Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:20]([C:23]1[C:32]2[CH:31]=[N:30][C:29]([S:33][CH3:34])=[N:28][C:27]=2[N:26]([CH:35]2[CH2:39][CH2:38][CH2:37][CH2:36]2)[C:25](=[O:40])[CH:24]=1)=[N+]=[N-].Cl.C([O-])(O)=O.[Na+]>C1COCC1>[NH2:20][C:23]1[C:32]2[CH:31]=[N:30][C:29]([S:33][CH3:34])=[N:28][C:27]=2[N:26]([CH:35]2[CH2:39][CH2:38][CH2:37][CH2:36]2)[C:25](=[O:40])[CH:24]=1
Reactant: CSc1ncc2c(N=[N+]=[N-])cc(=O)n(C3CCCC3)c2n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CSc1ncc2c(N)cc(=O)n(C3CCCC3)c2n1
Temperature: 35 °C
Reaction time: 2 h
Yield: 75.4 %

Procedure:
Triphenylphosphine (1.68 g, 6.40 mmol) was added, at RT, to a solution of 5-azido-8-cyclopentyl-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one (1.29 g, 4.27 mmol) in THF (43 mL) and the reaction mixture was stirred at 35° C. for 2 h. An HCl (1 M, 22 mL) was then added and the reaction mixture was heated at reflux for 2 h and then was stored at 4° C. overnight. The resulting mixture was neutralized to pH 8 with NaHCO3 (sat'd aq), and was extracted with EtOAc (2×200 mL). The combined organic layers were dried over MgSO4, filtered and evaporated under reduced pressure. The crude residue was purified by flash chromatography (from 2 to >5% MeOH/DCM in 20 min.) to give 0.89 g (75% yield) of 5-amino-8-cyclopentyl-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one as a yellow solid. MS=277 [M+1]+.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][N:2]1[C:10]1[N:11]=[C:12]2[C:18]([C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:17][N:16](COCC[Si](C)(C)C)[C:13]2=[N:14][CH:15]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][N:2]1[C:10]1[N:11]=[C:12]2[C:18]([C:19](=[O:24])[C:20]([CH3:22])([CH3:21])[CH3:23])=[CH:17][NH:16][C:13]2=[N:14][CH:15]=1
Reactant: CC(C)(C)C(=O)c1cn(COCC[Si](C)(C)C)c2ncc(N3Cc4ccccc4C3)nc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)c1c[nH]c2ncc(N3Cc4ccccc4C3)nc12
Temperature: 85 °C
Yield: 79.9 %

Procedure:
To a solution of 1-[2-(1,3-Dihydro-isoindol-2-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-2,2-dimethyl-propan-1-one (270 mg, 0.599 mmol) in 7 mL of THF was added 5.99 mL (5.99 mmol) of 1.0 M TBAF in THF. Heated the mixture to 85° C. for 2 h. The reaction was quenched with 5 mL acetone and 15 mL of saturated aqueous NaHCO3 then diluted with ethyl acetate and water and partitioned. The organic phase was washed with brine, dried over MgSO4, filtered, and concentrated. Recrystallization from dichloromethane afforded 153.3 mg (80% yield) of 1-[2-(1,3-Dihydro-isoindol-2-yl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-2,2-dimethyl-propan-1-one as a white solid.
Reaction SMILES: C(OC([N:8]1[CH:15]2[CH:11]([N:12]([C:26]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[O:27])[CH2:13][CH:14]2[CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([F:24])=[C:20]([F:25])[CH:19]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:29]([O:28][C:26]([N:12]1[CH2:13][CH:14]([CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([F:24])=[C:20]([F:25])[CH:19]=2)[CH:15]2[NH:8][CH2:9][CH2:10][CH:11]12)=[O:27])[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: CC(C)(C)OC(=O)N1CCC2C1C(COc1ccc(F)c(F)c1)CN2C(=O)OCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1CC(COc2ccc(F)c(F)c2)C2NCCC21
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A solution of phenol-ether 78 (0.86 g, 1.8 mmol) in DCM (10 mL) was treated with TFA (3 mL) at 0° C. After 20 min, the reaction was warmed to ambient temperature. After 1 h, the solution was concentrated, diluted with EtOAc, washed successively with saturated aqueous NaHCO3, and brine, dried over anhydrous Na2SO4, filtered and concentrated. The aqueous phase was back-extracted with DCM and the combined organic extracts were concentrated to give amine 80 as an orange-colored oil that was used without further purification. Mass spectrum, m/z [389.5] (M+H)+.
Reaction SMILES: [CH2:1]([S:3][C:4]1[N:23]=[CH:22][CH:21]=[CH:20][C:5]=1[C:6]([NH:8][C:9]1[C:10]([OH:19])=[N:11][CH:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:14]=1)=O)[CH3:2].N(C(OCCOC)=O)=NC(OCCOC)=O.COCCOC(/N=N/C(OCCOC)=O)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl-].[NH4+]>C1COCC1>[CH2:1]([S:3][C:4]1[C:5]([C:6]2[O:19][C:10]3[C:9]([N:8]=2)=[CH:14][C:13]([C:15]([F:18])([F:17])[F:16])=[CH:12][N:11]=3)=[CH:20][CH:21]=[CH:22][N:23]=1)[CH3:2]
Reactant: CCSc1ncccc1C(=O)Nc1cc(C(F)(F)F)cnc1O
Agent: COCCOC(=O)/N=N/C(=O)OCCOC
Agent: COCCOC(=O)N=NC(=O)OCCOC
Agent: [Cl-]
Solvent: C1CCOC1
Product: CCSc1ncccc1-c1nc2cc(C(F)(F)F)cnc2o1
Temperature: 50 °C
Reaction time: 4 h
Yield: 52 %

Procedure:
A mixture of 0.69 g of 2-ethylsulfanyl-N-(2-hydroxy-5-trifluoromethylpyridin-3-yl) nicotinamide, 0.75 g of bis(2-methoxyethyl) azodicarboxylate (hereinafter referred to as DMEAD), 0.79 g of triphenylphosphine and 7 ml of THF was stirred at 50° C. for 4 hours. A saturated aqueous ammonium chloride solution was poured to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, then dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue was applied to a silica gel column chromatography to obtain 0.34 g of 2-(2-ethylsulfanylpyridin-3-yl)-6-(trifluoromethyl)oxazolo[5,4-b]pyridine (hereinafter, referred to as Compound of Present Invention 32).
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([CH:25]([CH3:27])[CH3:26])=[CH:21][N:20]=3)(=[O:17])=[O:16])=[CH:11][CH:10]=2)=[C:5]([CH3:28])[O:4][N:3]=1.C(N=C(N(C)C)N(C)C)(C)(C)C.Br[CH2:42][CH:43]1[CH2:46][CH2:45][CH2:44]1>C(#N)C>[CH:43]1([CH2:42][N:18]([C:19]2[CH:24]=[CH:23][C:22]([CH:25]([CH3:26])[CH3:27])=[CH:21][N:20]=2)[S:15]([C:12]2[CH:11]=[CH:10][C:9]([O:8][CH2:7][C:6]3[C:2]([CH3:1])=[N:3][O:4][C:5]=3[CH3:28])=[CH:14][CH:13]=2)(=[O:17])=[O:16])[CH2:46][CH2:45][CH2:44]1
Reactant: Cc1noc(C)c1COc1ccc(S(=O)(=O)Nc2ccc(C(C)C)cn2)cc1
Reactant: BrCC1CCC1
Agent: CN(C)C(=NC(C)(C)C)N(C)C
Solvent: CC#N
Product: Cc1noc(C)c1COc1ccc(S(=O)(=O)N(CC2CCC2)c2ccc(C(C)C)cn2)cc1
Temperature: 20 °C
Reaction time: 1 h
Yield: 23.9 %

Procedure:
To a solution of 4-((3,5-dimethylisoxazol-4-yl)methoxy)-N-(5-isopropylpyridin-2-yl)benzenesulfonamide (150 mg, 0.374 mmol) in acetonitrile (4 mL) stirred in air at 20° C., was added 2-(tert-butyl)-1,1,3,3-tetramethylguanidine (128 mg, 0.747 mmol). The reaction mixture was stirred at 20° C. for 1 hour, then (bromomethyl)cyclobutane (0.084 ml, 0.747 mmol) was added. The reaction was heated by microwaves to 150° C. for 30 minutes. After cooling the solvent was removed in vacuo and the residue was dissolved in ethyl acetate. The organic phase was washed with water (5 mL) and dried using a hydrophobic frit. The solvent was removed in vacuo to give the crude product as an orange oil. The crude product was purified by flash silica (Si) chromatography (0-25% ethyl acetate-cyclohexane gradient). The appropriate fractions were combined and evaporated in vacuo to give the title product (42 mg) as a colourless oil. LCMS (2 min, High pH) Rt 1.48 mins, m/z (ES+) 470, (M+H).
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH3:4].C=CCC.[CH:9]([OH:13])([CH2:11][CH3:12])[CH3:10]>O>[CH:2]([O:13][CH:9]([CH2:11][CH3:12])[CH3:10])([CH2:3][CH3:4])[CH3:1]
Reactant: CCC(C)O
Reactant: CCCC
Agent: C=CCC
Solvent: O
Product: CCC(C)OC(C)CC

Procedure:
The procedure described in comparison Example 1 was altered so that by use of an additional dosing pump 54 kgs of the process water (total amount 204 kgs) were charged to the n-butane/n-butene mixture (feedgas and recycle gas=3,000 kgs/h) and transferred to the evaporator. Employing the same conditions as in comparison Example 1 (155° C. to 160° C., 70 bar) a temperature of 155° C. to 162° C. could be maintained in the reactor without additional heating or cooling. In the sump of a column, average amounts of 201.3 kgs (2,720 moles) of sec. butyl alcohol and 2.1 kgs (16.2 moles) of di-sec. butyl ether were obtained per hour as an approx. 99% purity crude alcohol. 101.5 kgs of n-butene and 46.4 kgs of n-butane were obtained as an approx. 59% mixture.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]([CH2:21][CH:22]([CH3:24])[CH3:23])[S:10]([C:13]1[CH:18]=[CH:17][C:16]([CH:19]=[CH2:20])=[CH:15][CH:14]=1)(=[O:12])=[O:11].ClC1C=C(C=CC=1)C(OO)=[O:30]>ClCCl>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]([CH2:21][CH:22]([CH3:24])[CH3:23])[S:10]([C:13]1[CH:18]=[CH:17][C:16]([CH:19]2[CH2:20][O:30]2)=[CH:15][CH:14]=1)(=[O:12])=[O:11]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=Cc1ccc(S(=O)(=O)N(CC(C)C)c2ccc(C)cc2C)cc1
Solvent: ClCCl
Product: Cc1ccc(N(CC(C)C)S(=O)(=O)c2ccc(C3CO3)cc2)c(C)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of N-(2,4-dimethylphenyl)-N-isobutyl-4-vinylbenzenesulfonamide (1.27 g, 3.70 mmol) in dichloromethane (DCM) (30 mL) stirred under nitrogen at 0° C., was added meta-chloroperoxybenzoic acid (mCPBA) (2.55 g, 14.79 mmol), portionwise. The reaction mixture was stirred at 0° C. for 30 minutes. The reaction was then stirred for 16 hours at 20° C. DCM (20 mL) was added to the mixture. The organic phase was washed with 0.1M sodium hydroxide solution (2×50 mL), dried using a hydrophobic frit and evaporated in vacuo to give the crude product. The sample was loaded in dichloromethane and purified on silica (Si) using a 0-50% ethyl acetate-cyclohexane gradient. The appropriate fractions were combined and evaporated in vacuo to give the required product, 935 mg, as an off-white oil which solidified on standing. LCMS [LCMS1] Rt 1.35 min, m/z (ES+) 360 (M+H).
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[C:5]([CH3:12])[C:4]=1[NH:13]C(=O)C.C(=O)([O-])[O-].[Na+].[Na+]>O>[CH3:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[C:5]([CH3:12])[C:4]=1[NH2:13]
Reactant: CC(=O)Nc1c(C)cc([N+](=O)[O-])cc1C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: Cc1cc([N+](=O)[O-])cc(C)c1N
Temperature: 140 °C
Yield: 97.5 %

Procedure:
Concentrated hydrochloric acid (17.5 mL) was added to N-(2,6-dimethyl-4-nitro-phenyl)-acetamide (5.05 g) and heated to 140° C. for 30 minutes in a sealed microwave process vial. The reaction mixture was neutralized with solid sodium carbonate in water and the precipitated product was collected by filtration and washed with water (100 mL) to furnish 3.93 g (97% yield) of the title compound as a yellow solid. 1H NMR (500 MHz, DMSO-d6): 2.15 (s, 6H), 6.15 (b, 2H), 7.79 (s, 2H).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8](F)=[CH:7][CH:6]=1)(=[O:4])=[O:3].C([O-])([O-])=O.[Cs+].[Cs+].[CH3:18][O:19][C:20]([C:22]1[CH:23]=[C:24]([OH:32])[CH:25]=[C:26]2[O:30][CH:29]([CH3:31])[CH2:28][C:27]=12)=[O:21]>CN(C=O)C>[CH3:18][O:19][C:20]([C:22]1[CH:23]=[C:24]([O:32][C:8]2[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:6][CH:7]=2)[CH:25]=[C:26]2[O:30][CH:29]([CH3:31])[CH2:28][C:27]=12)=[O:21]
Reactant: CS(=O)(=O)c1ccc(F)cc1
Reactant: COC(=O)c1cc(O)cc2c1CC(C)O2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Oc2ccc(S(C)(=O)=O)cc2)cc2c1CC(C)O2
Temperature: 120 °C
Yield: 54.9 %

Procedure:
4-Fluorophenyl methyl sulfone (307 mg, 1.76 mmol) and Cs2CO3 (1.15 g, 3.52 mmol) were added to a solution of 6-hydroxy-2-methyl-2,3-dihydro-benzofuran-4-carboxylic acid methyl ester (1e) (366 mg, 1.76 mmol) in DMF (8 mL). The mixture was heated to 120° C. for 1 hr, cooled to room temperature, quenched with H2O (50 mL) and extracted with EtOAc (2×50 mL). The organic layers were washed with H2O (2×80 mL), dried over MgSO4 and concentrated. The residue was purified by flash column chromatography eluting with 40% EtOAc in hexanes to give a pale brown solid (350 mg, 55% yield). 1H NMR (400 MHz, CDCl3) δ 7.84-7.93 (m, 2 H) 7.18 (d, J=2.02 Hz, 1 H) 7.04-7.14 (m, 2 H) 6.67 (d, J=2.27 Hz, 1 H) 4.94-5.17 (m, 1 H) 3.89 (s, 3 H) 3.68 (dd, J=17.43, 8.84 Hz, 1 H) 3.13 (dd, J=17.43, 7.58 Hz, 1 H) 3.07 (s, 3H) 1.51 (d, J=6.32 Hz, 3 H);); LCMS for C18H18O6S m/z 363.0 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[O:13][N:12]=[C:11]([OH:14])[CH:10]=1.[C:15]([O:19][C:20]([NH:22][CH2:23][CH2:24]O)=[O:21])([CH3:18])([CH3:17])[CH3:16]>>[C:15]([O:19][C:20]([NH:22][CH2:23][CH2:24][O:14][C:11]1[CH:10]=[C:9]([C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])[O:13][N:12]=1)=[O:21])([CH3:18])([CH3:17])[CH3:16]
Reactant: Oc1cc(-c2ccc(Cl)cc2Cl)on1
Reactant: CC(C)(C)OC(=O)NCCO
Product: CC(C)(C)OC(=O)NCCOc1cc(-c2ccc(Cl)cc2Cl)on1
Yield: 80.1 %

Procedure:
5-(2,4-Dichlorophenyl)-3-hydroxyisoxazole (0.2 g) and 2-(N-tert-butoxycarbonylamino)ethanol (0.17 g) were subjected to reaction and post-treatment in a similar manner to that described in Example 9(a) to obtain the title compound (0.26 g, 81%) as a colorless powder.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].Br[C:8]1[CH:9]=[C:10]([NH:15][S:16]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[C:11]([Cl:14])=[N:12][CH:13]=1.CC1(C)C(C)(C)OB([C:35]2[CH:52]=[CH:51][C:38]3[N:39]=[C:40]([NH:42][C:43]([CH:45]4[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46]4)=[O:44])[S:41][C:37]=3[CH:36]=2)O1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl.O1CCOCC1>[Cl:14][C:11]1[N:12]=[CH:13][C:8]([C:35]2[CH:52]=[CH:51][C:38]3[N:39]=[C:40]([NH:42][C:43]([CH:45]4[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46]4)=[O:44])[S:41][C:37]=3[CH:36]=2)=[CH:9][C:10]=1[NH:15][S:16]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1)(=[O:18])=[O:17]
Reactant: COc1ccc(S(=O)(=O)Nc2cc(Br)cnc2Cl)cc1
Reactant: CC1(C)OB(c2ccc3nc(NC(=O)C4CCCCC4)sc3c2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: C1COCCO1
Product: COc1ccc(S(=O)(=O)Nc2cc(-c3ccc4nc(NC(=O)C5CCCCC5)sc4c3)cnc2Cl)cc1
Temperature: 90 °C
Yield: 21.8 %

Procedure:
A reaction tube was charged with 2.0 M aqeuous sodium carbonate (199 μL, 397 μmol), PdCl2(dppf)-CH2Cl2 (11 mg, 13 μmol), N-(5-bromo-2-chloropyridin-3-yl)-4-methoxybenzenesulfonamide (50 mg, 132 μmol), N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazol-2-yl)cyclohexanecarboxamide (77 mg, 199 μmol) and 0.7 mL dioxane. The tube was purged with argon, sealed and the mixture was heated at 90° C. for 3 h. The reaction mixture was concentrated, dissolved in CH2C2Cl2/MeOH, and purified by silica gel chromatography 0-5% MeOH/CH2Cl2 to provide N-(6-(6-chloro-5-(4-methoxyphenylsulfonamido)pyridin-3-yl)benzo[d]thiazol-2-yl)cyclohexanecarboxamide (16 mg, 22% yield) as a white solid. This material contained a single impurity and was further purified by reverse phase chromatography, Gilson, 20-90% gradient of 0.1% TFA/ACN in water over 15 min to provide N-(6-(6-chloro-5-(4-methoxyphenylsulfonamido)pyridin-3-yl)benzo[d]thiazol-2-yl)cyclohexanecarboxamide (16 mg, 22% yield) as a white solid. MS (ESI pos. ion) m/z calc'd for C26H25ClN4O4S2: 557.1/559.1. found 557.0/558.9. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.16-1.51 (m, 6H), 1.73-1.83 (m, 2H), 1.83-1.93 (m, 2H), 2.54-2.62 (m, 1H), 3.83 (s, 3H), 7.07-7.15 (m, 2H), 7.65-7.74 (m, 3H), 7.81-7.88 (m, 1H), 7.99 (s, 1H), 8.32 (s, 1H), 8.61 (s, 1H), 10.23 (s, 1H), 12.39 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[C:5]([C:10](=[O:19])[CH2:11][CH2:12][CH:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[CH:4][C:3]=1[Cl:20].I[CH2:22][CH2:23][CH2:24][CH3:25].C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.C(OCC)(=O)C>[NH2:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[C:5]([C:10](=[O:19])[CH2:11][CH2:12][CH:13]2[CH2:18][CH2:17][N:16]([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:15][CH2:14]2)=[CH:4][C:3]=1[Cl:20]
Reactant: COc1nc(N)c(Cl)cc1C(=O)CCC1CCNCC1
Reactant: CCCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCCN1CCC(CCC(=O)c2cc(Cl)c(N)nc2OC)CC1
Temperature: 25 °C
Yield: 70.5 %

Procedure:
A mixture of 1-[6-amino-5-chloro-2-(methyloxy)-3-pyridinyl]-3-(4-piperidinyl)-1-propanone (step 5 in example 9, 110 mg, 0.369 mmol), 1-iodobutane (0.046 ml, 0.406 mmol) and potassium carbonate (102 mg, 0.738 mmol) in tetrahydrofuran (3 ml) was refluxed for 2 h. After cooling to room temperature, the mixture was diluted with ethyl acetate (50 ml), washed with water (5 ml) and brine (10 ml), and dried over potassium carbonate. Removal of solvent gave a pale yellow oil, which was crystallized from methanol to afford 92 mg (64%) of the title compound as a white crystal.
Reaction SMILES: [CH3:1][C:2]1([CH3:30])[C@@H:4](/[CH:5]=[C:6](/[F:10])\[C:7](=[O:9])[OH:8])[C@H:3]1[C:11]([O:13][C@H:14]([C:28]#[N:29])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:16]=1)=[O:12].[F:31][C:32]([F:36])([F:35])[CH2:33]O>C(Cl)(Cl)Cl>[CH3:1][C:2]1([CH3:30])[C@@H:4](/[CH:5]=[C:6](/[F:10])\[C:7](=[O:8])[O:9][CH2:33][C:32]([F:36])([F:35])[F:31])[C@H:3]1[C:11]([O:13][C@H:14]([C:28]#[N:29])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:16]=1)=[O:12]
Reactant: CC1(C)[C@H](C(=O)O[C@H](C#N)c2cccc(Oc3ccccc3)c2)[C@@H]1/C=C(/F)C(=O)O
Reactant: OCC(F)(F)F
Solvent: ClC(Cl)Cl
Product: CC1(C)[C@H](C(=O)O[C@H](C#N)c2cccc(Oc3ccccc3)c2)[C@@H]1/C=C(/F)C(=O)OCC(F)(F)F

Procedure:
(S)α-cyano-3-phenoxy-benzyl (1R,cis,E) 2,2-dimethyl-3-(2-fluoro-3-oxo-3-hydroxy-1-propenyl)-cyclopropane carboxylate and 2,2,2-trifluoro-ethanol were reacted to obtain (S)α-cyano-3-phenoxy-benzyl (1R,cis,E) 2,2-dimethyl-3-[2-fluoro-3-oxo-3-(2,2,2-trifluoroethoxy)-1-propenyl]-cyclopropanecarboxylate with a specific rotation of [α]D20 =+36.5°±2° (c=0.5% in chloroform).
Reaction SMILES: C[O:2][C:3](=[O:25])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[C:6]([C:21]([CH3:24])([CH3:23])[CH3:22])[CH:5]=1.[OH-].[K+].CO.C(O)C>O>[CH2:11]([O:10][C:7]1[CH:8]=[CH:9][C:4]([C:3]([OH:25])=[O:2])=[CH:5][C:6]=1[C:21]([CH3:22])([CH3:24])[CH3:23])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCCCCCCOc1ccc(C(=O)OC)cc1C(C)(C)C
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: CO
Product: CCCCCCCCCCOc1ccc(C(=O)O)cc1C(C)(C)C
Temperature: 25 °C
Yield: 90.3 %

Procedure:
A mixture of 15.0 g of product from Example 130, 7.24 g of potassium hydroxide, 100 ml methyl alcohol, 40 ml ethyl alcohol and 10 ml of water is heated at reflux temperature for 18 hours. The reaction is cooled to room temperature, made acidic to pH 2, concentrated in vacuo, swirled with water and the solid collected. The solid residue is washed with water and dried in a vacuum oven to give 13 g of the desired product as colorless needles.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7]Cl)([O-:3])=[O:2].[Br:12][C:13]1[CH:14]=[C:15]([OH:19])[CH:16]=[CH:17][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[C:6]([CH2:7][O:19][C:15]2[CH:16]=[CH:17][CH:18]=[C:13]([Br:12])[CH:14]=2)[CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cccc(CCl)c1
Reactant: Oc1cccc(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=[N+]([O-])c1cccc(COc2cccc(Br)c2)c1

Procedure:
To a solution of 3-nitrobenzyl chloride (1.0 g, 5.83 mmol), 3-bromophenol (1.01 g, 5.83 mmol) and potassium carbonate (806 mg, 5.83 mmol) in acetone (25 mL) was heated to reflux for 23 hours. After cooling the solid was filtered off and the filtrate was concentrated under vacuum to a yellow residue which was dissolved in ethyl acetate (50 mL) and washed with 1N aqueous sodium hydroxide solution (25 mL) and water (25 mL) then dried and concentrated under vacuum to the title compound as a white solid (1.64 g, 91%).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([NH:7][C:8]([C:10]2[C:15]([NH2:16])=[CH:14][CH:13]=[C:12]([CH3:17])[N:11]=2)=[O:9])=[N:3]1.Br[C:19]1[CH:20]=[N:21][CH:22]=[N:23][CH:24]=1>>[CH3:1][N:2]1[CH:6]=[CH:5][C:4]([NH:7][C:8]([C:10]2[C:15]([NH:16][C:19]3[CH:20]=[N:21][CH:22]=[N:23][CH:24]=3)=[CH:14][CH:13]=[C:12]([CH3:17])[N:11]=2)=[O:9])=[N:3]1
Reactant: Brc1cncnc1
Reactant: Cc1ccc(N)c(C(=O)Nc2ccn(C)n2)n1
Product: Cc1ccc(Nc2cncnc2)c(C(=O)Nc2ccn(C)n2)n1

Procedure:
The title compound, light brown solid, MS (ISP): m/e=310.4 (M+H+), was prepared from 3-Amino-6-methyl-pyridine-2-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide in accordance with the general method of example 20 using 5-bromopyrimidine instead of 3-bromo-pyridine.
Reaction SMILES: Cl.[F:2][C:3]([F:25])([F:24])[CH2:4][N:5]=[C:6]([NH2:23])[NH:7][C:8]1[S:9][CH:10]=[C:11]([C:13]2[CH:14]=[C:15]([CH:20]=[CH:21][CH:22]=2)[C:16]([O:18]C)=O)[N:12]=1.[CH3:26][NH2:27]>>[CH3:26][NH:27][C:16](=[O:18])[C:15]1[CH:20]=[CH:21][CH:22]=[C:13]([C:11]2[N:12]=[C:8]([NH:7][C:6]([NH2:23])=[N:5][CH2:4][C:3]([F:2])([F:25])[F:24])[S:9][CH:10]=2)[CH:14]=1
Reactant: CN
Reactant: COC(=O)c1cccc(-c2csc(NC(N)=NCC(F)(F)F)n2)c1
Agent: Cl
Product: CNC(=O)c1cccc(-c2csc(NC(N)=NCC(F)(F)F)n2)c1
Reaction time: 96 h
Yield: 20 %

Procedure:
A solution of crude methyl 3-[2-(2-[2,2,2-trifluoroethyl]guanidino)thiazol-4-yl]benzoate hydrochloride (1 g.) in ethanolic methylamine (33% w/v, 20 ml.) was allowed to stand at room temperature for 4 days. The mixture was then evaporated to dryness and the residue triturated with water to give 0.16 g. of N-methyl-3-[2-(2-[2,2,2-trifluoroethyl]guanidino)thiazol-4-yl]benzamide (yield 20%). The n.m.r. spectrum in d6DMSO included the following resonances: 2.8 (d, 3H); 4.1 (m, 2H); 7.3 (s, 1H); 7.0-8.4 (complex, 7H).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[N:11]([CH3:12])[C@@H:10]([CH3:13])[CH2:9][N:5]2[C:6](=[O:8])[N:7]=1.[F:14][C:15]1[C:20]([F:21])=[CH:19][CH:18]=[CH:17][C:16]=1[CH2:22][OH:23]>>[F:14][C:15]1[C:20]([F:21])=[CH:19][CH:18]=[CH:17][C:16]=1[CH2:22][O:23][C:2]1[CH:3]=[C:4]2[N:11]([CH3:12])[C@@H:10]([CH3:13])[CH2:9][N:5]2[C:6](=[O:8])[N:7]=1
Reactant: C[C@H]1Cn2c(cc(Cl)nc2=O)N1C
Reactant: OCc1cccc(F)c1F
Product: C[C@H]1Cn2c(cc(OCc3cccc(F)c3F)nc2=O)N1C

Procedure:
The title compound was prepared by a procedure similar to that described for E1 starting from (S)-7-chloro-1,2-dimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one and (2,3-difluorophenyl)methanol.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[C@H:7]([O:16][C:17](=[O:19])[CH3:18])[C@@H:8]([O:12][C:13](=[O:15])[CH3:14])[C:9]([OH:11])=O)([CH3:4])([CH3:3])[CH3:2].[C:21]([C:25]1[CH:34]=[CH:33][C:28]([NH:29][CH2:30][CH2:31][Cl:32])=[CH:27][CH:26]=1)([CH3:24])([CH3:23])[CH3:22].Cl.C(N=C=NCCCN(C)C)C.O>C(Cl)Cl>[C:17]([O:16][C@H:7]([C@@H:8]([O:12][C:13](=[O:15])[CH3:14])[C:9]([N:29]([CH2:30][CH2:31][Cl:32])[C:28]1[CH:27]=[CH:26][C:25]([C:21]([CH3:24])([CH3:22])[CH3:23])=[CH:34][CH:33]=1)=[O:11])[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:20])(=[O:19])[CH3:18]
Reactant: CC(=O)O[C@@H](C(=O)O)[C@@H](OC(C)=O)C(=O)OC(C)(C)C
Reactant: CC(C)(C)c1ccc(NCCCl)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: CC(=O)O[C@@H](C(=O)OC(C)(C)C)[C@@H](OC(C)=O)C(=O)N(CCCl)c1ccc(C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 105.3 %

Procedure:
To a solution of (R,R)-2,3-bis(acetyloxy)-butanedioic acid mono tert-butyl ester (9 g: Tetrahedron, 45, 3071-3080, 1989) in CH2Cl2 (90 mL), were added compound 11-1 (6.6 g) and 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride at 0° C. The reaction mixture was stirred for 5 hours at room temperature. Then water was added into the mixture and it was extracted with CH2Cl2. The organic layer was washed with brine, dried with anhyd. Na2SO4. The solvent was removed under reduced pressure to obtain compound 52-1 (15.8 g) as a brown amorphous solid.