Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13](/[C:16](/[CH3:36])=[CH:17]/[CH2:18][O:19][C:20]3[CH:25]=[CH:24][C:23]([CH2:26][C@H:27]([O:33][CH2:34][CH3:35])[C:28]([O:30]CC)=[O:29])=[CH:22][CH:21]=3)=[CH:12][CH:11]=2)=[CH:6][CH:5]=1>C(O)C>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:11]=[CH:12][C:13](/[C:16](/[CH3:36])=[CH:17]/[CH2:18][O:19][C:20]3[CH:25]=[CH:24][C:23]([CH2:26][C@H:27]([O:33][CH2:34][CH3:35])[C:28]([OH:30])=[O:29])=[CH:22][CH:21]=3)=[CH:14][CH:15]=2)=[CH:8][CH:9]=1
Reactant: CCOC(=O)[C@H](Cc1ccc(OC/C=C(\C)c2ccc(-c3ccc(Cl)cc3)cc2)cc1)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCO[C@@H](Cc1ccc(OC/C=C(\C)c2ccc(-c3ccc(Cl)cc3)cc2)cc1)C(=O)O
Temperature: 80 °C

Procedure:
Sodium hydroxide (1M, 2.3 ml, 2.3 mmol) was added to a solution of (E)-(S)-ethyl 3-{4-[3-(4′-chloro-biphenyl-4-yl)-but-2-enyloxy]-phenyl}-2-ethoxy-propionate (example 52) (0.600 g, 1.25 mmol) in ethanol (10 ml) and the mixture stirred at room temperature for 18h, then heated to 80° C. for 2 h. The resulting mixture was partitioned between water (50 ml) and ethyl acetate (50 ml) and the aqueous layer acidified to pH1 by addition of 1N HCl. The aqueous layer was separated and further extracted with ethyl acetate (2×50 ml). The combined organic layers were washed with brine, dried (MgSO4), evaporated, and the product and vacuum dried at 40° C. for 72 h, to give (E)-(S)-3-{4-[3-(4′-chloro-biphenyl-4-yl)-but-2-enyloxy]-phenyl}-2-ethoxy-propionic acid as a colourless solid; 0.53 g (94%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[N:11][C:12]([N+:15]([O-:17])=[O:16])=[CH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.[CH3:18][N:19]1[CH:23]=[C:22]([Sn](CCCC)(CCCC)CCCC)[N:21]=[CH:20]1.[F-].[K+].CCOC(C)=O>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:18][N:19]1[CH:23]=[C:22]([C:2]2[CH:7]=[C:6]([O:8][C:9]3[CH:10]=[N:11][C:12]([N+:15]([O-:17])=[O:16])=[CH:13][CH:14]=3)[CH:5]=[CH:4][N:3]=2)[N:21]=[CH:20]1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn(C)cn1
Reactant: O=[N+]([O-])c1ccc(Oc2ccnc(Cl)c2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [F-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Cn1cnc(-c2cc(Oc3ccc([N+](=O)[O-])nc3)ccn2)c1
Temperature: 110 °C
Reaction time: 2 h
Yield: 90.9 %

Procedure:
A mixture of Example A1 (1.5 g, 5.96 mmol), N-methyl-4-(tributylstannyl)imidazole (3.32 g, 8.94 mmol) and Pd(PPh3)4 (0.344 g, 0.298 mmol) in toluene (30 mL) sparged with Ar and heated at 110° C. overnight. The mixture was cooled to RT, treated with 10% KF and EtOAc, stirred at RT for 2 h, the solids removed via filtration through diatomaceous earth and washed with 5% MeOH/DCM. The layers of the filtrate were separated and the organic layer was washed with brine, dried over Na2SO4, concentrated to dryness and purified via silica gel chromatography (MeOH/DCM). The material was washed with a small amount of Et2O and dried to afford 2-(1-methyl-1H-imidazol-4-yl)-4-((6-nitropyridin-3-yl)oxy)pyridine (1.61 g, 91%). 1H NMR (400 MHz, Acetone-d6): δ 8.54 (d, J=2.8 Hz, 1H), 8.50 (d, J=5.6 Hz, 1H), 8.44-8.43 (m, 1H), 7.98 (dd, J=8.9, 2.8 Hz, 1H), 7.69 (d, J=1.4 Hz, 1H), 7.62 (d, J=2.6 Hz, 1H), 7.55 (s, 1H), 6.97 (dd, J=5.6, 2.6 Hz, 1H), 3.81 (s, 3H); MS (ESI) m/z: 298.1 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]([O:13][S:14]([C:17]([F:20])([F:19])[F:18])(=[O:16])=[O:15])[CH:10]=[CH:9][C:4]=1[C:5]([O:7]C)=[O:6].S(=O)(=O)(O)O.C(O)(=O)C>O>[CH3:1][O:2][C:3]1[CH:12]=[C:11]([O:13][S:14]([C:17]([F:20])([F:18])[F:19])(=[O:16])=[O:15])[CH:10]=[CH:9][C:4]=1[C:5]([OH:7])=[O:6]
Reactant: COC(=O)c1ccc(OS(=O)(=O)C(F)(F)F)cc1OC
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: COc1cc(OS(=O)(=O)C(F)(F)F)ccc1C(=O)O
Yield: 37.5 %

Procedure:
A mixture of methyl 2-methoxy-4-trifluoromethanesulfonyloxybenzoate (3.49 g), sulfuric acid (90%, 0.1 mL), acetic acid (10 mL) and water (2 mL) was heated under reflux for 16 hrs. The reaction mixture was diluted with water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by recrystallization (solvent: ethyl acetate/n-hexane) to afford the title compound (1.25 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][S:16][CH3:17])[N:9]=[CH:8][NH:7][C:6]2=O.S(Cl)([Cl:21])=O>CN(C=O)C>[Cl:21][C:6]1[C:5]2[C:10](=[CH:11][C:12]([O:13][CH2:14][CH2:15][S:16][CH3:17])=[C:3]([O:2][CH3:1])[CH:4]=2)[N:9]=[CH:8][N:7]=1
Reactant: O=S(Cl)Cl
Reactant: COc1cc2c(=O)[nH]cnc2cc1OCCSC
Solvent: CN(C)C=O
Product: COc1cc2c(Cl)ncnc2cc1OCCSC
Yield: 71 %

Procedure:
A mixture of 6-methoxy-7-(2-methylthioethoxy)-3,4-dihydroquinazolin-4-one (1.07 g, 4.0 mmol), thionyl chloride (20 ml) and DMF (4 drops) was heated at reflux for 2 hours and then allowed to cool. The excess thionyl chloride was removed by evaporation and the residue was azeotroped with toluene. The solid residue was partitioned between aqueous sodium hydrogen carbonate and methylene chloride, the organic phase was separated and washed with brine. The organic phase was passed through phase separating paper, and the solvent removed by evaporation to give 4-chloro-6-methoxy-7-(2-methylthioethoxy)quinazoline (810 mg, 71%).
Reaction SMILES: P(Br)(Br)[Br:2].N1C=CC=CC=1.[Cl:11][C:12]1[CH:13]=[C:14]([CH2:21][CH2:22]O)[CH:15]=[C:16]([O:19][CH3:20])[C:17]=1[Cl:18]>C1(C)C=CC=CC=1>[Cl:18][C:17]1[C:12]([Cl:11])=[CH:13][C:14]([CH2:21][CH2:22][Br:2])=[CH:15][C:16]=1[O:19][CH3:20]
Reactant: BrP(Br)Br
Reactant: COc1cc(CCO)cc(Cl)c1Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: COc1cc(CCBr)cc(Cl)c1Cl
Temperature: -5 °C
Reaction time: 0.25 h

Procedure:
In a four-necked flask fitted with a stirrer, internal thermometer, dropping funnel and calcium chloride tube is placed freshly distilled phosphorous tribromide (9.6 g., 0.036 mole) and dry toluene (50 ml.). To this is added dry pyridine (1.5 g.). The mixture is stirred for 15 minutes and then cooled to -5° C. A mixture of 2-(3,4-dichloro-5-methoxyphenyl)ethanol (22.1 g., 0.1 mole) and dry pyridine (0.5 g.) in toluene (50 ml.) is added dropwise with stirring at -5° to -3° C. over a one hour period. The reaction mixture is stirred at -5° to -3° C. for an additional hour and then allowed to warm up to 20°-25° C. The mixture is kept for 48 hours and then added to ice water (ca. 500 ml.). The toluene layer is separated and washed with water, dilute hydrochloric acid, sodium bicarbonate solution and again with water. After drying over Na2SO4 and evaporation of the toluene under reduced pressure there is obtained 2,3-dichloro-5-(2-bromoethyl)anisole.
Reaction SMILES: [NH2:1][C:2](=[O:46])[CH2:3][C:4]1[C:41]([C:42]([F:45])([F:44])[F:43])=[CH:40][CH:39]=[CH:38][C:5]=1[CH2:6][CH2:7][C:8]1[C:13]([C:14]([F:17])([F:16])[F:15])=[CH:12][N:11]=[C:10]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([CH:25]3[CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27][CH2:26]3)=[CH:21][CH:20]=2)[N:9]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:28]1[CH2:29][CH2:30][CH:25]([C:22]2[CH:23]=[CH:24][C:19]([NH:18][C:10]3[N:9]=[C:8]([CH2:7][CH2:6][C:5]4[CH:38]=[CH:39][CH:40]=[C:41]([C:42]([F:43])([F:44])[F:45])[C:4]=4[CH2:3][C:2]([NH2:1])=[O:46])[C:13]([C:14]([F:17])([F:15])[F:16])=[CH:12][N:11]=3)=[CH:20][CH:21]=2)[CH2:26][CH2:27]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(Nc3ncc(C(F)(F)F)c(CCc4cccc(C(F)(F)F)c4CC(N)=O)n3)cc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC(=O)Cc1c(CCc2nc(Nc3ccc(C4CCNCC4)cc3)ncc2C(F)(F)F)cccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h
Yield: 84.6 %

Procedure:
To a solution of tert-butyl 4-(4-((4-(2-(2-amino-2-oxoethyl)-3-(trifluoromethyl)phenethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate (A97) (0.075 g, 0.12 mmol) in DCM (5 mL) was added TFA (0.20 mL, 2.6 mmol) and the resulting mixture was stirred at room temperature for 16 hours. The volatiles were evaporated under reduced pressure and the residue partitioned between water (20 mL) and EtOAc. The layers were separated and the aqueous layer extracted with EtOAc (2×20 mL). The combined organic extracts were dried using a phase separation cartridge then the volatiles were removed under reduced pressure. The residue was triturated with Et2O and the resulting precipitate collected by filtration to give the title compound 22 (56 mg, 88%); 1H NMR (400 MHz, d6-DMSO) δ 10.22 (s, 1H), 8.67 (s, 1H), 8.29 (brs, 1H), 7.68 (d, J=8.6 Hz, 2H), 7.57 (d, J=7.9 Hz, 1H), 7.52 (d, J=7.6 Hz, 1H), 7.48 (s, 1H), 7.41 (t, J=7.8 Hz, 1H), 7.19 (d, J=8.6 Hz, 2H), 6.94 (s, 1H), 3.73 (s, 2H), 3.38 (m, 2H), 3.10 (m, 4H), 2.98 (td, J=12.8, 2.6 Hz, 2H), 2.79 (tt, J=11.7, 2.7 Hz, 1H), 1.93 (d, J=15.8 Hz, 2H), 1.74 (qd, J=13.8, 4.0 Hz, 2H). LCMS-A: rt 4.99 min; m/z 552.3 [M+H]+.
Reaction SMILES: [CH3:1][NH2:2].[O:3]=[C:4]1[CH:9]=[C:8]([CH3:10])O[CH:6]=[C:5]1[O:11][CH2:12][C:13]([OH:15])=[O:14]>O>[CH3:1][N:2]1[C:8]([CH3:10])=[CH:9][C:4](=[O:3])[C:5]([O:11][CH2:12][C:13]([OH:15])=[O:14])=[CH:6]1
Reactant: Cc1cc(=O)c(OCC(=O)O)co1
Reactant: CN
Solvent: O
Product: Cc1cc(=O)c(OCC(=O)O)cn1C
Reaction time: 3 h

Procedure:
To a stirred solution of 40% aqueous methylamine (9.0 ml) and water (9.0 ml) was added 2-(4-oxo-6-methyl-4H-pyran-3-yloxy)acetic acid (6.0 g) in small portions at room temperature. The mixture was stirred at the same temperature for 3 hours and concentrated. To the residue was added water (5 ml) and the mixture was adjusted to pH 3. The resulting precipitates were collected and washed with water to give crystals of 2-(1,6-dimethyl-4-oxo-1,4-dihydropyridin-3-yloxy)acetic acid (1.53 g), mp 240° to 242° C. The filtrate and the washings were combined together and adsorbed on Amberlite IRA-400 (Tradename, prepared by Rohm and Haas Co.) and eluted with water and then 0.3 N hydrochloric acid. The hydrochloric acid fraction was concentrated and dried to give crystals (3.7 g) of 2-(1,6-dimethyl-4-oxo-1,4-dihydropyridin-3-yloxy)acetic acid hydrochloride. The hydrochloride was dissolved in a small amount of water and the solution was adjusted to pH 3. The resulting crystals were collected by filtration and washed with water to give an additional amount of the same product (2.2 g) as obtained above.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[C:5]#[N:6].C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:17][O:18][C:19](=[O:28])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH2:26]Br>CC(C)=O>[CH3:17][O:18][C:19](=[O:28])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH2:26][O:10][C:9]1[CH:8]=[CH:7][C:4]([C:5]#[N:6])=[CH:3][C:2]=1[F:1]
Reactant: N#Cc1ccc(O)c(F)c1
Reactant: COC(=O)c1ccccc1CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: COC(=O)c1ccccc1COc1ccc(C#N)cc1F
Yield: 90 %

Procedure:
To a solution of 3-fluoro-4-hydroxy-benzonitrile (1.2 g, 8.7 mmol; CAS Reg. No. 405-04-9) in acetone (20 ml) was added cesium carbonate (4.2 g, 13.05 mmol) and 2-bromomethyl-benzoic acid methyl ester (2 g, 8.7 mmol; CAS Reg. No. 2417-73-4) and the resulting solution was heated to reflux for 12 h. The reaction mixture was filtered and evaporated in vacuo. The residue was purified by column chromatography over silica gel (8-10% ethyl acetate/n-hexane) to give the desired product as a yellow sticky solid (90%). MS (Turbo Spray): m/z=286.1 (M+H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][OH:4].[CH:5]1([C:8]2[CH:32]=[CH:31][C:11](/[CH:12]=[C:13]3\[N:14]=[C:15]([C:19]4[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][CH:28]5[CH2:30][CH2:29]5)=[CH:21][CH:20]=4)[O:16][C:17]\3=[O:18])=[CH:10][CH:9]=2)[CH2:7][CH2:6]1>C(O)C>[CH:28]1([CH2:27][CH2:26][O:25][C:22]2[CH:23]=[CH:24][C:19]([C:15]([NH:14]/[C:13](/[C:17]([NH:1][CH2:2][CH2:3][OH:4])=[O:18])=[CH:12]\[C:11]3[CH:31]=[CH:32][C:8]([CH:5]4[CH2:6][CH2:7]4)=[CH:9][CH:10]=3)=[O:16])=[CH:20][CH:21]=2)[CH2:30][CH2:29]1
Reactant: O=C1OC(c2ccc(OCCC3CC3)cc2)=N/C1=C\c1ccc(C2CC2)cc1
Reactant: NCCO
Solvent: CCO
Product: O=C(NCCO)/C(=C/c1ccc(C2CC2)cc1)NC(=O)c1ccc(OCCC2CC2)cc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 87.5 %

Procedure:
2-Aminoethanol (20 μL, 0.33 mmol) was added to a solution of ethanol (1.6 mL) containing (4Z)-4-(4-cyclopropylbenzylidene)-2-[4-(2-cyclopropylethoxy)phenyl]-1,3-oxazol-5(4H)-one (95 mg, 0.25 mmol) prepared in Example 9 (9c). The mixture was stirred at 60° C. for 1 hour, and then the solvent was removed. The residue was washed with hexane:ethyl acetate (3:1, v/v). The precipitate was collected by filtration and dried under reduced pressure to give 95 mg of the title compound (white powder, yield: 86%).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([S:11](Cl)(=[O:13])=[O:12])[CH:8]=[CH:7][C:5]=2[N:6]=1.C(N(CC)CC)C.[CH3:22][N:23]([CH3:27])[CH2:24][CH2:25][NH2:26]>C1COCC1>[CH3:22][N:23]([CH3:27])[CH2:24][CH2:25][NH:26][S:11]([C:9]1[CH:8]=[CH:7][C:5]2[N:6]=[C:2]([CH3:1])[S:3][C:4]=2[CH:10]=1)(=[O:13])=[O:12]
Reactant: CN(C)CCN
Reactant: Cc1nc2ccc(S(=O)(=O)Cl)cc2s1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1nc2ccc(S(=O)(=O)NCCN(C)C)cc2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.9 %

Procedure:
To a solution of Compound 8 (7.0 g, 28.26 mmol) in THF (70 mL), a mixture of triethylamine (7.9 mL, 56.52 mmol) and N,N-dimethylethylene-diamine (4.67 mL, 42.38 mmol) in 20 mL THF was added dropwise. The combined mixture was stirred at room temperature for 2 hours during which time TLC showed complete disappearance of Compound 8. Solvents were removed in the rotary evaporator and the residue thus obtained was partitioned between chloroform (100 mL) and water (100 mL). The organic layer was washed with water (2×100 mL), brine (1×100 mL), dried (sodium sulfate) and evaporated to provide Compound 9 as a sticky oily solid (7.1 g, 84% yield). It was used further in the synthesis without any purification. The structure of Compound 9 is given below:
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6]Cl.[C-:13]#[N:14].[Na+].CS(C)=O>O>[F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[C:5]([CH2:6][C:13]#[N:14])[CH:8]=[CH:9][CH:10]=1
Reactant: FC(F)(F)c1cccc(CCl)c1
Reactant: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: N#CCc1cccc(C(F)(F)F)c1
Yield: 107.1 %

Procedure:
A mixture of 12.0 g (61.5 mmole) m-trifluoromethylbenzyl chloride, 9.56 g (195 mmole) sodium cyanide and 60 ml dimethylsulfoxide was heated at 50° to 80° C. for four hours and poured into water. The aqueous mixture was extracted with methylene chloride, the extracts dried over sodium sulfate and the solvent evaporated in vacuo to give 12.2 g of yellow oil which was used in the next step. 1H-NMR(CDCl3)ppm(delta): 3.80 (s, 2H), 7.60 (s, 4H).
Reaction SMILES: [N+:1]([C:4]1[C:9]([CH3:10])=[CH:8][CH:7]=[CH:6][C:5]=1[CH3:11])([O-:3])=[O:2].[CH3:12][N:13]([CH3:16])[CH:14]=O>C(O)C>[CH3:12][N:13]([CH3:16])/[CH:14]=[CH:11]/[C:5]1[CH:6]=[CH:7][CH:8]=[C:9]([CH3:10])[C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: CN(C)C=O
Reactant: Cc1cccc(C)c1[N+](=O)[O-]
Solvent: CCO
Product: Cc1cccc(/C=C/N(C)C)c1[N+](=O)[O-]
Reaction time: 46 h

Procedure:
A 500 -ml. three-necked flask fitted with a thermometer, a 15-cm. Vigreux column connected to a descending condenser and receiver with a nitrogen inlet was charged with 30.23 g. of 2-nitro-m-xylene, 64.77 g. of N,N-domethylformamide diethyl acetal, and 200 ml. of N,N-dimethylformamide. The reaction vessel was then immersed in an oil bath, preheated to 165°, for 46 hours. The pot temperature was maintained above 140° by continuous distillation of the formed ethanol.
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@H:10]([CH2:14][O:15][CH3:16])[C:11]([OH:13])=O.CN1CCOCC1.ClC(OCC(C)C)=O.[CH2:32]([NH2:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C1COCC1>[CH2:32]([NH:39][C:11](=[O:13])[C@H:10]([N:2]1[CH2:1][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3]1)[CH2:14][O:15][CH3:16])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: COC[C@H](C(=O)O)N1Cc2ccccc2C1
Reactant: NCc1ccccc1
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: COC[C@H](C(=O)NCc1ccccc1)N1Cc2ccccc2C1
Reaction time: 0.08 h
Yield: 88 %

Procedure:
To the crude acid (R)-2-(Isoindolin-2-yl)-3-methoxypropanoic acid (FIG. 2, No. 5)(1.25 g, 5 mmol) in dry THF was added N-methylmorpholine (0.66 mL, 6.0 mmol) at −78° C. under an argon atmosphere. After 5 min, isobutyl chloroformate (0.78 mL, 6.0 mmol) was added and stirred for another 5 min. To this reaction mixture benzylamine (0.65 mL, 6.0 mmol) was added at −78° C. after which the reaction mixture was stirred at room temperature for 1 h. After completion of the reaction, the reaction mixture was filtered through a celite pad, washed with ethyl acetate, and dried over anhydrous MgSO4. The solvent was removed in vacuo and the crude product was subjected to silica gel column chromatography (Ethyl acetate/Hexane, 4:6) to yield 1.48 g, 88% yield of (R)—N—Benzyl-2-(isoindolin-2-yl)-3-methoxypropanamide (FIG. 2, No. 6) as a crystalline solid. [Rf=0.26, ethyl acetate/hexane (4:6)]; [α]D25 +81.8 (c 1, CH2Cl2); IR (CH2Cl2) v: 1718, 1685, 1535, and 1387 cm−1; 1H NMR (400 MHz, CDCl3) δ:3.38 (bs, 3H), 3.75 (m, 1H), 4.34 (t, J=9.64 Hz, 1H), 4.46 (m, 2H), 5.0 (m, 1H), 7.1 (bs, 1H), 7.21-7.33 (m, 5H), 7.7 (dd, J=3.2, 5.48 Hz, 2H), 7.83 (dd, J=3.2, 5.48 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ: 29.6, 43.5, 51.7, 58.9, 70.1, 123.5, 127.1, 127.3, 127.4, 128.4, 128.6, 131.8, 134.1, 137.9, 167.3, 167.9; HRMS (ESI-TOF) m/z calcd for C19H18N2O4Na [M+Na+] 361.120. Found 361.116.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH2:8])=[CH:5][CH:4]=1.ClC(Cl)(Cl)[C:15]([NH:17][C:18]1[CH:19]=[CH:20][CH:21]=[C:22]2[C:27]=1[CH:26]=[N:25][CH:24]=[CH:23]2)=[O:16].C1CCN2C(=NCCC2)CC1>O>[CH:26]1[C:27]2[C:22](=[CH:21][CH:20]=[CH:19][C:18]=2[NH:17][C:15]([NH:8][CH2:7][C:6]2[CH:9]=[CH:10][C:3]([C:2]([F:11])([F:12])[F:1])=[CH:4][CH:5]=2)=[O:16])[CH:23]=[CH:24][N:25]=1
Reactant: O=C(Nc1cccc2ccncc12)C(Cl)(Cl)Cl
Reactant: NCc1ccc(C(F)(F)F)cc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Product: O=C(NCc1ccc(C(F)(F)F)cc1)Nc1cccc2ccncc12

Procedure:
The title compound was prepared using 4-(trifluoromethyl)benzylamine, the product from Example 57D, DBU and the procedure described in Example 1B. MS (ESI+) m/z 346 (M+H)+; 1H NMR (DMSO-d6) δ 9.58 (s, 1H), 9.10 (s, 1H), 8.49 (d, 1H), 8.12 (d, 1H), 7.81-7.54 (m, 7H), 7.20 (t, 1H), 4.47 (d, 2H); Anal. Calcd for C18H14F3N3O.0.2 H2O: C, 61.96, H 4.16, N 12.04. Found: C, 62.06, H 4.23, N 11.91.
Reaction SMILES: C([O:5][C:6](=[O:30])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([Cl:17])=[CH:14][CH:15]=2)[C:10]([C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21](=[O:28])[NH:20][N:19]=2)=[C:9]1[CH3:29])(C)(C)C.Cl[CH2:32][C:33]1[S:34][C:35]2[CH:41]=[CH:40][CH:39]=[CH:38][C:36]=2[N:37]=1>>[S:34]1[C:35]2[CH:41]=[CH:40][CH:39]=[CH:38][C:36]=2[N:37]=[C:33]1[CH2:32][N:20]1[C:21](=[O:28])[C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:18]([C:10]2[C:11]3[C:16](=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=3)[N:8]([CH2:7][C:6]([OH:5])=[O:30])[C:9]=2[CH3:29])=[N:19]1
Reactant: Cc1c(-c2n[nH]c(=O)c3ccccc23)c2cc(Cl)ccc2n1CC(=O)OC(C)(C)C
Reactant: ClCc1nc2ccccc2s1
Product: Cc1c(-c2nn(Cc3nc4ccccc4s3)c(=O)c3ccccc23)c2cc(Cl)ccc2n1CC(=O)O

Procedure:
The title compound was prepared from the product of example 16, step c) and 2-chloromethyl-benzothiazole using the procedure described in example 14. 1H NMR (DMSO-d6) δ 8.44-8.41 (m, 1H), 8.08 (d, J=8.1 Hz, 1H), 7.99 (d, J=8.1 Hz, 1H), 7.96-7.92 (m, 2H), 7.50 (t, J=7.5 Hz, 1H), 7.44 (t, J=7.5 Hz, 1H), 7.24 (d, J=1.8 Hz, 1H), 7.15 (dd, J=8.7, 2.1 Hz, 1H), 5.86 (s, 2H), 5.12 (s, 2H), 2.28 (s, 3H); MS: ESI (negative): 513, 515 (M−H).
Reaction SMILES: [CH3:1][N:2]([S:18]([C:21]1[CH:26]=[CH:25][C:24]([O:27][C:28]2[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=2)=[CH:23][CH:22]=1)(=[O:20])=[O:19])[C:3]1[N:8]2[N:9]=[C:10]([CH3:12])[CH:11]=[C:7]2[N:6]=[CH:5][C:4]=1[C:13]([O:15]CC)=[O:14].[OH-].[K+:35]>O1CCCC1>[CH3:1][N:2]([S:18]([C:21]1[CH:22]=[CH:23][C:24]([O:27][C:28]2[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=2)=[CH:25][CH:26]=1)(=[O:20])=[O:19])[C:3]1[N:8]2[N:9]=[C:10]([CH3:12])[CH:11]=[C:7]2[N:6]=[CH:5][C:4]=1[C:13]([O-:15])=[O:14].[K+:35]
Reactant: CCOC(=O)c1cnc2cc(C)nn2c1N(C)S(=O)(=O)c1ccc(Oc2ccncc2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1cc2ncc(C(=O)[O-])c(N(C)S(=O)(=O)c3ccc(Oc4ccncc4)cc3)n2n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 1.25 g (2.67 mmol) of the preceding ester and 3.21 ml of 1N KOH in 15 ml of tetrahydrofuran was stirred at room temperature overnight. The mixture was filtered and the solid washed with diethyl ether and ethyl acetate to give 0.5 g of potassium 7-{methyl-[4-(4-pyridinyloxy)benzene-sulfonyl]amino}-2-methylpyrazolo[1,5-a]pyrimidine-6-carboxylate. A 0.15 g sample of the preceding compound was dissolved in water and the pH adjusted to pH 6 with 2 N citric acid. The mixture was filtered to give 0.12 g of 7-{methyl-[4-(4-pyridinyloxy)benzenesulfonyl]amino}-2-methylpyrazolo[1,5-a]pyrimidine-6-carboxylic acid as a white solid, m.p. 246-248° C.
Reaction SMILES: Cl[CH2:2][SiH:3]([CH3:5])[CH3:4].[Mg].[CH3:7][SiH:8](Cl)Cl.O>O1CCCC1>[CH3:4][SiH:3]([CH2:2][SiH:8]([CH3:7])[CH2:2][SiH:3]([CH3:5])[CH3:4])[CH3:5]
Reactant: C[SiH](Cl)Cl
Reactant: C[SiH](C)CCl
Agent: [Mg]
Solvent: O
Solvent: C1CCOC1
Product: C[SiH](C)C[SiH](C)C[SiH](C)C
Temperature: 25 °C
Yield: 91.4 %

Procedure:
A solution of 70 g of chloromethyldimethylsilane in 400 ml of anhydrous tetrahydrofuran (THF) was added dropwise to 20 g of magnesium powder in a flask equipped with a mechanical stirrer and a condenser. The rate of addition was regulated to maintain reflux for the Grignard solution. To this Grignard reagent solution was then added dropwise 37 g of methyldichlorosilane in 300 ml THF. The resultant mixture was stirred overnight with gentle reflux. After cooled down to room temperature, the reaction was worked up by adding water. The organic phase was separated and dried over anhydrous sodium sulfate. Solvent (THF) was removed by atmospheric pressure distillation. Vacuum distillation at 85° C./20 mm yielded 56 g of 2,4,6-trimethyl-2,4,6-trisila-heptane.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7]2.[Cl:16][C:17]1[S:21][C:20]([S:22](Cl)(=[O:24])=[O:23])=[CH:19][CH:18]=1>N1C=CC=CC=1>[Cl:16][C:17]1[S:21][C:20]([S:22]([NH:1][C:2]2[CH:3]=[CH:4][CH:5]=[C:6]3[C:10]=2[NH:9][C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7]3)(=[O:24])=[O:23])=[CH:19][CH:18]=1
Reactant: CCOC(=O)c1cc2cccc(N)c2[nH]1
Reactant: O=S(=O)(Cl)c1ccc(Cl)s1
Solvent: c1ccncc1
Product: CCOC(=O)c1cc2cccc(NS(=O)(=O)c3ccc(Cl)s3)c2[nH]1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.6 %

Procedure:
To a mixture of ethyl 7-amino-1H-indole-2-carboxylate (0.70 g) and pyridine (10 mL) was added 5-chlorothiophene-2-sulfonyl chloride (0.89 g) at 0° C., and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated, 10% aqueous citric acid solution was added, and the resulting crystals were filtrated, washed with water and dried. The obtained crystals were subjected to silica gel column chromatography, and eluted with ethyl acetate. The eluate was treated with activated carbon and concentrated to give the title compound (1.09 g, yield 83%) as colorless crystals. The crystals were recrystallized from ethyl acetate-hexane. melting point 180-181° C.