Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH:17]=2)[N:10]=1.[F:27][CH:28]([F:31])[CH2:29][OH:30]>>[F:27][CH:28]([F:31])[CH2:29][O:30][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH:17]=2)[N:10]=1
Reactant: CS(=O)(=O)Cc1cccc(Nc2ncnc(-c3ccc(F)cc3F)n2)c1
Reactant: OCC(F)F
Product: CS(=O)(=O)Cc1cccc(Nc2ncnc(-c3ccc(F)cc3OCC(F)F)n2)c1

Procedure:
Starting with 4-(2,4-difluorophenyl)-N-{3-[(methylsulfonyl)methyl]phenyl}-1,3,5-triazin-2-amine (70 mg; 0.184 mmol), intermediate 42.1, and 2,2-difluoroethanol (48 μl; 0.736 mmol), example 60 was prepared analogously to the procedure for the preparation of example 42.
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH3:7])[C:5]2[CH:8]=[C:9]([C:22]([OH:24])=O)[C:10]3[CH2:11][CH2:12][CH:13]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[O:14][C:15]=3[C:4]=2[N:3]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[CH3:47][O:48][CH2:49][CH2:50][NH2:51].O>ClCCl>[CH3:47][O:48][CH2:49][CH2:50][NH:51][C:22]([C:9]1[C:10]2[CH2:11][CH2:12][CH:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:14][C:15]=2[C:4]2[N:3]=[C:2]([CH3:1])[N:6]([CH3:7])[C:5]=2[CH:8]=1)=[O:24]
Reactant: COCCN
Reactant: Cc1nc2c3c(c(C(=O)O)cc2n1C)CCC(c1ccccc1)O3
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: O
Product: COCCNC(=O)c1cc2c(nc(C)n2C)c2c1CCC(c1ccccc1)O2
Temperature: 25 °C
Reaction time: 64 h
Yield: 25.8 %

Procedure:
To a suspension of 0.3 g (0.93 mmol) 2,3-dimethyl-8-phenyl-3,6,7,8-tetrahydro-chromeno[7,8-d]imidazole-5-carboxylic acid in dichloromethane (9 ml) were added 0.45 g (1.4 mmol) O-(1H-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TBTU) and the suspension was stirred for 64 h at room temperature. 409 μl (4.7 mmol) 2-Methoxy-ethylamine were added and the mixture was stirred for 24 h at room temperature. The reaction was poured into water and the precipitate filtered off. After drying of the residue in vacuo at 40° C., 91 mg (29%) of the title compound were isolated as a yellow solid. m.p. 254°-256° C.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[NH:16][N:15]=[N:14][N:13]=2)[CH:7]=[C:6]([CH3:17])[C:3]=1[CH:4]=O.[NH2:18][C:19]1[CH:20]=[C:21]([CH:33]=[CH:34][C:35]=1[NH2:36])[C:22]([NH:24][C:25]1[CH:30]=[CH:29][C:28]([CH3:31])=[C:27]([CH3:32])[CH:26]=1)=[O:23].C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.[Yb+3].CO>CS(C)=O.C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.[Cu+2]>[CH3:32][C:27]1[CH:26]=[C:25]([NH:24][C:22]([C:21]2[CH:33]=[CH:34][C:35]3[N:36]=[C:4]([C:3]4[C:2]([CH3:1])=[CH:9][C:8]([O:10][CH2:11][C:12]5[NH:16][N:15]=[N:14][N:13]=5)=[CH:7][C:6]=4[CH3:17])[NH:18][C:19]=3[CH:20]=2)=[O:23])[CH:30]=[CH:29][C:28]=1[CH3:31]
Reactant: Cc1ccc(NC(=O)c2ccc(N)c(N)c2)cc1C
Reactant: Cc1cc(OCc2nnn[nH]2)cc(C)c1C=O
Agent: [Cu+2]
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: CO
Solvent: CS(C)=O
Product: Cc1ccc(NC(=O)c2ccc3nc(-c4c(C)cc(OCc5nnn[nH]5)cc4C)[nH]c3c2)cc1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2,6-dimethyl-4-(1H-tetrazol-5-yl-methoxy)-benzaldehyde (50 mg) in DMSO (1 mL) were added 3,4-diamino-N-(3,4-dimethyl-phenyl)-benzamide (55 mg), Yb(OTf)3 (13 mg), and Cu(OTf)2 (8 mg). The reaction mixture was stirred in open air at ambient temperature overnight. The mixture was then diluted by MeOH and the whole was loaded onto a solid phase extraction (SPE) cartridge that contained strong cation exchange (SCX) (1 g media in 6 mL cartridge, United Chemical Technology). Wash-to-waste (5 mL MeOH) was followed by elute-to-collect (5 mL 20:2:1 ethyl acetate-MeOH-Et3N) and, after evaporation of volatiles, the crude was further purified by silica gel column chromatography to give 2-[2,6-dimethyl-4-(1H-tetrazol-5-yl-methoxy)-phenyl]-3H-benzoimidazole-5-carboxylic acid (3,4-dimethyl-phenyl)-amide: MS (m/z) 468.16 (M+1).
Reaction SMILES: [OH:1][CH:2]1[C:6](=[O:7])[C:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])=[CH:4][CH2:3]1.[O:18]1[CH:23]=[CH:22][CH2:21][CH2:20][CH2:19]1.N1C=CC=CC=1>ClCCl.C1(C)C=CC(S(O)(=O)=O)=CC=1>[O:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]1[O:1][CH:2]1[C:6](=[O:7])[C:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])=[CH:4][CH2:3]1
Reactant: C1=COCCC1
Reactant: COC(=O)CCCCCCC1=CCC(O)C1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)CCCCCCC1=CCC(OC2CCCCO2)C1=O
Reaction time: 1 h

Procedure:
A solution of p-toluenesulphonic acid (20 mg) in dry dichloromethane (5 ml) was added, dropwise, to a stirred mixture of methyl (±)-7-[4-hydroxy-5-oxocyclopent-1-enyl]-hepatanoate (1.2 g; prepared as described in Example 3) and 2,3-dihydropyran in dry dichloromethane (20 ml), with cooling to maintain the temperature below 30° C. After one hour, a further quantity of 2,3-dihydropyran (0.3 g) was added dropwise, and the mixture was stirred for one hour further. Pyridine (100 mg) was added, and the mixture was washed with saturated aqueous sodium chloride solution, dried over magnesium sulphate, and evaporated in vacuo, finally at 0.1 mm Hg and 50° C. for 4 hours, to give methyl (±)-7-[4-(2-tetrahydropyranyloxy)-5-oxocyclopent-1-enyl]heptanoate (1.9 g), in the form of a brown oil, pure enough for use in the next stage without further purification.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([F:11])=[C:4]([F:12])[C:3]=1[CH3:13].[F-:14].[K+].CS(C)=O>C1C=CC=CC=1>[F:14][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([F:11])=[C:4]([F:12])[C:3]=1[CH3:13]
Reactant: Cc1c(F)c(F)cc([N+](=O)[O-])c1Cl
Reactant: [F-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: c1ccccc1
Product: Cc1c(F)c(F)cc([N+](=O)[O-])c1F
Reaction time: 3.5 h
Yield: 48.9 %

Procedure:
To 2-chloro-5,6-difluoro-3-nitrotoluene (1.0 g) are added spray-dried potassium fluoride (1.4 g), anhydrous dimethylsulfoxide (10 ml) and benzene (10 ml), and the moisture is removed by azeotropic distillation together with benzene. Subsequently, the mixture is stirred at 170°-180° C. under argon stream for 3.5 hours. After cooling, the reaction mixture is poured into ice water and extracted with diethyl ether. The extract is washed with water, dried and then the solvent is distilled off. The residue is purified by silica gel column chromatography (solvent, n-hexane) to give 2,5,6-trifluoro-3-nitrotoluene (0.45 g).
Reaction SMILES: [CH3:1][C@H:2]([C:15]([OH:17])=[O:16])[C:3]1[CH:8]=[CH:7][C:6]2[CH:9]=[C:10]([O:13][CH3:14])[CH:11]=[CH:12][C:5]=2[CH:4]=1.O[C:19]1[C:27]2N=N[NH:24][C:23]=2[CH:22]=[CH:21][CH:20]=1.C1CCC(N=C=NC2CCCCC2)CC1.OC1C=CC(C2S[S:53][C:52](=S)C=2)=CC=1>CN(C)C=O.C(OCC)(=O)C>[CH3:14][O:13][C:10]1[CH:11]=[CH:12][C:5]2[C:6](=[CH:7][CH:8]=[C:3]([CH:2]([CH3:1])[C:15]([O:17][C:20]3[CH:21]=[CH:22][C:23]([N:24]=[C:52]=[S:53])=[CH:27][CH:19]=3)=[O:16])[CH:4]=2)[CH:9]=1
Reactant: Oc1ccc(-c2cc(=S)ss2)cc1
Reactant: COc1ccc2cc([C@H](C)C(=O)O)ccc2c1
Reactant: Oc1cccc2[nH]nnc12
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc2cc(C(C)C(=O)Oc3ccc(N=C=S)cc3)ccc2c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 21 %

Procedure:
To the solution of 1 (naproxene, 691 mg, 3 mmol) in 20 mL of dimethylformamide, hydroxybenzotriazole (446 mg, 3.3 mmol) and DCC (619 mg, 3.3 mmol) were added with stirring at 0° C. for 1 h. To the reaction mixture 4-hydroxyphenylisothiocyanate (2; 500 mg, 3.3 mmol) was added and stirred for 1 h at 0° C. and 2 h at room temperature. After filtration, the filtrate was evaporated under reduced pressure to remove the solvent. The oily residue thus obtained was dissolved in ethyl acetate and the precipitate was removed. The solvent was evaporated and the crude product was loaded on a silica gel open column and eluted with dichloromethane, from which 4-(isothiocyano)-phenyl 2-(2-methoxynaphthalen-6-yl)propanoate (3) was obtained (230 mg, 21% yield).
Reaction SMILES: [C:1]1([CH3:15])[CH:6]=[CH:5][C:4]([O:7][C:8]2[CH:14]=[CH:13][C:11]([NH2:12])=[CH:10][CH:9]=2)=[CH:3][CH:2]=1.[CH2:16]([O:23][CH2:24][C@H:25]([NH:29]C(OC(C)(C)C)=O)[C:26](O)=[O:27])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[NH2:29][C@@H:25]([CH2:24][O:23][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:26]([NH:12][C:11]1[CH:13]=[CH:14][C:8]([O:7][C:4]2[CH:3]=[CH:2][C:1]([CH3:15])=[CH:6][CH:5]=2)=[CH:9][CH:10]=1)=[O:27]
Reactant: Cc1ccc(Oc2ccc(N)cc2)cc1
Reactant: CC(C)(C)OC(=O)N[C@@H](COCc1ccccc1)C(=O)O
Product: Cc1ccc(Oc2ccc(NC(=O)[C@@H](N)COCc3ccccc3)cc2)cc1
Yield: 92 %

Procedure:
Proceeding as in Reference 5, but substituting 4-(p-tolyloxy)aniline and (S)-3-(benzyloxy)-2-(tert-butoxycarbonylamino)propanoic acid, gave (S)-2-amino-3-(benzyloxy)-N-(4-(p-tolyloxy)phenyl)propanamide (350 mg, 92%).
Reaction SMILES: COC(C1[NH:6][C:7]2[CH:8]=[C:9]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH:10]=[C:11]3[C:17](=[O:18])[NH:16][N:15]=[CH:14][C:13]=1[C:12]=23)=O.[Cl:27]N1C(=O)CCC1=O.O.[CH:36]([Cl:39])(Cl)Cl>CN(C)C=O>[C:23]([O:22][C:20](=[O:21])[NH:19][C:9]1[CH:10]=[C:11]2[C:17](=[O:18])[NH:16][N:15]=[CH:14][C:13]3=[C:36]([Cl:39])[NH:6][C:7]([C:8]=1[Cl:27])=[C:12]23)([CH3:26])([CH3:25])[CH3:24]
Reactant: O=C1CCC(=O)N1Cl
Reactant: COC(=O)c1[nH]c2cc(NC(=O)OC(C)(C)C)cc3c2c1C=NNC3=O
Reactant: ClC(Cl)Cl
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1cc2c3c(c(Cl)[nH]c3c1Cl)C=NNC2=O
Temperature: 60 °C
Reaction time: 3 h

Procedure:
To a solution of Intermediate 147(c) of Example 147 (1.5 g, 5 mmol) in CHCl3 (10 mL) and N,N-dimethylformamide (15 mL), was added N-chlorosuccinimide (701 mg, 5.25 mmol). The mixture was heated to 60° C. and stirred for 3 hours. Chloroform, N,N-dimethylformamide and water were added. Following extractive work-up with chloroform, the organic layer was dried over Na2SO4 and filtered. Evaporation of the volatile components gave a deep brown residue to which methanol was added. Filtration and collection of the solids gave the title compound (648 mg) as deep brown solid whose purity by NMR and HPLC was estimated to be about 70%.
Reaction SMILES: [F:1][C:2]1([F:24])[CH2:5][N:4]([C:6]([C:8]2[C:12]3[CH:13]=[C:14]([CH:19](OC)[O:20]C)[C:15]([F:18])=[C:16]([F:17])[C:11]=3[O:10][N:9]=2)=[O:7])[CH2:3]1.O>C1COCC1.C(OCC)(=O)C>[F:24][C:2]1([F:1])[CH2:3][N:4]([C:6]([C:8]2[C:12]3[CH:13]=[C:14]([CH:19]=[O:20])[C:15]([F:18])=[C:16]([F:17])[C:11]=3[O:10][N:9]=2)=[O:7])[CH2:5]1
Reactant: COC(OC)c1cc2c(C(=O)N3CC(F)(F)C3)noc2c(F)c1F
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: O=Cc1cc2c(C(=O)N3CC(F)(F)C3)noc2c(F)c1F
Temperature: 25 °C
Yield: 92.2 %

Procedure:
(3,3-Difluoroazetidin-1-yl)(5-(dimethoxymethyl)-6,7-difluorobenzo[d]isoxazol-3-yl)methanone (Intermediate 228, 3.336 g, 9.58 mmol) was dissolved in a 4:1 THF:water mixture (62.5 ml) and heated at 75° C. with tosic acid monohydrate (0.911 g, 4.79 mmol) for three hours. The reaction was allowed to cool to room temperature, diluted with ethyl acetate, washed 3× with saturated NaHCO3, dried over MgSO4 and concentrated. The residue was purified by silica gel column chromatography using a gradient of hexanes to ethyl acetate. Fractions were combined and concentrated to give the title compound (2.66 g, 8.83 mmol).
Reaction SMILES: [NH3:1].Cl[C:3]1[NH:4][SH:5](=[O:21])([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:6]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:8]=1.O>C(O)C>[NH2:1][C:3]1[NH:4][SH:5](=[O:21])([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:6]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:8]=1
Reactant: O=[SH]1(c2ccccc2)C=C(c2ccccc2)N=C(Cl)N1
Reactant: N
Solvent: O
Solvent: CCO
Product: NC1=NC(c2ccccc2)=C[SH](=O)(c2ccccc2)N1
Temperature: 100 °C
Yield: 93 %

Procedure:
To 75 ml of saturated a solution of ammonia in ethanol was added 3 g (0.01 mole) of 3-chloro-1,5-diphenyl-1H-1,2,4-thiadiazine-1-oxide and the mixture was heated in an autoclave at 100° C. for 3 hours. The mixture was cooled, poured into water and the product was filtered off, washed with water and dried to obtain 2.6 g (93%) of 3-amino-1,5-diphenyl-1H-1,2,4-thiadiazine-1-oxide melting at 169°-170° C.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:20])=[C:11]([N:14]4[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]4)[CH:12]=3)[C:7](=[O:21])[C:6]([C:22]([OH:24])=[O:23])=[CH:5]2)[CH2:3][CH2:2]1.[CH2:25]([Br:28])[CH:26]=[CH2:27].C(N(CC)CC)C>CN(C)C=O>[BrH:28].[CH2:27]([N:17]1[CH2:18][CH2:19][N:14]([C:11]2[CH:12]=[C:13]3[C:8]([C:7](=[O:21])[C:6]([C:22]([OH:24])=[O:23])=[CH:5][N:4]3[CH:1]3[CH2:2][CH2:3]3)=[CH:9][C:10]=2[F:20])[CH2:15][CH2:16]1)[CH:26]=[CH2:25]
Reactant: C=CCBr
Reactant: O=C(O)c1cn(C2CC2)c2cc(N3CCNCC3)c(F)cc2c1=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Br
Product: C=CCN1CCN(c2cc3c(cc2F)c(=O)c(C(=O)O)cn3C2CC2)CC1
Yield: 48.6 %

Procedure:
3.3 g (10 mmol) of 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic acid are heated at 60° C. in 50 ml of dimethylformamide with 1.8 g (15 mmol) of allyl bromide and 2.1 g of triethylamine for 8 hours. The mixture is concentrated in vacuo, the residue is stirred with 30 ml of water and the precipitate is filtered off with suction, washed with methanol and dried. 2.2 g of 7-(4-allyl-1-piperazinyl)-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid hydrobromide of melting point 295°-298° (with decomposition) are obtained; after recrystallization from water, 1.5 g of melting point 300°-302° (with decomposition) are isolated.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([C:12]2[C:13](=[S:18])[NH:14][CH:15]=[CH:16][CH:17]=2)=[O:11])[CH:5]=[C:6]([CH3:8])[CH:7]=1.[C:19]([NH:22][C:23]1[CH:28]=[C:27]([CH2:29]OS(C)(=O)=O)[CH:26]=[CH:25][N:24]=1)(=[O:21])[CH3:20].C(N(CC)CC)C.C(OCC)(=O)C>CN(C)C=O>[C:19]([NH:22][C:23]1[CH:28]=[C:27]([CH2:29][S:18][C:13]2[C:12]([C:10]([NH:9][C:4]3[CH:5]=[C:6]([CH3:8])[CH:7]=[C:2]([CH3:1])[CH:3]=3)=[O:11])=[CH:17][CH:16]=[CH:15][N:14]=2)[CH:26]=[CH:25][N:24]=1)(=[O:21])[CH3:20]
Reactant: Cc1cc(C)cc(NC(=O)c2ccc[nH]c2=S)c1
Reactant: CC(=O)Nc1cc(COS(C)(=O)=O)ccn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(=O)Nc1cc(CSc2ncccc2C(=O)Nc2cc(C)cc(C)c2)ccn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 81 %

Procedure:
Or the compound is also synthesized in the following method. N-(3,5-Dimethylphenyl)-2-thioxo-1,2-dihydropyridine-3-carboxamide (Reference compound No. 10-1, 200 mg, 0.77 mmol) and 2-acetylamino-4-methanesulfonyloxymethylpyridine (Reference compound No. 13-1, 190 mg, 0.77 mmol) were suspended in N,N-dimethylformamide (2.0 mL) under ice-cooling and under nitrogen atmosphere, then triethylamine (0.22 mL, 1.5 mmol) was added thereto, and then the mixture was stirred for 2 hours at room temperature. Ethyl acetate (40 mL) was added to the reaction mixture, and then the whole was washed with water (30 mL) and brine (20 mL). The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The resulting solid was filtered off with the solvent mixture consisting of diisopropyl ether and ethyl acetate and dried under reduced pressure at 40° C. to give 250 mg of the target compound as a pale yellow solid. (Yield 81%)
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH2:6][CH2:5][O:4][C:3]1([OH:13])[CH2:7][N:8]1[CH:12]=[N:11][CH:10]=[N:9]1.[OH-].[K+].[Cl:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Cl)=[CH:20][CH:19]=1>CS(C)=O.O>[Cl:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][CH:7]([C:3]2([OH:13])[C:2]([CH3:14])([CH3:1])[CH2:6][CH2:5][O:4]2)[N:8]2[CH:12]=[N:11][CH:10]=[N:9]2)=[CH:20][CH:19]=1
Reactant: ClCc1ccc(Cl)cc1
Reactant: CC1(C)CCOC1(O)Cn1cncn1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CC1(C)CCOC1(O)C(Cc1ccc(Cl)cc1)n1cncn1
Yield: 39.4 %

Procedure:
10.3 g (0.052 mole) of 3,3-dimethyl-2-hydroxy-2-(1,2,4-triazol-1-yl-methyl)-tetrahydrofuran, 2.9 g (0.052 mole) of potassium hydroxide and 8.4 g (0.052 mole) of 4-chlorobenzyl chloride are stirred in a mixture of 100 ml of dimethylsulphoxide and 6 ml of water at 30° C. for 2 hours. The reaction solution is then poured onto water and extracted with ethyl acetate. The organic phase is dried over sodium sulphate and concentrated. After trituration in n-hexane, the residue crystallizes. 6.6 g (39.5% of theory) of 1-(4-chlorophenyl)-2-(3,3-dimethyl-2-hydroxy-tetrahydrofuran-2-yl)-2-(1,2,4-triazol-1-yl)ethane of melting point 98° C. are obtained. ##STR100##
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1.CN1CCOCC1.[NH2:21][C:22]1[CH:23]=[CH:24][C:25]([Cl:31])=[C:26]([CH:30]=1)[C:27]([OH:29])=[O:28].C([O-])(O)=O.[Na+]>C(Cl)Cl>[F:12][C:2]([F:1])([F:13])[C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:21][C:22]2[CH:23]=[CH:24][C:25]([Cl:31])=[C:26]([CH:30]=2)[C:27]([OH:29])=[O:28])=[O:9])=[CH:10][CH:11]=1
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1
Reactant: Nc1ccc(Cl)c(C(=O)O)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: O=C(Nc1ccc(Cl)c(C(=O)O)c1)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.8 %

Procedure:
To a suspension of 4-(trifluoromethyl)benzoic acid (1.0 g, 5.3 mmol) in DCM (20 mL) were added CDMT (1.1 g, 6.3 mmol) and NMM (2.3 mL, 21 mmol). The mixture was stirred at RT for 30 min under an argon atmosphere. 5-amino-2-chlorobenzoic acid (1.4 g, 7.9 mmol) was added and the mixture stirred at RT for additional 2 h. The reaction mixture was poured into saturated NaHCO3 solution and then extracted with DCM. The organic layer was dried (Na2SO4), filtered and the filtrate concentrated to afford the title compound (1.6 g, 88%) as a cream solid.
Reaction SMILES: [C:1]([C:5]([NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[CH:11]=[CH:10][N:9]=1)=[O:6])([CH3:4])([CH3:3])[CH3:2].C([Li])(C)(C)C.[CH3:20][S:21]SC>C(OCC)C.O>[C:1]([C:5]([NH:7][C:8]1[CH:13]=[C:12]([CH2:14][S:21][CH3:20])[CH:11]=[CH:10][N:9]=1)=[O:6])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccnc(NC(=O)C(C)(C)C)c1
Reactant: CSSC
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Solvent: O
Product: CSCc1ccnc(NC(=O)C(C)(C)C)c1
Temperature: -78 °C
Reaction time: 3 h

Procedure:
A solution of 2-tert-butylcarbonylamino-4-picoline (Step A, 250 mg) in anhydrous ethyl ether (5 mL) was cooled to -78° C. and treated with tert-butyllithium (1.7 mL, 1.7 M), and stirred at -78° C. for 3 hrs. To this was added dimethyl disulfide (0. 177 mL) and the reaction was allowed to warm to room temperature. The mixture was diluted with water and ethyl ether. The aqueous layer was extracted with ether. The combined organic layers were washed with saturated sodium chloride, dried over sodium sulfate, and concentrated in vacuo. The resulting oil was purified by medium pressure liquid chromatography on a 21×300 mm silica column eluted with 40% ethyl acetate/methylene chloride to afford the title compound (260 mg, lower Rf spot) and 2-tert-butylcarbonylamino-4-methylthiomethylpyridine (40 mg, higher Rf spot).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[CH:9][NH:8][N:7]=1)=[O:5])[CH3:2].[I:11]I>C(#N)C>[CH2:1]([O:3][C:4]([C:6]1[C:10]([I:11])=[CH:9][NH:8][N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc[nH]n1
Reactant: II
Solvent: CC#N
Product: CCOC(=O)c1n[nH]cc1I
Temperature: 0 °C
Reaction time: 24 h
Yield: 39 %

Procedure:
A suspension of Intermediate 74a (5.00 g, 35.7 mmol) in acetonitrile (90 mL) was treated with iodine (9.10 g, 35.7 mmol) then ceric ammonium nitrate (19.6 g, 35.7 mmol) and the mixture was stirred at RT overnight. Another portion of iodine (2.28 g, 9.0 mmol) was added and the mixture was stirred for a further 24 h then treated with ice-cold aqueous sodium hydrogensulphite solution (5%, 100 mL). The mixture was filtered through Celite rinsing with EtOAc and water. The phases were separated and the aqueous phase was extracted with EtOAc (2×). The combined organic layers were washed with water and brine, dried (Na2SO4), filtered and evaporated in vacuo. The resulting solid was triturated with ether/cyclohexane, filtered off, washed with cyclohexane and dried at 50° C. in vacuo to give the title compound (3.70 g, 39%). LCMS (Method 3): Rt 2.88 min, m/z 267 [MH+] (weak).
Reaction SMILES: [F:1][C:2]1[C:3](=O)[NH:4][C:5](=O)[NH:6][CH:7]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:11].P(Cl)(Cl)(Cl)=O.[Cl-:21].[Na+]>>[Cl:21][C:5]1[N:4]=[C:3]([Cl:11])[C:2]([F:1])=[CH:7][N:6]=1
Reactant: [Cl-]
Reactant: O=c1[nH]cc(F)c(=O)[nH]1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Product: Fc1cnc(Cl)nc1Cl
Temperature: 25 °C
Yield: 84 %

Procedure:
To a stirred mixture of 5-fluoropyrimidine-2,4(1H,3H)-dione (3.0 g, 23 mmol) and phosphorous pentachloride (14.41 g, 69 mmol) was added phosphorous oxychloride (12.6 mL, 130 mmol). The reaction mixture was stirred and heated to reflux for 5 hours and then cooled to ambient temperature and stirred overnight. The mixture was carefully poured onto ice/water (600 mL) and then stirred for 1 hour. Sodium chloride was added and the product was extracted into dichloromethane. The combined organic layer was dried (MgSO4), filtered and evaporated to give the title compound (84%) as a yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Cl[C:18]1[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][N:19]=1>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:18]2[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][N:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: N#Cc1ccc(Cl)nc1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(C#N)cn2)CC1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 94.9 %

Procedure:
Add dropwise a solution of 4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (1210 mg, 6.01 mmol) in DMF (1.8 mL) to a suspension of NaH (360 mg, 9.02 mmol) in DMF (7.2 mL). Stir at room temperature for 45 min then at 50° C. for additional 40 min. Add a solution of 6-chloro-nicotinonitrile (1000 mg, 7.22 mmol) in DMF (3.6 mL) dropwise and stir overnight at 60° C. Cool down the reaction mixture and evaporate the solvent. Wash the residue with water (10) and extract with EtOAc/hex (2/1, 15 mL). Combine the organic layers and dry over sodium sulfate. Filter and concentrate. Purify the resulting residue through an SCX column. Further purified by chromatography [CH2Cl2/NH3 (2.0M in methanol) 20/1] to provide the title compound (1.73 g, 94%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:16][CH:17]([O:20][CH3:21])[O:18][CH3:19]>CC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:16][CH:17]([O:20][CH3:21])[O:18][CH3:19])=[CH:4][CH:3]=1
Reactant: COC(CBr)OC
Reactant: Sc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(CSc1ccc(Cl)cc1)OC
Reaction time: 24 h
Yield: 98 %

Procedure:
To a solution of 4-chlorobenzenethiol (5.78 g; 40 mmol) in anhydrous acetone (50 mL) was added potassium carbonate (5.52 g, 40 mmol) and dropwise at room temperature 2-bromo-1,1-dimethoxy-ethane (4.7 mL, 40 mmol). After 24 h of stirring, the precipitate was filtered, the filtrate concentrated, the residue diluted with water and diethyl ether (150 mL), the organic layer washed successively with water (60 mL), NaOH 4N (30 mL) and water (60 mL), dried over Na2SO4 and concentrated to give 1-chloro-4-(2,2-dimethoxy-ethylsulfanyl)-benzene (compound PRE9) (9.12 g; orange oil) (Yield=98%).