Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([O:5][C:6]1[CH:7]=[C:8]([CH:28]=[CH:29][CH:30]=1)[CH2:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=2)[C:13]([CH2:24][C:25]([OH:27])=[O:26])=[CH:12][N:11]=1)([CH2:3][CH3:4])[CH3:2].[N+](=[CH2:33])=[N-]>ClCCl.C(OCC)C>[CH3:33][O:26][C:25](=[O:27])[CH2:24][C:13]1[C:14]2[C:19](=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH3:23])[CH:15]=2)[C:10]([CH2:9][C:8]2[CH:28]=[CH:29][CH:30]=[C:6]([O:5][CH:1]([CH2:3][CH3:4])[CH3:2])[CH:7]=2)=[N:11][CH:12]=1
Reactant: CCC(C)Oc1cccc(Cc2ncc(CC(=O)O)c3cc(OC)c(OC)cc23)c1
Reactant: C=[N+]=[N-]
Solvent: ClCCl
Solvent: CCOCC
Product: CCC(C)Oc1cccc(Cc2ncc(CC(=O)OC)c3cc(OC)c(OC)cc23)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 96 %

Procedure:
To a stirred solution of [1-(3-sec-butoxy-benzyl)-6,7-dimethoxy-isoquinolin-4-yl]-acetic acid (200 mg, 0.49 mmol) in dichloromethane (4 Ml) was added 0.2N diazomethane in diethyl ether solution (6 mL). The reaction mixture was stirred at room temperature for 15 hrs. The solvent was evaporated to afford of [1-(3-sec-butoxy-benzyl)-6,7-dimethoxy-isoquinolin-4-yl]-acetic acid methyl ester (200 mg, 96% yield) as a light yellow oil. The crude product was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8](=[N:12][O:13][CH3:14])[C:9]([OH:11])=O)[N:3]=1.P(Cl)(Cl)(Cl)=O.[NH2:20][CH:21]1[C:41](=[O:42])[N:23]2[C:24]([C:28]([O:30][CH2:31][C:32]3[CH:37]=[CH:36][C:35]([N+:38]([O-:40])=[O:39])=[CH:34][CH:33]=3)=[O:29])=[CH:25][CH2:26][S:27][C@H:22]12.C[Si](CC(N)=O)(C)C>C(Cl)Cl.CN(C)C=O>[NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8](=[N:12][O:13][CH3:14])[C:9]([NH:20][CH:21]2[C:41](=[O:42])[N:23]3[C:24]([C:28]([O:30][CH2:31][C:32]4[CH:33]=[CH:34][C:35]([N+:38]([O-:40])=[O:39])=[CH:36][CH:37]=4)=[O:29])=[CH:25][CH2:26][S:27][C@H:22]23)=[O:11])[N:3]=1
Reactant: NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=CCS[C@H]12
Reactant: CON=C(C(=O)O)c1nccc(N)n1
Agent: C[Si](C)(C)CC(N)=O
Solvent: ClCCl
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=CCS[C@H]12)c1nccc(N)n1
Temperature: 3 °C
Reaction time: 0.5 h
Yield: 63.3 %

Procedure:
A mixture of 2-(4-aminopyrimidin-2-yl)-2-methoxyiminoacetic acid (syn isomer) (2.32 g) and phosphoryl chloride (4.6 g) in methylene chloride (15 ml) was stirred for 30 minutes at 3° C. To the mixture was added dropwise a solution of N,N-dimethylformamide (3.0 ml) in methylene chloride (15 ml) and stirred for 40 minutes at 3° C. A solution of 4-nitrobenzyl 7-amino-3-cephem-4-carboxylate (3.20 g) and trimethylsilyl acetamide (15 g) in methylene chloride (60 ml) was cooled to -5° C. and added to the activated acid solution obtained above. The mixture was stirred for 30 minutes at 3° to 5° C. and for additional 30 minutes at ambient temperature. The solvent was evaporated to dryness and the residue was dissolved in ethyl acetate (200 ml). The solution was washed with an aqueous solution of sodium bicarbonate and water, dried over anhydrous magnesium sulfate and evaporated to dryness. The residue was washed with diethyl ether to give 4-nitrobenzyl 7-[2-(4-aminopyrimidin-2-yl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylate (syn isomer) (3.1 g) as a powder, mp 125°-131° C. (dec.).
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][CH:5]=1.[NH2:11][C:12]1[CH:22]=[CH:21][C:15]([C:16]([O:18]CC)=[O:17])=[CH:14][CH:13]=1.[I-].[K+].CN(C)P(N(C)C)(N(C)C)=O>O>[F:10][C:7]1[CH:8]=[CH:9][C:4]([CH2:3][CH2:2][NH:11][C:12]2[CH:22]=[CH:21][C:15]([C:16]([OH:18])=[O:17])=[CH:14][CH:13]=2)=[CH:5][CH:6]=1
Reactant: Fc1ccc(CCCl)cc1
Reactant: CCOC(=O)c1ccc(N)cc1
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: O=C(O)c1ccc(NCCc2ccc(F)cc2)cc1

Procedure:
A mixture of 15.8 g. of 1-(2-chloroethyl)-4-fluorobenzene, 33 g. of ethyl p-aminobenzoate, 16.6 g. of potassium iodide and 100 ml. of hexamethylphosphoramide is heated at 95° C. for 15 hours. The mixture is poured into water and extracted with ether. The ether extracts are washed with water, dried over magnesium sulfate and concentrated in vacuo to an oil. To the oil is added 200 ml. of ethanol-water (9:1) and 21 g. of potassium hydroxide and the mixture is refluxed for 3.5 hours. The mixture is acidified with concentrated hydrochloric acid, diluted with water, cooled and filtered to give gray crystals. Recrystallization from ethanol gives light gray crystals, m.p. 161°-163° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[C:10]([C:24]2[C:25]([CH3:34])=[N:26][N:27]3[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][C:28]=23)[S:11][C:12]=1[C:13]1[N:17]=[CH:16][N:15]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)[N:14]=1.Cl.Cl[CH2:37][CH2:38][N:39]1[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>CCOC(C)=O.O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[C:10]([C:24]2[C:25]([CH3:34])=[N:26][N:27]3[CH:32]=[CH:31][C:30]([O:33][CH2:37][CH2:38][N:39]4[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]4)=[CH:29][C:28]=23)[S:11][C:12]=1[C:13]1[N:17]=[CH:16][N:15]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)[N:14]=1
Reactant: Cc1nn2ccc(O)cc2c1-c1nc(-c2ccccc2F)c(-c2ncn(C3CCCCO3)n2)s1
Reactant: ClCCN1CCCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1nn2ccc(OCCN3CCCCC3)cc2c1-c1nc(-c2ccccc2F)c(-c2ncn(C3CCCCO3)n2)s1
Temperature: 50 °C
Reaction time: 1 h
Yield: 95.3 %

Procedure:
A mixture of 3-{4-(2-fluorophenyl)-5-[1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl]-1,3-thiazol-2-yl}-2-methylpyrazolo[1,5-a]pyridin-5-ol (100 mg, 0.20 mmol) obtained in Example 74-B(vi), 1-(2-chloroethyl)piperidine hydrochloride (112 mg, 0.61 mmol), potassium carbonate (260 mg, 1.9 mmol) and DMF (10 mL) was stirred at 50° C. for 1 h. The mixture was allowed to cool to rt. To the reaction mixture were added water (100 mL) and EtOAc (100 mL), and the mixture was stirred for 30 min. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. Insoluble materials were removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (MeOH/EtOAc=0/100→45/95) to give the title compound (112 mg, 95%) as a yellow solid.
Reaction SMILES: C(OC([NH:8][C:9]1([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[N:20]=[C:21]4[CH:26]=[CH:25][C:24]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[N:23][N:22]4[C:32]=3[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[CH:15][CH:14]=2)[CH2:12][CH2:11][CH2:10]1)=O)(C)(C)C.CO.Cl.[OH-].[Na+]>C(Cl)Cl.O1CCOCC1>[NH2:8][C:9]1([C:13]2[CH:14]=[CH:15][C:16]([C:19]3[N:20]=[C:21]4[CH:26]=[CH:25][C:24]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[N:23][N:22]4[C:32]=3[C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)=[CH:17][CH:18]=2)[CH2:10][CH2:11][CH2:12]1
Reactant: CCOC(=O)c1ccc2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)n2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Solvent: C1COCCO1
Product: CCOC(=O)c1ccc2nc(-c3ccc(C4(N)CCC4)cc3)c(-c3ccccc3)n2n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of ethyl 2-(4-{1-[(tert-butoxycarbonyl)amino]cyclobutyl}phenyl)-3-phenylimidazo[1,2-b]pyridazine-6-carboxylate that was prepared in a manner analgous to that described for Intermediate Example Int-4 (0.96 g, 1.87 mmol) in DCM (12.0 mL) and methanol (7.6 mL) was added a solution of 4 M hydrochloric acid in dioxane (9.4 mL) and the mixture was stirred for 2 hours at rt. The mixture was poured onto ice, made alkaline with aqueous sodium hydroxide (2 N) and extracted with DCM. The combined organic phases were washed with brine, dried and concentrated in vacuo. The reaction was repeated using 2.5 g of the carbamate and the crude product from both reactions were combined. Purification was achieved by chromatography on silica (gradient elution: 95:5 DCM:ethanol to 8:2 DCM:ethanol) to give two fractions of the title compound (0.8 g, 88% purity & 1.6 g, 93% purity).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3](=O)[CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]([Cl:15])[CH:8]=1)=O.Cl.[NH:20]([C:22]1[CH:27]=[CH:26][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:24][N:23]=1)[NH2:21]>C(O)C>[CH2:22]([NH:23][CH2:24][CH3:25])[CH3:27].[Cl:15][C:9]1[CH:8]=[C:7]([C:5]2[N:20]([C:22]3[CH:27]=[CH:26][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:24][N:23]=3)[N:21]=[C:3]([C:2]([F:18])([F:17])[F:1])[CH:4]=2)[CH:12]=[CH:11][C:10]=1[O:13][CH3:14]
Reactant: CS(=O)(=O)c1ccc(NN)nc1
Reactant: COc1ccc(C(=O)CC(=O)C(F)(F)F)cc1Cl
Agent: Cl
Solvent: CCO
Product: CCNCC
Product: COc1ccc(-c2cc(C(F)(F)F)nn2-c2ccc(S(C)(=O)=O)cn2)cc1Cl
Temperature: 25 °C
Yield: 59.2 %

Procedure:
4,4,4-Trifluoro-1-(3-chloro-4-methoxylphenyl)-1,3-butanedione (1.2 g, 4.29 mmol) and 2-hydrazino-5-(methylsulfonyl)pyridine hydrochloride (1.00 g, 4.46 mmol) were mixed in ethanol (60 ml), and the resulting reaction mixture was heated at reflux temperature overnight. The reaction mixture was then cooled to room temperature, and the solvent was removed in vacuo. The residue was dissolved in EtOAc (250 ml), and the organic layer was washed with saturated NaHCO3 solution, brine, dried (MgSO4), and concentrated in vacuo. The residue was purified by flash chromatography first using 7:3:1 of hexane:diethylamine:methanol and then 20% hexane in methylene chloride to give the title compound (570 mg, 31%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:17](=[O:18])[C:16]2[C@@H:15]3[C:19]([CH3:21])([CH3:20])[C@@:12]([CH3:22])([CH2:13][CH2:14]3)[C:11]=2[NH:10]1.[F:23][C:24]([F:34])([F:33])[C:25]1[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=1[CH2:27]Br.ClCCl>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:17](=[O:18])[C:16]2[C@@H:15]3[C:19]([CH3:21])([CH3:20])[C@@:12]([CH3:22])([CH2:13][CH2:14]3)[C:11]=2[N:10]1[CH2:27][C:26]1[CH:29]=[CH:30][CH:31]=[CH:32][C:25]=1[C:24]([F:23])([F:33])[F:34]
Reactant: CC1(C)[C@@H]2CC[C@@]1(C)c1[nH]n(-c3ccc(F)cc3F)c(=O)c12
Reactant: FC(F)(F)c1ccccc1CBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC1(C)[C@@H]2CC[C@@]1(C)c1c2c(=O)n(-c2ccc(F)cc2F)n1Cc1ccccc1C(F)(F)F
Temperature: 100 °C
Yield: 34.1 %

Procedure:
A mixture of (4S,7R)-2-(2,4-difluoro-phenyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 14; 100 mg, 0.33 mmol), tetrabutylammonium iodide (120 mg, 0.32 mmol) and 2-(trifluoromethyl)benzyl bromide (200 μL, 1.3 mmol) in dimethylformamide (2 mL) was heated at 100° C. overnight. Dichloromethane (50 mL) was added and the solution was washed with 1:1 water/brine (20 mL), aqueous sodium thiosulfate, water, and brine. The solution was dried (magnesium sulfate), filtered, evaporated, and purified by column chromatography, eluting with 50-70% ethyl acetate/petroleum ether, to give (4S,7R)-2-(2,4-difluoro-phenyl)-7,8,8-trimethyl-1-(2-trifluoromethyl-benzyl)-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (52 mg, 34%) as a white solid. APCI(+)-MS (M+H) 463.
Reaction SMILES: Cl[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([Cl:11])[S:10][C:5]=2[S:4](=[O:13])(=[O:12])[N:3]=1.[NH2:14][C@H:15]([CH2:17][OH:18])[CH3:16]>O>[Cl:11][C:9]1[S:10][C:5]2[S:4](=[O:13])(=[O:12])[N:3]=[C:2]([NH:14][C@@H:15]([CH3:16])[CH2:17][OH:18])[NH:7][C:6]=2[CH:8]=1
Reactant: O=S1(=O)N=C(Cl)Nc2cc(Cl)sc21
Reactant: C[C@H](N)CO
Solvent: O
Product: C[C@@H](CO)NC1=NS(=O)(=O)c2sc(Cl)cc2N1

Procedure:
The title compound was prepared from 3,6dichloro-4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxide and L-alaninol by a procedure analogous to the procedure described in example 1Bb; mp 204°-206° C. (water), 1H-NMR (DMSO-d6): δ 1.11 (d, 3H), 3.4 (d, 2H), 3.78 (m, 1H), 4.95 (br. s, 1H), 7.05 (br. s, 1H), 7.09 (s, 1H), 10.8 (br. s, 1H).
Reaction SMILES: C(OC([CH2:8][NH:9][C:10]1[CH:11]=[C:12]([C:16]2[N:21]=[CH:20][C:19]([CH:22]=[CH:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:18][CH:17]=2)[CH:13]=[CH:14][CH:15]=1)=O)(C)(C)C.FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+]>CO.ClCCl.[Pd]>[CH3:8][NH:9][C:10]1[CH:11]=[C:12]([C:16]2[N:21]=[CH:20][C:19]([CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:18][CH:17]=2)[CH:13]=[CH:14][CH:15]=1
Reactant: CCOC(=O)C=Cc1ccc(-c2cccc(NCC(=O)OC(C)(C)C)c2)nc1
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)CCc1ccc(-c2cccc(NC)c2)nc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 112 %

Procedure:
A solution of 852 mg (2.23 mmol) of ethyl 3-{6-[3-(tert-butoxycarbonylmethylamino)phenyl}pyrid-3-yl}acrylate in 10 mL of methanol is stirred for 4 hours at room temperature in the presence of 100 mg of 10% palladium-on-charcoal under a hydrogen atmosphere. The catalyst is filtered off and the solvents are then evaporated off. The oil obtained is dissolved in 15 mL of dichloromethane. 2 mL of trifluoroacetic acid are added and the reaction mixture is stirred for 4 hours at room temperature. The reaction is stopped by adding 100 mL of saturated sodium hydrogen carbonate solution and is then extracted with ethyl acetate. The organic phases are combined and dried over sodium sulfate. The solvents are evaporated off and the residue is then chromatographed on silica gel (70/30 heptane/ethyl acetate). 710 mg of ethyl 3-[6-(3-methylaminophenyl)pyrid-3-yl]propanoate are obtained. Yield=68%.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][C@H:8]([CH2:14][C:15]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=1[F:22])[C@@H:9]([OH:13])[CH2:10][NH:11][CH3:12])([CH3:4])([CH3:3])[CH3:2].[C:24](Cl)(=[O:26])[CH3:25]>>[C:1]([O:5][C:6](=[O:23])[NH:7][C@H:8]([CH2:14][C:15]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=1[F:22])[C@@H:9]([OH:13])[CH2:10][N:11]([C:24](=[O:26])[CH3:25])[CH3:12])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)Cl
Reactant: CNC[C@H](O)[C@@H](Cc1cc(F)ccc1F)NC(=O)OC(C)(C)C
Product: CC(=O)N(C)C[C@H](O)[C@@H](Cc1cc(F)ccc1F)NC(=O)OC(C)(C)C

Procedure:
Using general procedure 5 with [(1R,2S)-1-(2,5-difluoro-benzyl)-2-hydroxy-3-methylamino-propyl]-carbamic acid tert-butyl ester (0.107 g, 0.32 mmol) and acetyl chloride (0.020 mL, 0.32 mmol) gives the title compound.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl[C:8]1[CH:13]=[C:12]([Cl:14])[N:11]=[C:10]([CH3:15])[N:9]=1.[OH:16][C:17]1[CH:26]=[C:25]([CH3:27])[C:20]2[NH:21][C:22](=[O:24])[O:23][C:19]=2[CH:18]=1.O>CN(C=O)C>[Cl:14][C:12]1[N:11]=[C:10]([CH3:15])[N:9]=[C:8]([O:16][C:17]2[CH:26]=[C:25]([CH3:27])[C:20]3[NH:21][C:22](=[O:24])[O:23][C:19]=3[CH:18]=2)[CH:13]=1
Reactant: Cc1nc(Cl)cc(Cl)n1
Reactant: Cc1cc(O)cc2oc(=O)[nH]c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nc(Cl)cc(Oc2cc(C)c3[nH]c(=O)oc3c2)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
100 mg (0.724 mmol) potassium carbonate and 110 mg (0.655 mmol) 4,6-dichloro-2-methyl-pyrimidine were added to 100 mg (0.575 mmol) 6-hydroxy-4-methyl-3H-benzoxazol-2-one in 1.5 mL DMF and the mixture was stirred for 2 h at RT. Then 15 mL water were added and the mixture was stirred overnight at RT. The precipitate formed was suction filtered, washed with water and dried i. vac.
Reaction SMILES: [IH:1].Cl[C:3]1[N:8]=[C:7]([CH3:9])[CH:6]=[C:5]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)[N:4]=1>C(Cl)Cl>[I:1][C:3]1[N:8]=[C:7]([CH3:9])[CH:6]=[C:5]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)[N:4]=1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(Cl)n1
Reactant: I
Solvent: ClCCl
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(I)n1
Reaction time: 18 h
Yield: 85.8 %

Procedure:
Hydroiodic acid (57% in water, 9.68 mL, 73.41 mmol) was added portionwise to 2-chloro-4-methyl-6-[4-(trifluoromethyl)phenyl]pyrimidine (which may be prepared as described in Description 11) (1.38 g, 5.06 mmol) in DCM (30 mL) at 20° C. and the dark mixture was stirred for 18 hrs. The mixture was quenched by the addition of sat. aq. K2CO3 (care: gas evolved). After basification, satd. aq. sodium metabisulphite was added and stirring was continued for 5 mins. The mixture was diluted with further DCM and the phases were separated. The organic layer was dried (Na2SO4) and the solvent evaporated to afford 2-iodo-4-methyl-6-[4-(trifluoromethyl)phenyl]pyrimidine (D12) (1.58 g, 4.34 mmol, 85.7% yield) a yellow solid, containing about 20% of the reduced H-compound.
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4](/[C:7](=[N:11]/[O:12][CH3:13])/[C:8](O)=[O:9])[N:3]=1.P(Cl)(Cl)([Cl:16])=O.CN(C)C=O>C(#N)C>[NH2:1][C:2]1[S:6][N:5]=[C:4](/[C:7](=[N:11]/[O:12][CH3:13])/[C:8]([Cl:16])=[O:9])[N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CO/N=C(\C(=O)O)c1nsc(N)n1
Solvent: CC#N
Solvent: CN(C)C=O
Product: CO/N=C(\C(=O)Cl)c1nsc(N)n1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
In 80.0 ml of acetonitrile, 10.0 g of 2-(5-amino-1,2,4-thiadiazol-3-yl)-2(Z)-methoxyiminoacetic acid were stirred at -20° C., followed by the dropwise addition of a chlorinating reagent, which had been prepared beforehand by gradually adding 8.4 g of phosphorus oxychloride at 5° C. to a mixture of 25 ml of acetonitrile and 4.0 g of N,N-dimethylformamide (DMF) and then reacting them for 30 minutes. After they were reacted for 5 minutes, 200 ml of ice water were poured into the reaction mixture to precipitate crystals. The crystals were collected by filtration, washed with 100 ml of ice water and then stirred for 30 minutes in 100 ml of n-hexane. After filtration, the resulting crystals were dried under reduced pressure, whereby the title compound was obtained. Yield: 8.90 g (81.6%). Purity: 97.9%.
Reaction SMILES: [CH2:1]([SH:3])[CH3:2].C[O-].[Na+].[Cl:7][C:8]1[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=1[CH:15]=[C:16]([N:24]1[CH:28]=[N:27][CH:26]=[N:25]1)[C:17](=[O:23])[C:18]([CH3:22])([CH3:21])[CH2:19][F:20]>C(OCC)C>[Cl:7][C:8]1[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=1[CH:15]([S:3][CH2:1][CH3:2])[CH:16]([N:24]1[CH:28]=[N:27][CH:26]=[N:25]1)[C:17](=[O:23])[C:18]([CH3:22])([CH3:21])[CH2:19][F:20]
Reactant: CCS
Reactant: CC(C)(CF)C(=O)C(=Cc1ccc(Cl)cc1Cl)n1cncn1
Agent: C[O-]
Agent: [Na+]
Solvent: CCOCC
Product: CCSC(c1ccc(Cl)cc1Cl)C(C(=O)C(C)(C)CF)n1cncn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 54.5 %

Procedure:
4.4 ml (0.059 mol) of ethylmercaptan were added to a suspension of 3.19 g (0.059 mol) of sodium methylate in 200 ml of diethyl ether. After 2 hours, 20.2 g (0.059 mol) of 1-(2,4-dichlorophenyl)-4,4-dimethyl-5-fluoro-2-(1,2,4-triazol-1-yl)-pent-1-en-3-one (E isomer) were introduced. The mixture was stirred for 18 hours at 25° C. and was then evaporated down in vacuo. The residue was introduced into water and the mixture was extracted with methylene chloride. The methylene chloride solution was dried over sodium sulphate, filtered and evaporated down in vacuo. The oil which remained was caused to crystallize by stirring with diisopropyl ether. 13 g (54.6% of theory) of 1-(2,4-dichlorophenyl)-4,4-dimethyl-1-ethylthio-5-fluoro-2-(1,2,4-triazol-1-yl)-pentan-3-one, of melting point 130° C., were obtained.
Reaction SMILES: [C:1]([NH2:5])(=[O:4])[CH:2]=[CH2:3].C1(C)C=CC(S(O)(=O)=O)=CC=1.[Cl:17][C:18]1[CH:19]=[C:20]2[C:25](=[C:26]([Cl:28])[CH:27]=1)[CH2:24][CH:23](N1CCCC1)[CH2:22][CH2:21]2>C(Cl)(Cl)Cl.C(OCC)(=O)C>[Cl:17][C:18]1[CH:27]=[C:26]([Cl:28])[C:25]2[C:24]3[CH2:3][CH2:2][C:1](=[O:4])[NH:5][C:23]=3[CH2:22][CH2:21][C:20]=2[CH:19]=1
Reactant: C=CC(N)=O
Reactant: Clc1cc(Cl)c2c(c1)CCC(N1CCCC1)C2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: O=C1CCC2=C(CCc3cc(Cl)cc(Cl)c32)N1

Procedure:
16.2 g of acrylamide and 0.9 g of anhydrous p-toluenesulphonic acid were added to 30.6 g of 1-(6,8-dichloro-3,4-dihydro-2(1H)-naphthyl)pyrrolidine. The mixture was heated under nitrogen to 100° for 2 hours and to 150° for 2 hours. After cooling, the reaction mixture was stirred at room temperature in 80 ml of a mixture of chloroform-ethyl acetate (1:1). There was obtained 8,10-dichloro-1,4,5,6-tetrahydrobenzo[f]quinolin-3(2H)-one which melts at 212°-214° after recrystallization from ethyl acetate.
Reaction SMILES: [C:1]1([C:7]2[O:11][CH:10]=[N:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:12]1CCC[CH2:13]1.C(OCC)C.C([Li])CCC.CN(C1C=CC=CN=1)C=O>O1CCCC1>[C:1]1([C:7]2[O:11][C:10]([CH:13]=[O:12])=[N:9][CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C1CCOC1
Reactant: c1ccc(-c2cnco2)cc1
Agent: CN(C=O)c1ccccn1
Agent: [Li]CCCC
Solvent: CCOCC
Product: O=Cc1ncc(-c2ccccc2)o1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A solution of 5-phenyloxazole (0.192 g) in 2:1 tetrahydrofuran/diethyl ether (7 mL) was cooled to −78° C., and treated with n-butyl lithium (0.582 mL) dropwise under Argon. The mixture was stirred for 30 minutes at −78° C., at this time a solution of N-methyl-N-(pyridin-2-yl) formamide (0.270 g) in tetrahydrofuran (2.6 mL) was added dropwise to the solution. After stirring at −78° C. for 30 minutes, the mixture was allowed to warm up to room temperature and stirring continued overnight. The mixture was quenched by the addition of water and extracted with ethyl acetate. The combined extracts were washed with 10% hydrochloric acid, saturated aqueous solution of sodium bicarbonate and brine, dried and concentrated in vacuo and purified by column chromatography on silica gel (10-50% ethyl acetate in hexane) to provide the title compound (0.016 g) with the following physical data.
Reaction SMILES: [C@@H:1]1([N:8]2[CH:15]=[CH:14][C:12]([NH2:13])=[N:11][C:9]2=[O:10])[O:7][C@H:4]([CH2:5][OH:6])[CH2:3][CH2:2]1.[I:16]I>CO.ClCCl>[I:16][C:14]1[C:12]([NH2:13])=[N:11][C:9](=[O:10])[N:8]([CH:15]=1)[C@@H:1]1[O:7][C@H:4]([CH2:5][OH:6])[CH2:3][CH2:2]1
Reactant: Nc1ccn([C@H]2CC[C@@H](CO)O2)c(=O)n1
Reactant: II
Solvent: CO
Solvent: ClCCl
Product: Nc1nc(=O)n([C@H]2CC[C@@H](CO)O2)cc1I
Reaction time: 4 h
Yield: 82.8 %

Procedure:
A solution of 2',3'-dideoxycytidine (2.11 g, 10 mmol, Raylo) and mercuric acetate (3.35 g, 10.5 mmol, Fisher) in 50 mL of methanol was refluxed for 19 hours. The resulting white suspension was diluted with methanol (50 mL) and dichloromethane (100 mL). Iodine (3.05 g, 12 mmol) was added and the suspension was stirred at 25°. After 4 hours, the free base form of AG3 X4A resin (20 mL, 38 meq, Bio-Rad) was added and hydrogen sulfide was bubbled into the reaction for 15 minutes. Complete precipitation of mercury(II) was verified by TLC. The reaction was filtered through filter aid and the filter aid was washed with 1:1 methanol-dichloromethane. The filtrate was evaporated onto silica gel (10 g) and the loaded silica gel was placed on top of a 150 g silica gel column. Elution with 5%, 10% and 20% methanol in dichloromethane afforded 2.79 g (83%) of iodide 19 as a colorless crystalline solid. Two recrystallizations from boiling water afforded, after vacuum-drying at 50°, large, analytically-pure prisms (mp: d 178°).
Reaction SMILES: [Li+].[CH3:2]C([N-]C(C)C)C.C(=O)=O.CO.[CH3:14][CH2:15][O:16][C:17](/[CH:19]=[CH:20]/[CH2:21]P(OCC)(OCC)=O)=[O:18].C(=O)[C:31]1[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=1>C1COCC1.C(O)(=O)C>[N:34]1[CH:33]=[CH:32][CH:31]=[C:36]([CH:2]=[CH:21][CH:20]=[CH:19][C:17]([O:16][CH2:15][CH3:14])=[O:18])[CH:35]=1
Reactant: O=Cc1ccncc1
Reactant: CC(C)[N-]C(C)C
Reactant: CCOC(=O)/C=C/CP(=O)(OCC)OCC
Agent: O=C=O
Agent: [Li+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CO
Product: CCOC(=O)C=CC=Cc1cccnc1

Procedure:
A solution of LDA (16.5 ml of 2M solution, 3.5 g, 0.033 mol) in THF (100 ml) was cooled to −78° C. or below (dry ice-methanol bath) under a nitrogen flow and treated dropwise with triethyl 4-phosphonocrotonate (8.6 g, 0.037 mmol) while stirring. The mixture was further stirred for 15 minutes, treated dropwise with isonicotinaldehyde (3.2 g, 0.030 mol), and then stirred at 0° C. for 1.5 hours. Next, the mixture was treated with acetic acid and evaporated. To the residue was added saturated aqueous sodium hydrogen carbonate and the mixture was extracted with ethyl acetate. The extract was treated according to conventional techniques. Evaporation of solvent yielded ethyl 5-(pyridin-3-yl)-2,4-pentadienoate as a crystalline product (3.3 g).