Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].[P:2]([OH:7])([O:5][CH3:6])[O:3][CH3:4].[CH:8]([C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=[O:13])=O.CS(O)(=O)=O>CO>[O:13]=[C:12]1[C:11]2[C:10](=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:8]([P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4])[O:14]1
Reactant: O=Cc1ccccc1C(=O)O
Reactant: COP(O)OC
Agent: CS(=O)(=O)O
Agent: [Na]
Solvent: CO
Product: COP(=O)(OC)C1OC(=O)c2ccccc21
Yield: 67.3 %

Procedure:
To dry methanol (40 ml) was slowly added sodium (1.15 g, 50 mmol) at 0 under N2 atmosphere while stirring, then added dimethyl hydrogen phosphite (5.5 g, 50 mmol), and 2-formylbenzoic acid (5.25 g, 35 mmol). The ice bath was removed and the reaction mixture was stirred for 30 min at room temperature, and then the reaction mixture was slowly added methanesulfonic acid (5.5 g, 55 mmol) and concentrated at reduced pressure to give the crude residue. The crude residue was partitioned between DCM and cold water (100 ml each), and the organic phase was washed with water and brine, dried over sodium sulphate, filtered, and concentrated to give the crude product (5.7 g, 67%) as an off white solid, used in next step without further purification.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[C:15]2([OH:19])[CH2:18][CH2:17][CH2:16]2)[CH2:3][CH2:2]1.Cl.[F:21][C:22]1([F:30])[CH2:26][NH:25][C@H:24]([C:27]([NH2:29])=[O:28])[CH2:23]1>>[CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([N:25]3[CH2:26][C:22]([F:30])([F:21])[CH2:23][C@H:24]3[C:27]([NH2:29])=[O:28])=[O:14])[CH:9]=[CH:8][C:7]=2[C:15]2([OH:19])[CH2:18][CH2:17][CH2:16]2)[CH2:2][CH2:3]1
Reactant: NC(=O)[C@@H]1CC(F)(F)CN1
Reactant: O=C(O)c1ccc(C2(O)CCC2)c(OCC2CC2)n1
Agent: Cl
Product: NC(=O)[C@@H]1CC(F)(F)CN1C(=O)c1ccc(C2(O)CCC2)c(OCC2CC2)n1
Yield: 26.6 %

Procedure:
In analogy to the procedure described in Example 127 e), 6-(cyclopropylmethoxy)-5-(1-hydroxycyclobutyl)pyridine-2-carboxylic acid (CAN 1415899-53-4, 15 mg, 57 μmol) was reacted with (S)-4,4-difluoropyrrolidine-2-carboxamide hydrochloride (CAN 426844-51-1, 10.6 mg, 57 μmol) to give the title compound (6 mg, 21%) as light yellow oil, LC-MS (UV peak area, ESI) 100%, 396.1740 [MH+].
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:5]=1[O:11][CH2:12][CH3:13].[I:15]I>FC(F)(F)S([O-])(=O)=O.[Ag+].CO>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[C:8]([I:15])[C:7]([CH3:10])=[CH:6][C:5]=1[O:11][CH2:12][CH3:13]
Reactant: CCOc1cc(C)ccc1C(=O)OC
Reactant: II
Agent: [Ag+]
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: CO
Product: CCOc1cc(C)c(I)cc1C(=O)OC
Yield: 95.3 %

Procedure:
A methanol solution (12 ml) of 2-ethoxy-4-methylbenzoic acid methyl ester (1.1 g, 5.9 mmol) obtained in Step 2 above, silver trifluoromethanesulfonate (1.7 g, 6.6 mmol), and iodine (1.7 g, 6.6 mmol) was stirred at room temperature for 2.5 hours. The reaction solution was concentrated under reduced pressure. Ethyl acetate (100 ml) was added to the resulting residue. Insoluble material was separated by filtration, and washed with ethyl acetate (100 ml). The filtrate and washing solution were combined together, and sequentially washed twice with an 5% aqueous sodium thiosulfate solution (100 ml), and with a saturated aqueous sodium chloride solution (100 ml). Then, the washed solution was dried over anhydrous sodium sulfate. After the anhydrous sodium sulfate was removed by filtration, the solution was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (developing solvent: n-hexane:ethyl acetate=10:1) to yield 5-iodo-2-ethoxy-4-methylbenzoic acid methyl ester (1.8 g) as a pale yellow oily material.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:39])[CH2:6][O:7][C:8]2[CH:9]=[C:10]([S:14]([N:17]3[C:21]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[F:28])=[CH:20][C:19]([CH2:29][N:30](C)[C:31](=O)OC(C)(C)C)=[CH:18]3)(=[O:16])=[O:15])[CH:11]=[CH:12][CH:13]=2)[CH2:3][CH2:2]1.FC(F)(F)C(O)=O>ClCCl>[CH:1]1([NH:4][C:5](=[O:39])[CH2:6][O:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([S:14]([N:17]3[CH:18]=[C:19]([CH2:29][NH:30][CH3:31])[CH:20]=[C:21]3[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[F:28])(=[O:16])=[O:15])[CH:9]=2)[CH2:2][CH2:3]1
Reactant: CN(Cc1cc(-c2ccccc2F)n(S(=O)(=O)c2cccc(OCC(=O)NC3CC3)c2)c1)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNCc1cc(-c2ccccc2F)n(S(=O)(=O)c2cccc(OCC(=O)NC3CC3)c2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
tert-Butyl ((1-((3-(2-(cyclopropylamino)-2-oxoethoxy)phenyl)sulfonyl)-5-(2-fluorophenyl)-1H-pyrrol-3-yl)methyl)(methyl)carbamate 3a (122 mg, 0.22 mmol) was dissolved in 8 mL of dichloromethane. The reaction solution was cooled in an ice bath, and 2 mL of trifluoroacetic acid were dropwise added. After removing the ice bath, the reaction solution was stirred at room temperature for 2 h. 20 mL of saturated sodium bicarbonate solution were added, and the reaction solution was extracted with dichloromethane (20 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography with elution system A to obtain the title product N-cyclopropyl-2-(3-((2-(2-fluorophenyl)-4-((methylamino)methyl)-1H-pyrrol-1-yl)sulfonyl)phenoxy)acetamide 3 (80 mg, a colorless oil) in 80% yield.
Reaction SMILES: C([C:3]1([C:15]2[N:20]=[C:19]([O:21][CH3:22])[CH:18]=[C:17]([O:23][CH3:24])[N:16]=2)[C:12]2[C:7](=[C:8]([Cl:14])[CH:9]=[CH:10][C:11]=2[Cl:13])[C:5](=[O:6])[O:4]1)#N.[OH-:25].[Na+]>CO.O>[Cl:13][C:11]1[CH:10]=[CH:9][C:8]([Cl:14])=[C:7]2[C:12]=1[C:3]([C:15]1[N:16]=[C:17]([O:23][CH3:24])[CH:18]=[C:19]([O:21][CH3:22])[N:20]=1)([OH:25])[O:4][C:5]2=[O:6]
Reactant: [OH-]
Reactant: COc1cc(OC)nc(C2(C#N)OC(=O)c3c(Cl)ccc(Cl)c32)n1
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1cc(OC)nc(C2(O)OC(=O)c3c(Cl)ccc(Cl)c32)n1
Reaction time: 8 h

Procedure:
70 g of 3-cyano-4,7-dichloro-3-(4,6-dimethoxy-2-pyrimidinyl)phthalide are slurried in 100 ml of methanol and 16 g of NaOH pellets with 125 ml of water added. The mixture is stirred and heated to reflux for 30 mins., the solution cooled and the methanol stripped. The aqueous solution was diluted with 400 ml of water, washed with 100 ml of ether and then added dropwise to 400 ml of 1 NH2SO4 to give a solid which is filtered and dried in vacuum for 1 hr at 60°. The solid is triturated with 100 ml of ether and the suspension left overnight at RT and the solid isolated by filtration to give the title product m.p. 161°-175° C.
Reaction SMILES: C([O:3][C:4](=O)[C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]([O:12][CH2:13][CH3:14])[CH:6]=1)C.[H-].C([Al+]CC(C)C)C(C)C>C1COCC1>[Cl:11][C:8]1[CH:9]=[CH:10][C:5]([CH2:4][OH:3])=[CH:6][C:7]=1[O:12][CH2:13][CH3:14]
Reactant: CCOC(=O)c1ccc(Cl)c(OCC)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Product: CCOc1cc(CO)ccc1Cl
Temperature: -78 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To a solution of 4-chloro-3-hydroxy-benzoic acid (3.0 g, 17.4 mmol, 1.0 equiv) in DMF (15 mL) was added K2CO3 (4.81 g, 34.8 mmol, 2.0 equiv) and ethyl iodide (4.03 mL, 5.97 g, 38.2 mmol, 2.2 equiv). The reaction mixture was stirred for 6 h at rt, diluted with water (20 mL) and extracted with ethyl acetate (3×50 mL). The organic phases were dried over Na2SO4 and concentrated to afford 3.6 g (91%) of 4-chloro-3-ethoxy-benzoic acid ethyl ester. The crude ester was then dissolved in THF (20 mL) and cooled to −78° C. under Ar. A solution of diisobutylaluminium hydride (95 mL, 95.0 mmol, 6.0 equiv; 1.0 M solution in THF) was slowly added over a time period of 15 min, the cooling bath removed on completion of addition and the reaction allowed to reach 0° C. After stirring for 1 h, the reaction was cooled to −78° C. and the excess hydride quenched by cautious addition of a solution of 1 M HCl (10 mL). The mixture was brought to rt, the organic phase separated and the aqueous layer extracted with ethyl acetate (3×100 mL). The combined organic phases were dried over Na2SO4 and concentrated by evaporation under reduced pressure providing 2.94 g (100%) of 4-chloro-3-ethoxy-benzyl alcohol. The crude alcohol (2.94 g, 15.75 mmol, 1.0 equiv) was dissolved in dichloromethane (15 mL) and activated MnO2 (5.48 g, 63.0 mmol, 4.0 equiv) was added. The reaction mixture was stirred for 16 h, after which time the reaction was filtered through Hyflo Super Cel and concentrated. The residue was purified by flash column chromatography on silica eluting with heptane/ethyl acetate (4:1) to yield 1.51 g (52%) of the title compound. 1H NMR (300 MHz, CDCl3): δ1.51 (t, J=7.1 Hz, 3H), 4.19 (q, J=7.1 Hz, 2H), 7.37-7.42 (m, 2H), 7.55 (d, J=9.0 Hz, 1H), 9.94 (s, 1H).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:15](=[O:17])[NH:14][C:13](=[O:18])[N:12]([CH3:19])[C:11]=2[N:10]=[C:9]1Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:21]([O:25][C:26]([N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)=[O:27])([CH3:24])([CH3:23])[CH3:22]>C(OCC)(=O)C>[C:21]([O:25][C:26]([N:28]1[CH2:33][CH2:32][N:31]([C:9]2[N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:16]3[C:15](=[O:17])[NH:14][C:13](=[O:18])[N:12]([CH3:19])[C:11]=3[N:10]=2)[CH2:30][CH2:29]1)=[O:27])([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Cn1c(=O)[nH]c(=O)c2c1nc(Cl)n2Cc1ccccc1
Solvent: CCOC(C)=O
Product: Cn1c(=O)[nH]c(=O)c2c1nc(N1CCN(C(=O)OC(C)(C)C)CC1)n2Cc1ccccc1
Yield: 96.5 %

Procedure:
7-Benzyl-8-chloro-3-methyl-3,7-dihydropurine-2,6-dione (130 mg) and 1-piperazine carboxylic acid tert-butyl ester (250 mg) were stirred at 150° C. for 1 hour. The reaction mixture was diluted with ethyl acetate, and the resulting suspension was filtered to give white solid. This solid was purified by silica gel column chromatography to obtain 190 mg of the title compound from a fraction eluted with ethyl acetate.
Reaction SMILES: C[N:2]1[C:6]([C:7](OCC)=[O:8])=[C:5]([C:12](OCC)=[O:13])[N:4]=[C:3]1[S:17][CH3:18].[H-].[Al+3].[Li+].[H-].[H-].[H-].[H-].[OH-].[Na+]>CCOCC.O.ClCCl>[CH3:18][S:17][C:3]1[NH:4][C:5]([CH2:12][OH:13])=[C:6]([CH2:7][OH:8])[N:2]=1
Reactant: CCOC(=O)c1nc(SC)n(C)c1C(=O)OCC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Solvent: ClCCl
Product: CSc1nc(CO)c(CO)[nH]1
Reaction time: 3 h

Procedure:
A solution of the above diethyl 2- (methylthio)-4,5-imidazoledicarboxylate (23 mmol) in freshly distilled anhydrous dichloromethane (50 mL) is added slowly to a stirred suspension of lithium aluminum hydride (69 mmol) in anhydrous ether (140 mL) at 0°-5° C. The mixture is stirred at about 0°-5° C. for about 3 hours after the addition is completed, then for about 1 hour at room temperature. The excess hydride is carefully decomposed by the slow, sequential addition of water (2.6 mL), 15% sodium hydroxide solution (2.6 mL), and water (7.8 mL). The precipitate of inorganic salts is filtered and extracted continuously for about 24 hours with tetrahydrofuran heated under reflux in a Soxhlet apparatus. The tetrahydrofuran solution is combined with the filtrate from the reaction mixture and concentrated to dryness in vacuo. The product is dried in vacuo and crystallized from tetrahydrofuran to give 2-(methylthio)-4,5-bis(hydroxymethyl) imidazole.
Reaction SMILES: C[O:2][C:3](=[O:22])/[C:4](/[C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=1)=[CH:5]/[CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.[OH-].[Na+]>C(O)C>[CH:6]1(/[CH:5]=[C:4](\[C:12]2[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=2)/[C:3]([OH:22])=[O:2])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COC(=O)/C(=C/C1CCCCC1)c1ccc(S(C)(=O)=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CS(=O)(=O)c1ccc(/C(=C\C2CCCCC2)C(=O)O)cc1
Temperature: 47.5 °C
Yield: 93.6 %

Procedure:
A solution of (E)-3-cyclohexyl-2-(4-methanesulfonyl-phenyl)-acrylic acid methyl ester (5.7 g, 17.95 mmol) in ethanol (65 mL) was treated with a 1N aqueous sodium hydroxide solution (54 mL). The solution was heated at 45-50° C. for 15 h, at which time, thin layer chromatography analysis of the mixture indicated the absence of starting material. The reaction mixture was then concentrated in vacuo to remove ethanol, and the residue was diluted with water (100 mL) and extracted with diethyl ether (1×150 mL) to remove any neutral impurities. The aqueous layer was acidified with a 1N aqueous hydrochloric acid solution. The resulting acid was extracted into ethyl acetate (2×150 mL). The combined organic layers were washed with a saturated aqueous sodium chloride solution (1×250 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to afford (E)-3-cyclohexyl-2-(4-(methanesulfonyl)-phenyl)-acrylic acid (5.18 g, 94%) as a white solid: mp 195-197° C.; EI-HRMS m/e calcd for C16H20O4S (M+H)+309.1160, found 309.1165.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[C:9](=O)[CH2:8][CH2:7][CH2:6][C:5]2=1.[Cl:16][C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH:21][C:20]3[CH:22]=[CH:23][C:17]([Cl:16])=[CH:18][CH:19]=3)[CH2:8][CH2:7][CH2:6][C:5]2=1
Reactant: Nc1ccc(Cl)cc1
Reactant: O=C1CCCc2c1[nH]c1ccc(Br)cc21
Product: Clc1ccc(NC2CCCc3c2[nH]c2ccc(Br)cc32)cc1

Procedure:
6-Bromo-N-(4-chlorophenyl)-2,3,4,9-tetrahydro-1H-carbazol-1-amine was prepared from 6-bromo-2,3,4,9-tetrahydro-1H-carbazol-1-one (100 mg, 0.38 mmol) and 4-chloroaniline (97 mg, 0.76 mmol) in a similar manner as described in Example 13 to give 29 mg (20%) of an off-white solid. 1H-NMR (DMSO-d6): δ 11.07 (s, 1H), 7.56 (s, 1H), 7.23 (d, 1H), 7.13-7.08 (m, 3H), 6.71 (d, 2H), 6.20 (d, 1H), 4.76-4.72 (m, 1H), 2.68-2.54 (m, 2H), 1.99-1.85 (m, 2H), 1.80-1.74 (m, 2H); MS m/z (M−1) 373, 375.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][S:5]([OH:8])(=[O:7])=[O:6].[OH-].[Na+].[C:11](Cl)(=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13]>O1CCOCC1.O>[C:11]([NH:1][CH2:2][CH2:3][CH2:4][S:5]([OH:8])(=[O:7])=[O:6])(=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)C(=O)Cl
Reactant: NCCCS(=O)(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)C(=O)NCCCS(=O)(=O)O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
3-amino-1-propanesulfonic acid (2.0 g, 14.4 mmol) was dissolved a NaOH (1.2 g, 30.2 mmol) solution in a mixture of 1,4-dioxane (5 mL) and water (15 mL). The mixture was cooled to 0° C. before pivaloyl chloride (2.8 mL, 21.6 mmol) in 1,4-dioxane (5 mL) was added dropwise. The reaction mixture was allowed to warm up to room temperature and it was stirred at 65° C. for 4 h. The solvent was evaporated under reduced pressure. The resulting solid was dissolved in water (30 mL), and treated with Dowex 50WX8 resin. The suspension was stirred for 5 minutes and the resin was removed by filtration. The filtrate was evaporated under reduced pressure. The residual material was suspended in 20% EtOH/Acetone. The mixture was stirres at reflux for 30 seconds. The solid product was collected by filtration, and dried in vacuo, to afford compound DT (1.3 g, 41%). 1H NMR (D2O, 500 MHz) δ ppm 3.16 (t, 2H, J=6.8 Hz), 2.75 (t, 2H, J=7.8 Hz), 1.78 (m, 2H), 1.1 (s, 9H). 13C NMR (D2O, 125 MHz) δ ppm 182.75, 48.70, 38.57, 38.18, 26.65, 24.27. ES-MS 222 (M−1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:13][CH2:12]2)=[CH:4][CH:3]=1.[C:23](#[N:26])[CH:24]=[CH2:25]>C(O)(=O)C>[C:23]([CH2:24][CH2:25][NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][N:11]2[CH2:12][CH2:13][N:14]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:15][CH2:16]2)=[CH:6][CH:7]=1)#[N:26]
Reactant: C=CC#N
Reactant: Nc1ccc(CCCN2CCN(c3ccccc3)CC2)cc1
Solvent: CC(=O)O
Product: N#CCCNc1ccc(CCCN2CCN(c3ccccc3)CC2)cc1
Yield: 81.2 %

Procedure:
A mixture consisting of 29.5 gm (0.1 mol) of N-[γ-(p-amino-phenyl)-n-propyl]-N'-phenyl-piperazine (m.p. 102° C.), 5.8 gm (0.11 mol) of acrylonitrile and 20 ml of glacial acetic acid was refluxed for 20 hours. Thereafter, the solvent was distilled off in vacuo, and the residue was recrystallized from dilute methanol, yielding 28.3 gm (81.3% of theory) of N-[γ-(p-[β-cyanoethyl-amino]-phenyl)n-propyl]-N'-phenyl-piperazine, M.P.141°-143° C.
Reaction SMILES: [CH2:1](O)[CH2:2][CH2:3][OH:4].[OH-].[Na+].C1(C)C=CC=CC=1.[CH2:15]([C:17]1([CH2:21][O:22]S(C)(=O)=O)[CH2:20][O:19][CH2:18]1)[CH3:16]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[CH2:15]([C:17]1([CH2:21][O:22][CH2:1][CH2:2][CH2:3][OH:4])[CH2:20][O:19][CH2:18]1)[CH3:16]
Reactant: OCCCO
Reactant: CCC1(COS(C)(=O)=O)COC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCC1(COCCCO)COC1
Temperature: 80 °C
Yield: 58.2 %

Procedure:
In a glass flask having an internal volume of 2000 ml equipped with a stirrer, a thermometer, a dropping funnel, and a reflux condenser, 285 g (3.7 mol) of 1,3-propanediol, 12.1 g (37.5 mmol) of tetrabutylammonium bromide, 72 g (2.2 mol) of 96 mass % sodium hydroxide, and 150 ml of toluene were added and heated up to 80° C. while stirring. Then, 324 g (1.5 mol) of 3-ethyl-3-methanesulfonyloxymethyloxetane with a purity of 90 mass % synthesized in (1) above was gently dropped while keeping the liquid temperature from 80° C. to 90° C. to carry out a reaction at the same temperature range for two hours. After completing the reaction, the reaction solution (a bisoxetane ether compound was generated as little as 7%; value analyzed by gas chromatography) was added with 300 ml of water to separate into a water layer and an organic layer. The water layer thus obtained was extracted with 200 ml of toluene, and the extract (toluene layer) was mixed with the previous organic layer to concentrate under reduced pressure. By distilling the concentrate thus obtained under reduced pressure (from 135° C. to 137° C., 1.1 kPa), 152 g of 3-ethyl-3-(3-hydroxypropyl)oxymethyl-oxetane with a purity of 97% (value analyzed by gas chromatography) as a colorless liquid was obtained (isolated yield based on 3-ethyl-3-methanesulfonyloxymethyloxetane=56%).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH3:11])[C:3]=1[C:4]#[N:5].N1C=CC=CC=1.[C:18]([O:21][CH2:22][C:23](Cl)=[O:24])(=[O:20])[CH3:19]>C(Cl)Cl>[C:18]([O:21][CH2:22][C:23]([NH:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH3:11])[C:3]=1[C:4]#[N:5])=[O:24])(=[O:20])[CH3:19]
Reactant: COc1cccc(N)c1C#N
Reactant: CC(=O)OCC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1cccc(NC(=O)COC(C)=O)c1C#N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-amino-6-methoxybenzonitrile (3.7 g) in methylene chloride (50 ml) is added pyridine (2.4 ml), and thereto is added dropwise acetoxyacetyl chloride (2.7 ml) which is cooled in an ice bath. The mixture is stirred at room temperature for 1 hour, and thereafter, the solvent is distilled off under reduced pressure. The resulting crude crystals are washed with water and ether and then are recrystallized from ethanol to give the title compound (5.4 g) having the following physical properties.
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:6]=[C:7]([C:11]2[N:15]=[CH:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=3)[N:12]=2)[CH:8]=[CH:9][CH:10]=1)=[C:2]=[O:3].[CH:27]([C:30]1[CH:35]=[C:34]([CH3:36])[CH:33]=[CH:32][C:31]=1[NH:37][C:38]([NH2:40])=[S:39])([CH3:29])[CH3:28]>>[CH:27]([C:30]1[CH:35]=[C:34]([CH3:36])[CH:33]=[CH:32][C:31]=1[NH:37][C:38]([NH:40][C:2]([NH:1][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]2[N:15]=[CH:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]([F:25])([F:24])[F:26])=[CH:18][CH:17]=3)[N:12]=2)[CH:6]=1)=[O:3])=[S:39])([CH3:29])[CH3:28]
Reactant: Cc1ccc(NC(N)=S)c(C(C)C)c1
Reactant: O=C=NCc1cccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)c1
Product: Cc1ccc(NC(=S)NC(=O)NCc2cccc(-c3ncn(-c4ccc(OC(F)(F)F)cc4)n3)c2)c(C(C)C)c1

Procedure:
The title compound was prepared as described in Example 75 using 3-(3-(isocyanatomethyl)phenyl)-1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazole (CB34) and 1-(2-isopropyl-4-methylphenyl)thiourea and isolated as an off-white solid (0.216 g, 50%).
Reaction SMILES: [CH:1]#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]C.C1(C#C)C=CC=CC=1.[O:17]1[CH:21]=[CH:20][CH:19]=[C:18]1[C:22]#N>C(#N)C1C=CC=CC=1>[C:22]([C:18]1[O:17][CH:21]=[CH:20][CH:19]=1)#[C:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: C#CCCCCCC
Reactant: N#Cc1ccco1
Solvent: C#Cc1ccccc1
Solvent: N#Cc1ccccc1
Product: CCCCCCC#Cc1ccco1
Reaction time: 22 h
Yield: 62 %

Procedure:
The procedure was identical to Example 2, with the exception that 1-octyne (0.590 ml; 0.441 g; 4.00 mmol) was used as a substrate instead of phenylacetylene and 2-furonitrile (0.175 ml; 0.186 g; 2.00 mmol) was used as a substrate instead of benzonitrile. GC analysis of the organic phase of the hydrolyzed reaction sample after 22 h at 65° C. showed the presence of 1.24 mmol (62% yield) of 2-(1-octynyl)furan and no remaining 2-furonitrile in the reaction mixture.
Reaction SMILES: C(O)(C(F)(F)F)=O.[Cl:8][C:9]1[C:14]([N:15]2[CH2:26][CH2:25][C:18]3([C:22](=[O:23])[N:21]([CH3:24])[CH2:20][CH2:19]3)[CH2:17][CH2:16]2)=[CH:13][C:12]([C:27]#[N:28])=[CH:11][C:10]=1[NH:29][C:30]1[N:35]=[C:34]([N:36]([CH:46]2[CH2:48][CH2:47]2)CC2C=CC(OC)=CC=2)[C:33]2=[N:49][CH:50]=[C:51]([C:52]#[N:53])[N:32]2[N:31]=1.C1(OC)C=CC=CC=1>ClCCCl>[Cl:8][C:9]1[C:14]([N:15]2[CH2:16][CH2:17][C:18]3([C:22](=[O:23])[N:21]([CH3:24])[CH2:20][CH2:19]3)[CH2:25][CH2:26]2)=[CH:13][C:12]([C:27]#[N:28])=[CH:11][C:10]=1[NH:29][C:30]1[N:35]=[C:34]([NH:36][CH:46]2[CH2:47][CH2:48]2)[C:33]2=[N:49][CH:50]=[C:51]([C:52]#[N:53])[N:32]2[N:31]=1
Reactant: COc1ccc(CN(c2nc(Nc3cc(C#N)cc(N4CCC5(CCN(C)C5=O)CC4)c3Cl)nn3c(C#N)cnc23)C2CC2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Solvent: COc1ccccc1
Product: CN1CCC2(CCN(c3cc(C#N)cc(Nc4nc(NC5CC5)c5ncc(C#N)n5n4)c3Cl)CC2)C1=O
Temperature: 60 °C
Reaction time: 0.33 h
Yield: 43.1 %

Procedure:
TFA (0.417 mL, 5.41 mmol) was added to a solution of 2-((2-chloro-5-cyano-3-(2-methyl-1-oxo-2,8-diazaspiro[4.5]decan-8-yl)phenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (50 mg, 0.078 mmol) and anisole (0.034 mL, 0.314 mmol) in DCE (1 mL) and the reaction mixture was heated at 60° C. for 1 hours. The solvent was removed in vacuo and the material azeotroped with toluene 3× to remove the excess TFA. 10 ml of 2N NH3 in MeOH was added, and the solution was stirred for 20 min. The solvent was removed in vacuo and the material was purified by prep-HPLC to give 2-((2-chloro-5-cyano-3-(2-methyl-1-oxo-2,8-diazaspiro[4.5]decan-8-yl)phenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (17.4 mg).
Reaction SMILES: C([O:8][C:9]1[CH:28]=[CH:27][C:12]([O:13][C:14]2[CH:26]=[CH:25][C:17]3[NH:18][CH2:19][CH2:20][NH:21][S:22](=[O:24])(=[O:23])[C:16]=3[CH:15]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1>C(O)C.Cl.O1CCOCC1.[Pd]>[O:24]=[S:22]1(=[O:23])[C:16]2[CH:15]=[C:14]([O:13][C:12]3[CH:27]=[CH:28][C:9]([OH:8])=[CH:10][CH:11]=3)[CH:26]=[CH:25][C:17]=2[NH:18][CH2:19][CH2:20][NH:21]1
Reactant: O=S1(=O)NCCNc2ccc(Oc3ccc(OCc4ccccc4)cc3)cc21
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: C1COCCO1
Product: O=S1(=O)NCCNc2ccc(Oc3ccc(O)cc3)cc21

Procedure:
The product of Example 8 (0.76 mmol) is hydrogenated for 1 hour at atmospheric pressure in 60 ml of ethanol in the presence of 30 mg of 10% palladium-on-carbon and 2 drops of 4N HCl solution in dioxane. The catalyst is removed by filtration and the filtrate is evaporated to dryness. The residue is taken up in the hot state in ethyl acetate. The organic phase is washed with 1% NaHCO3 solution and then with saturated NaCl solution, dried (MgSO4), filtered and evaporated. The residue is triturated in a mixture of ethyl acetate/ethyl ether to yield, after filtration, the title product.