Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1([F:25])[CH2:7][CH2:6][CH2:5][C:4]([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17](Cl)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])([OH:8])[CH2:3]1.CCN(C(C)C)C(C)C.[CH3:35][N:36]([CH3:42])[C@H:37]1[CH2:41][CH2:40][NH:39][CH2:38]1>>[F:1][C:2]1([F:25])[CH2:7][CH2:6][CH2:5][C:4]([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17]([N:39]4[CH2:40][CH2:41][C@H:37]([N:36]([CH3:42])[CH3:35])[CH2:38]4)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])([OH:8])[CH2:3]1
Reactant: CN(C)[C@H]1CCNC1
Reactant: O=C(NCC1(O)CCCC(F)(F)C1)c1c(Cl)ccc2nc(Cl)ccc12
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)[C@H]1CCN(c2ccc3c(C(=O)NCC4(O)CCCC(F)(F)C4)c(Cl)ccc3n2)C1

Procedure:
The title compound was synthesized according to the procedure described in example 1 using 2,6-dichloro-quinoline-5-carboxylic acid (3,3-difluoro-1-hydroxy-cyclohexylmethyl)-amide, DIPEA and (S)-3-dimethylamino-pyrrolidine. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.73 (m, 1H), 7.85 (1H), 7.48 (m, 2H), 6.69 (1H), 4.66 (s, 1H), 3.89 (m, 1H), 3.70 (m, 1H), 3.45 (m, 1H), 3.26 (m, 2H), 2.85 (m, 1H), 2.54 (m, 4H), 2.22 (s, 6H), 2.15 (m, 1H), 2.06 (m, 2H), 1.85 (m, 3H), 1.74-1.76 (m, 5H). m/z: 467 [M+H]
Reaction SMILES: [CH3:1][S:2][C:3]1[C:8]([F:9])=[CH:7][NH:6][C:5](=[O:10])[N:4]=1.Cl[CH2:12][C:13]([OH:15])=[O:14]>[OH-].[K+]>[C:13]([CH2:12][N:6]1[CH:7]=[C:8]([F:9])[C:3]([S:2][CH3:1])=[N:4][C:5]1=[O:10])([OH:15])=[O:14]
Reactant: CSc1nc(=O)[nH]cc1F
Reactant: O=C(O)CCl
Agent: [K+]
Agent: [OH-]
Product: CSc1nc(=O)n(CC(=O)O)cc1F
Yield: 36 %

Procedure:
4-Methylthio-5-fluoropyrimid-2-one (0.01 mol) was added to 2 M potassium hydroxide solution (10 ml) and dissolved. Chloroacetic acid (0.01 mol) was then added and the reaction mixture heated under reflux for 60 min when the pH was close to neutral. Some precipitate was removed by filtration from the cold reaction mixture and the filtrate brought to pH 2 with HCl. The precipitated product was recrystallised from aqueous methanol; yield 36%, m.p. 244°-245° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH2:6][NH2:7].[CH3:13][O:14][C:15](=[O:36])[C:16]1[CH:21]=[CH:20][C:19]([C:22]2[N:23]=[C:24](Cl)[C:25]3[C:30]4[CH2:31][CH2:32][CH2:33][CH2:34][C:29]=4[S:28][C:26]=3[N:27]=2)=[CH:18][CH:17]=1>>[CH3:13][O:14][C:15](=[O:36])[C:16]1[CH:17]=[CH:18][C:19]([C:22]2[N:23]=[C:24]([NH:7][CH2:6][C:5]3[CH:8]=[CH:9][C:10]([O:11][CH3:12])=[C:3]([O:2][CH3:1])[CH:4]=3)[C:25]3[C:30]4[CH2:31][CH2:32][CH2:33][CH2:34][C:29]=4[S:28][C:26]=3[N:27]=2)=[CH:20][CH:21]=1
Reactant: COC(=O)c1ccc(-c2nc(Cl)c3c4c(sc3n2)CCCC4)cc1
Reactant: COc1ccc(CN)cc1OC
Product: COC(=O)c1ccc(-c2nc(NCc3ccc(OC)c(OC)c3)c3c4c(sc3n2)CCCC4)cc1

Procedure:
The reaction procedure as above wherein 3,4-dimethoxy-benzylamine is reacted with 4-(4-chloro-5,6,7,8-tetrahydro-[1]-benzothieno-[2,3-d]-pyrimidin-2-yl)-benzoic acid methylester yields 4-[4-(3,4-dimethoxybenzylamino)-5,6,7,8-tetrahydro-[1]-benzothieno-[2,3-d]-pyrimidin-2-yl]-benzoic acid methylester
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C([O:9][C:10](=O)[CH2:11][C:12]1[C:13]([CH2:19][CH3:20])=[N:14][NH:15][C:16]=1[CH2:17][CH3:18])C.O>O1CCCC1>[CH2:17]([C:16]1[C:12]([CH2:11][CH2:10][OH:9])=[C:13]([CH2:19][CH3:20])[NH:14][N:15]=1)[CH3:18]
Reactant: CCOC(=O)Cc1c(CC)n[nH]c1CC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CCc1n[nH]c(CC)c1CCO
Temperature: 25 °C
Reaction time: 16 h
Yield: 0.1 %

Procedure:
Lithium aluminum hydride (190 mg, 4.8 mmol) was added slowly to tetrahydrofuran (10 mL) under 0° C. (3,5-Diethyl-1H-pyrazol-4-yl)-acetic acid ethyl ester (1.0 g, 4.8 mol) in tetrahydrofuran (5 mL) was slowly added under nitrogen atmosphere. The reaction was allowed to slowly warm to room temperature and stirred for 16 h. After the reaction was cooled at 0° C., water (0.3 mL) was added slowly and the reaction was stirred for 30 minutes, filtered through a short silica gel column, which was rinsed with ethyl acetate followed by 20% methanol/methylene chloride. The solution was concentrated in vacuo to provide 2-(3,5-diethyl-1H-pyrazol-4-yl)-ethanol (0.8 g, 100% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([Cl:20])[C:5]2[O:9][CH:8]([CH2:10][N:11]([CH2:15][CH2:16][CH2:17][CH3:18])[C:12](Cl)=[O:13])[CH2:7][C:6]=2[CH:19]=1.[NH:21]1[CH:25]=[CH:24][N:23]=[CH:22]1>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([Cl:20])[C:5]2[O:9][CH:8]([CH2:10][N:11]([CH2:15][CH2:16][CH2:17][CH3:18])[C:12]([N:21]3[CH:25]=[CH:24][N:23]=[CH:22]3)=[O:13])[CH2:7][C:6]=2[CH:19]=1
Reactant: c1c[nH]cn1
Reactant: CCCCN(CC1Cc2cc(Cl)cc(Cl)c2O1)C(=O)Cl
Solvent: C1CCOC1
Product: CCCCN(CC1Cc2cc(Cl)cc(Cl)c2O1)C(=O)n1ccnc1
Temperature: 70 °C
Reaction time: 6 h
Yield: 86.9 %

Procedure:
13.5 g (0.04 mole) of N-(5,7-dichloro-2,3-dihydrobenzofuran-2-ylmethyl)-N-butylcarbamyl chloride were added dropwise to a solution of 6.8 g (0.1 mole) of imidazole in 150 ml of dry tetrahydrofuran at 20° C. The mixture was stirred for 6 hours at 70° C., after which it was cooled to 20° C., and the resulting precipitate was filtered off under suction. The filtrate was evaporated down under reduced pressure, the residue was dissolved in 200 ml of methylene chloride, the solution was washed with three times 80 ml of water, dried and evaporated down, the resin which remained was left to stand for 3 hours at 0° C. with 30 ml of diethyl ether, and the crystals formed were filtered off under suction. 12.8 g of 1-(N-(5,7-dichloro-2,3-dihydrobenzofuran-2-ylmethyl)-N-butylcarbamyl)imidazole of melting point 98°-100° C. were obtained (compound No. 1).
Reaction SMILES: [O-:1][CH2:2][CH3:3].[Na+].Cl[C:6]1[C:19]2[C:10](=[C:11]3[C:16](=[CH:17][CH:18]=2)[CH:15]=[CH:14][CH:13]=[N:12]3)[N:9]=[C:8]([CH3:20])[CH:7]=1>C(O)C>[CH3:20][C:8]1[CH:7]=[C:6]([O:1][CH2:2][CH3:3])[C:19]2[C:10](=[C:11]3[C:16](=[CH:17][CH:18]=2)[CH:15]=[CH:14][CH:13]=[N:12]3)[N:9]=1
Reactant: Cc1cc(Cl)c2ccc3cccnc3c2n1
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOc1cc(C)nc2c1ccc1cccnc12
Yield: 77.8 %

Procedure:
Solid sodium ethoxide (2.97 g, 48.0 mmol) was added to a 100 mL round-bottomed flask containing a solution of 4-chloro-2-methyl-[1,10]phenanthroline (1.10 g, 4.8 mmol) in ethanol (50 mL). The reaction mixture was refluxed for 18 hours. The solvent was removed in a rotary evaporator and the residue was treated with methylene choride (100 mL) and saturated NaHCO3 (100 mL) and transferred to a separatory funnel. The organic layer was washed with brine (100 mL), dried (Na2SO4), filtered and concentrated in vacuo. The solid residue was treated with ethyl ether, filtered, and dried yielding 0.89 g of a brown solid (78%).
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C:6](=[S:20])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([S:14]([CH3:16])=[O:15])=[CH:10][C:9]=1[N+:17]([O-])=O)=[O:4].CO>[Fe].O>[NH2:17][C:9]1[CH:10]=[C:11]([S:14]([CH3:16])=[O:15])[CH:12]=[CH:13][C:8]=1[NH:7][C:6]([NH:5][C:3]([O:2][CH3:1])=[O:4])=[S:20]
Reactant: COC(=O)NC(=S)Nc1ccc(S(C)=O)cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: O
Solvent: CO
Product: COC(=O)NC(=S)Nc1ccc(S(C)=O)cc1N

Procedure:
1.5 G. of 1-(3-methoxycarbonyl-2-thioureido)-4-methylsulfinyl-2-nitrobenzene is treated in a boiling mixture of 240 ml. methanol and 60 ml. water with 1.5 g. iron powder and 0.75 g. ferrous sulfate for 3 hours. The mixture is filtered and the filtrate concentrated to a small volume, and diluted with water. The white solid is collected and recrystallized from ethanol, yielding pure 2-amino-4-methylsulfinyl-1-(3-methoxycarbonyl-2-thioureido)-benzene.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[S:15][CH:16]=[C:17]([C:19]([O:21]CC)=[O:20])[CH:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>[OH-].[Na+]>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]2[S:15][CH:16]=[C:17]([C:19]([OH:21])=[O:20])[CH:18]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1csc(C2CCN(C(=O)OC(C)(C)C)CC2)c1
Agent: [Na+]
Agent: [OH-]
Product: CC(C)(C)OC(=O)N1CCC(c2cc(C(=O)O)cs2)CC1
Temperature: 130 °C
Yield: 88.3 %

Procedure:
Aqueous sodium hydroxide (1 N, 10 mL) was added to a solution of 4-(4-ethoxycarbonyl-thiophen-2-yl)-piperidine-1-carboxylic acid t-butyl ester (1.0 g) in IMS (10 mL). The reaction was heated at 130° C. for 10 minutes by microwave irradiation. The solution was acidified to pH 7 and the resulting precipitate isolated by filtration and dried under vacuum to give the title compound as a white solid (0.81 g). 1H NMR (400 MHz, CHCl3-d): δ 8.05 (s, 1H), 7.25 (s, 1H), 4.2 (m, 2H), 2.9 (m, 1H), 2.8 (m, 2H), 2.0 (m, 2H), 1.6 (m, 2H), 1.5 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=O.ClC1C=C(Cl)C=CC=1C1[C:24]([C:25]2[NH:26][CH:27]=[CH:28][N:29]=2)=[CH:23][N:22]=[C:21]([NH:30][CH2:31][CH2:32][NH:33][C:34]2[CH:39]=[CH:38][C:37]([N+:40]([O-:42])=[O:41])=[CH:36][N:35]=2)[N:20]=1>>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]1[C:24]([C:25]2[NH:29][CH:28]=[CH:27][N:26]=2)=[CH:23][N:22]=[C:21]([NH:30][CH2:31][CH2:32][NH:33][C:34]2[CH:39]=[CH:38][C:37]([N+:40]([O-:42])=[O:41])=[CH:36][N:35]=2)[N:20]=1
Reactant: O=[N+]([O-])c1ccc(NCCNc2ncc(-c3ncc[nH]3)c(-c3ccc(Cl)cc3Cl)n2)nc1
Reactant: O=C(Cl)c1ccccc1F
Product: O=[N+]([O-])c1ccc(NCCNc2ncc(-c3ncc[nH]3)c(-c3ccccc3F)n2)nc1

Procedure:
[4-(2-fluorophenyl)-5-imidazol-2-ylpyrimidin-2-yl]{2-[(5-nitro(2-pyridyl))amino]ethyl}amine was prepared from 2-fluorbenzoyl chloride using the general method for [4-(2,4-dichlorophenyl)-5-imidazol-2-ylpyrimidin-2-yl]{2-[(5-nitro(2-pyridyl))amino]ethyl}amine.
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][O:7][C:8]2[CH:16]=[CH:15][C:11]([C:12](O)=[O:13])=[C:10]([CH2:17][C:18]([O:20][CH3:21])=[O:19])[CH:9]=2)=[CH:4][CH:3]=1.CO>C1COCC1>[CH3:21][O:20][C:18](=[O:19])[CH2:17][C:10]1[CH:9]=[C:8]([O:7][CH2:6][C:5]2[CH:22]=[CH:23][C:2]([F:1])=[CH:3][CH:4]=2)[CH:16]=[CH:15][C:11]=1[CH2:12][OH:13]
Reactant: COC(=O)Cc1cc(OCc2ccc(F)cc2)ccc1C(=O)O
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)Cc1cc(OCc2ccc(F)cc2)ccc1CO
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The 4-(4-fluoro-benzyloxy)-2-methoxycarbonylmethyl-benzoic acid (1.15 g, 3.6 mmol) is solved in THF (28 mL) and borane-dimethylsulfide complex is added (0.69 mL, 7.26 mmol) at 0° C. The reaction is stirred for 2 hours at room temperature and more borane-dimethylsulfide complex (0.69 mL, 7.26 mmol) is added at 0° C. The reaction mixture was stirred at room temperature for 7 h. Methanol was added very slowly and the mixture stirred 20 min. Filtration and concentration in a rotatory evaporator left a solid that was purified through a Silica-gel column using hexane/ethyl acetate 3/1 to 1/2 as eluents (0.927 g, 71.4%). MS: m/e=304 (M+).
Reaction SMILES: C([O:8][C@@H:9]1[C@H:13]2[O:14][CH2:15][C@:10]1([CH2:25][O:26]C(C1C=CC=CC=1)(C1C=CC(OC)=CC=1)C1C=CC(OC)=CC=1)[O:11][C@H:12]2[N:16]1[CH:24]=[C:22]([CH3:23])[C:20](=[O:21])[NH:19][C:17]1=[O:18])C1C=CC=CC=1>CO.[Pd]>[OH:8][C@@H:9]1[C@H:13]2[O:14][CH2:15][C@:10]1([CH2:25][OH:26])[O:11][C@H:12]2[N:16]1[CH:24]=[C:22]([CH3:23])[C:20](=[O:21])[NH:19][C:17]1=[O:18]
Reactant: COc1ccc(C(OC[C@@]23CO[C@@H]([C@H](n4cc(C)c(=O)[nH]c4=O)O2)[C@H]3OCc2ccccc2)(c2ccccc2)c2ccc(OC)cc2)cc1
Agent: [Pd]
Solvent: CO
Product: Cc1cn([C@@H]2O[C@@]3(CO)CO[C@@H]2[C@H]3O)c(=O)[nH]c1=O
Reaction time: 26 h
Yield: 81.8 %

Procedure:
Nucleoside 8 (3.09 g, 4.66 mmol) was dissolved in methanol (40 cm3) and 10% palladium on carbon (3 g, suspended in methanol (20 cm3)) was added. The mixture was degassed and stirred under an atmosphere of hydrogen. After 26 h, the mixture was filtered (silica gel, washed with dichloromethane/methanol (700 cm3; 1:3, v/v)) and the volume of the filtrate was concentrated to 25% of its initial volume. After repeated filtration, the filtrate was evaporated to dryness under reduced pressure and the residue was subjected to column chromatography on silica gel using dichloromethane/methanol (5–12% methanol, v/v) as eluent furnishing nucleoside 9 (1.03 g, 82%) as a white solid material after evaporation of the solvents under reduced pressure.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH3:16])[C:13]([OH:15])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].CS(O[CH2:24][CH2:25][S:26]([CH3:29])(=[O:28])=[O:27])(=O)=O>C1COCC1>[CH2:1]([O:8][C:9]([N:11]([CH2:24][CH2:25][S:26]([CH3:29])(=[O:28])=[O:27])[C@@H:12]([CH3:16])[C:13]([OH:15])=[O:14])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)CCOS(C)(=O)=O
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[C@@H](C(=O)O)N(CCS(C)(=O)=O)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 41.2 %

Procedure:
In a 100 mL round-bottomed flask, (S)-2-(benzyloxycarbonylamino)propanoic acid (331 mg, 1.48 mmol, Eq: 1.00) was combined with THF (9 mL) to give a colorless solution. Sodium hydride (131 mg, 3.26 mmol, Eq: 2.2) was added. The reaction was stirred at rt for 30 min, then 2-(methylsulfonyl)ethyl methanesulfonate (300 mg, 1.48 mmol, Eq: 1.00) was added and the reaction was stirred at rt overnight. The reaction was quenched with saturated aqueous NH4Cl and extracted with EtOAc. The combined organic layers were washed with water and brine then dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 40 g, 10% to 60% EtOAc in hexanes) to give (S)-2-[benzyloxycarbonyl-(2-methanesulfonyl-ethyl)-amino]-propionic acid (201 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:12]2[C:20]3[CH2:19][CH2:18][CH:17]([NH2:21])[C:16]=3[CH:15]=[N:14][CH:13]=2)[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].C(N(CC)C(C)C)(C)C.[CH:31]1([S:34](Cl)(=[O:36])=[O:35])[CH2:33][CH2:32]1>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([C:12]2[C:20]3[CH2:19][CH2:18][CH:17]([NH:21][S:34]([CH:31]4[CH2:33][CH2:32]4)(=[O:36])=[O:35])[C:16]=3[CH:15]=[N:14][CH:13]=2)[CH:5]=[CH:6][C:7]=1[C:8]([F:9])([F:11])[F:10]
Reactant: NC1CCc2c(-c3ccc(C(F)(F)F)c(F)c3)cncc21
Reactant: O=S(=O)(Cl)C1CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=S(=O)(NC1CCc2c(-c3ccc(C(F)(F)F)c(F)c3)cncc21)C1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 2.7 %

Procedure:
A solution of (rac)-4-(3-fluoro-4-trifluoromethyl-phenyl)-6,7-dihydro-5H-[2]pyrindin-7-ylamine (example 89) (40 mg, 0.14 mmol) and N,N-diisopropylethylamine (0.071 mL, 0.41 mmol) in DMF (0.5 mL) was treated with cyclopropanesulfonyl chloride (0.021 mL, 0.20 mmol) and the reaction mixture stirred at room temperature overnight. Purification by preparative HPLC on reversed phase eluting with a gradient of acetonitrile/water provided 1.5 mg (3%) of the title compound as a light brown oil. MS: 401.4 (M+H)+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:3][CH2:2]1.[CH2:22]([C@@H:29]1[CH2:31][O:30]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[OH:30][C@H:29]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:31][N:1]1[CH2:2][CH2:3][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:5][CH2:6]1
Reactant: c1ccc(C[C@@H]2CO2)cc1
Reactant: O=C1C(=O)c2ccccc2C2=C1SCC1(CCNCC1)O2
Product: O=C1C(=O)c2ccccc2C2=C1SCC1(CCN(C[C@H](O)Cc3ccccc3)CC1)O2

Procedure:
Compound 186 was synthesized using spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, (2R)-2-benzyloxirane and conditions outlined in procedure Y. M.p.=82-84° C.; 400 MHz 1H NMR (DMSO) δ: 7.92-7.88 (m, 1H), 7.8-7.74 (m, 2H), 7.6-7.52 (m, 1H), 7.3-7.14 (m, 5H), 4.44 (brd, J=4.4 Hz, 1H), 3.9-3.8 (m, 1H), 3.07 (s, 2H), 2.82-2.7 (m, 3H), 2.64-2.56 (m, 1H), 2.46-2.28 (m, 4H), 2.04-1.94 (m, 2H), 1.88-1.76 (m, 2H); LCMS: 436 [M+H]; enantiomeric excess determined from chiral HPLC: >99%; Chiral HPLC Rt=50.74 min.
Reaction SMILES: [F:1][C:2]1([CH3:19])[C@@:6]([OH:8])([CH3:7])[CH:5]([CH2:9][OH:10])[O:4][C@H:3]1[N:11]1[CH:16]=[CH:15][C:14](=[O:17])[NH:13][C:12]1=[O:18].[C:20](Cl)(=[O:24])[CH2:21][CH2:22][CH3:23].O>ClCCl>[C:20]([O:10][CH2:9][C@@H:5]1[C:6]([OH:8])([CH3:7])[C@:2]([F:1])([CH3:19])[CH:3]([N:11]2[CH:16]=[CH:15][C:14](=[O:17])[NH:13][C:12]2=[O:18])[O:4]1)(=[O:24])[CH2:21][CH2:22][CH3:23]
Reactant: CC1(F)[C@H](n2ccc(=O)[nH]c2=O)OC(CO)[C@@]1(C)O
Reactant: CCCC(=O)Cl
Solvent: ClCCl
Solvent: O
Product: CCCC(=O)OC[C@H]1OC(n2ccc(=O)[nH]c2=O)[C@](C)(F)C1(C)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 40 %

Procedure:
To a solution of 1-((2R,4R)-3-fluoro-4-hydroxy-5-(hydroxymethyl)-3,4-dimethyltetrahydrofuran-2-yl)pyrimidine-2,4(1H,3H)-dione (about 0.30 g, 1.09 mmol) in dichloromethane (about 5 ml) was added solution of butyroylchloride (about 0.28 ml, 2.70 mmol) in dichloromethane (about 5 ml) at about 0° C. and stirred at room temperature for overnight. Completion of the reaction monitored by thin-layer chromatography, water added to the reaction mixture and extracted with dichloromethane and the combined organic layers were washed with saturated sodium bicarbonate, dried over sodium sulphate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using 2% methanol in dichloromethane to elude title compound (0.15 g) as a colorless solid. Yield: 40%; 1H NMR (300 MHz, CDCl3): δ 8.42 (bs, 1H), 7.39-7.35 (dd, 1H, J1=8.4 Hz, J2=8.1 Hz), 6.37 (d, 1H, J=22.8 Hz), 5.76-5.73 (dd, 1H, J1=8.4 Hz, J2=8.1 Hz), 4.58-4.52 (m, 1H), 4.39-4.37 (m, 1H), 4.26-4.20 (m, 1H), 2.68 (s, 1H), 2.38-2.33 (t, 2H), 1.69-1.61 (m, 2H), 1.48-1.25 (m, 6H), 0.99-0.94 (t, 3H); ES Mass: [M+Na]+: 367 (100%), [M+1]+ 345 (30%); IR cm−: 3504, 3147, 1725, 1677, 1560, 1180, 1086, 1062, 994; HPLC: 99%.
Reaction SMILES: [CH:1]([CH:3]1[CH2:5][CH:4]1[C:6]([O:8][CH2:9][CH3:10])=[O:7])=[O:2].[C:11]([Mg]Br)#[CH:12]>O1CCCC1>[OH:2][CH:1]([C@@H:3]1[CH2:5][C@H:4]1[C:6]([O:8][CH2:9][CH3:10])=[O:7])[C:11]#[CH:12]
Reactant: C#C[Mg]Br
Reactant: CCOC(=O)C1CC1C=O
Solvent: C1CCOC1
Product: C#CC(O)[C@@H]1C[C@H]1C(=O)OCC
Temperature: -70 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
A solution of ethyl 2-formyl-1-cyclopropanecarboxylate (predominately trans, 331 μL, 2.5 mmol) in tetrahydrofuran (5 mL) was cooled down to −70° C. Ethynylmagnesium bromide (0.5 M in tetrahydrofuran, 5 mL, 2.5 mmol) was added to the above solution under an atmosphere of nitrogen dropwise, and stirred at −70° C. for 1 h. The reaction was quenched with water, and extracted with ethyl acetate. The organic phase was washed with brine, dried over MgSO4, filtered and concentrated to get 419 mg of the title compound (yield 100%, unpurified) as a pale yellow oil.
Reaction SMILES: CN(C)[CH:3]=[C:4]1[CH2:9][CH2:8][CH2:7][CH:6]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[C:5]1=O.[N+]([O-])(O)=O.[N+]([O-])(O)=O.[CH3:26][O:27][C:28]1[CH:29]=[C:30]([NH:40][C:41]([NH2:43])=[NH:42])[CH:31]=[CH:32][C:33]=1[N:34]1[CH:38]=[C:37]([CH3:39])[N:36]=[CH:35]1>>[CH3:26][O:27][C:28]1[CH:29]=[C:30]([NH:40][C:41]2[N:43]=[CH:3][C:4]3[CH2:9][CH2:8][CH2:7][CH:6]([N:10]4[CH2:11][CH2:12][O:13][CH2:14][CH2:15]4)[C:5]=3[N:42]=2)[CH:31]=[CH:32][C:33]=1[N:34]1[CH:38]=[C:37]([CH3:39])[N:36]=[CH:35]1
Reactant: COc1cc(NC(=N)N)ccc1-n1cnc(C)c1
Reactant: CN(C)C=C1CCCC(N2CCOCC2)C1=O
Solvent: O=[N+]([O-])O
Product: COc1cc(Nc2ncc3c(n2)C(N2CCOCC2)CCC3)ccc1-n1cnc(C)c1

Procedure:
The title compound was prepared from 2-[1-dimethylamino-methylidene]-6-morpholin-4-yl-cyclohexanone (260 mg, 1.0 mmol) and N-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-guanidine dinitrate (223 mg, 0.60 mmol) using in analogous manner the procedure described in example 45b). Obtained as a white solid (38 mg, 15%). MS ISP (m/e): 421.1 (100) [(M+H)+]. mp 214-216° C.
Reaction SMILES: [C:1]1([C:7]#[CH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:9]([C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[C:13](I)[CH:12]=1)#[N:10]>>[C:9]([C:11]1[CH:16]=[CH:15][C:14]2[O:17][C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[CH:8][C:13]=2[CH:12]=1)#[N:10]
Reactant: N#Cc1ccc(O)c(I)c1
Reactant: C#Cc1ccccc1
Product: N#Cc1ccc2oc(-c3ccccc3)cc2c1

Procedure:
The general procedure was used to convert phenylacetylene and 4-cyano-2-iodophenol to the title product. Purification by flash chromatography (15% ethyl acetate in hexanes as the eluent) gave the analytically pure product as a white solid (421 mg, 96% yield). 1H NMR (300 MHz, CDCl3) δ 7.88-7.82 (m, 3H), 7.58-7.40 (m, 5H), 7.01 (s, 1H). 13C NMR (75 MHz, CDCl3) δ 158.30, 156.41, 129.85, 129.55, 129.23, 128.98, 127.84, 125.72, 125.22, 119.49, 112.25, 106.85, 100.72. Anal. Calcd. for C15H9NO: C, 82.18; H, 4.14; N, 6.39. Found C, 82.04; H, 4.21; N, 6.21. m.p.: 143-145° C.
Reaction SMILES: [CH2:1]([C:3]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:4]=1[C:5]([OH:7])=O)[CH3:2].CCN=C=NCCCN(C)C.Cl.[CH:27]1([CH2:30][NH2:31])[CH2:29][CH2:28]1.OC1C2N=NNC=2C=CC=1>CN(C)C=O>[CH:27]1([CH2:30][NH:31][C:5](=[O:7])[C:4]2[CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=[CH:11][C:3]=2[CH2:1][CH3:2])[CH2:29][CH2:28]1
Reactant: NCC1CC1
Reactant: CCc1ccc([N+](=O)[O-])cc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Product: CCc1ccc([N+](=O)[O-])cc1C(=O)NCC1CC1
Reaction time: 18 h
Yield: 78.6 %

Procedure:
2-Ethyl-5-nitrobenzoic acid (0.40 g), EDC.HCl (0.45 g), cyclopropylmethylamine (0.17 g) and hydroxybenzotriazole (0.04 g) were combined in dimethylformamide (10 ml) and stirred for 18 h. Solvent was removed at reduced pressure, the residue dissolved in dichloromethane and washed with 2N HCl and water. The organic phase was dried (MgSO4) and solvent removed at reduced pressure to give the title compound (0.4 g). 1H NMR (CDCl3) δ: 0.31 (2H, m), 0.59 (2H, m), 1.09 (1H, m), 1.28(3H, t, J=7.6Hz), 2.92 (2H, m), 3.33 (2H, m), 5.97 (1H, brs), 7.45 (1H, d, J=8.4 Hz), 8.20 (2H, m).
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][C:8]1[S:9][C:10]([CH:13]=[O:14])=[CH:11][N:12]=1)([CH3:4])([CH3:3])[CH3:2].C[Si]([C:20]#[N:21])(C)C>ClCCl.[Zn+2].[I-].[I-]>[C:1]([O:5][C:6](=[O:15])[NH:7][C:8]1[S:9][C:10]([CH:13]([OH:14])[CH2:20][NH2:21])=[CH:11][N:12]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: C[Si](C)(C)C#N
Reactant: CC(C)(C)OC(=O)Nc1ncc(C=O)s1
Agent: [I-]
Agent: [Zn+2]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1ncc(C(O)CN)s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of compound 62.3 (4.5 mmol) in dichloromethane is added trimethylsilyl cyanide (“TMSCN”; 2.1 equivalents) and ZnI2 (10% mol). After stirring at room temperature overnight, the reaction is concentrated under vacuum. The crude cyanohydrin is dissolved in THF and treated with AlH3 (2.2 equivalents of a 0.5 M solution in THF). After stirring for 15 minutes, the reaction is quenched with the addition of saturated aqueous Na2SO4, is filtered through a pad of Celite, is dried and concentrated. Purification by flash column chromatography on silica gel (10% 7.0 M NH3/MeOH in dichloromethane) provides [5-(2-amino-1-hydroxy-ethyl)-thiazol-2-yl]-carbamic acid tert-butyl ester (compound 62.4).
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][CH:21]4[CH2:26][CH2:25][CH:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH:6]=[CH:5]1.[CH3:28][O:29][CH2:30][CH2:31][C:32](O)=[O:33]>>[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:32](=[O:33])[CH2:31][CH2:30][O:29][CH3:28])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH:6]=[CH:5]1
Reactant: COCCC(=O)O
Reactant: NC1CCC(CCN2CCN(c3nccc4ccoc34)CC2)CC1
Agent: Cl
Product: COCCC(=O)N[C@H]1CC[C@H](CCN2CCN(c3nccc4ccoc34)CC2)CC1

Procedure:
The title compound, off-white solid (25 mg, 30%), MS (ISP) m/z=415.4 [(M+H)+], mp 146° C., was prepared in accordance with the general method of example 6 from 4-[2-(4-furo[2,3-c]pyridin-7-yl-piperazin-1-yl)-ethyl]-cyclohexylamine trihydrochloride (intermediate C) (88 mg, 0.2 mmol) and 3-methoxypropionic acid.