Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:6](=O)[N:7](C)[C@@H:8]([C:20](=[O:40])[N:21]([CH3:39])[C@@H:22]([C:30](=[O:38])[NH:31][CH2:32][CH:33]1[CH2:37][CH2:36][CH2:35][O:34]1)[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:9][C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][CH:11]=1)(C)(C)C.FC(F)(F)C(O)=O.O.C(=O)([O-])O.[Na+]>C(Cl)Cl>[CH3:39][N:21]([C@@H:22]([C:30](=[O:38])[NH:31][CH2:32][CH:33]1[CH2:37][CH2:36][CH2:35][O:34]1)[CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:20](=[O:40])[C@H:8]([NH:7][CH3:6])[CH2:9][C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: CN(C(=O)OC(C)(C)C)[C@H](Cc1cccc2ccccc12)C(=O)N(C)[C@H](Cc1ccccc1)C(=O)NCC1CCCO1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: O
Product: CN[C@H](Cc1cccc2ccccc12)C(=O)N(C)[C@H](Cc1ccccc1)C(=O)NCC1CCCO1
Reaction time: 0.08 h
Yield: 98.3 %

Procedure:
Methyl-((1R)-1-(methyl-((1R)-2-phenyl-1-(((tetrahydrofuran-2-yl)methyl)carbamoyl)ethyl)carbamoyl)-2-(1-naphtyl)ethyl)carbamic acid tert butylester (0.84 g; 1.46 mmol) was dissolved in methylene chloride (3 mL) and trifluoroacetic acid (2 mL) was added. The reaction mixture was stirred for 5 min at roomtemperature. Water (3 mL) and methylene chloride (5 mL) was added. Sodium hydrogen carbonate (solid) was added until pH 8. The reaction mixture was extracted with methylene chloride (3×10 mL). The combined organic layers were dried (magnesium sulfate) and evaporated in vacuo to afford 0.68 g of (2R)-N-methyl-2-methylamino-3-(1-naphtyl)-N-((1R)-2-phenyl-1-((tetrahydrofuran-2-yl-methyl)carbamoyl)ethyl)propionamide.
Reaction SMILES: [OH:1][CH2:2][CH:3]([CH2:5]O)[OH:4]>O>[OH:1][CH2:2][C:3](=[O:4])[CH3:5].[CH2:2]([OH:1])[CH:3]([OH:4])[CH3:5]
Reactant: OCC(O)CO
Solvent: O
Product: CC(=O)CO
Product: CC(O)CO

Procedure:
20 wt % glycerol was dehydrated at nitrogen ambient pressure at 220° C. using 80 g of water as solvent. 1 g of 50% Cu+50% Zr catalyst of nano size catalyzed the reaction to give glycerol conversion of 20% with 87% selectivity to hydroxyacetone and 13% to 1,2-propylene glycol.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH2:12][CH:13]([CH2:19][CH3:20])[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])([OH:3])=O.C(N(CC)CC)C.C(Cl)(=O)OCC.[F:34][C:35]([F:45])([F:44])[C:36]1[CH:43]=[CH:42][C:39]([CH2:40][NH2:41])=[CH:38][CH:37]=1>ClC(Cl)C.ClCCl>[CH2:19]([CH:13]([CH2:12][C:6]1[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:4]([C:1](=[O:3])[NH:41][CH2:40][C:39]2[CH:38]=[CH:37][C:36]([C:35]([F:34])([F:44])[F:45])=[CH:43][CH:42]=2)[CH:5]=1)[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH3:20]
Reactant: NCc1ccc(C(F)(F)F)cc1
Reactant: CCOC(=O)C(CC)Cc1ccc(OC)c(C(=O)O)c1
Agent: CCOC(=O)Cl
Solvent: CC(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C(CC)Cc1ccc(OC)c(C(=O)NCc2ccc(C(F)(F)F)cc2)c1

Procedure:
Ethyl 3-(3-carboxy-4-methoxyphenyl)-2-ethylpropanoate (5.00 g, 17.8 mmol) was dissolved in 80 ml of dehydrated dichloroethane, which was cooled to −10° C. to −15° C. Triethylamine (6.21 ml, 44.5 mmol) was added under stirring. Next, ethyl chlorocarbonate (1.86 ml, 19.5 mmol), dissolved in 10 ml of dehydrated dichloromethane was added dropwise. After stirring for 10 minutes at −10° C., 4-(trifluoromethyl)benzylamine (2.51 ml, 17.8 mmol), dissolved in 10 ml of dehydrated dichloromethane was added dropwise.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([CH2:7][C:8]([O:10]C)=[O:9])[C:4]([O:12][CH2:13][C:14]2[CH:15]=[N:16][C:17]([O:20][CH2:21][C:22]3[N:23]=[C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[S:25][CH:26]=3)=[CH:18][CH:19]=2)=[N:3]1.[OH-].[Na+].O1CCCC1.Cl>C(O)C>[CH3:1][N:2]1[CH:6]=[C:5]([CH2:7][C:8]([OH:10])=[O:9])[C:4]([O:12][CH2:13][C:14]2[CH:15]=[N:16][C:17]([O:20][CH2:21][C:22]3[N:23]=[C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[S:25][CH:26]=3)=[CH:18][CH:19]=2)=[N:3]1
Reactant: COC(=O)Cc1cn(C)nc1OCc1ccc(OCc2csc(-c3ccccc3)n2)nc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cn1cc(CC(=O)O)c(OCc2ccc(OCc3csc(-c4ccccc4)n3)nc2)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 89.9 %

Procedure:
A mixture of methyl [1-methyl-3-[6-(2-phenyl-4-thiazolylmethoxy)-3-pyridylmethoxy]-1H-pyrazol-4-yl]acetate (496 mg), 1N aqueous sodium hydroxide solution (3 ml), tetrahydrofuran (6 ml) and ethanol (6 ml) was stirred at room temperature for 3 hrs. 1N Hydrochloric acid (3 ml) was added to the reaction mixture and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The obtained colorless crystals were collected by filtration to give [1-methyl-3-[6-(2-phenyl-4-thiazolylmethoxy)-3-pyridylmethoxy]-1H-pyrazol-4-yl]acetic acid (432 mg, yield 90%), which was then recrystallized from ethanol-hexane. melting point: 156–157° C.
Reaction SMILES: C([O:8][C:9]1[C:14]([CH2:15][N:16]2[CH2:25][CH2:24][C:23]3[C:18](=[C:19]([Cl:34])[C:20]([C:27]4[N:31]([CH3:32])[N:30]=[N:29][C:28]=4[CH3:33])=[CH:21][C:22]=3[Cl:26])[C:17]2=[O:35])=[C:13]([CH3:36])[CH:12]=[C:11]([CH3:37])[N:10]=1)C1C=CC=CC=1.ClCCl.CO>FC(F)(F)C(O)=O>[Cl:26][C:22]1[CH:21]=[C:20]([C:27]2[N:31]([CH3:32])[N:30]=[N:29][C:28]=2[CH3:33])[C:19]([Cl:34])=[C:18]2[C:23]=1[CH2:24][CH2:25][N:16]([CH2:15][C:14]1[C:9](=[O:8])[NH:10][C:11]([CH3:37])=[CH:12][C:13]=1[CH3:36])[C:17]2=[O:35]
Reactant: Cc1cc(C)c(CN2CCc3c(Cl)cc(-c4c(C)nnn4C)c(Cl)c3C2=O)c(OCc2ccccc2)n1
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Solvent: ClCCl
Product: Cc1cc(C)c(CN2CCc3c(Cl)cc(-c4c(C)nnn4C)c(Cl)c3C2=O)c(=O)[nH]1
Temperature: 45 °C
Reaction time: 3 h
Yield: 54.8 %

Procedure:
A solution of 229a (1.1 g, 2.1 mmol) was dissolved in trifluoroacetic acid (25 mL) and stirred at 45° C. for 3 hours. TLC (dichloromethane/methanol=10:1, Rf: 0.5) showed the reaction was complete. The mixture was concentrated and diluted with dichloromethane (30 mL), washed with aqueous sodium bicarbonate (4×50 mL) and brine (2×20 mL), dried over sodium sulfate, and concentrated to dryness. The residue was purified by flash chromatography (eluting with 10:1 dichloromethane methanol) to afford 5,8-dichloro-2-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-7-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-3,4-dihydroisoquinolin-1(2H)-one (Example 229, 514 mg, 51% yield) as a white solid. 1H NMR (400 MHz, CDCl3): δ 11.73 (s, 1H), 7.31 (s, 1H), 5.95 (s, 1H), 4.77 (s, 2H), 3.85 (s, 3H), 3.77 (t, J=12.8 Hz, 2H), 3.06-3.02 (m, 2H), 2.38 (s, 3H), 2.29 (s, 3H), 2.21 (s, 3H). MS: 446.1 [M+1].
Reaction SMILES: [CH2:1]([N:5]1[CH:9]=[C:8](B2OC(C)(C)C(C)(C)O2)[CH:7]=[N:6]1)C(C)C.Br[C:20]1[CH:38]=[CH:37][C:23]([C:24]([NH:26][CH2:27][C:28]2[CH:33]=[CH:32][N:31]3[CH:34]=[CH:35][N:36]=[C:30]3[CH:29]=2)=[O:25])=[CH:22][CH:21]=1.Br[C:40]1[CH:46]=[CH:45][C:43]([NH2:44])=C[CH:41]=1>>[N:36]1[CH:35]=[CH:34][N:31]2[CH:32]=[CH:33][C:28]([CH2:27][NH:26][C:24](=[O:25])[C:23]3[CH:37]=[CH:38][C:20]([C:46]4[CH2:45][CH2:43][N:44]([C:9]5[CH:8]=[CH:7][N:6]=[CH:1][N:5]=5)[CH2:41][CH:40]=4)=[CH:21][CH:22]=3)=[CH:29][C:30]=12
Reactant: Nc1ccc(Br)cc1
Reactant: CC(C)Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: O=C(NCc1ccn2ccnc2c1)c1ccc(Br)cc1
Product: O=C(NCc1ccn2ccnc2c1)c1ccc(C2=CCN(c3ccncn3)CC2)cc1

Procedure:
The title compound was prepared as described in Example 51A, substituting 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridin-1(2H)-yl)pyrimidine for 1-isobutyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole and 4-bromo-N-(imidazo[1,2-a]pyridin-7-ylmethyl)benzamide for 4-bromoaniline. 1H NMR (400 MHz, DMSO d6) δ ppm 9.32 (t, J=5.9 Hz, 1H), 8.90-8.80 (m, 2H), 8.38 (dd, J=7.5, 1.2 Hz, 1H), 8.31 (d, J=2.0 Hz, 1H), 8.14 (d, J=2.1 Hz, 1H), 7.95 (d, J=8.5 Hz, 2H), 7.80 (s, 1H), 7.63 (d, J=8.4 Hz, 2H), 7.47 (dd, J=7.0, 1.5 Hz, 1H), 7.32-7.18 (m, 1H), 6.48-6.40 (m, 1H), 4.68 (d, J=5.8 Hz, 2H), 4.57-4.47 (m, 2H), 4.19-4.04 (m, 2H), 2.74-2.64 (m, 2H); MS (ESI(+)) m/e 411 (M+H)+.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[C:13]([N:20]1[CH2:25][CH2:24][C@H:23]([OH:26])[CH2:22][C@@H:21]1[CH3:27])([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].[N+:28]([C:31]1[CH:39]=[CH:38][C:34]([C:35](O)=[O:36])=[CH:33][CH:32]=1)([O-:30])=[O:29].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1>[C:13]([N:20]1[CH2:25][CH2:24][C@@H:23]([O:26][C:35](=[O:36])[C:34]2[CH:33]=[CH:32][C:31]([N+:28]([O-:30])=[O:29])=[CH:39][CH:38]=2)[CH2:22][C@@H:21]1[CH3:27])([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14]
Reactant: C[C@H]1C[C@@H](O)CCN1C(=O)OC(C)(C)C
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C[C@H]1C[C@H](OC(=O)c2ccc([N+](=O)[O-])cc2)CCN1C(=O)OC(C)(C)C

Procedure:
With stirring, a solution of 2 ml (0.012 mol) of diethyl azodicarboxylate (93%) in 10 ml of toluene is added dropwise at 5°-10° C. to a suspension of 2.15 g (0.01 mol) of cis-N-BOC-2-methyl-4-hydroxypiperidine (cf. Example 1b), 2.0 g (0.012 mol) of 4-nitrobenzoic acid and 3.15 g (0.012 mol) of triphenylphosphine in 30 ml of toluene. The reaction mixture is further stirred for 15 hours at room temperature and then filtered to remove precipitated diethyl hydrazinedicarboxylate. The filtrate is then concentrated under vacuum and the oily residue is purified by flash chromatography over silica gel using ethyl acetate:hexane (1:5). Concentration of the fractions containing the product gives the title compound as a crystalline residue which melts at 106°-108° C.
Reaction SMILES: Cl[CH2:2][Si:3]([CH3:6])([CH3:5])[CH3:4].[CH2:7]([NH2:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O>C(#N)C>[CH2:7]([NH:14][CH2:2][Si:3]([CH3:6])([CH3:5])[CH3:4])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: C[Si](C)(C)CCl
Reactant: NCc1ccccc1
Solvent: CC#N
Solvent: O
Product: C[Si](C)(C)CNCc1ccccc1
Temperature: 25 °C
Yield: 63.4 %

Procedure:
To a stirred solution of chloromethyl-trimethyl-silane (25 g, 203.79 mmol, 1 eq.) in acetonitrile (250 mL) was added distilled benzyl amine (44.56 mL, 407.59 mmol, 2 eq) at room temperature. Resulting reaction mixture was refluxed for 16 hours. After consumption of starting material, reaction mixture was cooled to room temperature; benzyl amine hydrochloride salt was precipitate out. Solid was removed by filtration and filtrate was concentrated under reduced pressure to get yellow semi solid. Water was added to residue and extracted with ethyl acetate (3×100 mL). Combined organic layer was washed with brine (200 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford product as yellow liquid (25 g, crude). Crude used as such for next reaction. 1H-NMR (400 MHz, CDCl3) δ: 0.03 (s, 9H), 2.04 (s, 2H), 3.79 (s, 2H), 3.86 (s, 1H), 7.29-7.33 (m, 5H). (m/z): 193.8 (M+H)
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[N:6][C:5]([N:9]2[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]2)=[C:4](Br)[N:3]=1.O.[NH2:18][NH2:19]>CCO>[Br:1][C:2]1[C:7]([CH3:8])=[N:6][C:5]([N:9]2[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]2)=[C:4]([NH:18][NH2:19])[N:3]=1
Reactant: NN
Reactant: Cc1nc(N2CCN(C)CC2)c(Br)nc1Br
Solvent: CCO
Solvent: O
Product: Cc1nc(N2CCN(C)CC2)c(NN)nc1Br
Yield: 53.6 %

Procedure:
A 100 mL round bottom flask was charged with 2,6-dibromo-3-methyl-5-(4-methylpiperazin-1-yl)pyrazine (2.0 g, 5.7 mmol), hydrazine hydrate (3.5 g, 0.065 mol) and absolute EtOH (30 mL). The resulting solution was refluxed under N2 atmosphere overnight. Work-up: the solvent was evaporated. The residue was washed with EtOH (10 mL) and dried, to afford 0.92 g (54%) of the product as a yellow solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)[CH:5]=[C:4]([C:15]([F:18])([F:17])[F:16])[N:3]=1.[Br:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1>>[Br:19][C:20]1[CH:25]=[C:24]([C:2]2[N:7]=[C:6]([C:8]3[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=3)[CH:5]=[C:4]([C:15]([F:18])([F:17])[F:16])[N:3]=2)[CH:23]=[CH:22][CH:21]=1
Reactant: OB(O)c1cccc(Br)c1
Reactant: FC(F)(F)c1cc(-c2ccc(Cl)cc2)nc(Cl)n1
Product: FC(F)(F)c1cc(-c2ccc(Cl)cc2)nc(-c2cccc(Br)c2)n1

Procedure:
The title compound was prepared from 2-chloro-4-(4-chloro-phenyl)-6-trifluoromethyl-pyrimidine (example A.1) (0.59 g, 2.0 mmol) and commercially available 3-bromo-benzene-boronic acid (0.44 g, 2.20 mmol) according to the general procedure IVa. Obtained as a white solid (0.71 g, 86%). MS (EI) 413.9 [(M)+]; mp 146° C.
Reaction SMILES: CO[C:3](=[C:11]([C:14]#[N:15])[C:12]#[N:13])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH3:16][NH:17][NH2:18]>C(O)C>[NH2:13][C:12]1[N:17]([CH3:16])[N:18]=[C:3]([CH2:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:11]=1[C:14]#[N:15]
Reactant: COC(Cc1ccccc1)=C(C#N)C#N
Reactant: CNN
Solvent: CCO
Product: Cn1nc(Cc2ccccc2)c(C#N)c1N

Procedure:
A mixture of (1-methoxy-2-phenylethylidene)malononitrile (prepared by the method of B. C. Kraybill et al., J. Am. Chem. Soc. 2002, 124, 12118-12128; 10 g, 50 mmol) and methylhydrazine (2.3 g, 50 mmol) in ethanol (120 mL) was heated to reflux for 10 minutes. The reaction was concentrated in vacuo, and the residue was diluted with water (200 mL) and extracted with EtOAc (3×100 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to afford C10 as a yellow solid. Yield: 10 g, 47 mmol, 94%.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH:9]=O)=[C:7]([O:11][CH3:12])[N:6]=[CH:5][N:4]=1.[C:13]1(=[O:20])[CH2:18][CH2:17][CH2:16][C:15](=O)[CH2:14]1.[CH2:21]([O:23][C:24](=[O:29])[CH2:25][C:26](=[NH:28])[NH2:27])[CH3:22]>C(O)C>[CH2:21]([O:23][C:24]([C:25]1[CH:9]([C:8]2[C:7]([O:11][CH3:12])=[N:6][CH:5]=[N:4][C:3]=2[O:2][CH3:1])[C:14]2[C:13](=[O:20])[CH2:18][CH2:17][CH2:16][C:15]=2[NH:27][C:26]=1[NH2:28])=[O:29])[CH3:22]
Reactant: CCOC(=O)CC(=N)N
Reactant: COc1ncnc(OC)c1C=O
Reactant: O=C1CCCC(=O)C1
Solvent: CCO
Product: CCOC(=O)C1=C(N)NC2=C(C(=O)CCC2)C1c1c(OC)ncnc1OC
Yield: 65 %

Procedure:
Upon boiling a solution of 5.7 g of 4,6-dimethoxypyrimidin-5-aldehyde, 3.8 g of cyclohexane-1,3-dione and 4.4 g of amidinoacetic acid ethyl ester in 80 ml of ethanol for 8 hours, 2-amino-4-(4,6-dimethoxypyrimid-5-yl)-1,4,5,6,7,8-hexahydro-5-oxoquinoline-3-carboxylic acid ethyl ester of melting point 273°C (alcohol) is obtained.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[C:9]=1[OH:10])[CH:5]=O.[N:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1>C(OC(=O)C)(=O)C>[N+:11]([C:8]1[CH:7]=[C:4]([CH:5]=[CH:20][C:17]2[CH:18]=[CH:19][N:14]=[CH:15][CH:16]=2)[CH:3]=[C:2]([OH:1])[C:9]=1[OH:10])([O-:13])=[O:12]
Reactant: O=Cc1cc(O)c(O)c([N+](=O)[O-])c1
Reactant: Cc1ccncc1
Solvent: CC(=O)OC(C)=O
Product: O=[N+]([O-])c1cc(C=Cc2ccncc2)cc(O)c1O

Procedure:
A solution containing 2.0 g (0.011 mole) of 3,4-dihydroxy-5-nitrobenzaldehyde and 2.23 g (0,024 mole) of 4-picoline in9.0 ml of acetic anhydride was refluxed for 1 h. About 15 ml of isopropanolwas then added and the solution was cooled to 0° C. where upon the diacetyl-derivative of the desired product crystallized. After filtration the product was suspended in 100 ml of 0.5 N hydrochloric acid and refluxed for 1.5 h. After cooling the precipitate was filtered, washed with water and acetone and dried. Yield 1.89 g (67%), m.p. above 350° C.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH3:14])[CH:9]=[C:8]2[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:30])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:18][CH:17]=1)=[O:4].[OH-].[Na+].CO.O>C1COCC1>[C:23]([NH:22][C:19]1[CH:18]=[CH:17][C:16]([CH2:15][C:8]2[C:7]3[C:11](=[CH:12][CH:13]=[C:5]([C:3]([OH:4])=[O:2])[CH:6]=3)[N:10]([CH3:14])[CH:9]=2)=[CH:21][CH:20]=1)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: COC(=O)c1ccc2c(c1)c(Cc1ccc(NC(=O)c3ccccc3)cc1)cn2C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Cn1cc(Cc2ccc(NC(=O)c3ccccc3)cc2)c2cc(C(=O)O)ccc21
Temperature: 25 °C
Yield: 97.9 %

Procedure:
A solution of 3-(4-benzoylamino-phenylmethyl)-1-methyl-1H-indole-5-carboxylic acid methyl ester (69 mg, 0.17 mmol), sodium hydroxide (21 mg, 0.52 mmol), methanol (3 mL), water (1 mL) and THF (3 mL) was heated to 60° C. for 24 hr. The reaction solution was then cooled to room temperature and concentrated in vacuo. The remaining residue was diluted with ethyl acetate (20 mL) and washed with 1N HCl (20 mL). The organic layer was dried over MgSO4, filtered and concentrated to provide 3-(4-benzoylamino-phenylmethyl)-1-methyl-1H-indole-5-carboxylic acid (64 mg, 98% yield).
Reaction SMILES: Cl.[CH3:2][NH:3][CH3:4].C=O.[C:7](OC(=O)C)(=O)C.[C:14]([C:17]1[CH:18]=[C:19]([C:28]2[NH:29][C:30](=[O:43])[C:31]3[C:32](=[C:34]([CH2:41][CH3:42])[N:35]([CH2:37][CH2:38][O:39][CH3:40])[N:36]=3)[N:33]=2)[C:20]([O:23][CH2:24][CH2:25][CH2:26][CH3:27])=[N:21][CH:22]=1)(=[O:16])[CH3:15]>>[CH2:24]([O:23][C:20]1[C:19]([C:28]2[NH:29][C:30](=[O:43])[C:31]3[C:32](=[C:34]([CH2:41][CH3:42])[N:35]([CH2:37][CH2:38][O:39][CH3:40])[N:36]=3)[N:33]=2)=[CH:18][C:17]([C:14](=[O:16])[CH2:15][CH2:2][N:3]([CH3:7])[CH3:4])=[CH:22][N:21]=1)[CH2:25][CH2:26][CH3:27]
Reactant: CNC
Reactant: CCCCOc1ncc(C(C)=O)cc1-c1nc2c(CC)n(CCOC)nc2c(=O)[nH]1
Reactant: CC(=O)OC(C)=O
Agent: C=O
Agent: Cl
Product: CCCCOc1ncc(C(=O)CCN(C)C)cc1-c1nc2c(CC)n(CCOC)nc2c(=O)[nH]1

Procedure:
Dimethylamine hydrochloride (280 mg, 31 mmol) was added to formaldehyde (72 mg, 2 mL of a 37-41% aqueous solution) and the mixture sonicated until the white solid dissolved. After 30 min acetic anhydride (1.2 mL) was added and the mixture warmed in a water bath until a clear solution was obtained. A portion of this solution (0.16 mL) was added to 5-(5-acetyl-2-butoxy-3-pyridinyl)-3-ethyl-2-(2-methoxyethyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (Example 16) (100 mg, 0.24 mmol) and the resulting solution heated in a water bath. After 1 h the reaction was cooled and extracted from saturated sodium bicarbonate solution with ethyl acetate. The organics were washed with a further portion of sodium bicarbonate solution then brine, dried (MgSO4) and concentrated. The residue was purified by flash column chromatography (gradient elution from 100% dichloromethane to 10% methanol:dichloromethane) to give 50 mg product.
Reaction SMILES: [F:1][C:2]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:3]=1[CH2:4][N:5]1[C:9]2=[CH:10][N:11]=[C:12]([C:14]([OH:16])=O)[CH:13]=[C:8]2[C:7]([CH2:17][N:18]([CH3:20])[CH3:19])=[CH:6]1.Cl.[CH3:27][O:28][NH2:29]>>[F:1][C:2]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:3]=1[CH2:4][N:5]1[C:9]2=[CH:10][N:11]=[C:12]([C:14]([NH:29][O:28][CH3:27])=[O:16])[CH:13]=[C:8]2[C:7]([CH2:17][N:18]([CH3:19])[CH3:20])=[CH:6]1
Reactant: CN(C)Cc1cn(Cc2ccc(F)cc2F)c2cnc(C(=O)O)cc12
Reactant: CON
Agent: Cl
Product: CONC(=O)c1cc2c(CN(C)C)cn(Cc3ccc(F)cc3F)c2cn1

Procedure:
The title compound was prepared by coupling of 1-(2,4-difluoro-benzyl)-3-dimethylaminomethyl-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid and O-methyl hydroxylamine hydrochloride in a manner similar to step (c) of example 1. 1H NMR (CD3OD) δ; 8.90 (s, 1H), 8.50 (s, 1H), 7.89 (s, 1H), 7.41 (m, 1H), 7.00–7.07 (m, 2H), 5.64 (s, 2H), 4.52 (s, 2H), 3.82 (s, 3H), 2.85 (s, 6H). LCMS (APCI, M+H+): 375.0. HRMS calcd for C19H21F2N4O2 (M+H) 375.1633. found 375.1644. HPLC: 100% purity.
Reaction SMILES: I[C:2]1[C:3]([C:18]([F:24])([F:23])[C:19]([F:22])([F:21])[F:20])=[N:4][N:5]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[C:10]([CH3:17])[CH:9]=2)[CH:6]=1.[F:25][C:26]([Si](C)(C)C)([F:28])[F:27].[F-].[K+].O>CN(C=O)C.[Cu]I>[CH3:17][C:10]1[CH:9]=[C:8]([CH:13]=[CH:12][C:11]=1[N+:14]([O-:16])=[O:15])[CH2:7][N:5]1[CH:6]=[C:2]([C:26]([F:28])([F:27])[F:25])[C:3]([C:18]([F:24])([F:23])[C:19]([F:22])([F:21])[F:20])=[N:4]1
Reactant: Cc1cc(Cn2cc(I)c(C(F)(F)C(F)(F)F)n2)ccc1[N+](=O)[O-]
Reactant: C[Si](C)(C)C(F)(F)F
Agent: [Cu]I
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(Cn2cc(C(F)(F)F)c(C(F)(F)C(F)(F)F)n2)ccc1[N+](=O)[O-]
Yield: 19.9 %

Procedure:
4-Iodo-1-(3-methyl-4-nitrobenzyl)-3-pentafluoroethyl-1H-pyrazole (1.84 g), (trifluoromethyl)trimethylsilane (1.14 g), copper(I) iodide (1.52 g), potassium fluoride (0.28 g) were stirred in DMF (8 ml) at 100° C. for 8 hours. After cooling, the mixture was poured into water and extracted with ethyl acetate. The combined organic phase was washed with saturated aqueous solution of sodium chloride. After drying the organic layer with sodium sulfate, the solvent was distilled off under the reduced pressure and the obtained residue was purified by silica gel column chromatography to obtain 1-(3-methyl-4-nitro-benzyl)-3-pentafluoroethyl-4-trifluoromethyl-1H-pyrazole (0.32 g).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BrH:13]>C(OCC)(=O)C>[Br:13][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OCCCCCc1ccccc1
Reactant: Br
Solvent: CCOC(C)=O
Product: BrCCCCCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
At 0° C., 50 g (0.304 mmol) of 5-phenylpentan-1-ol are added to a solution of 416.7 ml (1.83 mol) of 48% strength hydrobromic acid, and the mixture is stirred at 0° C. for 30 min. The reaction solution is then stirred at 100° C. for 12 hours. After complete conversion, the mixture is cooled to room temperature and 200 ml of ethyl acetate are added. After extraction, the organic phase is separated off, washed with saturated sodium bicarbonate solution and dried over sodium sulfate. After filtration, the filtrate is concentrated to dryness. The crude product obtained is purified by flash chromatography on silica gel (mobile phase: cyclohexane). This gives 59.4 g (0.26 mol, 86% of theory) of a colorless liquid.
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4]([C:6]1[CH2:7][NH:8][CH2:9][CH2:10][CH:11]=1)=[O:5].[C:12]1([C:18]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:19][CH2:20][CH2:21]Br)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[ClH:1].[CH3:2][O:3][C:4]([C:6]1[CH2:7][N:8]([CH2:21][CH2:20][CH:19]=[C:18]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:9][CH2:10][CH:11]=1)=[O:5]
Reactant: COC(=O)C1=CCCNC1
Reactant: BrCCC=C(c1ccccc1)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)C1=CCCN(CCC=C(c2ccccc2)c2ccccc2)C1

Procedure:
A mixture of 5.0 g. (0.0282 mole) of 1,2,5,6-tetrahydro-3-pyridinecarboxylic acid methyl ester, hydrochloride, 8.08 g. (0.282 mole) of 4,4-diphenyl-3-butenyl bromide and 10 g. of crushed potassium carbonate was refluxed in 200 ml. of acetone for 15 hours. The reaction mixture was evaporated, extracted into ethyl acetate from water, dried, evaporated and chromatographed on silica (dry column) eluted with hexane/hexane:ethyl acetate to give 1,2,5,6-tetrahydro-1-(4,4-diphenyl-3-butenyl)-3-pyridinecarboxylic acid methyl ester hydrochloride.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[CH2:6][CH2:7][NH2:8].[C:9]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:18]=[N:19][N:20]([C:23]3[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][N:24]=3)[C:21]=2[OH:22])=[C:13]([CH3:32])[CH:12]=1)#[N:10]>>[C:9]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:18]=[N:19][N:20]([C:23]3[CH:31]=[CH:30][C:26]([C:27]([NH:8][CH2:7][CH2:6][CH:2]4[CH2:3][CH2:4][CH2:5][O:1]4)=[O:28])=[CH:25][N:24]=3)[C:21]=2[OH:22])=[C:13]([CH3:32])[CH:12]=1)#[N:10]
Reactant: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Reactant: NCCC1CCCO1
Product: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)NCCC3CCCO3)cn2)c1O

Procedure:
The title compound was prepared in a manner similar to Example 227 using 2-(tetrahydrofuran-2-yl)ethanamine and 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid. 1H NMR (400 MHz, DMSO-d6) δ 1.21-1.29 (m, 1H) 1.37-1.51 (m, 1H) 1.68-1.89 (m, 4H) 1.99 (dddd, J=11.8, 8.2, 6.6, 5.2 Hz, 1H) 2.44 (s, 3H) 3.26-3.47 (m, 3H) 3.61 (td, J=7.9, 6.4 Hz, 1H) 3.70-3.88 (m, 2H) 7.63-7.68 (m, 1H) 7.71-7.81 (m, 2H) 8.18 (br. s., 1H) 8.41 (d, J=6.3 Hz, 1H) 8.72 (t, J=5.4 Hz, 1H) 8.88-8.95 (m, 1H). MS m/z [M+H]+ 418.4.