Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]([NH:16][C:17]([C:19]2[N:20]=[C:21](Cl)[O:22][CH:23]=2)=[O:18])[CH3:15])[CH:5]=[C:6]([F:13])[C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10].[CH:25]([C:28]1[CH:29]=[C:30]([OH:38])[CH:31]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:33]=1)([CH3:27])[CH3:26]>>[F:1][C:2]1[CH:3]=[C:4]([CH:14]([NH:16][C:17]([C:19]2[N:20]=[C:21]([O:38][C:30]3[CH:31]=[C:32]([C:34]([F:35])([F:36])[F:37])[CH:33]=[C:28]([CH:25]([CH3:27])[CH3:26])[CH:29]=3)[O:22][CH:23]=2)=[O:18])[CH3:15])[CH:5]=[C:6]([F:13])[C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10]
Reactant: CC(C)c1cc(O)cc(C(F)(F)F)c1
Reactant: CC(NC(=O)c1coc(Cl)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Product: CC(C)c1cc(Oc2nc(C(=O)NC(C)c3cc(F)c(NS(C)(=O)=O)c(F)c3)co2)cc(C(F)(F)F)c1
Yield: 81.5 %

Procedure:
2-Chloro-oxazole-4-carboxylic acid [1-(3,5-difluoro-4-methanesulfonylamino-phenyl)-ethyl]-amide (50 mg, 0.13 mmol) was reacted with 3-isopropyl-5-trifluoromethyl-phenol (54 mg, 0.26 mmol) to give the title compound (58 mg, 81%) after purification by column chromatography (gradient 12% to 100% EtOAc in n-hexane).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][N:3]=1.CCCCCC.C([Li])CCC.[CH3:20][O:21][CH2:22][C:23](OC)=[O:24].Cl>C(OCC)C>[Br:1][C:2]1[N:3]=[CH:4][C:5]([C:23](=[O:24])[CH2:22][O:21][CH3:20])=[CH:6][CH:7]=1
Reactant: Brc1ccc(Br)nc1
Reactant: COCC(=O)OC
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: COCC(=O)c1ccc(Br)nc1
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 32.6 %

Procedure:
To a suspension of 2,5-dibromopyridine (50.0 g) in diethyl ether (1 L) was added under nitrogen atmosphere a 1.6M n-butyllithium hexane solution (140 mL) at −70° C. over 20 min. The reaction mixture was stirred at −70° C. for 30 min, methyl methoxyacetate (44.0 g) was added at −70 to −45° C. over 15 min. The reaction mixture was warmed to room temperature, 2M hydrochloric acid (110 mL) was added, and the diethyl ether layer was separated. The aqueous layer was extracted with ethyl acetate, the ethyl acetate layer was combined with the diethyl ether layer, and the layers were washed with saturated brine, dried (MgSO4) and concentrated. Cold ether was added to the obtained residue, and the resulting crystals were collected by filtration, washed with cold ether and dried to give the title compound (15.85 g, yield 33%) as colorless crystals. melting point 110-112° C.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([NH:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][N:22]=[N+]=[N-])=[CH:17][CH:16]=2)(=[O:14])=[O:13])=[CH:3]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.O>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([NH:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][NH2:22])=[CH:17][CH:16]=2)(=[O:14])=[O:13])=[CH:3]1
Reactant: Cn1cc(NS(=O)(=O)c2ccc(CN=[N+]=[N-])cc2)c2ccccc21
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: Cn1cc(NS(=O)(=O)c2ccc(CN)cc2)c2ccccc21
Temperature: 25 °C
Reaction time: 17 h
Yield: 270.4 %

Procedure:
To a solution of 1-methyl-3-[4-(azidomethyl)phenylsulfonylamino]indole (674 mg, 1.97 mmol), prepared as in step 1, in 8:2 THF/H2O (10 mL) was added triphenylphosphine (1.03 g, 3.9 mmol) and the reaction mixture was stirred for 17 hours at ambient temperature. The reaction mixture was concentrated in vacuo and the residue was partitioned between ethyl acetate and brine. The organic phase was dried over Na2SO4, filtered, and concentrated in vacuo to give 1-methyl-3-[4-(aminomethyl)phenylsulfonylamino]indole (1.68 g) as a yellow-orange foam.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][S:6]([NH:9][CH3:10])(=[O:8])=[O:7].[C-:11]#[N:12].[K+]>CC#N>[C:11]([CH2:2][CH2:3][CH2:4][CH2:5][S:6]([NH:9][CH3:10])(=[O:8])=[O:7])#[N:12]
Reactant: CNS(=O)(=O)CCCCCl
Reactant: [C-]#N
Agent: [K+]
Solvent: CC#N
Product: CNS(=O)(=O)CCCCC#N

Procedure:
4-Chloro-N-methylbutane-1-sulfonamide (54 mmol), KCN (108 mmol) and 18-crown ether-6 (11 mmol) were dissolved in CH3CN (100 ml). The mixture was stirred at reflux temperature overnight. The mixture was cooled and filtered. The residue was purified by flash column chromatography over silica gel (eluent: CH2Cl2, then ethyl acetate). Yield: 3.2 g (70% purity).
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:18])=[CH:4][C:5]([CH3:17])=[C:6]2[C:10]=1[N:9]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:8][CH2:7]2.[CH2:19]([N:23]=[C:24]=[O:25])[CH2:20][CH2:21][CH3:22].O>C(Cl)(Cl)Cl>[CH2:19]([NH:23][C:24]([NH:1][C:2]1[C:3]([CH3:18])=[CH:4][C:5]([CH3:17])=[C:6]2[C:10]=1[N:9]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:8][CH2:7]2)=[O:25])[CH2:20][CH2:21][CH3:22]
Reactant: CCCCN=C=O
Reactant: CCCCCCN1CCc2c(C)cc(C)c(N)c21
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCCCCCN1CCc2c(C)cc(C)c(NC(=O)NCCCC)c21
Temperature: 25 °C
Reaction time: 18 h
Yield: 40.1 %

Procedure:
7-Amino-4,6-dimethyl-1-hexylindoline (800 mg) was dissolved in chloroform (20 ml) and butyl isocyanate (400 mg) was added, which was followed by stirring at room temperature for 18 hours. Water was added to the reaction mixture, and the mixture was washed with saturated brine and dried over sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent : chloroform-methanol=1:0-50:1) and recrystallized from ethanol to give 450 mg of the title compound.
Reaction SMILES: [S:1]([C:5]1[S:13][C:12]2[C:7](=[N:8][CH:9]=[C:10]([O:14]C)[CH:11]=2)[CH:6]=1)(=[O:4])(=[O:3])[NH2:2].Cl.N1C=CC=CC=1>O>[S:1]([C:5]1[S:13][C:12]2[C:7](=[N:8][CH:9]=[C:10]([OH:14])[CH:11]=2)[CH:6]=1)(=[O:3])(=[O:4])[NH2:2]
Reactant: COc1cnc2cc(S(N)(=O)=O)sc2c1
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: NS(=O)(=O)c1cc2ncc(O)cc2s1
Temperature: 190 °C
Yield: 68 %

Procedure:
A mixture of 2-sulfamoyl-6-methoxythieno[3,2-b]pyridine (512 mg, 2.1 mmol) and pyridine hydrochloride (1.62 g, 14 mmol), under a nitrogen atmosphere, was placed in an oil bath heated at 190° C. for 3/4 hour. The cooled mixture was diluted with water as the product slowly crystallized out. The mixture was extracted into ethyl acetate/methanol, washed with water, dried over anhydrous sodium sulfate, filtered through a pad of charcoal and evaporated. The residue was triturated with diethyl ether and the product was collected by filtration (330 mg, 68% yield). Crystallization from hot ethyl acetate/methanol by boiling off the methanol gave pure product, m.p. 248°-250° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6](Cl)[N:5]=[C:4]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[N:3]=1.[CH3:15][O-:16].[Na+].O>COCCOC>[NH2:1][C:2]1[CH:7]=[C:6]([O:16][CH3:15])[N:5]=[C:4]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[N:3]=1
Reactant: Nc1cc(Cl)nc(N2CCOCC2)n1
Reactant: C[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COc1cc(N)nc(N2CCOCC2)n1
Temperature: 20 °C
Reaction time: 22 h
Yield: 66 %

Procedure:
60.46 g of 4-amino-6-chloro-2-morpholinopyrimidine (described in Chem. Pharm. Bull. 13, 557) are suspended in 190 ml of 1,2-dimethoxyethane and to this suspension are added 35.4 g of sodium methylate. The suspension is subsequently stirred for 22 hours under reflux and then cooled to 20° C. After addition of 180 ml of water the precipitated product is collected by suction and dried in vacuo at 80° C., affording 39.1 g (66% of theory) of 4-amino-6-methoxy-2-morpholinopyrimidine with a melting point of 162° C.-164° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]=[C:4]([CH2:9][CH3:10])[N:3]=1.O.[NH2:12][NH2:13]>CO>[Cl:1][C:2]1[CH:7]=[C:6]([NH:12][NH2:13])[N:5]=[C:4]([CH2:9][CH3:10])[N:3]=1
Reactant: NN
Reactant: CCc1nc(Cl)cc(Cl)n1
Solvent: O
Solvent: CO
Product: CCc1nc(Cl)cc(NN)n1
Temperature: 0 °C
Reaction time: 2 h
Yield: 86.9 %

Procedure:
To a stirred, cold (0° C.) solution of 60 g (0.34 mole) of 4,6-dichloro-2-ethylpyrimidine in 500 ml of methanol was added 35 g (0.7 mole) of hydrazine hydrate while maintaining the temperature below 10° C. Stirring was continued for 2 hours after completion of the addition, the temperature being maintained at 0° C. The mixture was allowed to warm to about 20° C. and was stirred for 16 hours. The white solid was collected by filtration and the filtrate was partially evaporated to provide a second crop. The combined solids were washed with water and air dried to provide 51 g (77%) of 4-chloro-2-ethyl-6-hydrazinylpyrimidine, m.p. 147°-150° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:7]([C:8]([NH2:10])=[O:9])[C:6]([NH2:12])=[CH:5][CH:4]=1.Cl[C:14]1[S:15][C:16]([C:19]([O:21][CH3:22])=[O:20])=[CH:17]N=1>>[CH3:1][O:2][C:3]1[CH:11]=[C:7]2[C:6](=[CH:5][CH:4]=1)[N:12]=[C:14]1[S:15][C:16]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][N:10]1[C:8]2=[O:9]
Reactant: COc1ccc(N)c(C(N)=O)c1
Reactant: COC(=O)c1cnc(Cl)s1
Product: COC(=O)c1cn2c(=O)c3cc(OC)ccc3nc2s1

Procedure:
16.5 g of 5-methoxyanthranilamide and 18.64 g of methyl 2-chlorothiazole-5-carboxylate were stirred for 11/2 hours at 160° C. After working up in the conventional manner 24.7 g (85%) of the above compound was obtained; m.p. 187°-192° C.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11](=O)[CH2:12][CH2:13][C:14](=O)[CH3:15])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH:18]1([NH2:24])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH:18]1([N:24]2[C:11]([C:8]3[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:6][CH:7]=3)=[CH:12][CH:13]=[C:14]2[CH3:15])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: CC(=O)CCC(=O)c1ccc(S(C)(=O)=O)cc1
Reactant: NC1CCCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2ccc(S(C)(=O)=O)cc2)n1C1CCCCC1
Yield: 34.1 %

Procedure:
A mixture of 1-(4-methylsulfonylphenyl)-1,4-pentanedione (Example 1, Step 2) (820 mg, 3.23 mmol), cyclohexylamine (410>1, 3.55 mmol) and p-toluenesulfonic acid (50 mg) in toluene (75 ml) was heated to reflux for 24 hours. The reaction mixture was cooled, filtered and concentrated. The crude solid (1.14 g) was purified by chromatography (silica gel, hexane/ethyl acetate, 1/1) to give 1-cyclohexyl-2-methyl-5-[4-(methylsulfonyl)phenyl]-1H-pyrrole (350 mg, p6%) as a white solid: mp (DSC) 141 ° C. Anal Calc'd. for C18H23NSO2 : C, 68.10; H, 7.30; N, 4.41; S, 10.10. Found: C, 68.22; H, 7.25; N, 4.30; S, 10.16.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.[C:12](OC([O-])=O)([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13]>O1CCCC1>[C:15]([O:14][C:12](=[O:13])[NH:1][C:2]1[CH:3]=[CH:4][C:5]([F:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1)([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)OC(=O)OC(=O)[O-]
Reactant: CC(=O)c1cc(N)ccc1F
Solvent: C1CCOC1
Product: CC(=O)c1cc(NC(=O)OC(C)(C)C)ccc1F
Temperature: 25 °C
Reaction time: 28 h
Yield: 73.7 %

Procedure:
To a solution of 1.19 g (7.77 mmol) of 1-(5-amino-2-fluorophenyl)ethanone in 18 ml of dry tetrahydrofuran at room temperature under an atmosphere of nitrogen was added 1.86 g (8.54 mol) of tert-butyl dicarbonate. The solution was stirred for 28 hours at room temperature followed by 17 hours at 45° C., cooled to room temperature and evaporated under reduced pressure. The residue was dissolved in ethyl acetate and the solution washed with sodium bicarbonate solution, dried over magnesium sulphate, evaporated to dryness and the residue chromatographed on silica gel using ethyl acetate/petrol 4:1 for the elution. There was obtained 1.45 g of (3-acetyl-4-fluorophenyl)carbamic acid tert-butyl ester MS: m/e 271 [M+CH3CN]+.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[C:12]([I:13])=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([NH2:8])=[O:7].[F:14][C:15]([F:22])([F:21])[C:16](OCC)=O.Cl>C(O)C.O>[I:13][C:12]1[CH:11]=[CH:10][CH:9]=[C:5]2[C:4]=1[NH:3][C:16]([C:15]([F:22])([F:21])[F:14])=[N:8][C:6]2=[O:7]
Reactant: NC(=O)c1cccc(I)c1N
Reactant: CCOC(=O)C(F)(F)F
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=c1nc(C(F)(F)F)[nH]c2c(I)cccc12
Yield: 98.6 %

Procedure:
EDCI hydrochloride (18.4 g) and 1-hydroxybenzotriazole (9.5 g) were added to a solution of 2-amino-3-iodobenzoic acid (16.4 g) synthesized using the method described in Journal of Medicinal Chemistry, 2004, 47 (6), 1448-1464 in DMF (120 mL), and subsequently ammonia water (21.2 ml) was added thereto. The reaction solution was stirred at room temperature for 3 hours. Water was added to the reaction solution, and the deposit was filtrated and dried under reduced pressure to obtain 2-amino-3-iodobenzamide (12.8 g). 60% sodium hydride (2.29 g) was added to a solution of the obtained 2-amino-3-iodobenzamide (5.0 g) in ethanol (95 ml), then ethyl trifluoroacetate (10.8 g) was added thereto, and the mixture was heated to reflux for 15 hours. After cooling, water was added thereto, and the reaction solution was rendered acidic by the addition of 6 N hydrochloric acid. Then, the deposit was filtrated and dried under reduced pressure to obtain compound (4a) (6.4 g, yield based on 2 steps: 77%).
Reaction SMILES: [CH3:1][O:2][C@@H:3]([C@@H:33]([N:38]([CH3:46])[C:39](=[O:45])[C@H:40]([CH:42]([CH3:44])[CH3:43])[NH2:41])[C@@H:34]([CH3:37])[CH2:35][CH3:36])[CH2:4][C:5]([N:7]1[CH2:11][CH2:10][CH2:9][C@H:8]1[C@H:12]([O:31][CH3:32])[C@@H:13]([CH3:30])[C:14](=[O:29])[NH:15][C@H:16]([C:24]1[S:25][CH:26]=[CH:27][N:28]=1)[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:6].[C:47]([O:51][C:52]([N:54]1[CH2:59][CH2:58][CH2:57][CH2:56][C@@:55]1([CH3:63])[C:60](O)=[O:61])=[O:53])([CH3:50])([CH3:49])[CH3:48].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>ClCCl>[CH3:1][O:2][C@@H:3]([C@@H:33]([N:38]([CH3:46])[C:39](=[O:45])[C@@H:40]([NH:41][C:60]([C@:55]1([CH3:63])[CH2:56][CH2:57][CH2:58][CH2:59][N:54]1[C:52]([O:51][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:53])=[O:61])[CH:42]([CH3:44])[CH3:43])[C@@H:34]([CH3:37])[CH2:35][CH3:36])[CH2:4][C:5]([N:7]1[CH2:11][CH2:10][CH2:9][C@H:8]1[C@H:12]([O:31][CH3:32])[C@@H:13]([CH3:30])[C:14](=[O:29])[NH:15][C@H:16]([C:24]1[S:25][CH:26]=[CH:27][N:28]=1)[CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)=[O:6]
Reactant: CC(C)(C)OC(=O)N1CCCC[C@@]1(C)C(=O)O
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1ccccc1)c1nccs1)OC)N(C)C(=O)[C@@H](N)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1ccccc1)c1nccs1)OC)N(C)C(=O)[C@@H](NC(=O)[C@]1(C)CCCCN1C(=O)OC(C)(C)C)C(C)C
Yield: 62.3 %

Procedure:
According to the general procedure D, from #86 (280 mg, 0.4 mmol, 1 eq.), #156 (100 mg, 0.4 mmol, 1 eq.), dichloromethane (5 mL), HATU (182 mg, 0.48 mmol, 1.2 eq.) and N,N-diisopropylethylamine (100 mg, 0.8 mmol, 2 eq.) was synthesized the crude desired material, which was purified by silica gel chromatography (Gradient: 0.01 to 0.05% methanol in dichloromethane) to afford #187 (220 mg, 62%) as a white solid. HPLC (Protocol V): m/z 883.57 [M+H+], retention time=3.23 minutes (purity=95%).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:11]([NH2:12])=[N:10][C:9]([C:13]([F:16])([F:15])[F:14])=[C:8]([Br:17])[N:7]=1)=O)C.O.[NH2:19][NH2:20].O>CCO>[NH2:12][C:11]1[C:6]([C:4]([NH:19][NH2:20])=[O:3])=[N:7][C:8]([Br:17])=[C:9]([C:13]([F:16])([F:15])[F:14])[N:10]=1
Reactant: NN
Reactant: CCOC(=O)c1nc(Br)c(C(F)(F)F)nc1N
Solvent: CCO
Solvent: O
Product: NNC(=O)c1nc(Br)c(C(F)(F)F)nc1N
Temperature: 90 °C

Procedure:
To a solution of 3-Amino-6-bromo-5-trifluoromethyl-pyrazine-2-carboxylic acid ethyl ester (Int. F1) (1.00 g, 3.18 mmol) in dry EtOH (25 ml) was added hydrazine monohydrate (309 ul, 6.37 mmol) and the mixture was stirred at reflux (ca. 90° C.). After 3 hr 45 min the reaction mixture was cooled in an ice bath and added to water. The resulting yellow ppt was filtered under vacuum and dried in a vacuum oven overnight to give the title compound as a yellow solid 1H NMR (400 MHz, DMSO-d6) 610.10 (1H, s), 8.00 (2H, s), 4.65 (2H, s).
Reaction SMILES: [O:1]1[C:6]([C:7](=[N:11][O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:8]([OH:10])=O)=[CH:5][S:4][CH2:3][CH2:2]1.[NH2:19][CH:20]1[C:30](=[O:31])[N:22]2[C:23]([C:27]([OH:29])=[O:28])=[CH:24][CH2:25][S:26][C@H:21]12.C[Si](CC(N)=O)(C)C.C[Si](C([Si](C)(C)C)C(N)=O)(C)C>C(OCC)(=O)C.O>[O:1]1[C:6]([C:7](=[N:11][O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:8]([NH:19][CH:20]2[C:30](=[O:31])[N:22]3[C:23]([C:27]([OH:29])=[O:28])=[CH:24][CH2:25][S:26][C@H:21]23)=[O:10])=[CH:5][S:4][CH2:3][CH2:2]1
Reactant: NC1C(=O)N2C(C(=O)O)=CCS[C@H]12
Reactant: CCCCCCON=C(C(=O)O)C1=CSCCO1
Agent: C[Si](C)(C)C(C(N)=O)[Si](C)(C)C
Agent: C[Si](C)(C)CC(N)=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCCCCCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12)C1=CSCCO1
Yield: 72.2 %

Procedure:
N,N-Dimethylformamide (0.579 g.), phosphoryl chloride (1.214 g.) and ethyl acetate (3 ml.) were treated in a conventional manner to give a Vilsmeier reagent and the reagent was added to ethyl acetate (7 ml.). To the solution was added 2-(2,3-dihydro-1,4-oxathiin-6-yl)-2-n-hexyloxyiminoacetic acid (syn isomer, 2.00 g.) under stirring to give an activated acid solution. On the other hand, 7-amino-3-cephem-4-carboxylic acid (1.46 g.), trimethylsilylacetamide (3.84 g.), bis(trimethylsilyl)acetamide (4.40 ml.) and ethyl acetate (24 ml.) were stirred to prepare a solution. To the solution was added all at once the activated acid solution at -10° C., and stirred at the same temperature for 1.5 hours. After adding water (30 ml.) and ethyl acetate (15 ml.) to the resultant solution, the solution was shaken sufficiently and the organic layer was separated. An aqueous solution of sodium bicarbonate (30 ml.) was added to the organic solution, shaken sufficiently and the aqueous layer was separated. The solution was adjusted to pH 2.0 with conc.hydrochloric acid and extracted with ethyl acetate (60 ml.). The extract was washed with water (20 ml.) twice, dried over magnesium sulfate and concentrated in vacuo. The residue was pulverized with diisopropyl ether (50 ml.) and the precipitates were collected by filtration to give 7-[2-(2,3-dihydro-1,4-oxathiin-6-yl)-2-n-hexyloxyiminoacetamido]-3-cephem-4-carboxylic acid (syn isomer, 2.40 g.).
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.O=[C:13]1[CH2:18][CH2:17][N:16]([C:19](=[O:31])[C:20]2[CH:25]=[CH:24][C:23]([N:26]3[CH:30]=[N:29][CH:28]=[N:27]3)=[CH:22][CH:21]=2)[CH2:15][CH2:14]1.[Cl:32][C:33]1[CH:38]=[CH:37][C:36]([CH2:39][CH2:40][NH2:41])=[CH:35][CH:34]=1>C1(C)C=CC=CC=1>[Cl:32][C:33]1[CH:38]=[CH:37][C:36]([CH2:39][CH2:40][NH:41][CH:13]2[CH2:18][CH2:17][N:16]([C:19](=[O:31])[C:20]3[CH:25]=[CH:24][C:23]([N:26]4[CH:30]=[N:29][CH:28]=[N:27]4)=[CH:22][CH:21]=3)[CH2:15][CH2:14]2)=[CH:35][CH:34]=1
Reactant: O=C1CCN(C(=O)c2ccc(-n3cncn3)cc2)CC1
Reactant: NCCc1ccc(Cl)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: O=C(c1ccc(-n2cncn2)cc1)N1CCC(NCCc2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A catalytic amount of p-toluenesulfonic acid was added to a solution of 0.45 g of 4-oxo-1-[4-(1,2,4-triazol-1-yl)benzoyl]piperidine and 0.39 g of 2-(4-chlorophenyl)ethylamine in 10 ml of toluene. The mixture was refluxed by heating, for 5 hours while removing the generated water using a Dean-Stark trap. The reaction mixture was concentrated under reduced pressure. To the residue was added 10 ml of ethanol. Thereto was added 70 mg of sodium borohydride at room temperature. The mixture was stirred at room temperature overnight. The reaction mixture was made acidic with cocentrated hydrochloric acid and then concentrated under reduced pressure. To the residue was added ice water. The mixture was made basic with an aqueous sodium hydroxide solution and extracted with two 30-ml portions of ethyl acetate. The extract was washed with water and a saturated aqueous sodium chloride solution in this order, dried with sodium sulfate, and concentrated under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography (eluant: methylene chloride/methanol=25/1) and then recrystallized from ethyl acetate to obtain 4-(2-(4-chlorophenyl)ethylamino]-1-[4-(1,2,4-triazol-1-yl)benzoyl]piperidine as a white powder.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[CH:10][C:9]2[C:8](SC)=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=1.[F:14][C:15]([F:25])([F:24])[C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH2:19][NH2:20]>>[NH2:1][C:2]1[N:11]=[CH:10][C:9]2[C:8]([NH:20][CH2:19][C:18]3[CH:21]=[CH:22][CH:23]=[C:16]([C:15]([F:14])([F:24])[F:25])[CH:17]=3)=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=1
Reactant: NCc1cccc(C(F)(F)F)c1
Reactant: CSc1ncnc2cc(N)ncc12
Product: Nc1cc2ncnc(NCc3cccc(C(F)(F)F)c3)c2cn1
Temperature: 140 °C
Reaction time: 1 h
Yield: 64.2 %

Procedure:
A mixture of 7-amino-4-methylthiopyrido[4,3-d]pyrimidine (225 mg, 1.17 mmole) and 3-(trifluoromethyl)benzylamine (0.63 mL, 4.40 mmole) is stirred under N2 at 140° C. for 1 h. The resulting product is chromatographed on silica gel (3-5% EtOH/EtOAc) to give 7-amino-4-[(3-trifluoromethylphenyl)methylamino]pyrido[4,3-d]pyrimidine (0.24 g, 63%) as a light brown solid. 1H NMR (DMSO) δ 9.10 (1H, s), 8.92 (1H, t, J=5.7 Hz), 8.26 (1H, s), 7.71 (1H, s), 7.66 (1H, d, J=7.4 Hz), 7.62 (1H, d, J=7.8 Hz), 7.57 (1H, t, J=7.6 Hz), 6.49 (2H, brs), 6.38 (1H, s), 4.82 (2H, d, J=5.8 Hz).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)#[N:2].N1C=CC=CC=1.[CH2:22]([O:30][C:31](Cl)=[O:32])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]>C1C=CC=CC=1>[C:31](=[O:32])([O:30][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[O:15][C:12]1[CH:13]=[CH:14][C:9]([C:6]2[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=2)=[CH:10][CH:11]=1
Reactant: N#Cc1ccc(-c2ccc(O)cc2)cc1
Reactant: CCCCCCCCOC(=O)Cl
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: CCCCCCCCOC(=O)Oc1ccc(-c2ccc(C#N)cc2)cc1

Procedure:
0.390 G. of 4'-cyano-4-hydroxy-biphenyl are dissolved in 10 ml. of absolute pyridine and reacted with 0.423 g. of chloroformic acid n-octyl ester as in Example 1. The 0.721 g. of brownish oil obtained according to the procedure described in Example 1 is dissolved in benzene and chromatographed on 40 g. of silica gel. Benzene elutes 0.620 g. of colorless crystals which are recrystallized from ether-hexane up to constant melting point and clearing point. The pure 4'-cyano-4-biphenylyl n-octyl carbonate obtained melts at 51.64° and has a clearing point of 67.7°. UV (EtOH): ε 270 = 26000.
Reaction SMILES: [Cl:1][CH:2]1[CH:13]([CH3:14])[CH:12]2[CH:4]([C@@:5]3([CH:42]=[O:43])[CH2:26][C@H:9]4[C@@:10]([CH2:15]OCC5C=CC(OC)=CC=5)([CH2:11]2)[C@:6]3([C:30]([O:32]CC2C=CC(OC)=CC=2)=[O:31])[C:7]([CH:27]([CH3:29])[CH3:28])=[CH:8]4)[CH2:3]1.[CH3:44][OH:45]>[OH-].[OH-].[Pd+2]>[OH:45][CH2:44][CH2:15][C@@:10]12[C@@H:9]3[CH2:26][C@@:5]([CH:42]=[O:43])([C@:6]1([C:30]([OH:32])=[O:31])[C:7]([CH:27]([CH3:29])[CH3:28])=[CH:8]3)[CH:4]1[CH:12]([CH:13]([CH3:14])[CH:2]([Cl:1])[CH2:3]1)[CH2:11]2
Reactant: CO
Reactant: COc1ccc(COC[C@@]23CC4C(C)C(Cl)CC4[C@@]4(C=O)C[C@@H]2C=C(C(C)C)[C@@]34C(=O)OCc2ccc(OC)cc2)cc1
Agent: [Pd+2]
Agent: [OH-]
Product: CC(C)C1=C[C@H]2C[C@]3(C=O)C4CC(Cl)C(C)C4C[C@@]2(CCO)[C@@]13C(=O)O
Reaction time: 0.25 h

Procedure:
To a solution of 40 (40 mg, 0.066 mmol) in CH3OH (5 mL) was added Pearlman's catalyst (10 mg). The mixture was stirred under hydrogen (balloon pressure) for about 15 minutes. After filtration and concentration in vacuo, about 23.7 mg of 41 was obtained and used directly in the next step.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[N:5]=[C:4]([NH2:18])[N:3]=1.C1C(=O)N([I:26])C(=O)C1>C(Cl)Cl.CO>[I:26][C:7]1[C:2]([CH3:1])=[N:3][C:4]([NH2:18])=[N:5][C:6]=1[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:15])[F:16])[CH:9]=1
Reactant: Cc1cc(-c2cccc(C(F)(F)F)c2)nc(N)n1
Reactant: O=C1CCC(=O)N1I
Solvent: ClCCl
Solvent: CO
Product: Cc1nc(N)nc(-c2cccc(C(F)(F)F)c2)c1I

Procedure:
The title compound is synthesized according to general procedure GP1 starting from 5.0 g (14 mmol) 4-methyl-6-(3-trifluoromethyl-phenyl)-pyrimidin-2-ylamine and 3.3 g (15 mmol) NIS. Yield after chromatography on silica gel with DCM/MeOH: 3.8 g (73%).