Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[N:2](C)[CH:3]=[CH:4][C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)[N:8]=1)=O.Cl.[CH3:26][O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[NH:34]N.CCN(CC)CC>C(O)C>[CH3:26][O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[N:34]1[C:5]([C:7]2[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=3)[N:8]=2)=[CH:4][CH:3]=[N:2]1
Reactant: COc1ccccc1NN
Reactant: CN(C)C=CC(=O)c1nn(-c2cccc(C(F)(F)F)c2)ccc1=O
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: COc1ccccc1-n1nccc1-c1nn(-c2cccc(C(F)(F)F)c2)ccc1=O
Temperature: 100 °C
Reaction time: 3 h
Yield: 18.9 %

Procedure:
To a solution of 3-[3-(dimethylamino)prop-2-enoyl]-1-[3-(trifluoromethyl)phenyl]pyridazin-4(1H)-one (337 mg, 1.0 mmol) in ethanol (100 mL) were added 2-methoxyphenylhydrazine hydrochloride (262 mg, 1.5 mmol) and Et3N (0.28 mL, 2.0 mmol). The mixture was stirred at 100° C. for 3 h and the solvent was removed under reduced pressure. Preparative HPLC chromatography provided 3-[1-(2-methoxyphenyl)-1H-pyrazol-5-yl]-1-[3-(trifluoromethyl)phenyl]pyridazin-4(1H)-one as a pale yellow solid (78 mg, 19%).
Reaction SMILES: Br[C:2]1[C:3]2[CH:10]=[C:9]([C:11]3[N:15]([CH3:16])[N:14]=[N:13][N:12]=3)[CH:8]=[CH:7][C:4]=2[S:5][CH:6]=1.[C-:17]#[N:18].[Na+].O.[CH3:21]S(C)=O>>[C:17]([CH2:21][C:2]1[C:3]2[CH:10]=[C:9]([C:11]3[N:15]([CH3:16])[N:14]=[N:13][N:12]=3)[CH:8]=[CH:7][C:4]=2[S:5][CH:6]=1)#[N:18]
Reactant: [C-]#N
Reactant: Cn1nnnc1-c1ccc2scc(Br)c2c1
Reactant: CS(C)=O
Agent: [Na+]
Solvent: O
Product: Cn1nnnc1-c1ccc2scc(CC#N)c2c1
Yield: 4 %

Procedure:
The crude 3-bromo-5-(1-methyltetrazol-5-yl) benzo[b]thiophene (0.504 g) was reacted with 97.7 mg (1.99 mmol) of sodium cyanide in 1.5 ml of DMSO at 100° C. for 2 h. After cooling, the reaction mixture was poured into water (25 ml ) and extracted with dichloromethane (6×50 ml). The combined extracts were dried (Na2SO4) and evaporated in vacuo to leave 0.37 g. Chromatography on flash silica, eluting with 30-60% ethyl acetate/petroleum ether yielded 28.0 mg (4%) of the title product. δ (CDCl3) 4.00 (2H, s), 4.23 (3H, s), 7.63 (1H, s), 7.73 (1H, dd), 8.08 (1H, d), 8.15 (1H, d).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:32])[CH2:4][O:5][C:6]1[CH:14]=[C:13]2[CH2:15][CH2:16][CH2:17][C:12]2=[C:11]2[C:7]=1[C:8]([C:27](=[O:31])[C:28]([NH2:30])=[O:29])=[C:9]([CH3:26])[N:10]2[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1Br.[C:33]1(B(O)O)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.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>[CH3:1][O:2][C:3](=[O:32])[CH2:4][O:5][C:6]1[CH:14]=[C:13]2[CH2:15][CH2:16][CH2:17][C:12]2=[C:11]2[C:7]=1[C:8]([C:27](=[O:31])[C:28]([NH2:30])=[O:29])=[C:9]([CH3:26])[N:10]2[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: OB(O)c1ccccc1
Reactant: COC(=O)COc1cc2c(c3c1c(C(=O)C(N)=O)c(C)n3Cc1ccccc1Br)CCC2
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: C1COCCO1
Product: COC(=O)COc1cc2c(c3c1c(C(=O)C(N)=O)c(C)n3Cc1ccccc1-c1ccccc1)CCC2
Temperature: 100 °C
Yield: 30.7 %

Procedure:
A mixture of 2-[[3-(2-amino-1,2-dioxoethyl)-2-methyl-1-(2-bromobenzyl)-1,6,7,8-tetrahydrocyclopent[g]indol-4-yl]oxy]acetic acid methyl ester (200 mg, 0.400 mmol), phenylboronic acid (49 mg, 0.40 mmol), cesium carbonate (260 mg, 0.800 mmol), and tetrakis(triphenylphosphine)palladium(0) (14 mg, 0.0012 mmol) in dioxane (20 mL) was sparged with nitrogen for 5 min then heated at 100° C. for 6 h. The mixture was allowed to cool to room temperature and filtered through a pad of silica gel that was subsequently washed with acetone. The filtrate was concentrated in vacuo. Reverse-phase chromatography (C18, water/acetonitrile) of the residue provided 61 mg (31%) of the title compound. 1H NMR (CDCl3) δ 7.49 (t, J=7.0 Hz, 2H), 7.42 (t, J=7.3 Hz, 1H), 7.37 (d, J=7.0 Hz, 2H), 7.29 (m, 2H), 7.17 (m, 1H), 6.56 (bs, 1H), 6.48 (d, J=8.0 Hz, 1H), 6.44 (s, 1H), 5.42 (bs, 1H), 5.26 (s, 2H), 4.68 (s, 2H), 3.76 (s, 3H), 2.86 (t, J=7.3 Hz, 4H), 2.34 (s, 3H), 2.01 (quintet, J=7.0 Hz, 2H); MS FD+ m/e 496 (p); IR (KBr, cm−1) 3461, 1757, 1699, 1642.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([O:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[NH:19]2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11].C(=O)([O-])[O-].[K+].[K+].Br[CH2:32][CH:33]1[CH2:38][CH2:37][CH2:36][O:35][CH2:34]1>CN(C)C=O>[CH2:8]([O:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[N:19]2[CH2:32][CH:33]2[CH2:38][CH2:37][CH2:36][O:35][CH2:34]2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11]
Reactant: BrCC1CCCOC1
Reactant: CCCCOc1nc(N)c2nc(OC)[nH]c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: CCCCOc1nc(N)c2nc(OC)n(CC3CCCOC3)c2n1
Temperature: 25 °C
Yield: 55.2 %

Procedure:
2-Butoxy-8-methoxy-9H-purin-6-amine trifluoroacetate salt (0.2 g) in dry N,N-dimethylformamide (5 mL) was heated at 60° C. with anhydrous potassium carbonate (0.315 g) for 1 hour and allowed to cool to room temperature before adding 3-(bromomethyl)tetrahydro-2H-pyran (0.112 g). The reaction mixture was heated at 50° C., overnight. The reaction mixture was quenched with water (20 mL) and extracted into ethyl acetate (3 times, 75 mL combined volume). The organic phase was separated, combined and passed through a hydrophobic frit to dry. The organic phase was evaporated under reduced pressure to give a yellow oil which was purified by C18 reverse phase chromatography using water (containing 0.1% formic acid)-acetonitrile (containing 0.05% formic acid) as eluant (20-60%) to afford the title compound as a white solid (105.4 mg).
Reaction SMILES: [Br:1][CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:11])[CH:8]=2)[C:3]1=[O:12].[Cl:13][C:14]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:15]=1[O:16][CH2:17][C:18]([NH2:20])=[S:19]>CC(C)=O>[BrH:1].[Cl:11][C:7]1[CH:6]=[CH:5][C:4]2[C:3]3([OH:12])[N:20]=[C:18]([CH2:17][O:16][C:15]4[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:14]=4[Cl:13])[S:19][CH:2]3[CH2:10][C:9]=2[CH:8]=1.[Cl:11][C:7]1[CH:6]=[CH:5][C:4]2[C:3]3([OH:12])[N:20]=[C:18]([CH2:17][O:16][C:15]4[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:14]=4[Cl:13])[S:19][CH:2]3[CH2:10][C:9]=2[CH:8]=1
Reactant: NC(=S)COc1ccc(Cl)cc1Cl
Reactant: O=C1c2ccc(Cl)cc2CC1Br
Solvent: CC(C)=O
Product: Br
Product: OC12N=C(COc3ccc(Cl)cc3Cl)SC1Cc1cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
At room temperature, 0.25 g of 2-bromo-5-chloroindan-1-on and 0.24 g of 2-(2,4-dichlorophenoxy)-thioacetamide ware dissolved in 5 ml of dry acetone, and the mixture was stirred at room temperature for 12 h. The resulting precipitate was filtered off with suction, washed with acetone and dried under high vacuum. This yielded the hydrobromide of 6-chloro-2-(2, 4-dichlorophenoxymethyl)-8,8a-dihydroindeno[1,2-d]thiazol-3a-ol having a melting point of 170° C. (decomposition).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH2:18]([NH2:21])[CH2:19][NH2:20].C(O)C.[OH-].[Na+]>O>[ClH:1].[ClH:1].[NH2:20][CH2:19][CH2:18][NH:21][C:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: NCCN
Reactant: Clc1nc(N2CCOCC2)c2ccccc2n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cl
Product: NCCNc1nc(N2CCOCC2)c2ccccc2n1

Procedure:
A mixture of 4 g of 2-chloro-4-morpholinoquinazoline, 5 ml of ethylenediamine, and 10 ml. of ethanol was heated at reflux overnight. The reaction mixture was diluted with 200 ml of water made alkaline with 15 ml of 50 percent aqueous sodium hydroxide solution, and extracted with one liter of ether. The ether extract was washed with water, dried over anhydrous sodium sulfate, filtered, and evaporated. The residue was dissolved in 500 ml of ether and treated with excess hydrogen chloride. The crude product was collected by filtration and recrystallized from the ether-ethanol, to give 1 g of 2-(2-aminoethylamino)-4-morpholinoquinazoline dihydrochloride; m.p. 292°-294° with decomposition. The following analytical data were obtained:
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.Br[C:16]1[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=1.C(C1C=C(NC2CCN(C(OC(C)(C)C)=O)CC2)C=CC=1)#N>>[C:20]([C:19]1[CH:22]=[CH:23][C:16]([NH:1][CH:2]2[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]2)=[CH:17][CH:18]=1)#[N:21]
Reactant: N#Cc1ccc(Br)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Agent: CC(C)(C)OC(=O)N1CCC(Nc2cccc(C#N)c2)CC1
Product: CC(C)(C)OC(=O)N1CCC(Nc2ccc(C#N)cc2)CC1

Procedure:
The title compound was prepared from 1,1-dimethylethyl 4-amino-1-piperidinecarboxylate and 4-bromobenzonitrile using a method similar to that described for D5 in Description 5.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[C:7]([OH:12])=[CH:8][CH:9]=[C:10]([OH:11])[C:4]2=[CH:3][CH:2]=1.[CH2:13](O)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].S(=O)(=O)(O)O>C(OCC)(=O)C.O>[CH2:13]([O:12][C:7]1[C:5]2[C:4](=[CH:3][CH:2]=[CH:1][CH:6]=2)[C:10]([OH:11])=[CH:9][CH:8]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCCCCCO
Reactant: Oc1ccc(O)c2ccccc12
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CCOC(C)=O
Product: CCCCCCCCCCOc1ccc(O)c2ccccc12
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
112 g of naphthohydroquinone and 560 ml of n-decanol were placed in a 1 l three-necked flask and 56 ml of concentrated sulfuric acid was dropwisely added thereto for 30 minutes under nitrogen gas stream while stirring. Thereafter, the mixture was further stirred for 30 minutes and, then, heated at 50° C. for 1 hour and 30 minutes. After cooling, ethyl acetate-water was added to the reaction mixture and the precipitated crystals were filtered off. An aqueous sodium hydroxide solution was added to the filtrate so as to water layer reach pH of 5 to 6. Then, the ethyl acetate layer was washed with water and dried with MgSO4 overnight. The dried ethyl acetate solution was evaporated under reduced pressure to remove ethyl acetate and n-decanol. The residue was dissolved in 1 l of ethyl acetate and treated with 26 g of active carbon followed by concentration under reduced pressure. The residue was recrystallized from a mixed solvent of ethyl acetate and n-hexane and, further, recrystallized from benzene to obtain 73 g of white crystals having a melting point of 89° to 90° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:16])=[C:4]([CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[C:17]1(=O)[CH2:21][CH2:20][CH2:19][CH2:18]1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[CH:17]1([NH:1][C:2]2[C:3]([CH3:16])=[C:4]([CH:9]=[C:10]([C:12]([F:13])([F:14])[F:15])[CH:11]=2)[C:5]([O:7][CH3:8])=[O:6])[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: COC(=O)c1cc(C(F)(F)F)cc(N)c1C
Reactant: O=C1CCCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)c1cc(C(F)(F)F)cc(NC2CCCC2)c1C
Reaction time: 3 h
Yield: 55.8 %

Procedure:
To a stirred solution of methyl 3-amino-2-methyl-5-(trifluoromethyl)benzoate (2.5 g, 10.7 mmol) and cyclopentanone (4.5 g, 53.49 mmol) in methanol (25 mL) was added acetic acid (1.98 g, 21.44 mmol). After 3 h, sodium cyanoborohydride (1.68 g, 24.3 mmol) was added and the reaction stirred overnight. On completion, the solvent was removed under reduced pressure and crude material was purified by column chromatography to afford methyl 3-(cyclopentylamino)-2-methyl-5-(trifluoromethyl)benzoate (1.8 g, 55.9%).
Reaction SMILES: [CH2:1]1[N:8]([CH2:9][CH2:10][NH+:11]([CH2:22][C:23]([O-:25])=[O:24])[CH2:12][CH2:13][N:14]2[CH2:21][C:19](=[O:20])[O:18][C:16](=[O:17])[CH2:15]2)[CH2:7][C:5](=[O:6])[O:4][C:2]1=[O:3].[NH2:26][CH2:27][CH2:28][CH2:29][NH2:30].C1CN2C(=NCCC2)C1.Cl>CN(C=O)C.CN(C=O)C.C1CN2C(=NCCC2)C1>[C:2]([CH2:1][N:8]1[CH2:7][C:5](=[O:6])[NH:30][CH2:29][CH2:28][CH2:27][NH:26][C:16](=[O:17])[CH2:15][N:14]([CH2:21][C:19]([OH:18])=[O:20])[CH2:13][CH2:12][N:11]([CH2:22][C:23]([OH:25])=[O:24])[CH2:10][CH2:9]1)([OH:4])=[O:3]
Reactant: O=C([O-])C[NH+](CCN1CC(=O)OC(=O)C1)CCN1CC(=O)OC(=O)C1
Reactant: NCCCN
Agent: C1CN=C2CCCN2C1
Agent: Cl
Solvent: CN(C)C=O
Product: O=C(O)CN1CCN(CC(=O)O)CC(=O)NCCCNC(=O)CN(CC(=O)O)CC1
Reaction time: 8 h
Yield: 17.7 %

Procedure:
A 500 mL three-neck round bottom flask was charged with 100 mL of dry DMF and the flask flushed with nitrogen. Two syringes were charged separately with solutions of diethylenetriaminepentaacetic acid dianhydride (2.00 g, 5.60 mmol) in 175 mL of DMF and 1,3-diaminopropane (0.415 g, 5.60 mmol) in DMF/DBN (172 mL/3 mL). The two syringes, mounted on a syringe pump were connected to the flask via two long needles passing through rubber septa. These solutions were added dropwise at ambient temperature at a rate of 40 mL/hour to a vigorously stirred solution. A syringe filled with DBN remained positioned in the flask such that additional DBN could be added dropwise to the reaction mixture when cloudiness was seen. A total of 2.5 mL of additional DBN was required to maintain a homogeneous reaction mixture. After the addition was complete, the reaction mixture was allowed to stir overnight, stripped to dryness, and 1N HCl added to adjust the pH to 10.5. This solution was then applied to AG1-X8 (100-200 MESH, OAc-) resin and eluted with 0.5N acetic acid to yield 0.428 g (18%) of the title product, as a white solid after removal of acetic acid followed by lyophilization.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][C:6]2[N:7]([CH3:13])[C:8](=[O:12])[CH2:9][NH:10][CH2:11][C:5]=2[CH:4]=1.Br[CH2:20][C:21]#N.C(N(CC)C(C)C)(C)C.CN(C)C=O>[I-].[Na+]>[CH2:20]([N:10]1[CH2:11][C:5]2[CH:4]=[C:3]([O:2][CH3:1])[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][C:6]=2[N:7]([CH3:13])[C:8](=[O:12])[CH2:9]1)[CH3:21]
Reactant: COc1cc2c(cc1[N+](=O)[O-])N(C)C(=O)CNC2
Reactant: N#CCBr
Agent: [I-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCN1CC(=O)N(C)c2cc([N+](=O)[O-])c(OC)cc2C1
Yield: 91.3 %

Procedure:
A mixture of 7-Methoxy-1-methyl-8-nitro-1,3,4,5-tetrahydro-benzo[e][1,4]diazepin-2-one (0.50 g, 0.0020 mol), Sodium iodide (0.0148 g, 0.0000987 mol), Bromoacetonitrile (0.276 mL, 0.00396 mol) and N,N-Diisopropylethylamine (1.04 mL, 0.00597 mol) in N,N-Dimethylformamide (6 mL, 0.08 mol) was reacted in an analogous manner to example 736-E to give 4-Ethyl-7-methoxy-1-methyl-8-nitro-1,3,4,5-tetrahydro-benzo[e][1,4]diazepin-2-one as a tan solid (0.51 g, 88%). Mp129-131° C.; LCMS (m/e) 291 (M+1); 1H-NMR (DMSO, 400 MHz) δ 7.96 (s, 1H), 7.51 (s, 1H), 3.93-92 (s, 3H), 3.86 (s, 2H), 3.82 (s, 2H), 3.27 (s, 3H), 3.16 (s, 2H).
Reaction SMILES: Cl[CH:2]1[C:7](=[O:8])[CH2:6][C:5]([CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([Cl:24])[CH:17]=2)([CH:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[O:4][C:3]1=[O:25].[N:26]1[CH:31]=[CH:30][C:29]([C:32]2[O:36][C:35]([SH:37])=[N:34][N:33]=2)=[CH:28][CH:27]=1>O>[Cl:24][C:18]1[CH:17]=[C:16]([CH2:15][CH2:14][C:5]2([CH:9]3[CH2:13][CH2:12][CH2:11][CH2:10]3)[O:4][C:3](=[O:25])[C:2]([S:37][C:35]3[O:36][C:32]([C:29]4[CH:30]=[CH:31][N:26]=[CH:27][CH:28]=4)=[N:33][N:34]=3)=[C:7]([OH:8])[CH2:6]2)[CH:21]=[CH:20][C:19]=1[O:22][CH3:23]
Reactant: Sc1nnc(-c2ccncc2)o1
Reactant: COc1ccc(CCC2(C3CCCC3)CC(=O)C(Cl)C(=O)O2)cc1Cl
Solvent: O
Product: COc1ccc(CCC2(C3CCCC3)CC(O)=C(Sc3nnc(-c4ccncc4)o3)C(=O)O2)cc1Cl

Procedure:
The title compound was prepared as described in Example C(70), where 3-chloro-6-[2-(3-chloro-4-methoxyphenyl)ethyl]-6-cyclopentyldihydro-2H-pyran-2,4(3H)-dione was used in place of 3-chloro-6-[2-(5-chloro-2,4-dimethoxyphenyl)ethyl]6-cyclopentyldihydro-2H-pyran-2,4(3H)-dione and 5-(4-pyridyl)-1,3,4-oxadiazole-2-thiol was used in place of 6-hydroxy-8-mercaptopurine monohydrate. 1H NMR (500 MHz, DMSO-d6, WET suppression of DMSO-h6 (2.5 ppm) and H2O (3.35 ppm) peak areas) δ 1.53-1.70 (m, 8H) 2.09 (m, 2H, overlap) 2.82 (d, J=18.1 Hz, 1H) 3.00 (d, J=18.1 Hz, 1H) 3.78 (s, 3H) 6.97 (d, J=8.5 Hz, 1H) 7.13 (dd, J=8.4, 2.1 Hz, 1H) 7.27 (d, J=1.9 Hz, 1H) 7.73 (d, J=5.5 Hz, 2H) 8.71 (d, J=5.8 Hz, 2H). MS (APCI) calcd C26H26ClN3O5S: 528.03; found M=528.1.
Reaction SMILES: [CH3:1][C@H:2]1[NH:7][CH2:6][CH2:5][N:4]([C:8]2[N:9]([CH2:30][C:31]([F:34])([F:33])[F:32])[C:10]3[C:15]([N:16]=2)=[C:14]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[N:13]=[C:12]([C:23]2[CH:24]=[N:25][C:26]([NH2:29])=[N:27][CH:28]=2)[N:11]=3)[CH2:3]1.[CH3:35]N(CCS(O)(=O)=O)C.[OH-:44].[Na+]>O1CCCC1>[NH2:29][C:26]1[N:27]=[CH:28][C:23]([C:12]2[N:11]=[C:10]3[C:15]([N:16]=[C:8]([N:4]4[CH2:5][CH2:6][N:7]([CH:35]=[O:44])[C@H:2]([CH3:1])[CH2:3]4)[N:9]3[CH2:30][C:31]([F:34])([F:32])[F:33])=[C:14]([N:17]3[CH2:18][CH2:19][O:20][CH2:21][CH2:22]3)[N:13]=2)=[CH:24][N:25]=1
Reactant: CN(C)CCS(=O)(=O)O
Reactant: C[C@@H]1CN(c2nc3c(N4CCOCC4)nc(-c4cnc(N)nc4)nc3n2CC(F)(F)F)CCN1
Reactant: [OH-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[C@@H]1CN(c2nc3c(N4CCOCC4)nc(-c4cnc(N)nc4)nc3n2CC(F)(F)F)CCN1C=O
Reaction time: 1.75 h
Yield: 90 %

Procedure:
5-{8-[(3R)-3-Methylpiperazin-1-yl]-6-morpholin-4-yl-9-(2,2,2-trifluoroethyl)-9H-purin-2-yl}pyrimidin-2-amine (101.9 mg, 0.21 mmol) was added to a tetrahydrofuran solution (5.0 ml) of 1H-benzotriazole-1-carboxyaldehyde (34.8 mg, 0.21 mmol) at room temperature and the resulting mixture was stirred for 105 minutes. The reaction mixture was poured into a 2 N aqueous sodium hydroxide solution and the resulting mixture was extracted with methylene chloride. The organic layer was dried over anhydrous sodium sulfate, the mixture was filtrated, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by preparative thin layer silica gel chromatography (methylene chloride:methanol=10:1) to give the title compound (96.8 mg, 90%) as a pale yellow solid.
Reaction SMILES: [C:1]1([CH:7]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][NH2:18])[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:25][C:26]1[CH:27]=[CH:28][C:29]2[N:30]([CH:32]=[C:33]([C:35]3([C:40]([O:42][CH:43]([CH3:45])[CH3:44])=[O:41])[CH2:39][CH2:38][CH2:37][CH2:36]3)[N:34]=2)[N:31]=1.C(=O)(O)[O-].[Na+]>>[ClH:25].[ClH:25].[C:19]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][NH:18][C:26]3[CH:27]=[CH:28][C:29]4[N:30]([CH:32]=[C:33]([C:35]5([C:40]([O:42][CH:43]([CH3:45])[CH3:44])=[O:41])[CH2:39][CH2:38][CH2:37][CH2:36]5)[N:34]=4)[N:31]=3)[CH2:11][CH2:10]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: NCCCN1CCC(OC(c2ccccc2)c2ccccc2)CC1
Reactant: CC(C)OC(=O)C1(c2cn3nc(Cl)ccc3n2)CCCC1
Agent: O=C([O-])O
Agent: [Na+]
Product: CC(C)OC(=O)C1(c2cn3nc(NCCCN4CCC(OC(c5ccccc5)c5ccccc5)CC4)ccc3n2)CCCC1
Product: Cl
Yield: 116 %

Procedure:
1.67 g of 4-(diphenylmethoxy)-1-piperidinepropaneamine and 793 mg of isopropyl 1-(6-chloroimidazo[1,2-b]pyridazin-2-yl)cyclopentanecarboxylate were stirred at 165° C. for 5.5 hours. After cooling, aqueous sodium bicarbonate was added, followed by extraction with ethyl acetate; the extract was washed with saturated saline, dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate:methanol:triethylamine (100:5:2). The desired fraction was collected, concentrated under reduced pressure and dissolved in 5 ml of ethyl acetate; 0.84 ml of a 4 N solution of hydrogen chloride in ethyl acetate was added, followed by concentration. The residue was powdered by the addition of ethyl ether; the resulting powder was collected by filtration, washed with ethyl ether and dried to yield 999 mg of the title compound.
Reaction SMILES: Br[C:2]1[S:6][C:5]([CH:7]=[O:8])=[CH:4][CH:3]=1.[C:9]1(B(O)O)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C([O-])([O-])=O.[Na+].[Na+].CCOCC>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>[C:9]1([C:2]2[S:6][C:5]([CH:7]=[O:8])=[CH:4][CH:3]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: OB(O)c1ccccc1
Reactant: O=Cc1ccc(Br)s1
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: CCOCC
Solvent: C1CCOC1
Product: O=Cc1ccc(-c2ccccc2)s1
Reaction time: 0.08 h
Yield: 91.9 %

Procedure:
5-Bromothiophene-2-carboxaldehyde (1.0 g, 5.2 mmol) is added to a solution of tetrakis(triphenylphosphine)palladium(0) (180 mg, 0.16 mol) in degassed THF (10 mL). The resulting solution is stirred for 5 minutes and then a solution of phenylboronic acid (760 mg, 6.2 mmol) in THF (10 mL) is added followed by aqueous Na2CO3 (2M, 5.2 mL). The mixture is heated at reflux for 24 h. The reaction mixture is allowed to cool, poured into ether, and washed twice with water. The ether layer is dried over Na2SO4 and concentrated in vacuo. The crude product is purified by flash column chromatography (1:1 hexanes/CH2Cl2) to yield 900 mg (91%) of 5-phenylthiophene-2-carboxaldehyde. 1H NMR (300MHz, CDCl3)δ7.38-7.45, 7.65-7.68, 7.73, 9.88.
Reaction SMILES: [C:1]([CH:4]([C:10]1[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=1)[CH:5]([CH3:9])[CH2:6][C:7]#[N:8])(=O)[CH3:2].S(=O)(=O)(O)[OH:17]>C(O)(=O)C>[CH3:9][CH:5]1[C:4]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)=[C:1]([CH3:2])[NH:8][C:7](=[O:17])[CH2:6]1
Reactant: O=S(=O)(O)O
Reactant: CC(=O)C(c1ccncc1)C(C)CC#N
Solvent: CC(=O)O
Product: CC1=C(c2ccncc2)C(C)CC(=O)N1
Reaction time: 4 h

Procedure:
To a 2.0 g portion of 4-acetyl-3-methyl-4-(4-pyridinyl)butanenitrile dissolved in 20 ml of acetic acid was added dropwise 3 ml of sulfuric acid whereupon an exothermic reaction ensued. The reaction mixture was stirred for 4 hours, the acetic acid was evaporated off in vacuo and to the remaining material was added 10 ml of water followed by basification with 35% aqueous sodium hydroxide solution. The alkaline solution was extracted four times with ethyl acetate; the combined extracts were dried over anhydrous magnesium sulfate; the ethyl acetate was distilled off in vacuo; and, the remaining white solid was recrystallized from acetonitrile to produce 2.0 g of 3,4-dihydro-4,6-dimethyl-5-(4-pyridinyl)-2(1H)-pyridinone, m.p. 184°-186° C.