Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:14]([CH3:15])=[CH:13][C:5]2[C:6]([CH2:9][C:10]([OH:12])=[O:11])=[CH:7][O:8][C:4]=2[C:3]=1[CH3:16].[CH2:17](O)[CH3:18]>S(=O)(=O)(O)O>[OH:1][C:2]1[C:14]([CH3:15])=[CH:13][C:5]2[C:6]([CH2:9][C:10]([O:12][CH2:17][CH3:18])=[O:11])=[CH:7][O:8][C:4]=2[C:3]=1[CH3:16]
Reactant: CCO
Reactant: Cc1cc2c(CC(=O)O)coc2c(C)c1O
Agent: O=S(=O)(O)O
Product: CCOC(=O)Cc1coc2c(C)c(O)c(C)cc12
Yield: 75 %

Procedure:
3.1 g (14 mmol) of 2-(6-hydroxy-5,7-dimethyl-1-benzofuran-3-yl) acetic acid are heated at reflux overnight in 1.72 ml of conc. sulfuric acid in 861 ml of ethanol. The mixture is concentrated down to 50 ml and then diluted with water and ethyl acetate; the phases are separated and the aqueous phase is extracted with ethyl acetate. The combined phases are washed with a saturated solution of NaCl, dried over sodium sulfate and concentrated. Chromatographic purification (dichloromethane) yields 2.6 g (75%) of ethyl 2-(6-hydroxy-5,7-dimethyl-1-benzofuran-3-yl)acetate.
Reaction SMILES: CS([C:4]1[N:9]=[C:8]([N:10]2[C:18]3[C:13](=[C:14]([O:19][CH2:20][CH2:21][CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH:15]=[CH:16][CH:17]=3)[CH:12]=[CH:11]2)[CH:7]=[CH:6][N:5]=1)=O.C([O-])(=O)C.[OH:31][C:32]([CH:35]1[CH2:40][CH2:39][CH:38]([NH3+:41])[CH2:37][CH2:36]1)([CH3:34])[CH3:33].CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[CH3:26][S:23]([CH2:22][CH2:21][CH2:20][O:19][C:14]1[CH:15]=[CH:16][CH:17]=[C:18]2[C:13]=1[CH:12]=[CH:11][N:10]2[C:8]1[CH:7]=[CH:6][N:5]=[C:4]([NH:41][CH:38]2[CH2:39][CH2:40][CH:35]([C:32]([OH:31])([CH3:33])[CH3:34])[CH2:36][CH2:37]2)[N:9]=1)(=[O:25])=[O:24]
Reactant: CS(=O)c1nccc(-n2ccc3c(OCCCS(C)(=O)=O)cccc32)n1
Reactant: CC(C)(O)C1CCC([NH3+])CC1
Agent: CC(=O)[O-]
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(O)C1CCC(Nc2nccc(-n3ccc4c(OCCCS(C)(=O)=O)cccc43)n2)CC1
Temperature: 126 °C
Yield: 57.4 %

Procedure:
1-(2-Methanesulfinyl-pyrimidin-4-yl)-4-(3-methanesulfonyl-propoxy)-1H-indole (538 mg, 1.4 mmol), 4-(2-hydroxyprop-2-yl)-cyclohexylammonium acetate (400 mg, 2 mmol), and DIEA (0.8 mL, 5 mmol) were combined in NMP (10 mL) and heated to 126° C. in a sealed tube for 4 h, cooled, and partitioned between water and EtOAc. The organic layer was separated and washed twice with water, dried over sodium sulfate, filtered and purified by flash chromatography (SiO2) with 3:97 MeOH/DCM, and recrystallized from MeOH/DCM, triturated with EtOAc and solvent evaporated to yield 2-(4-{4-[4-(3-methanesulfonyl-propoxy)-indol-1-yl]-pyrimidin-2-ylamino}-cyclohexyl)-propan-2-ol (Compound 166, 391 mg, 59%) as a white powder.
Reaction SMILES: [H-].[Na+].[C:3]([SH:7])(=[S:6])[CH2:4][CH3:5].[CH2:8]([O:11][C:12]([N:14]1[CH2:18][C@H:17](OS(C)(=O)=O)[CH2:16][C@H:15]1[CH2:24][O:25][CH2:26][CH2:27][F:28])=[O:13])[CH:9]=[CH2:10]>O1CCCC1>[CH2:8]([O:11][C:12]([N:14]1[CH2:18][C@@H:17]([S:6][C:3](=[S:7])[CH2:4][CH3:5])[CH2:16][C@H:15]1[CH2:24][O:25][CH2:26][CH2:27][F:28])=[O:13])[CH:9]=[CH2:10]
Reactant: C=CCOC(=O)N1C[C@H](OS(C)(=O)=O)C[C@H]1COCCF
Reactant: CCC(=S)S
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCOC(=O)N1C[C@@H](SC(=S)CC)C[C@H]1COCCF
Temperature: 0 °C
Yield: 60 %

Procedure:
To a suspension of sodium hydride (60% in oil, 2.0 g) in anhydrous tetrahydrofuran (50 ml) was added propanedithioic acid (5.0 g) with ice-cooling. A solution of (2S,4R)-1-allyloxycarbonyl-2-(2-fluoroethyloxymethyl)-4-methylsulfonyloxypyrrolidine (16.25 g) in anhydrous tetrahydrofuran (50 ml) was added dropwise to the mixture and the mixture was heated at 60°-70° C. for 4 hours. The solution was poured into ice-water (100 ml) and extracted with diethyl ether. The organic layer was washed with 1N aqueous sodium hydroxide solution (50 ml) and brine, dried, and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel [n-hexane-ethyl acetate (10:1, V/V)] to afford (2S,4S)-1-allyloxycarbonyl-2-(2-fluoroethyloxymethyl)-4-[(1-thioxopropyl)thio]pyrrolidine (9.47 g).
Reaction SMILES: Cl.[NH2:2][OH:3].CC([O-])=O.[Na+].[C:9]([C:12]1[CH:17]=[C:16]([CH3:18])[C:15]([Br:19])=[CH:14][C:13]=1[OH:20])(=O)[CH3:10].CCO>O>[Br:19][C:15]1[C:16]([CH3:18])=[CH:17][C:12]([CH2:9][CH:10]=[N:2][OH:3])=[C:13]([OH:20])[CH:14]=1
Reactant: NO
Reactant: CC(=O)c1cc(C)c(Br)cc1O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1cc(CC=NO)c(O)cc1Br
Temperature: 80 °C
Reaction time: 1 h
Yield: 97.5 %

Procedure:
A solution of hydroxylamine hydrochloride (400 mg, 5 8 mmol) in 1 ml water was added to a solution of NaOAc in 1 ml water. To the resulting solution was added 1-acetyl-4-bromo-2-hydroxy-5-methylbenzene (101) (1.14 g, 5 mmol) followed by addition of 15 ml EtOH. The reaction mixture was stirred at 80° C. for 1 h. After concentrated to half of it's volume, the reaction mixture was poured in to 60 ml ice-water. Precipitate formed was filtered, washed with water and dried to give 1.19 g (yield: 97.5%, purity>95%) 5-bromo-2-((hydroxyimino)ethyl)-4-methylphenol (102) as white solid.
Reaction SMILES: [C:1]([OH:5])(=O)[CH2:2]O.[Cl:6][C:7]1[N:12]=[C:11]([NH2:13])[C:10]([NH2:14])=[CH:9][CH:8]=1.Cl.N>>[Cl:6][C:7]1[N:12]=[C:11]2[NH:13][C:2]([CH2:1][OH:5])=[N:14][C:10]2=[CH:9][CH:8]=1
Reactant: Nc1ccc(Cl)nc1N
Reactant: O=C(O)CO
Agent: Cl
Agent: N
Product: OCc1nc2ccc(Cl)nc2[nH]1
Temperature: 150 °C
Reaction time: 4 h
Yield: 83.4 %

Procedure:
6.60 g of glycolic acid were added to 5.00 g of 6-chloro-2,3-diaminopyridine (prepared as described in Preparation 42), and the resulting mixture was stirred at 150° C. for 4 hours. At the end of this time, the reaction mixture was treated with 3 N aqueous hydrochloric acid and subsequently made alkaline by the addition of aqueous ammonia. The aqueous mixture was evaporated to dryness, and the resulting residue was purified by column chromatography through silica gel, using a gradient elution method, with mixtures of ethyl acetate and methanol in ratios ranging from 1:0 to 10:1 by volume as the eluent. The product was then crystallized by trituration with ethyl acetate, to give 5.33 g of the title compound, melting at 224-226° C.
Reaction SMILES: [Si:1]([O:18][CH2:19][CH2:20][CH:21]([C:30]1[C:34](I)=[C:33]([CH:36]2[CH2:39][CH:38]([CH2:40][CH:41]([CH3:43])[CH3:42])[CH2:37]2)[O:32][N:31]=1)[CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:44]1(B2OC(C)(C)C(C)(C)O2)[CH2:46][CH2:45]1>CN(C=O)C>[Si:1]([O:18][CH2:19][CH2:20][CH:21]([C:30]1[C:34]([CH:44]2[CH2:46][CH2:45]2)=[C:33]([CH:36]2[CH2:39][CH:38]([CH2:40][CH:41]([CH3:43])[CH3:42])[CH2:37]2)[O:32][N:31]=1)[CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(C)OB(C2CC2)OC1(C)C
Reactant: CC(C)CC1CC(c2onc(C(CCO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)CC(=O)OC(C)(C)C)c2I)C1
Solvent: CN(C)C=O
Product: CC(C)CC1CC(c2onc(C(CCO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)CC(=O)OC(C)(C)C)c2C2CC2)C1
Temperature: 80 °C
Reaction time: 8 h
Yield: 61.3 %

Procedure:
tert-Butyl 5-(tert-butyldiphenylsilanyloxy)-3-[4-iodo-5-(3-isobutylcyclobutyl)isoxazol-3-yl]valerate (37.44 g), 2-cyclopropyl-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (17.58 g) and DMF (262 mL) were mixed. After the resulting solution was degassed by bubbling argon, tripotassium phosphate (33.32 g) and PdCl2(PPh3)2 (3.67 g) were added to the mixture. The mixture was stirred at 80° C. overnight. After water (200 mL) was poured into the reaction, the resultant precipitate was removed by filtration and the filtrate was extracted with toluene (600 mL). The organic layer was washed with water (200 mL×2, 320 mL) and brine (160 mL), then dried over sodium sulfate. The sodium sulfate was filtered off and the filtrate was concentrated in vacuo. After an addition of silica gel (45 g) and ethyl acetate/hexane=1/20 (400 mL) to the residue, the mixture was stirred at RT. The silica gel was filtered off and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (Eluent: ethyl acetate/hexane=1/80→1/60→1/50) to give the title compound (20.2 g).
Reaction SMILES: [C:1]([OH:12])(=[O:11])[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[CH2:13]=O.O>OS(O)(=O)=O.O=S(=O)=O>[C:6]([C:5]1[CH:9]=[C:10]2[C:2](=[CH:3][CH:4]=1)[C:1](=[O:12])[O:11][CH2:13]2)([OH:8])=[O:7]
Reactant: O=C(O)c1ccc(C(=O)O)cc1
Reactant: C=O
Agent: O=S(=O)(O)O
Agent: O=S(=O)=O
Solvent: O
Product: O=C(O)c1ccc2c(c1)COC2=O
Temperature: 150 °C
Reaction time: 4 h

Procedure:
A solution of terephthalic acid (30 g) in oleum (20-25% SO3, 70 ml) is heated to 150° C. To this solution is added a solution of paraformaldehyde (8.8 g) in oleum (20-25% SO3, 37 ml) over a period of 1-2h. The reaction mixture is stirred at 150° C. for additional 4 h and cooled to 90° C. Water (190 ml) is added to the mixture at a rate so that the temperature stays below 100° C. The precipitate is filtered of, washed with hot (90-95° C.) water and suspended in water (200 ml) and dicalite (1.1 g) is added. The pH of the suspension is adjusted to about 7 with NaOH (approximately 60 ml) and activated carbon (1.1 g) is added. The mixture is filtered and the precipitate is rinsed with water. The temperature of the filtrate is adjusted to about 85° C., and the pH is adjusted to about 2 with sulphuric acid (96%, approximated 8 ml). The 5-carboxyphthalide precipitated is separated by filtration and dried.
Reaction SMILES: [C:1]([C:3](=[C:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][C:15]([N:18]3[CH2:22][C@H:21]([CH2:23][NH:24][C:25](=[O:27])[CH3:26])[O:20][C:19]3=[O:28])=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)[C:4]#[N:5])#[N:2].[I-].[CH3:30][S+](C)(C)=O.CC(C)([O-])C.[K+]>CS(C)=O>[C:1]([C:3]1([C:4]#[N:5])[C:6]2([CH2:11][CH2:10][N:9]([C:12]3[CH:13]=[CH:14][C:15]([N:18]4[CH2:22][C@H:21]([CH2:23][NH:24][C:25](=[O:27])[CH3:26])[O:20][C:19]4=[O:28])=[CH:16][CH:17]=3)[CH2:8][CH2:7]2)[CH2:30]1)#[N:2]
Reactant: C[S+](C)(C)=O
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N3CCC(=C(C#N)C#N)CC3)cc2)C(=O)O1
Agent: CC(C)(C)[O-]
Agent: [I-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC(=O)NC[C@H]1CN(c2ccc(N3CCC4(CC3)CC4(C#N)C#N)cc2)C(=O)O1
Yield: 52 %

Procedure:
The title compound was prepared by reacting (S)-N-[3-{4-[4-dicyanomethylidenepiperidin-1-yl]-phenyl}-2-oxo-1,3-oxazolidin-5-ylmethyl]-acetamide (1.0 mmol, Example D), trimethyloxosulphonium iodide (1.3 mmol), potassium tert-butoxide (1.3 mmol) in dimethylsulfoxide (10 ml) at a temperature 25° C. for 14 hours in 52% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21](O)=[O:22])=[CH:17][C:9]1=2.[N:32]1[CH:37]=[CH:36][CH:35]=[C:34]([CH:38]2[CH2:42][CH2:41][CH2:40][NH:39]2)[CH:33]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:29])([F:31])[F:30])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[C:20]([C:21]([N:39]4[CH2:40][CH2:41][CH2:42][CH:38]4[C:34]4[CH:33]=[N:32][CH:37]=[CH:36][CH:35]=4)=[O:22])[CH:24]=[CH:25][CH:26]=3)=[CH:17][C:9]1=2
Reactant: O=C(O)c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1
Reactant: c1cncc(C2CCCN2)c1
Product: O=C(c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1)N1CCCC1c1cccnc1

Procedure:
3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 2-(3-pyridinyl)pyrrolidine as in General Procedure 10 to give the title compound. LCMS: m/z=577.95 (M+H+); retention time=0.65 minutes.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1>C(O)C.C(OCC)(=O)C.[Pt](=O)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[C:11]1[CH:12]=[CH:13][N:14]=[CH:15][CH:16]=1
Reactant: O=[N+]([O-])c1ccc(F)c(-c2ccncc2)c1
Agent: O=[Pt]=O
Solvent: CCOC(C)=O
Solvent: CCO
Product: Nc1ccc(F)c(-c2ccncc2)c1
Reaction time: 0.58 h
Yield: 82.1 %

Procedure:
To a solution of 4-(2-fluoro-5-nitrophenyl)pyridine (1.0 g, 5.58 mmol) in ethanol (30 mL) and ethyl acetate (10 mL) was added platinum(IV) oxide (52 mg) and the mixture stirred for 35 min under hydrogen (40 psi). The reaction was filtered through glass microfibre filter paper and the filtrate evaporated to dryness to give 4-fluoro-3-(pyridin-4-yl)phenylamine (862 mg, 100%) as a white solid: δH (360 MHz, CDCl3) 3.49 (2H, s), 6.66-6.70 (1H, m), 6.71-6.76 (1H, m), 6.99 (1H, t, J 9), 7.44-7.46 (2H, m), 8.66 (2H, d, J 5).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[C:13]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)[NH:14][CH:15]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:24][O:25][C:26]1[CH:34]=[CH:33][CH:32]=[CH:31][C:27]=1[C:28](Cl)=[O:29]>C1(C)C=CC=CC=1>[CH3:24][O:25][C:26]1[CH:34]=[CH:33][CH:32]=[CH:31][C:27]=1[C:28]([C:15]1[NH:14][C:13]([C:16]2[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=2)=[CH:12][C:11]=1[C:8]1[CH:7]=[CH:6][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:10][CH:9]=1)=[O:29]
Reactant: COc1ccccc1C(=O)Cl
Reactant: COc1ccc(-c2cc(-c3ccc(C(C)(C)C)cc3)c[nH]2)cc1
Solvent: Cc1ccccc1
Product: COc1ccc(-c2cc(-c3ccc(C(C)(C)C)cc3)c(C(=O)c3ccccc3OC)[nH]2)cc1
Temperature: 25 °C
Yield: 60.2 %

Procedure:
A mixed solution of 300 mg of 4-(4-tert-butylphenyl)-2-(4-methoxyphenyl)pyrrole, 201 mg of 2-methoxybenzoylchloride, and 10 mL of toluene was heated at 120° C. for 6 hours under a nitrogen flow. After cooling to room temperature, evaporation was performed. After washing with 20 mL of ethanol and vacuum drying, 260 mg of 2-(2-methoxybenzoyl)-3-(4-tert-butylphenyl)-5-(4-methoxyphenyl)pyrrole was obtained.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:26][CH3:27])=[C:7]([C:9]2[C:13]([NH:14][C:15]([C:17]3[CH:18]=[N:19][N:20]4[CH:25]=[CH:24][CH:23]=[N:22][C:21]=34)=[O:16])=[CH:12][NH:11][N:10]=2)[CH:8]=1)#[N:2].Cl[CH2:29][C:30]1[N:34]([CH3:35])[N:33]=[CH:32][CH:31]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:26][CH3:27])=[C:7]([C:9]2[C:13]([NH:14][C:15]([C:17]3[CH:18]=[N:19][N:20]4[CH:25]=[CH:24][CH:23]=[N:22][C:21]=34)=[O:16])=[CH:12][N:11]([CH2:29][C:30]3[N:34]([CH3:35])[N:33]=[CH:32][CH:31]=3)[N:10]=2)[CH:8]=1)#[N:2]
Reactant: COc1ccc(C#N)cc1-c1n[nH]cc1NC(=O)c1cnn2cccnc12
Reactant: Cn1nccc1CCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(C#N)cc1-c1nn(Cc2ccnn2C)cc1NC(=O)c1cnn2cccnc12
Temperature: 60 °C
Reaction time: 6 h
Yield: 32.1 %

Procedure:
To a solution of N-(3-(5-cyano-2-methoxyphenyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (144 mg, 0.40 mmol) in 3 mL of DMF was added 5-(chloromethyl)-1-methyl-1H-pyrazole (78 mg, 0.6 mmol) and cesium carbonate (391 mg, 1.20 mmol). The reaction mixture was stirred at 60° C. for 6 hours, then cooled to room temperature, diluted with ethyl acetate and filtered. The filtrate was washed with brine, dried over magnesium sulfate, and concentrated. The crude product was purified by reverse phase HPLC and lyophilized to give 58.3 mg (32%) of N-(3-(5-cyano-2-methoxyphenyl)-1-((1-methyl-1H-pyrazol-5-yl)methyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide. LCMS (ESI) m+H=454.1; 1H NMR (400 MHz, CDCl3) δ: 9.58 (s, 1H), 8.74 (dd, 1H), 8.64 (s, 1H), 8.48 (dd, 1H), 8.21 (s, 1H), 7.81 (s, 1H), 7.69 (dd, 1H), 7.39 (s, 1H), 7.07 (d, 1H), 6.96 (dd, 1H), 6.31 (s, 2H), 5.33 (s, 2H), 3.86 (d, 6H).
Reaction SMILES: [C:1]1([C:7]2[C:15]([CH:16]=[CH:17][C:18]([N:20]3[CH2:25][CH2:24][CH2:23][CH2:22][C@@H:21]3[CH2:26][C:27]([O:29]C)=[O:28])=[O:19])=[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][N:9]3[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>CO>[C:1]1([C:7]2[C:15]([CH:16]=[CH:17][C:18]([N:20]3[CH2:25][CH2:24][CH2:23][CH2:22][C@@H:21]3[CH2:26][C:27]([OH:29])=[O:28])=[O:19])=[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][N:9]3[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)C[C@H]1CCCCN1C(=O)C=Cc1c(-c2ccccc2)nn2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C[C@H]1CCCCN1C(=O)C=Cc1c(-c2ccccc2)nn2ccccc12
Yield: 75.3 %

Procedure:
A mixture of (2R)-1-[3-(2-phenylpyrazolo[1,5-a]-pyridin-3-yl)acryloyl]-2-(methoxycarbonylmethyl-)piperidine (trans isomer) (210 mg) and 1N sodium hydroxide solution (0.573 ml) in methanol (2.0 ml) was heated to reflux for 2 hours. Methanol was evaporated in vacuo and water (20 ml) was added to the residue. The solution was acidified with 1N hydrochloric acid and extracted with methylene chloride (10 ml×2). The combined extracts were washed with brine (10 ml), dried over sodium sulfate and evaporated in vacuo. The crude crystals were recrystallized from a mixture of ethyl acetate and diethyl ether to give colorless crystals of (2R)-1-[3-(2-phenylpyrazolo[1,5-a]-pyridin-3-yl)acryloyl]-2-(carboxymethyl)piperidine (trans isomer) (152.7 mg).
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].Cl>C(O)C.[OH-].[Na+].O>[CH2:1]([S:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[C:1]([OH:10])=[O:9])[CH2:2][CH2:8][CH3:7]
Reactant: O=C(O)c1ccccc1S
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCCSc1ccccc1C(=O)O
Reaction time: 8 h

Procedure:
A stirred solution of n-bromobutane (12.4 g, 0.09 mole) in 90 mL of ethanol under argon at room temperature was treated with a solution of thiosalicylic acid (13.5 g, 0.09 mole) in 72 mL of 10% sodium hydroxide. After stirring overnight, volatiles were stripped in vacuo and the residue was diluted with water and acidified with concentrated hydrochloric acid to precipitate the product. The crude product was collected and air dried, then dissolved in hot acetonitrile containing 1-2 mL of water. Upon cooling there was obtained 13.7 g of the title A compound, m.p. 96°-101°.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[CH:10]=O.[CH:12]([CH:14]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:13]>C1(C)C=CC=CC=1>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1/[CH:10]=[CH:14]/[CH:12]=[O:13]
Reactant: O=Cc1cc2ccccc2[nH]1
Reactant: O=CC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: O=C/C=C/c1cc2ccccc2[nH]1
Yield: 62.6 %

Procedure:
Indole 2-carboxaldehyde (6.72 g, 46.3 mmol) was dissolved in dry toluene (450 ml) and treated with (formylmethylene)triphenylphosphorane (21.3 g, 70 mmol). The reaction mixture was treated under reflux for 4 h, allowed to cool and chromatographed over silica gel using toluene (2×500 ml) and then hexane/EtOAc (3:1) (2×500 ml) as the eluent. Evaporation of the solvent and recrystallization of the residue from toluene yielded 4.96 g (62.6%) of the title compound, m.p.=203-204° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.Cl.[C:19]([O:23][C:24](=[O:31])[C@H:25]([CH2:27][CH:28]([CH3:30])[CH3:29])[NH2:26])([CH3:22])([CH3:21])[CH3:20]>CO.C(Cl)Cl>[C:19]([O:23][C:24](=[O:31])[C@H:25]([CH2:27][CH:28]([CH3:29])[CH3:30])[NH:26][C:15](=[O:17])[C@H:13]([CH3:14])[NH:12][C:10](=[O:11])[CH2:9][C:4]1[CH:5]=[C:6]([F:8])[CH:7]=[C:2]([F:1])[CH:3]=1)([CH3:22])([CH3:21])[CH3:20]
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Reactant: CC(C)C[C@H](N)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: CC(C)C[C@H](NC(=O)[C@H](C)NC(=O)Cc1cc(F)cc(F)c1)C(=O)OC(C)(C)C

Procedure:
Following General Procedure B and using N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and L-leucine tert-butyl ester hydrochloride (Bachem), the title compound was prepared as a solid (mp=128° C.). The reaction was monitored by tlc (Rf=0.85 in 5% MeOH/methylene chloride) and the product was purified by flash column chromatography using 5% MeOH/methylene chloride as the eluent.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17]1([N:23]=[C:24]=[S:25])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CC(C)=O>[NH:23]([C:24]([N:14]1[CH2:15][CH2:16][N:11]([C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])[CH2:12][CH2:13]1)=[S:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(OCc1ccccc1)N1CCNCC1
Reactant: S=C=Nc1ccccc1
Solvent: CC(C)=O
Product: O=C(OCc1ccccc1)N1CCN(C(=S)Nc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1-Benzyloxycarbonylpiperazine (5.00 g) was dissolved in acetone (50 mL), and phenyl isothiocyanate (2.9 mL) was added thereto under ice-cooling. The mixture was stirred at room temperature for 1 hr. The precipitated solid was collected by filtration to give 1-(anilinocarbothioyl)-4-(benzyloxycarbonyl)piperazine (5.08 g) as a white powder.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][S:5][CH2:4][CH:3]1[C:7]#[N:8].[CH3:9][S:10](Cl)(=[O:12])=[O:11]>C(Cl)Cl.O>[CH3:9][S:10]([O:1][CH:2]1[CH:3]([C:7]#[N:8])[CH2:4][S:5][CH2:6]1)(=[O:12])=[O:11]
Reactant: CS(=O)(=O)Cl
Reactant: N#CC1CSCC1O
Solvent: ClCCl
Solvent: O
Product: CS(=O)(=O)OC1CSCC1C#N
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 4-hydroxytetrahydrothiophene-3-carbonitrile (1.0 g, 7.7 mmol) in DCM (15 mL) was stirred at 0° C. TEA (4.3 mL, 31 mmol) was added followed by the dropwise addition of methanesulfonyl chloride (1.77 g, 15.5 mmol). The resulting mixture was stirred at 0° C. for 30 minutes then warmed to ambient temperature and stirred for an additional 30 minutes. The mixture was carefully diluted with water and extracted with DCM (2×). The combined organic extracts were washed with 1N aqueous HCl, brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified by MPLC on silica gel (using a gradient elution of 0-5% MeOH/DCM) to afford the title compound, which was used without further purification.
Reaction SMILES: [CH3:1][N:2]1[C:14]2[C:5](=[C:6]3[C:11](=[CH:12][CH:13]=2)[N:10]=[CH:9][CH:8]=[CH:7]3)[N:4]=[C:3]1[CH:15]([CH3:21])[CH2:16][C:17]([O:19]C)=[O:18].O.[OH-].[Li+]>C(#N)C.O>[CH3:1][N:2]1[C:14]2[C:5](=[C:6]3[C:11](=[CH:12][CH:13]=2)[N:10]=[CH:9][CH:8]=[CH:7]3)[N:4]=[C:3]1[CH:15]([CH3:21])[CH2:16][C:17]([OH:19])=[O:18]
Reactant: COC(=O)CC(C)c1nc2c3cccnc3ccc2n1C
Agent: [Li+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Product: CC(CC(=O)O)c1nc2c3cccnc3ccc2n1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.5 %

Procedure:
To a solution of methyl 3-(3-methyl-3H-imidazo[4,5-f]quinolin-2-yl)butanoate (560 mg, 1.97 mmol) in acetonitrile (20 mL) and water (8 mL) was added lithium hydroxide hydrate (249 mg, 5.94 mmol). The mixture was stirred at room temperature overnight. The mixture was concentrated to about 8 mL. The pH of the solution was adjusted to ˜4 with 1N HCl aqueous solution. The mixture was concentrated to dryness and to the residue was added 50 mL of DCM/MeOH v/v 10:1. The precipitate was removed by filtration and the filtrate was concentrated to dryness to give the product as a yellow solid (480 mg, 90% yield). ESI MS: m/z 270.1 [M+H]+.
Reaction SMILES: [CH2:1]([CH:5]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][OH:21])=[CH:14][CH:13]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:2][CH2:3][CH3:4].[CH3:22][S:23](Cl)(=[O:25])=[O:24]>C(N(CC)CC)C>[CH2:1]([CH:5]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][O:21][S:23]([CH3:22])(=[O:25])=[O:24])=[CH:14][CH:13]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CS(=O)(=O)Cl
Reactant: CCCCC(Cc1ccc(OCCO)cc1)C(=O)OCC
Solvent: CCN(CC)CC
Product: CCCCC(Cc1ccc(OCCOS(C)(=O)=O)cc1)C(=O)OCC

Procedure:
In a similar manner to that described in Reference example 3(g), a reaction was carried out using ethyl 2-butyl-3-[4-(2-hydroxyethoxy)phenyl]propionate (1.44 g), which is the product of Reference example 6(e), triethylamine (2.04 ml) and methanesulfonyl chloride (0.76 ml) and the reaction mixture was treated to afford the desired compound (1.65 g) as a syrup.