Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]2[CH:25]=[CH:24][C:15]([C:16]([N:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)=[O:17])=[CH:14][CH:13]=2)=[N:2]1.C(OC([NH:33][CH2:34][CH2:35][C:36](O)=[O:37])=O)(C)(C)C.O.ON1C2C=CC=CC=2N=N1.[ClH:50].C(N=C=NCCCN(C)C)C.CN1CCOCC1.Cl.CO>CO>[ClH:50].[ClH:50].[NH2:33][CH2:34][CH2:35][C:36]([N:21]1[CH2:22][CH2:23][N:18]([C:16](=[O:17])[C:15]2[CH:14]=[CH:13][C:12](/[CH:11]=[CH:10]/[C:3]3[C:4]4[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=4)[NH:1][N:2]=3)=[CH:25][CH:24]=2)[CH2:19][CH2:20]1)=[O:37]
Reactant: O=C(c1ccc(/C=C/c2n[nH]c3ccccc23)cc1)N1CCNCC1
Reactant: CC(C)(C)OC(=O)NCCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CO
Solvent: O
Solvent: CN1CCOCC1
Product: NCCC(=O)N1CCN(C(=O)c2ccc(/C=C/c3n[nH]c4ccccc34)cc2)CC1
Temperature: 60 °C
Yield: 0 %

Procedure:
In a similar manner to Example 5, the product obtained using Compound 18 (300 mg, 0.90 mmol), 3-(tert-butoxycarbonylamino)propionic acid (143 mg, 0.75 mmol), 1-hydroxybenzotriazole monohydrate (132 mg, 0.98 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (202 mg, 1.05 mmol) and N-methylmorpholine (0.16 mL, 1.50 mmol) was dissolved in methanol (2.00 mL), and the solution was added with 4 mol/L hydrogen chloride-methanol solution (1.50 mL), followed by heating under reflux at 60° C. for 40 minutes. The reaction mixture was concentrated under reduced pressure, and the residue was crystallized from acetone to obtain Compound 129 (0.11 mg, 24%).
Reaction SMILES: [F-:1].[Cs+].[Cl:3][C:4](=[CH2:12])[CH2:5][O:6][C:7](=[O:11])[C:8](Cl)=[O:9]>>[Cl:3][C:4](=[CH2:12])[CH2:5][O:6][C:7](=[O:11])[C:8]([F:1])=[O:9]
Reactant: C=C(Cl)COC(=O)C(=O)Cl
Reactant: [F-]
Agent: [Cs+]
Product: C=C(Cl)COC(=O)C(=O)F
Temperature: 25 °C
Reaction time: 16 h
Yield: 77.5 %

Procedure:
Under dry N2 in flame dried glass apparatus, cesium fluoride (167 g, 1.1 mol) was placed in a 1 liter single neck flask and placed under high vacuum and gently heated with a flame until the solid became free flowing, then cooled to room temperature. Acetonitrile, distilled from CaH2 (183 ml) was added and the mixture cooled to -20° C. internal temperature. 2-Chloroallyl oxalochloride (183 g, 1.0 mol) was added dropwise over a 30 minute period and the mixture slowly warmed to room temperature, stirred at that temperature for 16 hours, and byproduct cesium chloride recovered by filtration with acetonitrile wash. The filtrate and wash were combined and stripped, and the residue distilled at reduced temperature to yield 129 g (77%) of the desired product, b.p. 62°-64° C./22 mm.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([C:7]([C:9]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][C:10]=2[C:11](O)=[O:12])=O)=[CH:5][CH:4]=1.O.[NH2:22][NH2:23]>>[CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([C:7]2[C:9]3[C:10](=[CH:14][C:15]([CH3:18])=[CH:16][CH:17]=3)[C:11](=[O:12])[NH:23][N:22]=2)=[CH:5][CH:4]=1
Reactant: NN
Reactant: COc1ccc(C(=O)c2ccc(C)cc2C(=O)O)cc1
Solvent: O
Product: COc1ccc(-c2n[nH]c(=O)c3cc(C)ccc23)cc1

Procedure:
This compound is obtained according to the procedure described in 1.2. by reacting unpurified 2-(4-methoxybenzoyl)-5-methylbenzoic acid with hydrazine hydrate.
Reaction SMILES: [CH3:1][C:2]1[NH:11][C:10](=[O:12])[C:9]2[C:4](=[CH:5][C:6]3[CH2:15][CH2:14][C@H:13]([N:16]([C:20]4[CH:28]=[CH:27][C:23]([C:24]([OH:26])=[O:25])=[CH:22][CH:21]=4)[CH2:17][C:18]#[CH:19])[C:7]=3[CH:8]=2)[N:3]=1.[F:29][C:30]1[C:35](O)=[C:34]([F:37])[C:33]([F:38])=[C:32]([F:39])[C:31]=1[F:40]>CC(N(C)C)=O>[CH3:1][C:2]1[NH:11][C:10](=[O:12])[C:9]2[C:4](=[CH:5][C:6]3[CH2:15][CH2:14][C@H:13]([N:16]([C:20]4[CH:21]=[CH:22][C:23]([C:24]([O:26][C:35]5[C:34]([F:37])=[C:33]([F:38])[C:32]([F:39])=[C:31]([F:40])[C:30]=5[F:29])=[O:25])=[CH:27][CH:28]=4)[CH2:17][C:18]#[CH:19])[C:7]=3[CH:8]=2)[N:3]=1
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Reactant: C#CCN(c1ccc(C(=O)O)cc1)[C@H]1CCc2cc3nc(C)[nH]c(=O)c3cc21
Solvent: CC(=O)N(C)C
Product: C#CCN(c1ccc(C(=O)Oc2c(F)c(F)c(F)c(F)c2F)cc1)[C@H]1CCc2cc3nc(C)[nH]c(=O)c3cc21

Procedure:
A solution of p-[N-((6S)-2-methyl-4-oxo-3,4,7,8-tetrahydro-6H-cyclopenta-[g]quinazolin-6-yl)-N-(prop-2-ynyl)amino]benzoic acid (0.7 g) in DMA (25 ml) was added to a stirred mixture of pentafluorophenol (1.2 g), N,N-dicyclohexylcarbodiimide (0.45 g) and DMA (50 ml). The resultant mixture was stirred at 50° C. for 18 hours. The mixture was evaporated and the residue was purified by column chromatography using initially a 40:1 and then a 20:1 mixture of methylene chloride and methanol as eluant. There was thus obtained pentafluorophenyl p-[N-((6S)-2-methyl-4-oxo-3,4,7,8-tetrahydro-6H-cyclopenta[g]quinazolin-6-yl)-N-(prop-2-ynyl)-amino]benzoate as a solid (0.57 g);
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]2[N:20]=[CH:19][C:18]3[C:13](=[CH:14][C:15]([C:21](O)=[O:22])=[CH:16][CH:17]=3)[N:12]=2)=[CH:5][CH:4]=1)#[N:2].S(Cl)(Cl)=O.[C:28]1([NH:34][CH2:35][CH2:36][C:37]([O:39][CH3:40])=[O:38])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(N(C(C)C)C(C)C)C>>[C:28]1([N:34]([CH2:35][CH2:36][C:37]([O:39][CH3:40])=[O:38])[C:21]([C:15]2[CH:14]=[C:13]3[C:18]([CH:19]=[N:20][C:11]([CH2:10][CH2:9][C:6]4[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=4)=[N:12]3)=[CH:17][CH:16]=2)=[O:22])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: N#Cc1ccc(CCc2ncc3ccc(C(=O)O)cc3n2)cc1
Reactant: COC(=O)CCNc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=S(Cl)Cl
Product: COC(=O)CCN(C(=O)c1ccc2cnc(CCc3ccc(C#N)cc3)nc2c1)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
0.4 g (1.3 mmol) of 2-[2-(4-cyanophenyl)-ethyl]-quinazoline-7-carboxylic acid and 5 ml of thionyl chloride were stirred for 60 minutes at 50° C. Then the thionyl chloride was distilled off, the residue was dissolved in methylene chloride, mixed with 0.24 g (1.3 mmol) of methyl 3-(N-phenylamino)-propionate and 0.22 ml of (1.3 mmol) of N-ethyldiisopropylamine and stirred for 18 hours at ambient temperature. After evaporation of the solvent in vacuo the residue was chromatographed on silica gel and eluted with methylene chloride containing 1% methanol. Yield: 230 mg (37% of theory), Rf value: 0.64 (silica gel, methylene chloride/methanol=9:1)
Reaction SMILES: S(Cl)(Cl)(=O)=O.CS[S:8][CH3:9].CSCl.[CH3:13][N:14]1[C@H:28]2[C@@H:18]([C:19]3[CH:20]=[CH:21][CH:22]=[C:23]4[C:29]=3[C:26]([CH2:27]2)=[CH:25][NH:24]4)[CH:17]=[C:16]([CH3:30])[CH2:15]1.N>ClCCl>[CH3:13][N:14]1[C@H:28]2[C@@H:18]([C:19]3[CH:20]=[CH:21][CH:22]=[C:23]4[C:29]=3[C:26]([CH2:27]2)=[C:25]([S:8][CH3:9])[NH:24]4)[CH:17]=[C:16]([CH3:30])[CH2:15]1
Reactant: CC1=C[C@@H]2c3cccc4[nH]cc(c34)C[C@H]2N(C)C1
Reactant: CSSC
Agent: CSCl
Agent: N
Solvent: ClCCl
Solvent: O=S(=O)(Cl)Cl
Product: CSc1[nH]c2cccc3c2c1C[C@@H]1[C@@H]3C=C(C)CN1C
Reaction time: 8 h

Procedure:
A solution of sulphuryl chloride (0.74 g,) in dichloromethane (15 ml) was added dropwise over 15 minutes at -20° C. to a stirred solution of dimethyl disulphide (0.46 g), in dichloromethane (15 ml). After allowing it to reach room temperature the solution of methyl sulphenyl chloride was added dropwise to a suspension of 8,9-didehydro-6,8-dimethylergoline (2.4 g) in dichloromethane (150 ml) at -70° C. The reaction mixture was stirred and allowed to reach room temperature overnight. Cold ammonia solution was added and the mixture extracted with dichloromethane (3×100 ml). The combined extracts were washed with water, dried (MgSO4) and evaporated to dryness. Chromatography on neutral alumina (CH2Cl2) and crystallisation from cyclohexane gave the title compound, m.p. 148°-150° C. The mesylate was also prepared, m.p. 220°-222° C.
Reaction SMILES: [C:1]1([C@@H:7]([N:9]2[C:13](=[O:14])[CH2:12][C@H:11]([C:15]([O:17]C)=O)[CH2:10]2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH3:19]>CO>[C:1]1([C@@H:7]([N:9]2[C:13](=[O:14])[CH2:12][C@H:11]([C:15]([NH2:19])=[O:17])[CH2:10]2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)[C@H]1CC(=O)N([C@@H](C)c2ccccc2)C1
Reactant: N
Solvent: CO
Product: C[C@@H](c1ccccc1)N1C[C@@H](C(N)=O)CC1=O
Reaction time: 8 h

Procedure:
Methyl (3S)-1-((S)-1-phenylethyl)-5-oxo-3-pyrrolidinecarboxylate (738 g) was dissolved in methanol (3.5 l). The solution was stirred for 8 hr under ice-cooling while blowing in ammonia gas, and concentrated under reduced pressure to give 537 g of (3S)-1-((S)-1-phenylethyl)-5-oxo-3-pyrrolidinecarboxamide.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH2:8])[CH:2]=1.[F:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:17]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[N:19]=[C:18]2[NH:26][CH:27]2[CH2:32][CH2:31][N:30]([CH2:33][CH2:34][N:35]=[C:36]=[S:37])[CH2:29][CH2:28]2)=[CH:12][CH:11]=1>O1CCCC1>[F:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:17]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[N:19]=[C:18]2[NH:26][CH:27]2[CH2:28][CH2:29][N:30]([CH2:33][CH2:34][NH:35][C:36]([NH:8][CH2:7][C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)=[S:37])[CH2:31][CH2:32]2)=[CH:12][CH:11]=1
Reactant: Fc1ccc(Cn2c(NC3CCN(CCN=C=S)CC3)nc3ccccc32)cc1
Reactant: NCc1cccnc1
Solvent: C1CCOC1
Product: Fc1ccc(Cn2c(NC3CCN(CCNC(=S)NCc4cccnc4)CC3)nc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 65.7 %

Procedure:
A mixture of 1 part of 3-pyridinemethanamine, 3.9 parts of 1-(4-fluorophenylmethyl)-N-[1-(2-isothiocyanatoethyl)-4-piperidinyl]-1H-benzimidazol-2-amine and 45 parts of tetrahydrofuran was stirred for 4 hours at room temperature. The reaction mixture was evaporated in vacuo. The residue was purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (94:6 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from a mixture of 2-propanone and 2,2'-oxybispropane, yielding 3.4 parts (65.7%) of N-[2-[4-[[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]amino]-1-piperidinyl]ethyl]-N'-(3-pyridinylmethyl)thiourea; mp. 147.2° C. (compound 102).
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:43])[CH2:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:42])[CH2:21][CH2:22][NH:23][C:24]([C:26]3[N:27]=[C:28]([C:35]4[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=4)[O:29][C:30]=3[C:31]([F:34])([F:33])[F:32])=[O:25])=[CH:15][CH:14]=2)[CH2:9][CH2:8]1>C1COCC1.CO.O>[F:41][C:38]1[CH:39]=[CH:40][C:35]([C:28]2[O:29][C:30]([C:31]([F:33])([F:32])[F:34])=[C:26]([C:24]([NH:23][CH2:22][CH2:21][C:20]([NH:19][C:16]3[CH:17]=[CH:18][C:13]([C@H:10]4[CH2:9][CH2:8][C@H:7]([CH2:6][C:5]([OH:43])=[O:4])[CH2:12][CH2:11]4)=[CH:14][CH:15]=3)=[O:42])=[O:25])[N:27]=2)=[CH:36][CH:37]=1
Reactant: COC(=O)C[C@H]1CC[C@H](c2ccc(NC(=O)CCNC(=O)c3nc(-c4ccc(F)cc4)oc3C(F)(F)F)cc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(O)C[C@H]1CC[C@H](c2ccc(NC(=O)CCNC(=O)c3nc(-c4ccc(F)cc4)oc3C(F)(F)F)cc2)CC1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
NaOH (30.9 mg, 0.8 mmol) was added to trans-{4-[4-(3-{[2-(4-fluorophenyl)-5-trifluoromethyloxazole-4-carbonyl]amino}propionylamino)phenyl]cyclohexyl}acetic acid methyl ester solution (89 mg, 0.16 mmol) dissolved in THF/MeOH/water (20 mL, 3:2:1). The reaction mixture was stirred at 25° C. for 15 hours and concentrated under vacuum. The residue was acidified with 1M HCl up to pH 2, stirred for 30 minutes, and filtered. The filtrate was eluted with a gradient of methanol/DCM (5-10%) on a silica gel by column chromatography and purified to obtain the desired compound (75 mg, 86%) as a white solid.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]([C:7]1[NH:8][C:9]2[C:14]([CH:15]=1)=[CH:13][C:12]([O:16][CH3:17])=[CH:11][CH:10]=2)=[O:6])[CH3:3].[Sn].C(=O)=O>C(O)C>[CH2:2]([O:4][C:5]([CH:7]1[CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:16][CH3:17])[CH:13]=2)[NH:8]1)=[O:6])[CH3:3]
Reactant: CCOC(=O)c1cc2cc(OC)ccc2[nH]1
Agent: Cl
Agent: O=C=O
Agent: [Sn]
Solvent: CCO
Product: CCOC(=O)C1Cc2cc(OC)ccc2N1
Reaction time: 1 h

Procedure:
A three neck 3-liter round bottom flask equipped with a mechanical stirrer, water condenser, and a gas inlet tube was charged with 500 ml. of absolute ethanol and chilled in a dry ice-acetone bath. Dry hydrogen chloride gas was added at a rapid rate for 0.5 hours. Fifty grams of 5-methoxyindole-2-carboxylic acid ethyl ester (B. Heath-Brown and P. G. Philpott, J. Chem. Soc. 1965, 7185) followed by 100 g. of tin metal (30 mesh) were added to the solution with stirring. With the dry ice bath in place, but with no additional cooling the reaction mixture was stirred gently for 6 hours. The crystalline solid that separated was removed by filtration. The mother liquor was evaporated under reduced pressure to give an oil. The oil dissolved in 500 ml. of absolute ethanol, was placed in a 3-liter round bottom flask equipped with a stirrer and thermometer, and chilled to 10°. Gaseous ammonia was bubbled into the mixture until the pH was 9 (by wet pH paper) and the mixture was allowed to stand at 10° for one hour. The white precipitate was filtered and the filtrate was evaporated on a rotary evaporator to dryness. The initial white precipitate and the residue from the evaporation were combined and triturated repeatedly with warm ether. The combined ether triturates were washed with a sodium chloride solution (a water:saturated salt solution, 1:1) with vigorous shaking; whereupon most of the basic tin salts were suspended and separated in the aqueous phase. Both phases were filtered through Celite and separated. The ether solution was dried over magnesium sulfate and evaporated under reduced pressure on the rotary evaporator. The oily residue was dried in vacuo to give 22 g. of d,l-2,3-dihydro-5-methoxy-1H-indole-2-carboxylic acid ethyl ester.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2/[CH:10]=[N:11]\O)[CH:3]=[CH:2]1>CO.[OH-].[OH-].[Pd+2]>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[CH2:10][NH2:11])[CH:3]=[CH:2]1
Reactant: O/N=C\c1cccc2cc[nH]c12
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: NCc1cccc2cc[nH]c12
Reaction time: 4 h

Procedure:
(Z)-1H-indole-7-carbaldehyde oxime (100 mg, 0.60 mmol) in MeOH (5 mL), Pd(OH)2 (50 mg) was added and stirred under hydrogen atmosphere (balloon pressure) for 4 h. Reaction mixture was then filtered and solvent evaporated to yield (1H-indol-7-yl)methanamine in quantitative yield.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13]C)[N:9]=[C:8]([C:15]([OH:17])=[O:16])[C:7]([C:18]([OH:20])=[O:19])=[CH:6]2>I>[OH:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[OH:13])[N:9]=[C:8]([C:15]([OH:17])=[O:16])[C:7]([C:18]([OH:20])=[O:19])=[CH:6]2
Reactant: COc1cc2cc(C(=O)O)c(C(=O)O)nc2cc1OC
Agent: I
Product: O=C(O)c1cc2cc(O)c(O)cc2nc1C(=O)O
Yield: 60.5 %

Procedure:
A suspension of 8.64 g (31.17 mmol) of 6,7-dimethoxy-2,3-quinolinedicarboxylic acid in 125 ml of aqueous hydrogen iodide solution (57%) was refluxed for 3 hours. After cooling, the precipitate was filtered off by suction, washed with water and dried in vacuo to give 4.7 g (60.5%) of desired acid with melting point >300° C.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[N:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N:27]1[CH2:31][CH2:30][CH:29]([NH2:32])[CH2:28]1>C(Cl)Cl>[N:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N:27]1[CH2:31][CH2:30][CH:29]([NH:32][C:2]2[C:7]([C:8]([NH:10][C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=3)=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=2)[CH2:28]1
Reactant: O=C(Nc1cccc(C(F)(F)F)c1)c1cccnc1Cl
Reactant: NC1CCN(c2ccccn2)C1
Solvent: ClCCl
Product: O=C(Nc1cccc(C(F)(F)F)c1)c1cccnc1NC1CCN(c2ccccn2)C1
Temperature: 130 °C

Procedure:
A mixture of (2-chloro(3-pyridyl))-N-(3-trifluoromethylphenyl)carboxamide and 1-(2-pyridyl)pyrrolidine-3-ylamine (Step A) was heated at 130° C. neat for 3 h. The reaction was cooled and diluted with CH2Cl2 and washed with H2O twice followed by brine. The organic layer was dried with Na2SO4 and evaporated under reduced pressure. The residue was purified by column chromatography with EtOAc and further mixed with MeOH and 1 N HCl/Et2O (2 ml). The solution was evaporated to furnish the titled compound. MS (ES+): 428 (M+H); (ES−): 426 (M−H). Calc'd. for C22H20F3N5O—427.2.
Reaction SMILES: [CH2:1]([N:8]([CH2:16][C@@H:17](O)[CH3:18])[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20]1(=[O:30])[NH:24][C:23](=[O:25])[C:22]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:21]12.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>O1CCCC1>[CH2:1]([N:8]([CH2:16][C@H:17]([N:24]1[C:20](=[O:30])[C:21]2[C:22](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:23]1=[O:25])[CH3:18])[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: C[C@H](O)CN(Cc1ccccc1)C(=O)OC(C)(C)C
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C[C@H](CN(Cc1ccccc1)C(=O)OC(C)(C)C)N1C(=O)c2ccccc2C1=O
Temperature: 0 °C
Reaction time: 10 h
Yield: 89.5 %

Procedure:
209 mg of (S)-tert-butyl benzyl(2-hydroxypropyl)carbamate was dissolved in 10 mL of tetrahydrofuran in a nitrogen atmosphere and cooled to 0° C. 173 mg of phthalimide, 413 mg of triphenylphosphine, and 0.31 mL of diisopropyl azodicarboxylate were added thereto, and the mixture was stirred at room temperature for 10 hours. The reaction solution was concentrated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (hexane:ethyl acetate=6:1) to obtain 278 mg of the title compound as a pale yellow oil (89%).
Reaction SMILES: [CH2:1]([O:4][CH2:5][CH2:6]Cl)[CH2:2]Cl.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[O:16]=[C:17]([CH2:23][CH3:24])[CH2:18][C:19]([O:21][CH3:22])=[O:20].Cl>O.CN(C)C=O>[C:17]([C:18]1([C:19]([O:21][CH3:22])=[O:20])[CH2:6][CH2:5][O:4][CH2:1][CH2:2]1)(=[O:16])[CH2:23][CH3:24]
Reactant: CCC(=O)CC(=O)OC
Reactant: ClCCOCCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: O
Solvent: CN(C)C=O
Product: CCC(=O)C1(C(=O)OC)CCOCC1
Temperature: 80 °C
Yield: 56 %

Procedure:
In a flask made of glass having an inner volume of 200 ml and equipped with a stirring device, a thermometer, a dropping funnel and a reflux condenser were charged 13.0 g (0.09 mol) of 2,2′-dichloroethyl ether, 35.9 g (0.26 mol) of anhydrous potassium carbonate, 1.3 g (7.8 mmol) of potassium iodide and 80 ml of N,N-dimethylformamide, and the temperature of the mixture was raised to 80° C. with stirring. Then, 20.0 g (0.15 mol) of methyl 3-oxopentanoate was gently added dropwise to the mixture, and the mixture was reacted at the same temperature for 7 hours. After completion of the reaction, to the reaction mixture were added 200 ml of water and 32.3 g (0.31 mol) of conc. hydrochloric acid to adjust a pH of the mixture to 4.5. Said reaction mixture was extracted three times with 200 ml of ethyl acetate. The organic layer was dried over magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained concentrate was purified by silica gel column chromatography (Eluent; hexane/ethyl acetate=3/1 (volume ratio)) to give 10.1 g (Isolation yield: 55%) of 4-propionyl-4-methoxycarbonyltetrahydropyran as a pale yellow liquid.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4](Cl)[CH:3]=1.[CH2:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12][NH:11]1.C(N(CC)CC)C>CN(C)C=O>[CH3:1][C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([N:11]2[CH2:12][CH2:13][C:14]3[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:10]2)[CH:3]=1
Reactant: c1ccc2c(c1)CCNC2
Reactant: Cc1cc(Cl)nc(Cl)n1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cc(N2CCc3ccccc3C2)nc(Cl)n1
Yield: 59.7 %

Procedure:
In accordance with the same procedure as in Step 1 of Example 1, except that 6-methyl-2,4-dichloropyrimidine (3.26 g, 20 mmol), 1,2,3,4-tetrahydroisoquinoline(2.6 ml, 20.5 mmol), triethylamine(3.4 ml, 24.4 mmol) and N,N-dimethyl formamide (10 ml) were used as starting materials, 3.1 g of the titled compound was prepared. (Yield: 59.7%)
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[CH3:11][NH:12][C:13]1[CH:18]=[C:17](Cl)[CH:16]=[CH:15][C:14]=1[N+:20]([O-:22])=[O:21]>CN(C=O)C>[CH3:11][NH:12][C:13]1[CH:18]=[C:17]([CH:16]=[CH:15][C:14]=1[N+:20]([O-:22])=[O:21])[O:10][C:7]1[CH:8]=[CH:9][C:4]([NH2:3])=[CH:5][CH:6]=1
Reactant: CNc1cc(Cl)ccc1[N+](=O)[O-]
Reactant: Nc1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CNc1cc(Oc2ccc(N)cc2)ccc1[N+](=O)[O-]
Temperature: 90 °C
Reaction time: 8 h
Yield: 94.1 %

Procedure:
To a mixture of NaH (60% oily, 440 mg, 11.0 mmol) in DMF (30 mL) was added a solution of 4-aminophenol (1.20 g, 11.0 mmol) in DMF (15 mL) followed by N-methyl-5-chloro-2-nitroaniline (Intermediate 8D-2.02 g, 10.0 mmol) in DMF (20 mL). The mixture was stirred at 90° C. overnight. After cooling, the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over Na2SO4 then evaporated. Sequence purification on SiO2 column chromatography gave the title compound (2.44 g, 94%): MS m/e 260 (M+1).
Reaction SMILES: [CH2:1]([NH:10][C:11](=O)[CH3:12])[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=O.COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:23]2)=CC=1>C1(C)C=CC=CC=1>[CH3:12][C:11]1[S:23][C:2]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)=[CH:1][N:10]=1
Reactant: CC(=O)NCC(=O)c1ccccc1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: Cc1ncc(-c2ccccc2)s1
Yield: 31.4 %

Procedure:
A mixture of N-phenacylacetamide (0.70 g, 4 mmol), 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulphide (Lawesson's reagent) (0.80 g, 2 mmol) and toluene (10 ml) was heated for 1.5 h at reflux and then evaporated under reduced pressure. The residue was purified by chromatography (10 g silica, dichloromethane) to give 2-methyl-5-phenylthiazole as a yellowish solid (0.11 g, 16%) m.p. 72°-4° C.; δH (CDCl3) 7.85(1H, S, CH), 7.3-7.7(5H, m, C6H5), 2.7(3H, S, CH3).
Reaction SMILES: [CH:1]1([CH2:7][C@H:8]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C@H:9](OS(C)(=O)=O)[CH3:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C=O)C.[N-:29]=[N+:30]=[N-:31].[Na+]>CCOC(C)=O.O>[N:29]([C@@H:9]([CH3:10])[C@@H:8]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)=[N+:30]=[N-:31]
Reactant: [N-]=[N+]=[N-]
Reactant: C[C@@H](OS(C)(=O)=O)[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C[C@H](N=[N+]=[N-])[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C
Temperature: 80 °C
Yield: 55 %

Procedure:
tert-Butyl (2S,3R)-1-cyclohexyl-3-(methanesulfonyloxy)butan-2-ylcarbamate (0.46 g, 1.32 mmol) was dissolved into anhydrous DMF (10 mL), solid NaN3 (0.26 g, 4 mmol) was added and the reaction mixture was heated to 80° C. overnight. The reaction mixture was cooled to rt and diluted with EtOAc (100 mL) and water (30 mL). The organic phase was washed with water (3×30 mL), dried over Na2SO4 and evaporated. The residue was separated by chromatography on a silica gel column to give tert-butyl (2S,3S)-3-azido-1-cyclohexylbutan-2-ylcarbamate (0.215 g, 55%). 1H NMR (400 MHz, CDCl3): 4.38 (d, J=9.2 Hz, 1H), 3.72 (m, 1H), 3.60 (m, 1H), 1.82 (m, 1H), 1.67 (m, 4 h), 1.44 (s, 9H), 1.40-1.00 (m, 6H), 1.28 (d, J=6.4 Hz, 3H), 1.00-0.75 (m, 2H); MS (E/Z): 297 (M+H+).