Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=O.C1(N=C=NC2CCCCC2)CCCCC1.[NH2:26][CH2:27][CH2:28][CH2:29][NH:30][CH2:31][CH2:32][CH2:33][CH2:34][NH:35][CH2:36][CH2:37][CH2:38][NH2:39]>ClCCl>[OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH:39][CH2:38][CH2:37][CH2:36][NH:35][CH2:34][CH2:33][CH2:32][CH2:31][NH:30][CH2:29][CH2:28][CH2:27][NH2:26])=[O:7]
Reactant: O=C(O)c1cccc(O)c1
Reactant: NCCCNCCCCNCCCN
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: NCCCNCCCCNCCCNC(=O)c1cccc(O)c1
Reaction time: 17 h

Procedure:
According to the General Procedure using 3-Hydroxybenzoic acid (138 mg, 1.00 mMol), dicyclohexylcarbodiimide (226 mg, 1.10 mMol), and spermine (400 mg, 1.98 mMol) in dichloromethane (6 ml), activation during 3 h and coupling over 17 h. The product was eluted over silica gel with dichloromethane/methanol/0.880 ammonia solution (4:2:1). The desired amide was in fractions 8-13 was homogeneous when monitored by tlc on silica (CH2Cl2 /MeOH/NH4OH, 4:2:1), Rf =0.29, (76 mg, 24%), lyophilisation gave 52 mg of a colorless, viscous oil whose spectroscopic data include:pmr (90 MHz, 2H2O) 1.4-1.9 (m, 8H, 4×CH2 --CH2), 2.5-2.9 (m, 10H, 5×CH2 --N), 3.25 (t, J=7, 2H, CON2H--CH2 --CH2), 6.5-6.8 (m, 3H, 3× ArH 2,4,6), and 7.0-7.3 (m, 1H, ArH 5) ppm; M+1 323 (FAB matrix m-nitrobenzyl alcohol and sodium chloride) C17H30N4O2 requires M+ 322).
Reaction SMILES: [N:1]1([S:6]([C:9]2[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=2)[C:12]([OH:14])=O)(=[O:8])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:18][C:19]1[CH:20]=[C:21]([O:26][CH3:27])[C:22]([NH2:25])=[N:23][CH:24]=1>>[Br:18][C:19]1[CH:20]=[C:21]([O:26][CH3:27])[C:22]([NH:25][C:12](=[O:14])[C:11]2[CH:15]=[CH:16][CH:17]=[C:9]([S:6]([N:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)(=[O:7])=[O:8])[CH:10]=2)=[N:23][CH:24]=1
Reactant: COc1cc(Br)cnc1N
Reactant: O=C(O)c1cccc(S(=O)(=O)N2CCCC2)c1
Product: COc1cc(Br)cnc1NC(=O)c1cccc(S(=O)(=O)N2CCCC2)c1

Procedure:
The intended substance was produced according to the method of Example 92 but using 3-(pyrrolidin-1-ylsulfonyl)benzoic acid and 5-bromo-3-methoxypyridine-2-amine as the starting materials.
Reaction SMILES: C([O:3][C:4]([CH:6]1[C:15]([CH2:16][NH:17][C@H:18]([C:26]([O:28][CH3:29])=[O:27])[CH2:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[Cl:30])[O:7]1)=O)C>C(#N)C>[CH3:29][O:28][C:26](=[O:27])[C@@H:18]([N:17]1[CH2:16][C:15]2=[CH:14][C:13]3[C:12]([Cl:30])=[CH:11][CH:10]=[CH:9][C:8]=3[O:7][CH:6]2[C:4]1=[O:3])[CH2:19][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: CCOC(=O)C1Oc2cccc(Cl)c2C=C1CN[C@@H](CC1CCCCC1)C(=O)OC
Solvent: CC#N
Product: COC(=O)[C@H](CC1CCCCC1)N1CC2=Cc3c(Cl)cccc3OC2C1=O
Yield: 48.9 %

Procedure:
A solution of 5-chloro-3-[((S)-2-cyclohexyl-1-methoxycarbonyl-ethylamino)-methyl]-2H-chromene-2-carboxylic acid ethyl ester (0.55 g, 1.26 mmol) and N,N′-diisopropylethyl amine (0.87 mL, 5.05 mmol) in acetonitrile (2 mL) was heated in a sealed tube at 140° C. for 48 hours. The reaction mixture, after aqueous work-up, was extracted with ethyl acetate (3×). The combined ethyl acetate layer was washed with brine, and dried over anhydrous sodium sulfate. The organic layer was concentrated in vacuo and the residue was purified over neutral alumina using hexanes-ethyl acetate (1:1.2) as eluents to afford (S)-2-(8-chloro-3-oxo-3,3a-dihydro-1H-chromeno[2,3-c]pyrrol-2-yl)-3-cyclohexyl-propionic acid methyl ester (0.24 g, 48.8%) as a off white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11](OS(C)(=O)=O)[CH2:10][C@H:9]1[CH3:18])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C-:19]#[N:20].[Na+].O.C(OCC)(=O)C>CS(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([C:19]#[N:20])[CH2:10][C@H:9]1[CH3:18])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: [C-]#N
Reactant: C[C@@H]1C[C@@H](OS(C)(=O)=O)CN1C(=O)OC(C)(C)C
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: C[C@@H]1C[C@H](C#N)CN1C(=O)OC(C)(C)C
Yield: 71.6 %

Procedure:
A solution of (2R,4R)-1-(tert-butoxycarbonyl)-4-methanesulfonyloxy-2-methylpyrrolidine (2.3 g) and sodium cyanide (1.37 g) in dimethyl sulfoxide (25 ml) was heated for two and a half hours at 90° C. The reaction mixture was poured into a mixture of water (100 ml) and ethyl acetate (100 ml). The organic layer was separated, washed with brine, and dried over magnesium sulfate. Evaporation of the solvent gave an oil, which was chromatographed on silica gel (100 ml) eluting with a mixture of hexane and ethyl acetate (4:1, V/V) to give (2R,4S)-1-(tert-butoxycarbonyl)-4-cyano-2-methylpyrrolidine (1.24 g).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[CH2:3][CH2:4][CH:5]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=1)[CH2:6][C:7]([OH:9])=O.C(Cl)(=O)C(Cl)=O.[Al+3].[Cl-].[Cl-].[Cl-]>>[CH3:18][O:17][C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[C:7](=[O:9])[CH2:6][CH:5]([CH2:4][CH2:3][C:2]([F:1])([F:20])[F:19])[CH2:10]2
Reactant: COc1cccc(CC(CCC(F)(F)F)CC(=O)O)c1
Agent: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Product: COc1ccc2c(c1)CC(CCC(F)(F)F)CC2=O
Yield: 73 %

Procedure:
6,6,6-Trifluoro-3-{[3-(methyloxy)phenyl]methyl}hexanoic acid (120) (1.56 g, 5.38 mmol) was treated with oxalyl chloride followed by AlCl3 in CH2Cl to give 1.07 g (73%) of the title compound (121) as pale yellow solid. 1H NMR (400 MHz, CDCl3): δ 1.65-1.75 (m, 2H), 2.10-2.35 (m, 4H), 2.65-2.80 (m, 2H), 2.90-3.05 (m, 1H), 3.85 (s, 3H), 6.70 (d, J=2.4 Hz, 1H), 6.84 (dd, J1=8.8 Hz, J2=2.5 Hz, 1H), 7.99 (d, J=8.8 Hz, 1H). LCMS (ESI): m/z 273 (M+H)+.
Reaction SMILES: O.[CH2:2]([SH:10])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[C:11]1(=[O:16])[O:15][CH2:14][CH2:13][CH2:12]1>C(O)C>[CH2:2]([S:10][CH2:14][CH2:13][CH2:12][C:11]([OH:16])=[O:15])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCCCCS
Reactant: O=C1CCCO1
Solvent: O
Solvent: CCO
Product: CCCCCCCCSCCCC(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
An apparatus was provided including a two liter, 4-neck, round bottom flask equipped with an alcohol thermometer, an overhead mechanical stirrer, a water-cooled condenser and a nitrogen purge. Into this reactor gradually were added 23 g of sodium into 1,200 ml of absolute ethanol previously added. After all of the sodium had reacted the solution was stirred overnight under a slow nitrogen flow. 1-octanethiol, 146.28 g, was added to the mixture and an addition funnel and heating mantel were added to the reactor. In 200 ml of ethanol, 129.13 g of butyrolactone was added dropwise to the ethanol solution at reflux temperature. The resulting mixture was heated at reflux overnight. The ethanol was then removed from the reaction mixture and the residue was dissolved in water. The aqueous solution was washed with methylene chloride. The aqueous solution was then added to an ice/sulfuric acid mixture and the product extracted with methylene chloride. The methylene chloride solution was washed with water, dried with sodium sulfate, filtered and concentrated under vacuum with heating. The liquid product solidified upon cooling to room temperature. There was provided 219 g of 4-(n-octylthio)butyric acid. The solid exhibited a melting point of 33°-34.5° C.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10]CC)=[O:9])=[CH:6][N:5]=[C:4]2[O:13][N:14]=[C:15]([CH3:16])[C:3]=12.[CH3:17][N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>O1CCCC1>[CH3:16][C:15]1[C:3]2[C:4](=[N:5][CH:6]=[C:7]([C:8]([OH:10])=[O:9])[C:2]=2[N:21]2[CH2:22][CH2:23][N:18]([CH3:17])[CH2:19][CH2:20]2)[O:13][N:14]=1
Reactant: CN1CCNCC1
Reactant: CCOC(=O)c1cnc2onc(C)c2c1Cl
Solvent: C1CCOC1
Product: Cc1noc2ncc(C(=O)O)c(N3CCN(C)CC3)c12
Temperature: 60 °C
Reaction time: 1 h

Procedure:
A solution of ethyl 4-chloro-3-methylisoxazolo[5,4-b]pyridin-5-carboxylate (1.02 g) and 1-methylpiperazine (1.12 ml) in tetrahydrofuran (10 ml) was stirred at room temperature for 1 hr and then concentrated under reduced pressure. The residue was treated with water, the precipitated solid was filtered, washed with water, and dried under high vacuum. This solid was suspended in ethanol (1 ml), added 5N NaOH (11 ml , and the mixture was stirred at 60° C. for 1 hr. The reaction mixture was treated with 5N HCl and purified by ODS column (VARIAN MEGABOND ELUT C18) to give 3-methyl-4-(4-methyl-piperazin-1-yl)isoxazolo[5,4-b]pyridine-5-carboxylic acid as an amorphous solid. A portion of this amorphous solid (417 mg) was dissolved in thionyl chloride (40 ml) and heated at 50° C. for 3.5 hrs. The mixture was concentrated under reduced pressure, the residue was dissolved in THF (20 ml), and reacted with ammonia gas at room temperature for 3 hrs. The reaction mixture was concentrated under reduced pressure, the residue was treated with water, the resulting solid was filtered, washed with water, and dried under high vacuum to give the 3-methyl-4-(4-methylpiperazin-1-yl)-isoxazolo[5,4-b]pyridin-5-carboxylic acid amide.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10](O)=[O:11])=[CH:4][C:3]=1[CH3:13].C(Cl)(=O)C(Cl)=O.CN(C)C=O>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[CH2:10][OH:11])=[CH:4][C:3]=1[CH3:13]
Reactant: Cc1cc(/C=C/C(=O)O)ccc1F
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1cc(/C=C/CO)ccc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 12.5 %

Procedure:
A mixture of trans-3-(4-fluoro-3-methylphenyl)prop-2-enoic acid (6.18 g) and oxalyl chloride (3.72 mL) in dichloromethane (40 mL) containing N,N-dimethylformamide (60 μL) is stirred at room temperature for three hours, concentrated under reduced pressure and redissolved in tetrahydrofurane (50 mL). The solution is maintained at a temperature below −8° C. during the addition of a suspension of sodium borohydride (2.9 g) in N,N-dimethylformamide (15 mL). The mixture is stirred for one hour at a temperature close to −12° C., hydrolysed by the successive addition of water (10 mL) and 1N hydrochloric acid and extracted with ethyl acetate. The organic layers are pooled, washed with water, dired over magnesium sulfate, concentrated under reduced pressure and purified by chromatography over silica gel, with heptane/ethyl acetate 3/1 as eluant, to give 710 mg of trans-3-(4-fluoro-3-methylphenyl)prop-2-en-1-ol as a colorless oil used without further purification.
Reaction SMILES: [CH3:1][Si:2]([CH3:40])([CH3:39])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[C:8]1[N:13]2[N:14]=[CH:15][C:16](I)=[C:12]2[N:11]=[C:10]([CH:18]2[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]2)[CH:9]=1.[C:41]1([C:47]2[CH:52]=[CH:51][C:50](B3OC(C)(C)C(C)(C)O3)=[CH:49][N:48]=2)[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.ClCCl.C([O-])([O-])=O.[K+].[K+]>O.COCCOC>[CH3:1][Si:2]([CH3:40])([CH3:39])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:50]3[CH:49]=[N:48][C:47]([C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)=[CH:52][CH:51]=3)=[C:12]2[N:11]=[C:10]([CH:18]2[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]2)[CH:9]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3ncc(I)c3n2)CC1
Reactant: CC1(C)OB(c2ccc(-c3ccccc3)nc2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CCC(c2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3ncc(-c4ccc(-c5ccccc5)nc4)c3n2)CC1
Temperature: 100 °C
Reaction time: 8 h
Yield: 57 %

Procedure:
To a pressure tube were charged tert-butyl 4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-iodopyrazolo[1,5-a]pyrimidin-5-yl)piperidine-1-carboxylate (Int-9g, 1.7 g, 2.4 mmol), 2-phenyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (800 mg, 2.8 mmol), [1,1′-bis(diphenylphosphino)-ferrocene]dichloropalladium(II) complex with dichloromethane (1:1) (100 mg, 0.12 mmol), K2CO3 (666 mg, 4.8 mmol), DME (10 mL) and water (5 mL). The tube was degassed with Ar briefly, capped and heated at 100° C. with stirring overnight. After cooling, the reaction mixture was diluted with EtOAc and water, the organic layer was isolated, washed with brine and dried (MgSO4). After the solvent was removed under reduced pressure, the residue was purified on silica. Elution with EtOAc in hexanes (0-50%) gave tert-butyl 4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-(6-phenyl pyridin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)piperidine-1-carboxy late (Int-9h) (1 g, 57%). LC/MS: m/z=731 (M+H+).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:8](=[O:12])[CH2:7][C:6]([CH3:14])(C)[CH2:5][C:4]=2[N:3]=1.[CH2:15]([OH:19])[CH:16]([CH3:18])[CH3:17]>>[CH2:15]([O:19][C:2]1[CH:11]=[CH:10][C:9]2[C:8](=[O:12])[CH2:7][CH:6]([C:14]3[CH:6]=[CH:5][CH:4]=[CH:9][CH:8]=3)[CH2:5][C:4]=2[N:3]=1)[CH:16]([CH3:18])[CH3:17]
Reactant: CC1(C)CC(=O)c2ccc(Cl)nc2C1
Reactant: CC(C)CO
Product: CC(C)COc1ccc2c(n1)CC(c1ccccc1)CC2=O
Yield: 35 %

Procedure:
In analogy to the procedure described in Example 8, 2-chloro-7,7-dimethyl-7,8-dihydro-6H-quinolin-5-one was treated with iso-butyl alcohol to give the title compound in 35% yield.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:9]=1[CH2:10][C:11](=[O:17])[NH:12]2.[CH3:18][C@H:19]1[NH:24][C@@H:23]([CH3:25])[CH2:22][N:21]([C:26]([C:28]2[CH:32]=[C:31]([CH3:33])[NH:30][C:29]=2[CH:34]=O)=[O:27])[CH2:20]1>C(O)C.N1CCCCC1>[CH3:25][C@H:23]1[NH:24][C@@H:19]([CH3:18])[CH2:20][N:21]([C:26]([C:28]2[CH:32]=[C:31]([CH3:33])[NH:30][C:29]=2[CH:34]=[C:10]2[C:9]3[C:13](=[CH:14][CH:15]=[CH:16][C:8]=3[C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])[NH:12][C:11]2=[O:17])=[O:27])[CH2:22]1
Reactant: Cc1cc(C(=O)N2C[C@@H](C)N[C@@H](C)C2)c(C=O)[nH]1
Reactant: O=C1Cc2c(cccc2-c2ccccc2F)N1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1cc(C(=O)N2C[C@@H](C)N[C@@H](C)C2)c(C=C2C(=O)Nc3cccc(-c4ccccc4F)c32)[nH]1
Temperature: 25 °C
Reaction time: 72 h
Yield: 90.3 %

Procedure:
To a solution of 4-(2-fluoro-phenyl)-1,3-dihydro-indol-2-one (56.8 mg, 0.25 mmol) and 3-[(cis)-3,5-dimethyl-piperazine-1-carbonyl]-5-methyl-1H-pyrrole-2-carbaldehyde (62.3 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 3-{3-((cis)-3,5-dimethyl-piperazine-1-carbonyl]-5-methyl-1H-pyrrol-2-ylmethylene}-4-(2-fluoro-phenyl)-1,3-dihydro-indol-2-one as a yellow solid (103.5 mg, 90%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[CH:9]=[CH:10][C:11]2[CH2:17][CH2:16][CH2:15][C:14](SC)=[N:13][C:12]=2[CH:20]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:22][O:23][CH:24]([O:27][CH3:28])[CH2:25][NH2:26]>C(O)C>[C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[CH:9]=[CH:10][C:11]2[CH2:17][CH2:16][CH2:15][C:14]([NH:26][CH2:25][CH:24]([O:27][CH3:28])[O:23][CH3:22])=[N:13][C:12]=2[CH:20]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CSC1=Nc2cc(NC(=O)OC(C)(C)C)ccc2CCC1
Reactant: COC(CN)OC
Solvent: CCO
Product: COC(CNC1=Nc2cc(NC(=O)OC(C)(C)C)ccc2CCC1)OC
Yield: 61.1 %

Procedure:
A solution of (2-methylsulfanyl-4,5-dihydro-3H-benzo[b]azepin-8-yl)-carbamic acid tert-butyl ester (2.2 g, 7.2 mmol) and 2,2-dimethoxyethanamine (1.0 g, 9.5 mmol) in ethanol (200 mL) was heated in an oil bath at 100° C. for 14 hours. The mixture was concentrated and purified by silica gel chromatography with DCM/MeOH (9:1) to give [2-(2,2-dimethoxy-ethylamino)-4,5-dihydro-3H-benzo[b]azepin-8-yl]-carbamic acid tert-butyl ester (1.6 g, 4.4 mmol, 61%): 1H NMR (300 MHz, CDCl3) δ 7.1 (m, 2H), 6.93 (s, 1H), 6.48 (s, 1H), 4.69 (t, 1H), 3.66 (d, 2H), 3.54 (s, 6H), 2.61 (t, 2H), 2.2 (br, 4H), 1.61 (s, 9H); MS (m/e) 364 (M+1).
Reaction SMILES: [CH3:1][C:2]1([C:8]([C:10]2[C:18]3[C:13](=[N:14][CH:15]=[C:16]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([N:25]5[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]5)[CH:20]=4)[N:17]=3)[NH:12][CH:11]=2)=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[C:31]([O:35][C:36]([N:38]1[CH2:43][CH2:42][CH:41]([C:44](O)=[O:45])[CH2:40][CH2:39]1)=[O:37])([CH3:34])([CH3:33])[CH3:32]>>[C:31]([O:35][C:36]([N:38]1[CH2:43][CH2:42][CH:41]([C:44]([N:28]2[CH2:29][CH2:30][N:25]([C:21]3[CH:22]=[CH:23][CH:24]=[C:19]([C:16]4[N:17]=[C:18]5[C:10]([C:8]([C:2]6([CH3:1])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]6)=[O:9])=[CH:11][NH:12][C:13]5=[N:14][CH:15]=4)[CH:20]=3)[CH2:26][CH2:27]2)=[O:45])[CH2:40][CH2:39]1)=[O:37])([CH3:34])([CH3:33])[CH3:32]
Reactant: CC1(C(=O)c2c[nH]c3ncc(-c4cccc(N5CCNCC5)c4)nc23)CCCCC1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Product: CC(C)(C)OC(=O)N1CCC(C(=O)N2CCN(c3cccc(-c4cnc5[nH]cc(C(=O)C6(C)CCCCC6)c5n4)c3)CC2)CC1

Procedure:
4-(4-{3-[7-(1-Methyl-cyclohexanecarbonyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-phenyl}-piperazine-1-carbonyl)-piperidine-1-carboxylic acid tert-butyl ester was prepared starting from (1-methyl-cyclohexyl)-[2-(3-piperazin-1-yl-phenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-methanone and piperidine-1,4-dicarboxylic acid mono-tert-butyl ester following general procedures as described in these Examples. M+H=615.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([S:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)[O:11][C:12]=2[CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[CH:4][CH:3]=1.I[CH2:26][CH3:27]>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([S:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)[O:11][C:12]=2[CH2:13][CH2:14][C:15]([O:17][CH2:26][CH3:27])=[O:16])=[CH:6][CH:7]=1
Reactant: O=C(O)CCc1oc(Sc2ccccn2)nc1-c1ccc(Cl)cc1
Reactant: CCI
Solvent: O
Product: CCOC(=O)CCc1oc(Sc2ccccn2)nc1-c1ccc(Cl)cc1
Yield: 96 %

Procedure:
Water was added to a mixture which was obtained by ) reacting 4-(4-chlorophenyl)-2-(2-pyridylthio)-5-oxazolepropionic acid with iodoethane in the same manner as Example 52. This was extracted with ethyl acetate. The ethyl acetate layer was washed with water, and dried (MgSO4). The residue obtained by evaporated the solvent was subjected to silica gel column chromatography. From the fraction eluted with ethyl acetate-hexane (1:4, v/v), obtained was ethyl 4-(4-chlorophenyl)-2-(2-pyridylthio)-5-oxazolepropionate(yield: 96%) as an oily substance.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:24]=[CH:23][C:6]2[N:7]=[C:8]([N:10]3[CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][CH2:11]3)[S:9][C:5]=2[CH:4]=1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[N:10]1([C:8]2[S:9][C:5]3[CH:4]=[C:3]([CH2:2][OH:1])[CH:24]=[CH:23][C:6]=3[N:7]=2)[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nc3ccc(CO)cc3s2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: OCc1ccc2nc(N3CCNCC3)sc2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 98.1 %

Procedure:
The tert-butyl 4-(6-(hydroxymethyl)benzo[d]thiazol-2-yl)piperazine-1-carboxylate (1.0 g) was dissolved in a mixture of TFA (2 mL) and DCM (20 mL) and stirred at room temperature. After four hours, the resulting mixture was concentrated to yield (2-(piperazin-1-yl)benzo[d]thiazol-6-yl)methanol as a yellow oil (0.7 g). MS: 250.3 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[C:4]1[CH:9]=[C:8]([C:10]2[N:11]([CH2:15][CH2:16][O:17][CH3:18])[N:12]=[CH:13][CH:14]=2)[C:7]([C:19]([F:22])([F:21])[F:20])=[CH:6][C:5]=1[NH:23]C(=O)C.OS(O)(=O)=O>CO>[CH3:1][O:2][C:3](=[O:27])[C:4]1[CH:9]=[C:8]([C:10]2[N:11]([CH2:15][CH2:16][O:17][CH3:18])[N:12]=[CH:13][CH:14]=2)[C:7]([C:19]([F:22])([F:20])[F:21])=[CH:6][C:5]=1[NH2:23]
Reactant: COCCn1nccc1-c1cc(C(=O)OC)c(NC(C)=O)cc1C(F)(F)F
Agent: O=S(=O)(O)O
Solvent: CO
Product: COCCn1nccc1-c1cc(C(=O)OC)c(N)cc1C(F)(F)F
Yield: 75.9 %

Procedure:
2-Acetylamino-5-[2-(2-methoxy-ethyl)-2H-pyrazol-3-yl]-4-trifluoromethyl-benzoic acid methyl ester (352 mg, 0.913 mmol) was treated with MeOH containing 10% of concd H2SO4 (10 mL) and the resultant solution was stirred at 70° C. for 2 h. The solvents were removed in vacuo and the residue was dissolved into water. The pH was adjusted to 10-11 by addition of 2N aq NaOH. The aqueous phase was extracted with AcOEt (2×). The organic phases were combined, dried (Na2SO4) and concentrated in vacuo to afford the title compound (238 mg, 76%). ES-MS: m/z 344.3 [M+H]+, rt 5.52 min.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]([CH2:35][O:36][CH3:37])[O:5][C:6]1[CH:7]=[C:8]([O:24][C:25]2[CH:26]=[N:27][C:28]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:29][CH:30]=2)[CH:9]=[C:10]2[C:14]=1[NH:13][C:12]([C:15]1[S:16][CH:17]([CH2:20][C:21](O)=[O:22])[CH2:18][N:19]=1)=[CH:11]2.Cl.[CH2:39]([N:41]=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.[Cl-].C[NH3+]>CN(C)C=O.C(N(CC)CC)C>[CH3:37][O:36][CH2:35][CH:4]([CH2:3][O:2][CH3:1])[O:5][C:6]1[CH:7]=[C:8]([O:24][C:25]2[CH:26]=[N:27][C:28]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:29][CH:30]=2)[CH:9]=[C:10]2[C:14]=1[NH:13][C:12]([C:15]1[S:16][CH:17]([CH2:20][C:21]([NH:41][CH3:39])=[O:22])[CH2:18][N:19]=1)=[CH:11]2
Reactant: COCC(COC)Oc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc2cc(C3=NCC(CC(=O)O)S3)[nH]c12
Reactant: CCN=C=NCCCN(C)C
Agent: C[NH3+]
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CNC(=O)CC1CN=C(c2cc3cc(Oc4ccc(S(C)(=O)=O)nc4)cc(OC(COC)COC)c3[nH]2)S1
Temperature: 25 °C
Reaction time: 14 h
Yield: 76 %

Procedure:
A mixture of [2-(7-[2-methoxy-1-(methoxymethyl)ethoxy]-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indol-2-yl)-4,5-dihydro-1,3-thiazol-5-yl]acetic acid (180 mg), N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride (126 mg), 1-hydroxybenzotriazole (88 mg), methylammonium chloride (44 mg), triethylamine (0.09 mL) and N,N-dimethylformamide (5 mL) was stirred at room temperature for 14 h. The mixture was concentrated under reduced pressure. The residue was dissolved in water and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered and concentrated. The residue was purified by basic silica gel column chromatography (methanol/ethyl acetate/hexane=0/50/50 to 5/95/0, volume ratio) to give a white solid. The solid was recrystallized from acetonitrile-diethyl ether to give the title compound (140 mg, 75%) as colorless crystals. MS 563 (MH+). mp 149-151° C.
Reaction SMILES: CC[Hg]N1C(=O)C2C3(Cl)C(Cl)(Cl)C(Cl)(C2C1=O)C(Cl)=C3Cl.C[CH:23](O)[C:24]([O-:26])=[O:25].CC(O)C([O-])=O.[CH:34]1[CH:39]=[CH:38][C:37]([Hg+:40])=[CH:36][CH:35]=1.C([NH3+])CO.N#CN.[Ca]>[Ni]>[CH3:23][C:24]([O:26][Hg:40][C:37]1[CH:38]=[CH:39][CH:34]=[CH:35][CH:36]=1)=[O:25]
Reactant: [Hg+]c1ccccc1
Reactant: CC(O)C(=O)[O-]
Agent: [Ni]
Agent: CC[Hg]N1C(=O)C2C(C1=O)C1(Cl)C(Cl)=C(Cl)C2(Cl)C1(Cl)Cl
Agent: N#CN
Product: CC(=O)O[Hg]c1ccccc1

Procedure:
N-ethylmercuri-1,2,3,6tetrahydro-3,6-endomethano-3,4,5,6,7,7-hexachlorophthalimide, phenylmercuric monoethanolammonium lactate, nickel-containing compounds and calcium cyanamide.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]#[C:10][C:11](=[O:15])[CH:12]([CH3:14])[CH3:13])=[CH:5][CH:4]=1.[I-].[NH2:17][N+:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C1CCN2C(=NCCC2)CC1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([C:11](=[O:15])[CH:12]([CH3:13])[CH3:14])=[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][N:18]3[N:17]=2)=[CH:5][CH:4]=1
Reactant: N[n+]1ccccc1
Reactant: COc1ccc(C#CC(=O)C(C)C)cc1
Agent: [I-]
Solvent: C1CCC2=NCCCN2CC1
Product: COc1ccc(-c2nn3ccccc3c2C(=O)C(C)C)cc1
Yield: 44.4 %

Procedure:
Starting with 5.0 g (36.7 mmol) of 4-methoxyethynylbenzene, 3.85 ml of isobutyryl chloride, and 5.0 g ZnCl2, the corresponding 1-(4-methoxyphenyl)-4-methylpent-1-yn-3-one was prepared using the same procedure as in Example 5(a) to obtain 7.87 g of crude oil intermediate. Starting with 7.5 g (37 mmol) of 1-(4-methoxyphenyl)-4-methylpent-1-yn-3-one, 8.22 g (37 mmol) of 1-aminopyridinium iodide and 11.6 g DBU, 4.84 g (45%) of 1-(2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-3-yl)-2-methylpropan-1-one was obtained as in Example 5(b). Compound 1021.