Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH:12]1[CH2:15][CH:14]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:13]1.CCN(C(C)C)C(C)C>C(O)C>[S:8]([C:5]1[CH:4]=[CH:3][C:2]([N:12]2[CH2:15][CH:14]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:21])([CH3:20])[CH3:22])[CH2:13]2)=[N:7][CH:6]=1)(=[O:10])(=[O:9])[NH2:11]
Reactant: CC(C)(C)OC(=O)NC1CNC1
Reactant: NS(=O)(=O)c1ccc(Cl)nc1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NC1CN(c2ccc(S(N)(=O)=O)cn2)C1
Temperature: 0 °C

Procedure:
6-chloropyridine-3-sulfonamide (0.32 g, 1.66 mmol) was added to a stirred solution of tert-butyl azetidin-3-ylcarbamate (0.30 g, 1.74 mmol) and DIPEA (0.9 ml, 0.65 g, 4.98 mmol) in 10 ml of ethanol and heated to reflux for 16 h. Reaction mass was cooled to 0° C. The solid formed was filtered and dried under vacuum to obtain desired product.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH:10]=[N:11]O)[CH:8]=2)[CH:3]=[CH:2]1.C(N(CC)CC)C>C1COCC1>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]#[N:11])[CH:8]=2)[CH:3]=[CH:2]1
Reactant: ON=Cc1ccc2cc[nH]c2c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: N#Cc1ccc2cc[nH]c2c1
Temperature: 50 °C
Reaction time: 0.17 h
Yield: 102.2 %

Procedure:
2-Chloro-1-methylpyridium iodide (1.316 g) was added to a solution of 1H-indole-6-carbaldehyde oxime (D11) (750 mg) in dry THF (80 mL) at RT. After stirring for 10 min, triethylamine (2.284 mL) was added to the reaction mixture. The reaction mixture was heated to 50° C. and stirred at 50° C. for 3.5 hours, then left overnight with stirring at RT. The mixture was heated to refluxed for 5 hours. The solvent was evaporated. The residue was dissolved in EtOAc (100 mL) and water (100 mL) was added. The organic fraction was separated. The organic fraction was dried over anhydrous magnesium sulfate. The dried solution was concentrated to afford 1H-indole-6-carbonitrile (D12) as a brown solid (680 mg). δH (DMSO-d6, 400 MHz): 6.60 (1H, m), 7.32 (1H, dd), 7.68 (1H, m), 7.72 (1H, d), 7.88 (1H, m), 11.68 (1H, br s). MS (ES): C9H6N2 requires 142; found 141.0 (M−H+).
Reaction SMILES: S(=O)(=O)(O)O.[Br:6][C:7]1[C:8]([F:16])=[C:9]([C:12]([Cl:15])=[CH:13][CH:14]=1)[C:10]#[N:11].[OH-:17].[NH4+]>>[Br:6][C:7]1[C:8]([F:16])=[C:9]([C:12]([Cl:15])=[CH:13][CH:14]=1)[C:10]([NH2:11])=[O:17]
Reactant: N#Cc1c(Cl)ccc(Br)c1F
Reactant: [OH-]
Agent: O=S(=O)(O)O
Agent: [NH4+]
Product: NC(=O)c1c(Cl)ccc(Br)c1F
Temperature: 55 °C

Procedure:
Concentrated sulfuric acid (15 mL) was placed in a 100 mL 3-neck flask equipped with an internal thermometer and then heated to 55° C. 3-Bromo-2-fluoro-6-chlorobenzonitrile (11.0 g, 47 mmol) was added portion-wise to the acid with stirring maintaining the temperature above 50° C. The dark solution was heated at 65° C. for 24 hours then cooled to room temperature and poured over ice and cautiously neutralized with concentrated ammonium hydroxide. The mixture was extracted with two portions of ethyl acetate and the combined organic layers dried over Na2SO4 (with charcoal). Filtration and concentration gave 3-bromo-2-fluoro-6-chlorobenzamide (11.5 g, 45.5 mmol) as a light orange solid: mp 157-158° C., 1H NMR (CDCl3): δ 7.54 (t, 1H), 7.14 (dd, 1H), 6.03 (bs, 1H) 5.81 (bs, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4](=O)[CH:5](Cl)[C:6]1[CH:11]=[C:10]([CH3:12])[CH:9]=[C:8]([CH3:13])[CH:7]=1.[C:17]([NH2:20])(=[S:19])[CH3:18]>>[CH3:1][O:2][C:3]([C:4]1[N:20]=[C:17]([CH3:18])[S:19][C:5]=1[C:6]1[CH:11]=[C:10]([CH3:12])[CH:9]=[C:8]([CH3:13])[CH:7]=1)=[O:16]
Reactant: COC(=O)C(=O)C(Cl)c1cc(C)cc(C)c1
Reactant: CC(N)=S
Product: COC(=O)c1nc(C)sc1-c1cc(C)cc(C)c1

Procedure:
prepared by reaction of 3-Chloro-3-(3,5-dimethyl-phenyl)-2-oxo-propionic acid methyl ester with thioacetamide. LC-MS: tR=0.97 min; [M+H]+=262.3.
Reaction SMILES: [C:1]([C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17]([O:22]C)[CH:18]=2)[CH:13]=1)(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[OH-].[K+].O.NN.O>C(O)COCCO>[CH2:1]([C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCC(=O)c1ccc2cc(OC)ccc2c1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: OCCOCCO
Product: CCCCCCCCCCc1ccc2cc(O)ccc2c1
Yield: 85.5 %

Procedure:
Under a nitrogen atmosphere, 2-decanoyl-6-methoxynaphthalene (9.4 g, 30 mmol) and potassium hydroxide (67 g, 1.2 mol) were dissolved in hydrazine monohydrate (70 ml, 1.4 mol) and diethylene glycol (200 ml). The solution was refluxed for 17 hours, and water (36 ml) was added. Under a stream of nitrogen, the solution was distilled to distill away an excessive amount of hydrazine and water. Further, the solution was refluxed under a nitrogen atmosphere for 41 hours. Subsequently, while using an ice bath, the solution was cooled by putting ice into the reaction solution, hydrochloric acid was slowly added until the solution became neutral. The reaction solution was extracted with ether (100 ml×3), and the obtained organic layer was washed with saturated saline water (100 ml×5). The organic layer was dried with anhydrous magnesium sulfate, and filtered. Then, the solvent was distilled away under reduced pressure. The obtained brown solid was recrystallized from hexane to obtain 6-decyl-2-hydroxynaphthalene (7.3 g, 90%) as a white solid.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[O:15]1[CH2:20][CH2:19][CH:18]([CH2:21][NH2:22])[CH2:17][CH2:16]1.C(N(CC)CC)C.Cl>O1CCCC1>[N+:12]([C:3]1[CH:4]=[C:5]([S:8]([NH2:11])(=[O:10])=[O:9])[CH:6]=[CH:7][C:2]=1[NH:22][CH2:21][CH:18]1[CH2:19][CH2:20][O:15][CH2:16][CH2:17]1)([O-:14])=[O:13]
Reactant: NS(=O)(=O)c1ccc(F)c([N+](=O)[O-])c1
Reactant: NCC1CCOCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: NS(=O)(=O)c1ccc(NCC2CCOCC2)c([N+](=O)[O-])c1

Procedure:
A mixture of 4-fluoro-3-nitrobenzenesulfonamide (2.18 g), 1-(tetrahydropyran-4-yl)methylamine (1.14 g), and triethylamine (1 g) in tetrahydrofuran (30 mL) were stirred overnight, neutralized with concentrated HCl and concentrated. The residue was suspended in ethyl acetate and the precipitates were collected, washed with water and dried to provide the title compound.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]([F:15])([F:14])[F:13])[N:3]=1.O.[NH2:17][NH2:18]>C(O)C>[NH:17]([C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]([F:15])([F:14])[F:13])[N:3]=1)[NH2:18]
Reactant: NN
Reactant: FC(F)(F)c1nc(Cl)c2ccccc2n1
Solvent: CCO
Solvent: O
Product: NNc1nc(C(F)(F)F)nc2ccccc12

Procedure:
4-Chloro-2-trifluoromethylquinazoline (46.4 g, 0.2 mole) was taken up in ethanol (500 ml). Hydrazine hydrate (20 ml, 0.4 mole) was added and the contents refluxed for 2 hours. On cooling, the yellow precipitate was filtered and slurried in water (500 ml) to removed hydrazine hydrochloride. Filtration gave the product as a yellow crystalline solid, 34.5 g (76%).
Reaction SMILES: [CH3:1][NH:2][NH2:3].[Cl:4][C:5]1[CH:18]=[C:17]([Cl:19])[C:16]([CH3:20])=[CH:15][C:6]=1[C:7]([CH2:9][C:10](OCC)=[O:11])=O>COCCOCCOC>[Cl:4][C:5]1[CH:18]=[C:17]([Cl:19])[C:16]([CH3:20])=[CH:15][C:6]=1[C:7]1[NH:3][N:2]([CH3:1])[C:10](=[O:11])[CH:9]=1
Reactant: CCOC(=O)CC(=O)c1cc(C)c(Cl)cc1Cl
Reactant: CNN
Solvent: COCCOCCOC
Product: Cc1cc(-c2cc(=O)n(C)[nH]2)c(Cl)cc1Cl
Temperature: 0 °C
Reaction time: 4 h

Procedure:
13.5 g (292 mmol) of methylhydrazine were slowly added to 80.4 g (292 mmol) of ethyl 2,4-dichloro-5-methylbenzoylacetate in 300 ml of diethylene glycol dimethyl ether. After 4 hours at 100° C., the solution was stirred into 1 l of ice-water. The precipitate formed was filtered off, washed with a small amount of methylene chloride and dried. Yield: 38.8 g.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@:6]1([C:20]([OH:22])=O)[CH2:10][C:9](=[O:11])[N:8]([C@@H:12]([CH3:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:7]1)=[O:5])[CH3:2].OC1C2N=NNC=2C=CC=1.C1(N=C=NC2CCCCC2)CCCCC1.[CH2:48]([NH2:55])[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1>O1CCCC1>[CH2:48]([NH:55][C:20]([C@@:6]1([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:10][C:9](=[O:11])[N:8]([C@@H:12]([CH3:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:7]1)=[O:22])[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1
Reactant: CCOC(=O)[C@]1(C(=O)O)CC(=O)N([C@@H](C)c2ccccc2)C1
Reactant: NCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Oc1cccc2[nH]nnc12
Solvent: C1CCOC1
Product: CCOC(=O)[C@]1(C(=O)NCc2ccccc2)CC(=O)N([C@@H](C)c2ccccc2)C1
Reaction time: 48 h

Procedure:
(R)-3-Ethoxycarbonyl-1-((S)-α-methylbenzyl)-5-oxopyrrolidine-3-carboxylic acid (10 g) was dissolved in tetrahydrofuran (100 ml). Hydroxybenztriazole (0.89 g) was added and the mixture was stirred. Dicyclohexylcarbodiimide (6.76 g) and benzylamine (3.86 g) were added under ice-cooling, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was allowed to stand for 2 days and filtered through Celite. The filtrate was concentrated under reduced pressure. Ethyl acetate was added, and the mixture was washed with an aqueous solution of potassium carbonate, water, dilute hydrochloric acid and a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate. The obtained oil was purified by silica gel column chromatography (developing solvent, n-hexane:ethyl acetate=4:1) to give the object compound as a pale yellow oil.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([O:30][CH3:31])[CH:23]=2)[C:10]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([O:30][CH3:31])[CH:23]=3)[C:10]3[CH:15]=[C:14]([C:16]([F:17])([F:18])[F:19])[S:13][C:11]=3[N:12]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: c1nc[nH]n1
Reactant: COc1ccc(CNc2nc(Cl)nc3sc(C(F)(F)F)cc23)cc1OC
Product: COc1ccc(CNc2nc(-n3cncn3)nc3sc(C(F)(F)F)cc23)cc1OC

Procedure:
Following the procedure of Example 97, the reaction of 1,2,4-triazole with yields 2-chloro-6-trifluoromethyl-4-(3,4-dimethoxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(1,2,4-triazol-1-yl)-6-trifluoromethyl-4-(3,4-dimethoxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [OH-].[K+].[O:3]1[CH2:8][CH2:7][CH:6]([CH2:9][S:10]C(=O)C)[CH2:5][CH2:4]1.Br[C:15]([CH3:22])([CH3:21])[C:16]([O:18][CH2:19][CH3:20])=[O:17]>C(O)C>[CH2:19]([O:18][C:16](=[O:17])[C:15]([CH3:22])([S:10][CH2:9][CH:6]1[CH2:7][CH2:8][O:3][CH2:4][CH2:5]1)[CH3:21])[CH3:20]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: CC(=O)SCC1CCOCC1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)C(C)(C)SCC1CCOCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66.2 %

Procedure:
A solution of 0.86 g (15.2 mmol) of potassium hydroxide in ethanol (78 mL, degassed and under nitrogen) was added to 0.81 g (4.66 mmol) of thioacetic acid S-(tetrahydro-pyran-4-ylmethyl) ester. The reaction was stirred at room temperature under nitrogen for 0.5 h. Then 2.1 mL (14.1 mmol) of ethyl α-bromoisobutyrate were added and the reaction stirred for 4 h. The resulting precipitate was removed by filtration and the filtrate concentrated under reduced pressure. The residue was dissolved in DCM (100 mL) and washed with saturated aqueous NaHCO3 (50 mL), brine (50 mL) and dried over Na2SO4. Filtration and concentration of the filtrate under reduced pressure, followed by column chromatography of the residue (silica, eluent: heptanes, 0-20% ethyl acetate) afforded 0.76 g of 2-methyl-2-(tetrahydro-pyran-4-ylmethylsulfanyl)-propionic acid ethyl ester.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[CH2:6][CH2:7][OH:8].CC(C)([O-])C.[K+].F[C:21]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=1[N+:28]([O-:30])=[O:29].O>C1COCC1>[F:27][C:25]1[CH:26]=[CH:21][C:22]([N+:28]([O-:30])=[O:29])=[C:23]([O:8][CH2:7][CH2:6][C:5]2[CH:9]=[CH:10][CH:11]=[C:3]([C:2]([F:12])([F:13])[F:1])[CH:4]=2)[CH:24]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Reactant: OCCc1cccc(C(F)(F)F)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: O=[N+]([O-])c1ccc(F)cc1OCCc1cccc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Dissolved 3-(trifluoromethyl)phenethyl alcohol (657 mg, 3.46 mmol) in THF (5 mL). After cooling to 0° C., potassium tert-butoxide (1M THF, 4.08 mmol, 4.08 mL) was added and the mixture was warmed to ambient temperature and stirred for 30 min. The reaction mixture was cooled to −78° C., and 2,4-difluoronitrobenzene (500 mg, 3.14 mmol) was added. The reaction mixture was allowed to slowly warm to ambient temperature. The mixture was poured into H2O and extracted with EtOAc (2×). The combined organics were washed with brine and dried over Na2SO4. The title compound was purified by crystallization from a EtOAc:Hexane mixture.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[C:10]#[C:11][CH2:12][CH2:13][CH2:14]O.CS(Cl)(=O)=O.[I-:21].[Na+]>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[C:10]#[C:11][CH2:12][CH2:13][CH2:14][I:21]
Reactant: OCCCC#Cc1cc(F)c(F)cc1F
Reactant: [I-]
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Product: Fc1cc(F)c(C#CCCCI)cc1F

Procedure:
Reacting 5-(2,4,5-trifluorophenyl)-4-pentyn-1-ol (Compound 43) with methanesulfonyl chloride and sodium iodide gives 5-(2,4,5-trifluorophenyl)-1-iodo-4-pentyne. Treatment of this iodide with zinc and copper cyanide, as in Example 2, gives the corresponding mixed cuprate. Addition of this cuprate to 4-[(3-oxo-4,4,4-trifluoro)-1-butynyl]-2-trimethylsilylfuran (Compound 37) and hydrogenating the adduct gives 4-[1-(2-oxo-3,3,3-trifluoro)propyl-6-(2,4,5-trifluorophenyl)]hexyl-2-trimethylsilylfuran (Compound 44). Oxidizing this furan (Compound 44) with singlet oxygen gives 4-[1-(2-oxo-3,3,3-trifluoro)propyl-6-(2,4,5-trifluorophenyl)]hexyl-5-hydroxy-2(5H)-furanone (Compound 14).
Reaction SMILES: [Li]CCCC.[CH3:6][S:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:9])=[O:8].[O:16]1[CH2:19][C:18](=O)[CH2:17]1>C1COCC1>[C:10]1([S:7]([CH:6]=[C:18]2[CH2:19][O:16][CH2:17]2)(=[O:9])=[O:8])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CS(=O)(=O)c1ccccc1
Reactant: O=C1COC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=S(=O)(C=C1COC1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of BuLi (2.5 M in hexanes, 22.5 mL, 56.3 mmol) was added over 10 min to a solution of methylphenylsulfone (4.00 g, 25.6 mmol) in THF (70 mL) at 0° C. The solution went from clear to light green to a heterogeneous yellow suspension. The mixture was stirred for 30 min at 0° C. and then chlorodiethylphosphonate (4.46 mL, 30.7 mmol) was added dropwise and the stirring was continued for 30 min, at which point the solution turned clear orange. The reaction mixture was then cooled to −78° C. and oxetan-3-one (1.85 g, 25.6 mmol) was added in THF (3 mL). The reaction mixture turned pale brown/yellow in color. After stirring for another 1.5 h, the reaction mixture was filtered through a plug of silica gel. The filtrate was triturated with solid NH4Cl until pH reached 7. The mixture was then filtered and the filtrate was concentrated. The residue was purified by silica gel chromatography (0-60% EtOAc/heptane) to provide 3-((phenylsulfonyl)methylene)oxetane. 1H NMR (400 MHz, CD2Cl2) δ ppm 7.86-7.99 (m, 2 H) 7.68-7.77 (m, 1 H) 7.57-7.68 (m, 2 H) 6.18 (t, J=2.40 Hz, 1 H) 5.59-5.70 (m, 2 H) 5.30 (td, J=3.41, 2.27 Hz, 2 H)
Reaction SMILES: [CH:1]1([CH:7]([O:37][CH3:38])[C:8]2[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][C:9]=2[CH2:10][N:11]([CH2:14][C:15]2[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[C:17]([C:25]([F:28])([F:27])[F:26])[CH:16]=2)[C:12]#[N:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N-:39]=[N+:40]=[N-:41].[Na+].O>C1(C)C=CC=CC=1>[CH:1]1([CH:7]([O:37][CH3:38])[C:8]2[CH:32]=[CH:31][C:30]([C:33]([F:34])([F:35])[F:36])=[CH:29][C:9]=2[CH2:10][N:11]([CH2:14][C:15]2[CH:20]=[C:19]([C:21]([F:22])([F:23])[F:24])[CH:18]=[C:17]([C:25]([F:28])([F:27])[F:26])[CH:16]=2)[C:12]2[N:39]=[N:40][NH:41][N:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: [N-]=[N+]=[N-]
Reactant: COC(c1ccc(C(F)(F)F)cc1CN(C#N)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCCC1
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: COC(c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nn[nH]n1)C1CCCCC1
Temperature: 115 °C
Reaction time: 8 h
Yield: 58.7 %

Procedure:
To solution of (2-(cyclohexyl(methoxy)methyl)-5-(trifluoromethyl)benzyl)(3,5-bis(trifluoromethyl)benzyl)cyanamide (144 mg, 0.26 mmol) in toluene was added sodium azide (84.9 mg, 1.31 mmol) followed by TEA-HCl (178.8 mg, 1.3 mmol). The mixture was stirred at 115° C. overnight. Water was added and the mixture was extracted with ethyl acetate. Combined organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by chromatography over 25+S Biotage silica column (eluted with 5-50% ethyl acetate in heptane) to afford the title compound (90.9 mg, 59%). 1H NMR (400 MHz, CDCl3) δ ppm 0.90-1.16 (m, 5H) 1.23-1.32 (m, 1H) 1.49-1.61 (m, 3H) 1.69 (s, 1H) 1.97 (d, J=12.45 Hz, 1H) 3.21 (s, 3H) 4.05 (d, J=7.88 Hz, 1H) 4.74-4.93 (m, 4H) 7.31 (s, 1H) 7.41 (d, J=7.88 Hz, 1H) 7.52 (d, J=7.88 Hz, 1H) 7.69 (s, 2H) 7.78 (s, 1H). MS (ES+) Calc: 595.2, Found: 596.5 (M+1).
Reaction SMILES: [CH3:1][N:2]([S:23]([C:26]1[S:27][CH:28]=[CH:29][CH:30]=1)(=[O:25])=[O:24])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:13][CH:14]([CH2:17][C:18]([O:20]CC)=[O:19])[CH2:15][N:16]=1)=[CH:8]2.[OH-].[K+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1.CO>[CH3:1][N:2]([S:23]([C:26]1[S:27][CH:28]=[CH:29][CH:30]=1)(=[O:25])=[O:24])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:13][CH:14]([CH2:17][C:18]([OH:20])=[O:19])[CH2:15][N:16]=1)=[CH:8]2
Reactant: CCOC(=O)CC1CN=C(c2cc3cccc(N(C)S(=O)(=O)c4cccs4)c3[nH]2)S1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CN(c1cccc2cc(C3=NCC(CC(=O)O)S3)[nH]c12)S(=O)(=O)c1cccs1
Temperature: 25 °C
Yield: 83.3 %

Procedure:
Ethyl (2-{7-[methyl(2-thienylsulfonyl)amino]-1H-indol-2-yl}-4,5-dihydro-1,3-thiazol-5-yl)acetate (0.52 g) was dissolved in a mixed solvent of tetrahydrofuran (6 mL)-methanol (6 mL), and the mixture was ice-cooled. Aqueous potassium hydroxide solution (prepared by dissolving potassium hydroxide (0.25 g) in water (5 mL))) was added to this solution, and the mixture was stirred from under ice-cooling to room temperature for 7 hr. The reaction solution was acidified with aqueous citric acid solution, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained amorphous solid was crystallized from ethyl acetate-hexane to give the title compound (407 mg, yield: 83%) as pale-yellow prism crystals. MS: 436 (MH+). melting point 232-234° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]1[CH:16]=[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:14][N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.[CH:28](=[O:33])[CH2:29][CH:30]([CH3:32])[CH3:31]>>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]1[C:16]([CH:28]([OH:33])[CH2:29][CH:30]([CH3:32])[CH3:31])=[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:14][N:13]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCOc1cc(-c2ccccc2)on1
Reactant: CC(C)CC=O
Agent: [Li]CCCC
Product: CC(C)CC(O)c1c(OCCNC(=O)OC(C)(C)C)noc1-c1ccccc1
Yield: 77 %

Procedure:
3-(2-(N-tert-Butoxycarbonylamino)ethoxy)-5-phenylisoxazole (0.2 g), butyllithium (1.6M hexane solution, 0.9 ml) and isovaleraldehyde (0.09 ml) were subjected to reaction and post-treatment in a similar manner to that described in Example 44(a) to obtain the title compound (0.2 g, 77%) as a colorless oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([CH2:17][CH3:18])=[N:15][CH:16]=[C:10]2[CH:9]1[CH2:19][CH2:20][C:21]1[CH:26]=[C:25]([F:27])[C:24]([O:28][CH3:29])=[C:23]([F:30])[CH:22]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)[Cl:32].CO>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([CH2:17][CH3:18])=[N:15][C:16]([Cl:32])=[C:10]2[CH:9]1[CH2:19][CH2:20][C:21]1[CH:22]=[C:23]([F:30])[C:24]([O:28][CH3:29])=[C:25]([F:27])[CH:26]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCc1ncc2n1CCN(C(=O)OC(C)(C)C)C2CCc1cc(F)c(OC)c(F)c1
Reactant: ClCCl
Solvent: CO
Product: CCc1nc(Cl)c2n1CCN(C(=O)OC(C)(C)C)C2CCc1cc(F)c(OC)c(F)c1

Procedure:
Subsequent chlorination (70° C.; 3h30) of 8-[2-(3,5-difluoro-4-methoxy-phenyl)-ethyl]-3-ethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazine-7-carboxylic acid tert-butyl ester (1.330 g; 3.156 mmol), and purification by FC (DCM/MeOH=25/1) afforded 1-chloro-8-[2-(3,5-difluoro-4-methoxy-phenyl)-ethyl]-3-ethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazine-7-carboxylic acid tert-butyl ester as a yellow oil (0.730 g; 51%). LC-MS: tR=1.04 min.; [M+H]+=456.05 g/mol.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:17]([Br:18])=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:20][C@@H:21]1[CH2:26][CH2:25][CH2:24][CH2:23][C@H:22]1[OH:27].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C)C(=O)C>[CH2:1]([O:8][C:9]1[C:17]([Br:18])=[CH:16][C:12]([C:13]([NH:20][C@@H:21]2[CH2:26][CH2:25][CH2:24][CH2:23][C@H:22]2[OH:27])=[O:15])=[CH:11][N:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N[C@@H]1CCCC[C@H]1O
Reactant: O=C(O)c1cnc(OCc2ccccc2)c(Br)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: O=C(N[C@@H]1CCCC[C@H]1O)c1cnc(OCc2ccccc2)c(Br)c1

Procedure:
In analogy to example 1f, 6-benzyloxy-5-bromo-nicotinic acid was coupled with (1R,2R)-2-amino-cyclohexanol hydrochloride (CAS [5456-63-3]) using TBTU and N,N-diisopropyl ethyl amine in N,N-dimethylacetamide to give 6-benzyloxy-5-bromo-N-((1R,2R)-2-hydroxy-cyclohexyl)-nicotinamide as an orange solid.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][NH:5][S:6]([CH:9]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[O:13][CH2:12][CH2:11][CH2:10]1)(=[O:8])=[O:7].[F:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([N:34]3[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]3)=[CH:30][CH:29]=2)=[CH:23][CH:22]=1>>[F:20][C:21]1[CH:22]=[CH:23][C:24]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([N:34]3[CH2:35][CH2:36][N:37]([CH2:2][CH2:3][CH2:4][NH:5][S:6]([CH:9]4[C:15]5[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=5[O:13][CH2:12][CH2:11][CH2:10]4)(=[O:8])=[O:7])[CH2:38][CH2:39]3)=[CH:30][CH:29]=2)=[CH:25][CH:26]=1
Reactant: Fc1ccc(Cc2ccc(N3CCNCC3)cc2)cc1
Reactant: O=S(=O)(NCCCCl)C1CCCOc2ccccc21
Product: O=S(=O)(NCCCN1CCN(c2ccc(Cc3ccc(F)cc3)cc2)CC1)C1CCCOc2ccccc21

Procedure:
The compound (10) synthesized in Reference Example 10 and the compound (5) synthesized in Reference Example 5 were used to produce the above compound in the same way as Example 1.