Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][S:9]([N:12]([CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([B:28]2[O:32][C:31]([CH3:34])([CH3:33])[C:30]([CH3:36])([CH3:35])[O:29]2)=[CH:24][CH:23]=1)C(=O)OC(C)(C)C)(=[O:11])=[O:10].[OH-].[Na+]>ClCCl>[CH3:33][C:31]1([CH3:34])[C:30]([CH3:35])([CH3:36])[O:29][B:28]([C:25]2[CH:24]=[CH:23][C:22]([CH2:21][CH2:20][NH:12][S:9]([CH3:8])(=[O:11])=[O:10])=[CH:27][CH:26]=2)[O:32]1
Reactant: CC(C)(C)OC(=O)N(CCc1ccc(B2OC(C)(C)C(C)(C)O2)cc1)S(C)(=O)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1(C)OB(c2ccc(CCNS(C)(=O)=O)cc2)OC1(C)C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Trifluoroacetic acid (10 mL) was added to a 0° C. solution of tert-butyl (methylsulfonyl){2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethyl}carbamate (from the previous step, assumed 19.7 mmol) in dichloromethane (100 mL). The reaction mixture was allowed to warm to room temperature and stir for 18 hours. It was then cooled to 0° C. and brought to pH 10.5 with a 4N aqueous sodium hydroxide solution. The organic layer was washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified via silica gel chromatography (Gradient: 0% to 5% methanol in dichloromethane) to provide the title compound as an off-white solid. Yield: 2.5 g, 7.7 mmol, 39% over two steps. LCMS m/z 326.1 (M+1). 1H NMR (400 MHz, CDCl3) δ 1.35 (s, 12H), 2.84 (s, 3H), 2.90 (t, J=6.8 Hz, 2H), 3.42 (dt, J=6.6, 6.6 Hz, 2H), 4.18 (br t, J=6 Hz, 1H), 7.23 (d, J=8.1 Hz, 2H), 7.78 (d, J=8.1 Hz, 2H).
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[NH2:12][C:13]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][C:14]=1[C:15]#[N:16].O.[OH-].[Li+]>CS(C)=O>[F:8][C:6]1[CH:5]=[CH:4][C:3]([N+:9]([O-:11])=[O:10])=[C:2]([NH:12][C:13]2[CH:20]=[CH:19][C:18]([C:21]([F:22])([F:23])[F:24])=[CH:17][C:14]=2[C:15]#[N:16])[CH:7]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Reactant: N#Cc1cc(C(F)(F)F)ccc1N
Agent: [Li+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: N#Cc1cc(C(F)(F)F)ccc1Nc1cc(F)ccc1[N+](=O)[O-]
Temperature: 55 °C
Reaction time: 1 h
Yield: 95.7 %

Procedure:
Combine 2,4-difluoro-1-nitro-benzene (5.36 g, 33.69 mmol), 2-amino-5-trifluoromethyl-benzonitrile (5.701 g, 30.63 mmol) and lithium hydroxide monohydrate (2.57 g, 61.25 mmol) in methyl sulfoxide (DMSO, 70 ml). Heat the resulting mixture to 55° C. for 16 hours. Cool the reaction mixture to ambient temperature, then pour into approximately 250 ml of ice water and stir for one hour. Filter the resulting mixture, wash with a large amount of water and collect the precipitate to obtain 9.53 g of the title compound (29.30 mmol, 96% yield) as a yellow amorphous solid: Mass Spectrum (m/e): 324(M−1).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[OH:8][C:9]1[CH:10]=[C:11]([N:16]2[CH2:20][CH2:19][N:18]([C:21]([NH:23][S:24]([NH:27][C:28]([N:30]3[CH2:33][C@H:32]([NH:34]C(=O)OCC4C=CC=CC=4)[C:31]3=[O:45])=[O:29])(=[O:26])=[O:25])=[O:22])[C:17]2=[O:46])[CH:12]=[CH:13][C:14]=1[OH:15].[Na]>C1(SC)C=CC=CC=1>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:34][C@H:32]1[CH2:33][N:30]([C:28]([NH:27][S:24]([NH:23][C:21]([N:18]2[CH2:19][CH2:20][N:16]([C:11]3[CH:12]=[CH:13][C:14]([OH:15])=[C:9]([OH:8])[CH:10]=3)[C:17]2=[O:46])=[O:22])(=[O:25])=[O:26])=[O:29])[C:31]1=[O:45]
Reactant: O=C(N[C@H]1CN(C(=O)NS(=O)(=O)NC(=O)N2CCN(c3ccc(O)c(O)c3)C2=O)C1=O)OCc1ccccc1
Agent: [Na]
Solvent: O=C(O)C(F)(F)F
Solvent: CSc1ccccc1
Product: N[C@H]1CN(C(=O)NS(=O)(=O)NC(=O)N2CCN(c3ccc(O)c(O)c3)C2=O)C1=O
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A mixture of 20 ml of thioanisole and 75 ml of trifluoroacetic acid was cooled to 0° C. and 15.25 g of (S)-[1-[[[[[[3-(3,4-dihydroxyphenyl)-2-oxo-1-imidazolidinyl]carbonyl]amino]sulfonyl]amino]carbonyl]-2-oxo-3-azetidinyl]carbamic acid, phenylmethyl ester, monosodium salt was added. After stirring overnight at room temperature, the excess trifluoroacetic acid was evaporated in vacuo and the residue triturated with ether. The precipitate was filtered off by suction, washed with ether, and dried in vacuo; yield: 15.69 g.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]2[N:5]=[C:4]([NH:12][C:13]([CH:15]2[CH2:17][CH:16]2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:14])[CH:3]=1.[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1.O1CCOCC1>CO.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([C:2]2[N:7]3[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]3[N:5]=[C:4]([NH:12][C:13]([CH:15]3[CH2:17][CH:16]3[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:14])[CH:3]=2)=[CH:28][CH:27]=1
Reactant: Cc1cc2nc(NC(=O)C3CC3c3ccccc3)cc(Cl)n2n1
Reactant: COc1ccc(B(O)O)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CO
Solvent: C1COCCO1
Product: COc1ccc(-c2cc(NC(=O)C3CC3c3ccccc3)nc3cc(C)nn23)cc1
Temperature: 100 °C
Yield: 68.9 %

Procedure:
A suspension of N-(7-chloro-2-methylpyrazolo[1,5-a]pyrimidin-5-yl)-2-phenylcyclopropanecarboxamide (8C, 200 mg, 0.612 mmol), 4-methoxyphenylboronic acid (186 mg, 1.22 mmol), and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (35 mg, 49 mmol) in 2:1 1,4-dioxane/saturated aqueous NaHCO3 (660 microliters of 1,4-dioxane and 330 microliters of saturated aqueous NaHCO3) was prepared in a 2 mL microwave reaction vessel and the sealed reaction vessel warmed to 100° C. for 10 minutes. The reaction mixture was cooled to rt, diluted with methanol, filtered, and purified via preparative HPLC (70-75% MeCN/H2O gradient+0.01% TFA). Lyophilization of the combined fractions gave the titled compound as a yellow solid (168 mg, 69%). 1H NMR (DMSO-d6) δ: 11.23 (s, 1H), 8.01-8.18 (m, 2H), 7.89 (s, 1H), 7.26-7.37 (m, 2H), 7.08-7.26 (m, 5H), 6.30 (s, 1H), 3.87 (s, 3H), 2.42-2.48 (m, 1H), 2.26-2.43 (m, 4H), 1.49-1.59 (m, 1H), 1.39-1.47 (m, 1H). ESI-MS: m/z 399.0 (M+H)+.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:11]=[CH:10][C:8]([NH2:9])=[CH:7][CH:6]=1)(=[O:4])=[O:3].C[Al](C)C.[F:16][C:17]1[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=1>C1(C)C=CC=CC=1.C(Cl)(Cl)Cl>[F:16][C:17]1[CH:24]=[CH:23][C:20]([C:21](=[NH:22])[NH:9][C:8]2[CH:10]=[CH:11][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:6][CH:7]=2)=[CH:19][CH:18]=1
Reactant: CS(=O)(=O)c1ccc(N)cc1
Reactant: N#Cc1ccc(F)cc1
Agent: C[Al](C)C
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: CS(=O)(=O)c1ccc(NC(=N)c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a suspension of 4-(methylsulfonyl)aniline (10 mmol) in toluene (100 mL), trimethylaluminum (2M solution in toluene, 15 mmol) is added over 15 minutes. The reaction mixture is warmed to room temperature and stirred for 2.5 hours. A solution of 4-fluorobenzonitrile (20 mmol) in toluene (50 mL) is added over 10 minutes and the reaction mixture is heated to 80°-85° C. After 20 hours, the reaction mixture is cooled to room temperature and poured over a slurry of silica gel in chloroform. After filtration, the residue is washed with a mixture of methylene chloride/methanol (2/1). The combined filtrates are concentrated in vacuo and the resulting yellowish solid is stirred with a mixture of hexane/ether (2/1, 1000 mL). The intermediate is filtered and washed with more of hexane/ether (2/1). The pale yellow solid 4-fluoro-N-[4-(methylsulfonyl)phenyl]benzenecarboximidamide is used in the next reaction without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]([S:13]([NH2:16])(=[O:15])=[O:14])[C:9]([OH:12])([CH3:11])[CH3:10])[CH:5]=[CH:6][CH:7]=1.[CH:17]1([N:23]=[C:24]=S)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].BrN1C(=O)CCC1=O>CN1C(=O)CCC1.O>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:9]([CH3:10])([CH3:11])[O:12][C:24]([NH:23][CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)=[N:16][S:13]2(=[O:14])=[O:15])[CH:5]=[CH:6][CH:7]=1
Reactant: S=C=NC1CCCCC1
Reactant: CC(C)(O)C(c1cccc(Br)c1)S(N)(=O)=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C1CCC(=O)N1Br
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: CC1(C)OC(NC2CCCCC2)=NS(=O)(=O)C1c1cccc(Br)c1
Reaction time: 0.33 h
Yield: 30.5 %

Procedure:
A solution of 1.00 g of 1-(3-bromophenyl)-2-hydroxy-2-methylpropane-1-sulfonamide and 0.483 g of cyclohexyl isothiocyanate in 7 ml of NMP was admixed with 1.62 ml of a 2 N solution of sodium bis(trimethylsilyl)amide. After stirring for 20 minutes, 578 mg of N-bromosuccinimide were added and the mixture was stirred at room temperature for a further 60 minutes. The reaction solution was admixed with 150 ml of water and extracted twice with 150 ml of ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over MgSO4 and concentrated by rotary evaporation. The residue was purified in a purification laboratory by means of preparative HPLC, and the product-containing fractions were lyophilized. This gave the product (411 mg) with a molecular weight of 415.3 g/mol (C17H23BrN2O3S); MS (ESI): m/e=416 (M+H+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:7]2[N:11]3[CH:12]=[CH:13][C:14]([C:16]([F:19])([F:18])[F:17])=[N:15][C:10]3=[N:9][CH:8]=2)[S:5][CH:6]=1.B1([C:26]2[CH:31]=[CH:30][CH:29]=[N:28][CH:27]=2)OCCCO1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.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>[N:28]1[CH:29]=[CH:30][CH:31]=[C:26]([C:2]2[CH:3]=[C:4]([C:7]3[N:11]4[CH:12]=[CH:13][C:14]([C:16]([F:19])([F:18])[F:17])=[N:15][C:10]4=[N:9][CH:8]=3)[S:5][CH:6]=2)[CH:27]=1
Reactant: c1cncc(B2OCCCO2)c1
Reactant: FC(F)(F)c1ccn2c(-c3cc(Br)cs3)cnc2n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: FC(F)(F)c1ccn2c(-c3cc(-c4cccnc4)cs3)cnc2n1
Yield: 79.9 %

Procedure:
A mixture of 3-(4-bromothien-2-yl)-7-trifluoromethylimidazo[1,2-α]pyrimidine (104 mg, 0.3 mmol), pyridine-3-boronic acid-1,3-propanediol cyclic ester (73 g, 0.45 mmol), cesium carbonate (0.29 g, 0.9 mmol) and tetrakis(triphenylphosphine)palladium(0) (34 mg, 0.03 mmol) in 1,4-dioxane (5 ml) and H2O (0.5 ml) were degassed with a stream of N2 for 10 min. The reaction mixture was then heated at reflux for 1 h. The mixture was concentrated under reduced pressure to remove the organic solvents and H2O (20 ml) was added. The organics were extracted with dichloromethane (2×50 ml) and concentrated under reduced pressure while dry loading onto silica. The resulting crude residue was purified by column chromatography on silica using 70% EtOAc in hexanes containing 1% Et3N and 1% MeOH as the eluent. The resulting material was taken up in MeOH and was poured onto a strong cation exchange cartridge and eluted with methanol. The product was then eluted with 2.0M NH3 in MeOH and evaporated to give 3-[4-(pyridin-3-yl)thien-2-yl]-7-trifluoromethylimidazo[1,2-α]pyrimidine (83 mg, 80%): δH (400 MHz, d6-DMSO) 7.46-7.53 (1H, m), 7.60 (1H, d, J 7.1), 8.18 (1H, d, J 1.5), 8.22-8.30 (1H, m), 8.26 (1H, d, J 1.5), 8.42 (1H, s), 8.56-8.60 (1H, m), 9.10 (1H, s), 10.20 (1H, d, J 7.1); m/z (ES+) 346 (M+).
Reaction SMILES: F[C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][CH:3]=1.[CH3:11][CH:12]1[CH2:17][NH:16][CH2:15][CH2:14][NH:13]1>O>[CH3:11][CH:12]1[NH:13][CH2:14][CH2:15][N:16]([C:2]2[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][CH:3]=2)[CH2:17]1
Reactant: CC1CNCCN1
Reactant: NC(=O)c1ccc(F)cc1
Solvent: O
Product: CC1CN(c2ccc(C(N)=O)cc2)CCN1
Temperature: 100 °C
Yield: 87.9 %

Procedure:
A mixture of 4-fluorobenzamide (Aldrich; 2.432 g), (RS)-2-methylpiperazine (Aldrich; 4.247 g), and water (9 mL) is heated at 100° C. for 7 days. The mixture is then cooled to 41° C. and water is added. The solid is collected, washed with water and toluene and dried under reduced pressure to give 3.37 g of (RS)-4-(3-methylpiperazin-1-yl)benzamide; 1H NMR (CDCl3, CD3OD) δ 1.17, 2.48, 2.82, 2.94-3.15, 3.04, 3.68, 6.89, 7.73.
Reaction SMILES: [N:1]1([C:6]2[CH:7]=[C:8]([C:12](Cl)=[O:13])[CH:9]=[N:10][CH:11]=2)[CH:5]=[CH:4][CH:3]=[CH:2]1.[NH2:15][C:16]1[CH:28]=[C:27]([O:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:26]=[CH:25][C:17]=1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19].C(=O)([O-])O.[Na+]>C(N(CC)CC)C.C(Cl)Cl>[O:29]([C:27]1[CH:26]=[CH:25][C:17]([C:18]([O:20][C:21]([CH3:24])([CH3:22])[CH3:23])=[O:19])=[C:16]([NH:15][C:12]([C:8]2[CH:9]=[N:10][CH:11]=[C:6]([N:1]3[CH:5]=[CH:4][CH:3]=[CH:2]3)[CH:7]=2)=[O:13])[CH:28]=1)[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: O=C(Cl)c1cncc(-n2cccc2)c1
Reactant: CC(C)(C)OC(=O)c1ccc(Oc2ccccc2)cc1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1ccc(Oc2ccccc2)cc1NC(=O)c1cncc(-n2cccc2)c1
Reaction time: 2 h

Procedure:
0.059 mL of triethylamine and 65 mg of 5-(1H-pyrrol-1-yl)pyridine-3-carbonyl chloride were added to 5.0 mL of methylene chloride solution containing 60 mg of tert-butyl 2-amino-4-phenoxybenzoate at room temperature sequentially and stirred at the same temperature for 2 hours, 0.029 mL of triethylamine and 22 mg of 5-(1H-pyrrol-1-yl)pyridine-3-carbonyl chloride were added to the reaction mixture at room temperature sequentially and stirred at the same temperature for 1 hour. 0.58 g aminomethylated polystyrene was added to the reaction mixture and stirred at room temperature overnight. A saturated sodium hydrogen carbonate aqueous solution was added to the reaction mixture, the organic layer was separated, and the solvent was evaporated under reduced pressure. The obtained residue was purified with silica gel column chromatography [Flash Tube 2008 manufactured by Trikonex Company, eluent; hexane:ethyl acetate=4:1] to obtain tert-butyl 4-phenoxy-2-(5-(1H-pyrrol-1-yl)pyridine-3-carboxamido)benzoate.
Reaction SMILES: [NH2:1][CH:2]1[CH:6]([CH2:7][NH2:8])[C:5]([CH3:10])([CH3:9])[CH2:4][CH:3]1[CH3:11].[C:12]([O:18][CH2:19][CH3:20])(=[O:17])[CH2:13][C:14]([CH3:16])=O>CO>[CH2:19]([O:18][C:12]([CH:13]=[C:14]([NH:1][CH:2]1[CH:3]([CH3:11])[CH2:4][C:5]([CH3:10])([CH3:9])[CH:6]1[CH:7]([NH:8][C:14]([CH3:16])=[CH2:13])[C:12]([O:18][CH2:19][CH3:20])=[O:17])[CH3:16])=[O:17])[CH3:20]
Reactant: CCOC(=O)CC(C)=O
Reactant: CC1CC(C)(C)C(CN)C1N
Solvent: CO
Product: C=C(C)NC(C(=O)OCC)C1C(NC(C)=CC(=O)OCC)C(C)CC1(C)C
Reaction time: 8 h
Yield: 95.2 %

Procedure:
To 5-amino-2,2,4-trimethylcyclopentylmethylamine (127.76 g, 0.819 mol) in methanol (700 ml) was slowly added with stirring ethyl acetoacetate (215.85 g, 1.660 mol) in methanol (700 ml) over 35 minutes, during which the temperature increased from 22° C. to 31° C. The reaction mixture was allowed to stand at 21° C. overnight (17 h). Further methanol was added, and removal of solvent and drying (91°/100 Pa) gave 1-(1-ethoxycarbonyl-2-prop-1-enylamino)-2-(1-ethoxycarbonyl-2-prop-1-enylaminomethyl)-3,3,5-trimethylcyclopentane (EEMTCP, formula shown below) as a clear light yellow pourable viscous oil (296.54 g, 95%) identified by 1H-NMR, 13C-NMR, FT-IR and Raman spectra.
Reaction SMILES: [C:1]([O:10]C)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].[CH2:12]([O:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]#[N:27])[N:21]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:12]([O:19][C:20]1[N:21]=[C:22]([C:26]2[S:4][C:3]3[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=3[C:1](=[O:10])[N:27]=2)[CH:23]=[CH:24][CH:25]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: COC(=O)c1ccccc1S
Reactant: N#Cc1cccc(OCc2ccccc2)n1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=c1nc(-c2cccc(OCc3ccccc3)n2)sc2ccccc12
Yield: 25.3 %

Procedure:
A mixture of methyl thiosalicylate (0.40 g, 2.4 mmol), 2-benzyloxy-6-cyanopyridine (0.50 g, 2.4 mmol), triethylamine (0.50 ml, 3.6 mmol) and toluene (30 ml) was refluxed for 48 hrs as described in Example 1. The reaction mixture was concentrated under reduced pressure and recrystallized from ethanol to give the titled compound (0.21 g, 26%) as crystals.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:22]=[CH:21][C:7]([NH:8][C:9]2[NH:10][C:11](=[O:20])[C:12]([C:15]([O:17]CC)=[O:16])=[CH:13][N:14]=2)=[CH:6][CH:5]=1)[CH3:2].[OH-].[Na+].O>C(O)(=O)C>[CH2:1]([O:3][C:4]1[CH:22]=[CH:21][C:7]([NH:8][C:9]2[NH:10][C:11](=[O:20])[C:12]([C:15]([OH:17])=[O:16])=[CH:13][N:14]=2)=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCOC(=O)c1cnc(Nc2ccc(OCC)cc2)[nH]c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: CCOc1ccc(Nc2ncc(C(=O)O)c(=O)[nH]2)cc1
Reaction time: 1 h
Yield: 55.1 %

Procedure:
Ethyl 1,6-dihydro-2-(4-ethoxyanilino)-6-oxo-5-pyrimidinecarboxylate (10 g) and sodium hydroxide (3 g) are added to water (50 ml), and the mixture is refluxed with stirring for 1 hour. After cooling, the reaction mixture is acidified with acetic acid, and the resulting solid is collected by filtration and recrystallized from DMF. The precipitate is collected by filtration and added to water (50 ml), and the mixture is refluxed with stirring for 1 hour. After cooling, the resulting product is collected by filtration and dried at 80° C. under reduced pressure to give 1,6-dihydro-2-(4-ethoxyanilino)-6-oxo-5-pyrimidinecarboxylic acid (5 g). M.p. 250°-252° C.
Reaction SMILES: [CH2:1]([C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[S:29]1[CH:33]=[N:32][N:31]=[C:30]1[NH2:34].Cl>N1C=CC=CC=1>[CH2:1]([C:19]1[CH:24]=[CH:23][C:22]([S:25]([NH:34][C:30]2[S:29][CH:33]=[N:32][N:31]=2)(=[O:27])=[O:26])=[CH:21][CH:20]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: Nc1nncs1
Reactant: CCCCCCCCCCCCCCCCCCc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCCCCc1ccc(S(=O)(=O)Nc2nncs2)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 51.3 %

Procedure:
To a solution of p-octadecylbenzenesulfonyl chloride (500 mg, 1.17 mmol) in pyridine (8 mL) was added 1,3,4-thiadiazol-2-amine (177 mg, 1.75 mmol). The reaction mixture was stirred at room temperature for 6 hours, then 2 M HCl (40 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (3×50 mL), the organic layer was washed with water (40 mL) and brine (40 mL), dried over anhydrous Na2SO4 and concentrated. The residue was purified by chromatography over silica gel (70-230 mesh) eluted with methanol:DCM 1:19 to give the product as a solid (296 mg, 0.60 mmol, 51% yield), mp 116-117° C.; 1H NMR (300 MHz, CDCl3) δ 0.86 (t, 3H, J=6.9 Hz), 1.25 (m, 30H), 1.60 (m, 2H), 2.64 (t, 2H, J=7.8 Hz), 7.29 (d, 2H, J=7.8 Hz), 7.82 (d, 2H, J=7.8 Hz), 8.21 (s, 1H); 13C NMR (75 MHz, CDCl3) 14.0, 22.7, 29.2, 29.3, 29.4, 29.5, 29.6, 29.7, 31.1, 31.9, 35.9, 126.5, 128.9, 138.1, 142.6, 148.6, 167.4; MS (LCQ, ESI+) Calcd for C26H44N3O2S2 494.3, found 494.2 (M+H)+; HRMS (ESI+, m/z) Calcd for C26H44N3O2S2 494.2869, found 494.2869 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][CH2:9][N:10]2C(=O)C3C(=CC=CC=3)C2=O)[CH:2]=1.O.NN>C(O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][CH2:9][NH2:10])[CH:2]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCc1cccnc1
Agent: NN
Solvent: CCO
Solvent: O
Product: NCCCc1cccnc1
Yield: 82.5 %

Procedure:
A mixture of 11.3 g of 2-[3-(3-pyridyl)propyl]-1H-isoindole-1,3(2H)-dione and 10.1 g of hydrazine hydrate was refluxed in 200 ml of ethanol for 6 hours, allowed to cool, and was filtered. The filtrate was concentrated and the residue distilled to give 4.77 g (70%) of 3-pyridinepropanamine, bp 84°-86° C./0.35 mm.
Reaction SMILES: Br[CH2:2][CH:3]=[C:4]([CH3:14])[CH2:5][CH2:6][CH:7]=[C:8]([CH3:13])[CH2:9][CH:10]([CH3:12])[CH3:11].[OH:15][C:16]1[CH:25]=[C:24]2[C:19]([CH2:20][CH2:21][CH2:22][O:23]2)=[CH:18][CH:17]=1>>[CH3:14][C:4]([CH2:5][CH2:6][CH:7]=[C:8]([CH3:13])[CH2:9][CH:10]([CH3:12])[CH3:11])=[CH:3][CH2:2][O:15][C:16]1[CH:25]=[C:24]2[C:19]([CH2:20][CH2:21][CH2:22][O:23]2)=[CH:18][CH:17]=1
Reactant: Oc1ccc2c(c1)OCCC2
Reactant: CC(=CCBr)CCC=C(C)CC(C)C
Product: CC(=CCOc1ccc2c(c1)OCCC2)CCC=C(C)CC(C)C

Procedure:
Following the procedure of Example 1, 1-bromo-3,7,9-trimethyl-2,6-decadiene and 7-hydroxy-chromane are reacted to form 7-(3,7,9-trimethyl-2,6-decadienyloxy)-chromane, nD20 = 1.5920.
Reaction SMILES: [S:1]1[CH2:5][CH2:4][CH:3]([CH2:6][CH2:7][CH2:8][CH2:9][NH:10][C:11]([N:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15][CH:14]2[C:22]([O:24]C)=[O:23])=[O:12])[S:2]1.CO.[OH-].[Na+]>O1CCCC1>[S:1]1[CH2:5][CH2:4][CH:3]([CH2:6][CH2:7][CH2:8][CH2:9][NH:10][C:11]([N:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15][CH:14]2[C:22]([OH:24])=[O:23])=[O:12])[S:2]1
Reactant: COC(=O)C1Cc2ccccc2N1C(=O)NCCCCC1CCSS1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)C1Cc2ccccc2N1C(=O)NCCCCC1CCSS1
Yield: 50.9 %

Procedure:
The reaction was carried out as described in Example 48, but using 200 mg of methyl 1-[4-(1,2-dithiolan-3-yl)butylcarbamoyl]indoline-2-carboxylate (prepared as described in Example 93), 4 ml of methanol, 2 ml of tetrahydrofuran and 1.0 ml of a 1N aqueous solution of sodium hydroxide. The solvent was removed from the reaction mixture by evaporation under reduced pressure, and water was added to the residue. The mixture was neutralized by the addition of 2N aqueous hydrochloride acid and extracted with ethyl acetate. The extraction solution was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The ethyl acetate was removed from the extraction solution by evaporation under reduced pressure, and the residue was dissolved in dioxane and then lyophilised, to obtain 98 mg of the title compound as a pale yellow amorphous substance having an Rf value of 0.12 (silica gel thin layer chromatography, using a 2:1 by volume mixture of ethyl acetate and hexane as developing solvent).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH:9]2[CH2:25][CH2:24][C:12]3([CH2:16][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:14][CH2:13]3)[CH2:11][CH2:10]2)[C:5]([CH3:26])=[CH:4][N:3]=1.Cl.[CH3:28][N:29]1[CH:33]=[C:32]([NH2:34])[CH:31]=[N:30]1.CCN(C(C)C)C(C)C>CCCCO>[CH3:26][C:5]1[C:6]([NH:8][CH:9]2[CH2:25][CH2:24][C:12]3([CH2:16][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:14][CH2:13]3)[CH2:11][CH2:10]2)=[N:7][C:2]([NH:34][C:32]2[CH:31]=[N:30][N:29]([CH3:28])[CH:33]=2)=[N:3][CH:4]=1
Reactant: Cn1cc(N)cn1
Reactant: Cc1cnc(Cl)nc1NC1CCC2(CC1)CCN(C(=O)OC(C)(C)C)C2
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: Cc1cnc(Nc2cnn(C)c2)nc1NC1CCC2(CC1)CCN(C(=O)OC(C)(C)C)C2
Temperature: 150 °C
Reaction time: 8 h
Yield: 100.4 %

Procedure:
To a suspension of tert-butyl 8-((2-chloro-5-methylpyrimidin-4-yl)amino)-2-azaspiro[4.5]decane-2-carboxylate (1.04 g, 2.73 mmol) and 1-methyl-1H-pyrazol-4-amine hydrochloride (365.4 mg, 2.73 mmol) in n-BuOH (8 mL) was added DIPEA (1.06 g, 8.20 mmol) and the reaction mixture was stirred in a sealed tube at 150° C. overnight then concentrated in vacuo. The residue was purified by silica gel column chromatography (MeOH/DCM (v/v)=1/100) to give the title compound as yellow oil (1.21 g, 100%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.C1(=O)O[CH2:13][CH2:12][O:11]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.ClCCl>[N:1]1([CH2:13][CH2:12][OH:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: c1ccc2[nH]ccc2c1
Reactant: O=C1OCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: OCCn1ccc2ccccc21

Procedure:
A mixture of indole (5.71 g, 48.7 mmol), ethylene carbonate (4.72 g, 53.6 mmol) and K2CO3 (6.73 g, 48.7 mmol) in DMF (20 mL) was heated under reflux for 2 h. The reaction mixture was diluted with dichloromethane, filtered, and concentrated in vacuo. The light brown oily residue was purified by chromatography on silica gel (13×6 cm) using n-hexane/ethyl acetate (1:1) as eluent. This gave 1.78 g (23%) of the title compound as a beige oil. HRMS m/z calcd for C10H11NO (M)+ 161.0841, found 161.0849. Anal. (C10H11NO.0.1H2O) C, H, N. *Previously described in a) J. Med. Chem. 1992, 35, 994-1001; b) ibid. 1998, 41, 1619-1630.