixture then washed with water (2×30 mL). Organic layer dried with Na2SO4 and evaporated to yield crude product which was purified by prep-TLC (Eluent —CH2Cl2:MeOH (8%) to give 162b (0.04 g, 60%) as olive green solid. 1H NMR (400 MHz, CDCl3) δ 8.47 (s, 1H), 7.82 (m, 3H), 7.50 (d, J=6.5 Hz, 1H), 7.43 (t, J=7.5 Hz, 2H), 7.34 (t, J=7.4 Hz, 1H), 6.97 (m, 1H), 6.66 (m, 1H), 4.62 (t, J=6.9 Hz, 2H), 4.48 (m, 2H). 13C NMR (100 MHz, CDCl3) δ 168.59, 155.22, 148.03, 131.85, 130.17, 128.84, 128.29, 125.61, 119.84, 113.87, 112.28, 54.99, 46.95, 28.02. HRMS (EI) calcd for C16H16N4OS [M]+ 312.104. found 312.1060.
Reaction SMILES: [CH2:1]([OH:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[H-].[Na+].Cl[C:10]1[C:11]2[CH:20]=[CH:19][N:18]([C:21]3[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][C:22]=3[CH3:28])[C:12]=2[C:13](=[O:17])[N:14]([CH3:16])[N:15]=1>CN(C=O)C.O>[CH3:28][C:22]1[CH:23]=[C:24]([CH3:27])[CH:25]=[CH:26][C:21]=1[N:18]1[C:12]2[C:13](=[O:17])[N:14]([CH3:16])[N:15]=[C:10]([O:6][CH2:1][C:2]([CH3:5])([CH3:4])[CH3:3])[C:11]=2[CH:20]=[CH:19]1
Reactant: Cc1ccc(-n2ccc3c(Cl)nn(C)c(=O)c32)c(C)c1
Reactant: CC(C)(C)CO
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(-n2ccc3c(OCC(C)(C)C)nn(C)c(=O)c32)c(C)c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 62.9 %

Procedure:
To a solution of neopentyl alcohol (39.7 mg, 0.45 mmol) in DMF (1 ml) was added sodium hydride (60% in oil, 18 mg, 0.45 mmol). The mixture was stirred for 10 min before addition of 4-chloro-1-(2,4-dimethylphenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-d]pyridazin-7-one (43.2 mg, 0.15 mmol). The mixture was stirred at 60° C. for 2 hours, then diluted with water (30 ml) and extracted with ethyl acetate (30 ml). The extract was washed with water, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with hexane/ethyl acetate (10:1) to give 32 mg (63%) of the title compounds as crystals.
Reaction SMILES: [N:1]1([C:10]2[N:18]=[C:17](Cl)[N:16]=[C:15]3[C:11]=2[N:12]=[CH:13][NH:14]3)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[NH:20]([CH2:24][CH2:25][OH:26])[CH2:21][CH2:22][OH:23]>CS(C)=O>[N:1]1([C:10]2[N:18]=[C:17]([N:20]([CH2:24][CH2:25][OH:26])[CH2:21][CH2:22][OH:23])[N:16]=[C:15]3[C:11]=2[N:12]=[CH:13][NH:14]3)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: Clc1nc(-n2cnc3ccccc32)c2nc[nH]c2n1
Reactant: OCCNCCO
Solvent: CS(C)=O
Product: OCCN(CCO)c1nc(-n2cnc3ccccc32)c2nc[nH]c2n1
Temperature: 120 °C
Yield: 7042.7 %

Procedure:
200 mg of product obtained in stage 1 above are mixed with 3 ml of DMSO and 0.388 mg (5 equivalents) of diethanolamine, and the mixture is then heated at 120° C. for approximately 48 hours. The mixture is allowed to return to ambient temperature. Purification is carried out by chromatography on silica with a CH2Cl2-MeOH—NH4OH: 90-9-1 mixture for eluent. Evaporation is carried out and a paste is formed in methylene chloride. Partial drying and drying under vacuum at 50° C. are carried out. 88.2 mg of expected product are obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:13])[CH:5]=[CH:6][C:7]=1[O:8][C:9]([F:12])([F:11])[F:10].N1C=CC=CC=1.C1(C)C=CC=CC=1.[CH2:27]([C@H:30]1[CH2:35][CH2:34][C@H:33]([C:36]2[CH:44]=[CH:43][C:39]([C:40](Cl)=[O:41])=[CH:38][CH:37]=2)[CH2:32][CH2:31]1)[CH2:28][CH3:29]>O>[CH2:27]([C@H:30]1[CH2:31][CH2:32][C@H:33]([C:36]2[CH:44]=[CH:43][C:39]([C:40]([O:13][C:4]3[CH:5]=[CH:6][C:7]([O:8][C:9]([F:11])([F:12])[F:10])=[C:2]([F:1])[CH:3]=3)=[O:41])=[CH:38][CH:37]=2)[CH2:34][CH2:35]1)[CH2:28][CH3:29]
Reactant: Oc1ccc(OC(F)(F)F)c(F)c1
Reactant: CCC[C@H]1CC[C@H](c2ccc(C(=O)Cl)cc2)CC1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCC[C@H]1CC[C@H](c2ccc(C(=O)Oc3ccc(OC(F)(F)F)c(F)c3)cc2)CC1

Procedure:
Then, 1.3 g (6.5 mmol) of 3-fluoro-4-trifluoromethoxyphenol, 0.8 ml of pyridine, and 3 ml of toluene were mixed. To this mixture was added dropwise 3 ml of toluene solution containing 6.5 mmol of 4-(trans-4-propylcyclohexyl)benzoyl chloride at room temperature in 5 minutes. After the dropping was finished, they were reacted at 50° C. for 3 hours. After finishing of the reaction, 15 ml of water was added to the reaction product, and then extracted with 40 ml of toluene. The organic layer thus obtained was washed with 6N-hydrochloric acid thrice, 2N-sodium hydroxide thrice, and water thrice, and then dried over anhydrous magnesium sulfate. Solvent was distilled off at a reduced pressure and the residue was subjected to a silica gel column chromatography (eluent: toluene) to obtain 2.6 g of a crude 3-fluoro-4-trifluoromethoxyphenyl 4-(trans-4-propyl-cyclohexyl)benzoate. This product was recrystallized from a mixed solvent of heptane/ether (1/1) to obtain 2.4 g (yield: 85.6%) of the subject compound.
Reaction SMILES: [CH3:1][C:2]1[N:6]2[C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[NH:9][CH2:10][CH2:11][C:5]2=[N:4][N:3]=1.[Cl:16][C:17]1[CH:18]=[CH:19][C:20](F)=[N:21][CH:22]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([N:9]2[CH2:10][CH2:11][C:5]3=[N:4][N:3]=[C:2]([CH3:1])[N:6]3[C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]2=3)=[N:21][CH:22]=1
Reactant: Fc1ccc(Cl)cn1
Reactant: Cc1nnc2n1-c1ccccc1NCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nnc2n1-c1ccccc1N(c1ccc(Cl)cn1)CC2
Temperature: 170 °C
Reaction time: 0.5 h

Procedure:
A mixture of 1-methyl-5,6-dihydro-4H-benzo[b][1,2,4]triazolo[4,3-d][1,4]diazepine (300 mg, 1.5 mmol), 5-chloro-2-fluoropyridine (600 mg, 4.5 mmol) and K2CO3 (621 mg, 4.5 mmol) in 10 mL of DMF was stirred at 170° C. for 30 min. After the solvent was removed in vacuo, the product was purified by flash chromatography eluting with DCM:MeOH=10:1 to give 6-(5-chloropyridin-2-yl)-1-methyl-5,6-dihydro-4H-benzo[b][1,2,4]triazolo[4,3-d][1,4]diazepine as a yellow solid. (50 mg, 11.3%).
Reaction SMILES: C[O:2][C:3](=O)[C@H:4]([C@H:13]([CH2:15][CH3:16])[CH3:14])[NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].[H-].C([Al+]CC(C)C)C(C)C>C1(C)C=CC=CC=1.CCCCCC>[C:9]([O:8][C:6]([NH:5][C@H:4]([CH:3]=[O:2])[C@H:13]([CH2:15][CH3:16])[CH3:14])=[O:7])([CH3:10])([CH3:12])[CH3:11]
Reactant: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)OC
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: CC[C@H](C)[C@@H](C=O)NC(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 98 %

Procedure:
A mixture of L-isoleucine methyl ester (24.3 g., 0.134 mmoles) and triethylamine (13.5 g., 0.134 mmoles) in methylene chloride (210 ml.) was prepared and a solution of ditertbutyldicarbonate (Aldrich, 29.1 g., 0.134 mmoles) in methylene chloride (25 ml.) was added dropwise to this mixture at 0° C. After completion of this addition, the mixture was allowed to warm to room temperature overnight and was then filtered. The filtrate was washed successively with H2O (3×75 ml.), aqueous 0.1N HCl solution, H2O (1×100 ml.) and saturated aqueous NaHCO3 solution (1×75 ml.), dried (MgSO4) and evaporated to yield N-(t-butyloxycarbonyl)-L -isoleucine methyl ester as an oil [30.7 g; 93% yield; lH-NMR (CDCl3): delta 0.92 (d, J=7, 6H), 1.43 (s, 9H), 3.70 (s, 3H), 4.17 (dd, J=5, 9, 1H), 5.03 (d, J=9, 1H)]. A solution of the N-(t-butyloxycarbonyl)-L-isoleucine methyl ester oil (15.0 g., 61.1 mmoles) in dry toluene (260 ml.) was cooled to -78° C., and a 1M solution of diisobutyl aluminum hydride in hexane (153 ml.) was added dropwise thereto at such a rate that the temperature of the exothermic reaction did not exceed -65° C. Followed by 15 minutes of additional stirring at -78° C. After completion of this addition, the mixture was carefully quenched with 15 ml. of methanol (the mixture temperature was not allowed to exceed -65° C.) followed by 200 ml. of Rochelle salt solution. After warming to room temperature, the organic layer was separated and extracted with ether (3×200 ml.); additional Rochelle salt solution was added when necessary to dissolve the aluminum salts. The combined organic extract was dried (Na2SO4 ) and evaporated to afford a crude product as an oil. The oil was stored at -78° C. to avoid possible racemization and was used without purification in the next step [132 g.; 98% yield; Rf =0.32 in 35% ether in hexane; 1H-NMR (CDCl3) delta 1.00 (d, J=7, 6 H), 1.46 (s, 9H), 9.65 (s, 1H)].
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7](Cl)[CH:6]=1.[F:13][C:14]([F:26])([F:25])[O:15][C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C(Cl)Cl.N#N>C1(C)C=CC=CC=1.CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([C:19]2[CH:18]=[CH:17][C:16]([O:15][C:14]([F:13])([F:25])[F:26])=[CH:21][CH:20]=2)[CH:6]=1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Reactant: COC(=O)Cc1ccnc(Cl)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: N#N
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COC(=O)Cc1ccnc(-c2ccc(OC(F)(F)F)cc2)c1
Temperature: 25 °C
Yield: 74.4 %

Procedure:
A mixture of methyl(2-chloropyridin-4-yl)acetate (1.0 g, 5.4 mmol), 4-(trifluoromethoxy)phenylboronic acid (1.67 g, 8.0 mmol) and potassium phosphate (1.7 g, 8.0 mmol) in toluene (15 ml) was degassed, evacuated and N2 filled (×3). [1,1′-bis(diphenylphosphino)ferrocene]dichloro palladium (H), complex with DCM (1:1) (330 mg, 0.4 mmol, 5 mol %) was added and following a further degassing, evacuation and N2 fill (×3), the mixture was heated at reflux for 16 hours. The reaction was cooled to room temperature and diluted with EtOAc (100 ml). The mixture was filtered through a Celite® pad, washing through with EtOAc and the filtrate was evaporated. The residue was purified by chromatography on silica, eluting with 15-20% EtOAc/isohexane to give the ester (1.25 g, 75%) as a pale gum. 1H NMR (400 MHz, CDCl3) δ: 3.70 (2H, s), 3.74 (3H, s), 7.20 (1H, dd, J 1.5, 5.0), 7.31 (2H, d, J 8.8), 7.64 (1H, s), 8.00-8.04 (2H, m), 8.64 (1H, d, J 5.0).
Reaction SMILES: [CH3:1]CN=C=NCCCN(C)C.[C:12]([O:20][C:21]([N:23]1[CH2:28][CH2:27][CH:26]([N:29]2[CH2:34][CH2:33][CH2:32][N:31]([CH2:35][C:36](O)=[O:37])[C:30]2=[O:39])[CH2:25][CH2:24]1)=[O:22])(=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.CN.C1C=CC2N(O)N=NC=2C=1>C1COCC1.C1COCC1.ClCCl>[CH3:1][C:36]([CH2:35][N:31]1[CH2:32][CH2:33][CH2:34][N:29]([CH:26]2[CH2:27][CH2:28][N:23]([C:21]([O:20][CH2:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)=[O:22])[CH2:24][CH2:25]2)[C:30]1=[O:39])=[O:37]
Reactant: O=C(O)CN1CCCN(C2CCN(C(=O)OC(=O)c3ccccc3)CC2)C1=O
Reactant: CCN=C=NCCCN(C)C
Agent: CN
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(=O)CN1CCCN(C2CCN(C(=O)OCc3ccccc3)CC2)C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 104.3 %

Procedure:
WSC (0.39 g) was added to a solution of [3-{1-[(benzoyloxy)carbonyl]piperidin-4-yl}-2-oxotetrahydropyrimidin-1(2H)-yl]acetic acid (0.70 g) obtained in Example 36a), a solution of methylamine in THF (1.85 mL) and HOBt (0.31 g) in THF/dichloromethane (1/1, 30 mL) and the mixture was stirred at room temperature overnight. The solvent were distilled off under reduced pressure, and the residue was diluted with ethyl acetate. The mixture was washed with an aqueous saturated sodium bicarbonate solution and saturated saline solution, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified with basic silica gel column chromatography (ethyl acetate) to obtain the title compound (0.70 g, 97%) as a white powder.