Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:17]=[CH:16][C:13]([CH:14]=O)=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:18][C:19](=[O:24])[CH2:20][C:21](=[O:23])[CH3:22].S(Cl)(Cl)=O>CC(O)C>[C:1]1([S:7]([C:10]2[CH:17]=[CH:16][C:13]([CH:14]=[C:20]([C:19](=[O:24])[CH3:18])[C:21](=[O:23])[CH3:22])=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)CC(C)=O
Reactant: O=Cc1ccc(S(=O)(=O)c2ccccc2)cc1
Solvent: CC(C)O
Solvent: O=S(Cl)Cl
Product: CC(=O)C(=Cc1ccc(S(=O)(=O)c2ccccc2)cc1)C(C)=O
Temperature: 20 °C

Procedure:
To a solution containing 2.1 g of 4-phenylsulfonylbenzaldehyde and 1.5 g of 2,4-pentanedione in 10 ml of 2-propanol was added 1 ml of thionyl chloride with stirring at 20° C. The solution was stirred for 1 h at 20° C. and evaporated to dryness in vacuo. The residue was crystallized from toluene, mp 102°-105° C.
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:22](Cl)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CN(C)C=O>[CH2:22]([N:11]1[C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[N:8]=[C:7]1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: c1ccc(-c2nc3ccccc3[nH]2)cc1
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: c1ccc(Cn2c(-c3ccccc3)nc3ccccc32)cc1

Procedure:
To a flask were added 3 g 2-phenylbenzimidazole, 2.8 g potassium carbonate, 40 ml N,N-dimethylformamide and the mixture was stirred under nitrogen. 3.6 g Benzyl chloride were added and the mixture was heated to 75 C for 8 hrs. The reaction was cooled to 50 C and quenched with 40 ml of water and cooled to 5 C. The product was filtered, washed with water. The product was recrystallized by dissolving in 57 ml acetonitrile at reflux and 39 ml water were added. After cooling to 5 C, the product was filtered, washed and dried giving 3.1 g.
Reaction SMILES: Br[C:2]1[CH:12]=[C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:5]2[S:6][CH2:7][C:8]([CH3:10])([CH3:9])[C:4]=2[CH:3]=1.C([Sn](CCCC)(CCCC)[C:22]1[O:23][CH:24]=[CH:25][CH:26]=1)CCC>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.C1(C)C=CC=CC=1>[C:13]([C:11]1[C:5]2[S:6][CH2:7][C:8]([CH3:10])([CH3:9])[C:4]=2[CH:3]=[C:2]([C:22]2[O:23][CH:24]=[CH:25][CH:26]=2)[CH:12]=1)([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)c1cc(Br)cc2c1SCC2(C)C
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccco1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CC(C)(C)c1cc(-c2ccco2)cc2c1SCC2(C)C
Temperature: 25 °C
Yield: 40.1 %

Procedure:
A mixture of 5-bromo-7-tert-butyl-2,3-dihydro-3,3-dimethylbenzo[b]thiophene (1.20 g, 4.0 mmol), 2-(tributylstannyl)furan (1.71 g, 4.8 mmol), tetrakis(triphenylphosphine)palladium (0.46 g, 0.4 mmol), and 20 mL of toluene is heated under argon at reflux for 30 min. The reaction mixture is cooled to room temperature, concentrated in vacuo, diluted with ether, washed with 10% aqueous ammonium hydroxide solution and with brine, dried over anhydrous magnesium sulfate, and concentrated to give a dark oil. Purification by flash column chromatography on silica gel (1% ethyl acetate-hexane) yields about 0.46 g (40%) of the title compound as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:27]=[CH:26][C:6]([CH2:7][S:8][C:9](=[NH:25])[C:10]([C:23]#[N:24])=[C:11]([SH:22])[NH:12][C:13]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:14])=[CH:5][CH:4]=1.N1C=CC=CC=1.II.Cl>C(OCC)(=O)C>[C:16]1([O:15][C:13](=[O:14])[NH:12][C:11]2[S:22][N:25]=[C:9]([S:8][CH2:7][C:6]3[CH:26]=[CH:27][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[C:10]=2[C:23]#[N:24])[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: COc1ccc(CSC(=N)C(C#N)=C(S)NC(=O)Oc2ccccc2)cc1
Agent: Cl
Agent: II
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: COc1ccc(CSc2nsc(NC(=O)Oc3ccccc3)c2C#N)cc1
Reaction time: 1 h
Yield: 62.9 %

Procedure:
To a mixture of 2-Cyano-3-mercapto-3-phenoxycarbonylamino-thioacrylimidic acid 4-methoxy-benzyl ester (11 g, 28 mmol) and ethyl acetate (250 mL) was added, at 0° C., pyridine (4.4 g, 55 mmol). A solution of iodine (7.0 g, 28 mmol) in 350 mL of ethyl acetate was added dropwise over 1 hour. The resulting suspension was stirred for 1 hour, treated with 200 mL of 1 M HCl and filtered, affording 7.0 g (64%) of [4-cyano-3-(4-methoxy-benzylsulfanyl)-isothiazol-5-yl]-carbamic acid phenyl ester as a colorless solid. The filtrate was extracted with 1 l of ethyl acetate, and the organic phase was washed with aqueous NaHCO3, dried over Na2SO4, filtered and concentrated, yielding an additional 2.8 g (26%) of [4-cyano-3-(4-methoxy-benzylsulfanyl)-isothiazol-5-yl]-carbamic acid phenyl ester. 1H NMR (400 MHz, CDCl3) δ 11.95 (s, 1H), 7.35 (t, 2H, J=8.4 Hz), 7.20 (m, 3H), 7.13 (d, 2H, J=8.0 Hz), 6.78 (t, 2H, J=8.6 Hz), 4.34 (s, 2H), 3.73 (s, 3H) ppm; MS (APCl, m/z): 398 [M+H]+.
Reaction SMILES: [CH2:1]([C:3]1[C:8](/[CH:9]=[CH:10]/[O:11]C)=[CH:7][CH:6]=[CH:5][C:4]=1[C:13]1[S:17][C:16]([C:18]2[CH:19]=[CH:20][C:21]([CH2:26][CH:27]([CH3:29])[CH3:28])=[C:22]([CH:25]=2)[C:23]#[N:24])=[N:15][N:14]=1)[CH3:2].[I-].[Na+].C[Si](Cl)(C)C.O>C(#N)C>[CH2:1]([C:3]1[C:8]([CH2:9][CH:10]=[O:11])=[CH:7][CH:6]=[CH:5][C:4]=1[C:13]1[S:17][C:16]([C:18]2[CH:19]=[CH:20][C:21]([CH2:26][CH:27]([CH3:28])[CH3:29])=[C:22]([CH:25]=2)[C:23]#[N:24])=[N:15][N:14]=1)[CH3:2]
Reactant: CCc1c(/C=C/OC)cccc1-c1nnc(-c2ccc(CC(C)C)c(C#N)c2)s1
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CCc1c(CC=O)cccc1-c1nnc(-c2ccc(CC(C)C)c(C#N)c2)s1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 89.8 %

Procedure:
To a solution of 5-(5-{2-ethyl-3-[(E)-2-(methyloxy)ethenyl]phenyl}-1,3,4-thiadiazol-2-yl)-2-(2-methylpropyl)benzonitrile (D30) (120 mg) and sodium iodide (89 mg) in acetonitrile (20 mL) stirred under nitrogen at room temperature was added TMSCl (0.076 mL) dropwise. The reaction mixture was stirred at room temperature for 10 min. Water was added. The aqueous solution was extracted with EA for 3 times. The organic phase was washed with saturated Na2S2O3 solution and saturated brine, dried over sodium sulphate and evaporated in vacuo to afford the crude product 5-{5-[2-ethyl-3-(2-oxoethyl)phenyl]-1,3,4-thiadiazol-2-yl}-2-(2-methylpropyl)benzonitrile (D31) (104 mg) as a yellow oil. MS (ES): C23H23N3OS requires 389. found 390.1 (M+H+).
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25]CC)=O)[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH3:2].[CH2:28]([NH2:31])[CH2:29][CH3:30]>C1COCC1>[CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([NH:31][CH2:28][CH2:29][CH3:30])=[O:25])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH3:2]
Reactant: CCOCc1nc2cnc3ccccc3c2n1CCCCCC(=O)OCC
Reactant: CCCN
Solvent: C1CCOC1
Product: CCCNC(=O)CCCCCn1c(COCC)nc2cnc3ccccc3c21
Temperature: 25 °C

Procedure:
A solution of ethyl 6-(2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)hexanoate (3.73 g, 10.1 mmol, prepared in Parts A and B of Example 13), n-propylamine (5 mL), and THF (5 mL) was heated at 80° C. for three days in a high-pressure vessel, allowed to cool to ambient temperature, and concentrated under reduced pressure. The work-up procedure described in Part C of Example 13 was followed to provide 4.1 g of 6-[2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]-N-propylhexanamide.
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.[CH3:10][O:11][C:12](=[O:49])[CH2:13][CH2:14]/[CH:15]=[CH:16]\[CH2:17][CH2:18][C@@H:19]1[C@@H:23](/[CH:24]=[CH:25]/[C@@H:26]([O:34]C2CCCCO2)[C:27]([CH3:33])([CH3:32])[CH2:28][CH2:29][CH2:30][CH3:31])[C@H:22]([O:41]C2CCCCO2)[CH2:21][C@@H:20]1O.C(=O)(O)[O-].[Na+]>C(Cl)Cl.N1C=CC=CC=1>[CH3:10][O:11][C:12](=[O:49])[CH2:13][CH2:14]/[CH:15]=[CH:16]\[CH2:17][CH2:18][C@@H:19]1[C@@H:23](/[CH:24]=[CH:25]/[C@@H:26]([OH:34])[C:27]([CH3:33])([CH3:32])[CH2:28][CH2:29][CH2:30][CH3:31])[C@H:22]([OH:41])[CH2:21][C@H:20]1[F:7]
Reactant: CCN(CC)S(F)(F)F
Reactant: CCCCC(C)(C)[C@@H](/C=C/[C@@H]1[C@@H](CC/C=C\CCC(=O)OC)[C@@H](O)C[C@H]1OC1CCCCO1)OC1CCCCO1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCC(C)(C)[C@H](O)/C=C/[C@@H]1[C@@H](CC/C=C\CCC(=O)OC)[C@H](F)C[C@H]1O
Temperature: -70 °C
Reaction time: 3.5 h

Procedure:
0.56 ml of diethylaminosulfur trifluoride (DAST) is instilled in a solution of 2.05 g of (4Z,13E)-(9S,11R,15R)-9-hydroxy-16,16-dimethyl-11,15-bis-(tetrahydropyran-2-yloxy)-4,13-prostadienoic acid methyl ester in 43 ml of methylene chloride and 1.1 ml of pyridine at −70° C. and stirred for 3.5 hours at −70° C. Then it is added to 200 ml of 5% sodium bicarbonate solution cooled to 0° C. and allowed to stir vigorously for 10 minutes. Then it is extracted several times with methylene chloride, the extract is washed with water, dried over MgSO4 and concentrated by evaporation in a vacuum. The residue is stirred for 24 hours at 20° C. with 60 ml of a mixture of acetic acid/water/tetrahydrofuran (65/35/10), concentrated by evaporation in a vacuum after addition of toluene and the raw product is purified by chromatography on silica gel with toluene/0-10% isopropanol. 306 mg of the title compound is obtained as oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([CH2:11]Cl)[N:10]=2)[CH:7]=1.Cl.[C:14]1([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([CH2:11][N:23]3[CH2:24][CH2:25][N:20]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[CH2:21][CH2:22]3)[N:10]=2)[CH:7]=1
Reactant: ClCc1cn2cc(Cl)ccc2n1
Reactant: c1ccc(N2CCNCC2)cc1
Agent: Cl
Product: Clc1ccc2nc(CN3CCN(c4ccccc4)CC3)cn2c1
Yield: 58 %

Procedure:
Following the general procedure of Example 11 and making non-critical variations, 6-chloro-2-(chloromethyl)imidazo[1,2-α]pyridine (Example 4, Step 1; 0.296 g) and 1-phenylpiperazine hydrochloride (Aldrich; 0.333 g) are converted to 0.279 g of the title compound after chromatography on silica gel and crystallization from dichloromethane/ethyl ether/hexane; mp 128.5-130.5° C.; MS m/z 326, 328; IR (mineral oil) 1217, 1073, 1501, 921, 1600 cm-1 ; 1H NMR (CDCl3) δ2.74, 3.24, 3.77, 6.85, 6.92, 7.12, 7.26. 7.52. 8.13.
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][C:12]([CH:14]=[O:15])=[CH:13][C:8]=2[NH:7][C:6]1=[O:16].C(Br)(Br)(Br)[Br:18].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[Br:18][CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][C:12]([CH:14]=[O:15])=[CH:13][C:8]=2[NH:7][C:6]1=[O:16]
Reactant: O=Cc1ccc2c(c1)[nH]c(=O)n2CCCO
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=Cc1ccc2c(c1)[nH]c(=O)n2CCCBr
Temperature: 25 °C
Reaction time: 24 h
Yield: 19.7 %

Procedure:
1185 mg (5.38 mmol) of 1-(3-hydroxypropyl)-2-oxo-2,3-dihydro-1H-benzimidazole-5-carbaldehyde (Intermediate 14) are suspended in 56 ml of dichloromethane. 2285 mg (6.89 mmol) of carbon tetrabromide and then 6890 mg of polymer-supported triphenyl phosphine (1 mmol/g; 6.89 mmol) are added. The mixture is shaken at rt for 24 hr. The polymer is filtered and sequentially washed with dichloromethane, EtOH and MeOH. The filtrates are concentrated and the residue (2.2 g) is chromatographically purified over silicagel eluting with chloroform/EtOH (100/0 to 90/10). 0.3 g of pure title compound are obtained (20% yield).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[O:5]([P:12]1(=[O:20])[CH2:17][CH2:16][CH2:15][CH:14]([CH2:18]I)[O:13]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1C=CC=CC=1.CN(C=O)C>[O:5]([P:12]1(=[O:20])[CH2:17][CH2:16][CH2:15][CH:14]([CH2:18][N:1]=[N+:2]=[N-:3])[O:13]1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: [N-]=[N+]=[N-]
Reactant: O=P1(Oc2ccccc2)CCCC(CI)O1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCC1CCCP(=O)(Oc2ccccc2)O1
Yield: 96 %

Procedure:
A suspension containing two equivalents of sodium azide, one equivalent of the above-prepared iodonated oxaphosphorinane and a catalytic amount of about 0.1 equivalent of tetrabutylammonium bromide in benzene/DMF (1:1) was heated to 60-80 degrees C. for 16 hours to produce 2-phenoxy-2-oxo-6-(azidomethyl)-1,2-oxaphosphorinane in 96 percent yield as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]([C:8]2[C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)[CH:6]=[CH:5][N:4](C(OCC)=O)[N:3]=1>[O-2].[Mn+4].[O-2].C(Cl)(Cl)Cl>[Cl:1][C:2]1[N:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[C:9]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[N:10][N:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=12
Reactant: CCOC(=O)N1C=CC(c2c(-c3ccccc3)nn3ccccc23)C(Cl)=N1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: Clc1nnccc1-c1c(-c2ccccc2)nn2ccccc12
Yield: 76.9 %

Procedure:
A mixture of 3-(3-chloro-1-ethoxycarbonyl-1,4-dihydropyridazin-4-yl)-2-phenylpyrazolo[1,5-a]pyridine (1.26 g), manganese (IV) oxide (12.6 g) and chloroform (12.6 ml) was refluxed for 10 hours. After filtration, organic layer was dried over magnesium sulfate. The solvent was removed and chromatographed on silica gel (12.6 g) with a mixture of hexane and ethyl acetate as an eluent. The fractions containing the objective compound were combined and evaporated in vacuo and recrystallized from a mixture of ethyl acetate and n-hexane to give 3-(3-chloropyridazin-4-yl)-2-phenylpyrazolo[1,5-a]pyridine (0.78 g).
Reaction SMILES: O[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[NH:4][C:5]([S:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[N:6]2.C(N(CC)C1C=CC=CC=1)C.P(Cl)(Cl)([Cl:32])=O>>[Cl:32][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[NH:4][C:5]([S:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[N:6]2
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1ncnc2nc(SCc3ccccc3)[nH]c12
Solvent: CCN(CC)c1ccccc1
Product: Clc1ncnc2nc(SCc3ccccc3)[nH]c12
Reaction time: 0.25 h

Procedure:
6-Hydroxy-8-benzylthiopurine (7.33 g) is added to a mixture of phosphorous oxychloride (70 ml) and N,N-diethylaniline (7.5 ml), and the mixture refluxed for 2 hours to give a dark-red product. The mixture is concentrated under vacuum and the resulting syrup poured slowly with stirring onto ice (400 g). The mixture is allowed to stand for 15 min., then made strongly alkaline with cold concentrated KOH. The mixture is triturated thoroughly to dissolve most of the syrup and acidified to pH 1 by the slow addition of cold concentrated HCl, with excess ice still present.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[CH2:10][CH2:9][CH:8]([CH2:11][CH2:12][Se]C2C=CC=CC=2[N+]([O-])=O)[N:7]1[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[O:5])[CH3:2].N1C=CC=CC=1.OO>C(Cl)Cl>[CH2:1]([O:3][C:4]([C@@H:6]1[CH2:10][CH2:9][CH:8]([CH:11]=[CH2:12])[N:7]1[C:23]([O:25][C:26]([CH3:27])([CH3:29])[CH3:28])=[O:24])=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@@H]1CCC(CC[Se]c2ccccc2[N+](=O)[O-])N1C(=O)OC(C)(C)C
Agent: OO
Solvent: c1ccncc1
Solvent: ClCCl
Product: C=CC1CC[C@@H](C(=O)OCC)N1C(=O)OC(C)(C)C
Reaction time: 8 h
Yield: 95.1 %

Procedure:
A solution of 576 mg of selenyl ether 171 (1.22 mmol) in 15 ml of anhydrous CH2Cl2 was cooled to 0° C., added with 0.4 ml of pyridine and 0.8 ml H2O2 (30%) and stirred overnight. The intensely orange-colored solution was subsequently concentrated and purified using silica gel column chromatography (CH2Cl2) to obtain 312 mg of vinylproline 172 (1.16 mmol, 95%) as a yellowish oil.
Reaction SMILES: [Cl:1][C:2]1[C:7](=[O:8])[N:6]([CH3:9])[CH:5]=[C:4]([N:10]2[CH:17]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:16]3[C:12](=[N:13][N:14](CC4C=CC(OC)=CC=4)[CH:15]=3)[C:11]2=[O:34])[CH:3]=1>C(Cl)Cl.CO>[Cl:1][C:2]1[C:7](=[O:8])[N:6]([CH3:9])[CH:5]=[C:4]([N:10]2[CH:17]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:16]3[C:12](=[N:13][NH:14][CH:15]=3)[C:11]2=[O:34])[CH:3]=1
Reactant: COc1ccc(Cn2cc3c(n2)C(=O)N(c2cc(Cl)c(=O)n(C)c2)C3c2ccc(Cl)cc2)cc1
Solvent: ClCCl
Solvent: CO
Product: Cn1cc(N2C(=O)c3n[nH]cc3C2c2ccc(Cl)cc2)cc(Cl)c1=O

Procedure:
The title compound was prepared in analogy to the procedure described in Example 2 using 5-(5-chloro-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-4-(4-chlorophenyl)-2-(4-methoxybenzyl)-4,5-dihydropyrrolo[3,4-c]pyrazol-6(2H)-one (Step 9.6). tR: 3.39 min (HPLC 1); tR: 0.74 min (LC-MS 2); ESI-MS: 375/377 [M+H]+ (LC-MS 2); Rf=0.30 (CH2Cl2/MeOH 9:1); 1H NMR (400 MHz, DMSO-d6) δ ppm 3.44 (s, 3H) 6.19 (s, 1H) 7.24 (d, J=8.6 Hz, 2H) 7.35 (d, J=8.6 Hz, 2H) 7.77-7.85 (m, 1H) 7.89-7.93 (m, 1H) 7.94-7.97 (m, 1H) 13.70 (br. s, 1H).
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@H:24]([NH:27]C(=O)OC(C)(C)C)[CH2:23]2)=[N:4][CH:5]=[C:6]([C:8](=[O:21])[NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=2)[CH:7]=1.[CH3:35][C:36]1[N:41]=[CH:40][C:39](B(O)O)=[CH:38][CH:37]=1>>[NH2:27][C@H:24]1[CH2:25][CH2:26][N:22]([C:3]2[C:2]([C:39]3[CH:40]=[N:41][C:36]([CH3:35])=[CH:37][CH:38]=3)=[CH:7][C:6]([C:8]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=3)=[O:21])=[CH:5][N:4]=2)[CH2:23]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(c2ncc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cc2Br)C1
Reactant: Cc1ccc(B(O)O)cn1
Product: Cc1ccc(-c2cc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cnc2N2CC[C@H](N)C2)cn1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 93 using (S)-tert-butyl (1-(3-bromo-5-((4-(trifluoromethoxy)phenyl)carbamoyl)pyridin-2-yl)pyrrolidin-3-yl)carbamate (Stage 96.1) and (6-methylpyridin-3-yl)boronic acid. LC-MS (Condition 6) tR=0.79 min, m/z=448.0 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:11]2[CH2:20][C:19]3[C:14](=[N:15][C:16](S(C)=O)=[N:17][CH:18]=3)[NH:13][C:12]2=[O:24])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[CH3:25][N:26]1[CH2:31][CH2:30][N:29]([CH2:32][CH2:33][CH2:34][CH2:35][NH2:36])[CH2:28][CH2:27]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:11]2[CH2:20][C:19]3[C:14](=[N:15][C:16]([NH:36][CH2:35][CH2:34][CH2:33][CH2:32][N:29]4[CH2:28][CH2:27][N:26]([CH3:25])[CH2:31][CH2:30]4)=[N:17][CH:18]=3)[NH:13][C:12]2=[O:24])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1
Reactant: COc1cc(OC)cc(N2Cc3cnc(S(C)=O)nc3NC2=O)c1
Reactant: CN1CCN(CCCCN)CC1
Product: COc1cc(OC)cc(N2Cc3cnc(NCCCCN4CCN(C)CC4)nc3NC2=O)c1
Yield: 31 %

Procedure:
Using the general procedure above, 3-(3,5-dimethoxy-phenyl)-7-methanesulfinyl-3,4-dihydro-pyrimido[4,5-d]pyrimidin-2(1H)-one and 0.1354 g (0.791 mmol) of 4-(4-methyl-piperazin-1-yl)-butylamine were reacted. The residue was chromatographed over silica gel, eluting with ethyl acetate/ethanol/triethylamine (9:2:1 v/v/v) then ethyl acetate/ethanol/triethylamine (9:3:2 v/v/v) to give 0.0401 g (31%) of the title compound: HPLC=99% pure.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[C:8]([C:9]#[N:10])[C:7]([NH2:12])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:13][N:14]([CH3:17])[CH:15]=O>C(Cl)(Cl)Cl>[C:9]([C:8]1[CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[CH:6][C:7]=1[N:12]=[CH:13][N:14]([CH3:17])[CH3:15])#[N:10]
Reactant: CN(C)C=O
Reactant: N#Cc1cc([N+](=O)[O-])ccc1N
Solvent: ClC(Cl)Cl
Product: CN(C)C=Nc1ccc([N+](=O)[O-])cc1C#N
Temperature: 170 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
—Fifteen grams of 5-nitroanthranilonitrile (compound 1, 92 mmol) was added to 25 ml of N,N-dimethylformamide in 200 ml of chloroform and the reaction mixture was heated under reflux for 5 hrs at 170° C. After cooling the reaction mixture at room temperature for 30 min and at 4° C. for 1 hr, the solid residue was washed with diethyl ether to give 19.23 g of compound 2 (yield, 96%). 1H-NMR (300 MHz, d6-DMSO): δ 8.48 (s, 1H), 8.27 (s, 1H), 7.38 (s, 1H), 3.06 (s, 3H), 3.17 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH2:10][C:9](=O)[CH2:8][CH2:7]2.[CH2:13]([NH2:16])[C:14]#[CH:15]>>[Br:1][C:2]1[C:11]2[C:10]3[CH:15]=[CH:14][CH:13]=[N:16][C:9]=3[CH2:8][CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: C#CCN
Reactant: O=C1CCc2cccc(Br)c2C1
Product: Brc1cccc2c1-c1cccnc1CC2
Yield: 49 %

Procedure:
The title compound is prepared from 8-bromo-2-tetralone and propargylamine following a procedure analogous to that described in Step 1 of Intermediates 1 and 2. Yield: 49% of theory; LC (method 1): tR=2.68 min; Mass spectrum (ESI+): m/z=260/262 (Br) [M+H]+.
Reaction SMILES: [OH-].[Na+].[CH2:3]([NH2:6])[C:4]#[CH:5].[Cl:7][C:8]1[CH:9]=[C:10]([S:14](Cl)(=[O:16])=[O:15])[CH:11]=[CH:12][CH:13]=1>O>[CH2:3]([NH:6][S:14]([C:10]1[CH:11]=[CH:12][CH:13]=[C:8]([Cl:7])[CH:9]=1)(=[O:16])=[O:15])[C:4]#[CH:5]
Reactant: C#CCN
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: C#CCNS(=O)(=O)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 95.8 %

Procedure:
Sodium hydroxide (0.60 g, 15 mmol) was dissolved in 10 ml of water and this solution was added to 0.66 g of propargylamine (12 mmol). Under ice-cooling, 2.11 g of 3-chlorobenzenesulfonyl chloride (10 mmol) was added dropwise to the mixture. The reaction temperature was raised again to room temperature and the mixture was stirred for 3 hours. The reaction mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and concentrated to obtain N-propargyl-3-chlorobenzenesulfonamide (2.20 g). NMR spectrum of this product was as follows.
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH3:24])[C:4](=[O:23])[C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13](Br)[CH:14]=3)[O:9][CH:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:7]2)[N:6]=1.[C:25]([C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[CH:31][C:32]=1[F:33])#[N:26]>O1CCOCC1.C([O-])([O-])=O.[Cs+].[Cs+].Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:1][C:2]1[N:3]([CH3:24])[C:4](=[O:23])[C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:29]4[CH:30]=[CH:31][C:32]([F:33])=[C:27]([CH:28]=4)[C:25]#[N:26])[CH:14]=3)[O:9][CH:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:7]2)[N:6]=1
Reactant: CN1C(=O)C2(CC(c3ccccc3)Oc3ccc(Br)cc32)N=C1N
Reactant: N#Cc1cc(B(O)O)ccc1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CN1C(=O)C2(CC(c3ccccc3)Oc3ccc(-c4ccc(F)c(C#N)c4)cc32)N=C1N
Temperature: 120 °C
Yield: 31.6 %

Procedure:
Pd(PPh3)2Cl2 (10 mg, 0.01 mmol) in a 10 mL flask under Ar was treated sequentially with 2′-amino-6-bromo-1′-methyl-2-phenylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (20 mg, 0.052 mmol) in 1,4-dioxane (1 mL), Cs2CO3 (2 N, 0.3 mL) and 3-cyano-4-fluorophenylboronic acid (17 mg, 0.104 mmol). The mixture was heated under Ar at 120° C. under microwave for 30 min. The reaction mixture was concentrated in vacuo to give the residue, which was purified by preparative HPLC twice to give pure 5-(2′-amino-1′-methyl-5′-oxo-2-phenyl-1′,5′-dihydrospiro[chroman-4,4′-imidazole]-6-yl)-2-fluorobenzonitrile (7 mg, 32%). 1H-NMR (MeOD): 2.15 (m, 1H), 2.29 (t, 1H), 3.12 & 3.18 (s, 3H), 5.30 & 5.89 (m, 1H), 7.03 (m, 1H), 7.21 (m, 1H), 7.31-7.50 (m, 6H), 7.85 (m, 2H).
Reaction SMILES: [CH:1]1[N:2]=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.C([Li])CCC.CN(C)[CH:17]=[O:18]>O1CCCC1>[CH:1]1[N:2]=[C:3]([CH:17]=[O:18])[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: CN(C)C=O
Reactant: c1ccn2cncc2c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=Cc1ncc2ccccn12
Temperature: -40 °C
Reaction time: 3.5 h
Yield: 61.6 %

Procedure:
To imidazo[1,5-a]pyridine (2.337 g, 19.78 mmol) in tetrahydrofuran (40 mL) was added n-butyl lithium (2.5 M in hexane, 15.76 mL, 39.4 mmol) at −40° C. The mixture was stirred at −40° C. for 3.5 hours, followed by the addition of dimethylformamide (3.1 mL, 40 mmol). The reaction mixture was stirred at 25° C. overnight and quenched with water. The mixture was then partitioned between dichloromethane (80 mL) and water (15 mL). The organic phase layer was dried with anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by chromatography eluting with 0-50% ethyl acetate/dichloromethane to give the title compound (1.78 g, 62% yield).