Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([C@@H:8]1[CH2:13][C@H:12]([O:14][Si:15]([C:28]([CH3:31])([CH3:30])[CH3:29])([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:11][CH2:10][C@H:9]1[C:32](O)=[O:33])=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.S(C1C=CC(C)=CC=1)(O)(=O)=O.[CH3:68][NH:69][CH2:70][CH2:71][CH2:72][CH2:73][CH:74]=[CH2:75].C(N(C(C)C)CC)(C)C>CN(C=O)C>[Si:15]([O:14][C@H:12]1[CH2:13][C@@H:8]([C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])[C@H:9]([C:32](=[O:33])[N:69]([CH2:70][CH2:71][CH2:72][CH2:73][CH:74]=[CH2:75])[CH3:68])[CH2:10][CH2:11]1)([C:28]([CH3:29])([CH3:31])[CH3:30])([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)(C)OC(=O)[C@@H]1C[C@H](O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CC[C@H]1C(=O)O
Reactant: C=CCCCCNC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C=CCCCCN(C)C(=O)[C@@H]1CC[C@@H](O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C[C@H]1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
To a cold solution of compound 38 (1.80 mmol), TBTU (2.17 mmol), and N-methylhex-5-en-1-amine tosylate salt 31a (2.17 mmol) in DMF (100 mL) was added diisopropyl ethyl amine (5.4 mmol) dropwise under nitrogen at 0° C. The reaction mixture was stirred overnight at room temperature, then quenched with water and extracted with diethyl ether. The organic layer was washed with brine, then dried on magnesium sulphate, concentrated under reduced pressure, and purified by chromatography on silica gel to yield compound 39 as a beige solid in 85% yield. MS (ESI, EI+): m/z=578 (MH+).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][NH:3][C:2]1=[O:6].[CH2:7]([S:9](Cl)(=[O:11])=[O:10])[CH3:8].Cl.C1C=CC=CC=1>CC(C)=O.C(OCC)(=O)C>[CH2:7]([S:9]([N:1]1[CH2:5][CH2:4][NH:3][C:2]1=[O:6])(=[O:11])=[O:10])[CH3:8]
Reactant: CCS(=O)(=O)Cl
Reactant: O=C1NCCN1
Agent: Cl
Solvent: c1ccccc1
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: CCS(=O)(=O)N1CCNC1=O

Procedure:
This substance was obtained by heating molar amounts of imidazolidin-2-one and ethylsulphonyl chloride at 150° to 180° (until the evolution of HCl had ceased). The pure substance was isolated by extraction with hot benzene, acetone and ethyl acetate from the crude product, and recrystallization from acetone (with addition of active charcoal).
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:24](=[O:27])[NH:25][CH3:26])[C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([O:11][C:12]1[CH:17]=[CH:16][N:15]=[C:14]3[CH:18]=[C:19]([C:21](O)=[O:22])[S:20][C:13]=13)=[CH:6][CH:5]=2.[CH3:28][NH:29][CH2:30][CH2:31][OH:32].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.C([O-])(O)=O.[Na+]>CCOC(C)=O.CN(C=O)C>[OH:32][CH2:31][CH2:30][N:29]([CH3:28])[C:21]([C:19]1[S:20][C:13]2[C:14](=[N:15][CH:16]=[CH:17][C:12]=2[O:11][C:7]2[CH:8]=[C:9]3[C:4](=[CH:5][CH:6]=2)[N:3]([C:24](=[O:27])[NH:25][CH3:26])[C:2]([CH3:1])=[CH:10]3)[CH:18]=1)=[O:22]
Reactant: CNC(=O)n1c(C)cc2cc(Oc3ccnc4cc(C(=O)O)sc34)ccc21
Reactant: CNCCO
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)n1c(C)cc2cc(Oc3ccnc4cc(C(=O)N(C)CCO)sc34)ccc21
Reaction time: 3 h
Yield: 36 %

Procedure:
To a solution of DMF was added 7-(2-Methyl-1-methylcarbamoyl-1H-indol-5-yloxy)-thieno[3,2-b]pyridine-2-carboxylic acid (0.1 g, 0.26 mmol), as prepared in step (iv), 2-Methylamino-ethanol (0.025 mL, 0.35 mmol) as well as HATU (0.12 g, 0.32) and DIEA (0.051 mL, 0.32 mmol) then stirred for 3 h. To the solution was added 30 mL of EtOAc portioned between 50/50 NaHCO3 (2×30 mL) and the organic layer dried over Na2SO4 then concentrated via rotor evaporator. The title compound was purified with flash chromatography eluting with EtOAc/CH2Cl2/MeOH (2:1:0.1) and the purified fraction concentrate to afford 7-(2-Methyl-1-methylcarbamoyl-1H-indol-5-yloxy)-thieno[3,2-b]pyridine-2-carboxylic acid (2-hydroxy-ethyl)-methyl-amide as an off-white solid (0.041 g, 36%). HPLC: Rt 3.35 min. (96% area). 1H NMR (DMSO-d3, 400 MHz) δ: 8.46 (1H, d, J=4.3 Hz), 8.22 (1H, bs), 7.90-7.81 (1H, m), 7.61 (1H, d, J=8.6 Hz), 7.34 (1H, s), 7.01 (1H, dd, J=8.6, 2.3 Hz), 6.57 (1H, d, J=5.5 Hz), 6.33 (1H, s), 3.56 (5H, m), 2.96 (2H, bs), 2.81 (3H, d, J=5.5 Hz), 2.43 (3H, s). LCMS (ACPI) M+H+ m/z: 439.1. Anal. (C22H22N4O4S.1.0 H2O.0.3 EtOAc) Calc'd: C, 57.60; H, 5.07; N, 11.63. Found: C, 57.87; H, 4.93; N, 11.25.
Reaction SMILES: [CH2:1]([N:3]([CH2:11][CH3:12])[C:4]1[N:9]=[C:8]([CH3:10])[CH:7]=[CH:6][CH:5]=1)[CH3:2].[N+:13]([O-])([OH:15])=[O:14].[OH-].[Na+]>S(=O)(=O)(O)O>[CH2:11]([N:3]([CH2:1][CH3:2])[C:4]1[N:9]=[C:8]([CH3:10])[C:7]([N+:13]([O-:15])=[O:14])=[CH:6][CH:5]=1)[CH3:12]
Reactant: CCN(CC)c1cccc(C)n1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: CCN(CC)c1ccc([N+](=O)[O-])c(C)n1
Temperature: 5 °C
Reaction time: 1 h

Procedure:
To a 1900 ml of concentrated sulfuric acid 630 g of 6-diethylamino-2-picoline were dropwise added while cooling with ice water. A 70% nitric acid solution of 347 g were dropwise added at not more than 5° C. over about 2 hours to the resulting mixture and stirred at 5° C. for additional one hour. The reation mixture was added to 4 kg of ice, neutralized with a sodium hydroxide solution, and extracted two times with ethyl acetate. The extract solution was washed two times with water, dried over anhydrous magnesium sulfate, concentrated and dried. Thus, 775 g of 6-diethylamino-3-nitro-2-picoline were obtained.
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]([OH:9])=[O:8])=[CH:4][CH:3]=1.[C:10]1([OH:16])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C([O-])([O-])=O.[Na+].[Na+].O>C1COCC1.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>[OH:16][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:2]1[S:6][C:5]([C:7]([OH:9])=[O:8])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(Br)s1
Reactant: Oc1ccccc1
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: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc(-c2ccccc2O)s1
Reaction time: 0.08 h
Yield: 84.3 %

Procedure:
Tetrakis(triphenylphosphine)palladium(0) (133 mg, 0.12 mmol) is added to a solution of 5-bromothiophene-2-carboxylic acid (850 mg, 4.1 mmol) in degassed THF (10 mL). The resulting solution is stirred for 5 minutes and then 2-(4,4,5,5-tetramethyl)-1,3,2-dioxaborolan-2-yl) phenol (1 g, 4.6 mmol) is added followed by aqueous Na2CO3 (2M, 6.9 mL). The mixture is heated at reflux overnight. The reaction mixture is allowed to cool, poured into water (50 mL), and washed with ether (3×50 mL). The aqueous layer is acidified with concentrated HCl to pH<2. The resulting precipitate is collected by filtration, washed with water and dried in vacuo to yield the desired product (761 mg, 83%). MS for C11H7O3S (ESI) (M−H)+ m/z 219.
Reaction SMILES: [O-]CC.[Na+].[CH2:5]([N:12]1[CH2:17][CH2:16][CH:15]([NH:18][C:19]([NH:21][C@H:22]([C:30](OC)=[O:31])[CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:20])[CH2:14][CH2:13]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C(O)C>[CH2:23]([CH:22]1[NH:21][C:19](=[O:20])[N:18]([CH:15]2[CH2:16][CH2:17][N:12]([CH2:5][C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH2:13][CH2:14]2)[C:30]1=[O:31])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)NC1CCN(Cc2ccccc2)CC1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: O=C1NC(Cc2ccccc2)C(=O)N1C1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Yield: 97.7 %

Procedure:
Sodium ethoxide (0.1301 mL, 1.66 mmol, 21% wt.) was added to a solution of methyl N-{[(1-benzylpiperidin-4-yl)amino]carbonyl}phenylalaninate (546 mg, 1.38 mmol) in ethanol (715 mL) at 0° C. and then warmed to ambient temperature. The reaction was concentrated and partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated to give the title compound (490 mg). MS 364.2 (M+1)
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[C:8]([C:16]([F:19])([F:18])[F:17])[C:3]=1[C:4]([NH:6][NH2:7])=[O:5].[C:20]1([S:26](Cl)(=[O:28])=[O:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(O)(=O)C.C(Cl)(Cl)Cl>[OH-].[Na+].O.C(OCC)(=O)C>[NH2:1][C:2]1[N:11]=[C:10]([C:12]([F:13])([F:14])[F:15])[CH:9]=[C:8]([C:16]([F:19])([F:17])[F:18])[C:3]=1[C:4]([NH:6][NH:7][S:26]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)(=[O:28])=[O:27])=[O:5]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: NNC(=O)c1c(C(F)(F)F)cc(C(F)(F)F)nc1N
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: Nc1nc(C(F)(F)F)cc(C(F)(F)F)c1C(=O)NNS(=O)(=O)c1ccccc1

Procedure:
2-Amino-4,6-di(trifluoromethyl)-nicotinic acid hydrazide (4.35 g., 15.1 mmole) is stirred in 1N sodium hydroxide solution (36.3 ml.) untila clear solution is obtained. Benzenesulfonyl chloride (2.94 g., 16.6 mmole) is added in one portion and the mixture stirred rapidly until solution is complete. On pouring this solution into a stirred solution of acetic acid (0.9 g., 15 mmole) in water (40 ml.), a fine precipitate is formed. The pH of the suspension is adjusted to circa 6.5 with acetic acid and the product collected, washed with water and dried giving 6.52 g. (theoretical) of product sintering at circa 230° C., m.p. 235°-238° C. (dec.). The product is obtained pure by precipitation from a filtered solution of the crude product in ethyl acetate (4 parts volume by weight) by addition of chloroform (10 parts volume by weight) providing product with m.p. 243°-245° C. (dec.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[O:24][CH2:25][C:26]1[N:27]=[C:28]([C:32]2[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=2)[O:29][C:30]=1[CH3:31])[CH2:6][O:7][C:8]1[C:12]([CH:13]=O)=[CH:11][N:10]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:9]=1.[CH2:38]([P:47](=[O:54])([O:51][CH2:52][CH3:53])[O:48][CH2:49][CH3:50])P(=O)(OCC)OCC.CN(C)C=O.[H-].[Na+]>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[O:24][CH2:25][C:26]1[N:27]=[C:28]([C:32]2[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=2)[O:29][C:30]=1[CH3:31])[CH2:6][O:7][C:8]1[C:12](/[CH:13]=[CH:38]/[P:47](=[O:54])([O:48][CH2:49][CH3:50])[O:51][CH2:52][CH3:53])=[CH:11][N:10]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:9]=1
Reactant: CCOP(=O)(CP(=O)(OCC)OCC)OCC
Reactant: COc1cc(COc2nn(-c3ccccc3)cc2C=O)ccc1OCc1nc(-c2cccnc2)oc1C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOP(=O)(/C=C/c1cn(-c2ccccc2)nc1OCc1ccc(OCc2nc(-c3cccnc3)oc2C)c(OC)c1)OCC
Reaction time: 15 h
Yield: 75.9 %

Procedure:
To a mixture of 3-({3-methoxy-4-[(5-methyl-2-pyridin-3-yl-1,3-oxazol-4-yl)methoxy]benzyl}oxy)-1-phenyl-1H-pyrazole-4-carbaldehyde (0.55 g), tetraethyl methylenediphosphonate (0.35 g) and N,N-dimethylformamide (30 mL) was added sodium hydride (60% in oil, 0.050 g) at room temperature, and the mixture was stirred at the same temperature for 15 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give diethyl (E)-2-[3-({3-methoxy-4-[(5-methyl-2-pyridin-3-yl-1,3-oxazol-4-yl)methoxy]benzyl}oxy)-1-phenyl-1H-pyrazol-4-yl]ethenylphosphonate as colorless crystals (0.53 g, yield 77%) from a fraction eluted with ethyl acetate-hexane (19:1, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 128-129° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][C:8]([Cl:14])=[CH:9][CH:10]=2)[N:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:4]=1.[Cl:21][C:22]1[CH:38]=[CH:37][C:25]([CH2:26][N:27]2[CH:32]=[CH:31][C:30]([C:33](O)=[O:34])=[CH:29][C:28]2=[O:36])=[CH:24][CH:23]=1>>[Cl:14][C:8]1[CH:7]=[C:6]2[C:11]([C:12](=[O:13])[C:3]([CH2:2][NH:1][C:33]([C:30]3[CH:31]=[CH:32][N:27]([CH2:26][C:25]4[CH:24]=[CH:23][C:22]([Cl:21])=[CH:38][CH:37]=4)[C:28](=[O:36])[CH:29]=3)=[O:34])=[CH:4][N:5]2[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[CH:10][CH:9]=1
Reactant: NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O
Reactant: O=C(O)c1ccn(Cc2ccc(Cl)cc2)c(=O)c1
Product: O=C(NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O)c1ccn(Cc2ccc(Cl)cc2)c(=O)c1

Procedure:
1-(4-Chloro-benzyl)-2-oxo-1,2-dihydro-pyridine-4-carboxylic acid (7-chloro-4-oxo-1-phenyl-1,4-dihydro-quinolin-3-ylmethyl)-amide was prepared starting from intermediate D and 1-(4-chlorobenzyl)-2-oxo-1,2-dihydropyridine-4-carboxylic acid. MS calcd. for C29H21Cl2N3O3 [(M+H)+] 530.1, obsd. 530.0.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]([CH3:24])[C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:25](O)(=[O:34])[C:26]1[C:27]([O:32][CH3:33])=[CH:28][CH:29]=[CH:30][CH:31]=1.C(N=C=NC(C)C)(C)C>C(Cl)Cl>[CH3:33][O:32][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[C:25]([NH:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]([CH3:24])[C:17](=[O:23])[O:18][C:19]([CH3:20])([CH3:21])[CH3:22])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1)=[O:34]
Reactant: COc1ccccc1C(=O)O
Reactant: CN(CCN1CC=C(c2cccc(N)c2)CC1)C(=O)OC(C)(C)C
Agent: CC(C)N=C=NC(C)C
Solvent: ClCCl
Product: COc1ccccc1C(=O)Nc1cccc(C2CCN(CCN(C)C(=O)OC(C)(C)C)CC2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 34.2 %

Procedure:
To a solution of 190 (177 mg, 0.530 mmol) and o-Anisic acid (97 mg, 0.636 mmol) in DCM (5 mL) was added drop-wise a solution of 1,3-Diisopropylcarbodiimide (0.100 mL, 0.636 mmol) in 2 mL of DCM and the resulting mixture was stirred at room temperature for 3 hours. After the usual work-up the residue was purified by flash chromatography using 4 to 6% MeOH in DCM to afford 191 (84.7 mg, 0.181 mmol, 34% yield) as a yellow oil. LRMS (ESI): calc. 467.3, found 468.2 (MH)+.
Reaction SMILES: C1(C2(CCC3C=CC(OC)=C(F)C=3)OC(=O)CC(=O)C2)CCCC1.[Cl:25][C:26]1[CH:27]=[C:28]([CH2:36][CH2:37][C:38]2([CH:46]3[CH2:50][CH2:49][CH2:48][CH2:47]3)[O:43][C:42](=[O:44])[CH2:41][C:40](=[O:45])[CH2:39]2)[CH:29]=[CH:30][C:31]=1[O:32][CH:33](C)C.[Cl:51][C:52]1[CH:63]=[CH:62][C:55]2[N:56]([CH3:61])[C:57]([CH:59]=O)=[N:58][C:54]=2[CH:53]=1.CC1C=C(C)N2N=C(C=O)N=C2N=1>>[Cl:25][C:26]1[CH:27]=[C:28]([CH2:36][CH2:37][C:38]2([CH:46]3[CH2:50][CH2:49][CH2:48][CH2:47]3)[O:43][C:42](=[O:44])[C:41]([CH2:59][C:57]3[N:56]([CH3:61])[C:55]4[CH:62]=[CH:63][C:52]([Cl:51])=[CH:53][C:54]=4[N:58]=3)=[C:40]([OH:45])[CH2:39]2)[CH:29]=[CH:30][C:31]=1[O:32][CH3:33]
Reactant: Cn1c(C=O)nc2cc(Cl)ccc21
Reactant: CC(C)Oc1ccc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)cc1Cl
Agent: COc1ccc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)cc1F
Agent: Cc1cc(C)n2nc(C=O)nc2n1
Product: COc1ccc(CCC2(C3CCCC3)CC(O)=C(Cc3nc4cc(Cl)ccc4n3C)C(=O)O2)cc1Cl

Procedure:
The title compound was prepared analogously to Example B(31), where 6-cyclopentyl-6-[2-(3-fluoro-4-methoxyphenyl)ethyl]dihydro-2H-pyran-2,4(3H)-dione was substituted in place of 6-[2-(3-chloro-4-isopropoxyphenyl)ethyl]-6-cyclopentyldihydro-2H-pyran-2,4(3H)-dione and 5-chloro-1-methyl-1H-benzimidazole-2-carbaldehyde was substituted in place of 5,7-Dimethyl-[1,2,4]triazolo[1,5-α]pyrimidine-2-carbaldehyde.
Reaction SMILES: Cl[C:2]1[C:7]([N:8]=[C:9]=[S:10])=[CH:6][CH:5]=[CH:4][N:3]=1.[O:11]([C:18]1[C:19]([NH2:31])=[N:20][CH:21]=[C:22]([S:24][C:25]2[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=2)[CH:23]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[O:11]([C:18]1[C:19]([NH:31][C:9]2[S:10][C:2]3[C:7]([N:8]=2)=[CH:6][CH:5]=[CH:4][N:3]=3)=[N:20][CH:21]=[C:22]([S:24][C:25]2[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=2)[CH:23]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Nc1ncc(Sc2ccncc2)cc1Oc1ccccc1
Reactant: S=C=Nc1cccnc1Cl
Product: c1ccc(Oc2cc(Sc3ccncc3)cnc2Nc2nc3cccnc3s2)cc1

Procedure:
Prepared according to the method of Example 292 from 2-chloro-3-isothiocyanatopyridine (0.116 g, 0.677 mmol) and 3-phenoxy-5-(pyridin-4-ylthio)pyridin-2-amine. 1H NMR (d6-DMSO)S 7.10 (d, 2H), 7.17-7.23 (m, 3H), 7.40-7.47 (m, 4H), 7.97 (bs, 1H), 8.36-8.41 (m, 4H), 11.88 (bs, 1H).
Reaction SMILES: [N:1]([CH:4]([CH3:21])[CH2:5][N:6]1[C:10]2=[CH:11][C:12]3[C:17]([CH2:16][CH:15]=[CH:14][C:13]=3[O:18][CH3:19])=[C:9]2[C:8](C)=[N:7]1)=[N+]=[N-].[C:22]([OH:29])(=[O:28])/[CH:23]=[CH:24]/[C:25]([OH:27])=[O:26]>C(O)C.C(OCC)C.CO.[Pt]=O>[C:22]([OH:29])(=[O:28])/[CH:23]=[CH:24]/[C:25]([OH:27])=[O:26].[CH3:19][O:18][C:13]1[CH:14]=[CH:15][CH:16]([CH3:22])[C:17]2[C:12]=1[CH:11]=[C:10]1[C:9]=2[CH:8]=[N:7][N:6]1[CH2:5][CH:4]([NH2:1])[CH3:21]
Reactant: COC1=C2C=c3c(c(C)nn3CC(C)N=[N+]=[N-])=C2CC=C1
Agent: O=[Pt]
Agent: O=C(O)/C=C/C(=O)O
Solvent: CO
Solvent: CCOCC
Solvent: CCO
Product: COC1=C2C=c3c(cnn3CC(C)N)=C2C(C)C=C1
Temperature: 25 °C
Reaction time: 15 h
Yield: 165.7 %

Procedure:
1.1 g (3.88 mmol) of (RS)-1-(2-azido-propyl)-7-methoxy-3-methyl-1,4-dihydro-indeno[2,1-c]pyrazole dissolved in 60 ml of anhydrous ethanol were hydrogenated over 110 mg of platinum oxide for 2 hours. The catalyst was subsequently filtered off, rinsed with ethanol and the solvent was removed in a vacuum. The colorless oil obtained was dissolved in 120 ml of anhydrous diethyl ether, filtered and treated while stirring with a solution of 450 mg (3.88 mmol) of fumaric acid in 5 ml of methanol. The mixture was stirred at room temperature for 15 hours and the white crystals were subsequently filtered off. 1.2 g (83%) of (RS)-2-(7-methoxy-4-methyl-1,4-dihydroindeno[2,1-c]pyrazol-1-yl)-1-methyl-ethylamine fumarate (1:1) with m.p. 184° were obtained.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:19]=[CH:18][C:6]([C:7]([NH:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=S)=[CH:5][CH:4]=1.C([O-])(=[O:22])C.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Pb+4]>O>[Cl:2][C:3]1[CH:19]=[CH:18][C:6]([C:7]([NH:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[O:22])=[CH:5][CH:4]=1
Reactant: CC(=O)[O-]
Reactant: S=C(NCCN1CCOCC1)c1ccc(Cl)cc1
Agent: Cl
Agent: [Pb+4]
Solvent: O
Product: O=C(NCCN1CCOCC1)c1ccc(Cl)cc1

Procedure:
900 Mg. of p-chloro-N-(2-morpholinoethyl)-thiobenzamide hydrochloride are boiled in 100 ml. of water with 2 g. of lead tetraacetate for 10 hours under reflux. The mixture is filtered and the filtrate is evaporated to dryness. The residue is chromatographed over a silica gel column with a mixture of chloroform and ethanol. The product is recrystallized from isopropanol, and 0.3 g. of p-chloro-N-(2-morpholinoethyl)-benzamide is obtained, which is identical to the product obtained in Example 1.
Reaction SMILES: [CH3:1][C@:2]12[C:11](=O)[O:10][C:8](=[O:9])[C@@:7]1([CH3:13])[C@H:6]1[O:14][C@@H:3]2[CH2:4][CH2:5]1.[NH2:15]C1SC2C=C(C(O)=O)C=CC=2N=1.C1(C)C=CC=CC=1>C(N(CC)CC)C>[CH3:1][C@:2]12[C:11](=[O:10])[NH:15][C:8](=[O:9])[C@@:7]1([CH3:13])[C@H:6]1[O:14][C@@H:3]2[CH2:4][CH2:5]1
Reactant: Nc1nc2ccc(C(=O)O)cc2s1
Reactant: C[C@@]12C(=O)OC(=O)[C@]1(C)[C@H]1CC[C@@H]2O1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: C[C@@]12C(=O)NC(=O)[C@]1(C)[C@H]1CC[C@@H]2O1
Temperature: 180 °C

Procedure:
A mixture of cantharidin (50 mg, 0.26 mmol), 2-amino-6-carboxybenzothiazole (294 mg, 1.27 mmol), and a mixture of dried toluene and dried triethylamine (4 mL; 2:1, v/v) may be sealed in a tube and heated for 3 hours at 180° C. The reaction mixture may be concentrated, followed by flash chromatography (dichloromethane:methanol, 10:1) that may give the product CAN039 (51.9 mg, 55%) of formula (3) as a white solid with the following characterization: mp=180-181° C.; Rf=0.27 (hexane:acetone, 2:1); 1H NMR (CD3OD, 500 MHz): δ 1.34 (6H, s), 1.72-1.74 (2H, m), 1.97-2.00 (2H, m), 4.69-4.70 (2H, m), 8.08 (1H, d, J=8.5 Hz), 8.18 (1H, dd, J=8.5 Hz and 1.5 Hz), 8.70-8.71 (1H, m); 13C NMR (CDCl3): δ 12.1, 23.7, 54.6, 85.0, 85.1, 122.5, 123.9, 127.9, 128.3, 132.7, 151.9, 155.3, 168.0, 178.7; MS (EI) m/z (%): 372 (M+); HRMS calcd. for C18H16N2O5S [M]+ found 358.0776.
Reaction SMILES: [CH:1]1([C:7]([OH:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:10]1(CO)[CH2:15]CCC[CH2:11]1>[Sn]=O.C(O)(C)C>[CH:10]([C:1]1([C:7]([OH:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)([CH3:15])[CH3:11]
Reactant: OCC1CCCCC1
Reactant: O=C(O)C1CCCCC1
Agent: O=[Sn]
Solvent: CC(C)O
Product: CC(C)C1(C(=O)O)CCCCC1

Procedure:
The reaction between cyclohexane carboxylic acid and isopropanol was conducted under the same conditions as in Example 1, except that 1 g of hydrous tin oxide catalyst prepared in Example C was used in place of 2 g of the hydrous zirconium oxide catalyst used in Example 1. It was discovered by gas chromatography that cyclohexyl methanol was formed at a conversion rate of 95% and selectivity of 39%. Isopropyl cyclohexane carboxylic acid was also obtained as a by-product in an amount of 41%.
Reaction SMILES: Cl.[S:2]1[C:10]2[CH:9]=[CH:8][N:7]=[CH:6][C:5]=2[CH:4]=[C:3]1[CH2:11][NH2:12].S1C2C=CN=CC=2C=[C:14]1C(O)C>>[S:2]1[C:10]2[CH:9]=[CH:8][N:7]=[CH:6][C:5]=2[CH:4]=[C:3]1[CH:11]([NH2:12])[CH3:14]
Reactant: CC(O)c1cc2cnccc2s1
Reactant: NCc1cc2cnccc2s1
Agent: Cl
Product: CC(N)c1cc2cnccc2s1

Procedure:
Intermediate D′ was prepared from 1-(thieno[3,2-c]pyridin-2-yl)ethanol (D′-4) following similar procedures for synthesizing intermediate A from A-3, as described above.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[S:5]1[CH2:9][CH2:8][CH2:7][CH:6]1[C:10](Cl)=[O:11]>O.C(OCC)C>[S:5]1[CH2:9][CH2:8][CH2:7][CH:6]1[C:10]([N:1]=[N+:2]=[N-:3])=[O:11]
Reactant: O=C(Cl)C1CCCS1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: [N-]=[N+]=NC(=O)C1CCCS1
Yield: 86.2 %

Procedure:
A solution of sodium azide (4.14 g.) in water (16 ml.) was added dropwise to a solution of 2-tetrahydrothiophenecarboxylic acid chloride (9.60 g.) in diethyl ether (24 ml.) with stirring under ice-cooling and stirred for further 15 minutes at the same temperature. After the mixture was stirred for 1 hour at ambient temperature, nitrogen gas was introduced to remove off diethyl ether. The resultant mixture was extracted with diethyl ether (50 ml.). The extracts were washed with water, dried over magnesium sulfate and concentrated in vacuo to give oily 2-tetrahydrothiophenecarboxylic acid azide (8.63 g.).
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[CH2:11][CH2:10][O:9][CH2:8][C@H:7]1[NH:12][C@@H:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH3:14])=[O:5])C.[OH-].[Na+].Cl>O1CCCC1>[C:15]1([C@H:13]([NH:12][C@H:7]2[C@H:6]([C:4]([OH:5])=[O:3])[CH2:11][CH2:10][O:9][CH2:8]2)[CH3:14])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CCOC(=O)[C@@H]1CCOC[C@H]1N[C@H](C)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: C[C@@H](N[C@@H]1COCC[C@H]1C(=O)O)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of (3S,4R)-3-[(R)-1-Phenyl-ethylamino]-tetrahydro-pyran-4-carboxylic acid ethyl ester (726 mg, 2.6 mmol) in tetrahydrofuran (6 mL) was treated with 1.0 M sodium hydroxide solution (5.2 mL, 5.2 mmol) and the heterogeneous mixture was stirred at room temperature. After 16 h, the now homogeneous solution was treated with 1.0 M hydrochloric acid (5.2 mL, 5.2 mmol) and concentrated in vacuo. The residue was dissolved in water and lyophilized to provide the product, along with sodium chloride, as a fluffy white solid (943 mg, quantitative), used without further purification.