Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:9]([F:10])=[CH:8][CH:7]=[C:6]([F:11])[C:3]=1[CH:4]=O.Cl.[NH2:13][OH:14].C([O-])(=O)C.[Na+]>C(O)C>[Cl:1][C:2]1[C:9]([F:10])=[CH:8][CH:7]=[C:6]([F:11])[C:3]=1[CH:4]=[N:13][OH:14]
Reactant: O=Cc1c(F)ccc(F)c1Cl
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: ON=Cc1c(F)ccc(F)c1Cl

Procedure:
A solution of 2-chloro-3,6-difluoro-benzaldehyde (16.5 g, 93 mmol) in ethanol (80 ml) was treated with hydroxylamine HCl (7.80 g, 112 mmol) and sodium acetate (9.20 g, 112 mmol). The mixture was heated under reflux for 16 h, then the solvent was evaporated, and the residue stirred with water. The precipitate was filtered and dried to afford 2-chloro-3,6-difluoro-benzaldehyde oxime. It was dissolved in acetic anhydride (140 ml) and refluxed for 16 h, then the mixture was evaporated to afford 2-chloro-3,6-difluoro-benzonitrile as a light brown liquid (10.6 g, 65%). In analogy to example 5a, this compound was reacted with 4-methylimidazole and potassium carbonate for 20 h at 90° C. Aqueous workup, extraction with Ethyl acetate followed by chromatography (SiO2, dichloromethane:methanol=100:0 to 97:3) afforded the title compound as a white solid (yield: 6%). MS: m/e=336.1 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.CC1C=CC(S(O)(=O)=O)=CC=1.C1C=CC=CC=1.[CH3:26][C:27](=[O:30])[CH:28]=[CH2:29]>O(CC)CC>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:29][CH2:28][C:27](=[O:30])[CH3:26])=[CH:4][CH:3]=1
Reactant: Oc1ccc(F)cc1
Reactant: C=CC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: CCOCC
Product: CC(=O)CCOc1ccc(F)cc1
Reaction time: 96 h
Yield: 39.7 %

Procedure:
To a stirred solution of 134 parts of 4-fluorophenol and 2 parts of 4-methylbenzenesulfonic acid in 1080 parts of benzene were added 42 parts of 3-buten-2-one. Stirring was continued for 4 days at room temperature. 700 Parts of 1,1'-oxybisethane were added and the whole was washed four times with 500 parts of a cold sodium hydroxide solution 1N and with water. The organic phase was dried, filtered and evaporated. The oily residue was purified by column-chromatography over silica gel using trichloromethane as eluent. The pure fractions were collected and the eluent was evaporated. The oily residue solidified upon cooling. The product was suspended in cold petroleumether. The product was filtered off and dried at room temperature, yielding 43.4 parts (39.7%) of 4-(4-fluorophenoxy)-2-butanone (intermediate 26).
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:16]2[CH:17]=[N:18][C:19](F)=[CH:20][CH:21]=2)[C:8]([NH:10][C:11]2[S:12][CH:13]=[CH:14][N:15]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.C[S:24](C)=O>>[CH:1]1([CH2:6][CH:7]([C:16]2[CH:17]=[N:18][C:19]([SH:24])=[CH:20][CH:21]=2)[C:8]([NH:10][C:11]2[S:12][CH:13]=[CH:14][N:15]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(Nc1nccs1)C(CC1CCCC1)c1ccc(F)nc1
Reactant: CS(C)=O
Product: O=C(Nc1nccs1)C(CC1CCCC1)c1ccc(S)nc1
Temperature: 160 °C
Reaction time: 1 h

Procedure:
A solution of 3-cyclopentyl-2-(6-fluoropyridin-3-yl)-N-thiazol-2-ylpropionamide (EXAMPLE 14, 350 mg, 1.1 mmol) and NaSMe (1.53 g, 22.0 mmol) in anhydrous, degassed DMSO (4 mL) was stirred at 160° C. (bath) for 1 h. On cooling, the mixture was partitioned between EtOAc (50 mL) and 1M HCl (50 mL). The organic layer was washed with H2O (20 mL) and brine (50 mL). The solvent was evaporated and the residue recrystallised (EtOAc-1H) to give the title compound: RTA=3.24 min; m/z (ES+)=334.2 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[CH:6]=[C:5]2[OH:13].Cl[C:15]1[C:24]2[C:19](=[CH:20][C:21]([O:27][CH3:28])=[C:22]([O:25][CH3:26])[CH:23]=2)[N:18]=[CH:17][CH:16]=1.O>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[CH3:26][O:25][C:22]1[CH:23]=[C:24]2[C:19](=[CH:20][C:21]=1[O:27][CH3:28])[N:18]=[CH:17][CH:16]=[C:15]2[O:13][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([F:1])[CH:3]=2)[N:8]=[C:7]([CH3:12])[CH:6]=1
Reactant: Cc1cc(O)c2cc(F)ccc2n1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1Cl
Solvent: O
Product: COc1cc2nccc(Oc3cc(C)nc4ccc(F)cc34)c2cc1OC
Temperature: 130 °C
Reaction time: 8 h
Yield: 6.8 %

Procedure:
6-Fluoro-2-methyl-quinolin-4-ol (237 mg), 4-chloro-6,7-dimethoxyquinoline (100 mg), and 4-dimethylaminopyridine (164 mg) were suspended in o-dichlorobenzene (6 ml), and the suspension was stirred at 130° C. overnight. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using acetone-chloroform to give the title compound (11 mg, yield 7%).
Reaction SMILES: NCCCCCCNC(OC[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=O.[NH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][NH2:26].C(=O)C1C=CC=CC=1.S([O-])([O-])(=O)=O.[Mg+2]>C(Cl)Cl>[NH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][NH:26][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: NCCCCCCNC(=O)OCc1ccccc1
Reactant: NCCCCCCN
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: O=Cc1ccccc1
Solvent: ClCCl
Product: NCCCCCCNc1ccccc1
Yield: 100 %

Procedure:
To prepare 1-amino-6-phenylmethoxycarbonylaminohexane (23), an equimolar mixture (0.01 mol) of 1,6-diaminohexane and benzaldehyde in 25 mL of methylene chloride was stirred for 5 hr in the presence of 1.5 g of anhydrous magnesium sulfate at room temperature. After removing the drying agent by filtration the filtrate was evaporated to dryness under reduced pressure to give 2 g (100% yield) of crude 1-amino-6-phenylamino-hexane 22 as a colorless oil; NMR(CDCl3) 1.1-1.9(m, 10H, hexane CH2 -2,-3,-4,-5, NH2); 2.6(m, 2H, CH2 -1); 3.51(m, 2H, hexane CH2 -6); 7.1-7.8 (m, 5H, aromatic); 8.16(s, 1H, imine CH). To a mixture of 2 g (0.01 mol) of 22 and 1.4 mL (0.01 mol) of triethylamine in 20 mL of methylene chloride. Then 1.78 g (0.01 mol) of benzylchloroformate was added dropwise at -5° C. The resulting mixture was stirred for 0.5 hr at 0° C. and for 2 hr at room temperature then diluted to 50 mL with methylene chloride and washed with water (20 ml), 2% sodium bicarbonate (20 ml), water and saturated sodium chloride and dried over anhydrous magnesium sulfate. After evaporation of solvent under reduced pressure the residue was dissolved in 5 mL of ethanol and 10 mL of 2N hydrochloric acid was added. The resulting mixture was stirred for 6 hr at room temperature then evaporated to dryness under reduced pressure. The residue was diluted to 50 mL with water and washed with ethyl ether (2×15 ml). The water phase was evaporated under reduced pressure and the product 23 was purified by crystallization from a small portion of water with a yield of 42%; mp 175°-178° C.
Reaction SMILES: [F:1][C:2]1([F:21])[CH2:7][CH2:6][C:5]([C:14]2[CH:15]=[N:16][C:17]([CH3:20])=[N:18][CH:19]=2)([C:8](N(OC)C)=[O:9])[CH2:4][CH2:3]1.[CH3:22][Mg+].[Br-]>C1COCC1>[F:21][C:2]1([F:1])[CH2:3][CH2:4][C:5]([C:8](=[O:9])[CH3:22])([C:14]2[CH:19]=[N:18][C:17]([CH3:20])=[N:16][CH:15]=2)[CH2:6][CH2:7]1
Reactant: CON(C)C(=O)C1(c2cnc(C)nc2)CCC(F)(F)CC1
Reactant: C[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Product: CC(=O)C1(c2cnc(C)nc2)CCC(F)(F)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 58.8 %

Procedure:
A solution of 4,4-difluoro-N-methoxy-N-methyl-1-(2-methylpyrimidin-5-yl)cyclohexanecarboxamide (700 mg, 2.34 mmol) in THF (20 mL) was added MeMgBr (11.7 mL, 35.12 mmol, 3M in Et2O) at 0° C. and stirred at room temperature for 4 h. The reaction mixture was quenched by saturated NH4Cl at 0° C. and extracted with EtOAc (2×50 mL). The organic layer was washed with brine, dried over Na2SO4 and concentrated to give crude product, which was purified by flash chromatography (EtOAc: petroluem ether=1:3˜3:2) to give 1-(4,4-difluoro-1-(2-methylpyrimidin-5-yl)cyclohexyl)ethanone (350 mg, yield: 59%). 1H NMR (CDCl3 400 MHz): δ8.58 (s, 2H), 2.73 (s, 3H), 2.55-2.45 (m, 2H), 2.20-1.85 (m, 9H).
Reaction SMILES: C(C1C=C(C(C)C)C=C(C(C)C)C=1S(NN=[C:21]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:22][CH2:23][N:24]([CH3:26])[CH3:25])(=O)=O)(C)C.[CH2:33]1[CH2:43][C:41](=[O:42])[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:34]1>>[OH:42][C:41]1([C:21]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[CH:22][CH2:23][N:24]([CH3:25])[CH3:26])[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:34][CH2:33][CH2:43]1
Reactant: O=C1CCCc2ccccc21
Reactant: CC(C)c1cc(C(C)C)c(S(=O)(=O)NN=C(CCN(C)C)c2ccccc2)c(C(C)C)c1
Product: CN(C)CC=C(c1ccccc1)C1(O)CCCc2ccccc21

Procedure:
By using a method similar to that described in Example 22 but starting from β-dimethylaminopropiophenone 2,4,6-triisopropylbenzenesulphonylhydrazone (20 g) and from α-tetralone (6.4 cc), 1-(1-hydroxy-1,2,3,4-tetrahydro-1-naphthyl)-3-dimethylamino-1-phenyl-1-propene (Z) (3.8 g) is obtained in the form of a white powder melting at 108° C. after recrystallisation from a mixture (65 cc of petroleum ether and isopropanol (95/5 by volume).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[NH:11][C:12]([C:14]1[CH:19]=[CH:18][C:17](=[O:20])[N:16]([C:21]2[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][C:22]=2[Cl:28])[CH:15]=1)=[O:13].CN(C(ON1N=NC2[CH:40]=[CH:41][CH:42]=[N:43]C1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1(N)CC1.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:43][CH:42]2[CH2:40][CH2:41]2)=[O:8])=[CH:4][C:3]=1[NH:11][C:12]([C:14]1[CH:19]=[CH:18][C:17](=[O:20])[N:16]([C:21]2[C:22]([Cl:28])=[CH:23][CH:24]=[CH:25][C:26]=2[Cl:27])[CH:15]=1)=[O:13]
Reactant: O=C(O)c1ccc(Cl)c(NC(=O)c2ccc(=O)n(-c3c(Cl)cccc3Cl)c2)c1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: NC1CC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cc(C(=O)NC2CC2)ccc1Cl)c1ccc(=O)n(-c2c(Cl)cccc2Cl)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 47 %

Procedure:
To a solution of 4-chloro-3-({[1-(2,6-dichlorophenyl)-6-oxo-1,6-dihydro-3-pyridinyl]carbonyl}amino)benzoic acid (1.74 g) in DMF (17 mL) were added HATU (3.03 g), cyclopropanamine (680 mg) and iPr2NEt (3.08 g) successively at 0° C., and the mixture was stirred at room temperature for 16 hr under a nitrogen atmosphere. The mixture was partitioned between EtOAc (50 mL) and 1 M HCl (50 mL), and the precipitates produced were removed by filtration. The organic layer of the filtrate was separated and washed with 1 M HCl (50 mL), saturated aqueous NaHCO3 (50 mL×2) and brine successively, dried over MgSO4 and filtered. The filtrate was evaporated in vacuo, and the residue was triturated with a mixture of IPE and MeOH. The precipitates were collected by filtration, triturated with EtOH and collected by filtration to give N-{2-chloro-5-[(cyclopropylamino)carbonyl]phenyl}-1-(2,6-dichlorophenyl)-6-oxo-1,6-dihydro-3-pyridinecarboxamide (890 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:9]([N:12]2[C:16]3=[CH:17][N:18]=[CH:19][CH:20]=[C:15]3[C:14]([CH2:21][CH2:22][NH:23]C(=O)OC(C)(C)C)=[CH:13]2)(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:9]([N:12]2[C:16]3=[CH:17][N:18]=[CH:19][CH:20]=[C:15]3[C:14]([CH2:21][CH2:22][NH2:23])=[CH:13]2)(=[O:10])=[O:11])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(S(=O)(=O)n2cc(CCNC(=O)OC(C)(C)C)c3ccncc32)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cccc(S(=O)(=O)n2cc(CCN)c3ccncc32)c1
Reaction time: 2 h

Procedure:
A solution of t-Butyl [2-{1-(3-methoxybenzenesulfonyl)-1H-pyrrolo[2,3-c]pyridin-3-yl}-ethyl]carbamate in CH2Cl2 is treated with trifluoroacetic acid, stirred for 2 h and concentrated in vacuo. The resultant residue is purified by preparative reverse phase HPLC to afford the title-final product.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)[CH3:6].CS[C:15]1[NH:20][C:19](=[O:21])[C:18]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=2)=[CH:17][N:16]=1>N1C=CC=CC=1>[CH3:6][N:5]([CH2:4][CH2:3][CH2:2][NH:1][C:15]1[NH:20][C:19](=[O:21])[C:18]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=2)=[CH:17][N:16]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1
Reactant: CN(CCCN)c1ccccn1
Reactant: CSc1ncc(Cc2cccc(Cl)c2)c(=O)[nH]1
Solvent: c1ccncc1
Product: CN(CCCNc1ncc(Cc2cccc(Cl)c2)c(=O)[nH]1)c1ccccn1

Procedure:
2-[N-(3-aminopropyl)-N-methylamino]pyridine (0.74 g) and 2-methylthio-5-(3-chlorobenzyl)pyrimid-4-one (0.8 g) were heated together under reflux in pyridine (2.5 ml) for 26 hr. After stripping, the residue was recrystallised three times from ethanol/water to give 2-[3-(N-methyl-N-pyrid-2-ylamino) propylamino]-5-(3-chlorobenzyl)pyrimid-4-one 1H2O, 0.7 g (58%) mp 105°-7° C.
Reaction SMILES: [NH2:1][C@@H:2]1[C:8](=[O:9])[N:7]2[C@@H:3]1[S:4][C@@:5]([N:23]1[CH2:27][CH2:26][N:25]([N:28]=[CH:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:24]1=[O:36])([C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=1)=[O:11])[CH2:6]2.[C:37]([C:41]1[CH:42]=[C:43]([CH:46]=[C:47]([C:50]([CH3:53])([CH3:52])[CH3:51])[C:48]=1[OH:49])[CH:44]=O)([CH3:40])([CH3:39])[CH3:38]>C1C=CC=CC=1>[CH:29](=[N:28][N:25]1[CH2:26][CH2:27][N:23]([C@@:5]2([C:10]([O:12][CH2:13][C:14]3[CH:15]=[CH:16][C:17]([N+:20]([O-:22])=[O:21])=[CH:18][CH:19]=3)=[O:11])[S:4][C@H:3]3[N:7]([C:8](=[O:9])[C@H:2]3[N:1]=[CH:44][C:43]3[CH:42]=[C:41]([C:37]([CH3:38])([CH3:40])[CH3:39])[C:48]([OH:49])=[C:47]([C:50]([CH3:53])([CH3:52])[CH3:51])[CH:46]=3)[CH2:6]2)[C:24]1=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: N[C@@H]1C(=O)N2C[C@@](C(=O)OCc3ccc([N+](=O)[O-])cc3)(N3CCN(N=Cc4ccccc4)C3=O)S[C@H]12
Reactant: CC(C)(C)c1cc(C=O)cc(C(C)(C)C)c1O
Solvent: c1ccccc1
Product: CC(C)(C)c1cc(C=N[C@@H]2C(=O)N3C[C@@](C(=O)OCc4ccc([N+](=O)[O-])cc4)(N4CCN(N=Cc5ccccc5)C4=O)S[C@H]23)cc(C(C)(C)C)c1O
Yield: 98.3 %

Procedure:
30 ml of benzene was added to 1.00 g of (3R,5R,6R)-6-amino-3-(3-benzylideneamino-2-oxo-imidazolidin-1-yl)-3-(p-nitrobenzyloxycarbonyl)-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane and 0.46 g of 3,5-di-tert-butyl-4-hydroxybenzaldehyde. The mixture was subjected to azeotropy and dehydration under reflux for 1 hour using a Dean-Stark aparatus. The reaction mixture was cooled, and the solvent was removed by distillation under reduced pressure to obtain 1.40 g (yield: 98.6%) of (3R,5R,6R)-3-(3-benzylideneamino-2-oxoimidazolidin-1-yl)-6-(3,5-di-tert-butyl-4-hydroxybenzylideneamino)-3-(p-nitrobenzyloxycarbonyl)-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[C:12]([N:19]1[CH2:24][CH2:23][C:22](=O)[CH2:21][CH2:20]1)([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].[NH:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1.O>C1(C)C=CC=CC=1>[N:26]1([C:22]2[CH2:23][CH2:24][N:19]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:20][CH:21]=2)[CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: C1CCNC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)OC(=O)N1CC=C(N2CCCC2)CC1
Reaction time: 2 h

Procedure:
Catalytic amounts of p-toluenesulfonic acid (0.47 g, 0.27 mmol) were added to a solution of N-Boc-4-piperidone (5 g, 25.12 mmol) and pyrrolidine (1.96 g, 27.63 mmol) in toluene (100 ml), and the mixture was stirred for 2 hours under reflux with a water separator. The resulting solution was concentrated to dryness in vacuo and the resulting residue was used directly in the following stage.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:27][N:7]2[CH2:8][CH2:9][N:10]([C:12]3[N:17]=[C:16]([NH2:18])[N:15]4[N:19]=[C:20]([C:22]5[O:23][CH:24]=[CH:25][CH:26]=5)[N:21]=[C:14]4[N:13]=3)[CH2:11][CH:6]2[CH2:5][CH2:4]1.Cl[C:29]1[N:34]=[CH:33][CH:32]=[CH:31][N:30]=1.C([O-])([O-])=O.[K+].[K+]>CS(C)=O>[O:23]1[CH:24]=[CH:25][CH:26]=[C:22]1[C:20]1[N:21]=[C:14]2[N:13]=[C:12]([N:10]3[CH2:9][CH2:8][N:7]4[CH2:27][CH:3]([CH2:2][NH:1][C:29]5[N:34]=[CH:33][CH:32]=[CH:31][N:30]=5)[CH2:4][CH2:5][CH:6]4[CH2:11]3)[N:17]=[C:16]([NH2:18])[N:15]2[N:19]=1
Reactant: Clc1ncccn1
Reactant: NCC1CCC2CN(c3nc(N)n4nc(-c5ccco5)nc4n3)CCN2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Nc1nc(N2CCN3CC(CNc4ncccn4)CCC3C2)nc2nc(-c3ccco3)nn12
Temperature: 85 °C
Reaction time: 4 h

Procedure:
A solution of (7RS,9aRS)—S-(7-aminomethyl-octahydro-pyrido[1,2-a]pyrazin-2-yl)-2-furan-2-yl-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-ylamine (1 eq.; see Example 9 above) and 2-chloropyrimidine (2 eq.) in DMSO was treated with K2CO3 (2 eq.). The mixture was stirred at around 85° C. for 4 hours. The reaction mixture was then filtered, and the filtrate was concentrated and purified by preparative HPLC using aqueous CH3CN (buffered with 0.1% TFA) to afford (7RS,9aRS)-2-furan-2-yl-5-[7-(pyrimidin-2-ylaminomethyl)-octahydro-pyrido[1,2-a]pyrazin-2-yl]-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-ylamine as a white powder: 1H NMR (400 MHz, DMSO-d6) δ 1.60-1.86 (m, 4H), 2.21-2.30 (bs, 1H), 3.05-3.32 (m, 4H), 3.33-3.52 (m, 4H), 3.56-3.72 (m, 1H), 4.62-4.83 (m, 2H), 6.63 (t, J=4.8 Hz, 1H), 6.69 (dd, J=1.8, 3.4 Hz, 1H), 7.08 (d, J=3.4 Hz, 1H), 7.41 (t, J=5.6 Hz, 1H), 7.89 (d, J=1.8 Hz, 1H), 8.32 (d, J=4.8 Hz, 2H), 8.40-8.65 (m, 2H). MS m/z: 448 [M+H]+.
Reaction SMILES: [Br:1][CH2:2][C:3](Br)=[O:4].[Cl:6][C:7](=[CH2:10])[CH2:8][OH:9].CN(C)C1C=CC=CC=1>ClCCl>[Br:1][CH2:2][C:3]([O:9][CH2:8][C:7]([Cl:6])=[CH2:10])=[O:4]
Reactant: C=C(Cl)CO
Reactant: O=C(Br)CBr
Solvent: ClCCl
Solvent: CN(C)c1ccccc1
Product: C=C(Cl)COC(=O)CBr
Temperature: 23 °C
Reaction time: 2 h

Procedure:
To a cold (0° C.) solution of bromoacetyl bromide (51.5 g, 25.5 mmol) in dichloromethane (80 mL) kept under nitrogen atmosphere was added 2-chloroallyl alcohol (26.0 g, 28.1 mmol) over 5 minutes period and N,N-dimethylaniline (30.9 g, 25.5 mmol) at such a rate that the temperature was kept below 5° C. (30 minutes). When the addition was completed, the cooling bath was removed and, the mixture was stirred for 2 hours at 23° C. and washed with water (25 mL), 0.1N HCl (2×25 mL) and water (25 mL). The organic solution was dried (Na2SO4) and concentrated to a crude material from which the title compound was distilled; 44.8 g, 82%, bp 74°-6° C./1.25 torr; ir (neat) νmax : 1745 (C=O), 1635 (C=C) cm-1 ; 1Hmr (CDCl3) δ: 3.93 (s, BrCH2), 4.73 (s, COOCH2C(Cl)=CH2), 5.48 (m, COOCH2C(Cl)=CH2). Anal. calcd. for C5H6O2BrCl: C 28.13, H 2.83, Cl 16.61; found: C 28.49, H 2.92, Cl 16.78
Reaction SMILES: Br[C:2]1[CH:22]=[CH:21][C:5]2[NH:6][C:7]([CH2:9][O:10][C:11]3[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=3)=[N:8][C:4]=2[CH:3]=1.[CH:23]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1B(O)O)=[O:24].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O>[F:18][C:17]([F:20])([F:19])[C:14]1[CH:15]=[CH:16][C:11]([O:10][CH2:9][C:7]2[NH:6][C:5]3[CH:21]=[CH:22][C:2]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=4[CH:23]=[O:24])=[CH:3][C:4]=3[N:8]=2)=[CH:12][CH:13]=1
Reactant: FC(F)(F)c1ccc(OCc2nc3cc(Br)ccc3[nH]2)cc1
Reactant: O=Cc1ccccc1B(O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: O=Cc1ccccc1-c1ccc2[nH]c(COc3ccc(C(F)(F)F)cc3)nc2c1
Temperature: 90 °C
Yield: 75.8 %

Procedure:
A mixture of 5-bromo-2-(4-trifluoromethyl-phenoxymethyl)-1H-benzoimidazole (0.700 g, 1.89 mmol), 2-formylphenylboronic acid (0.424 g, 2.83 mmol), sodium carbonate (1.200 g, 11.3 mmol), and 1,1′-[bis(di-tert-butylphosphino)ferrocene]-palladium dichloride (0.123 g, 0.189 mmol) in DME (14 mL) and H2O (3.5 mL) was heated at 90° C. for 12 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by chromatography (silica, hexanes: EtOAc, 1:1) to afford the product as a yellow oil (0.568 g, 76%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:25]([F:28])([F:27])[F:26])[O:13][N:12]=[C:11]([C:14]3[CH:23]=[CH:22][C:17]([C:18]([NH:20][CH3:21])=[O:19])=[C:16]([CH3:24])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.C(N(CC)CC)C.[S:36]1(=O)[CH2:40][CH2:39][CH2:38][CH2:37]1>C1(C)C=CC=CC=1.[I-].[Zn+2].[I-]>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:25]([F:27])([F:26])[F:28])[O:13][N:12]=[C:11]([C:14]3[CH:23]=[CH:22][C:17]([C:18]([N:20]([CH3:21])[CH:37]4[CH2:38][CH2:39][CH2:40][S:36]4)=[O:19])=[C:16]([CH3:24])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CNC(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1C
Reactant: O=S1CCCC1
Agent: [I-]
Agent: [Zn+2]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)N(C)C1CCCS1
Temperature: 0 °C
Yield: 18.1 %

Procedure:
In a solution of 0.43 g of 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazole-3-yl]-2-methyl-N-methyl benzoic acid amide synthesized similarly to Synthetic Example 29 and 0.20 g of triethylamine in 5 ml of toluene, 0.45 g of trimethyl silyl trifurate was added and stirred vigorously. 10 minutes after the stirring, the reaction mixture was cooled to 0° C., 0.10 g of tetrahydrothiophene-1-oxide and 0.06 g of zinc iodide were added with stirring, and continued to stir at room temperature further for 4 days. After the completion of the reaction, 10 ml of ice water was added in the reaction mixture, and extracted with ethyl acetate (20 ml×2), the organic phase was dehydrated and dried with saturated sodium chloride aqueous solution and anhydrous sodium sulfate in that order, and the solvent was distilled under reduced pressure. The residue was purified with silica gel column chromatography that was eluated with ethyl acetate-hexane (1:2) to obtain 0.09 g of the aimed product as white crystal.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH:11]=O)=[CH:8][C:6]=2[N:7]=1.P(Br)(Br)[Br:20]>C1(C)C=CC=CC=1.ClCCl>[Br:20][CH2:11][C:9]1[S:10][C:5]2[C:4]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:3][C:2]([Cl:1])=[N:7][C:6]=2[CH:8]=1
Reactant: BrP(Br)Br
Reactant: O=Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: Clc1nc(N2CCOCC2)c2sc(CBr)cc2n1
Temperature: 100 °C

Procedure:
To a suspension of 2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carbaldehyde (900 mg) in toluene (20 mL) at 40° C. was added phosphorus tribromide (0.10 mL) and the reaction mixture was heated at 100° C. for 16 h. After cooling to room temperature, the reaction was diluted with dichloromethane (40 mL) and washed with saturated aqueous sodiumhydrogen carbonate solution (2×40 mL). The organic layer was dried (MgSO4) and reduced in vacuo to give 6-bromomethyl-2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine as a yellow solid.
Reaction SMILES: C(C1CCCN([CH2:14][C:15]([C:17]2[CH:26]=[CH:25][C:20]3[NH:21][C:22](=[O:24])[O:23][C:19]=3[CH:18]=2)=[O:16])C1)C1C=CC=CC=1.O1C2C=CC=CC=2NC1=O.[Cl:37]CC(Cl)=O>>[Cl:37][CH2:14][C:15]([C:17]1[CH:26]=[CH:25][C:20]2[NH:21][C:22](=[O:24])[O:23][C:19]=2[CH:18]=1)=[O:16]
Reactant: O=C(Cl)CCl
Reactant: O=C(CN1CCCC(Cc2ccccc2)C1)c1ccc2[nH]c(=O)oc2c1
Agent: O=c1[nH]c2ccccc2o1
Product: O=C(CCl)c1ccc2[nH]c(=O)oc2c1

Procedure:
from 6-(2-(3-benzylpiperidino)-1-oxoethyl)-2,3-dihydrobenzoxazol-2-one ("P"; obtainable by reaction of 2,3-dihydrobenzoxazol-2-one with chloroacetyl chloride to give 6-chloroacetyl-2,3-dihydrobenzoxazol-2-one ("Q"), then reaction with 3-benzylpiperidine):