Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]1[CH:7]([OH:8])[CH:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[O:5][C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:3]1.[C:21]1([N:27]=[C:28]=[O:29])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[C:15]1([C:4]2[O:5][CH:6]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:7]([O:8][C:28](=[O:29])[NH:27][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:2]([CH3:1])[N:3]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C=Nc1ccccc1
Reactant: CC1N=C(c2ccccc2)OC(c2ccccc2)C1O
Product: CC1N=C(c2ccccc2)OC(c2ccccc2)C1OC(=O)Nc1ccccc1
Yield: 15 %

Procedure:
Working in a manner similar to that described in Example 12, but starting with 4-methyl-2,6-diphenyl-5,6-dihydro-4H-1,3-oxazin-5-ol (mixture of 4SR, 5RS, 6SR and 4RS, 5RS, 6SR diastereoisomers, 50:50 mole/mole; 3.7 g) and phenyl isocyanate (5 g), then purifying the oil obtained by chromatography on a column (height: 45 cm; diameter: 4 cm) of silica, eluting with a mixture of cyclohexane and ethyl acetate (85:15 by volume) and collecting 25-cc fractions, fractions 22 to 25 being combined and concentrated to dryness under reduced pressure (4 kPa) at 45° C., followed by recrystallization of the solid obtained in acetonitrile, (4SR, 5RS, 6SR)-2,6-diphenyl-4-methyl-5-phenylcarbamoyloxy-5,6-dihydro-4H-1,3-oxazine (0.8 g), m.p. 150° C., is obtained.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.C1(N=C=NC2CCCCC2)CCCCC1.[OH:25]O>C(O)C>[CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]2[O:25][CH:2]12
Reactant: OO
Reactant: C1=Cc2ccccc2C1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCO
Product: c1ccc2c(c1)CC1OC21
Temperature: 25 °C
Yield: 19.4 %

Procedure:
To a mixture of indene (426 mg, 3.67 mmol), dicyclohexylcarbodiimide (150 mg, 0.73 mmol), hydrogen peroxide (1 mL of 30% aqueous, 9.8 mmol) and ethanol (5 mL) was added 10 mg of cation exchange resin (mild) beads. The reaction mixture was stirred at room temperature for twenty-four hours. Filtration removed the dicyclohexylurea and the resin beads. The filtrate was partitioned in a separatory funnel between ether (30 mL) and water (20 mL). Standard ethereal workup, followed by column chromatography on silica gel (elution with hexanes:ether, 10:1) afforded indene epoxide (94 mg, 98%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[N:14]([C:17]1[CH:26]=[CH:25][CH:24]=[C:23]2[C:18]=1[CH:19]=[CH:20][N:21]=[CH:22]2)=[C:15]=[O:16]>C(OCC)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:15]([NH:14][C:17]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:18]=3[CH:19]=[CH:20][N:21]=[CH:22]4)=[O:16])[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: O=C=Nc1cccc2cnccc12
Reactant: Clc1ccc(N2CCNCC2)cc1
Solvent: CCOCC
Product: O=C(Nc1cccc2cnccc12)N1CCN(c2ccc(Cl)cc2)CC1

Procedure:
1-(4-Chlorophenyl)piperazine (197 mg, 1.01 mmol) in diethyl ether (20 mL) was treated with an ethereal solution of 5-isocyanatoisoquinoline. The precipitate that formed was collected by filtration, washed with diethyl ether, and air-dried to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ 9.29 (d, 1H, J=10 Hz), 8.83 (s, 1H), 8.49 (d, 1H, 6.1 Hz), 7.93 (d, 1H, J=7.8 Hz), 7.77 (m, 1H), 7.61-7.72 (m, 2H), 7.26-7.29 (m, 2H), 7.01-7.04 (m, 2H), 3.68 (m, 4H), 3.23 (m, 4H); MS (ESI+) m/z 367 (M+H).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][C:15]([C:17]([CH3:27])([O:19][Si:20]([CH2:25][CH3:26])([CH2:23][CH3:24])[CH2:21][CH3:22])[CH3:18])=[N:16][C:11]3=[N:10][CH:9]=2)[CH:5]=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:36]2[CH:43]=[CH:42][CH:41]=[CH:40][C:37]=2[C:38]#[N:39])O1>>[CH3:18][C:17]([C:15]1[CH:14]=[CH:13][N:12]2[C:8]([C:6]3[N:7]=[C:2]([C:36]4[CH:43]=[CH:42][CH:41]=[CH:40][C:37]=4[C:38]#[N:39])[CH:3]=[CH:4][CH:5]=3)=[CH:9][N:10]=[C:11]2[N:16]=1)([O:19][Si:20]([CH2:25][CH3:26])([CH2:23][CH3:24])[CH2:21][CH3:22])[CH3:27]
Reactant: CC1(C)OB(c2ccccc2C#N)OC1(C)C
Reactant: CC[Si](CC)(CC)OC(C)(C)c1ccn2c(-c3cccc(Br)n3)cnc2n1
Product: CC[Si](CC)(CC)OC(C)(C)c1ccn2c(-c3cccc(-c4ccccc4C#N)n3)cnc2n1

Procedure:
3-(6-Bromopyridin-2-yl)-7-(1-methyl-1-triethylsilanyloxyethyl)-imidazo[1,2-α]pyrimidine was coupled to 2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)benzonitrile following the procedure in Example 2 to give 2-{6-[7-(1-methyl-1-triethylsilanyloxyethyl)imidazo[1,2-α]pyrimidin-3-yl]pyridin-2-yl}benzonitrile as an orange oil.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH3:11][Si:12]([CH3:27])([CH3:26])[CH2:13][CH2:14][S:15]([N:18]1[CH2:23][CH2:22][CH2:21][CH:20]([CH2:24][OH:25])[CH2:19]1)(=[O:17])=[O:16].C(N(CC)CC)C>C(Cl)Cl>[CH3:11][Si:12]([CH3:27])([CH3:26])[CH2:13][CH2:14][S:15]([N:18]1[CH2:23][CH2:22][CH2:21][CH:20]([CH:24]=[O:25])[CH2:19]1)(=[O:17])=[O:16]
Reactant: C[Si](C)(C)CCS(=O)(=O)N1CCCC(CO)C1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: C[Si](C)(C)CCS(=O)(=O)N1CCCC(C=O)C1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 73 %

Procedure:
A three neck 500-mL flask equipped with a dropping funnel was charged with of anhydrous CH2Cl2 (100 mL) and oxalyl chloride (2.64 g, 20.7 mmol, 1.1 equiv). The solution was cooled to −78° C. under nitrogen. A solution of DMSO (2.93 g, 37.6 mmol, 2.0 equiv) in CH2Cl2 (10 mL) was added dropwise to the oxalyl chloride over a 15 minute period, and the resulting solution stirred for 30 min at −78° C. A solution of 1-(2-(trimethylsilyl)ethanesulfonyl)-3-hydroxymethylpiperidine (5.25 g, 18.8 mmol, 1.0 equiv) in CH2Cl2 (30 mL) was added dropwise over a 30 min period, and the resulting mixture stirred for 30 min at −78° C. Triethylamine (9.51 g, 94.4 mmol, 5.0 equiv) was added dropwise to the mixture over a 30 min period. The resulting white slurry was allowed to warm to 0° C. and stir for 30 min. Analysis of the mixture by LC-MS showed consumption of the alcohol. Water (200 mL) was added and the layers were separated. The organic layer was washed with brine and dried over Na2SO4. The aldehyde was purified by flash chromatography on 120 g of silica, eluting with 0 to 50% EtOAc in hexanes. Fractions containing the desired aldehyde were visualized by staining with 2,4-dinitrophenylhydrazine on silica gel. Removal of the solvent afforded 1-(2-trimethylsilyl(ethanesulfonyl))piperidine-3-carbaldehyde (3.81 g, 73%) as a white solid. 1H NMR (CDCl3) δ−0.15 (s, 9H), 0.96 (m, 2H), 1.5-1.77 (m, 4H), 1.95 (M, 1H), 2.54 (m, 1H), 2.82 (m, 2H), 2.95 (m, 1H), 3.17 (d of d, 1H), 3.44 (m, 1H), 3.72 (m, 1H), 9.64 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[N:6]([CH2:13][C:14]([F:17])([F:16])[F:15])[C:5]2(O)[C:18]([F:21])([F:20])[F:19].C(N(CC)CC)C.S(Cl)(Cl)=O.[C:34]1([Mg]Br)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[N:6]([CH2:13][C:14]([F:17])([F:16])[F:15])[C:5]2([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:18]([F:21])([F:20])[F:19]
Reactant: O=C1Nc2ccc(Cl)cc2C(O)(C(F)(F)F)N1CC(F)(F)F
Reactant: Br[Mg]c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: O=C1Nc2ccc(Cl)cc2C(c2ccccc2)(C(F)(F)F)N1CC(F)(F)F
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
To a −78° C. mixture of 6-chloro-4-hydroxy-3-(2,2,2-trifluoroethyl)-4-(trifluoromethyl)-3,4-dihydroquinazolin-2(1H)-one (214 mg, 0.6 mmol) and tetrahydrofuran (2.0 ml) was added triethylamine (0.4 ml, 3.1 mmol) under nitrogen atmosphere. After stirring mixture at −78° C. for 20 minutes, thionyl chloride (0.05 ml, 0.64 mmol) was added dropwise whereupon a yellow solid precipitated in the reaction mixture forming a thick yellow emulsion. After the emulsion was stirred at −78° C. for 30 minutes, 3.0M phenyl magnesium bromide was added. Reaction was allowed to stir for one hour until no further increase in desired product was observed by LC/MS. Reaction was quenched with saturated aqueous ammonium chloride solution (10 ml) at −78° C. and mixture was allowed to warm to room temperature. Mixture was extracted with ethyl acetate (3×20 ml) and combined organic extracts were dried over Na2SO4, filtered and concentrated in vacuo. The resulting crude oil was purified by flash chromatography on silica gel (0-30% ethyl acetate/hexanes) to afford an oil which was further purified by reverse phase prep HPLC to give 6-chloro-4-phenyl-3-(2,2,2-trifluoroethyl)-4-(trifluoromethyl)-3,4-dihydroquinazolin-2(1H)-one as colorless oil. 1H NMR (CD3OD, 400 MHz) δ 7.52 (m, 5H), 7.34 (dd, J=2.4 and 8.4 Hz, 1H), 6.95 (d, J=8.4 Hz, 1H), 6.4 (m, 1H), 4.29 (m, 1H), 3.62 (m, 1H). Exact Mass (Electrospray, M+H): Calc'd, 409.0537; Found, 409.0533.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:16]2[CH:17]=[C:18]([CH:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)[N:19]3[C:24]=2[C:23]([NH2:25])=[N:22][CH:21]=[N:20]3)[CH:12]=[C:13]([F:15])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:32](Cl)(=[O:34])[CH3:33]>>[C:32]([N:29]1[CH2:30][CH2:31][CH:26]([C:18]2[N:19]3[C:24]([C:23]([NH2:25])=[N:22][CH:21]=[N:20]3)=[C:16]([C:11]3[CH:12]=[C:13]([F:15])[CH:14]=[C:9]([O:8][CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[CH:10]=3)[CH:17]=2)[CH2:27][CH2:28]1)(=[O:34])[CH3:33]
Reactant: Nc1ncnn2c(C3CCNCC3)cc(-c3cc(F)cc(OCc4ccccc4)c3)c12
Reactant: CC(=O)Cl
Product: CC(=O)N1CCC(c2cc(-c3cc(F)cc(OCc4ccccc4)c3)c3c(N)ncnn23)CC1
Yield: 26 %

Procedure:
In a manner similar to the procedure described for the preparation of Example 331 and using 5-[3-(benzyloxy)-5-fluorophenyl]-7-piperidin-4-ylpyrrolo[2,1-f][1,2,4]triazin-4-amine and acetyl chloride as starting material, 20 mg (26%) of the desired product was isolated. 1H NMR (400 MHz, CD2Cl2) δ 7.91 (s, 1H), 7.47-7.35 (m, 5H), 6.90 (s, 1H), 6.82 (d, 1H), 6.75 (d, 1H), 6.50 (s, 1H), 5.48 (s, 2H), 5.13 (s, 2H), 4.76-4.71 (m, 1H), 3.97-3.90 (m, 1H), 3.54-3.44 (m, 1H), 3.26 (td, 1H), 2.74 (td, 1H), 2.22-2.15 (m, 2H), 2.09 (s, 3H), 1.72-1.60 (m, 2H); LC-MS m/z[M+H]+ 460.4, RT 3.10 min.
Reaction SMILES: [C:1]1([N:7]([CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:8]([C:10]2[CH:11]=[CH:12][C:13]3[S:17][C:16]([CH2:18][NH:19][C:20]4[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][CH:21]=4)=[N:15][C:14]=3[CH:28]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.C(=O)([O-])[O-].[NH4+:41].[NH4+]>C(O)C>[C:1]1([N:7]([CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:8]([C:10]2[CH:11]=[CH:12][C:13]3[S:17][C:16]([CH2:18][NH:19][C:20]4[CH:25]=[CH:24][C:23]([C:26](=[NH:41])[NH2:27])=[CH:22][CH:21]=4)=[N:15][C:14]=3[CH:28]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)CCN(C(=O)c1ccc2sc(CNc3ccc(C#N)cc3)nc2c1)c1ccccc1
Reactant: [NH4+]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Product: CCOC(=O)CCN(C(=O)c1ccc2sc(CNc3ccc(C(=N)N)cc3)nc2c1)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
1.1 g (2.27 mMol) of 2-[N-(4-cyanophenyl)-aminomethyl]-benzothiazole-5-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide was stirred in 100 ml of ethanol saturated with hydrogen chloride for 5 hours first at 0° C. and then at room temperature until no more starting material could be detected by thin layer chromatography. Then the solvent was distilled off at a maximum bath temperature of 30° C. and the oily residue was taken up in 100 ml of absolute ethanol and mixed with 1.6 g (22 mMol) of ammonium carbonate. After 18 hours stirring at room temperature the solvent was distilled off in vacuo and the crude product was purified by flash chromatography (silica gel; gradient: water/methanol=19:1 to 4:1). When the eluates are evaporated down the desired compound is obtained as a white foam. Yield: 0.77 g (63% of theory), Rf value: 0.19 (silica gel; dichloromethane/ethanol=3:7) C27H27N5O3S (501.60) Mass spectrum: (M+H)+ =502
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[C@@H:7]([OH:8])[CH2:6][N:5]([CH2:9][CH2:10][N:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([F:21])[CH:19]=3)[CH:14]=[CH:13][C:12]2=[O:22])[CH2:4]1.[O:23]=[C:24]1[CH2:29][O:28][C:27]2[CH:30]=[CH:31][C:32]([CH:34]=O)=[N:33][C:26]=2[NH:25]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[ClH:50].C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>CO.CCOCC.C(Cl)Cl>[ClH:50].[ClH:50].[F:21][C:18]1[CH:19]=[C:20]2[C:15]([CH:14]=[CH:13][C:12](=[O:22])[N:11]2[CH2:10][CH2:9][N:5]2[CH2:6][C@H:7]([OH:8])[C@H:3]([CH2:2][NH:1][CH2:34][C:32]3[CH:31]=[CH:30][C:27]4[O:28][CH2:29][C:24](=[O:23])[NH:25][C:26]=4[N:33]=3)[CH2:4]2)=[CH:16][CH:17]=1
Reactant: O=Cc1ccc2c(n1)NC(=O)CO2
Reactant: NC[C@@H]1CN(CCn2c(=O)ccc3ccc(F)cc32)C[C@@H]1O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Solvent: ClCCl
Solvent: CCOCC
Solvent: CO
Product: O=C1COc2ccc(CNC[C@@H]3CN(CCn4c(=O)ccc5ccc(F)cc54)C[C@@H]3O)nc2N1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 1-{2-[(3R,4R)-3-(aminomethyl)-4-hydroxy-1-pyrrolidinyl]ethyl}-7-fluoro-2(1H)-quinolinone (90 mg; 0.3 mmol) and 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carboxaldehyde (for a synthesis see WO2003087098, Example 31(e)) (53 mg, 0.3 mmol) in methanol (2 mL), DCM (4 mL) was stirred at room temperature overnight. Sodium triacetoxyborohydride (0.127 g; 0.6 mmol) was added and the mixture was stirred at room temperature for 1 hour. The reaction was evaporated and chromatographed on silica gel, eluting with 0-15% methanol-DCM-1% NH4OH to give an oil. The oil was treated with 1M HCl in Et2O to give the title compound (36 mg) as the dihydrochloride salt.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16](I)[CH:17]=[CH:18][C:13]=2[N:12]2[C:20]([CH3:23])=[N:21][N:22]=[C:11]2[CH2:10][N:9]=1.[CH3:24][N:25]1[C:31](=[O:32])[C:30]2[CH:33]=[CH:34][CH:35]=[CH:36][C:29]=2[N:28]([CH2:37][C:38]#[CH:39])[C:27](=[O:40])[CH2:26]1.C(OCC)(=O)C.O.C#C>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([C:39]#[C:38][CH2:37][N:28]3[C:29]4[CH:36]=[CH:35][CH:34]=[CH:33][C:30]=4[C:31](=[O:32])[N:25]([CH3:24])[CH2:26][C:27]3=[O:40])[CH:17]=[CH:18][C:13]=2[N:12]2[C:20]([CH3:23])=[N:21][N:22]=[C:11]2[CH2:10][N:9]=1
Reactant: Cc1nnc2n1-c1ccc(I)cc1C(c1ccccc1F)=NC2
Reactant: C#CCN1C(=O)CN(C)C(=O)c2ccccc21
Agent: C#C
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1nnc2n1-c1ccc(C#CCN3C(=O)CN(C)C(=O)c4ccccc43)cc1C(c1ccccc1F)=NC2

Procedure:
Coupling of 6-(2-Fluorophenyl)-8-iodo-1-methyl-4H[1,2,4]triazolo[4,3-a] [1,4]benzodiazepine with 3,4-dihydro-4-methyl-1-(2-propynyl)-1H-1,4-benzodiazepine 2,5-dione as described in example 17 gave after chromatography and crystallization from ethyl acetate colorless crystals with m.p. 179°-182° C. The crystals of the title compound contained according to analytical and nmr-data 0.16 mol of ethyl acetate and 0.66 mol of water. The preparation of the required acetylene is described in Example 54.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:13])([CH2:11][OH:12])[CH2:9]O)=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:13])[CH2:11][O:12][CH2:9]2)=[CH:4][CH:3]=1
Reactant: CC(CO)(CO)c1ccc(Br)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CC1(c2ccc(Br)cc2)COC1
Yield: 41.9 %

Procedure:
2-(4-Bromophenyl)-2-methylpropane-1,3-diol (100 mg, 0.41 mmol), triphenyl phosphine (210 mg, 0.82 mmol), and diisopropyl azodicarboxylate (160 μL, 0.82 mmol) were combined in toluene (2 mL) and irradiated in the microwave at 140° C. for 10 minutes. The mixture was directly purified by silica gel chromatography eluting with 0-20% ethyl acetate in hexanes to give 3-(4-bromophenyl)-3-methyloxetane (39 mg, 42%) 1H NMR (400 MHz, DMSO-d6) δ 7.38-7.34 (m, 2H), 7.26-7.22 (m, 2H), 4.82-4.80 (m, 2H), 4.55-4.54 (m, 2H), 1.62 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH3:8])[CH:3]=1.[F:9][C:10]1[CH:20]=[CH:19][C:13]([C:14](OCC)=[O:15])=[CH:12][CH:11]=1.C[Si](C)(C)N[Si](C)(C)C.[Li]>O1CCCC1.C(OCC)(=O)C.O.C1CCCCC1>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][C:14]([C:13]2[CH:19]=[CH:20][C:10]([F:9])=[CH:11][CH:12]=2)=[O:15])[CH:3]=1
Reactant: Cc1cc(Br)ccn1
Reactant: CCOC(=O)c1ccc(F)cc1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Li]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(Cc1cc(Br)ccn1)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 87.7 %

Procedure:
5.0 g (29.07 mmol) of 4-bromo-2-picoline and 10.2 g (60.95 mmol) of ethyl 4-fluoro-benzoate are placed under a stream of nitrogen in a round-bottomed flask and dissolved in 50 ml of anhydrous tetrahydrofuran. The solution is cooled to 0° C. and 70 ml (70 mmol) of a lithium hexamethyldisilazane solution (1M in tetrahydrofuran) are added dropwise. After addition, the mixture is stirred at ambient temperature for 2 h before being cooled to 5° C. and gradually adding 100 ml of water to the medium. The medium is subsequently diluted with 250 ml of ethyl acetate and 100 ml of water. The organic phase is separated and the aqueous phase is extracted twice with 100 ml of ethyl acetate. The organic phases are subsequently combined, dried over sodium sulphate and filtered. 15 g of silica are subsequently added to the filtrate before concentrating it under reduced pressure. The powder obtained is used as solid deposit for chromatography on silica gel with a mixture of cyclohexane and ethyl acetate (9/1) as eluent. 7.5 g (88%) of compound are obtained in the form of a yellow powder.
Reaction SMILES: [NH2:1][C:2]1[CH:30]=[CH:29][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]3[CH2:21][CH2:20][CH:19]([N:22]4[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]4)[CH2:18][CH2:17]3)=[O:15])[CH:8]=2)=[CH:4][CH:3]=1.[C:31]1([CH2:37][C:38]([N:40]=[C:41]=[O:42])=[O:39])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>O1CCCC1.CCCCCC>[CH3:28][N:25]1[CH2:24][CH2:23][N:22]([CH:19]2[CH2:18][CH2:17][N:16]([C:14]([NH:13][C:9]3[CH:8]=[C:7]([O:6][C:5]4[CH:4]=[CH:3][C:2]([NH:1][C:41]([NH:40][C:38](=[O:39])[CH2:37][C:31]5[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=5)=[O:42])=[CH:30][CH:29]=4)[CH:12]=[CH:11][N:10]=3)=[O:15])[CH2:21][CH2:20]2)[CH2:27][CH2:26]1
Reactant: CN1CCN(C2CCN(C(=O)Nc3cc(Oc4ccc(N)cc4)ccn3)CC2)CC1
Reactant: O=C=NC(=O)Cc1ccccc1
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CN1CCN(C2CCN(C(=O)Nc3cc(Oc4ccc(NC(=O)NC(=O)Cc5ccccc5)cc4)ccn3)CC2)CC1
Reaction time: 8 h
Yield: 46 %

Procedure:
To a solution of 4-(4-aminophenoxy)-2-{[4-(1-methylpiperazin-4-yl)piperidin-1-yl]carbonylamino}pyridine (75.2 mg) in tetrahydrofuran (4.0 ml) was added a solution of 2-phenylacetyl isocyanate in hexane (0.25 M, 1.83 ml) at room temperature, followed by stirring overnight. The reaction mixture was partitioned between ethyl acetate and a saturated aqueous solution of sodium hydrogencarbonate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was evaporated to give a residue, which was then purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate, then ethyl acetate:methanol=98:2) to provide the titled compound (48.5 mg, 46%) as white powder.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[CH:8]=O.O.C([O-])([O-])=O.[K+].[K+].[C:17]([O:21][CH3:22])(=[O:20])[CH2:18][SH:19]>CN(C=O)C>[S:19]1[C:2]2[CH:7]=[CH:6][N:5]=[CH:4][C:3]=2[CH:8]=[C:18]1[C:17]([O:21][CH3:22])=[O:20]
Reactant: COC(=O)CS
Reactant: O=Cc1cnccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc2cnccc2s1
Temperature: 45 °C
Reaction time: 8 h
Yield: 63.7 %

Procedure:
To a solution of 4-chloropyridine-3-carboxaldehyde (D-1) (1.4 g, 10 mmol) dissolved in DMF (10 mL) and water (1 mL) were added K2CO3 (1.66 g, 12 mmol) and methyl thioglycolate (1.07 mL, 12 mmol) portion-wise. The reaction mixture was stirred at 45° C. overnight and then quenched with cold water. The flask was placed on ice to enhance precipitation. The precipitate was collected by filtration and air-dried to afford the title compound (1.23 g). MS (m/z): 194 (M+1)+.
Reaction SMILES: [NH2:1][C:2]1[C:7](Br)=[N:6][C:5]([Br:9])=[CH:4][N:3]=1.[CH:10]1([NH2:13])[CH2:12][CH2:11]1>>[Br:9][C:5]1[N:6]=[C:7]([NH:13][CH:10]2[CH2:12][CH2:11]2)[C:2]([NH2:1])=[N:3][CH:4]=1
Reactant: NC1CC1
Reactant: Nc1ncc(Br)nc1Br
Product: Nc1ncc(Br)nc1NC1CC1
Temperature: 120 °C

Procedure:
A glass microwave reaction vessel was charged with 2-amino-3,5-dibromopyrazine (1.00 g, 3.95 mmol) and cyclopropylamine (1.40 ml, 19.96 mmol). The reaction mixture was sealed under argon and heated in an Initiator microwave reactor (Personal Chemistry, Biotage AB, Inc., Upssala, Sweden) at 120° C. for 20 min. Additional cyclopropylamine (1.0 mL) was added and the reaction was heated at 120° C. for 30 min in the microwave. Excess cyclopropylamine was removed in vacuo and the residue was dissolved in MeOH and evaporated onto silica gel and purified by flash chromatography (Isco (40 gram)) eluting with EtOAc:hexanes (0:1→1:2) to give 740 mg (82%) of a golden-brown tar. ESI MS 228.9 [M+1].
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:13]([O:14][CH2:15][CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)=[CH:12][C:11]([CH2:21][CH2:22][NH2:23])=[CH:10][C:4]=2[S:5][C:6]=1[C:7]([NH2:9])=[O:8].C(N(CC)CC)C.[CH3:31][O:32][C:33](Cl)=[O:34]>CN(C=O)C>[CH3:31][O:32][C:33](=[O:34])[NH:23][CH2:22][CH2:21][C:11]1[CH:12]=[C:13]([O:14][CH2:15][CH:16]2[CH2:17][CH2:18][CH2:19][CH2:20]2)[C:3]2[C:2]([NH2:1])=[C:6]([C:7](=[O:8])[NH2:9])[S:5][C:4]=2[CH:10]=1
Reactant: COC(=O)Cl
Reactant: NCCc1cc(OCC2CCCC2)c2c(N)c(C(N)=O)sc2c1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)NCCc1cc(OCC2CCCC2)c2c(N)c(C(N)=O)sc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 45.6 %

Procedure:
To a stirred solution of 3-amino-6-(2-amino-ethyl)-4-cyclopentylmethoxy-benzo[b]thiophene-2-carboxylic acid amide (11) (HCl salt form, 0.050 g, 0.14 mmol) and triethylamine (0.07 mL, 0.5 mmol) in DMF (1 mL) at 0° C. was added methyl-chloroformate (0.02 mL, 0.3 mmol). The reaction was allowed to warm to room temperature and stirred for 1 h. The reaction was quenched with MeOH and the solvent was removed under reduced pressure. The residue was purified by flash silica gel chromatography to afford the title compound (0.025 g, 47%).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:3]=1[C:4]([OH:6])=O.[CH:12]([NH2:15])([CH3:14])[CH3:13]>>[CH:12]([NH:15][C:4](=[O:6])[C:3]1[C:7]([CH3:11])=[CH:8][CH:9]=[CH:10][C:2]=1[CH3:1])([CH3:14])[CH3:13]
Reactant: Cc1cccc(C)c1C(=O)O
Reactant: CC(C)N
Product: Cc1cccc(C)c1C(=O)NC(C)C

Procedure:
Using Preparation Method 1, 2,6-dimethylbenzoic acid was reacted with isopropylamine. The resulting reaction mixture was purified using SiO2 with CH2Cl2/MeOH 99:1. A white crystalline solid was obtained (73%). NMR 1H (ppm, CDCl3): 7.15-7.10 (m, 1H), 6.99 (d, J3=7.57 Hz, 2H), 5.44 (br. s., 1H), 4.40-4.24 (m, 1H), 2.31 (s, 6H), 1.24 (d, J3=6.58 Hz, 6H).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([CH3:13])=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9].C(Cl)(=O)C(Cl)=O.CS(C)=O.CCN(CC)CC>C(Cl)Cl>[CH:2]([C:3]1[CH:4]=[CH:5][C:6]([CH3:13])=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9])=[O:1]
Reactant: COC(=O)c1cc(CO)ccc1C
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(C=O)ccc1C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 71.9 %

Procedure:
A solution of 377 mg of methyl 5-(hydroxymethyl)-2-methylbenzoate and 0.8 mL (9.17 mmol) of oxalyl chloride in 20 mL of CH2Cl2 was cooled to −78° C. To this solution was added 1.1 mL (15.5 mmol) of DMSO dropwise, and after stirring for 10 min., 3.2 mL of Et3N was added and stirring was continued at −78° C. for 10 min. The dry ice-acetone bath was removed, and the mixture was allowed to warm to r.t. and after 2 h, 30 mL of sat. NH4Cl solution was added. The organic layer was washed with 25 mL of brine, dried over Na2SO4, filtered, and concentrated. Purification by flash silica gel chromatography (10% EtOAc/hexanes) provided 268 mg of methyl 5-formyl-2-methylbenzoate as a red liquid in 71% yield with some impurity.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[C:11](Cl)(=[O:17])[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]>>[C:11]([C:6]1[CH:5]=[C:4]2[C:9](=[CH:8][CH:7]=1)[NH:1][C:2](=[O:10])[CH2:3]2)(=[O:17])[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCC(=O)Cl
Reactant: O=C1Cc2ccccc2N1
Product: CCCCCC(=O)c1ccc2c(c1)CC(=O)N2

Procedure:
Prepared from 2-indolinone and hexanoic acid chloride