Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1.[N:28]1([C:34]2[CH:42]=[CH:41][C:37]([C:38](O)=[O:39])=[CH:36][CH:35]=2)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>>[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([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:38](=[O:39])[C:37]5[CH:41]=[CH:42][C:34]([N:28]6[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]6)=[CH:35][CH:36]=5)[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1
Reactant: O=C(O)c1ccc(N2CCCCC2)cc1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1)c1ccc(N2CCCCC2)cc1

Procedure:
The title compound, off-white solid (100 mg, 77%), MS (ISP) m/z=518.5 [(M+H)+], mp 214.5° C., was prepared in accordance with the general method of example 32 from trans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanamine trihydrochloride (intermediate C) (110 mg, 0.25 mmol) and 4-piperidin-1-yl-benzoic acid.
Reaction SMILES: Br[CH2:2][C:3]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=2)[CH:6]=[C:5]([N:16]2[CH2:21][CH2:20][N:19]([C:22]3[C:27]([C:28]([F:31])([F:30])[F:29])=[CH:26][CH:25]=[CH:24][N:23]=3)[CH2:18][CH2:17]2)[N:4]=1.[CH2:32]([NH:34][CH2:35][CH3:36])[CH3:33].CC(N(C)C)=O>O>[Cl:15][C:11]1[CH:10]=[C:9]([C:7]2[CH:6]=[C:5]([N:16]3[CH2:21][CH2:20][N:19]([C:22]4[C:27]([C:28]([F:31])([F:30])[F:29])=[CH:26][CH:25]=[CH:24][N:23]=4)[CH2:18][CH2:17]3)[N:4]=[C:3]([CH2:2][N:34]([CH2:35][CH3:36])[CH2:32][CH3:33])[N:8]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: CCNCC
Reactant: FC(F)(F)c1cccnc1N1CCN(c2cc(-c3cccc(Cl)c3)nc(CBr)n2)CC1
Solvent: O
Solvent: CC(=O)N(C)C
Product: CCN(CC)Cc1nc(-c2cccc(Cl)c2)cc(N2CCN(c3ncccc3C(F)(F)F)CC2)n1
Temperature: 25 °C

Procedure:
Combine 2-bromomethyl-4-(3-chloro-phenyl)-6-[4-(3-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-pyrimidine (32 mg, 0.06 mmol), diethylamine (0.5 mL), DMA (2 mL) and heat at 80° C. for 3 hours. Let cool to room temperature and add water (5 mL). Extract with EtOAc (10 mL), wash with water (10 mL), dry (Na2SO4) and evaporate. Purify by column chromatography (1:1 hexanes/EtOAc) to obtain {4-(3-chloro-phenyl)-6-[4-(3-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-pyrimidin-2-ylmethyl}-diethyl-amine as a yellow solid.
Reaction SMILES: S(Cl)([Cl:3])=O.[C:5]([O:8][CH2:9][C:10]1([C:14]([OH:16])=O)[CH2:13][CH2:12][CH2:11]1)(=[O:7])[CH3:6]>>[C:5]([O:8][CH2:9][C:10]1([C:14]([Cl:3])=[O:16])[CH2:13][CH2:12][CH2:11]1)(=[O:7])[CH3:6]
Reactant: O=S(Cl)Cl
Reactant: CC(=O)OCC1(C(=O)O)CCC1
Product: CC(=O)OCC1(C(=O)Cl)CCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Thionyl chloride (1.65 ml, 22.7 mmol) was added to neat 1-acetoxymethylcyclobutanecarboxylic acid (3.3 g, 18.9 mmol). The resulting mixture was stirred at room temperature for 1 hour, then heated on a steam bath for 5 minutes. After cooling, the excess thionyl chloride, HCl and SO2 were removed under reduced pressure (water aspirator). The remained residue was purified by distillation to provide the desired product as a colorless oil: bp 51-3° C. (0.02 mm); NMR (CDCl3) δ=1.8~2.7 (9H, m containing a singlet at 2.04 δ), 4.40 (2H, s).
Reaction SMILES: [N:1]1[C:6]2[CH:7]=[CH:8][N:9]=[CH:10][C:5]=2[C:4](=[S:11])[NH:3][CH:2]=1.[CH2:12](N(CC)CC)C.IC>CS(C)=O>[CH3:12][S:11][C:4]1[C:5]2[CH:10]=[N:9][CH:8]=[CH:7][C:6]=2[N:1]=[CH:2][N:3]=1
Reactant: S=c1[nH]cnc2ccncc12
Reactant: CCN(CC)CC
Solvent: CS(C)=O
Solvent: CI
Product: CSc1ncnc2ccncc12
Temperature: 25 °C
Reaction time: 12 h
Yield: 156.7 %

Procedure:
A mixture of 3H-pyrido[4,3-d]pyrimidin-4-thione (676 mg, 4.14 mmol), triethylamine (1.4 mL, 10.31 mmol), DMSO (4 mL), and iodomethane (0.48 mL, 7.72 mmol) is stirred for 12 h under N2 at 25° C. The mixture is poured onto water and extracted with EtOAc. The organic extracts are dried (MgSO4), and the solvent is removed under reduced pressure to yield 4-methylthiopyrido[4,3-d]pyrimidine (1.15 g, quant.) as a brown solid. 1H NMR (DMSO) δ 9.52 (1H, s), 9.16 (1H, s), 8.95 (1H, d, J=6 Hz), 7.86 (1H, d, J=8 Hz), 2.75 (1H, s).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH2:9][CH2:10][CH2:11]Br)=[CH:4][CH:3]=1.[C:20]([N:28]1[CH:34]=[CH:33][N:32]=[CH:31][CH2:30][N:29]1[C:35](=[O:42])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(=O)([O-])[O-].[Na+].[Na+].CN(C)C=O>CCOCC>[C:20]([N:28]1[CH2:34][CH2:33][N:32]([CH2:11][CH2:10][CH2:9][CH:8]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH2:31][CH2:30][N:29]1[C:35](=[O:42])[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(c1ccccc1)N1C=CN=CCN1C(=O)c1ccccc1
Reactant: Fc1ccc(C(CCCBr)c2ccc(F)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: O=C(c1ccccc1)N1CCN(CCCC(c2ccc(F)cc2)c2ccc(F)cc2)CCN1C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of 4,4-bis(4-fluorophenyl)butyl bromide (2.08 g), 1,2-dibenzoyl-1H-1,2,5-triazepine (2.0 g), powdered anhydrous sodium carbonate (2.71 g) and N,N-dimethylformamide (20 ml, dried over 4A molecular sieves) was stirred at room temperature under a nitrogen atmosphere for three days. The mixture was filtered and the filtrate was evaporated under oil pump vacuum to an oil. The oil was chromatographed on a column of silica gel; elution with ethyl acetate-dichloromethane (2:3) giving a major product. The hydrochloride salt of the titled compound was formed in ether from this material; wt. 2.0 g (52%), mp=216°-218°.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([CH2:24]OS(C3C=CC(C)=CC=3)(=O)=O)[N:20]=2)[CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:36][C:37]([CH3:41])([CH3:40])[CH2:38][OH:39]>>[CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([CH2:24][NH:36][C:37]([CH3:41])([CH3:40])[CH2:38][OH:39])[N:20]=2)[CH2:11][C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(N)CO
Reactant: Cc1ccc(S(=O)(=O)OCc2noc([C@H](CCCC3CCCCC3)CC(=O)OC(C)(C)C)n2)cc1
Product: CC(C)(CO)NCc1noc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1

Procedure:
Method as for preparation 5 using tert-butyl (3R)-6-cyclohexyl-3-[3-({[(4-methylphenyl)sulfonyl]oxy}methyl)-1,2,4-oxadiazol-5-yl]hexanoate (preparation 177) (3.71 g, 7.32 mmol) and 2-amino-2-methyl-1-propanol (2.10 ml, 22.0 mmol) as starting materials.
Reaction SMILES: C[Si](C)(C)N[Si](C)(C)C.[Li].[N:11]1[CH:16]=[CH:15][CH:14]=[C:13]([NH:17][C:18](=[O:41])[CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][C:27]3[C:36]4[C:31](=[CH:32][C:33]([O:39][CH3:40])=[C:34]([C:37]#[N:38])[CH:35]=4)[N:30]=[CH:29][CH:28]=3)=[CH:22][CH:21]=2)[CH:12]=1.S(OC)(O[CH3:46])(=O)=O>C1COCC1.CN(C=O)C>[CH3:46][N:17]([C:13]1[CH:12]=[N:11][CH:16]=[CH:15][CH:14]=1)[C:18](=[O:41])[CH2:19][C:20]1[CH:21]=[CH:22][C:23]([O:26][C:27]2[C:36]3[C:31](=[CH:32][C:33]([O:39][CH3:40])=[C:34]([C:37]#[N:38])[CH:35]=3)[N:30]=[CH:29][CH:28]=2)=[CH:24][CH:25]=1
Reactant: COS(=O)(=O)OC
Reactant: COc1cc2nccc(Oc3ccc(CC(=O)Nc4cccnc4)cc3)c2cc1C#N
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Li]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1cc2nccc(Oc3ccc(CC(=O)N(C)c4cccnc4)cc3)c2cc1C#N
Temperature: -5 °C
Reaction time: 0.08 h

Procedure:
Under an atmosphere of argon, a 1M solution of lithium hexamethyldisilazane in THF (0.27 ml) was added dropwise to a stirred solution of N-(3-pyridyl)-2-[4-(6-cyano-7-methoxyquinolin-4-yloxy)phenyl]acetamide (0.1 g) in DMF (2 ml) that had been cooled to −5° C. After 5 minutes, a solution of dimethyl sulphate (0.026 ml) in DMF (0.5 ml) was added dropwise and the resultant mixture was stirred at 0° C. for 30 minutes. The mixture was evaporated and the residue was purified by preparative HPLC using a Waters ‘Xterra’ reversed-phase column (5 microns silica) using decreasingly polar mixtures of water (containing 0.2% ammonium carbonate) and acetonitrile as eluent. There was thus obtained the title compound (0.04 g); 1H NMR: (CDCl3) 3.34 (s, 3H), 3.52 (s, 2H), 4.08 (s, 3H), 6.51 (d, 1H), 7.07 (d, 2H), 7.18 (d, 2H), 7.42 (m, 1H), 7.53 (br s, 2H), 8.5 (br s, 1H), 8.65 (br s, 1), 8.67 (d, 1H), 8.69 (s, 1H); Mass Spectrum: M+H+ 425.
Reaction SMILES: Cl.C([SiH2][O:7][C:8](C)(C)[C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]([C:18]2[CH:19]=[N:20][N:21]3[CH:26]=[CH:25][CH:24]=[N:23][C:22]=23)=[O:17])=[C:11]([O:27][CH3:28])[CH:10]=1)(C)(C)C.Cl[CH2:32]Cl>>[CH3:28][O:27][C:11]1[CH:10]=[C:9]([CH2:8][O:7][CH3:32])[CH:14]=[CH:13][C:12]=1[NH:15][C:16]([C:18]1[CH:19]=[N:20][N:21]2[CH:26]=[CH:25][CH:24]=[N:23][C:22]=12)=[O:17].[OH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]([C:18]2[CH:19]=[N:20][N:21]3[CH:26]=[CH:25][CH:24]=[N:23][C:22]=23)=[O:17])=[C:11]([O:27][CH3:28])[CH:10]=1
Reactant: ClCCl
Reactant: COc1cc(C(C)(C)O[SiH2]C(C)(C)C)ccc1NC(=O)c1cnn2cccnc12
Agent: Cl
Product: COCc1ccc(NC(=O)c2cnn3cccnc23)c(OC)c1
Product: COc1cc(CO)ccc1NC(=O)c1cnn2cccnc12
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of hydrochloric acid (1 M in Et2O, 2 mL) was added to a solution of pyrazolo[1,5-a]pyrimidine-3-carboxylic acid [4-(tert-butyl-dimethyl-silanyloxymethyl)-2-methoxy-phenyl]-amide (160 mg, 0.388 mmol) in dichloromethane (20 mL) and the resulting mixture was stirred at room temperature for 10 minutes. A second aliquot of solution of hydrochloric acid (1 M in Et2O, 2 mL) was added and the reaction mixture was stirred for 1 hour. The resulting mixture was evaporated under reduced pressure and the yellow solid residue was washed with hexane, ethyl acetate, diethyl ether and dichloromethane. The solid and the filtrate were then combined and partitioned between dichloromethane and aqueous solution of sodium bicarbonate (5%). The organic layer was separated and the aqueous layer was extracted 3 times with dichloromethane. The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The yellow solid residue was purified by flash chromatography (DCM/MeOH/NH4OH) to give 80 mg of pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (2-methoxy-4-methoxymethyl-phenyl)-amide and 40 mg of pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (4-hydroxymethyl-2-methoxy-phenyl)-amide. Pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (2-methoxy-4-methoxymethyl-phenyl)-amide compound was repurified by preparative TLC (DCM/MeOH/NH4OH) and was washed with diethyl ether and hexane to give, after drying in a vacuum oven, 64 mg of as a white solid. MS=313 [M+H]+.
Reaction SMILES: [C:1]([C:4]1[O:5][C:6]2[C:12]([O:13][CH2:14][CH:15]3[O:17][CH2:16]3)=[CH:11][CH:10]=[CH:9][C:7]=2[CH:8]=1)(=[O:3])[NH2:2].Cl.[CH3:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>>[C:1]([C:4]1[O:5][C:6]2[C:12]([O:13][CH2:14][CH:15]([OH:17])[CH2:16][N:29]3[CH2:30][CH2:31][N:26]([C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=4[CH3:19])[CH2:27][CH2:28]3)=[CH:11][CH:10]=[CH:9][C:7]=2[CH:8]=1)(=[O:3])[NH2:2]
Reactant: Cc1ccccc1N1CCNCC1
Reactant: NC(=O)c1cc2cccc(OCC3CO3)c2o1
Agent: Cl
Product: Cc1ccccc1N1CCN(CC(O)COc2cccc3cc(C(N)=O)oc23)CC1

Procedure:
The procedures of Example 10 were repeated except that 1.2 g (0.005 mole) of 2-carbamoyl-7-(2,3-epoxypropoxy)benzofuran and 1.2 g (0.0055 mole) of 1-(2-methylphenyl)piperazine hydrochloride were employed. The obtained concentrated residue was crystallized from ethyl acetate and petroleum ether.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10]O.N1C=CC=CC=1.S(Cl)([Cl:20])=O.Cl>C1C=CC=CC=1.O>[CH2:10]([Cl:20])[CH2:9][O:8][CH2:7][CH2:6][O:5][CH2:4][CH2:3][O:2][CH3:1]
Reactant: COCCOCCOCCO
Reactant: O=S(Cl)Cl
Agent: Cl
Solvent: O
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: COCCOCCOCCCl

Procedure:
19.02 g (0.116 mol) of triethylene glycol monomethyl ether and 21 ml (20.54 g=0.26 mol) of pyridine in 110 ml of benzene are heated to reflux, and 19 ml (31 g=0.26 mol) of thionyl chloride are added dropwise thereto. The mixture is boiled under reflux for a further 20 hours. When the reaction solution has cooled, a mixture consisting of 5 ml of concentrated hydrochloric acid and 20 ml of water is added thereto, with stirring. The organic phase is separated off and washed repeatedly with water and brine. The solvent is extensively distilled off using a Vigreux column and the residue is purified on silica gel in hexane/ethyl acetate (4:1). The product-containing fractions are concentrated and the residue is distilled, yielding 3,6,9-trioxadecyl chloride (J. Am. Chem. Soc. 89, 7017 (1967)); b.p. 76° C./2 mbar, NMR (CDCl3): 3.8-3.5 (m, 12H); 3.37 (s,3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](I)[CH:5]=[CH:4][C:3]=1[CH3:9].[CH3:10][C:11]([OH:15])([CH3:14])[C:12]#[CH:13]>[Pd].C1([PH+](C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1([PH+](C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1([PH+](C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1([PH+](C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cu](I)I.C(NCC)C>[F:1][C:2]1[CH:7]=[C:6]([C:13]#[C:12][C:11]([CH3:14])([OH:15])[CH3:10])[CH:5]=[CH:4][C:3]=1[CH3:9]
Reactant: C#CC(C)(C)O
Reactant: Cc1ccc(I)cc1F
Agent: I[Cu]I
Agent: [Pd]
Agent: c1ccc([PH+](c2ccccc2)c2ccccc2)cc1
Solvent: CCNCC
Product: Cc1ccc(C#CC(C)(C)O)cc1F
Yield: 70 %

Procedure:
The mixture of 2-fluoro-4-iodotoluene (0.05 mol), 3-methyl-3-hydroxy-1-butyne (0.06 mol), tetrakis (triphenylphosphonium) palladium (0) 0.35 g, copper iodide 50 mg, and diethylamine 100 ml was refluxed for 5.5 hours. Diethylamine was distilled away under reduced pressure, the residue was extracted with diethylether, and the extract was washed with water. From the extract, diethylether was distilled away, the residue was purified by column chromatography (elution liquid: heptane-ethyl acetate) to obtain colorless oily 2-fluoro-4-(3-methyl-3-hydroxy-1-butynyl)toluene (0.035 mol).
Reaction SMILES: C(OC([N:8]([S:20]([C:23]1[C:28]([CH3:29])=[CH:27][C:26]([CH3:30])=[CH:25][C:24]=1[CH3:31])(=[O:22])=[O:21])[C:9](=[NH:19])[NH:10][CH2:11][CH2:12][CH2:13][C@@H:14]([C:16]([OH:18])=[O:17])[NH2:15])=O)(C)(C)C.Cl.O1CCOC[CH2:34]1.O=S(Cl)Cl.CO>O1CCOCC1>[NH2:15][C@H:14]([C:16]([O:18][CH3:34])=[O:17])[CH2:13][CH2:12][CH2:11][NH:10][C:9](=[NH:19])[NH:8][S:20]([C:23]1[C:28]([CH3:29])=[CH:27][C:26]([CH3:30])=[CH:25][C:24]=1[CH3:31])(=[O:22])=[O:21]
Reactant: C1COCCO1
Reactant: Cc1cc(C)c(S(=O)(=O)N(C(=N)NCCC[C@H](N)C(=O)O)C(=O)OC(C)(C)C)c(C)c1
Agent: Cl
Solvent: O=S(Cl)Cl
Solvent: CO
Product: COC(=O)[C@@H](N)CCCNC(=N)NS(=O)(=O)c1c(C)cc(C)cc1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2.10 g of Nω -t-butoxycarbonyl-Nω -mesitylenesulfonyl-L-arginine [Boc-Arg(Mts)-OH] was dissolved in 31 ml of dry dioxane and 31 ml of 4N HCl-dioxane was added thereto. The obtained mixture was stirred at room temperature for 1 hour. The resulting solution was concentrated under reduced pressure to dryness and then crystallized by adding dry ether. The target product was collected by centrifugation, washed with dry ether several times and dried in a desiccator. Thus 1.1 g of HCl.H-Arg(Mts)-OH from which Boc groups had been removed was obtained. This product was next added to a solution, which had been prepared by slowly adding 2.9 ml of SOCl2 to 10.6 ml of methanol and stirring at -10° C. for 10 minutes, and the obtained mixture was stirred for 15 hours, concentrated to dryness, crystallized from dry ether, centrifuged, washed with dry ether several times and dried. Thus 0.94 g of HCl.H-Arg(Mts)-OMe was obtained.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH:8]1[CH2:12][C:11](=[O:13])[C:10]([S:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])=[CH:9]1.ClC(OCC(C)C)=O.C(N(CC)CC)C.[CH2:38](O)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>ClCCl>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH:8]1[CH2:12][C:11](=[O:13])[C:10]([S:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[O:21])=[CH:9]1
Reactant: O=C(O)CCCCCSC1=CC(OC2CCCCO2)CC1=O
Reactant: OCc1ccccc1
Agent: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CCCCCSC1=CC(OC2CCCCO2)CC1=O)OCc1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 51 %

Procedure:
2.09 g (6.1 mmoles) of 4(RS)-tetrahydropyranyloxy-2-(5-carboxypentylthio)-2-cyclopentenone was dissolved in 20 ml of dichloromethane, and to this solution were added 5 ml of a dichloromethane solution of 956 mg (7 mmoles) of isobutyl chloroformate and 5 ml of a dichloromethane solution of 808 mg (8 mmoles) of triethylamine. The mixture was stirred at -78° C. for 30 minutes. Then, 5 ml of a dichloromethane solution of 864 mg (8 mmoles) of benzyl alcohol was added, and the reaction was carried out for 18 hours while gradually raising the temperature to room temperature. After the reaction, the reaction mixture was extracted with ethyl acetate. The extract was washed with an aqueous solution of hydrogen chloride and an aqueous solution of sodium bicarbonate, then dried, and concentrated. The resulting crude product was chromatographed on a silica gel column using hexane/ethyl acetate (3.5/1) as an eluent to give 1.30 g (3.11 mmoles; yield 51%) of 4(RS)-tetrahydropyranyloxy-2-(5-benzyloxycarbonylpentyl-thio)-2-cyclopentenone.
Reaction SMILES: C([O:3][C:4]([C@H:6]1[CH2:11][CH2:10][C@H:9]([CH2:12][NH:13][C:14]([N:16]2[CH2:21][CH2:20][C:19]3([C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[C:23](=[O:30])[O:22]3)[CH2:18][CH2:17]2)=[O:15])[CH2:8][CH2:7]1)=[O:5])C.O.O[Li].O>C1COCC1>[C:4]([C@H:6]1[CH2:7][CH2:8][C@H:9]([CH2:12][NH:13][C:14]([N:16]2[CH2:17][CH2:18][C:19]3([C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[C:23](=[O:30])[O:22]3)[CH2:20][CH2:21]2)=[O:15])[CH2:10][CH2:11]1)([OH:5])=[O:3]
Reactant: CCOC(=O)[C@H]1CC[C@H](CNC(=O)N2CCC3(CC2)OC(=O)c2ccccc23)CC1
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: O=C1OC2(CCN(C(=O)NC[C@H]3CC[C@H](C(=O)O)CC3)CC2)c2ccccc21

Procedure:
Dissolve 1′-(trans-4-ethoxycarbonyl-cyclohexylmethyl)carbamoyl-spiro[isobenzofuran-1,4′piperidin]-3-one (21 mg, 0.05 mmol) in THF (2 mL) and add an equal volume of water. Add LiOH•H2O (11 mg, 0.26 mmol) to this mixture and heat at 60° C. for 3 hours with stirring. Evaporate the THF under reduced pressure, dilute the residue with water and acidify with 3N HCL. Extract the aqueous mixture with EtOAc, wash with brine, dry (Na2SO4) and concentrate under reduced pressure to obtain 1′-(trans-4-carboxy-cyclohexylmethyl)carbamoyl-spiro[isobenzofuran-1,4′piperidin]-3-one as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl.[CH3:14][NH:15][CH3:16].C(N(CC)CC)C>C(Cl)Cl>[N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([N:15]([CH3:16])[CH3:14])=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CNC
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)C(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 4-nitrobenzoyl chloride (7.20 g, 38.8 mmol) and dimethylamine hydrochloride (3.20 g, 39.2 mmol) in 100 mL DCM is added triethyl amine (14.0 mL, 99.6 mmol) at 0° C. The cooling bath is removed and the reaction mixture is stirred overnight at RT. Then 300 mL DCM is added and the reaction mixture is washed with 50% saturated aqueous ammonium chloride, water, 50% saturated aqueous sodium hydrogen carbonate and 0.1 M aqueous NaOH. The organic phase is dried over MgSO4 and concentrated in vacuo. Yield: 5.37 g.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[F:19])=[N:4][N:5]([CH3:11])[C:6]=1[C:7]([F:10])([F:9])[F:8].[N+:20]([O-])([OH:22])=[O:21]>>[Br:1][C:2]1[C:3]([C:12]2[CH:17]=[C:16]([F:18])[C:15]([N+:20]([O-:22])=[O:21])=[CH:14][C:13]=2[F:19])=[N:4][N:5]([CH3:11])[C:6]=1[C:7]([F:8])([F:9])[F:10]
Reactant: Cn1nc(-c2cc(F)ccc2F)c(Br)c1C(F)(F)F
Reactant: O=[N+]([O-])O
Product: Cn1nc(-c2cc(F)c([N+](=O)[O-])cc2F)c(Br)c1C(F)(F)F
Temperature: 28 °C
Reaction time: 4 h
Yield: 55 %

Procedure:
At 15° C.,9.5 g (0.03 mole) 4-bromo-3-(2,5-difluorophenyl)-1-methyl-5-(trifluoromethyl)-1H-pyrazole was slowly added to 100 mL of fuming nitric acid. The reaction warmed to 28° C. over a period of 20 minutes. The reaction mixture was stirred at 30° C. for 4 hours. The mixture was poured into 500 mL of ice. After stirring for 1 hour, the slurry was extracted 3 times with methylene chloride. The methylene chloride extracts were washed with water, dried over anhydrous MgSO4, and concentrated in vacuo. The residue was purified chroma-tographically using 10% ethyl acetate in hexane as the eluent to give 5.84 g (55%) of 4-bromo-3-(2,5-difluoro-4-nitrophenyl)-1-methyl-5-(trifluoromethyl)-1H-pyrazole as a white solid, mp 45.5° C.
Reaction SMILES: O[CH2:2][C:3]1[C:7]([S:8]([NH:11][CH3:12])(=[O:10])=[O:9])=[CH:6][S:5][CH:4]=1.S(Cl)([Cl:15])=O>>[Cl:15][CH2:2][C:3]1[C:7]([S:8]([NH:11][CH3:12])(=[O:10])=[O:9])=[CH:6][S:5][CH:4]=1
Reactant: CNS(=O)(=O)c1cscc1CO
Reactant: O=S(Cl)Cl
Product: CNS(=O)(=O)c1cscc1CCl

Procedure:
23.8 g (0.115 mol) of 3-hydroxymethyl-N-methyl-4-thiophenesulfonamide are treated within 10 minutes with 120 ml of thionyl chloride and the mixture is boiled under reflux for 20 minutes. Thereafter, the mixture is evaporated to dryness in a water-jet vacuum. The residue is taken up in 500 ml of methylene chloride and stirred with saturated sodium bicarbonate solution until the aqueous phase has an alkaline reaction. The phases are separated and the aqueous phase is extracted with two 100 ml portions of methylene chloride. The combined organic phases are dried over sodium sulfate and evaporated. The residual oil crystallizes out upon cooling. There is obtained 3-chloromethyl-N-methyl-4-thiophenesulfonamide of melting point 75°-76° C.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH:10]([CH:13]([CH3:15])[CH3:14])[C:11]#N)=[CH:5][CH:4]=1.[CH2:18]([OH:20])[CH3:19].Cl.[OH2:22]>>[F:1][C:2]([F:17])([F:16])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH:10]([CH:13]([CH3:15])[CH3:14])[C:11]([O:20][CH2:18][CH3:19])=[O:22])=[CH:5][CH:4]=1
Reactant: O
Reactant: CC(C)C(C#N)Nc1ccc(C(F)(F)F)cc1
Reactant: CCO
Agent: Cl
Product: CCOC(=O)C(Nc1ccc(C(F)(F)F)cc1)C(C)C

Procedure:
Following the procedure of Example 3, 2-(4-trifluoromethylphenylamino)-3-methylbutyronitrile was treated, at room temperature, with ethanol/HCl and then, at slightly lower temperature, with water to give ethyl 2-(4-trifluoromethylphenylamino)-3-methylbutanoate.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][N:8]=2)=[C:4]([CH3:16])[CH:3]=1.C(N(CC)CC)C.[C:24](Cl)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:24](=[O:31])[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:9][N:8]=2)=[C:4]([CH3:16])[CH:3]=1
Reactant: Cc1cc(Cl)ccc1Oc1ccc(N)cn1
Reactant: O=C(Cl)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(Cl)ccc1Oc1ccc(NC(=O)c2ccccc2)cn1
Temperature: 22 °C
Reaction time: 3 h

Procedure:
2-(4-Chloro-2-methyl-phenoxy)-5-aminopyridine (211 mg, 0.90 mmol) was dissolved in methylene chloride (2.7 mL) then treated with triethylamine (0.19 mL, 1.35 mmol) followed by benzoyl chloride (0.13 mL, 1.12 mmol). The reaction mixture was stirred for 3 hours at 22° C. then saturated aqueous NaHCO3 was added and the mixture was stirred for another hour. The organic layer was separated and washed 2× with 6% aqueous NaHCO3, dried over Na2SO4 and concentrated in vacuo. The residue was chromatographed on silica gel using 1:1 ethyl acetate/hexane as eluent. The product was recovered as a white solid. MS (m/z): 338/340 (M+H)+; C19H15N2O2Cl requires 338.8.