Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:10]2[CH2:19][CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:20][CH3:21])[CH:16]=3)[CH:11]=2)=[C:7]([NH2:9])[CH:8]=1.[C:22](Cl)(=[O:26])[O:23][CH2:24][CH3:25].[Cl-].[NH4+]>O1CCCC1.C(N(CC)C(C)C)(C)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:10]2[CH2:19][CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:20][CH3:21])[CH:16]=3)[CH:11]=2)=[C:7]([NH:9][C:22](=[O:26])[O:23][CH2:24][CH3:25])[CH:8]=1
Reactant: CCOC(=O)Cl
Reactant: COc1ccc(C2=Cc3ccc(OC)cc3CC2)c(N)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCOC(=O)Nc1cc(OC)ccc1C1=Cc2ccc(OC)cc2CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5-methoxy-2-(6-methoxy-3,4-dihydronaphthalen-2-yl)phenylamine (400 mg) in tetrahydrofuran (10 ml) and N,N-diisopropylethylamine (0.5 ml) was added ethyl chlorocarbonate (0.2 ml) on an ice bath, and the solution was stirred overnight at room temperature. A saturated aqueous solution of ammonium chloride was added thereto, the solution was extracted with ethyl acetate, then sequentially washed with water and brine, and the solvent was evaporated in vacuo. The residue was purified by silica gel column chromatography (hexane-ethyl acetate system) to provide ethyl [5-methoxy-2-(6-methoxy-3,4-dihydronaphthalen-2-yl)phenyl]carbamate (445 mg). This compound (438 mg) was used according to an analogous synthetic method to Example 337 described below to provide the title compound (286 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[CH2:9][CH2:10][CH2:11][NH:12][C:13](=[O:17])[CH2:14][NH:15][CH3:16])=[CH:4][CH:3]=1.[CH:25](=O)[CH:26]([CH3:28])[CH3:27].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl.CCOC(C)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:18]2[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=2)[CH2:9][CH2:10][CH2:11][NH:12][C:13](=[O:17])[CH2:14][N:15]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH3:16])=[CH:6][CH:7]=1
Reactant: CNCC(=O)NCCCC(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: CC(C)C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)CN(C)CC(=O)NCCCC(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 92 %

Procedure:
N-[4,4-Bis-(4-fluoro-phenyl)-butyl]-2-methylamino-acetamide (157 mg, 0.47 mmol) was dissolved in CH2Cl2 (5 mL), treated with isobutyraldehyde (43 mL, 0.47 mmol), stirred for 30 minutes, then cooled to 0° C., treated with NaBH(OAc)3 (150 mg, 0.71 mmol), and stirred overnight at room temperature. The reaction was diluted with EtOAc (100 mL), washed with saturated bicarbonate solution and brine, dried over Na2SO4, and concentrated. The crude material was chromatographed on silica gel eluting with 4% MeOH/CH2Cl2 to give 168 mg (92%) of the desired product as a sticky solid. MS: 389.3 (M+1 for C23H30N2O1F2); sticky solid; TLC (SiO2), Rf 0.44 (6% MeOH/CH2Cl2); HPLC (7:3 CH3CN/H2O with 0.1% TFA, C-18 column) 100%, RT=2.067 min.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:22]([OH:31])([C:27]([F:30])([F:29])[F:28])[C:23]([F:26])([F:25])[F:24])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[S:18][CH:19]=[CH:20][CH:21]=2)(=[O:16])=[O:15])[CH2:10][CH2:9]1.[CH:32]#[C:33][CH:34]([OH:37])[CH2:35][CH3:36]>>[S:18]1[CH:19]=[CH:20][CH:21]=[C:17]1[S:14]([N:11]1[CH2:12][CH2:13][N:8]([C:7]2[CH:6]=[CH:5][C:4]([C:22]([OH:31])([C:27]([F:30])([F:29])[F:28])[C:23]([F:26])([F:25])[F:24])=[CH:3][C:2]=2[C:32]#[C:33][CH:34]([OH:37])[CH2:35][CH3:36])[CH2:9][CH2:10]1)(=[O:16])=[O:15]
Reactant: C#CC(O)CC
Reactant: O=S(=O)(c1cccs1)N1CCN(c2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2Br)CC1
Product: CCC(O)C#Cc1cc(C(O)(C(F)(F)F)C(F)(F)F)ccc1N1CCN(S(=O)(=O)c2cccs2)CC1

Procedure:
Following the procedure outlined for Example 152, 2-(3-bromo-4-(4-(thiophen-2-ylsulfonyl)piperazin-1-yl)phenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol (Example 69) was coupled to 1-pentyn-3-ol (Aldrich, St. Louis, Mo.) to afford 1-(2-(4-(2-thiophenylsulfonyl)-1-piperazinyl)-5-(2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl)phenyl)-1-pentyn-3-ol as a mixture of enantiomers.
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:15][SiH:16]([CH2:18][SiH:19]([Cl:21])[Cl:20])[Cl:17]>C1C=CC=CC=1>[Cl:15][Si:16]1([Cl:17])[CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:8]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[Si:19]([Cl:21])([Cl:20])[CH2:18]1
Reactant: C(#Cc1ccccc1)c1ccccc1
Reactant: Cl[SiH](Cl)C[SiH](Cl)Cl
Solvent: c1ccccc1
Product: Cl[Si]1(Cl)C[Si](Cl)(Cl)C(c2ccccc2)C1c1ccccc1
Reaction time: 4 h
Yield: 73.7 %

Procedure:
Hydrosilation of diphenylacetylene with bis(dichlorosilyl)methane in the presence of Pt((CH2 =CHSiMe2)2O)2. Into the same apparatus as described in Example 1 were added 1 g of bis(dichlorosilyl)methane, 0.84 g of diphenylacetylene, 20 μl of Pt((CH2 =CHSiMe2)2O)2 in 1,1,3,3-tetramethyl-1,3-divinyl-1,3-disiloxane (4 weight percent Pt), and 20 ml of dried benzene. The flask content was refluxed, with stirring, for 4 hours and then the solvent removed at atmospheric presssure. The products were distilled at 67 Pa to give a mixture comprising 0.73 g of 1,1,3,3-tetrachloro-4,5-diphenyl-1,3-disilacyclopentane (TCD-GC area 73.7%) and 3,3,5,5-tetrachloro-1,2,6,7-tetraphenyl-3,5-disilahepta-1,6-diene (TCD-GC area 13.2%).
Reaction SMILES: [CH3:1][C:2]([CH3:7])([C:5]#[N:6])[C:3]#[N:4].[C:8](#[N:10])[CH3:9].O>C1(C)C=CC=CC=1>[NH2:4][C:3]([C:2]([CH3:7])([CH3:1])[C:5]#[N:6])=[CH:9][C:8]#[N:10]
Reactant: CC(C)(C#N)C#N
Reactant: CC#N
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C#N)C(N)=CC#N
Temperature: 40 °C
Reaction time: 2 h
Yield: 81 %

Procedure:
A solution of potassium tert amylate in toluene (25%, 11.8 mL, 23 mmol) is added slowly to a solution of 2,2-Dimethyl-malononitrile (2.0 g, 21 mmol) and acetonitrile (1.2 mL, 23 mmol) in toluene (20 mL) at 40° C. under argon. The reaction mixture is stirred at 40° C. for 2 h and then cooled to 12° C. Water (5 mL) is added and the mixture is stirred at 20° C. for 15 min and at 2° C. for 30 min. Filtration, washing with cold water (10 mL) and drying under vacuum provides 2.30 g 3-Amino-4,4-dimethyl-pent-2-endinitrile. Yield: 80%: ESI-MS: 136 [M+H]+; 1H-NMR (DMSO-d6): 1.5, 4.1, 6.8 ppm.
Reaction SMILES: [C:1]([C:4]1[N:5]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[CH:6]=[C:7]([C:9]([OH:11])=O)[N:8]=1)(=[O:3])[NH2:2].[NH2:20][C@@H:21]([CH3:38])[CH2:22][N:23]1[CH:27]=[CH:26][C:25]([C:28]2[CH:35]=[C:34]([F:36])[C:31]([C:32]#[N:33])=[C:30]([Cl:37])[CH:29]=2)=[N:24]1>>[Cl:37][C:30]1[CH:29]=[C:28]([C:25]2[CH:26]=[CH:27][N:23]([CH2:22][C@@H:21]([NH:20][C:9]([C:7]3[N:8]=[C:4]([C:1]([NH2:2])=[O:3])[N:5]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[CH:6]=3)=[O:11])[CH3:38])[N:24]=2)[CH:35]=[C:34]([F:36])[C:31]=1[C:32]#[N:33]
Reactant: C[Si](C)(C)CCOCn1cc(C(=O)O)nc1C(N)=O
Reactant: C[C@H](N)Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1
Product: C[C@@H](Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1)NC(=O)c1cn(COCC[Si](C)(C)C)c(C(N)=O)n1

Procedure:
The title compound was prepared using the procedure described in Example 32(e) starting from 2-carbamoyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carboxylic acid (500 mg, 1.7 mmol) and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-6-fluorobenzonitrile (472 mg, 1.7 mmol). The product was purified with flash-chromatography. Yield 420 mg. LC-MS: [M+1]=546.19.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([CH:9]=1)[CH:7]=[O:8].[NH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.C(=O)([O-])[O-].[K+].[K+].CS(C)=O>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: O=Cc1cc(Cl)ccc1F
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: O=Cc1cc(Cl)ccc1N1CCOCC1
Temperature: 100 °C
Reaction time: 8 h
Yield: 76 %

Procedure:
A 50 mL round-bottom flask was charged with 5-chloro-2-fluorobenzaldehyde (3.00 g, 18.9 mmol, 1.00 equiv), morpholine (2.50 g, 28.7 mmol, 1.52 equiv), potassium carbonate (6.50 g, 47.0 mmol, 2.49 equiv), methyl sulfoxide (20 mL). The resulting solution was stirred overnight at 100° C. in an oil bath and diluted with H2O (50 mL). The resulting solution was extracted with dichloromethane (3×20 mL) and the organic layers were combined, washed with H2O (2×50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with ethyl acetate/petroleum ether (1/9) to provide 3.24 g (76% yield) of 5-chloro-2-(morpholin-4-yl)benzaldehyde as brown oil. LCMS (ESI, m/z): 226 [M+H]+.
Reaction SMILES: C(O)(=O)C(O)=O.[C:7]([C:11]([CH2:13][N:14]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[N:18]([CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)[CH2:17][C@@H:16]([NH2:31])[C:15]1=[O:32])=[O:12])([CH3:10])([CH3:9])[CH3:8].C(=O)([O-])[O-].[K+].[K+].[C:39](Cl)(=[O:47])[O:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>C(OCC)(=O)C>[C:7]([C:11]([CH2:13][N:14]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[N:18]([CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)[CH2:17][C@@H:16]([NH:31][C:39]([O:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=[O:47])[C:15]1=[O:32])=[O:12])([CH3:10])([CH3:8])[CH3:9]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CC(C)(C)C(=O)CN1C(=O)[C@H](N)CN(C2CCCCC2)c2ccccc21
Agent: O=C(O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: CC(C)(C)C(=O)CN1C(=O)[C@H](NC(=O)Oc2ccccc2)CN(C2CCCCC2)c2ccccc21
Reaction time: 0.5 h
Yield: 96.8 %

Procedure:
To a suspension of 8.9 g of (R)-(−)-1-tert-butylcarbonylmethyl-2-oxo-3-amino-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine oxalate in 45 ml of ethyl acetate was added 45 ml of an aqueous solution of 8.25 g of potassium carbonate under ice cooling. The mixture was stirred at the same temperature for 30 minutes. After addition of 3.12 g of phenyl chlorocarbonate under ice cooling, the mixture was stirred for 5 minutes under ice cooling and then at room temperature for 30 minutes. The reaction mixture was then separated into layers. The aqueous layer was extracted with ethyl acetate and the organic layer thus obtained was combined with the organic layer obtained in advance. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure, whereby 9.19 g of the title compound was obtained.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:17]=[C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:19]=1[OH:20])[C:8](=[N:15][OH:16])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[C:25](Cl)(=[O:27])[CH3:26]>N1C=CC=CC=1>[C:25]([O:16][N:15]=[C:8]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:7]1[CH:17]=[C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:19]([OH:20])=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:6]=1)(=[O:27])[CH3:26]
Reactant: CC(=O)Cl
Reactant: CC(C)(C)c1cc(C(=NO)c2ccccc2)cc(C(C)(C)C)c1O
Solvent: c1ccncc1
Product: CC(=O)ON=C(c1ccccc1)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
0.93 g of 3,5-di-t-butyl-4-hydroxybenzophenone oxime was dissolved in pyridine, and 0.28 g of acetyl chloride was added dropwise at room temperature. Thereafter, the mixture was stirred for 20 minutes. The reaction mixture was poured into ice water, extracted with benzene, washed with 4% HCl, water and a saturated aqueous solution of sodium bicarbonate, and dried. The solvent was distilled off, and the resulting crystals were recrystallized from ether/n-hexane to give 3,5-di-t-butyl-4-hydroxybenzophenone O-acetyloxime.
Reaction SMILES: [C:1]([CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][C:5]1=[O:10])(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[C:17]([O:21][CH2:22][CH3:23])(=[O:20])[CH:18]=[CH2:19]>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.C1(C)C=CC=CC=1>[C:1]([C:4]1([CH2:19][CH2:18][C:17]([O:21][CH2:22][CH3:23])=[O:20])[CH2:9][CH2:8][CH2:7][CH2:6][C:5]1=[O:10])(=[O:3])[CH3:2]
Reactant: C=CC(=O)OCC
Reactant: CC(=O)C1CCCCC1=O
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: CCOC(=O)CCC1(C(C)=O)CCCCC1=O
Temperature: 40 °C
Yield: 96.4 %

Procedure:
To a solution of 2-acetylcyclohexanone (25 g, 0.18 mol), potassium carbonate (29.5 g, 0.21 mol) and benzyltriethylammonium chloride (0.8 g, 0.0035 mol) in toluene (70 ml) was added ethyl acrylate (29 ml, 27 g, 0.27 mol) at room temperature. The mixture was heated at 40° C. for 20 hours, filtered and partitioned between distilled water (200 ml) and toluene (200 ml). The organic layer was dried over magnesium sulphate, filtered and concentrated under reduced pressure to give the title compound as a brown oil, (41.7 g, 97%).
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]([NH2:14])[CH2:11][CH2:12][CH3:13])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CO[CH:17](O)[C:18]([F:21])([F:20])[F:19]>C1C=CC=CC=1>[Si:1]([O:8][CH2:9][C@@H:10]([N:14]=[CH:17][C:18]([F:21])([F:20])[F:19])[CH2:11][CH2:12][CH3:13])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CCC[C@H](N)CO[Si](C)(C)C(C)(C)C
Reactant: COC(O)C(F)(F)F
Solvent: c1ccccc1
Product: CCC[C@@H](CO[Si](C)(C)C(C)(C)C)N=CC(F)(F)F
Reaction time: 2 h

Procedure:
A mixture of (S)-1-(tert-butyldimethylsilanyloxymethyl)-butylamine (27 g, 126 mmol) and trifluoroacetaldehyde methyl hemiacetal (17.2 g, 132 mmol) in benzene (250 mL) was heated at reflux, using a Dean-Stark trap to remove water. After 2 hours, no more water was collected. The reaction mixture was cooled and concentrated to give (S)-[1-(tert-butyldimethylsilanyloxymethyl)-butyl]-(2,2,2-trifluoroethylidene)-amine which was used in the next step without further purification or extended drying due to its volatility.
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C@H:10]([CH2:17][C:18]([OH:20])=[O:19])[CH2:9]1)=O)(C)(C)C.Cl.[CH3:22]O>C(OCC)C>[NH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C@H:10]([CH2:17][C:18]([O:20][CH3:22])=[O:19])[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](CC(=O)O)c2ccccc21
Reactant: CO
Agent: Cl
Solvent: CCOCC
Product: COC(=O)C[C@@H]1CNc2ccccc21
Temperature: 5 °C
Reaction time: 16 h
Yield: 100 %

Procedure:
(+)-(S)-(1-tert-Butoxycarbonyl-2,3-dihydro-1H-indol-3-yl)acetic acid (14.2 g, 0.05 mol) was dissolved in methanol (600 mL), cooled (5° C.) and a saturated solution of HCl in diethyl ether (150 mL) was added. The resulting mixture was stirred at room temperature for 16 h, concentrated in vacuo to about 50 mL and poured onto an ice/water mixture. The aqueous phase was extracted with ethyl acetate and diethyl ether, and the combined organic phases were washed with aqueous ammonia and brine. The organic phase was dried and concentrated in vacuo to give the title compound (9.8 g, 100%).
Reaction SMILES: C([N:9]1[CH2:22][CH2:21][C:20]2[C:19]3[CH:18]=[C:17]([Cl:23])[C:16]([Cl:24])=[CH:15][C:14]=3[NH:13][C:12]=2[CH2:11][CH2:10]1)(=O)C1C=CC=CC=1.[OH-].[K+].C(O)CO>O>[Cl:24][C:16]1[C:17]([Cl:23])=[CH:18][C:19]2[C:20]3[CH2:21][CH2:22][NH:9][CH2:10][CH2:11][C:12]=3[NH:13][C:14]=2[CH:15]=1
Reactant: O=C(c1ccccc1)N1CCc2[nH]c3cc(Cl)c(Cl)cc3c2CC1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: OCCO
Product: Clc1cc2[nH]c3c(c2cc1Cl)CCNCC3
Temperature: 170 °C
Reaction time: 2 h
Yield: 73.2 %

Procedure:
A mixture of 3-benzoyl-8,9-dichloro-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (2.00 g, 5.57 mmol), potassium hydroxide (3.00 g, 53.5 mmol), and ethylene glycol (15 mL) was heated to 170° C. After 2 h, the reaction was cooled to room temperature, diluted with H2O, and extracted with CH2Cl2. The combined organic extracts were washed with brine, dried over Na2SO4, decanted, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography with CH2Cl2/MeOH/Et2NH (9:1:0 followed by 97:3:1 followed by 95:4:1) to give 1.04 g (73%) of 8,9-dichloro-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole as a dark yellow solid. 1H NMR (d-CHCl3) δ 7.75, 7.50, 7.34, 3.08, 2.92, 2.82, 1.91; MS (ESI) 255.1 (M++H).
Reaction SMILES: [CH3:1][C:2]([C:7]1[S:8][C:9]([C:12]2[CH:17]=[C:16]([NH:18][C:19]3[N:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[CH:21][N:20]=3)[CH:15]=[C:14]([CH3:29])[CH:13]=2)=[CH:10][N:11]=1)([CH3:6])[C:3]([OH:5])=O.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.[CH:44]([NH:46][NH2:47])=[O:45].CCN(C(C)C)C(C)C>O.O1CCOCC1>[CH:44]([NH:46][NH:47][C:3](=[O:5])[C:2]([CH3:1])([C:7]1[S:8][C:9]([C:12]2[CH:17]=[C:16]([NH:18][C:19]3[N:24]=[C:23]([C:25]([F:28])([F:26])[F:27])[CH:22]=[CH:21][N:20]=3)[CH:15]=[C:14]([CH3:29])[CH:13]=2)=[CH:10][N:11]=1)[CH3:6])=[O:45]
Reactant: NNC=O
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C(C)(C)C(=O)O)s2)c1
Agent: On1nnc2ccccc21
Solvent: C1COCCO1
Solvent: O
Solvent: ClCCCl
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C(C)(C)C(=O)NNC=O)s2)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 45.9 %

Procedure:
The product from Step 1 (HCl salt, 187 mg, 0.408 mmol), HOBT (125 mg, 0.815 mmol), and EDC (156 mg, 0.815 mmol) were combined with dioxane (5 mL) and stirred for 5 min at room temperature. Formic acid hydrazide (73 mg, 1.223 mmol) and DIEA (105 mg, 0.815 mmol) were subsequently added. The reaction was stirred overnight at room temperature. The reaction was diluted with water and extracted with ethyl acetate (2×). The combined organic layers were washed with brine, dried (Na2SO4), filtered and evaporated. Column chromatography on silica (50-100% EtOAc/hexanes) afforded N′-formyl-2-methyl-2-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]propanehydrazide (87 mg, 46%) as a colorless solid. MS ESI: [M+H]+ m/z 465.0.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:6]=[CH:7][CH:8]=1)=[O:2].[BH4-].[Na+]>CO>[OH:2][CH2:1][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:6]=[CH:7][CH:8]=1
Reactant: CC(C)(C)OC(=O)C=Cc1cccc(C=O)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)C=Cc1cccc(CO)c1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
A stirred solution of tert-butyl 3-(3-formylphenyl)acrylate (5 g) in methanol (150 mL) at 0° C. is treated with sodium borohydride (0.38 g) portionwise. After stirring at 0° C. for 20 minutes the reaction mixture is partitioned between ethyl acetate (200 mL) and water (100 mL). The organic phase is separated, dried over magnesium sulphate and evaporated to give tert-butyl 3-(3-hydroxymethylphenyl)acrylate which is dissolved in dry toluene (50 mL) and treated with tris(triphenylphosphine)rhodium(I) chloride (80 mg) and triethylsilane (8 mL). The mixture is stirred at room temperature for 3 hours, left standing at room temperature for 18 hours and evaporated. The residue is purified by flash chromatography on silica eluting with a mixture of cyclohexane and ethyl acetate (4:1 v/v). Fractions homogeneous in the required product are combined and evaporated to give tert-butyl 3-(3-hydroxymethylphenyl)propionate (1.5 g).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[C:5]([O:9][C:10](=[O:27])[C:11]1[C:16]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][C:19]=2[Cl:25])=[CH:15][C:14](Cl)=[N:13][CH:12]=1)([CH3:8])([CH3:7])[CH3:6]>CN(C=O)C.CCOC(C)=O>[C:5]([O:9][C:10](=[O:27])[C:11]1[C:16]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][C:19]=2[Cl:25])=[CH:15][C:14]([N:1]=[N+:2]=[N-:3])=[N:13][CH:12]=1)([CH3:8])([CH3:6])[CH3:7]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)c1cnc(Cl)cc1Nc1ccc(Br)cc1Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)c1cnc(N=[N+]=[N-])cc1Nc1ccc(Br)cc1Cl
Temperature: 80 °C
Reaction time: 16 h
Yield: 43 %

Procedure:
Sodium azide (1.51 g, 23.2 mmol) was added to a mixture of 4-(4-bromo-2-chlorophenylamino)-6-chloronicotinic acid tert-butyl ester (40) (3.23 g, 7.73 mmol) in DMF (60 mL). The reaction mixture was heated to 80° C. and stirred for 16 hours. After cooling to room temperature, the reaction was diluted with EtOAc and washed with water, saturated NaHCO3 and brine. The organic layer was dried (Na2SO4) and concentrated. Purification by flash column chromatography using the Biotage system (CH2Cl2) (repeated) provided the desired product (41) (1.41 g, 43%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)[CH2:3][CH2:2]1.[CH2:21](I)[CH3:22].C([O-])([O-])=O.[K+].[K+]>C(#N)C>[CH2:21]([N:1]1[CH2:2][CH2:3][CH:4]([CH2:7][CH:8]2[CH2:9][CH2:10][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:12][CH2:13]2)[CH2:5][CH2:6]1)[CH3:22]
Reactant: CCI
Reactant: CC(C)(C)OC(=O)N1CCC(CC2CCNCC2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCN1CCC(CC2CCN(C(=O)OC(C)(C)C)CC2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1,1-Dimethylethyl 4-(4-piperidinylmethyl)-1-piperidinecarboxylate (may be prepared as described in Description 2) (2 g), ethyl iodide (0.57 ml) and K2CO3 (1.96 g) were combined in acetonitrile (70 ml) and the reaction mixture was stirred at room temperature for 3 h. The reaction was filtered to remove solids and the solvent evaporated to give the title compound (D7) as a yellow solid (2.5 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]3[C:16]([NH:18][C:19]4[CH:20]=[C:21]([CH:26]=[CH:27][CH:28]=4)[O:22][CH2:23][C:24]#[N:25])=[N:15][CH:14]=[N:13][C:12]=3[O:11][C:10]=2[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:5][CH:4]=1.C[Si]([N:39]=[N+:40]=[N-:41])(C)C.C([Sn](=O)CCCC)CCC>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:17]3[C:16]([NH:18][C:19]4[CH:28]=[CH:27][CH:26]=[C:21]([O:22][CH2:23][C:24]5[NH:41][N:40]=[N:39][N:25]=5)[CH:20]=4)=[N:15][CH:14]=[N:13][C:12]=3[O:11][C:10]=2[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(Nc4cccc(OCC#N)c4)c23)cc1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Product: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(Nc4cccc(OCc5nnn[nH]5)c4)c23)cc1

Procedure:
Stir a mixture of 100 mg (0.223 mmol) of (3-{[5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]-pyrimidin-4-yl]amino}phenoxy)acetonitrile, 383 mg (3.345 mmol) of trimethylsilyl azide and 83.32 mg (0.334 mmol) of di-n-butyltin oxide in 5 ml of toluene at 80° C. overnight. After cooling, filter off the precipitated solid with suction, wash with toluene and dry at 50° C. under high vacuum overnight. 80.1 mg (73.1% of theory) of the target compound are obtained as a whitish solid.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].C(NC(C)C)(C)C.C([Li])CCC.[O:21]=[C:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1.Br[CH2:29]/[CH:30]=[CH:31]\[CH2:32][CH2:33][CH2:34][C:35]([O:37][CH3:38])=[O:36]>O1CCCC1>[CH3:38][O:37][C:35]([CH2:34][CH2:33][CH2:32]/[CH:31]=[CH:30]\[CH2:29][CH:23]1[C:22](=[O:21])[CH2:27][CH2:26][O:25][CH2:24]1)=[O:36]
Reactant: COC(=O)CCC/C=C\CBr
Reactant: O=C1CCOCC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COC(=O)CCC/C=C\CC1COCCC1=O
Reaction time: 0.5 h
Yield: 18.9 %

Procedure:
To a solution of lithium diisopropylamide (2.40 mmol) in tetrahydrofuran (5 ml), prepared from diisopropylamine (0.35 ml) with n-butyllithium (1.7 ml, 1.5 M solution in hexane) using an usual manner, was added 4-oxotetrahydropyran (220 mg) in tetrahydrofuran (2 ml) at -78° C. and the mixture was stirred for 30 minutes at the same temperature. To the resulting solution was added methyl(Z)-7-bromo-5-heptenate (500 mg) in tetrahydrofuran (2 ml) at -78° C. After being stirred at room temperature for 5 hours, the reaction mixture was quenched with saturated aqueous ammonium chloride and the solution was extracted with ethyl acetate. The organic layer was washed successively with water and brine and dried over magnesium sulfate. The solvent was evaporated in vacuo and the residue was chromatographed on a silica gel column (10 g) with a mixture of n-hexane and ethyl acetate (4:1) as an eluent to give 3-[(Z)-6-methoxycarbonyl-2-hexenyl]-4-oxo-tetrahydropyran (100 mg) as a colorless oil.