Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:22])=[C:6]([NH:8][C:9]2[N:10]=[CH:11][C:12]3[N:17]=[C:16]([NH:18][C:19](=[O:21])[CH3:20])[S:15][C:13]=3[N:14]=2)[CH:7]=1.[F:23][CH:24]([F:35])[O:25][C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=1)[C:29](O)=[O:30].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(=O)([O-])O.[Na+]>N1C=CC=CC=1>[C:19]([NH:18][C:16]1[S:15][C:13]2[N:14]=[C:9]([NH:8][C:6]3[CH:7]=[C:2]([NH:1][C:29](=[O:30])[C:28]4[CH:32]=[CH:33][CH:34]=[C:26]([O:25][CH:24]([F:23])[F:35])[CH:27]=4)[CH:3]=[CH:4][C:5]=3[CH3:22])[N:10]=[CH:11][C:12]=2[N:17]=1)(=[O:21])[CH3:20]
Reactant: O=C(O)c1cccc(OC(F)F)c1
Reactant: CC(=O)Nc1nc2cnc(Nc3cc(N)ccc3C)nc2s1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: c1ccncc1
Product: CC(=O)Nc1nc2cnc(Nc3cc(NC(=O)c4cccc(OC(F)F)c4)ccc3C)nc2s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.1 %

Procedure:
A solution of N-{5-[(5-amino-2-methylphenyl)amino][1,3]thiazolo[5,4-d]pyrimidin-2-yl}acetamide (120 mg, 382 μmol) produced in Example D35(v), 3-(difluoromethoxy)benzoic acid (86 mg, 458 μmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (174 mg, 458 μmol) in pyridine (3 mL) was stirred at room temperature for 1 hr. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution (15 mL), and the mixture was extracted with ethyl acetate (20 mL, 5 mL). The combined organic layer was washed with saturated brine (5 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (hexane/ethyl acetate=20/80→0/100), and the fractions containing the object product were concentrated under reduced pressure. The obtained residue was recrystallized from tetrahydrofuran and ethyl acetate to give the title compound (113 mg, 61%) as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:42])[N:10]([CH2:34][CH:35](OCC)OCC)[C:11]2[CH:12]=[N:13][N:14]([C@@H:16]([C@:18]([C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=3[F:33])([OH:25])[CH2:19][N:20]3[CH:24]=[N:23][CH:22]=[N:21]3)[CH3:17])[CH:15]=2)=[CH:4][CH:3]=1.Cl.C(=O)([O-])O.[Na+]>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:35]=[CH:34][N:10]([C:11]3[CH:12]=[N:13][N:14]([C@@H:16]([C@:18]([C:26]4[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=4[F:33])([OH:25])[CH2:19][N:20]4[CH:24]=[N:23][CH:22]=[N:21]4)[CH3:17])[CH:15]=3)[C:9]2=[O:42])=[CH:6][CH:7]=1
Reactant: CCOC(CN(C(=O)Nc1ccc(Cl)cc1)c1cnn([C@H](C)[C@](O)(Cn2cncn2)c2ccc(F)cc2F)c1)OCC
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: C[C@@H](n1cc(-n2ccn(-c3ccc(Cl)cc3)c2=O)cn1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Yield: 91.2 %

Procedure:
3-(4-Chlorophenyl)-1-(2,2-diethoxyethyl)-1-(1-((2R,3R)-3-(2,4-difluorophenyl)-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)butan-2-yl)-1H-pyrazol-4-yl)urea obtained in Step 4 (0.07 g, 0.12 mmol) was dissolved in methanol (2 mL) and 1N-HCl (2 mL) was added thereto. The mixture was refluxed for 2 hours, and neutralized using aqueous sodium hydrogen carbonate. The resulting mixture was extracted with ethyl acetate (10 mL), and the extract was washed successively with distilled water (10 mL) and brine (10 mL). The organic layer was dried over anhydrous magnesium sulfate and concentrated by evaporation under a reduced pressure. The resulting residue was purified by silica gel chromatography to obtain the title compound (0.056 g, yield 95%).
Reaction SMILES: [OH:1][CH2:2][C:3]1([N:16]2[CH2:21][CH2:20][CH2:19][NH:18][C:17]2=[O:22])[CH2:8][CH2:7][N:6](CC2C=CC=CC=2)[CH2:5][CH2:4]1.[H][H]>CO.[Pd]>[OH:1][CH2:2][C:3]1([N:16]2[CH2:21][CH2:20][CH2:19][NH:18][C:17]2=[O:22])[CH2:4][CH2:5][NH:6][CH2:7][CH2:8]1
Reactant: O=C1NCCCN1C1(CO)CCN(Cc2ccccc2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: O=C1NCCCN1C1(CO)CCNCC1
Yield: 47.7 %

Procedure:
A mixture of intermediate (16) (0.0059 mol) in methanol (100 ml) was hydrogenated with palladium on carbon (1 g) as a catalyst. After uptake of hydrogen (1 equivalent), the catalyst was filtered off, the filtrate was evaporated and crystallized from ACN, yielding 0.6 g of tetrahydro-1-[4(hydroxymethyl)-4-piperidinyl]-2(1H)-pyrimidinone (intermediate 17, mp. 162° C.).
Reaction SMILES: [F:1][C:2]1[C:11]2[O:10][CH2:9][CH:8]=[CH:7][C:6]=2[C:5]([C:12]([NH2:14])=[O:13])=[CH:4][CH:3]=1.[N:15]([O-:17])=[O:16].[Na+].C(OC(C)C)(=O)C.II>O>[F:1][C:2]1[C:11]2[O:10][CH2:9][C:8]([N+:15]([O-:17])=[O:16])=[CH:7][C:6]=2[C:5]([C:12]([NH2:14])=[O:13])=[CH:4][CH:3]=1
Reactant: O=N[O-]
Reactant: NC(=O)c1ccc(F)c2c1C=CCO2
Agent: II
Agent: [Na+]
Solvent: O
Solvent: CC(=O)OC(C)C
Product: NC(=O)c1ccc(F)c2c1C=C([N+](=O)[O-])CO2
Temperature: 50 °C
Yield: 77.1 %

Procedure:
Into a reactor, equipped with a reflux condenser and under inert gas, 8-fluoro-2H-chromene-5-carboxylic acid amide (4.94 g; 25.6 mmoles), sodium nitrite (4.4 g; 64 mmoles) and isopropyl acetate (40 ml) were charged. The mixture was kept under mechanic stirring and heated at 50° C. In one portion iodine (1.9 g; 7.5 mmoles) and then, in 3 hours, Oxistrong 15® (6 ml) were added. At the end of the addition the reaction mixture was kept under stirring for 1 hour and cooled to 20° C. After addition of water (30 ml), the mixture was further cooled at 5° C. for 1 hour. The solid was filtered and washed with isopropyl acetate (3×10 ml), pre-cooled at 0° C., and with water (2×10 ml). After drying in oven under vacuum at 50° C. overnight, 8-fluoro-3-nitro-2H-chromene-5-carboxylic acid amide (4.7 g; HPLC titre 90%; 70% yield) was obtained. The mother liquors of the reaction were treated with a 15% solution of sodium metabisulphite (20 ml) up to decoloration. The phases were separated, the organic phase was dried and the organic solvent was removed under reduced pressure obtaining a solid (0.8 g) containing 49% of 8-fluoro-3-nitro-2H-chromene-5-carboxylic acid amide. Overall yield: 76.4%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][CH:19]([CH3:21])[CH3:20])=[CH:14][C:13]=1[O:22][CH3:23])[C:6](=[O:24])[C:5]2([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[Cl:32])[CH3:25].[CH2:33]=O.[BH4-].[Na+].Cl>C(OCC)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]([CH:19]([CH3:21])[CH3:20])[CH3:33])=[CH:14][C:13]=1[O:22][CH3:23])[C:6](=[O:24])[C:5]2([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[Cl:32])[CH3:25]
Reactant: C=O
Reactant: COc1cc(NC(C)C)ccc1CN1C(=O)C(C)(c2ccccc2Cl)c2cc(Cl)ccc21
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOCC
Product: COc1cc(N(C)C(C)C)ccc1CN1C(=O)C(C)(c2ccccc2Cl)c2cc(Cl)ccc21

Procedure:
The compound of Example 56 is treated with aqueous formaldehyde and sodium borohydride. The compound obtained is salified with a solution of hydrochloric acid in diethyl ether. The hydrochloride is then isolated after filtration and drying at 45° C. under reduced pressure; M.p.=156° C. (HCl.1.5H2O).
Reaction SMILES: [OH:1][C:2]1[C:11]([CH2:12][CH:13]=[CH2:14])=[C:10]([OH:15])[CH:9]=[CH:8][C:3]=1[C:4]([NH:6][CH3:7])=[O:5]>C(O)C.[Pd]>[OH:1][C:2]1[C:11]([CH2:12][CH2:13][CH3:14])=[C:10]([OH:15])[CH:9]=[CH:8][C:3]=1[C:4]([NH:6][CH3:7])=[O:5]
Reactant: C=CCc1c(O)ccc(C(=O)NC)c1O
Agent: [Pd]
Solvent: CCO
Product: CCCc1c(O)ccc(C(=O)NC)c1O
Reaction time: 2 h

Procedure:
The compound of Example 6 (1.0 g) was dissolved in 30 ml of ethanol and hydrogenated at room temperature and 5 psi for 2 hours and 25 minutes using 200 mg of 4% Pd/C as catalyst. The solvent was removed under vacuum to give the product as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][N:6]2[C:11](=[O:27])[CH2:12][C:13]1[N:18]=[C:17]([O:19][CH3:20])[CH:16]=[C:15]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[N:14]=1.[CH3:28][Si]([N-][Si](C)(C)C)(C)C.[K+].CI>O1CCCC1.[Cl-].[NH4+].C(OCC)(=O)C>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][N:6]2[C:11](=[O:27])[CH:12]([C:13]1[N:18]=[C:17]([O:19][CH3:20])[CH:16]=[C:15]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[N:14]=1)[CH3:28]
Reactant: COc1cc(N2CCOCC2)nc(CC(=O)N2CCc3c(F)cccc32)n1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [K+]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CI
Solvent: C1CCOC1
Product: COc1cc(N2CCOCC2)nc(C(C)C(=O)N2CCc3c(F)cccc32)n1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
300 mg of 1-(4-fluoro-2,3-dihydroindol-1-yl)-2-(4-methoxy-6-morpholin-4-yl-pyrimidin-2-yl)ethanone dissolved in 10 ml of tetrahydrofuran are cooled to −78° C. using a dry ice bath. 2.65 ml of 1N potassium bis(trimethylsilyl)amide in THF are slowly added while maintaining the temperature at −75° C. After 30 minutes of stirring, 0.125 ml of methyl iodide is added and the stirring is continued for 2 h 15. The reaction mixture is diluted with 50 ml of a saturated ammonium chloride solution and 30 ml of ethyl acetate. After settling out, the organic phase is washed with 5 times 15 ml of water, dried over magnesium sulfate, filtered, and then concentrated under reduced pressure. The residue is purified by silica column chromatography, elution being carried out with a 99/01 mixture of dichloromethane and methanol, so as to give 215 mg of 1-(4-fluoro-2,3-dihydroindol-1-yl)-2-(4-methoxy-6-morpholin-4-ylpyrimidin-2-yl)propan-1-one in the form of a white solid, the characteristics of which are the following:
Reaction SMILES: C[O:2][C:3]([C:5]1([CH3:10])[NH:9][CH2:8][CH2:7][S:6]1)=[O:4].[OH-].[Na+:12]>O>[CH3:10][C:5]1([C:3]([O-:4])=[O:2])[NH:9][CH2:8][CH2:7][S:6]1.[Na+:12]
Reactant: COC(=O)C1(C)NCCS1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC1(C(=O)[O-])NCCS1
Temperature: 25 °C

Procedure:
3.22 g of the thus obtained 2-methylthiazolidine-2-carboxylic acid methyl ester was added to a solution of 0.80 g of caustic soda in 20 ml of water and stirred at room temperature to give an aqueous solution of sodium 2-methylthiazolidine-2-carboxylate. To the solution was added 3.76 g of 3,5-dichlorophenylisocyanate in 20 ml of chlorobenzene, followed by stirring at room temperature for 1.5 hours. Then the reaction mixture was extracted with ether and the water layer was neutralized with concentrated hydrochloric acid. The resulting crystals were separated, washed with water and dried to give 5.22 g (yield 77.9%) of 2-methyl-3-(3,5-dichlorophenylcarbamoyl)thiazolidine-2-carboxylic acid with a melting point of 164°-166° C. The results of the elementary analysis were as follows: Found (calculated in parentheses): C 43.21% (43.00%), H 3.58% (3.61%), N 8.28% (8.36%), Cl 21.28% (21.15%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:38])[C@@H:7]([NH:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:8][CH2:9][C:10]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])([CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1)C(O)=O)([CH3:4])([CH3:3])[CH3:2]>O1CCOCC1>[C:34]([O:33][C:31]([NH:30][C@@H:7]([CH2:8][CH2:9][CH:10]([CH2:14][CH2:15][C:16]1[CH:17]=[CH:18][C:19]([OH:22])=[CH:20][CH:21]=1)[C:23]([O:25][C:26]([CH3:27])([CH3:28])[CH3:29])=[O:24])[C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:38])=[O:32])([CH3:35])([CH3:36])[CH3:37]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCC(CCc1ccc(O)cc1)(C(=O)O)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N[C@@H](CCC(CCc1ccc(O)cc1)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 100 °C
Reaction time: 8 h
Yield: 49.6 %

Procedure:
To a solution of 370 mg (5S)-6-tert-butoxy-2-(tert-butoxycarbonyl)-5-[(tert-butoxycarbonyl)amino]-2-[2-(4-hydroxyphenyl)ethyl]-6-oxohexanoic acid (0.69 mmol) in 1,4-dioxane (30 mL) was added 210 mg of 4-N,N-dimethylaminopyridine (1.72 mmol) and the mixture was stirred overnight at 100° C. (bath temperature), followed by refluxing for another 18 h. After cooling to room temperature, the mixture was concentrated in vacuo. The residue was purified by preparative HPLC (Method A) to give 169 mg (50% yield) of the target compound. In addition, 38 mg of unreacted starting material were recovered.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)=[N:4][CH:5]=[CH:6][C:7]=1[C:8]([NH2:10])=[O:9].[N:21]([O-])=O.[Na+].[Na]>Cl.O.C(OCC)(=O)C>[F:19][C:17]([F:20])([F:18])[C:13]1[CH:12]=[C:11]([C:3]2[C:2]3[N:1]=[N:21][NH:10][C:8](=[O:9])[C:7]=3[CH:6]=[CH:5][N:4]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: O=N[O-]
Reactant: NC(=O)c1ccnc(-c2cccc(C(F)(F)F)c2)c1N
Agent: Cl
Agent: [Na+]
Agent: [Na]
Solvent: CCOC(C)=O
Solvent: O
Product: O=c1[nH]nnc2c(-c3cccc(C(F)(F)F)c3)nccc12
Yield: 68.5 %

Procedure:
562 mg of 3-amino-2-(3-trifluoromethylphenyl)-4-pyridinecarboxamide were stirred at 0° C. in 5 ml of concentrated hydrochloric acid during the addition of 160 mg of sodium nitrite in 1 ml of water. After 0.5 hour the mixture was diluted with water and ethyl acetate and made basic with sodium hicarbonate. The organic phase was separated, dried over sodium sulphate and evaporated, and the residue was purified by chromatography on silica gel using ethyl acetate/petroleum ether (1:1) for the elution. There were obtained 400 mg of 8-(3-trifluoromethylphenyl)pyrido[3,4-d]-1,2,3-triazin-4(3H)-one in the form of a solid of melting point 192°-193° C. (dec.).
Reaction SMILES: C([O:5][C:6]([C@H:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13](=[O:42])[CH2:14][O:15][C:16]1[C:25]([O:26][CH2:27][C:28]([N:30]2[CH2:34][CH2:33][CH2:32][C@@H:31]2[C:35]([O:37]C(C)(C)C)=[O:36])=[O:29])=[CH:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=1)=[O:7])(C)(C)C>FC(F)(F)C(O)=O>[C:35]([C@H:31]1[CH2:32][CH2:33][CH2:34][N:30]1[C:28](=[O:29])[CH2:27][O:26][C:25]1[C:16]([O:15][CH2:14][C:13]([N:9]2[CH2:10][CH2:11][CH2:12][C@@H:8]2[C:6]([OH:7])=[O:5])=[O:42])=[CH:17][C:18]2[C:23]([CH:24]=1)=[CH:22][CH:21]=[CH:20][CH:19]=2)([OH:37])=[O:36]
Reactant: CC(C)(C)OC(=O)[C@H]1CCCN1C(=O)COc1cc2ccccc2cc1OCC(=O)N1CCC[C@@H]1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)[C@H]1CCCN1C(=O)COc1cc2ccccc2cc1OCC(=O)N1CCC[C@@H]1C(=O)O
Reaction time: 8 h
Yield: 95.6 %

Procedure:
A solution of 230 mg (0.4 mmol) (R)-1-[[3-[2-[(R)-2-tert-butoxycarbonyl-pyrrolidin-1-yl]-2-oxo-ethoxy]naphthalen-2-yloxy]-acetyl]-pyrrolidine-2-carboxylic acid tert-butyl ester in 5 ml trifluoroacetic acid was stirred for 18 h at room temperature. The solvent was removed in vacuo and the residue suspended in 10 ml ether. The resulting suspension was stirred overnight. Filtration and drying gave 180 mg (96%) of the title compound as a white powder.
Reaction SMILES: Cl.[I:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:13][CH:14]1[CH2:18][CH2:17][NH:16][CH2:15]1)[CH:8]=[C:7]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:6]2=[O:24].[Si:25]([O:32][CH2:33][CH:34]=O)([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26].C([BH3-])#N.[Na+].O>CO>[Si:25]([O:32][CH2:33][CH2:34][N:16]1[CH2:17][CH2:18][CH:14]([CH2:13][N:9]2[C:10]3[C:5](=[CH:4][C:3]([I:2])=[CH:12][CH:11]=3)[C:6](=[O:24])[C:7]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:8]2)[CH2:15]1)([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26]
Reactant: CC(C)(C)[Si](C)(C)OCC=O
Reactant: CCOC(=O)c1cn(CC2CCNC2)c2ccc(I)cc2c1=O
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCOC(=O)c1cn(CC2CCN(CCO[Si](C)(C)C(C)(C)C)C2)c2ccc(I)cc2c1=O
Temperature: 23 °C
Reaction time: 16 h
Yield: 40.1 %

Procedure:
Ethyl 6-iodo-4-oxo-1-(pyrrolidin-3-ylmethyl)-1,4-dihydroquinoline-3-carboxylate hydrochloride (Intermediate 126, 500 mg, 1.08 mmol) was suspended in methanol (15 mL) then (tert-butyldimethylsilyloxy)acetaldehyde (1 mL, 5.4 mmol) and sodium cyanoborohydride (612 mg, 9.7 mmol) were added. The reaction was stirred at 23° C. for 16 h. The volume of the reaction was reduced by half and water (25 mL) was added. The suspension was extracted with 2:1 ethyl acetate: tetrahydrofuran (3×, 10 mL). The organic phases were combined, dried over sodium sulfate, and the solvent was removed in vacuo. The residue was chromatographed on a 4 g Analogix column eluting with 0-10% methanol in dichloromethane. The solid was then dried in a vacuum oven at 50° C. for 18 h to give 253 mg (39% yield) of ethyl 1-((1-(2-(tert-butyldimethylsilyloxy)ethyl)pyrrolidin-3-yl)methyl)-6-iodo-4-oxo-1,4-dihydroquinoline-3-carboxylate as an off white solid.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][C:6]1[CH:7]=[C:8]([CH:12]=[C:13]([CH3:19])[C:14]=1[O:15][C:16](=[O:18])[CH3:17])[C:9](O)=[O:10]>>[CH3:5][C:6]1[CH:7]=[C:8]([CH:12]=[C:13]([CH3:19])[C:14]=1[O:15][C:16](=[O:18])[CH3:17])[C:9]([Cl:3])=[O:10]
Reactant: O=S(Cl)Cl
Reactant: CC(=O)Oc1c(C)cc(C(=O)O)cc1C
Product: CC(=O)Oc1c(C)cc(C(=O)Cl)cc1C
Temperature: 25 °C

Procedure:
To 21 ml of thionyl chloride was suspended 9.3 g/45 mmol of 3,5-dimethyl-4-acetoxybenzoic acid, and the suspension was refluxed under heat for 90 minutes. After cooling to room temperature, excessive thionyl chloride was distilled off under reduced pressure to obtain 9.9 g of the desired 3,5-dimethyl-4-acetoxybenzoyl chloride.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:11]=[CH:10][C:9](/[C:12](/[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:13]\[CH2:14][OH:15])=[CH:8][CH:7]=1.C(P(CCCC)CCCC)CCC.[CH2:35]([O:37][C:38](=[O:51])[C@@H:39]([O:48][CH2:49][CH3:50])[CH2:40][C:41]1[CH:46]=[CH:45][C:44](O)=[CH:43][CH:42]=1)[CH3:36]>C1C=CC=CC=1>[CH2:35]([O:37][C:38](=[O:51])[C@@H:39]([O:48][CH2:49][CH3:50])[CH2:40][C:41]1[CH:46]=[CH:45][C:44]([O:15][CH2:14]/[CH:13]=[C:12](\[C:9]2[CH:10]=[CH:11][C:6]([C:2]3[O:1][CH:5]=[CH:4][CH:3]=3)=[CH:7][CH:8]=2)/[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[CH:43][CH:42]=1)[CH3:36]
Reactant: CCOC(=O)[C@H](Cc1ccc(O)cc1)OCC
Reactant: OC/C=C(/c1ccccc1)c1ccc(-c2ccco2)cc1
Agent: CCCCP(CCCC)CCCC
Solvent: c1ccccc1
Product: CCOC(=O)[C@H](Cc1ccc(OC/C=C(/c2ccccc2)c2ccc(-c3ccco3)cc2)cc1)OCC
Yield: 48 %

Procedure:
Reaction of (Z)-3-(4-furan-2-yl-phenyl)-3-phenyl-prop-2-en-1-ol (300 mg, 1.09 mmol), tributylphosphine (0.40 ml, 1.64 mmol), (2S)-2-ethoxy-3-(4-hydroxy-phenyl)-propionic acid ethyl ester (286 mg, 1.20 mmol) and azodicarboxylic dipiperidide (413 mg, 1.64 mmol) in benzene in an identical manner to example 3 gave the title compound (260 mg, 48%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:12]O.Cl>>[CH3:12][O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][C:9]([CH3:11])=[CH:10][C:2]=1[F:1]
Reactant: CO
Reactant: Cc1ccc(C(=O)O)c(F)c1
Agent: Cl
Product: COC(=O)c1ccc(C)cc1F
Reaction time: 48 h

Procedure:
2-Fluoro-4-methylbenzoic acid (30.0 g, 195 mmol) was dissolved in MeOH (600 mL, 10 mol), and 12 M HCl (3.2 mL, 39 mmol) was added. The mixture was heated to reflux and stirred for 48 hours, then cooled and concentrated. The recovered material was dried in vacuo for 24 hours to obtain Intermediate (6a) as a white solid that was used without further purification.
Reaction SMILES: [CH3:1][CH:2]([C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][CH:14]=1)[C:8]([O:10][CH3:11])=[O:9])[CH:3]=[CH2:4].I[CH2:16]Cl.C([Zn]CC)C>ClC(Cl)C>[CH:3]1([CH:2]([C:5]2[CH:6]=[C:7]([CH:12]=[CH:13][CH:14]=2)[C:8]([O:10][CH3:11])=[O:9])[CH3:1])[CH2:16][CH2:4]1
Reactant: ClCI
Reactant: C=CC(C)c1cccc(C(=O)OC)c1
Agent: CC[Zn]CC
Solvent: CC(Cl)Cl
Product: COC(=O)c1cccc(C(C)C2CC2)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of methyl 3-(1-methylprop-2-en-1-yl)benzoate (0.85 g, 4.49 mmol) in dichloroethane (20 mL) was added iodochloromethane (2.54 mL, 14.4 mmol). The solution was cooled to 0° C. and diethyl zinc (1.0 M in heptanes, 7.13 mL, 7.13 mmol) was added. The cooling bath was removed and the reaction was stirred at rt for 30 min. The reaction mixture was quenched with 1N HCl, extracted with methylene chloride (three times), dried with MgSO4 and concentrate under vacuum to afford the desired product.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:9]([CH2:10][O:11][C:12](=[O:14])[CH3:13])[O:8][C@@H:7]([N:15]2[C:19]([N:20]=[CH:21][N:22]([CH3:24])[CH3:23])=[C:18]([C:25](=[O:29])[CH:26]=[N+]=[N-])[N:17]=[CH:16]2)[C@@H:6]1[F:30])(=[O:3])[CH3:2].[ClH:31].C(OCC)C>ClCCl>[C:1]([O:4][C@@H:5]1[C@@H:9]([CH2:10][O:11][C:12](=[O:14])[CH3:13])[O:8][C@@H:7]([N:15]2[C:19]([N:20]=[CH:21][N:22]([CH3:24])[CH3:23])=[C:18]([C:25](=[O:29])[CH2:26][Cl:31])[N:17]=[CH:16]2)[C@@H:6]1[F:30])(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc(C(=O)C=[N+]=[N-])c2N=CN(C)C)[C@H](F)[C@@H]1OC(C)=O
Reactant: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: CC(=O)OC[C@H]1O[C@@H](n2cnc(C(=O)CCl)c2N=CN(C)C)[C@H](F)[C@@H]1OC(C)=O

Procedure:
In step 14, compound (20) is reacted in dichloromethane with hydrogen chloride in the form of a diethylether solution under ice-cooling, to convert the 4-diazoacetyl group of compound (20) into 4-chloroacetyl group. Thereby, 1-(3,5-di-O-acetyl-2-deoxy-2-fluoro-β-D-ribofuranosyl)-4-chloroacetyl-5-(dimethylaminomethyleneamino)imidazole [compound (21)] is produced.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:17]2[N:21]([CH2:22][CH3:23])[N:20]=[C:19]([CH:24]3[CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26][CH2:25]3)[N:18]=2)=[N:6][C:7]=1[C:8]1[O:9][C:10]([C:13]([CH3:16])([CH3:15])[CH3:14])=[N:11][N:12]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:13]([C:10]1[O:9][C:8]([C:7]2[C:2]([NH2:1])=[N:3][CH:4]=[C:5]([C:17]3[N:21]([CH2:22][CH3:23])[N:20]=[C:19]([CH:24]4[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]4)[N:18]=3)[N:6]=2)=[N:12][N:11]=1)([CH3:14])([CH3:15])[CH3:16]
Reactant: CCn1nc(C2CCN(C(=O)OC(C)(C)C)CC2)nc1-c1cnc(N)c(-c2nnc(C(C)(C)C)o2)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCn1nc(C2CCNCC2)nc1-c1cnc(N)c(-c2nnc(C(C)(C)C)o2)n1
Temperature: 7.5 °C
Reaction time: 1 h

Procedure:
A suspension of tert-butyl 4-(5-(5-amino-6-(5-tert-butyl-1,3,4-oxadiazol-2-yl)pyrazin-2-yl)-1-ethyl-1H-1,2,4-triazol-3-yl)piperidine-1-carboxylate (3009.5 g, 6.05 mol) in DCM (9 L) was cooled to 5-10° C. under N2. TFA (9 L) was added portionwise to the suspension whilst maintaining the temperature <30° C. The reaction mixture was stirred at room temperature for 1 h. The mixture was concentrated, the resulting residue was dissolved in water (30 L) and added slowly to a 35% aqueous ammonia solution (12 L) at 0-5° C. The suspension was stirred for 30 min then the product was filtered off and washed with water (2×6 L). The product was dried at 50° C. in vacuo for 2 days to afford 3-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-5-(1-ethyl-3-(piperidin-4-yl)-1H-1,2,4-triazol-5-yl)pyrazin-2-amine ((2496 g): 1H NMR Spectrum: (DMSO-d6) 1.4-1.52 (12H, m), 1.57-1.73 (2H, m), 1.83-1.93 (2H, nm), 2.57-2.7 (2H, m), 2.71-2.84 (1H, m), 2.96-3.09 (2H, m), 4.58 (2H, q), 8.06 (2H, s), 8.84 (1H, s): Mass Spectrum [M+H]+=398.
Reaction SMILES: C([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:21])=[C:10]([C:13]3[CH:18]=[C:17]([CH3:19])[N:16]=[C:15]([CH3:20])[CH:14]=3)[CH:11]=2)[C:6](=[O:22])[C:5]([C:23]([OH:25])=[O:24])=[CH:4]1)C.[CH:26]1C=CC(C2C=CC=CC=2)=C[CH:27]=1.C1C=CC(OC2C=CC=CC=2)=CC=1>>[F:21][C:9]1[CH:8]=[C:7]2[C:12](=[CH:11][C:10]=1[C:13]1[CH:18]=[C:17]([CH3:19])[N:16]=[C:15]([CH3:20])[CH:14]=1)[NH:3][CH:4]=[C:5]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:6]2=[O:22]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(-c3cc(C)nc(C)c3)cc21
Reactant: c1ccc(-c2ccccc2)cc1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCOC(=O)c1c[nH]c2cc(-c3cc(C)nc(C)c3)c(F)cc2c1=O

Procedure:
Preparation of 1-ethyl-6-fluoro-1,4-dihydro-7-(2,6-dimethyl-4-pyridinyl)-4-oxo-3-quinolinecarboxylic acid was then carried out by refluxing the EMME adduct of Example 4B in Dowtherm A to produce ethyl 6-fluoro-1,4-dihydro-7-(2,6-dimethyl-4-pyridinyl)-4-oxo-3-quinolinecarboxylate (Example 4C), ethylating the compound of Example 4C by heating it with ethyl iodide in dimethylformamide in the presence of anhydrous potassium carbonate to produce ethyl 1-ethyl-6-fluoro-1,4-dihydro-7-(2,6-dimethyl-4-pyridinyl)-4-oxo-3-quinolinecarboxylate (Example 4D) and hydrolyzing the compound of Example 4D by refluxing it in aqueous sodium hydroxide solution containing methanol to produce 1-ethyl 6-fluoro-1,4-dihydro-7-(2,6-dimethyl-4-pyridinyl)-4-oxo-3-quinolinecarboxylic acid (Example 4E).