Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2([CH2:11][C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)=[O:13])[CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BH4-].[Na+].ClCCl>ClCCl.CO>[C:1]1([C:7]2([CH2:11][CH:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)[OH:13])[CH2:10][CH2:9][CH2:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(CC1(c2ccccc2)CCC1)c1ccccn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: OC(CC1(c2ccccc2)CCC1)c1ccccn1
Yield: 26.8 %

Procedure:
To a solution of Example 68E (1.5 g) in 27 mL of dichloromethane:methanol (9:1) was added NaBH4 (0.1 g, 2.6 mmol). The reaction was monitored by LC/MS, dichloromethane was added to the solution upon completion of the reaction. The mixture was washed with water, dried over Na2SO4, and filtered. The crude product was purified by preparative-HPLC (eluted with petroleum ether/EtOAc=5:1) to afford title compound (0.4 g, 1.6 mmol, 37.2%). LC-Ms: ESI-MS (M+H+): m/e=254.2. 1H NMR (400 MHz, CDCl3), 6 (ppm): 10.82 (br, 2H), 8.59 (d, J=5.2 Hz, 1H), 8.06 (td, J=2.0 Hz, J2=7.8 Hz, 1H), 7.60 (t, J=6.4 Hz, 1H), 7.29-7.24 (m, 3H), 7.19-7.11 (m, 3H), 4.75 (q, J=4.8 Hz, J2=8.0 Hz 1H), 2.67 (q, J1=7.3 Hz, J2=14.2 Hz 1H), 2.54-2.50 (m, 2H), 2.39-2.08 (m, 4H), 1.89-1.82 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH2:10][CH2:11][N:12]3[CH2:16][CH2:15][CH2:14][CH2:13]3)=[N:7][C:6]=2[CH:17]=1.[Cl:18][C:19]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=1[C:26]#[C:27][C:28](O)=[O:29].ClCCl.CO.N>>[N:12]1([CH2:11][CH2:10][C:8]2[O:9][C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:28](=[O:29])[C:27]#[C:26][C:20]4[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:19]=4[Cl:18])=[CH:17][C:6]=3[N:7]=2)[CH2:13][CH2:14][CH2:15][CH2:16]1
Reactant: O=C(O)C#Cc1ccc(Cl)cc1Cl
Reactant: Nc1ccc2oc(CCN3CCCC3)nc2c1
Agent: N
Solvent: ClCCl
Solvent: CO
Product: O=C(C#Cc1ccc(Cl)cc1Cl)Nc1ccc2oc(CCN3CCCC3)nc2c1

Procedure:
Prepared analogously to Example 3.1.e. from 5-amino-2-(2-pyrrolidin-1-ylethyl)benzoxazole and (2,4-dichlorophenyl)propynoic acid. Yield: 43 mg (33.1% of theory); C22H19Cl2N3O2 (M=428.32); melting point: 130° C.; calc.: molecular ion peak (M+H)+: 428/430/432; found: molecular ion peak (M+H)+: 428/430/432; C13H17N3O (M=231.30); calc.: molecular ion peak (M+H)+: 232; found: molecular ion peak (M+H)+: 232; Rf value: 0.21 (silica gel, dichloromethane/methanol/ammonia (10:1:0.1)).
Reaction SMILES: C1(C2CC2C(Cl)=O)C=CC=CC=1.[CH3:13][O:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][C:24]=1[O:25][CH3:26])[N:21]=[CH:20][CH:19]=[C:18]2[O:27][C:28]1[CH:33]=[CH:32][C:31]([NH:34][CH2:35][CH3:36])=[CH:30][CH:29]=1.[C:37]1([CH:43]2[CH2:45][CH:44]2[C:46]([N:48]=[C:49]=[S:50])=[O:47])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>C1(C)C=CC=CC=1.C(O)C>[C:37]1([CH:43]2[CH2:45][CH:44]2[C:46]([N:48]=[C:49]=[S:50])=[O:47])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.[CH3:13][O:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][C:24]=1[O:25][CH3:26])[N:21]=[CH:20][CH:19]=[C:18]2[O:27][C:28]1[CH:33]=[CH:32][C:31]([N:34]([CH2:35][CH3:36])[C:49]([NH:48][C:46]([CH:44]2[CH2:45][CH:43]2[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[O:47])=[S:50])=[CH:30][CH:29]=1
Reactant: CCNc1ccc(Oc2ccnc3cc(OC)c(OC)cc23)cc1
Agent: O=C(Cl)C1CC1c1ccccc1
Agent: O=C(N=C=S)C1CC1c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCN(C(=S)NC(=O)C1CC1c1ccccc1)c1ccc(Oc2ccnc3cc(OC)c(OC)cc23)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 53 %

Procedure:
2-Phenyl-1-cyclopropanecarbonyl isothiocyanate was prepared using commercially available 2-phenyl-1-cyclopropanecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. N-{4-[(6,7-Dimethoxy-4-quinolyl)oxy]phenyl}-N-ethylamine (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 2-phenyl-1-cyclopropanecarbonyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (43 mg, yield 53%).
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH2:9][CH:8]([CH2:11][N:12]([CH2:24][CH2:25][CH3:26])[CH:13]2[CH2:22][CH2:21][C:20]3[C:15](=[CH:16][C:17]([NH2:23])=[CH:18][CH:19]=3)[CH2:14]2)[CH2:7][CH2:6]1)(=[O:4])=[O:3].[C:27](Cl)(=[O:31])[CH:28]([CH3:30])[CH3:29]>ClCCl.CCN(C(C)C)C(C)C>[CH3:1][S:2]([N:5]1[CH2:10][CH2:9][CH:8]([CH2:11][N:12]([CH2:24][CH2:25][CH3:26])[CH:13]2[CH2:14][C:15]3[CH:16]=[C:17]([NH:23][C:27](=[O:31])[CH:28]([CH3:30])[CH3:29])[CH:18]=[CH:19][C:20]=3[CH2:21][CH2:22]2)[CH2:7][CH2:6]1)(=[O:4])=[O:3]
Reactant: CCCN(CC1CCN(S(C)(=O)=O)CC1)C1CCc2ccc(N)cc2C1
Reactant: CC(C)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCN(CC1CCN(S(C)(=O)=O)CC1)C1CCc2ccc(NC(=O)C(C)C)cc2C1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of N-(1-methanesulfonyl-piperidin-4-ylmethyl)-N-propyl-1,2,3,4-tetrahydro-naphthalene-2,7-diamine (200 μL of a 0.25 M solution in dichloromethane, 50 μmole) was added 220 μL of a 0.25 M solution of isobutyryl chloride in dichloromethane and 30 μL of DIEA. The solution was allowed to stir for 72 h at 25° C. under N2 and was then concentrated in vacuo. The final product was isolated by preparative RPHPLC (YMC Combiprep ODS-A column, 10-90% acetonitrile: water (0.1% TFA)) to afford N-{7-[(1-methanesulfonyl-piperidin-4-ylmethyl)-propyl-amino]-5,6,7,8-tetrahydro-naphthalen-2-yl}-isobutyramide (10.4 mg) 86, [M+H]+=450.
Reaction SMILES: [CH2:1]([NH:3][NH2:4])[CH3:2].[C:5](OCC)(=[O:10])[CH2:6][C:7]([CH3:9])=O>CCO>[CH2:1]([N:3]1[C:5](=[O:10])[CH2:6][C:7]([CH3:9])=[N:4]1)[CH3:2]
Reactant: CCOC(=O)CC(C)=O
Reactant: CCNN
Solvent: CCO
Product: CCN1N=C(C)CC1=O
Temperature: 80 °C
Yield: 38.3 %

Procedure:
3.05 g of Ethylhydrazine and 6.54 g of Ethyl acetoacetate was dissolved in 10 mL of EtOH and the mixture was heated at 80° C. overnight. The mixture was cooled and partitioned between CHCl3 and water. The organic layer was drier over Na2SO4, concentrated to give 2.43 g of crude 2-ethyl-5-methyl-2,4-dihydro-3H-pyrazol-3-one. 2.35 g of the material was diluted with 4 mL of DMF and 6.2 mL of POCl3 was added dropwise thereto. The mixture was heated at 80° C. overnight, then cooled to room temperature. After addition of ice, the mixture was partitioned between CHCl3 and water. The organic layer was dried over Na2SO4 and concentrated to give 1.46 g of crude 5-chloro-1-ethyl-3-methyl-1H-pyrazole-4-carbaldehyde. 516 mg of the material was diluted with 10 mL of EtOH and 440 mg of HSCH2COOEt and 930 mg of K2CO3 was added thereto. The mixture was stirred at 80° C. overnight. The reaction mixture was cooled and 5 mL of 1N NaOHaq and 5 mL of MeOH was added thereto successively. Then the mixture was heated at 85° C. for 3 hrs. After cooled, the mixture was acidified with 1N HCl (to pH 1.5), then diluted with water. The precipitate was filtered, washed with water and n-hexane, dried in vacuo to afford 214 mg of the targeted compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11](=[O:26])[NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1)[C:5](O)=[O:6].[CH3:27][O:28][CH2:29][CH2:30][NH2:31]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]([NH:31][CH2:30][CH2:29][O:28][CH3:27])=[O:6])[CH:8]=[CH:9][C:10]=1[C:11]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1)=[O:26]
Reactant: COCCN
Reactant: O=C(O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1
Product: COCCNC(=O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1

Procedure:
75 mg of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoic acid was coupled to 2-methoxyethanamine via Procedure G. The product was purified on reverse phase HPLC to yield 2-chloro-N1-(4-chloro-3-(pyridin-2-yl)phenyl)-N4-(2-methoxyethyl)terephthalamide. MS (Q1) 444 (M)+.
Reaction SMILES: [S:1]([N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([CH:20]=O)=[CH:12]1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].[CH2:22]([C:25]1([NH2:38])[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH2:26]1)[CH:23]=[CH2:24].C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>ClCCCl>[CH2:22]([C:25]1([NH:38][CH2:20][C:13]2[C:14]3[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:11]([S:1]([C:4]3[CH:5]=[CH:6][C:7]([CH3:8])=[CH:9][CH:10]=3)(=[O:3])=[O:2])[CH:12]=2)[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH2:26]1)[CH:23]=[CH2:24]
Reactant: C=CCC1(N)CCN(C(=O)OC(C)(C)C)CC1
Reactant: Cc1ccc(S(=O)(=O)n2cc(C=O)c3ccccc32)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: C=CCC1(NCc2cn(S(=O)(=O)c3ccc(C)cc3)c3ccccc23)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 60 °C
Yield: 60.1 %

Procedure:
To a solution of 1-tosyl-1H-indole-3-carbaldehyde [50562-79-3] (1.90 g, 6.35 mmol) in 1,2-dichloroethane (30 mL) were added tert-butyl 4-allyl-4-aminopiperidine-1-carboxylate [741687-08-1] (1.52 g, 6.35 mmol) and acetic acid (381 mg, 6.35 mmol). The resulting solution was heated at 60° C. for 3 h. Then NaBH(OAc)3 was added and the reaction mixture was heated at 60° C. for 38 h. The mixture was cooled to rt, saturated NaHCO3 solution (30 mL) was added and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with water and brine, then dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude mixture was purified by flash-column chromatography over silicagel (eluent: 20% ethyl acetate/hexane) to yield the title compound (2.0 g, 60%). [LCMS RtE=0.34 min, [M+H]+=524.0]
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:3]=1[NH2:4].[C:10](Cl)(Cl)=[S:11].C(N(C(C)C)C(C)C)C>>[Cl:1][C:2]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:3]=1[N:4]=[C:10]=[S:11]
Reactant: Nc1ccc(Cl)cc1Cl
Reactant: S=C(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: S=C=Nc1ccc(Cl)cc1Cl
Yield: 63.5 %

Procedure:
The title compound was prepared following the procedure described for intermediate-2 using 2,4-dichloro aniline (5.0 g, 30.86 mmol), thiophosgene (3.54 g, 30.86 mmol) and N-ethyl di-isopropyl amine (7.94 g, 61.55 mmol) to afford 4.0 g of the desired product. 1HNMR (CDCl3): δ 7.39 (s, 1H), 7.39-7.12 (m, 2H).
Reaction SMILES: Br[C:2]1[C:7]2[C:8]([C:11]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)=[O:12])=[CH:9][O:10][C:6]=2[C:5]([Br:21])=[CH:4][C:3]=1[OH:22].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=[O:25]>CS(C)=O>[Br:21][C:5]1[C:6]2[O:10][CH:9]=[C:8]([C:11](=[O:12])[C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[C:7]=2[C:2](=[O:25])[C:3](=[O:22])[CH:4]=1
Reactant: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Reactant: COc1ccc(C(=O)c2coc3c(Br)cc(O)c(Br)c23)cc1
Solvent: CS(C)=O
Product: COc1ccc(C(=O)c2coc3c2C(=O)C(=O)C=C3Br)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of compound 7d (50 mg, 0.12 mmol) in DMSO (1.5 mL) was added Dess-Martin periodinane (100 mg, 0.24 mmol) at 0° C. The resulting mixture was stirred at room temperature for 20 min and poured into ice water (2 mL). The resulting precipitate was filtered, washed with water, and dried under high vacuum to obtain compound SKC-BF-07 (25 mg, 55%) as a red solid. TLC Rf=0.45 (petroleum ether-EtOAc, 6:4); 1H NMR (CDCl3) δ 7.89 (s, 1H), 7.85 (d, J=8.7 Hz, 2H), 6.95 (d, J=9.0 Hz, 2H), 6.78 (s, 1H), 3.89 (s, 3H); MS (ES) m/z 362 (M+H)+.
Reaction SMILES: [CH2:1]([S:8][CH:9]([CH2:19][N:20]1[CH2:25][CH2:24][S:23][CH2:22][CH2:21]1)[CH2:10][NH:11]C(=O)OCCCC)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OCC)(=O)C.C(OCC)(=O)C.Cl>CO>[CH2:1]([S:8][CH:9]([CH2:19][N:20]1[CH2:21][CH2:22][S:23][CH2:24][CH2:25]1)[CH2:10][NH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCOC(=O)NCC(CN1CCSCC1)SCc1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: NCC(CN1CCSCC1)SCc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 90.9 %

Procedure:
To a solution of tent-butyl [2-(benzylthio)-3-thiomorpholinopropyl]carbamate (21.46 g) in a mixed solvent of ethyl acetate (60 mL) and methanol (60 mL) was added hydrogen chloride-ethyl acetate solution (120 mL) at 0° C., and the mixture was stirred at room temperature for 4 hr. The reaction solution was concentrated, and the residue was partitioned between ethyl acetate and saturated aqueous potassium carbonate solution. The organic layer was washed with saturated brine, and dried over sodium sulfate, and the solvent was evaporated to give the title compound (14.41 g, yield 91%) as a yellow oil.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([CH:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH2:2]1.[CH3:25][N:26]=[C:27]=[O:28]>C(Cl)Cl>[CH3:25][NH:26][C:27]([N:1]1[CH2:6][CH2:5][CH2:4][CH:3]([CH:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH2:2]1)=[O:28]
Reactant: CN=C=O
Reactant: CC(Nc1nccc(-n2cnc3ccccc32)n1)C1CCCNC1
Solvent: ClCCl
Product: CNC(=O)N1CCCC(C(C)Nc2nccc(-n3cnc4ccccc43)n2)C1

Procedure:
To a solution of 2-[1-(piperidin-3-yl)-ethylamino]-4-[benzimidazol-1-yl]pyrimidine (EXAMPLE 18) (51 mg, 0.16 mmol) in CH2Cl2 (1.6 mL) was added methylisocyanate (10.5 lL, 0.176 mmol) at room temperature. After the reaction was complete (2-3 h), the solvent was removed under reduced pressure, and the crude product was purified by preparative thin layer chromatography (4:1 acetone:hexane system as an eluent) to obtain the title compound. Partial 1H NMR (500 MHz, CDCl3): δ 8.61 (s, 1H); 8.36 (d, J=5.0 Hz, 1H); 8.16 (d, J=7.6 Hz, 1H); 7.85 (d, J=7.1 Hz, 1H); 7.38 (m, 2H); 6.78 (d, J=5.5 Hz, 1H); 4.17 (m, 1H); 4.07 (d, J=11 Hz, 1H); 3.76 (d, J=12.6 Hz, 1H); 2.78 (d, J=4.6 Hz, 3H); 1.31 (d, J=6.6 Hz, 3H). Mass spectrum 380.3 (ESI, M+1).
Reaction SMILES: [Br:1][CH:2]([C:7](=O)C)[CH2:3][C:4]([OH:6])=[O:5].[NH2:10][C:11]([NH2:13])=[S:12].[CH2:14](O)C>>[BrH:1].[NH2:10][C:11]1[S:12][CH2:14][C:2]([CH2:3][C:4]([OH:6])=[O:5])([CH3:7])[N:13]=1
Reactant: CCO
Reactant: CC(=O)C(Br)CC(=O)O
Reactant: NC(N)=S
Product: Br
Product: CC1(CC(=O)O)CSC(N)=N1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of 3-bromo-4-oxovaleric acid (4.0 g.) in ethanol (50 ml.) was added powder of thiourea (1.6 g.) and the mixture was stirred for 3 hours at the room temperature, and then the precipitated crystals were collected by filtration and then dried to give 2-amino-4-methylthiazol-4-ylacetic acid hydrobromide (1.5 g.).
Reaction SMILES: [CH2:1]1[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][C:4](=[O:13])[N:3]3[CH2:2]1.[Cl:14][CH2:15][CH2:16][C:17](Cl)=[O:18]>>[Cl:14][CH2:15][CH2:16][C:17]([C:9]1[CH:8]=[C:7]2[C:12]3=[C:11]([CH2:1][CH2:2][N:3]3[C:4](=[O:13])[CH2:5][CH2:6]2)[CH:10]=1)=[O:18]
Reactant: O=C1CCc2cccc3c2N1CC3
Reactant: O=C(Cl)CCCl
Product: O=C(CCCl)c1cc2c3c(c1)CCN3C(=O)CC2

Procedure:
Using 1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one (10.0 g) and 3-chloropropanoyl chloride (6.06 ml) according to the same method as that of Reference Example 1, the title compound (12.0 g) was obtained as colorless crystals having a melting point of 154 to 155° C.
Reaction SMILES: C(Cl)(Cl)Cl.[CH3:5][C:6]1[CH:7]([OH:16])[CH:8]([OH:15])[CH:9]([C:12]([CH3:14])=[CH2:13])[CH2:10][CH:11]=1>C(Cl)Cl>[CH3:5][C:6]1[C@@H:7]([OH:16])[C@H:8]([OH:15])[C@H:9]([C:12]([CH3:14])=[CH2:13])[CH2:10][CH:11]=1
Reactant: C=C(C)C1CC=C(C)C(O)C1O
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: C=C(C)[C@@H]1CC=C(C)[C@@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 945 mg epoxide (−)-cis-verbenole (1R,2R,4S,5R,6S)-2 ([α]D25=−85.6 (c0.82, CHCl3)) in 12 ml methylene chloride was added, stiffing continuously, into a suspension of 2 g K10 (Fluka) clay (calcinated for 3 hours under 110° C.) in 15 ml of methylene chloride. The reaction mixture was stirred for 1 hour under room temperature. The catalyst was filtered, rinsed by ethyl acetate, the solvent was evaporated. The residue was separated by column chromatography using SiO2 (60-200μ; Merck), a solution of diethyl ether in hexane 5 to 100% was used as an eluent. 270 mg (29%) of (1R,2R,6s)-1a (ee 94%, ([α]D27=−84.0 (c 3.47, CHCl3)) was obtained as a result. Enantiomeric purity of the compound 1a was evaluated by the data of gas-liquid chromatography with mass spectroscopy in chiral column.
Reaction SMILES: [H-].[Na+].Cl[C:4]1[N:9]=[C:8]([N:10]2[CH2:14][CH2:13][CH2:12][CH:11]2[C:15]2[O:19][N:18]=[C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=3)[CH:16]=2)[N:7]=[C:6]([NH:26][C:27]2[CH:31]=[C:30]([CH:32]3[CH2:34][CH2:33]3)[NH:29][N:28]=2)[CH:5]=1.[CH2:35]([OH:38])[CH2:36][OH:37]>>[OH:37][CH2:36][CH2:35][O:38][C:4]1[N:9]=[C:8]([N:10]2[CH2:14][CH2:13][CH2:12][CH:11]2[C:15]2[O:19][N:18]=[C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=3)[CH:16]=2)[N:7]=[C:6]([NH:26][C:27]2[CH:31]=[C:30]([CH:32]3[CH2:34][CH2:33]3)[NH:29][N:28]=2)[CH:5]=1
Reactant: Clc1cc(Nc2cc(C3CC3)[nH]n2)nc(N2CCCC2c2cc(-c3ccccn3)no2)n1
Reactant: OCCO
Agent: [H-]
Agent: [Na+]
Product: OCCOc1cc(Nc2cc(C3CC3)[nH]n2)nc(N2CCCC2c2cc(-c3ccccn3)no2)n1
Temperature: 150 °C
Reaction time: 0.08 h
Yield: 14 %

Procedure:
Sodium hydride (60% dispersion in oil, 71 mg, 1.78 mmol) was added to ethylene glycol (4 ml) and the mixture stirred for 5 minutes. S-6-Chloro-2-{2-[3-(pyrid-2-yl)isoxazol-5-yl]pyrrolidin-1-yl}-4-(5-cyclopropyl-1H-pyrazol-3-ylamino)pyrimidine (Example 143) (160 mg, 0.35 mmol) was added and the mixture heated at 150° C. in a sealed vessel under microwave irradiation for 45 minutes. The crude mixture was purified by reverse phase HPLC using a C18 column eluting with water/acetonitrile/TFA (95:5:0.2 decreasing in polarity to 0:100:0.2). The product containing fractions were poured onto a 20 g SCX-2 column, eluting with methanol then with 2N methanolic ammonia to elute the product. The solvent was removed by evaporation to give the title compound (23 mg, 14%) as a pale yellow powder.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].C(O[C:10](=O)[NH:11][CH:12]1[CH2:17][CH2:16][N:15]([CH:18]([CH3:20])[CH3:19])[CH2:14][CH2:13]1)C>O.C(OCC)C>[CH:18]([N:15]1[CH2:14][CH2:13][CH:12]([NH:11][CH3:10])[CH2:17][CH2:16]1)([CH3:20])[CH3:19]
Reactant: CCOC(=O)NC1CCN(C(C)C)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: CNC1CCN(C(C)C)CC1
Temperature: 25 °C

Procedure:
100 ml absolute diethyl ether were placed in a dry three-necked flask equipped with a condenser. 4.35 g LiAlH4 (6 equiv.) were added and the mixture was stirred at room temperature under an argon atmosphere. Carefully, 4.10 g (19.13 mmol) (1-isopropyl-piperidin-4-yl)-carbamic acid ethyl ester were added portionwise and the resulting mixture was refluxed for 7 h. Since the conversion was not complete, 1.00 g (≈1.4 equiv.) LiAlH4 was added and the mixture was refluxed for further 2 h. The reaction mixture was cooled and, carefully, 14 ml water were added dropwise over a 20-minute period. The mixture was diluted with 40 ml water and 50 ml diethyl ether. The phases were separated. The aqueous phase (suspension) was treated with a 10% NaOH-solution and washed twice with 100 ml diethyl ether. The organic phases were combined, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was obtained as a colorless oil. Yield: 2.91 g MS (ES+): m/e=157.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][C:10]#[CH:11].C([Li])CCC.Br[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][F:26]>O1CCCC1.CN(P(N(C)C)(N(C)C)=O)C>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][C:10]#[C:11][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][F:26]
Reactant: C#CCCOC1CCCCO1
Reactant: FCCCCCCCCBr
Agent: [Li]CCCC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: FCCCCCCCCC#CCCOC1CCCCO1
Temperature: -78 °C
Reaction time: 1 h
Yield: 60.6 %

Procedure:
To a solution of 3-butyn-1-yl tetrahydropyranyl ether (0.4815 g, 3.05 mmol) (prepared as in Example 1 above) in dry tetrahydrofuran (15 mL) at -78° C. is added n-butyllithium (3.05 mmol, 2.80 mL of 1.09M n-BuLi in hexane). The resulting yellow mixture is stirred for 1 hour at -78° C., warmed to -5° C. for about 5 min and then a solution of 8-bromo-1-fluorooctane (0.7716 g, 3.65 mmol, 1.2 eq.) in HMPA (10 mL) is added dropwise over 45 minutes (Hendry et al., J. Chem. Ecol., 1, 317, 1975). After the addition is completed, the reaction is allowed to warm to room temperature and stirred overnight. After quenching the solution by the dropwise addition of water (about 10 mL), the aqueous solution is extracted with pentane (4×50 ml) and the combined pentane extracts are washed with saturated sodium chloride (50 mL) and dried (MgSO4). The volatiles are removed in vacuo and the crude product is flash chromatographed using hexane/ethyl acetate (9:1, v/v) to give 12-fluoro-3-dodecyn-1-yl tetrahydropyranyl ether (0.526 g, 60%) as a clear colorless oil: Rf=0.60, hexane/ethyl acetate (7:3, v/v); IR (film) ν2850-3000 (alkane CH) and 1H-NMR (CDCl3) δ1.20-1.90 (m, 18H), 2.05-2.20 (m, 2H), 2.30-2.55 (m,2H), 3.30-3.95(m, 4, 4.42 (dt, J=48 Hz, 6 Hz, 2H), 4.60 (br s, 1H).
Reaction SMILES: [F:1][CH:2]([F:24])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:23])[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]#[C:20][CH2:21]O)[CH:14]=2)=[O:12])=[CH:6][CH:5]=1.CCN(S(F)(F)[F:31])CC.C([O-])(O)=O.[Na+]>C(Cl)Cl>[F:1][CH:2]([F:24])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:23])[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]#[C:20][CH2:21][F:31])[CH:14]=2)=[O:12])=[CH:6][CH:5]=1
Reactant: O=C(C(=O)c1cccc(C#CCO)c1)c1ccc(OC(F)F)cc1
Reactant: CCN(CC)S(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=C(C(=O)c1cccc(C#CCF)c1)c1ccc(OC(F)F)cc1
Temperature: -78 °C
Yield: 77 %

Procedure:
1-(4-(Difluoromethoxy)phenyl)-2-(3-(3-hydroxyprop-1-ynyl)phenyl)ethane-1,2-dione (0.298 g, 0.90 mmol) is dissolved in CH2Cl2 (3.0 mL) and cooled to −78° C. DAST (0.160 g, 0.99 mmol) is added and the solution is slowly warmed to RT. After 1 h at RT a saturated solution of NaHCO3 is added and the mixture extracted with CH2Cl2. The CH2Cl2 is washed with H2O and brine. The solution is dried (MgSO4) and the material purified by flash chromatography to yield 1-(4-(difluoromethoxy)phenyl)-2-(3-(3-fluoroprop-1-ynyl)phenyl)ethane-1,2-dione (0.232, 77%).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[C:8]([C:11]([F:14])([F:13])[F:12])[C:7]([C:15]#[N:16])=[CH:6][CH:5]=2.Br[CH2:18][C:19]([NH2:21])=[O:20]>>[C:15]([C:7]1[C:8]([C:11]([F:12])([F:14])[F:13])=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]([CH2:18][C:19]([NH2:21])=[O:20])[C:2]([CH3:1])=[CH:10]2)#[N:16]
Reactant: Cc1cc2c(C(F)(F)F)c(C#N)ccc2[nH]1
Reactant: NC(=O)CBr
Product: Cc1cc2c(C(F)(F)F)c(C#N)ccc2n1CC(N)=O

Procedure:
Synthesized as described in Example 4 using 2-methyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile and 2-bromoacetamide: 1H NMR (400 MHz, DMSO-d6) δ 7.82 (d, J=8.5 Hz, 1H), 7.71 (bs, 1H), 7.67 (d, J=8.5 Hz, 1H), 7.35 (bs, 1H), 6.55 (s, 1H), 4.89 (s, 2H), 2.39 (s, 3H); MS (ES) m/z 282 (M+1).