Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].Cl[C:3]1[N:7]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)[N:6]=[CH:5][C:4]=1[C:15]([NH:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[C:20]([C:30]#[N:31])[CH:19]=1)=[O:16].[I-].[K+].[CH3:34][OH:35]>>[C:30]([C:20]1[CH:19]=[C:18]([NH:17][C:15]([C:4]2[CH:5]=[N:6][N:7]([C:8]3[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=3)[C:3]=2[O:35][CH3:34])=[O:16])[CH:23]=[CH:22][C:21]=1[O:24][CH2:25][C:26]([CH3:29])([CH3:28])[CH3:27])#[N:31]
Reactant: CO
Reactant: CC(C)(C)COc1ccc(NC(=O)c2cnn(-c3ccc(F)cc3)c2Cl)cc1C#N
Agent: [I-]
Agent: [K+]
Agent: [Na]
Product: COc1c(C(=O)Nc2ccc(OCC(C)(C)C)c(C#N)c2)cnn1-c1ccc(F)cc1

Procedure:
To a methanol solution (20 ml) containing metallic sodium (0.065 g) were added 5-chloro-N-(3-cyano-4-neopentyloxyphenyl)-1-(4-fluorophenyl)pyrazole-4-carboxamide (1 g) and a catalytic amount of potassium iodide, and the mixture was stirred at 65° C. for 5 h. The solvent was evaporated. Water was added to the residue to allow crystallization. The crystals were recrystallized from hydrous methanol to give the title compound (0.3 g), melting point: 120–123° C.
Reaction SMILES: [CH3:1][N:2]([CH3:5])[CH:3]=O.N1C2[C:9](=[CH:10][C:11]([C:15]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([CH3:26])=[C:23]([F:25])[F:24])=[O:16])=[CH:12][CH:13]=2)[CH:8]=C1.CI.[H-].[Na+]>O>[CH3:1][N:2]1[C:5]2[C:9](=[CH:10][C:11]([C:15]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([CH3:26])=[C:23]([F:24])[F:25])=[O:16])=[CH:12][CH:13]=2)[CH:8]=[CH:3]1
Reactant: CN(C)C=O
Reactant: CC(CCCCOC(=O)c1ccc2[nH]ccc2c1)=C(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: CC(CCCCOC(=O)c1ccc2c(ccn2C)c1)=C(F)F
Reaction time: 1 h
Yield: 86 %

Procedure:
To 5 ml of N,N-dimethylformamide were dissolved 0.40 g (1.4 mmol) of 6,6-difluoro-5-methyl-5-hexenyl 1H-indole-5-carboxylate and 0.40 g (2.8 mmol) of methyl iodide, followed by the addition of 0.07 g (1.7 mmol) of sodium hydride at room temperature and stirring at the same temperature for 1 hour. The reaction liquid was then poured in water and extracted with diethyl ether. The organic layer was washed with water and a saturated saline solution in this order, followed by drying over anhydrous magnesium sulfate and concentration under reduced pressure. The residue was purified with silica gel column chromatography (ethyl acetate:hexane=1:5) to obtain 0.36 g (yield: 86%) of 6,6-difluoro-5-methyl-5-hexenyl 1-methyl-1H-indole-5-carboxylate.
Reaction SMILES: [C:1](#[N:10])[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.P([O-])([O-])([O-])=[O:12]>>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([C:1]([NH2:10])=[O:12])=[CH:3][CH:4]=1)#[N:7]
Reactant: N#Cc1ccc(C#N)cc1
Reactant: O=P([O-])([O-])[O-]
Product: N#Cc1ccc(C(N)=O)cc1

Procedure:
The nitrile hydratase activity was measured as follows. The cells (about 1 g by wet mass) were added to a reaction solution obtained by suspending from 1 to 10 mass % of terephthalonitrile (TPN) as a substrate in 10 ml of 20 mM phosphate buffer solution (pH: 7.0) and reacted at 30° C. while shaking, and the p-cyanobenzoic acid amide produced in the reaction solution was quantitated by HPLC at fixed intervals. The solid matter was removed from the reaction solution by centrifugation, and the supernatant 100-fold diluted with the eluant was used as the HPLC sample. The amidase activity was measured by using p-cyanobenzamide or benzamide serving as a substrate, performing the reaction under the same conditions as above, and determining the generated p-cyanobenzoic acid or benzoic acid by HPLC.
Reaction SMILES: S([O-])([O-])(=O)=O.[NH2:6][OH:7].Cl[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])=[O:10].[OH-].[Na+]>>[OH:7][NH:6][C:9](=[O:10])[O:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: NO
Reactant: CCCCOC(=O)Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Product: CCCCOC(=O)NO

Procedure:
With respect to butyl N,O-dimethylcarbamate, a process disclosed in the specification of West German Patent Application Laid-open No. 3,245,503 is known. This process comprises reacting sulfate of hydroxylamine as a starting material with butyl chloroformate in the presence of sodium hydroxide, extracting the reaction product with dichloromethane, drying the extract, distilling the solvent away from the dried extract to obtain butyl hydroxycarbamate and dimethylating this product using dimethyl sulfate and a sodium hydroxide solution to obtain ethyl N,O-dimethylhydroxycarbamate in the total yield of 65%.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH3:10])[C:3]=1[NH2:4].[Li]CCCC.Cl[Si:17]([CH:20]1[C:24]2[S:25][CH:26]=[CH:27][C:23]=2[C:22]([CH3:28])=[C:21]1[CH3:29])([CH3:19])[CH3:18]>C1COCC1>[Br:1][C:2]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH3:10])[C:3]=1[NH:4][Si:17]([CH:20]1[C:24]2[S:25][CH:26]=[CH:27][C:23]=2[C:22]([CH3:28])=[C:21]1[CH3:29])([CH3:18])[CH3:19]
Reactant: CC1=C(C)C([Si](C)(C)Cl)c2sccc21
Reactant: Cc1cc(C)c(N)c(Br)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC1=C(C)C([Si](C)(C)Nc2c(C)cc(C)cc2Br)c2sccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Under an argon atmosphere, to a solution of 14.8 g (74.2 mmol) of 2-bromo-4,6-dimethylaniline in 200 ml of THF, 29.7 ml of 2.5 M (74.2 mmol) nBuLi in hexanes was added at −80° C. This mixture was warmed for ca. 1 hour to ambient temperature. Then, the resulting solution was added dropwise over ca. 1 hour, while vigorously stirring, to a solution of 18.0 g (74.2 mmol) of chloro(4,5-dimethyl-6H-cyclopenta[b]thien-6-yl)dimethylsilane in 100 ml of THF. The resulting mixture was stirred overnight at ambient temperature, and then, evaporated to dryness. To the residue, 150 ml of toluene was added. This mixture was filtered through a glass frit (G4). The filtrate was evaporated to dryness. Fractional distillation gave a yellow liquid, bp 168-172° C./0.2 mm Hg. The product crystallizes slowly at ambient temperature. Yield 16.5 g (55%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH3:8])=[C:6]([CH3:9])[C:5]([NH:10][C:11](=O)OCCCl)=[CH:4][C:3]=1[N+:17]([O-:19])=[O:18].[OH-].[Na+].[C:22](O)(=[O:24])C>O>[NH2:1][C:2]1[C:7]([CH3:8])=[C:6]([CH3:9])[C:5]([NH:10][CH2:11][CH2:22][OH:24])=[CH:4][C:3]=1[N+:17]([O-:19])=[O:18]
Reactant: CC(=O)O
Reactant: Cc1c(NC(=O)OCCCl)cc([N+](=O)[O-])c(N)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1c(NCCO)cc([N+](=O)[O-])c(N)c1C

Procedure:
0.0417 mole (12 g) of β-chloroethyl 4-amino-5,6-dimethyl-3-nitrophenylcarbamate is suspended in 36 ml of 96° alcohol. A solution of 6.2 g of caustic soda pellets of 97% strength in 15 ml of water is added in small portions with stirring; the reaction mixture is heated to the refluxing temperature of the alcohol. After being heated for 2 hours the reaction mixture is poured into 200 g of iced water and acidified with acetic acid.
Reaction SMILES: [C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][C:23]([Sn](C)(C)C)=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:29][C:30]1[N:35]=[C:34](Cl)[CH:33]=[C:32]([Cl:37])[N:31]=1>>[C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][C:23]([C:34]5[CH:33]=[C:32]([Cl:37])[N:31]=[C:30]([NH2:29])[N:35]=5)=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Nc1nc(Cl)cc(Cl)n1
Reactant: C[C@H](Nc1nccc(-n2cnc3cc([Sn](C)(C)C)ccc32)n1)c1ccccc1
Product: C[C@H](Nc1nccc(-n2cnc3cc(-c4cc(Cl)nc(N)n4)ccc32)n1)c1ccccc1

Procedure:
The title compound was prepared according to the procedure described in EXAMPLE 424, starting from 2-[(S)-1-Phenylethylamino]-4-[5-trimethylstannylbenzimidazol-1-yl]pyrimidine and 2-amino4,6-dichloropyrimidine. Mass spectrum (ESI) 443.4 (M+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[CH:15]=[CH:16][C:17]([N+:19]([O-])=O)=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CO>C(O)C.[Pd]>[NH2:19][C:17]1[CH:16]=[CH:15][C:12]2[CH2:13][CH2:14][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])[CH2:9][CH2:10][C:11]=2[CH:18]=1
Reactant: CC(C)(C)OC(=O)N1CCc2ccc([N+](=O)[O-])cc2CC1
Agent: [Pd]
Solvent: CO
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCc2ccc(N)cc2CC1

Procedure:
A solution of 3-tertiary-butoxycarbonyl-7-nitro-1,2,4,5-tetrahydro-3H-3-benzazepine (2.1 g) was stirred under a hydrogen atmosphere (50 p.s.i. equivalent to 344.7 kPa) in ethanol (20 ml) and methanol (20 ml) solution containing 5% Pd/C (0.21 g) for 3 hours. The catalyst was removed by filtration and the solvent evaporated to give the title compound as an oil, yield 2.0 g.
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]2[CH:12]=[CH:13][C:14]([NH2:17])=[N:15][CH:16]=2)=[CH:9][C:5]2[O:6][CH2:7][CH2:8][C:4]=2[CH:3]=1.[F:18][C:19]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:20]=1[C:21](Cl)=[O:22].CCN(C(C)C)C(C)C.C([O-])(O)=O.[Na+].C(Cl)Cl>C(Cl)Cl>[F:18][C:19]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:20]=1[C:21]([NH:17][C:14]1[CH:13]=[CH:12][C:11]([C:10]2[C:2]([Cl:1])=[CH:3][C:4]3[CH2:8][CH2:7][O:6][C:5]=3[CH:9]=2)=[CH:16][N:15]=1)=[O:22]
Reactant: O=C(Cl)c1c(F)cccc1F
Reactant: Nc1ccc(-c2cc3c(cc2Cl)CCO3)cn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(Nc1ccc(-c2cc3c(cc2Cl)CCO3)cn1)c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.3 %

Procedure:
To a solution of 5-(5-chloro-2,3-dihydrobenzo[3,4-b]furan-6-yl)-2-pyridylamine (151) (15 mg, 0.06 mmol) in 1 ml DCM was added 2,6-difluorobenzoyl chloride (11 μl, 0.088 mmol) followed by addition of DIEA (52 μl). The resulting solution was stirred at r.t. for overnight. The reaction mixture was worked up with aq. NaHCO3/DCM. DCM phase was washed with brine, concentrated to dryness. The residue was dissolved in 1 ml THF/MeOH/H2O (5:4:1) and stirred with 1N NaOH (120 μl) at r.t. for 2 h and before worked up with EA/aq. NaHCO3. Silica gel flash chromatography furnished (2,6-difluorophenyl)-N-[5-(5-chloro(2,3-dihydrobenzo[3,4-b]furan-6-yl))(2-pyridyl)]carboxamide (152) (14 mg, yield: 60.1%, purity>90%) as white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].Cl.Cl[CH2:13][C:14]1[N:15]([CH2:19][C:20]2[CH:25]=[C:24]([Cl:26])[CH:23]=[C:22]([Cl:27])[CH:21]=2)[CH:16]=[CH:17][N:18]=1>CN(C=O)C>[Cl:27][C:22]1[CH:21]=[C:20]([CH:25]=[C:24]([Cl:26])[CH:23]=1)[CH2:19][N:15]1[CH:16]=[CH:17][N:18]=[C:14]1[CH2:13][O:8][C:4]1[CH:3]=[C:2]([NH2:1])[CH:7]=[CH:6][CH:5]=1
Reactant: Nc1cccc(O)c1
Reactant: ClCc1nccn1Cc1cc(Cl)cc(Cl)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1cccc(OCc2nccn2Cc2cc(Cl)cc(Cl)c2)c1
Reaction time: 0.17 h
Yield: 70 %

Procedure:
3-Aminophenol (87 mg, 0.8 mmol) was dissolved in DMF and NaH (33 mg, 0.83 mmol) was added. After 10 min, 2-(chloromethyl)-1-(3,5-dichlorobenzyl)-1H-imidazole hydrochloride (see Example 1) (100 mg, 0.32 mmol) was added in one portion. After 20 min, the reaction was partitioned between water (10 mL) and EtOAc (10 mL). The layers were separated and the aqueous layer was re-extracted with EtOAc (1×10 mL). The combined organic layers were washed with 1M NaOH (3×10 mL), water (10 mL) and brine, dried over MgSO4, filtered and concentrated to yield the title compound as a pale yellow oil (78 mg, 70%); MS m/z 348 [C17H15Cl2N3O+H]+.
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.[Si:13]([O:20][CH2:21][CH:22]([CH2:25][O:26][Si:27]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28])[CH2:23][OH:24])([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14].[Br:34][C:35]1[N:40]=[CH:39][C:38](O)=[CH:37][CH:36]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[Br:34][C:35]1[CH:36]=[CH:37][C:38]([O:24][CH2:23][CH:22]([CH2:25][O:26][Si:27]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:28])[CH3:29])[CH2:21][O:20][Si:13]([C:16]([CH3:17])([CH3:19])[CH3:18])([CH3:15])[CH3:14])=[CH:39][N:40]=1
Reactant: Oc1ccc(Br)nc1
Reactant: CC(C)(C)[Si](C)(C)OCC(CO)CO[Si](C)(C)C(C)(C)C
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCC(COc1ccc(Br)nc1)CO[Si](C)(C)C(C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 96.4 %

Procedure:
Diethylazodicarboxylate (3.445 mL, 22.2 mmol) was added dropwise to a stirred mixture of 3-{[tert-butyl(dimethyl)silyl]oxy}-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)-1-propanol (184) (reported by Kim et al., 2001, via silylation and hydroboration of 2-methylene-1,3-propanediol) (5.706 g, 17.1 mmol), 6-bromo-3-pyridinol (3.571 g, 20.5 mmol) and triphenylphosphine (5.386 g, 20.5 mmol) in anhydrous THF (55 mL) at 0° C. under N2. After stirring at 0° C. for 1 h, and then at room temperature for 41 h, the mixture was concentrated under reduced pressure and the residue was chromatographed on silica gel. Elution with 0-5% Et2O/petroleum ether firstly gave foreruns, and then further elution with 5% Et2O/petroleum ether gave 2-bromo-5-[3-{[tert-butyl(dimethyl)silyl]oxy}-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)propoxy]pyridine (185) (8.09 g, 97%) as a colourless oil; 1H NMR (CDCl3) δ 8.06 (d, J=3.0 Hz, 1H), 7.35 (dd, J=8.7, 0.3 Hz, 1H), 7.11 (dd, J=8.7, 3.2 Hz, 1H), 4.03 (d, J=5.9 Hz, 2H), 3.73 (dd, J=10.1, 5.7 Hz, 1H), 3.69 (dd, J=10.0, 6.0 Hz, 1H), 2.16 (sept, J=5.8 Hz, 1H), 0.88 (s, 18H), 0.03 (2 s, 12H); HRESIMS calcd for C21H41BrNO3Si2 m/z [M+H]+ 492.1783, 490.1803. found 492.1786, 490.1804.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]([F:12])([F:11])[F:10])=[CH:4][C:3]=1[C:13]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1)=O.[C:22]([CH2:25][C:26](=O)[CH3:27])(=[O:24])[CH3:23]>CCCCCCC.C(OCC)(=O)C>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([C:13]2[C:3]3[C:2](=[CH:7][CH:6]=[C:5]([O:8][C:9]([F:12])([F:11])[F:10])[CH:4]=3)[N:1]=[C:26]([CH3:27])[C:25]=2[C:22](=[O:24])[CH3:23])=[CH:16][CH:17]=1
Reactant: CC(=O)CC(C)=O
Reactant: Nc1ccc(OC(F)(F)F)cc1C(=O)c1ccc(Cl)cc1
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: CC(=O)c1c(C)nc2ccc(OC(F)(F)F)cc2c1-c1ccc(Cl)cc1
Yield: 61 %

Procedure:
The title compound was prepared from (2-Amino-5-trifluoromethoxy-phenyl)-(4-chloro-phenyl)-methanone [example A3] and acetylacetone according to the method of example 1, except that heptane/ethyl acetate (1:2) was used. Yield: 61%. MS: m/z=379 (M).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4](Cl)[N:3]=1>C(N(CC)CC)C>[CH:11]1([N:8]2[CH:7]=[N:6][C:5]3[C:9]2=[N:10][CH:2]=[N:3][CH:4]=3)[CH2:12][CH2:13][CH2:14][CH2:15]1
Reactant: Clc1nc(Cl)c2ncn(C3CCCC3)c2n1
Solvent: CCN(CC)CC
Product: c1ncc2ncn(C3CCCC3)c2n1

Procedure:
(R,S)-2-Chloro-6-[4-(1-(3-(1-methyl)piperidinyl)methyl))piperidinylamino]-9-cyclopentylpurine is prepared from 2,6-dichloro-9-cyclopentylpurine, (R,S)-4-amino-1-(3-(1-methylpiperidinyl)methyl)piperidine, and triethylamine essentially as described above in Example 1, Scheme A, step b.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([C:9](=[O:11])[CH3:10])=[C:4]([OH:12])[CH:3]=1.[I:13]N1C(=O)CCC1=O>C(O)(=O)C>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([C:9](=[O:11])[CH3:10])=[C:4]([OH:12])[C:3]=1[I:13]
Reactant: O=C1CCC(=O)N1I
Reactant: CC(=O)c1cc(Cl)c(Cl)cc1O
Solvent: CC(=O)O
Product: CC(=O)c1cc(Cl)c(Cl)c(I)c1O
Temperature: 90 °C
Reaction time: 18 h
Yield: 46.1 %

Procedure:
A solution of 1-(4,5-dichloro-2-hydroxyphenyl)ethanone (12 g, 59 mmol) in acetic acid (70 mL) was treated with N-iodosuccinimide (16 g, 71 mmol) and stirred at 90° C. for 18 h. The reaction mixture was treated with additional N-iodosuccinimide (8 g, 36 mmol) and stirred at 90° C. for 4 h. The reaction mixture was concentrated, diluted with ethyl acetate, and quenched with saturated sodium bicarbonate until the bubbling stopped. The organic layer was separated and the aqueous was re-extracted with ethyl acetate. The combined organic layers were dried and concentrated to give a brown solid. This material was recrystallized from methanol to give desired product (9.0 g, 46%) as a tan solid. 1H NMR (300 MHz, CDCl3) δ 13.36 (s, 1H), 7.85 (s, 1H), 2.65 (s, 3H). LCMS for C8H6Cl2IO2 (M+H)+: m/z=330.9, 332.9; Found: 330.8, 332.9.
Reaction SMILES: CN1CCOCC1.[OH:8][C@H:9]1[C@@H:21]2[C@@H:17]([C@@H:18]([O:23][CH3:24])[O:19][C@H:20]2[CH3:22])[CH2:16][C@@H:15]2[C@@H:10]1[CH2:11][CH2:12][CH2:13][CH2:14]2>C(Cl)Cl>[CH3:24][O:23][C@@H:18]1[C@H:17]2[CH2:16][C@@H:15]3[C@@H:10]([C:9](=[O:8])[C@H:21]2[C@H:20]([CH3:22])[O:19]1)[CH2:11][CH2:12][CH2:13][CH2:14]3
Reactant: CO[C@H]1O[C@@H](C)[C@@H]2[C@H](O)[C@H]3CCCC[C@@H]3C[C@H]12
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CO[C@H]1O[C@@H](C)[C@@H]2C(=O)[C@H]3CCCC[C@@H]3C[C@H]12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 95.1 %

Procedure:
Also, the synthesis was possible separately through following process. Namely, 0.77 g(1.50 equivalents) of N-methylmorpholine and 2.50 g of molecular sieve 4A(MS4A) were added to 1.05 g(4.37 mmol) of (1S,3S,3aS,4R,4aS,8aR,9aS)-4-hydroxy-1-methoxy-3-methyl-dodecahydronaphtho[2,3-c]furan in 10 ml of methylene chloride solution, then 76.8 mg(0.05 equivalents) of tetrapropylammonium perruthenate(TPAP) were added, and the mixture was stirred for 1.5 hours at room temperature. The reaction mixture was filtered through celite and the residue was washed with ether(100 ml). The filtrate was washed with 10% aqueous solution of Na2S2O3 and then with brine (each 20 ml×1). The organic layer was dried over anhydrous magnesium sulfate, filtered and solvent was distilled off to obtain 0.99 g of (1S,3S,3aR,4aS,8aR,9aS)-1-methoxy-3-methyl-4-oxo-dodecahydronaphtho[2,3-c]furan (yield 95%).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[CH:5][C:6]([NH2:9])=[N:7][CH:8]=1.CCN(CC)CC.[CH3:19][C:20]([CH3:25])([CH3:24])[C:21](Cl)=[O:22]>C(Cl)Cl>[F:11][C:2]([F:1])([F:10])[C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:21](=[O:22])[C:20]([CH3:25])([CH3:24])[CH3:19])=[N:7][CH:8]=1
Reactant: Nc1ccc(C(F)(F)F)cn1
Reactant: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)C(=O)Nc1ccc(C(F)(F)F)cn1
Temperature: -5 °C
Reaction time: 0.25 h
Yield: 91.3 %

Procedure:
5-(trifluoromethyl)pyridin-2-amine (15 g, 92.5 mmole) was taken up in DCM (190 ml) under nitrogen and NEt3 (16 ml, 115.7 mmole) was added. The solution was cooled to −5° C., a solution of trimethyl acetyl chloride (12.5 ml, 101.8 mmole) in DCM (65 ml) was added dropwise, and the mixture was stirred for a further 15 minutes in an ice bath. The mixture was then stirred for 2 hours at RT. The suspension was washed with H2O (150 ml), then with dilute NaHCO3 solution, and the organic phase was dried over MgSO4. After filtering off the drying agent and removing the solvent on a rotary evaporator the residue was crystallised. N-(5-(trifluoromethyl)pyridin-2-yl)pivalamide (20.8 g, 91) was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([S:8][CH2:9][CH2:10][CH2:11][C:12]#[N:13])[N:3]=1.[F:14][C:15]([F:21])([F:20])[CH2:16][N:17]=[C:18]=[S:19]>C(#N)C>[F:14][C:15]([F:21])([F:20])[CH2:16][NH:17][C:18](=[S:19])[NH:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([S:8][CH2:9][CH2:10][CH2:11][C:12]#[N:13])[N:3]=1
Reactant: FC(F)(F)CN=C=S
Reactant: N#CCCCSc1nccc(N)n1
Solvent: CC#N
Product: N#CCCCSc1nccc(NC(=S)NCC(F)(F)F)n1
Reaction time: 72 h
Yield: 85.7 %

Procedure:
A mixture of 4-[4-aminopyrimid-2-ylthio]butyronitrile (0.25 g.), acetonitrile (3 ml.) and 2,2,2-trifluoroethyl isothiocyanate (0.21 g.) was stirred at 70° for 72 hours and then evaporated to dryness. The residue was crystallised from a mixture of ether and petroleum ether (b.p. 60°-80°) to give 4-[4-(3-[2,2,2-trifluoroethyl]thioureido)pyrimid-2-ylthio]butyronitrile (0.37 g.), m.p. 125°-126°.
Reaction SMILES: [Cl:1][C:2]1[C:10]([CH3:11])=[N:9][C:8]2[N:4]([N:5]=[C:6]3[CH2:14][N:13]([C:15]([C:17]4[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:18]=4[O:19][CH2:20][C:21](=O)[CH3:22])=[O:16])[CH2:12][C:7]3=2)[C:3]=1[CH3:29].[CH2:30]([NH:33][CH3:34])[CH:31]=[CH2:32].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.CC(=O)OCC>[CH2:30]([N:33]([CH3:34])[CH:21]([CH3:22])[CH2:20][O:19][C:18]1[CH:24]=[C:25]([F:28])[CH:26]=[CH:27][C:17]=1[C:15]([N:13]1[CH2:12][C:7]2=[C:8]3[N:4]([N:5]=[C:6]2[CH2:14]1)[C:3]([CH3:29])=[C:2]([Cl:1])[C:10]([CH3:11])=[N:9]3)=[O:16])[CH:31]=[CH2:32]
Reactant: C=CCNC
Reactant: CC(=O)COc1cc(F)ccc1C(=O)N1Cc2nn3c(C)c(Cl)c(C)nc3c2C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: C=CCN(C)C(C)COc1cc(F)ccc1C(=O)N1Cc2nn3c(C)c(Cl)c(C)nc3c2C1
Yield: 55.9 %

Procedure:
A mixture of Example 164 (150 mg; 0.36 mmol; 1 eq.) allyl-methyl-amine (51 mg; 0.72 mmol; 2 eq.) and sodium triacetoxyborohydride (99 mg; 0.47 mmol; 1.3 eq.) in DCE (5 mL) was stirred at 70° C. for 2 hours. The suspension was diluted with EA, washed with water, dried over magnesium sulfate and concentrated in vacuo. Purification by column chromatography (EA to 12% MeOH in EA) afforded the title compound (95 mg, 56%) as a white solid. 1H NMR (DMSO-d6) δ 7.45-7.29 (m, 1H), 7.17-7.02 (m, 1H), 6.87 (td, J=8.5, 2.4 Hz, 1H), 5.57-5.37 (m, 1H), 4.92 (dd, J=16.8, 5.8 Hz, 1H), 4.86-4.71 (m, 3H), 4.70-4.46 (m, 2H), 4.13-3.90 (m, 2H), 3.09-2.89 (m, 3H), 2.84 (s, 1.6H), 2.80 (s, 1.4H), 2.61 (s, 1.4H), 2.55 (s, 1.6H), 2.02 (d, J=4.9 Hz, 3H), 0.88 (dd, J=6.5, 1.9 Hz, 3H). HPLC (max plot) 94.9%, Rt 2.97 min. UPLC/MS: (MS+) 472.2 ([M+H]+).
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[O:14][C:6]2=[CH:7][C:8]3[C:9]([CH:13]=[C:5]2[CH:4]([NH2:15])[CH:3]1[OH:16])=[N:10][O:11][N:12]=3.C(N(CC)CC)C.[C:25](Cl)(=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27]>C(Cl)Cl>[CH3:1][C:2]1([CH3:17])[O:14][C:6]2=[CH:7][C:8]3[C:9]([CH:13]=[C:5]2[CH:4]([NH:15][C:25](=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27])[CH:3]1[OH:16])=[N:10][O:11][N:12]=3
Reactant: CC1(C)Oc2cc3nonc3cc2C(N)C1O
Reactant: CC(C)(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)NC1c2cc3nonc3cc2OC(C)(C)C1O
Temperature: 25 °C
Yield: 70 %

Procedure:
To a mixture of 200 mg (0.85 m mol) of 7,8-dihydro-6,6-dimethyl-7-hydroxy-8-amino-6H-pyrano [2,3-f] benzo-2,1,3-oxadiazole, 130 μl (0.935 m mol) of triethylamine and 20 ml of methylene chloride were added 115 μl (0.935 m mol) of pivaloyl chloride (trimethylacetyl chloride) with stirring at the room temperature, followed by further stirring for 3.5 hours. After the completion of the reaction, the mixture solution was washed thrice with water and dried over anhydrous magnesium sulfate. After the solvent was distilled off, the residue was recrystallized from ethanol to obtain the pure intended compound. (yield: 191 mg, yield: 70%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH2:4][C:5]1=[N:6][N:7]([CH3:19])[C:8](=[O:18])/[C:9]/1=[C:10](\OCC)/[CH2:11][CH2:12][CH2:13][CH3:14].[N:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH2:27][NH2:28]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:20])[CH2:4][C:5]1=[N:6][N:7]([CH3:19])[C:8](=[O:18])/[C:9]/1=[C:10](\[NH:28][CH2:27][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][N:21]=1)/[CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: NCc1ccccn1
Reactant: CCCC/C(OCC)=C1/C(=O)N(C)N=C1CC(=O)OC
Solvent: Cc1ccccc1
Product: CCCC/C(NCc1ccccn1)=C1/C(=O)N(C)N=C1CC(=O)OC
Yield: 92 %

Procedure:
The mixture of the above obtained methyl[(4Z)-4-(1-ethoxypentylidene)-1-methyl-5-oxo-4,5-dihydro-1H-pyrazol-3-yl]acetate (Compound of Formula (VII), 1.05 g) and 1-pyridin-2-ylmethanamine (0.262 mL) was stirred at room temperature in toluene (25 mL) for 0.5 h. The solvent was removed in vacuo. The resulting residue was dissolved in a minimum of CH2Cl2 and added dropwise to a stirred solution of 200 mL of cyclohexane resulting in the formation of a brown precipitate that was filtered off. This precipitate was proved to be the pure methyl[(4Z)-1-methyl-5-oxo-4-{1-[(pyridin-2-ylmethyl)amino]pentylidene}-4,5-dihydro-1H-pyrazol-3-yl]acetate (1.20 g). Yield 92%. MS (ESI+): 345.4; MS (ESI−): 342.5.