Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:12]([N:14]1[CH2:19][CH2:18][C:17]2[N:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)[CH:21]=[N:22][C:16]=2[CH:15]1[C:29](O)=[O:30])=[O:13].Cl.[CH3:33][NH:34][CH3:35].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>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[C:7]([C:8]([F:11])([F:9])[F:10])=[CH:6][CH:5]=[CH:4][C:3]=1[C:12]([N:14]1[CH2:19][CH2:18][C:17]2[N:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)[CH:21]=[N:22][C:16]=2[CH:15]1[C:29]([N:34]([CH3:35])[CH3:33])=[O:30])=[O:13]
Reactant: CNC
Reactant: O=C(O)C1c2ncn(-c3ccccn3)c2CCN1C(=O)c1cccc(C(F)(F)F)c1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN(C)C(=O)C1c2ncn(-c3ccccn3)c2CCN1C(=O)c1cccc(C(F)(F)F)c1Cl
Yield: 54.4 %

Procedure:
A solution of 5-{[2-chloro-3-(trifluoromethyl)phenyl]carbonyl}-1-pyridin-2-yl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-4-carboxylic acid (0.05 g, 0.10 mmol), dimethylamine hydrochloride (0.01 g, 0.10 mmol), HATU (0.04 g, 0.11 mmol), and DIPEA (0.05 mL, 0.26 mmol) in DMF (2 mL) was stirred for 30 min. The reaction was diluted with EtOAc (15 mL) and washed with H2O (3×10 mL). The organic layers were combined, dried (Na2SO4), and concentrated. Chromatography of the resulting residue (SiO2; MeOH(NH3):DCM) gave the title compound (26 mg, 53%). 1H NMR (500 MHz, CDCl3) δ 8.60-8.35 (m, 1H), 8.09-7.69 (m, 3H), 7.65-7.27 (m, 4H), 6.64-6.46 (m, 1H), 4.17 (tt, J=19.0, 5.6 Hz, 1H), 3.72-3.53 (m, 3H), 3.33-2.85 (m, 6H). MS (ESI): mass calculated for C22H19ClF3N5O2, 477.12. m/z found, 478.1 [M+H]+.
Reaction SMILES: [NH2:1][CH:2]1[CH2:11][CH:10]2[N:5]([CH2:6][CH2:7][C:8]3[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:9]=32)[CH2:4][CH2:3]1.CC1C=CC2CCN3C(CC(=O)CC3)C=2C=1.[CH3:33][S:34](Cl)(=[O:36])=[O:35]>>[CH3:33][S:34]([NH:1][CH:2]1[CH2:11][CH:10]2[N:5]([CH2:6][CH2:7][C:8]3[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:9]=32)[CH2:4][CH2:3]1)(=[O:36])=[O:35]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1ccc2c(c1)C1CC(N)CCN1CC2
Agent: Cc1ccc2c(c1)C1CC(=O)CCN1CC2
Product: Cc1ccc2c(c1)C1CC(NS(C)(=O)=O)CCN1CC2

Procedure:
2-Amino-1,3,4,6,7,11b-hexahydro-10-methyl-2H-benzo[a]quinolizine [prepared from 1,3,4,6,7,11b-hexahydro-10-methyl-2H-benzo[a]quinolizin-2-one (Neth.Appln. No. 6,508,468) by reduction of the oxime] is reacted with methane sulphonyl chloride by a process analogous to that of Example 7(a) to give the title compound.
Reaction SMILES: [CH3:1][C:2]([O:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][NH:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][C:27]([F:30])([F:29])[F:28])=[CH:22][CH:21]=2)=[CH:12][CH:11]=1)([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].Cl[C:32]1[CH:37]=[CH:36][C:35]([C:38](=[O:40])[CH3:39])=[CH:34][N:33]=1>>[C:38]([C:35]1[CH:36]=[CH:37][C:32]([N:18]([CH2:19][C:20]2[CH:21]=[CH:22][C:23]([O:26][C:27]([F:28])([F:29])[F:30])=[CH:24][CH:25]=2)[CH2:17][CH2:16][C:13]2[CH:14]=[CH:15][C:10]([O:9][C:2]([CH3:1])([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4])=[CH:11][CH:12]=2)=[N:33][CH:34]=1)(=[O:40])[CH3:39]
Reactant: CC(=O)c1ccc(Cl)nc1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(CCNCc2ccc(OC(F)(F)F)cc2)cc1
Product: CCOC(=O)C(C)(C)Oc1ccc(CCN(Cc2ccc(OC(F)(F)F)cc2)c2ccc(C(C)=O)cn2)cc1

Procedure:
Similarly prepared from ethyl 2-methyl-2-[4-(2-{[4-(trifluoromethoxy)benzyl]amino}ethyl)phenoxy]propanoate and 2-chloro-5-acetyl-pyridine.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([CH2:12][CH2:13][NH:14][C:15](=[O:17])[CH3:16])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:18][CH3:19])[CH:8]=2)[N:3]=1.[H][H]>C(O)C.[C].[Pd]>[CH3:19][O:18][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[CH:2][CH:11]=[C:10]2[CH2:12][CH2:13][NH:14][C:15](=[O:17])[CH3:16]
Reactant: COc1ccc2nc(Cl)cc(CCNC(C)=O)c2c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: COc1ccc2nccc(CCNC(C)=O)c2c1
Yield: 68.7 %

Procedure:
To a solution of N-[2-(2-chloro-6-methoxyquinolin-4-yl)ethyl]acetamide (3.65 g, 13.1 mmol) in ethanol (100 ml) was added 5% palladium carbon (containing water (50%), 9.0 g). The reaction mixture was subjected to catalytic reduction under an atmosphere of hydrogen at atmospheric pressure. After a theoretical amount of hydrogen was added, the palladium carbon was filtered off. The solvent was evaporated under reduced pressure. The resulting residue was purified by column chromatography on silica gel (ethyl acetate:methanol=95:5) to obtain the title compound (2.2 g, 69%).
Reaction SMILES: [CH2:1]([N:3]([CH2:17][CH3:18])[C:4]([CH:6]1[CH2:15][C:14](=O)[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[S:7]1)=[O:5])[CH3:2].Cl.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28]N)=[CH:24][CH:23]=1.S(=O)(=O)(O)O>C(O)C>[CH2:1]([N:3]([CH2:17][CH3:18])[C:4]([CH:6]1[C:15]2[C:26]3[C:25](=[CH:24][CH:23]=[C:22]([O:21][CH3:20])[CH:27]=3)[NH:28][C:14]=2[C:13]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[S:7]1)=[O:5])[CH3:2]
Reactant: CCN(CC)C(=O)C1CC(=O)c2ccccc2S1
Reactant: COc1ccc(NN)cc1
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: CCO
Product: CCN(CC)C(=O)C1Sc2ccccc2-c2[nH]c3ccc(OC)cc3c21
Yield: 57.3 %

Procedure:
To a solution of (+−)-4-Oxo-thiochroman-2-carboxylic acid diethyl amide (50) (1.32 g, 5.0 mmol) and 4-methoxyphenyl hydrazine hydrochloride (0.87 g, 5.0 mmol) in ethanol (10 ml) was added concentrated sulphuric acid (0.73 ml, 1.35 g, 13.8 mmol) under nitrogen. The reaction mixture was heated under reflux for 24 h. After cooling, the reaction mixture was filtered, the solid washed with ethanol, dried in vacuo (45° C.) to give the title compound (51) (1.05 g, 57%) as a pale yellow solid. The structure was confirmed by 13C NMR (75 MHz, DMSO-d6) δ 10.5, 12.7, 32.7, 37.9, 39.5, 53.0, 97.6, 103.3, 109.87, 109.92, 120.3, 123.5, 123.8, 124.3, 124.7, 124.9, 127.8, 129.4, 131.8, 151.3, 166.2.
Reaction SMILES: [Cl:1]C1SC(C2C=CC=CC=2)=NN=1.N[C:14]1[S:18][N:17]=[C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:15]=1>>[Cl:1][C:14]1[S:18][N:17]=[C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:15]=1
Reactant: Nc1nc(-c2ccccc2)ns1
Reactant: Clc1nnc(-c2ccccc2)s1
Product: Clc1nc(-c2ccccc2)ns1

Procedure:
Was prepare in the same manner as 2-Chloro-5-phenyl-1,3,4-thiadiazole, from 5-amino-3-phenyl-1,2,4-thiadiazole.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:15]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:14]([CH2:20][CH2:21][CH2:22][CH3:23])=[N:13][C:7]=3[C:8]([NH2:12])=[N:9][C:10]=2[CH:11]=1.[CH2:24]([O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1B(O)O)[CH2:25][CH3:26]>>[CH2:20]([C:14]1[N:15]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:6]2[C:5]3[CH:4]=[CH:3][C:2]([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=4[O:27][CH2:24][CH2:25][CH3:26])=[CH:11][C:10]=3[N:9]=[C:8]([NH2:12])[C:7]=2[N:13]=1)[CH2:21][CH2:22][CH3:23]
Reactant: CCCOc1ccccc1B(O)O
Reactant: CCCCc1nc2c(N)nc3cc(Br)ccc3c2n1CC(C)C
Product: CCCCc1nc2c(N)nc3cc(-c4ccccc4OCCC)ccc3c2n1CC(C)C

Procedure:
7-Bromo-2-butyl-1-isobutyl-1 H-imidazo[4,5-c]quinolin-4-amine and 2-propoxybenzeneboronic acid were coupled according to the general procedure described in Part J of Example 1. The product was recrystallized from isopropanol, collected by filtration, dissolved in CH2Cl2, and then precipitated with hexanes to afford 2-butyl-1-isobutyl-7-(2-propoxyphenyl)-1H-imidazo[4,5-c]quinolin-4-amine as a white powder, m.p. 174.5–176.0° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[C:11]3[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][C:12]=3[S:13][C:14]=2[C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)=[O:9])=[CH:4][CH:3]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.[CH3:49][N:50]([CH3:55])[C:51](=[O:54])[CH:52]=[CH2:53].C(#N)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(N(CC)CC)C>[OH:26][C:23]1[CH:24]=[CH:25][C:11]2[C:10]([C:8]([C:5]3[CH:6]=[CH:7][C:2](/[CH:53]=[CH:52]/[C:51]([N:50]([CH3:55])[CH3:49])=[O:54])=[CH:3][CH:4]=3)=[O:9])=[C:14]([C:15]3[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=3)[S:13][C:12]=2[CH:22]=1
Reactant: O=C(c1ccc(Br)cc1)c1c(-c2ccc(O)cc2)sc2cc(O)ccc12
Reactant: C=CC(=O)N(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CN(C)C(=O)/C=C/c1ccc(C(=O)c2c(-c3ccc(O)cc3)sc3cc(O)ccc23)cc1
Temperature: 85 °C
Yield: 71 %

Procedure:
To a screw cap seal tube is added 0.84 g (2.0 mmol) of the product from Example 2, 0.20 g (0.66 mmol) of tri-o-tolylphosphine, 0.21 g (2.1 mmol) of N,N-dimethyl acrylamide, 0.040 g (0.2 mmol) of palladium acetate, 40 mL of acetonitrile and 4 mL of triethylamine. The solution was purged with nitrogen then capped and heated to 85° C. for 3 hours. At the end of this time, the solution was concentrated, then taken up in 100 mL of water:ethyl acetate (1:2). The organic layer was separated and the water layer extracted once with ethyl acetate. The ethyl acetate layers were combined, dried (MgSO4) and concentrated an the residue subjected to column chromatography on silica. Elution with 50% ethyl acetate:hexane then ethyl acetate:hexane:isopropanol (60:35:5) yielded 0.63 g of product which was crystallized from chloroform:acetone:hexane to yield 0.47 g of product as a yellow solid, m.p. 208°-211° C.
Reaction SMILES: Cl.[F:2][C:3]([F:19])([F:18])[CH2:4][O:5][N:6]=[C:7]([C:10]1[C:15]([Cl:16])=[CH:14][C:13]([Cl:17])=[CH:12][N:11]=1)[CH2:8][NH2:9].[F:20][C:21]([F:32])([F:31])[C:22]1[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=1[C:24](Cl)=[O:25].C(=O)([O-])[O-].[K+].[K+]>O.ClCCl>[Cl:16][C:15]1[C:10]([C:7](=[N:6][O:5][CH2:4][C:3]([F:18])([F:2])[F:19])[CH2:8][NH:9][C:24](=[O:25])[C:23]2[CH:27]=[CH:28][CH:29]=[CH:30][C:22]=2[C:21]([F:20])([F:31])[F:32])=[N:11][CH:12]=[C:13]([Cl:17])[CH:14]=1
Reactant: NCC(=NOCC(F)(F)F)c1ncc(Cl)cc1Cl
Reactant: O=C(Cl)c1ccccc1C(F)(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: O=C(NCC(=NOCC(F)(F)F)c1ncc(Cl)cc1Cl)c1ccccc1C(F)(F)F
Yield: 92.8 %

Procedure:
To 2.0 g of 2-amino-1-(3,5-dichloropyridin-2-yl)ethanone-O-(2,2,2-trifluoroethyl)oxime hydrochloride in 12.0 ml of water, 1.4 g of 2-(trifluoromethyl)benzoyl chloride in 12.0 ml of dichloromethane and 2.4 g of potassium carbonate were added at room temperature with stirring, and the mixture was stirred at the same temperature for 2 hours. After completion of the reaction, the resulting organic layer was collected and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography using ethyl acetate-hexane (with a gradient of from 5:95 to 50:50) as the eluent to obtain 2.6 g of the desired product as a pale yellow resinous substance.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.I[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.[Cu]I>[C:15]1([N:1]2[CH:5]=[CH:4][CH:3]=[N:2]2)[C:16]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:12]=[CH:13][CH:14]=1
Reactant: Ic1cccc2ccccc12
Reactant: c1cn[nH]c1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: c1ccc2c(-n3cccn3)cccc2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 1H-pyrazole (300 mg, 4.4 mmol), iodonaphthalene (1.1 g, 4.4 mmol), copper (I) iodide (126 mg, 0.66 mmol), Cs2CO3 (2.15 g, 6.6 mmol) in DMF (5 mL) was evacuated and filled with nitrogen twice. The reaction was then stirred at room temperature for 30 minutes and then at 120° C. for 2 days. The reaction mixture was then cooled to room temperature, diluted with ethyl acetate, filtered through silica gel and concentrated to give 1-(naphthalen-1-yl)-1H-pyrazole as pure solid. (800 mg, 93%).
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:12])[NH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[OH-].[Na+].[CH2:15]([O:22][C:23](Cl)=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O1CCOCC1.O.C(Cl)Cl>[CH2:15]([O:22][C:23]([NH:1][C:2]1[C:3](=[O:12])[NH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2)=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Nc1cc2ccccc2[nH]c1=O
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Solvent: C1COCCO1
Product: O=C(Nc1cc2ccccc2[nH]c1=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 35.1 %

Procedure:
To a solution containing 0.5 g (3.10 mmol) of 3-amino-quinolin-2-(1H)-one described by Anderson, et. al. (J. Heterocyclic Chem., 1993, 30, 1533) in 40 mL of dioxane under a nitrogen atmosphere was added 0.14 g (3.4 mmol) of sodium hydroxide in 14 mL of water. The reaction mixture was cooled to 0° C., followed by the addition of 0.50 mL (3.4 mmol) of benzylchloroformate. The pH of the reaction was maintained above 8.0 with additional 1N sodium hydroxide. The reaction was allowed to warm to room temperature and stirred for 2 hours. The reaction was diluted with methylene chloride and washed with water. The organic phase was dried over magnesium sulfate. Filtration, removal of solvent under reduced pressure and column chromatography of the residue on silica gel with 2% methanol/dichloromethane afforded 0.32 g (35%) of product as a white solid. FAB MS [M+H]m/z; Calcd: 295, Found: 295
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[OH:12])[O:8][C:7](=[O:13])[CH2:6][CH:5]2[CH2:14]Cl.C1(C)C=CC=CC=1.N12CCCN=C1CCCCC2.[N:34]([CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][C:48]([OH:50])=[O:49])=[N+:35]=[N-:36]>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[OH:12])[O:8][C:7](=[O:13])[CH2:6][CH:5]2[CH2:14][O:50][C:48](=[O:49])[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][N:34]=[N+:35]=[N-:36]
Reactant: [N-]=[N+]=NCCCCCCCCCCCC(=O)O
Reactant: O=C1CC(CCl)c2cc(Br)c(O)cc2O1
Solvent: Cc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClC(Cl)Cl
Product: [N-]=[N+]=NCCCCCCCCCCCC(=O)OCC1CC(=O)Oc2cc(O)c(Br)cc21
Temperature: 25 °C
Yield: 60 %

Procedure:
A mixture of 6-bromo-4-chloromethyl-7-hydroxy-chroman-2-one (0.67 g, 2.3 mmol), dry toluene (3 mL), 1,8-diazabicyclo[5.4.0]undec-7-ene (1.4 g, 9.3 mmol) and 12-azido dodecanoic acid (0.84 g, 0.35 mmol) was refluxed for 2 h. The reaction mixture was allowed to cool to room temperature, diluted with chloroform (10 mL), quenched with 1N HCl, and the layers separated. The organic layer was dried over Na2SO4 and evaporated to yield the crude product Purification was done by column chromatography eluting with CH2Cl2 to afford the product (yield 60%). The characterization data were consistent with the proposed structure.
Reaction SMILES: [NH:1]1[C:5]([CH2:6][C:7](O)=O)=[N:4][N:3]=[N:2]1.[NH2:10][C:11]1[C:12](=[O:33])[N:13]([CH2:30][CH2:31][CH3:32])[C:14](=[O:29])[N:15]([CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=2)[C:16]=1[NH2:17]>>[N+:26]([C:23]1[CH:24]=[CH:25][C:20]([CH2:19][CH2:18][N:15]2[C:16]3[N:17]=[C:7]([CH2:6][C:5]4[NH:1][N:2]=[N:3][N:4]=4)[NH:10][C:11]=3[C:12](=[O:33])[N:13]([CH2:30][CH2:31][CH3:32])[C:14]2=[O:29])=[CH:21][CH:22]=1)([O-:28])=[O:27]
Reactant: CCCn1c(=O)c(N)c(N)n(CCc2ccc([N+](=O)[O-])cc2)c1=O
Reactant: O=C(O)Cc1nnn[nH]1
Product: CCCn1c(=O)c2[nH]c(Cc3nnn[nH]3)nc2n(CCc2ccc([N+](=O)[O-])cc2)c1=O

Procedure:
By the method of Example 2, 1H-tetrazole-5-acetic acid is reacted with 5,6-diamino-1-[2-(4-nitrophenyl)ethyl]-3-propyluracil (6) to yield 3-[2-(4-nitrophenyl)ethyl]-1-propyl-8-[(1H-tetrazol-5-yl)methyl]xanthine. By methods well known in the art, 3-[2-(4-nitrophenyl)ethyl]-1-propyl-8-[(1H-tetrazol-5-yl)methyl]xanthine is reduced with hydrazine hydrate or hydrogen gas in the presence of a palladium catalyst to yield 3-[2-(4-aminophenyl)ethyl]-1-propyl-8-[(1H-tetrazol-5-yl)methyl]xanthine.
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:19][C:20](O)=[O:21])[C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([NH:11][S:12]([C:15]([F:18])([F:17])[F:16])(=[O:14])=[O:13])=[CH:6][CH:5]=2.C([O:25][C:26](=[O:34])[C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([NH2:33])[CH:28]=1)C>>[CH3:1][C:2]1[N:3]([CH2:19][C:20]([NH:33][C:29]2[CH:28]=[C:27]([CH:32]=[CH:31][CH:30]=2)[C:26]([OH:25])=[O:34])=[O:21])[C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([NH:11][S:12]([C:15]([F:18])([F:16])[F:17])(=[O:14])=[O:13])=[CH:6][CH:5]=2
Reactant: Cc1cc2cc(NS(=O)(=O)C(F)(F)F)ccc2n1CC(=O)O
Reactant: CCOC(=O)c1cccc(N)c1
Product: Cc1cc2cc(NS(=O)(=O)C(F)(F)F)ccc2n1CC(=O)Nc1cccc(C(=O)O)c1

Procedure:
Same procedure as Example 82 except (2-Methyl-5-trifluoromethanesulfonylamino-indol-1-yl)-acetic acid and 3-aminobenzoic ethyl ester was used. 1H-NMR (400 MHz, DMSO-d6) δ 12.93 (s, 1H, COOH), 11.44 (s, 1H, SNH), 10.62 (s, 1H, NHCO), 8.23 (t, J=2 Hz, 1H, ArH), 7.82 (dq, J=1, 8 Hz, 1H, ArH), 7.65 (dt, J=1, 8 Hz, 1H, ArH), 7.45 (t, J=8 Hz, 1H, ArH), 7.39 (d, J=8.6 Hz, 1H, H-7), 7.33 (d, J=2.3 Hz, 1H, H-4), 6.94 (dd, J=2.3, 8.6 Hz, 1H, H-6), 6.30 (s, 1H, H-3), 5.02 (s, 2H, CH2), 2.39 (s, 3H, CH3), MS m/z 454 (M−H).
Reaction SMILES: [OH:1][CH2:2][C@:3]1([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:7][C:6](=[O:8])[N:5]([C@@H:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH3:10])[CH2:4]1.N1C=CN=C1.[Si:29](Cl)([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30].[Cl-].[NH4+]>CN(C)C=O>[Si:29]([O:1][CH2:2][C@:3]1([C:17]([O:19][C:20]([CH3:22])([CH3:21])[CH3:23])=[O:18])[CH2:7][C:6](=[O:8])[N:5]([C@@H:9]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH3:10])[CH2:4]1)([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C[C@H](c1ccccc1)N1C[C@@](CO)(C(=O)OC(C)(C)C)CC1=O
Agent: [Cl-]
Agent: [NH4+]
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: C[C@H](c1ccccc1)N1C[C@@](CO[Si](C)(C)C(C)(C)C)(C(=O)OC(C)(C)C)CC1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 71.3 %

Procedure:
To a solution of tert-butyl(3S)-3-hydroxymethyl-5-oxo-1-[(1R)-1-phenylethyl]pyrrolidine-3-carboxylate (8.23 g, 25.8 mmol) and imidazole (2.63 g, 38.7 mmol) in N,N-dimethylformamide (150 mL), tert-butyl dimethylsilyl chloride (4.66 g, 31.0 mmol) was added in an ice bath, and the mixture was stirred at room temperature for 4 hours. To the reaction mixture, saturated aqueous solution of ammonium chloride (300 mL) was added in an ice bath, and the mixture was extracted with diethylether (300 mL×2). The organic layer was washed with water (300 mL×2) and saturated aqueous solution of sodium chloride (200 mL), and dried with anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elusion by hexane:ethyl acetate, 10:1→1:1) to obtain 7.98 g (71%) of the title compound as a colorless oily substance.
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[C:8](O)(=O)[C:9](O)=O.[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21]1[CH:26]=[CH:25][C:24]([CH:27]([CH3:34])[C:28]([O:30][CH2:31][CH:32]=[O:33])=[O:29])=[CH:23][CH:22]=1>>[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21]1[CH:26]=[CH:25][C:24]([CH:27]([CH3:34])[C:28]([O:30][CH2:31][C:32]([N:3]2[CH2:4][CH2:5][CH:6]([C:9]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)[CH2:7][CH2:2]2)=[O:33])=[O:29])=[CH:23][CH:22]=1
Reactant: Nc1ccccn1
Reactant: CC(C(=O)OCC=O)c1ccc(-c2ccccc2Cl)cc1
Reactant: O=C(O)C(=O)O
Product: CC(C(=O)OCC(=O)N1CCC(c2ccccc2)CC1)c1ccc(-c2ccccc2Cl)cc1

Procedure:
2-(2-aminopyridine(-2-oxoethyl 2-(2'-chloro-4-biphenylyl)propionate oxalate.
Reaction SMILES: Br[CH2:2]/[CH:3]=[CH:4]/[CH2:5][O:6][CH2:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][N:15]([CH3:29])[S:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:10][CH2:9]1.[CH3:30][NH2:31]>CN(C)C(=O)C>[CH3:29][N:15]([CH2:14][C@H:11]1[CH2:12][CH2:13][C@H:8]([CH2:7][O:6][CH2:5]/[CH:4]=[CH:3]/[CH2:2][NH:31][CH3:30])[CH2:9][CH2:10]1)[S:16]([C:19]1[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=1)(=[O:18])=[O:17]
Reactant: CN(C[C@H]1CC[C@H](COC/C=C/CBr)CC1)S(=O)(=O)c1ccc(C(F)(F)F)cc1
Reactant: CN
Solvent: CC(=O)N(C)C
Product: CNC/C=C/COC[C@H]1CC[C@H](CN(C)S(=O)(=O)c2ccc(C(F)(F)F)cc2)CC1

Procedure:
In analogy to the method described in example 12. 1, trans-N-[4-(4-bromo-(E)-but-2-enyloxymethyl)-cyclohexylmethyl]-N-methyl-4-trifluoromethyl-benzenesulfonamide was reacted with methylamine in N,N-dimethylacetamide at room temperature to yield trans-N-methyl-N-[4-(4-methylamino-(E)-but-2-enyloxymethyl)-cyclohexylmethyl]-4-trifluoromethyl-benzenesulfonamide as light yellow solid, MS: 449 (MH+).
Reaction SMILES: [NH:1]1[C:5]2=[N:6][N:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[N:2]1.[I:10]I.[OH-].[K+].Br[CH2:15][C:16]([O:18][CH3:19])=[O:17]>CN(C=O)C.CCOC(C)=O>[I:10][C:3]1[C:4]2[C:5](=[N:6][N:7]=[CH:8][CH:9]=2)[N:1]([CH2:15][C:16]([O:18][CH3:19])=[O:17])[N:2]=1
Reactant: COC(=O)CBr
Reactant: II
Reactant: c1cc2cn[nH]c2nn1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)Cn1nc(I)c2ccnnc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 1H-pyrazolo[3,4-c]pyridazine [271-75-0] (450 mg, 3.75 mmol) in DMF (10 mL) was added iodine (951 mg, 3.75 mmol) and KOH (525 mg, 9.37 mmol). The mixture was stirred at RT for 16 h until completion of the reaction. Methyl 2-bromoacetate (0.380 mL, 4.12 mmol) was then added to the reaction mixture and stirring was continued at RT for 2 h. The mixture was diluted with EtOAc and washed with water (10 mL), the organic phase was dried (Na2SO4) and evaporated under vacuum. The crude mixture was purified by flash column chromatography on silica gel (c-Hex/EtOAc 66:33) to afford the title compound as a brown solid. TLC, Rf (c-Hex/EtOAc 1:1)=0.40; MS (LC/MS): 318.9 [M+H]+; tR (HPLC conditions c): 3.35 min.
Reaction SMILES: [CH3:1][CH:2]1[C:7]([CH:9]=[O:10])(C)[CH2:6][CH2:5][CH:4]=[CH:3]1.S([O-])([O-])(=O)=O.[Na+].[Na+].[CH2:18]([CH2:20][NH2:21])O.[CH3:22]O>>[CH3:1][CH:2]1[CH:3]=[C:4]([CH3:22])[CH2:5][CH2:6][CH:7]1[CH:9]1[NH:21][CH2:20][CH2:18][O:10]1
Reactant: NCCO
Reactant: CO
Reactant: CC1C=CCCC1(C)C=O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Product: CC1=CC(C)C(C2NCCO2)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a 0° C. stirred solution of 66 g (0.47 mol) triplal and 21 g sodium sulfate in 150 mL of methanol is added 29 g (0.47 mol) of ethanolamine. The reaction is allowed to warm to room temperature. After stirring for 24 h the mixture is cooled to 0° C. and the solids are removed via vacuum filtration through Celite. Evaporation of the solvent gives a clear, slightly yellow oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][C@H:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:13][C@H:9]1[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:24]1([CH2:34][NH2:35])[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][CH:25]=1>>[C:24]1([CH2:34][NH:35][C:10](=[O:12])[C@@H:9]2[CH2:13][C@@H:14]([O:16][CH2:17][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH2:15][N:8]2[C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][CH:25]=1
Reactant: CC(C)(C)OC(=O)N1C[C@H](OCc2ccccc2)C[C@H]1C(=O)O
Reactant: NCc1cccc2ccccc12
Product: CC(C)(C)OC(=O)N1C[C@H](OCc2ccccc2)C[C@H]1C(=O)NCc1cccc2ccccc12

Procedure:
The title compound was prepared using the procedure in Example 1 step H using N-t-butoxycarbonyl-4(R)- benzyloxyproline and naphth-1-ylmethylamine.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][CH2:6][S:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1.C(N(CC)CC)C.[N:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:24]=[CH:23][C:22]=1[C:31](Cl)=[O:32]>C(Cl)Cl>[N:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:24]=[CH:23][C:22]=1[C:31]([NH:3][CH2:4][CH2:5][CH2:6][S:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1)=[O:32]
Reactant: O=C(Cl)c1cnc2ccccc2n1
Reactant: NCCCSc1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCCCSc1ccncc1)c1cnc2ccccc2n1
Yield: 48.8 %

Procedure:
To a solution of 4.30 g (17.8 mmol) of 4-(3-aminopropylthio)pyridine dihydrochloride and 8.68 ml (62.3 mmol) of triethylamine in 200 ml of methylene chloride, 3.43 g (17.8 mmol) of 2-quinoxaloyl chloride was added with stirring under ice-cooling, and the mixture was stirred at room temperature for 4 hours. The reaction mixture was washed with saturated aqueous sodium bicarbonate and water, and dried. The solvent was distilled off and the residue was purified by column chromatography (eluent: ethyl acetate) and recrystallization (solvent: ethyl acetate-ether) to give 2.82 g of the desired compound (48.9% yield, white crystals).