Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[CH2:11][CH2:10][CH2:9][CH2:8][C:7]=2[C:6]([C:13](=[O:18])[CH2:14][CH2:15][CH2:16]Cl)=[CH:5][CH:4]=1.[NH:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1.[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)C>[CH3:1][O:2][C:3]1[C:12]2[CH2:11][CH2:10][CH2:9][CH2:8][C:7]=2[C:6]([C:13](=[O:18])[CH2:14][CH2:15][CH2:16][N:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C(=O)CCCCl)c2c1CCCC2
Reactant: C1CCNC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)CCCN2CCCC2)c2c1CCCC2
Temperature: 60 °C
Reaction time: 10 h
Yield: 81.9 %

Procedure:
A mixture of 1-(4-methoxy-5,6,7,8-tetrahydro-1-naphthyl)-4-chloro-1-butanone (4.0g), pyrrolidine (4.27g), potassium iodide (0.3g) and potassium carbonate (2.0g) in absolute N,N-dimethylformamide (30 ml) was stirred at 60° C. for 10 hours. The reaction mixture was filtered and then the filtrate was partitioned into water and ethyl acetate. The organic layer was extracted, washed with water and then dried over anhydrous magnesium sulfate. The mixture was filtered and the filtrate was evaporated in vacuo to give the residue. The residue was dissolved in ethyl ether. The ethyl ether solution was extracted with 1N hydrochloric acid. The aqueous layer was neutralized with ammonia water and then extracted with ethyl ether. The ethyl ether was dried over anhydrous magnesium sulfate. The solution was filtered and the filtrate was evaporated in vacuo to give 1-(4-methoxy-5,6,7,8-tetrahydro-1-naphthyl)-4-pyrrolidino-1-butanone (3.7 g; yield: 82%) as an oil.
Reaction SMILES: [CH3:1][C:2]([C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20]([NH2:22])=[O:21])([CH3:17])[CH2:3][C:4]([C:13]([F:16])([F:15])[F:14])([O:8][Si](C)(C)C)[CH2:5][C:6]#[CH:7].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.C(OCC)(=O)C>[OH:8][C:4]([C:13]([F:14])([F:15])[F:16])([CH2:5][C:6]#[CH:7])[CH2:3][C:2]([C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20]([NH2:22])=[O:21])([CH3:1])[CH3:17]
Reactant: C#CCC(CC(C)(C)c1ccccc1C(N)=O)(O[Si](C)(C)C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C#CCC(O)(CC(C)(C)c1ccccc1C(N)=O)C(F)(F)F
Reaction time: 1 h
Yield: 93.5 %

Procedure:
2-(1,1-dimethyl-3-trifluoromethyl-3-trimethylsilanyloxyhex-5-ynyl)benzamide (108 mg, 0.28 mmol) was treated with a 1M solution of TBAF in 3 mL of THF. The reaction mixture was stirred for 1 hour then diluted with 50 mL of ethyl acetate, washed with 25 mL of 1 M aqueous HCl, two 25 mL portions of saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude was purified by flash chromatography (12 g SiO2, hexanes to 1:1 hexanes:EtOAc) to give 2-(3-hydroxy-1,1-dimethyl-3-trifluoromethylhex-5-ynyl)benzamide as a white solid (82 mg, 93%). MS (ES+) m/z 314 [M+H]+.
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][C:10](=O)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:14]COCC.[OH-].[Na+]>C1COCC1.[CH3-].C[Al+]C.[CH-]1C=CC=C1.[CH-]1C=CC=C1.[Cl-].[Ti+3]>[C:1]1([CH:7]2[CH2:12][CH2:11][C:10](=[CH2:14])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOCC
Reactant: O=C1CCC(c2ccccc2)CC1
Agent: [Ti+3]
Agent: C[Al+]C
Agent: [CH3-]
Solvent: C1CCOC1
Product: C=C1CCC(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 61 %

Procedure:
μ-Chloro-μ-methylene[bis(cyclopentadienyl)titanium]dimethylaluminum (172 mL, 0.086 mol, 0.5 M in toluene) is added dropwise to a solution of 4-phenylcyclohexanone (15.0 g, 0.086 mol) in THF (100 mL) at 0° C. The mixture is allowed to come to 25° C. After 15 min., ether (100 mL) is added followed by dropwise addition of 0.1 M sodium hydroxide (120 mL). The mixture is stirred an 25° C. for 18 h, filtered, and the filtrate is dried over sodium sulfate and concentrated in vacuo . The residue is purified by column chromatography on silica gel using dichloromethane-hexanes (1:1) as eluent. The resulting yellow oil is rechromatographed using hexanes as eluent to give 8.9 g (61%) of 4-phenyl-1-methylenecyclohexane as an oil.
Reaction SMILES: OCC1(CN[C:10]([C:12]2[N:13]([CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([O:30][C:31]([F:34])([F:33])[F:32])[CH:25]=3)[C:14]3[C:19]([CH:20]=2)=[CH:18][C:17]([C:21]#[N:22])=[CH:16][CH:15]=3)=[O:11])CCCC1.C(C1C=C2C(=CC=1)N(CC1C=CC=C(OC(F)(F)F)C=1)C(C(O)=O)=C2)#N.Cl.[CH2:62]([O:64][C:65](=[O:70])[CH:66]([CH3:69])[CH2:67][NH2:68])[CH3:63]>>[CH2:62]([O:64][C:65](=[O:70])[CH:66]([CH3:69])[CH2:67][NH:68][C:10]([C:12]1[N:13]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([O:30][C:31]([F:34])([F:32])[F:33])[CH:25]=2)[C:14]2[C:19]([CH:20]=1)=[CH:18][C:17]([C:21]#[N:22])=[CH:16][CH:15]=2)=[O:11])[CH3:63]
Reactant: N#Cc1ccc2c(c1)cc(C(=O)NCC1(CO)CCCC1)n2Cc1cccc(OC(F)(F)F)c1
Reactant: CCOC(=O)C(C)CN
Agent: Cl
Agent: N#Cc1ccc2c(c1)cc(C(=O)O)n2Cc1cccc(OC(F)(F)F)c1
Product: CCOC(=O)C(C)CNC(=O)c1cc2cc(C#N)ccc2n1Cc1cccc(OC(F)(F)F)c1
Yield: 51 %

Procedure:
3-{[5-Cyano-1-(3-trifluoromethoxybenzyl)-1H-indole-2-carbonyl]amino}-2-methyl-propionic acid ethyl ester was prepared in the same manner as 5-cyano-1-(3-trifluoromethoxybenzyl)-1H-indole-2-carboxylic acid (1-hydroxymethyl-cyclopentylmethyl)amide from 5-cyano-1-(3-trifluoromethoxybenzyl)-1H-indole-2-carboxylic acid (300 mg, 83.3 mmol) and 3-aminoisobutyric acid ethyl ester, hydrochloride (168 mg, 0.10 mmol) giving 3-{[5-cyano-1-(3-trifluoromethoxybenzyl)-1H-indole-2-carbonyl]amino}-2-methylpropionic acid ethyl ester (204 mg, 51%).
Reaction SMILES: [CH3:1][NH:2]CC1C=CC=CC=1.C(=O)(O)[O-].[Na+].[F:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23](Cl)=O)=[CH:18][CH:17]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+]>ClCCl.O1CCCC1.CO.[C].[Pd].O>[F:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][NH:2][CH3:1])=[CH:18][CH:17]=1
Reactant: O=C(Cl)Cc1ccc(F)cc1
Reactant: CNCc1ccccc1
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Al+3]
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: CNCCc1ccc(F)cc1
Yield: 80.3 %

Procedure:
To a mixture solution of N-methyl benzylamine (11 g) in dichloromethane and an aqueous solution containing sodium bicarbonate (16 g) was added dropwise 4-fluorophenyl acetyl chloride (12 g) at room temperature with vigorously stirring. After stirring for 1 hour, the organic layer was separated and washed with 2N hydrochloric acid water, water, an aqueous solution of 2N sodium hydroxide and water, in this order. The organic layer was dried with anhydrous magnesium sulfate, and the colorless oily matter (18 g) was obtained. To a suspension of 4 lithium aluminum hydride (4.5 g) in tetrahydrofuran (250 mL) was added dropwise the oily substance (18 g) obtained above in tetrahydrofuran (250 mL) After stirring for 1 hour, water (4.5 mL), an aqueous solution of 15% sodium hydroxide (4.5 mL), and water (13.5 mL) were added in this order, and the resulting precipitate was removed by filtration. The residue that was obtained by evaporated the filtrate in vacuo was purified with NH silica gel (hexane/ethyl acetate), and the colorless oily matter (13.6 g) was obtained. This oily substance was dissolved in methanol (200 mL), a catalytic reduction by 5% palladium-carbon (1 g) was carried out at 50° C. under hydrogen atmosphere, and the title compound (8.55 g) was obtained as a light brown oily substance.
Reaction SMILES: FC1C=CC2OC(C(N3CCN(CC4C=CC=CC=4)CC3)=O)CC=2C=1.Cl.[CH3:27][O:28][C:29]1[CH:38]=[CH:37][CH:36]=[C:35]2[C:30]=1[CH:31]=[C:32]([C:39]([N:41]1[CH2:46][CH2:45][N:44]([CH2:47][C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)[CH2:43][CH2:42]1)=O)[CH2:33][O:34]2>>[CH3:27][O:28][C:29]1[CH:38]=[CH:37][CH:36]=[C:35]2[C:30]=1[CH:31]=[C:32]([CH2:39][N:41]1[CH2:42][CH2:43][N:44]([CH2:47][C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)[CH2:45][CH2:46]1)[CH2:33][O:34]2
Reactant: COc1cccc2c1C=C(C(=O)N1CCN(Cc3ccccc3)CC1)CO2
Agent: Cl
Agent: O=C(C1Cc2cc(F)ccc2O1)N1CCN(Cc2ccccc2)CC1
Product: COc1cccc2c1C=C(CN1CCN(Cc3ccccc3)CC1)CO2

Procedure:
By carrying out the preparation as in Example 1, but replacing 1-[(5-fluoro-2,3-dihydrobenzofur-2-yl)carbonyl]-4-benzylpiperazine with the 1-[(5-methoxychrom-3-en-3-yl)carbonyl]-4-benzylpiperazine hydrochloride in the preceding stage, the title product is obtained.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=3)[N:10]=2)=[CH:4][C:5](F)=[N:6][CH:7]=1.[NH2:24][C@@H:25]1[CH2:29][CH2:28][C@H:27]([C:30]([OH:32])=[O:31])[CH2:26]1.[OH-].[K+]>O1CCOCC1>[Cl:1][C:2]1[C:3]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=3)[N:10]=2)=[CH:4][C:5]([NH:24][C@@H:25]2[CH2:29][CH2:28][C@H:27]([C:30]([OH:32])=[O:31])[CH2:26]2)=[N:6][CH:7]=1
Reactant: N[C@@H]1CC[C@H](C(=O)O)C1
Reactant: Fc1cccc(CNc2cccc(-c3cc(F)ncc3Cl)n2)c1
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(O)[C@H]1CC[C@@H](Nc2cc(-c3cccc(NCc4cccc(F)c4)n3)c(Cl)cn2)C1
Temperature: 100 °C
Reaction time: 18 h
Yield: 7.5 %

Procedure:
To 5′-chloro-2′-fluoro-N-(3-fluorobenzyl)-2,4′-bipyridin-6-amine (100 mg, 0.301 mmol), was added (1S,3R)-3-aminocyclopentanecarboxylic acid (117 mg, 0.904 mmol), powdered potassium hydroxide (85 mg, 1.507 mmol) and dioxane (1 ml). The reaction mixture was stirred at 100° C. for 18 hr in a sealed vessel and followed by LCMS. The crude reaction mixture was partitioned between 30 mL saturated ammonium chloride and 30 mL ethyl acetate. The organic layer was removed, dried over sodium sulfate, and reduced. This was redissolved in 1.5 mL DMSO, filtered, and purified through prep LC. The product fractions were combined and extracted with 50 mL ethyl acetate, which was dried over sodium sulfate, and concentrated to constant mass. 10 mg of the desired compound was obtained. LCMS (m/z): 441.2 (MH+), retention time=0.68 min. 1H NMR (400 MHz, CHLOROFORM-d, 25° C.) δ ppm 1.59 (m, 2 H) 1.83 (m, 2 H) 1.99 (m, 1 H) 2.72 (m, 1 H) 3.40 (br. s., 1 H) 3.78 (br. s., 1 H) 4.42 (br. s., 1 H) 5.48 (br. s., 1 H) 6.29 (d, J=8.22 Hz, 1 H) 6.50 (s, 1 H) 6.80-6.92 (m, 2 H) 6.95-7.10 (m, 2 H) 7.16-7.25 (m, 1 H) 7.38 (t, J=8.02 Hz, 1 H) 7.89 (s, 1 H).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][OH:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:17][S:18](Cl)(=[O:20])=[O:19]>O1CCCC1>[CH3:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][O:9][S:18]([CH3:17])(=[O:20])=[O:19])=[CH:4][CH:3]=1
Reactant: Cc1ccc(CO)cn1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1ccc(COS(C)(=O)=O)cn1
Reaction time: 0.5 h

Procedure:
To a solution of (6-Methyl-pyridin-3-yl)-methanol (24.36 kg, 198 mol) dissolved in tetrahydrofuran (80 kg) under nitrogen at −3° C. was added triethylamine (22.14 kg, 218.8 mol) over 30 mins followed by methanesulphonyl chloride (23.16 kg, 202.2 mol) over 3 hr and the slurry stirred for an additional 30 mins. The slurry was then filtered to remove triethylamine hydrochloride and the cake washed four times with tetraydrofuran (21.6 kg). An aliquot was removed and concentrated and analysed.
Reaction SMILES: [F:1][C:2]1[C:7]2[O:8][CH2:9][CH2:10][O:11][C:6]=2[CH:5]=[C:4]([CH:12]([C:15](=O)[CH3:16])[C:13]#[N:14])[CH:3]=1.Cl.Cl.[NH2:20][NH2:21].C(N(CC)CC)C>C(O)C>[F:1][C:2]1[C:7]2[O:8][CH2:9][CH2:10][O:11][C:6]=2[CH:5]=[C:4]([C:12]2[C:15]([CH3:16])=[N:20][NH:21][C:13]=2[NH2:14])[CH:3]=1
Reactant: CC(=O)C(C#N)c1cc(F)c2c(c1)OCCO2
Reactant: NN
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1n[nH]c(N)c1-c1cc(F)c2c(c1)OCCO2
Temperature: 25 °C
Yield: 92.6 %

Procedure:
2-(8-fluoro-2,3-dihydro-1,4-benzodioxin-6-yl)-3-oxobutanenitrile (0.37 g; 1.56 mmol) was dissolved in dry ethanol (5 mL) and hydrazine dihydrochloride (0.20 g, 1.87 mmol) then triethylamine (217 μg, 1.56 mmol) were added. The reaction mixture was refluxed for 2 h, cooled to rt and the solvent was evaporated under vacuum. The residue was dissolved in ethyl acetate (50 ml), washed with saturated sodium bicarbonate (2×25 mL), brine (25 ml) then dried over sodium sulfate. Filtration and concentration gave 4-(8-fluoro-2,3-dihydro-1,4-benzodioxin-6-yl)-3-methyl-1H-pyrazol-5-amine (0.36 g, 93% yield) as an orange solid. 1H NMR (400 MHz, d6-DMSO) δ 6.75 (dd, 1H), 6.65 (m, 1H), 4.30 (m, 4H), 2.14 (s, 3H). MS (EI) for C12H12FN3O2: 250 (MH+).
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:12]=[CH:11][C:10]([N:13]([C:22]([O:24]CC(Cl)(Cl)Cl)=O)C(OCC(Cl)(Cl)Cl)=O)=[CH:9][CH:8]=1.[C:30]1([C:36]2[N:40]=[C:39]([N:41]3[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]3)[S:38][N:37]=2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(N(C(C)C)CC)(C)C.CS(C)=O>O>[O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:8]=[CH:9][C:10]([NH:13][C:22]([N:44]2[CH2:45][CH2:46][N:41]([C:39]3[S:38][N:37]=[C:36]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[N:40]=3)[CH2:42][CH2:43]2)=[O:24])=[CH:11][CH:12]=1
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Reactant: O=C1CCCN1c1ccc(N(C(=O)OCC(Cl)(Cl)Cl)C(=O)OCC(Cl)(Cl)Cl)cc1
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(N2CCCC2=O)cc1)N1CCN(c2nc(-c3ccccc3)ns2)CC1
Yield: 29.9 %

Procedure:
A solution of bis(2,2,2-trichloroethyl) [4-(2-oxopyrrolidin-1-yl)phenyl]imidodicarbonate (200 mg, 0.380 mmol), 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (140 mg, 0.569 mmol), diisopropylethylamine (0.198 ml, 1.14 mmol) and dimethyl sulfoxide (4 ml) was stirred at 70° C. for 24 hours, the reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was recrystallized from ethyl acetate to give 51.0 mg (30.0%) of the desired product as a solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:14]2[CH2:18][CH:17]([CH2:19][NH:20][C:21](=O)[CH3:22])[O:16][N:15]=2)[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][S:11][CH2:10][CH2:9]1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:33])=CC=1.ClCCl>O1CCOCC1>[F:1][C:2]1[CH:3]=[C:4]([C:14]2[CH2:18][CH:17]([CH2:19][NH:20][C:21](=[S:33])[CH3:22])[O:16][N:15]=2)[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][S:11][CH2:10][CH2:9]1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC(=O)NCC1CC(c2ccc(N3CCSCC3)c(F)c2)=NO1
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC(=S)NCC1CC(c2ccc(N3CCSCC3)c(F)c2)=NO1
Temperature: 80 °C
Reaction time: 1 h
Yield: 85.1 %

Procedure:
1.0 g (3.0 mmole) of N-({3-[3-fluoro-4-(4-thiomorpholinyl)phenyl]-4,5-dihydro-5-isoxazolyl}methyl)acetamide is suspended in 12 ml dioxane in a 50 ml one neck round bottom flask under nitrogen. The suspension is treated with Lawesson's Reagent (1.27 g, 3.15 mmole) and the reaction is stirred at 80° C. for 1 hour. The mixture is cooled to room temperature, brought to homogeneity with dichloromethane and is treated with 10 g silica gel (230-400 mesh) and is concentrated to dryness. The plug is loaded onto a SIM and the material is chromatographed twice over 40 g silica gel (BIOTAGE), eluting with 7% acetone/dichloromethane while collecting 25 ml fractions. Fractions 6-13 are combined and concentrated to afford 902 mg (85%) of the title compound as a solid. mp=219-220° C.
Reaction SMILES: CS([C:4]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[F:15])[S:6][N:5]=1)=O.CS(C1N=C(C2C=CC=CC=2F)SN=1)(=O)=O.[CH2:32]([OH:36])[C:33]#[C:34][CH3:35].[H-].[Na+].[Cl-].[Na+]>CN(C)C=O>[F:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[C:7]1[S:6][N:5]=[C:4]([O:36][CH2:32][C:33]#[C:34][CH3:35])[N:8]=1
Reactant: CS(=O)c1nsc(-c2ccccc2F)n1
Reactant: CC#CCO
Agent: CS(=O)(=O)c1nsc(-c2ccccc2F)n1
Agent: [Cl-]
Agent: [H-]
Solvent: CN(C)C=O
Product: CC#CCOc1nsc(-c2ccccc2F)n1
Reaction time: 0.17 h

Procedure:
To 2 ml of N,N-dimethylformamide were added 295 mg of a mixture of 3-methylsulfinyl-5-(2-fluorophenyl)-1,2,4-thiadiazole and 3-methylsulfonyl-5-(2-fluorophenyl)-1,2,4-thiadiazole (integration ratio of 1H-NMR sulfonyl form:sulfinyl form=4:1) and 85 mg of 2-butyne-1-ol, to the resulting mixture was added 55 mg of sodium hydride (60% oily) with ice-cooling, and the mixture was stirred for 10 minutes, and further stirred at room temperature for 3 hours. The reaction mixture was poured into an aqueous saturated sodium chloride solution, and the mixture was extracted with t-butyl methyl ether. The organic layer was concentrated, and the residue was subjected to silica gel column chromatography to obtain 227 mg of 5-(2-fluorophenyl)-3-(2-butynyloxy)-1,2,4-thiadiazole (the compound (5) of the present invention).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[N:3]=1.Br[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1>[CH3:8][C:4]1[N:3]=[C:2]([NH:1][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: Cc1cccc(N)n1
Reactant: Brc1ccccn1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cc1cccc(Nc2ccccn2)n1

Procedure:
To a flask were added 3.2 g of 2-amino-6-methylpyridine, 4.9 g of 2-bromopyridine, 3.5 g of sodium tert-butoxide, and 120 ml toluene. The mixture was purged thoroughly with nitrogen and 83 mg of 1,1′-bis(diphenylphosphino)ferrocene and 34 mg of palladium acetate were added. The reaction mixture was heated to 65 C for 3 hours, to 75 C for 2 hours, and then cooled to 22 C. After quenching with 75 ml of water, the product was extracted with 75 ml ethyl acetate. The product was extracted with 50 ml of 1M hydrochloric acid, and washed with 30 ml of ethyl acetate. After basifying with 3M sodium hydroxide, the product was extracted with 75 ml of ethyl acetate and washed with 30 ml of water. Following solvent removal, the product was purified by silica gel chromatography using 38% ethyl acetate, 50% hexane, and 12% methanol resulting in an orange oil.
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[O:14][CH3:15])[C:8]([OH:10])=[O:9])(=O)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O.O1CCOCC1>C1(C)C=CC=CC=1>[SH:2][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[O:14][CH3:15])[C:8]([OH:10])=[O:9]
Reactant: COc1ccc(C(=O)O)cc1S(=O)(=O)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccc(C(=O)O)cc1S
Temperature: 25 °C

Procedure:
A mixture of 3-chlorosulfonyl-4-methoxybenzoic acid (4.76 g; that is prepared as described in Reference Example 44) in dry toluene (500 mL) stirred at room temperature is treated with triphenylphosphine (19.9 g) in one portion. The mixture is stirred and heated at 80° C. overnight, and then it is cooled, and treated with water (25 mL) and dioxane (25 mL), and the resulting solution is heated on a steam bath for 1 hour. The reaction mixture is allowed to cool to room temperature, and the organic layer is collected and concentrated. The resulting residue is partitioned between ethyl acetate (200 mL) and aqueous sodium hydroxide solution (500 mL; 2N). The aqueous layer is separated, acidified by treatment with concentrated hydrochloric acid, and extracted with ethyl acetate (100 mL). The extract is washed with water (100 mL), dried over magnesium sulfate and concentrated, to give 3-mercapto-4-methoxybenzoic acid in the form of a white solid (3.4 g), m.p. 208-210° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]1[C:13]2[C:8](=[C:9]([CH3:15])[CH:10]=[CH:11][C:12]=2[CH3:14])[S:7][CH2:6][CH2:5]1.[Cl-].[Al+3].[Cl-].[Cl-].[C:20](Cl)(=[O:22])[CH3:21]>ClC(Cl)C>[C:20]([C:11]1[C:12]([CH3:14])=[C:13]2[C:8](=[C:9]([CH3:15])[CH:10]=1)[S:7][CH2:6][CH2:5][CH:4]2[CH2:3][O:2][CH3:1])(=[O:22])[CH3:21]
Reactant: CC(=O)Cl
Reactant: COCC1CCSc2c(C)ccc(C)c21
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Product: COCC1CCSc2c(C)cc(C(C)=O)c(C)c21
Temperature: 0 °C
Yield: 30 %

Procedure:
To a solution of 0.84 g (3.78 mmol) of 4-methoxymethyl-5,8-dimethylthiochroman and 0.60 g (4.54 mmol) of aluminum chloride in dichloroethane was dropwise added 0.36 g (4.54 mmol) of acetyl chloride at 0° C., and the mixture was further allowed to react at 0° C. for 1 hour. The reaction mixture was poured into ice water, and extracted with ethyl acetate. The extract was washed with a saturated sodium chloride aqueous solution, and an organic layer was dried over anhydrous sodium sulfate and filtered. Then, the solvent was distilled off under reduced pressure to give 0.30 g (yield 30%) of the titled compound as a crude product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[C:16]([CH:17]=[O:18])=[CH:15][N:14](C3CCCCO3)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10]>Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[C:16]([CH:17]=[O:18])=[CH:15][NH:14][N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10]
Reactant: CC(C)Oc1ccc(-c2nn(C3CCCCO3)cc2C=O)cc1Cl
Agent: Cl
Product: CC(C)Oc1ccc(-c2n[nH]cc2C=O)cc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 116.4 %

Procedure:
A mixture of 3-(3-chloro-4-isopropoxyphenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-4-carbaldehyde (600 mg, 1.72 mmol, 1.00 equiv) in a saturated methanolic HCl (50 mL) was stirred at 25° C. for 2 h. The resulting mixture was concentrated under vacuum to give 530 mg of crude 3-(3-chloro-4-isopropoxyphenyl)-1H-pyrazole-4-carbaldehyde as a white solid. LCMS (method C, ESI): RT=0.86 min, m/z=265.0 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:13][CH2:12][NH:11][CH:10]([C:14](O)=[O:15])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.CSC.B>>[NH2:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:13][CH2:12][NH:11][CH:10]([CH2:14][OH:15])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(N2CCNC(C(=O)O)C2)c1
Agent: B
Solvent: CSC
Product: Nc1cccc(N2CCNC(CO)C2)c1

Procedure:
In a manner similar to Preparation 18, react 4-(3-aminophenyl)-2-piperazinecarboxylic acid with borane dimethylsulfide to obtain the title compound.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]([F:15])([F:14])[CH2:8][N:7]([CH:16]3[CH2:19][CH2:18][CH2:17]3)[C:6]=2[N:20]=1.O.C1(C)C(S(O)(=O)=O)=CC=CC=1.[NH2:33][C:34]1[CH:47]=[CH:46][C:37]([C:38]([NH:40][CH2:41][CH2:42][N:43]([CH3:45])[CH3:44])=[O:39])=[CH:36][C:35]=1[O:48][CH3:49]>C(O)(C)C>[CH:16]1([N:7]2[CH2:8][C:9]([F:15])([F:14])[C:10](=[O:13])[N:11]([CH3:12])[C:5]3[CH:4]=[N:3][C:2]([NH:33][C:34]4[CH:47]=[CH:46][C:37]([C:38]([NH:40][CH2:41][CH2:42][N:43]([CH3:44])[CH3:45])=[O:39])=[CH:36][C:35]=4[O:48][CH3:49])=[N:20][C:6]2=3)[CH2:19][CH2:18][CH2:17]1
Reactant: CN1C(=O)C(F)(F)CN(C2CCC2)c2nc(Cl)ncc21
Reactant: COc1cc(C(=O)NCCN(C)C)ccc1N
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: O
Solvent: CC(C)O
Product: COc1cc(C(=O)NCCN(C)C)ccc1Nc1ncc2c(n1)N(C1CCC1)CC(F)(F)C(=O)N2C
Yield: 39.4 %

Procedure:
A mixture of 0.0663 g (0.219 mmole) 2-chloro-9-cyclobutyl-7,7-difluoro-5-methyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-1), 0.0625 g (0.33 mmole) of toluenesulfonic acid monohydrate, 0.052 g (0.219 mmole) of 4-amino-N-(2-dimethylamino-ethyl)-3-methoxy-benzamide and 1 mL of isopropanol was heated in a sealed vessel at 140 degrees for 19.5 hours, cooled and concentrated under reduced pressure. The residue taken up in ethyl acetate and washed successively with 50 mL of saturated aqueous sodium bicarbonate, 50 mL of water, 50 mL of brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with acetonitrile-methanol-triethylamine (85:15:1) and then recrystallization from acetonitrile to give 0.0434 g of 4-(9-cyclobutyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(2-dimethylamino-ethyl)-3-methoxy-benzamide (I-8) as a white solid.