Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:26]=[CH:25][C:6]([C:7]([NH:9][C:10]2[C:11]([NH2:24])=[CH:12][C:13]([O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])=[CH:14][CH:15]=2)=[O:8])=[CH:5][CH:4]=1.N1C=CC=CC=1.[CH2:33]([C:36]1[CH:44]=[CH:43][C:39]([C:40](Cl)=[O:41])=[CH:38][CH:37]=1)[CH2:34][CH3:35]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:26]=[CH:25][C:6]([C:7]([NH:9][C:10]2[C:11]([NH:24][C:40](=[O:41])[C:39]3[CH:43]=[CH:44][C:36]([CH2:33][CH2:34][CH3:35])=[CH:37][CH:38]=3)=[CH:12][C:13]([O:16][Si:17]([C:20]([CH3:23])([CH3:21])[CH3:22])([CH3:19])[CH3:18])=[CH:14][CH:15]=2)=[O:8])=[CH:5][CH:4]=1
Reactant: COc1ccc(C(=O)Nc2ccc(O[Si](C)(C)C(C)(C)C)cc2N)cc1
Reactant: CCCc1ccc(C(=O)Cl)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCc1ccc(C(=O)Nc2cc(O[Si](C)(C)C(C)(C)C)ccc2NC(=O)c2ccc(OC)cc2)cc1
Reaction time: 4 h

Procedure:
To a solution of N1-(4-methoxybenzoyl)-4-(tert-butyldimethylsilyloxy)-1,2-benzenediamine (300 mg, 0.81 mmol) in methylene chloride (20 mL) was added pyridine (0.13 mL, 1.6 mmol) followed by 4-propylbenzoyl chloride (0.15 mL, 0.89 mmol). The reaction mixture was stirred for 4 h, diluted with methylene chloride, washed with saturated aqueous cupric sulfate solution, dried (magnesium sulfate), filtered, and concentrated in vacuo. The residue was chromatographed (silica gel, methylene chloride to 20% ethyl acetate/80% methylene chloride) to give 400 mg (95%) of the the title compound as a solid.
Reaction SMILES: [CH3:1][C:2]1[C:7]2[C:8](=[O:30])[NH:9][N:10](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[C:6]=2[CH:5]=[C:4]([NH:31][C:32]([NH:34][C@@H:35]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH3:36])=[O:33])[N:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].I[CH:50]1[CH2:55][CH2:54][O:53][CH2:52][CH2:51]1.C([SiH](CC)CC)C>CN(C=O)C.CS(C)=O>[CH3:1][C:2]1[C:7]2[C:8]([O:30][CH:50]3[CH2:55][CH2:54][O:53][CH2:52][CH2:51]3)=[N:9][NH:10][C:6]=2[CH:5]=[C:4]([NH:31][C:32]([NH:34][C@@H:35]([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH3:36])=[O:33])[N:3]=1
Reactant: IC1CCOCC1
Reactant: Cc1nc(NC(=O)N[C@H](C)c2ccccc2)cc2c1c(=O)[nH]n2C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC[SiH](CC)CC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CS(C)=O
Product: Cc1nc(NC(=O)N[C@H](C)c2ccccc2)cc2[nH]nc(OC3CCOCC3)c12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of (R)-1-(4-methyl-3-oxo-1-trityl-2,3-dihydro-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-(1-phenylethyl)urea (50 mg, 0.090 mmol), Cs2CO3 (91 mg, 0.279 mmol), and 4-iodotetrahydro-2H-pyran (25 μL, 0.209 mmol) in DMF (1 mL) was stirred at room temperature for 18 h. The reaction was quenched with MeOH and concentrated in vacuo. The residue was dissolved in TFA (2 mL), charged with triethylsilane (0.02 mL, 0.125 mmol), and stirred at room temperature for 2 h. The reaction mixture was diluted with DMSO (4 mL) and purified by mass-triggered reverse-phase HPLC. Fractions containing pure compound were filtered through a PS—HCO3 cartridge and the filtrate was concentrated in vacuo to give (R)-1-(4-methyl-3-((tetrahydro-2H-pyran-4-yl)oxy)-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-(1-phenylethyl)urea. MS ESI calc'd. For C21H25N5O3 [M+1]+ 396. found 396. 1H NMR (500 MHz, DMSO-d6) δ 8.96 (s, 1H), 8.12 (br s, 1H), 7.33 (m, 4H), 7.22 (m, 1H), 7.16 (br s, 1H), 4.95 (m, 1H), 4.84 (quintuplet, J=7.1 Hz, 1H), 3.84 (m, 2H), 3.52 (m, 2H), 2.59 (s, 3H), 2.06 (m, 1H), 1.71 (m, 1H), 1.39 (d, J=7.1 Hz, 3H).
Reaction SMILES: [F:1][C:2]([F:37])([F:36])[C:3]1[CH:4]=[C:5]([CH:29]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:31]=1)[C:6]([N:8]1[CH2:28][CH2:27][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:14][N:13]([CH2:22][CH2:23][CH2:24]O)[C:12]2=[O:26])[CH2:10][CH2:9]1)=[O:7].[CH3:38][NH:39][CH3:40]>>[F:37][C:2]([F:36])([F:1])[C:3]1[CH:4]=[C:5]([CH:29]=[C:30]([C:32]([F:33])([F:35])[F:34])[CH:31]=1)[C:6]([N:8]1[CH2:9][CH2:10][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:14][N:13]([CH2:22][CH2:23][CH2:24][N:39]([CH3:40])[CH3:38])[C:12]2=[O:26])[CH2:27][CH2:28]1)=[O:7]
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCC2(CC1)C(=O)N(CCCO)CN2c1ccccc1
Reactant: CNC
Product: CN(C)CCCN1CN(c2ccccc2)C2(CCN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC2)C1=O

Procedure:
The title compound, MS: m/e=557.2 (M+H+), was prepared in accordance with the general method of example 48 from 8-(3,5-bis-trifluoromethyl-benzoyl)-3-(3-hydroxy-propyl)-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one and dimethylamine.
Reaction SMILES: [N+:1]([C:4]1[NH:5][CH:6]=[CH:7][N:8]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].[C:15]([O:19][C:20](=[O:23])[CH2:21]Br)([CH3:18])([CH3:17])[CH3:16]>C(#N)C>[C:15]([O:19][C:20](=[O:23])[CH2:21][N:5]1[CH:6]=[CH:7][N:8]=[C:4]1[N+:1]([O-:3])=[O:2])([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: O=[N+]([O-])c1ncc[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)Cn1ccnc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 71 %

Procedure:
To a mixture of 2-nitroimidazole 1 (17.7 mmol, 1 equiv.) and anhydrous potassium carbonate (70.74 mmol, 4 equiv.) in 20 mL of acetonitrile is added dropwise a solution of tert-butylbromoacetate (17.7 mmol, 1 equiv.) in 10 ml of acetonitrile. The mixture is stirred one night at room temperature and concentrated under vacuum. The residue is purified by chromatography on silica gel using a mixture CH2Cl2/MeOH 95/5 as eluent to give the expected compound as white powder in 71% yield. mp 95-97° C.; 1H NMR (DMSO-d6, 400 MHz) δ 1.46 (s, 9H), 4.99 (s, 2H), 7.06 (d, 1H, J=1.01 Hz), 7.17 (d, 1H, J=1.01 Hz). MS (ESI+/ESI−) m/z 226.15 [M−H]−, 262.13 [M+Cl]−, 250.20 [M+H]+
Reaction SMILES: [CH2:1]([OH:14])[CH:2]([OH:13])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[C:15](=O)(OCC)[O:16]CC>[H-].[Na+].C1C=CC=CC=1>[CH2:3]([CH:2]1[CH2:1][O:14][C:15](=[O:16])[O:13]1)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCOC(=O)OCC
Reactant: CCCCCCCCCCC(O)CO
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Product: CCCCCCCCCCC1COC(=O)O1
Yield: 108.1 %

Procedure:
A 125 ml round bottom flask equipped with a Dean-Stark trap was charged with 10 g of 1,2-dodecanediol, 7.1 g of diethyl carbonate and 50 ml of benzene. The solution was stirred until homogeneous and then 50 mg of 60% NaH was added. The reaction mixture was refluxed for 6 hours and then concentrated to afford 12.2 g of oil. This was taken up in 100 ml of pet. ether and allowed to crystallize in freezer whereupon 1.1 g of starting diol was recovered. Concentration of the filtrate gave 9.53 g (89.66%) of a colorless oil.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1.[CH:13]1([NH2:16])[CH2:15][CH2:14]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[CH:13]1([NH:16][CH:2]2[CH2:7][CH2:6][CH:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]2)[CH2:15][CH2:14]1
Reactant: CCOC(=O)C1CCC(=O)CC1
Reactant: NC1CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)C1CCC(NC2CC2)CC1
Reaction time: 8 h

Procedure:
To a solution of ethyl 4-oxocyclohexanecarboxylate (3.4 g) in dichloromethane (30 mL) was added cyclopropanamine (1.14 g) followed by sodium triacetoxyborohydride (4.24 g). The mixture was stirred overnight. The mixture was diluted with dichloromethane (300 mL) and washed with 2N NaOH, water, brine and dried over Na2SO4. Filtration and evaporation of the solvent gave the title compound.
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[O:7])=[CH:4][CH:3]=1.[CH3:15][C:16]1[N:17]([CH2:25][CH2:26][CH2:27]CO)[C:18]2[CH:23]=[CH:22][N:21]=[CH:20][C:19]=2[N:24]=1>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6](=[O:7])[CH2:8][C:9]([O:11][CH2:12][CH2:27][CH2:26][CH2:25][N:17]2[C:18]3[CH:23]=[CH:22][N:21]=[CH:20][C:19]=3[N:24]=[C:16]2[CH3:15])=[O:10])=[CH:13][CH:14]=1
Reactant: COC(=O)CC(=O)c1ccc(F)cc1
Reactant: Cc1nc2cnccc2n1CCCCO
Solvent: Cc1ccccc1
Product: Cc1nc2cnccc2n1CCCCOC(=O)CC(=O)c1ccc(F)cc1
Reaction time: 2 h
Yield: 71.5 %

Procedure:
Methyl 4-fluorobenzoylacetate (0.78 g, 4 mM) and 4-(2-methylimidazo[4,5-c]pyrid-1-yl)butanol (0.82 g, 4 mM--see Preparation 16) were heated at reflux in toluene (100 cm3) allowing the toluene to reduce to about 20 cm3 over a period of 2 hours. The remaining toluene was removed in vacuo and the residue purified by column chromatography on silica (Merck "Kieselgel 60"--Trade Mark) eluting with dichloromethane:methanol 19:1. Evaporation of the appropriate fractions gave the title compound as a colourless oil, (1.05 g, 71%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:3]=1[C:4]([OH:6])=[O:5].[N:12]1[CH:17]=[CH:16][C:15]([CH:18]=O)=[CH:14][CH:13]=1>>[CH3:11][C:7]1[CH:8]=[CH:9][CH:10]=[C:2]([NH:1][CH2:18][C:15]2[CH:16]=[CH:17][N:12]=[CH:13][CH:14]=2)[C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=Cc1ccncc1
Reactant: Cc1cccc(N)c1C(=O)O
Product: Cc1cccc(NCc2ccncc2)c1C(=O)O

Procedure:
Prepared by a similar procedure as described for preparation 1A, starting from 2-amino-6-methylbenzoic acid (Fluka) and pyridine-4-carbaldehyde. 13C-NMR (DMSO-d6) δ 170.4, 149.5, 149.3, 147.8, 138.5, 131.2, 121.9, 118.7, 115.8, 109.1, 45.1, 22.1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:13]2[CH:15]([C:16]([O:18]CC)=[O:17])[C:14]2([CH3:22])[CH3:21])[CH:5]=[CH:6][C:7]=1[O:8][C:9]([F:12])([F:11])[F:10].[OH-].[Na+]>C(O)C.O>[Br:1][C:2]1[CH:3]=[C:4]([C@H:13]2[C@H:15]([C:16]([OH:18])=[O:17])[C:14]2([CH3:22])[CH3:21])[CH:5]=[CH:6][C:7]=1[O:8][C:9]([F:12])([F:11])[F:10]
Reactant: CCOC(=O)C1C(c2ccc(OC(F)(F)F)c(Br)c2)C1(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC1(C)[C@@H](C(=O)O)[C@@H]1c1ccc(OC(F)(F)F)c(Br)c1

Procedure:
16 g (0.042 mol) of ethyl 3-(3-bromo-4-trifluoromethoxyphenyl)-2,2-dimethyl-cyclopropanecarboxylate were dissolved in 50 ml of ethanol, a solution of 3.4 g (0.085 mol) of sodium hydroxide in 50 ml of water was then added, and the mixture was heated under reflux for 4 hours, while stirring. The ethanol was then distilled off in the vacuum from a water jet, the residue was taken up in 300 ml of water, and the solution was extracted once with 300 ml of methylene chloride. The aqueous phase was separated off, acidified with concentrated hydrochloric acid and then extracted twice with 300 ml of methylene chloride. The organic phase was then separated off and dried over magnesium sulphate, and the solvent was distilled off in the vacuum from a water jet. The last residues of solvent were removed by incipient distillation for a short time, at a bath temperature of 50° C./2 mm Hg. 9.8 g (66.3% of theory) of (±)cis/trans-3-(3-bromo-4-trifluoromethoxyphenyl)- 2,2-dimethyl-cyclopropanecarboxylic acid were then obtained as a yellow viscous oil. The structure was confirmed by the 1H-NMR spectrum.
Reaction SMILES: C(OC([N:8]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:9]1[C:10]([C:16]([O:18][CH3:19])=[O:17])=[N:11][C:12](Br)=[CH:13][N:14]=1)=O)(C)(C)C.BrC1N=[C:32]([C:34](OC)=[O:35])C(NC(OC(C)(C)C)=O)=NC=1.Cl>C1(C)C=CC=CC=1>[CH3:19][O:18][C:16]([C:10]1[C:9]([NH:8][C:20]([O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[O:21])=[N:14][CH:13]=[C:12]([C:34](=[O:35])[CH3:32])[N:11]=1)=[O:17]
Reactant: COC(=O)c1nc(Br)cnc1NC(=O)OC(C)(C)C
Reactant: COC(=O)c1nc(Br)cnc1N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: Cl
Solvent: Cc1ccccc1
Product: COC(=O)c1nc(C(C)=O)cnc1NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 18 h
Yield: 45 %

Procedure:
To a stirred solution of an 1:4 mixture of methyl 3-(bis(tert-butoxycarbonyl)amino)-6-bromopyrazine-2-carboxylate and methyl 6-bromo-3-(tert-butoxycarbonylamino)pyrazine-2-carboxylate (ca. 4.1 g, 11.6 mmol) at rt in toluene (55 ml) under an argon atmosphere were added bis(triphenylpohsphine)palladium(II) chloride (81.1 mg, 0.12 mmol) and 1-ethoxyvinyl tri-N-butyltin (3.0 g, 2.8 ml, 12.7 mmol). The clear yellow solution was heated to reflux and stirring was continued for 18 h. The mixture was cooled to 0° C. 1 N HCl (55 ml) was added dropwise within 15 min. The biphasic mixture was stirred vigourously for 22 h, slowly warming up to rt. The layers were separated. The organic layer was diluted with 150 ml EtOAc (150 ml). Then, a 10% aqueous ammonium fluoride solution (150 ml) was added. The biphasic mixture was then stirred at rt for 5 h and then filtered. The organic phase of the filtrate was washed with 50 ml brine, dried (MgSO4), filtered and concentrated. The product was purified by silica gel chromatography using a n-heptane/ethyl acetate gradient. The product-containing fractions were concentrated. The residue was triturated with n-heptane/cyclohexane 9:1 (20 ml). The suspension was stirred for 2 hrs. The solid was filtrated, washed with n-heptane and dried to give the title compound (1.54 g, 45%) as off-white solid.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][CH2:19][CH:20]2[O:22][CH2:21]2)[O:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH:23]1([NH2:26])[CH2:25][CH2:24]1>>[C:1]([C:5]1[CH:9]=[C:8]([CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][CH2:19][CH:20]([OH:22])[CH2:21][NH:26][CH:23]2[CH2:25][CH2:24]2)[O:7][N:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: NC1CC1
Reactant: CC(C)(C)c1cc(C=Cc2ccccc2OCC2CO2)on1
Product: CC(C)(C)c1cc(C=Cc2ccccc2OCC(O)CNC2CC2)on1
Yield: 70.7 %

Procedure:
7 g (0.023 mole) of 3-tert.-butyl-5-[2-(2,3-epoxypropoxy)-styryl]-isoxazole and 2.7 g (0.047 mole) of cyclopropylamine are reacted by the method described in Example 1. 5.8 g of an oil are obtained; this is dissolved in diethyl ether and precipitated with 2 g of oxalic acid dissolved in a small amount of ethanol. 2.7 g (26% of theory) of colorless crystals are obtained. Melting point 170°-174° C.
Reaction SMILES: [CH2:1]([C@H:6]1[CH2:11][CH2:10][C@H:9]([CH2:12][CH2:13][CH2:14][CH2:15][C:16]2[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][CH:17]=2)[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5].[CH2:24]([CH:29](CO)[CH2:30][OH:31])CCCC.S(=O)(=O)(O)O>C1(C)C=CC=CC=1>[CH2:1]([C@H:6]1[CH2:7][CH2:8][C@H:9]([CH2:12][CH2:13][CH2:14][CH2:15][C:16]2[CH:17]=[CH:18][C:19]([CH:20]3[O:31][CH2:30][CH2:29][CH2:24][O:21]3)=[CH:22][CH:23]=2)[CH2:10][CH2:11]1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCC[C@H]1CC[C@H](CCCCc2ccc(C=O)cc2)CC1
Reactant: CCCCCC(CO)CO
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Product: CCCCC[C@H]1CC[C@H](CCCCc2ccc(C3OCCCO3)cc2)CC1
Reaction time: 2 h

Procedure:
A solution of 3 g of 4-[4-(trans-4-pentylcyclohexyl)-1-butyl]benzaldehyde and 1.7 g of 2-pentyl-1,3-propanediol in 50 ml of toluene was treated with 2 drops of 10% (vol.) sulfuric acid. The mixture was heated to boiling for 2 hours, whereby the resulting water was distilled off simultaneously. Then, 4 drops of triethylamine were added to the reaction mixture. After cooling the mixture was washed with 50 ml of 1N sodium hydrogen carbonate solution and twice with 50 ml of water each time, dried over magnesium sulfate, filtered and subsequently concentrated. Chromatography of the residue on silica gel with toluene and recrystallization from acetone gave 1.2 g of trans-5-pentyl-2-(4-[4-(trans-4-pentylcyclohexyl)-1-butyl]phenyl-1,3-dioxane with m.p. (C-N) 73° C. and clop. (N-Z) 106° C.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)[S:4][C:3]=1[C:14]([NH:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][N:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)=[C:19]([O:31][CH3:32])[CH:18]=1)=[O:15].[C:33](O)(=O)[CH3:34]>>[Cl:13][C:10]1[CH:9]=[CH:8][C:7]([C:5]2[S:4][C:3]3[C:14](=[O:15])[N:16]([C:17]4[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][N:26]5[CH2:30][CH2:29][CH2:28][CH2:27]5)=[C:19]([O:31][CH3:32])[CH:18]=4)[C:33]([CH3:34])=[N:1][C:2]=3[CH:6]=2)=[CH:12][CH:11]=1
Reactant: COc1cc(NC(=O)c2sc(-c3ccc(Cl)cc3)cc2N)ccc1OCCN1CCCC1
Reactant: CC(=O)O
Product: COc1cc(-n2c(C)nc3cc(-c4ccc(Cl)cc4)sc3c2=O)ccc1OCCN1CCCC1

Procedure:
A mixture of 3-amino-5-(4-chlorophenyl)-N-[3-methoxy-4-(2-pyrrolidin-1-ylethoxy) phenyl]thiophene-2-carboxamide and glacial acetic acid was refluxed overnight, concentrated to an amber viscous oil, triturated with water then filtered to give the title compound as its acetic acid salt as a tan solid (0.032 g, 64%). LCMS m/z 496 (MH+). 1H NMR (300 MHz, DMSO-d6) δ 8.35 (br, 1H), 8.00 (s, 1H), 7.95 (d, 2H), 7.55 (d, 2H), 7.20 (s, 1H), 7.10 (d, 1H), 6.95 (d, 1H), 4.20 (m, 2H), 3.75 (s, 3H), 2.75 (m, 2H), 2.55 (m, 4H), 2.20 (s, 3H), 2.00 (s, 3H), 1.65 (m, 4H) ppm.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:20])=[CH:4][C:5]([F:19])=[C:6]([N:8]=[C:9]2[N:17]3[N:12]([CH2:13][CH2:14][CH2:15][CH2:16]3)[C:11](=[S:18])[S:10]2)[CH:7]=1.[CH2:21]([S:23](Cl)(=[O:25])=[O:24])[CH3:22].N1C=CC=CC=1>C(Cl)Cl>[Cl:20][C:3]1[C:2]([NH:1][S:23]([CH2:21][CH3:22])(=[O:25])=[O:24])=[CH:7][C:6]([N:8]=[C:9]2[N:17]3[N:12]([CH2:13][CH2:14][CH2:15][CH2:16]3)[C:11](=[S:18])[S:10]2)=[C:5]([F:19])[CH:4]=1
Reactant: CCS(=O)(=O)Cl
Reactant: Nc1cc(N=c2sc(=S)n3n2CCCC3)c(F)cc1Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCS(=O)(=O)Nc1cc(N=c2sc(=S)n3n2CCCC3)c(F)cc1Cl
Temperature: 25 °C
Reaction time: 48 h
Yield: 20.3 %

Procedure:
A mixture of 0.45 g (0.0014 mole) of 9-(5-amino-4-chloro-2-fluorophenyl)imino-8-thia-1,6-diazabicyclo[4.3.0]nonane-7-thione, 0.18 g (0.0014 mole) of ethanesulfonyl chloride, and 0.22 g (0.027 mole) of pyridine in approximately 30 mL of methylene chloride was stirred at room temperature for two days. The reaction mixture was heated at 26° C. for approximately 24 hours, then at reflux for 36 hours. The solvent was evaporated from the mixture leaving an oily residue. The residue was washed with an aqueous, 10% hydrochloric acid solution. The washed residue crystallized upon standing and was recrystallized from ethyl acetate and n-heptane to give 0.12 g of 9-(4-chloro-5-ethylsulfonylamino-2-fluorophenyl)imino-8-thia-1,6-diazabicyclo[4.3.0]nonane-7-thione, mp 146°-148° C., Compound 11 of Table 1.
Reaction SMILES: [CH3:1][NH:2][S:3]([C:6]1[NH:7][C:8](=[O:12])[CH:9]=[CH:10][CH:11]=1)(=[O:5])=[O:4].[CH3:13][Si:14]([CH3:20])([C:16]([CH3:19])([CH3:18])[CH3:17])Cl>>[CH3:1][NH:2][S:3]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][Si:14]([CH3:20])([CH3:13])[C:16]([CH3:19])([CH3:18])[CH3:17])[N:7]=1)(=[O:5])=[O:4]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CNS(=O)(=O)c1cccc(=O)[nH]1
Product: CNS(=O)(=O)c1cccc(O[Si](C)(C)C(C)(C)C)n1

Procedure:
2-(N-methylsulphamoyl)pyrid-6-one was silylated with dimethyl-(1,1-dimethylethyl)chlorosilane in the presence of imadazole under standard conditions to give 2-[N-methylsulphamoyl]-6-[dimethyl-(1,1-dimethylethyl)silyloxy]pyridine
Reaction SMILES: [CH3:1][C:2](=[CH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:3](Cl)=[O:4].[CH3:13][CH:14]([CH3:28])[CH:15]([C:21]1[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][CH:22]=1)[N:16]1[CH:20]=[N:19][CH:18]=[N:17]1>C(Cl)Cl.N1C=CC=CC=1>[CH3:1]/[C:2](=[CH:6]\[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)/[C:3]([NH:27][C:24]1[CH:25]=[CH:26][C:21]([CH:15]([N:16]2[CH:20]=[N:19][CH:18]=[N:17]2)[CH:14]([CH3:28])[CH3:13])=[CH:22][CH:23]=1)=[O:4]
Reactant: CC(C)C(c1ccc(N)cc1)n1cncn1
Reactant: CC(=Cc1ccccc1)C(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: C/C(=C\c1ccccc1)C(=O)Nc1ccc(C(C(C)C)n2cncn2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 20.2 %

Procedure:
A solution of 2-methyl-3-phenyl-2-propenoyl chloride (0.0554 mol) in CH2Cl2 (50 ml) was added dropwise to a solution of (±)-4-[2-methyl-1-(1H-1,2,4-triazol-1-yl)propyl]-benzenamine (0.037 mol) in pyridine (8 ml) and CH2Cl2 (100 ml) and the mixture was stirred at RT for 4 hours. The solvent was evaporated and the residue was taken up in water/EtOAc. The organic layer was dried, filtered and the solvent evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH/NH4OH 99/1/0.1). The pure fractions were collected and evaporated. The residue was crystallized from (C2H5)2O/methylethylketone, yielding 2.7 g (21%) of (±)-(E)-2-methyl-N-[4-[2-methyl-1-(1H-1,2,4-triazol-1-yl)propyl]phenyl]-3-phenyl-2-propenamide (compound 154).
Reaction SMILES: [OH:1][N:2]=[C:3]([C:5]1[C:9]([NH:10][CH2:11][CH2:12][NH:13][S:14]([CH3:17])(=[O:16])=[O:15])=[N:8][O:7][N:6]=1)[NH2:4].[Cl:18][C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][C:25]=1[F:26])N>>[Cl:18][C:19]1[CH:20]=[C:21]([NH:4][C:3]([C:5]2[C:9]([NH:10][CH2:11][CH2:12][NH:13][S:14]([CH3:17])(=[O:16])=[O:15])=[N:8][O:7][N:6]=2)=[N:2][OH:1])[CH:23]=[CH:24][C:25]=1[F:26]
Reactant: CS(=O)(=O)NCCNc1nonc1C(N)=NO
Reactant: Nc1ccc(F)c(Cl)c1
Product: CS(=O)(=O)NCCNc1nonc1C(=NO)Nc1ccc(F)c(Cl)c1

Procedure:
The title compound was prepared according to the procedure of Example 17 step E, using N′-hydroxy-4-({2-[(methylsulfonyl)amino]ethyl}amino)-1,2,5-oxadiazole-3-carboximidamide and 3-chloro-4-fluoroaniline [Aldrich, product #228583] as the starting materials. LCMS for C12H15ClFN6O4S (M+H)+: m/z=393.0. 1H NMR (400 MHz, DMSO-d6): δ 11.50 (s, 1H), 8.91 (s, 1H), 7.19 (m, 2H), 6.96 (dd, J=6.7, 2.5 Hz, 1H), 6.71 (m, 1H), 6.26 (t, J=6.4 Hz, 1H), 3.32 (m, 2H), 3.13 (q, J=5.8 Hz, 2H), 2.89 (s, 3H).
Reaction SMILES: [CH3:1][N:2]1[C:7]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][OH:16])[CH2:10][CH2:9]2)=[CH:6][C:5](=[O:17])[N:4]([CH3:18])[C:3]1=[O:19].[N+:20]([C:23]1[CH:28]=[CH:27][C:26](O)=[CH:25][CH:24]=1)([O-:22])=[O:21].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[CH3:1][N:2]1[C:7]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][O:16][C:26]3[CH:27]=[CH:28][C:23]([N+:20]([O-:22])=[O:21])=[CH:24][CH:25]=3)[CH2:10][CH2:9]2)=[CH:6][C:5](=[O:17])[N:4]([CH3:18])[C:3]1=[O:19]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: Cn1c(N2CCN(CCO)CC2)cc(=O)n(C)c1=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cn1c(N2CCN(CCOc3ccc([N+](=O)[O-])cc3)CC2)cc(=O)n(C)c1=O
Yield: 69.3 %

Procedure:
To 100 ml of anhydrous tetrahydrofuran were added 5.37 g of 1,3-dimethyl-6-[4-(2-hydroxyethyl)piperazin-1-yl]-2,4(1H,3H)-pyrimidinedione (compound 41), 3.20 g of 4-nitrophenol and 6.03 g of triphenylphosphine, and the resulting mixture was treated in the same manner as in Example 20-(2) to obtain 5.40 g of crystalline 1,3-dimethyl-6-{4-[2-(4-nitrophenoxy)ethyl]piperazin-1-yl}-2,4(1H,3H)-pyrimidinedione.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][C:11]#[N:12].[H-].[Na+].Cl[C:16]1[N:21]=[CH:20][CH:19]=[CH:18][N:17]=1.Cl>C1COCC1.O>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]1=[C:10]([C:16]1[N:21]=[CH:20][CH:19]=[CH:18][N:17]=1)[C:11]#[N:12]
Reactant: Clc1ncccn1
Reactant: N#CCc1nc2ccccc2s1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: N#CC(=C1Nc2ccccc2S1)c1ncccn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2-(Benzothiazol-2-yl)acetonitrile (0.69 g, 4 mmol) was added in portions to a suspension of 95% sodium hydride ((0.21 g, 6 mmol) in THF (12 mL). The resulting yellow suspension was stirred at room temperature for 30 min, and 2-chloropyrimidine (0.45 g, 4 mmol) was added. The mixture was stirred for 3 d, and water was added to the dark solution. The mixture was acidified with 1N hydrochloric acid, and the precipitate that formed was collected by filtration, washed with water and acetonitrile, and dried under vacuum to give 2-[benzothiazol-2(3H)-ylidene]-2-(pyrimidin-2-yl)acetonitrile as a brown solid.