Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[S:8](=[O:13])(=[O:12])[CH2:7][CH2:6][C:5]2=NNC(N)=S.S1C2C(=CC=CC=2)C(=[O:29])CC1.NNC(N)=S>CC1C=CC(S(O)(=O)=O)=CC=1.CO>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[S:8](=[O:13])(=[O:12])[CH2:7][CH2:6][C:5]2=[O:29]
Reactant: O=C1CCSc2ccccc21
Reactant: NC(=S)NN=C1CCS(=O)(=O)c2ccc(Br)cc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: NNC(N)=S
Solvent: CO
Product: O=C1CCS(=O)(=O)c2ccc(Br)cc21
Yield: 33 %

Procedure:
6-Bromo-1,1-dioxo-1-thiochroman-4-one thiosemicarbazone (23) Into a round bottom flask containing 0.198 g of the appropriate thiochroman-4-one (0.147 g, 0.534 mmol), 10 mL of anhydrous methanol were added and the solution was refluxed for about 15 minutes before adding thiosemicarbazide (0.0598 g, 0.657 mmol) and 1.4 mg of TsOH. After the reaction mixture was refluxed under nitrogen atmosphere for 10 h, a solid was formed which was filtered and, then purified by column chromatography (30% EtOAc/70% hex). 0.0618 g (0.178 mmol) of the product was obtained in a 33% yield.
Reaction SMILES: [OH-].[Na+].C([O:5][C:6](=[O:20])[CH2:7][CH2:8][C:9]1([CH3:19])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][CH2:11][CH2:10]1)C>O.C(O)C>[CH3:19][C:9]1([CH2:8][CH2:7][C:6]([OH:20])=[O:5])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][CH2:11][CH2:10]1
Reactant: CCOC(=O)CCC1(C)CCCc2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC1(CCC(=O)O)CCCc2ccccc21
Reaction time: 2 h

Procedure:
A solution of 14 g NaOH in 60 ml of water was added to a solution of 21 g of 5 in 600 ml ethanol. The mixture was stirred for 2 hours. The bulk of the ethanol was then evaporated and the residue poured into 1 liter of water. The mixture was acidified with 2N HCl and the product extracted with ether. The organic layer was dried and evaporated. This yielded 17.5 g of carboxylic acid 6 in the form of an oil; Rf =0.47 (toluene/ethyl acetate/ethanol/acetic acid 8/2/1/0 1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][NH:21][CH:22](C(OC(C)(C)C)=O)[CH2:23][CH3:24])=[CH:15][CH:14]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:12][C:13]2[CH:14]=[CH:15][C:16]([CH2:19][CH2:20][NH:21][CH2:22][CH2:23][CH3:24])=[CH:17][CH:18]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: CCC(NCCc1ccc(N)cc1)C(=O)OC(C)(C)C
Product: CCCNCCc1ccc(NS(=O)(=O)c2ccc(Cl)cc2)cc1

Procedure:
Using procedure 4, 4-chlorobenzenesulfonyl chloride was added to 2-(4-aminophenyl)ethyl-1-(tert-butoxycarbonyl)propylamine to give the title compound as a solid, m.p. 137-140° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([Cl:18])[CH:14]=3)[C:9]2=[O:19])[CH:5]=[N:6][CH:7]=1.[N:20]([CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1)=[C:21]=[O:22]>C(Cl)Cl>[Cl:18][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:19])[N:8]([C:4]1[CH:3]=[C:2]([NH:1][C:21]([NH:20][CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)=[O:22])[CH:7]=[N:6][CH:5]=1)[CH2:17][CH2:16]2
Reactant: O=C=NC1CCCCC1
Reactant: Nc1cncc(N2CCc3cc(Cl)ccc3C2=O)c1
Solvent: ClCCl
Product: O=C(Nc1cncc(N2CCc3cc(Cl)ccc3C2=O)c1)NC1CCCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 20.1 %

Procedure:
2-(5-Amino-pyridin-3-yl)-6-chloro-3,4-dihydro-2H-isoquinolin-1-one (27.3 mg, 0.1 mmol, example 17) was added to a solution of isocyanato-cyclohexane (12.5 mg, 0.1 mmol) in DCM (2 mL). The reaction mixture was stirred at RT for 2 hours. After evaporation of solvent under reduced pressure, a crude product was obtained which was purified by prep-HPLC to give title compound as a white solid (8.0 mg, 20%). MS: 399.2 (M+H+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][N:13]([CH3:15])[CH3:14].[CH3:16][N:17](C)C=O.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>O.[C-]#N.[Zn+2].[C-]#N.[Zn].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:14][N:13]([CH3:15])[CH2:12][CH2:11][C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([C:16]#[N:17])[CH:3]=2)[NH:7][CH:6]=1
Reactant: CN(C)CCc1c[nH]c2ccc(Br)cc12
Reactant: CN(C)C=O
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Product: CN(C)CCc1c[nH]c2ccc(C#N)cc12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
[2-(5-Bromo-1H-indol-3-yl)-ethyl]-dimethylamine (16) (500.0 mg, 1.872 mmol) (U.S. Pat. No. 5,998,438) was placed in an argon purged oven dried flask fitted with a stirbar. Zinc cyanide (395.0 mg, 3.368 mmol, 1.8 equivalents); Zinc powder (14.7 mg. 0.225 mmol, 0.12 equivalents) and tris(dibenzylideneacetone)dipalladium(0) (42.9 mg, 0.0468 mmol, 0.025 equivalents) were added sequentially followed by anhydrous N,N-dimethylformamide (15 mL). A solution of tri-t-butylphosphine in hexanes (10 wt %, 189.0 mg, 280 μl, 0.05 equivalents) was added and the mixture was stirred for 15 minutes at room temperature and then heated in an oil bath at 60° C. for 30 minutes. After cooling to room temperature the mixture was transferred into a separatory funnel and diluted with distilled water (15 mL). The aqueous phase was extracted with ethyl acetate (3×30 mL). The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated. The residue was purified via silica gel column chromatography (10% 2M NH3 in methanol/90% dichloromethane) to provide 3-(2-(dimethylamino)ethyl)-1H-indole-5-carbonitrile (57) as a yellow residue (150 mg, 37.6% yield). 1H NMR (DMSO) δ: 2.21 (s, 6H), 2.54 (m, 2 H), 2.84 (t, 2H), 7.36-7.41 (m, 2H), 7.49 (d, 1H), 8.07 (s, 1H), 11.38 (br s, 1H).
Reaction SMILES: [CH2:1]([N:3]([CH2:25][CH3:26])[CH2:4][CH2:5][NH:6][C:7]1[C:20]2[C:19](=[O:21])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[S:12][C:11]=2[C:10]([CH2:22][NH:23][CH3:24])=[CH:9][CH:8]=1)[CH3:2].C(N(CC)CC)C.[CH2:34]([S:36](Cl)(=[O:38])=[O:37])[CH3:35]>C(Cl)Cl>[CH2:25]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][NH:6][C:7]1[C:20]2[C:19](=[O:21])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[S:12][C:11]=2[C:10]([CH2:22][N:23]([CH3:24])[S:36]([CH2:34][CH3:35])(=[O:38])=[O:37])=[CH:9][CH:8]=1)[CH3:26]
Reactant: CCN(CC)CCNc1ccc(CNC)c2sc3ccccc3c(=O)c12
Reactant: CCS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCN(CC)CCNc1ccc(CN(C)S(=O)(=O)CC)c2sc3ccccc3c(=O)c12
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 95.9 %

Procedure:
A solution of 2.03 g (5.49 mmol) of 1-[[2-(diethylamino)ethyl]amino]-4-[(methylamino)methyl]thioxanthen-9-one (prepared by the method described in Example 5) and triethylamine in 45 mL of methylene chloride was cooled to 0° C. and treated with ethanesulfonyl chloride (0.74 g, 5.76 mmol). After 15 min at 0° C., the reaction mixture was stirred at room temperature for 72 h. The mixture was concentrated in vacuo, the residue dissolved in chloroform and purified by passing through a pad of silica gel (chloroform; then 1% triethylamine/chloroform) affording 2.43 g (96%) of N-[[1-[[2-(diethylamino)ethyl]amino]-9-oxothioxanthen-4-yl]methyl]-N-methylethanesulfonamide. The sulfonamide was recrystallized from ethyl acetate and treated with methanesulfonic acid in isopropanol to afford the product as the methanesulfonate salt, m.p. 159°-161° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.Br[CH:14]([CH3:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>C(O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH2:8][CH2:9][N:10]([CH:14]([CH3:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:11][CH2:12]1
Reactant: CCOC(=O)C(C)Br
Reactant: c1ccc(N2CCNCC2)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C)N1CCN(c2ccccn2)CC1

Procedure:
A mixture of 1-(2-pyridyl)piperazine (15.0 grams; 0.092 moles), ethyl 2-bromopropionate (16.7 grams; 0.092 moles) and potassium carbonate (12.7 grams; 0.092 moles) in absolute ethanol (150 cc) is boiled under reflux for about three hours. After cooling, the mixture is filtered, the filtrate is allowed to evaporate and finally the residue is distilled under vacuo, giving the product, b.p. 130°-132° C. (0.01 mm); Rf=0.37 (from ethyl acetate); IR (neat) νmax: 1730, 1600, 1490, 1440, 1320, 1250, 1160, 985, 780 cm-1.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:15]3=[N:17][C@H:18]([CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH2:19][N:14]3[C:13](=[O:27])[NH:12][C:11]=2[N:10]=[C:9]1[CH:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:39][O:40][C:41](=[O:44])[CH2:42]Br>CN(C)C=O>[CH2:1]([N:8]1[C:16]2[C:15]3=[N:17][C@H:18]([CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH2:19][N:14]3[C:13](=[O:27])[N:12]([CH2:42][C:41]([O:40][CH3:39])=[O:44])[C:11]=2[N:10]=[C:9]1[CH:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1Nc2nc(C3CCCC3)n(Cc3ccccc3)c2C2=N[C@H](Cc3ccccc3)CN12
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)CN1C(=O)N2C[C@@H](Cc3ccccc3)N=C2c2c1nc(C1CCCC1)n2Cc1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 74.4 %

Procedure:
Compound 66 (1.87 g, 4.21 mmol) obtained in Example 66 was dissolved in 1,4-dioxane (30 mL), to the solution was added 2 mol/L aqueous sodium hydroxide (15 mL), and the mixture was stirred with heating at 70° C. for 3 hours. The reaction solution was concentrated under reduced pressure, and then the residue was neutralized by addition of concentrated hydrochloric acid. The deposited crystals were collected by filtration, washed with water and dried to obtain (R)-1,8-dibenzyl-2-cyclopentyl-7,8-dihydro-1H-imidazo[2,1-i]purin-5(4H)-one (Compound 77a, 1.61 g, 90%). Compound 77a (500 mg, 1.08 mmol) was dissolved in N,N-dimethylformamide (5 mL), to the solution were added potassium carbonate (192 mg, 1.41 mmol, 1.2 equivalents) and bromoacetic acid methyl ester (140 μL, 1.41 mmol, 1.2 equivalents), and the mixture was stirred at room temperature for 12 hours. The reaction solution was concentrated under reduced pressure, water was added to the concentrate, the mixture was extracted with chloroform, and the extract was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=90:10) to obtain (R)-1,8-dibenzyl-2-cyclopentyl-7,8-dihydro-4-methoxycarbonylmethyl-1H-imidazo[2,1-i]purin-5(4H)-one (Compound 77b, 400 mg, 69%). From Compound 77b (850 mg, 1.71 mmol), (R)-8-benzyl-2-cyclopentyl-7,8-dihydro-4-methoxycarbonylmethyl-1H-imidazo[2,1-i]purin-5(4H)-one (Compound 77c, 220 mg, 29%) was obtained in a manner similar to the method by which Compound 40 was obtained from Adduct 40a in Example 40. Compound 77c (200 mg, 0.49 mmol) was dissolved in a mixed solvent of tetrahydrofuran (1 mL) and water (1 mL), to the solution was added lithium hydroxide hydrate (0.04 g, 0.98 mmol), and the mixture was stirred at room temperature for 2.5 hours. The reaction mixture was adjusted to pH 3 with 1 mol/L hydrochloric acid, and the resulting solid was washed with ethanol and collected by filtration to obtain the title compound (180 mg, 93%).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[C:7]([O:20][CH3:21])=[CH:8][C:9]2[O:14][C:13](=[O:15])[C:12]3[CH2:16][CH2:17][CH2:18][C:11]=3[C:10]=2[CH:19]=1.[N:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1.C(Cl)(Cl)Cl.C([O-])(=O)/C=C/C([O-])=O>CC(C)=O.C(O)C>[CH3:21][O:20][C:7]1[C:6]([O:5][CH2:4][CH2:3][CH2:2][N:31]2[CH2:32][CH2:33][N:28]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][N:22]=3)[CH2:29][CH2:30]2)=[CH:19][C:10]2[C:11]3[CH2:18][CH2:17][CH2:16][C:12]=3[C:13](=[O:15])[O:14][C:9]=2[CH:8]=1
Reactant: c1ccc(N2CCNCC2)nc1
Reactant: COc1cc2oc(=O)c3c(c2cc1OCCCCl)CCC3
Agent: O=C([O-])/C=C/C(=O)[O-]
Solvent: CC(C)=O
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: COc1cc2oc(=O)c3c(c2cc1OCCCN1CCN(c2ccccn2)CC1)CCC3
Yield: 68 %

Procedure:
Method B (75 h at 45° C.); starting materials: 8-(3-chloropropoxy)-2,3-dihydro-7-methoxy-cyclopenta[c][1]benzopyran-4(1H)-one (example 83) and 1-(2-pyridinyl)piperazine; yield 68%; fusion point 152°-154° C. (from chloroform and ethanol). Fumarate: method E; yield 96%; fusion point 205°-207° C. (from acetone).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][NH:8][C:9](=[O:31])[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[CH:12][CH:11]=1.[C:32](OC(=O)C)(=[O:34])[CH3:33].N1C=CC=CC=1>CN(C)C1C=CN=CC=1.O>[C:32]([N:8]([CH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)[C:9](=[O:31])[C:10]1[CH:11]=[CH:12][C:13]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[CH:14][CH:15]=1)(=[O:34])[CH3:33]
Reactant: CC(=O)OC(C)=O
Reactant: CCCCCCCCCCCCCCOc1ccc(C(=O)NCc2ccccn2)cc1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCOc1ccc(C(=O)N(Cc2ccccn2)C(C)=O)cc1

Procedure:
A mixture of 2.0 g of product from Example 4, 8.9 ml acetic anhydride, 0.0863 g 4-dimethylaminopyridine and 30 ml pyridine is heated at reflux temperature for 23 hours, cooled, poured into 150 ml of water and extracted with methylene chloride. The organic layer is washed with saturated sodium chloride, dried and concentrated in vacuo. The residue is purified by column chromatogaphy (silica ge1:15-20% ethyl acetate/hexane) to give 1.4 g of the desired product as light yellow crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:8][C:3]=1[C:4](OC)=[O:5].[CH:22]([NH2:24])=O.C(O)(=O)C>O>[CH2:15]([O:14][C:9]1[CH:8]=[C:3]2[C:2](=[CH:11][C:10]=1[O:12][CH3:13])[N:1]=[CH:22][NH:24][C:4]2=[O:5])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: NC=O
Reactant: COC(=O)c1cc(OCc2ccccc2)c(OC)cc1N
Solvent: CC(=O)O
Solvent: O
Product: COc1cc2nc[nH]c(=O)c2cc1OCc1ccccc1
Temperature: 130 °C

Procedure:
A mixture of methyl 2-amino-5-(benzyloxy)-4-methoxybenzoate (7.36 g, 0.025 mol), formamide (25 mL) and acetic acid (6.25 mL) was heated at 130° C. for 24 hr. After letting cooling down to room temperature, water was added and the resulting solid was filtered and washed with plenty of cold water. The solid was dried under vacuum at 120° C. for 3 hr to yield 6-(benzyloxy)-7-methoxyquinazolin-4(3H)-one. Yield: 7.45 g (100%). 1HNMR (DMSO-d6): δ 12.15 (1H, s), 8.05 (1H, s), 7.66 (1H, s), 7.44 (5H, m), 7.23 (1H, s), 5.28 (2H, s), 3.92 (3H, s). LC-MS (ESI) m/z 207 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[N:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1.[C:23]1([CH2:29][C:30]([N:32]=[C:33]=[S:34])=[O:31])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CCOC(C)=O.CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[N:21]=[CH:20][C:19]([NH:22][C:33]([NH:32][C:30](=[O:31])[CH2:29][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[S:34])=[CH:18][CH:17]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cn3)c2cc1OC
Reactant: O=C(Cc1ccccc1)N=C=S
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)Cc4ccccc4)cn3)c2cc1OC
Reaction time: 12 h
Yield: 298.7 %

Procedure:
To a round bottom flask equipped with a magnetic stir bar was added 6-(6,7-dimethoxy-quinolin-4-yloxy)-pyridin-3-ylamine (85 mg, 0.0285 mmol, 1.0 eq.), and Phenyl-acetyl isothiocyanate (256 mg, 1.44 mmol, 5.0 eq.) dissolved in EtOAc/MeOH 50:50 (2 mL). The reaction mixture was sittred at room temperature for 12 hours, and the solvent was evaporated via rotary evaporation. Purification was done on Biotage with solvent system 95% EtOAc, 4% TEA and 1% MeOH. The combined pure fractions were concentrated and dried under vacuum overnight to yield 1-[6-(6,7-dimethoxy-quinolin-4-yloxy)-pyridin-3-yl]-3-phenylacetyl-thiourea as a light yellow solid (40.4 mg, 29.7%). 1H NMR (400 MHz, CDCl3): 8.65 (d, 1H), 8.33 (d, 1H), 8.27 (dd, 1H), 7.35 (m, 7H), 7.15 (d, 1H), 6.92 (d, 1H), 4.05 (s, 3H), 3.99 (s, 3H), 3.76 (s, 2H); MS (EI) for C25H22N4O4S: 475 (M+H+).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[C:8]([C:15]2[C:24]3[C:19](=[CH:20][C:21]([OH:25])=[CH:22][CH:23]=3)[N:18]=[CH:17][CH:16]=2)=[C:9]2[CH2:14][CH2:13][CH2:12][N:10]2[N:11]=1.Br[CH2:27][CH2:28][CH2:29][N:30]1[C:34](=[O:35])[C:33]2=[CH:36][CH:37]=[CH:38][CH:39]=[C:32]2[C:31]1=[O:40].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[C:8]([C:15]2[C:24]3[C:19](=[CH:20][C:21]([O:25][CH2:27][CH2:28][CH2:29][N:30]4[C:34](=[O:35])[C:33]5[C:32](=[CH:39][CH:38]=[CH:37][CH:36]=5)[C:31]4=[O:40])=[CH:22][CH:23]=3)[N:18]=[CH:17][CH:16]=2)=[C:9]2[CH2:14][CH2:13][CH2:12][N:10]2[N:11]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Reactant: Oc1ccc2c(-c3c(-c4ccccn4)nn4c3CCC4)ccnc2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1c2ccccc2C(=O)N1CCCOc1ccc2c(-c3c(-c4ccccn4)nn4c3CCC4)ccnc2c1
Temperature: 60 °C

Procedure:
4-(2-Pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinolin-7-ol (0.100 g, 0.305 mmol), N-(3-bromopropyl)-phthalimide (0.163 g, 0.609 mmol, 2.0 equiv) and cesium carbonate (0.248 g, 0.761 mmol, 2.50 equiv) are combined in N,N-dimethylformamide (1.0 mL) and the reaction is heated at 60° C. for 48 hours. The reaction is diluted with water (1 mL) and the reaction mixture is partitioned between ethyl acetate (6 mL) and water (5 mL). The organic layer is removed and placed on a 10 g SCX resin column. The resin is washed sequentially with dichloromethane (20 mL) and 4:1 dichloromethane/2 N ammonia in methanol (125 mL). The latter fractions are evaporated to dryness and the residue is subjected to chromatography on silica gel (20 g) (9:1 ethyl acetate: methanol (2 N ammonia)) to yield the desired product as a tan solid, 0.117 g (75%).
Reaction SMILES: Cl[C:2]1[C:3]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:21])([F:20])[F:19])(=[O:11])=[O:10])=[N:4][CH:5]=[CH:6][N:7]=1.[CH2:22]([OH:25])[C:23]#[CH:24].CC(O[K])=O>CN(C=O)C.[Cu]I.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>[OH:25][CH2:22][C:23]#[C:24][C:2]1[C:3]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:21])([F:20])[F:19])(=[O:11])=[O:10])=[N:4][CH:5]=[CH:6][N:7]=1
Reactant: C#CCO
Reactant: O=S(=O)(Nc1nccnc1Cl)c1ccccc1C(F)(F)F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: CC(=O)O[K]
Solvent: CN(C)C=O
Product: O=S(=O)(Nc1nccnc1C#CCO)c1ccccc1C(F)(F)F
Temperature: 100 °C
Yield: 50 %

Procedure:
N-(3-chloropyrazin-2-yl)-2-(trifluoromethyl)benzenesulfonamide (1.35 g; 4.0 mmol; 1.00 eq.) and 2-propyn-1-ol (336 mg 6.0 mmol; 1.5 eq.) were dissolved in 10 mL of DMF under nitrogen atmosphere. To the reaction mixture was added CH3COOK (588 mg; 6.0 mmol; 1.5 eq.) CuI (40 mg; 0.2 mmol; 0.05 eq.) and Pd(PPh3)2Cl2 (28 mg; 0.04 mmol) under nitrogen. The reaction mixture was then heated at 100° C. under nitrogen for 2 hours. After removal of the solvent by distillation in vacuo, the residue was triturated with water (40 mL) and extracted with diethyl ether (3×30 mL). The organic layer was dried over MgSO4 and evaporated down. The crude product was purified by silica gel column chromatography using a mixture of hexane and AcOEt to give pure N-[3-(3-hydroxyprop-1-yn-1-yl)pyrazin-2-yl]-2-(trifluoromethyl)benzenesulfonamide as a yellowish solid (702 mg, 50% yield, 98% HPLC purity).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=O)[CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=2)[CH2:15][CH2:14]1.Cl.[CH3:33][O:34][C:35]1[CH:40]=[CH:39][C:38]([NH:41]N)=[CH:37][CH:36]=1>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:41][C:38]2[C:39]([C:9]=1[CH2:10][CH2:11][CH2:12][N:13]1[CH2:14][CH2:15][CH:16]([C:19]3[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=3)[CH2:17][CH2:18]1)=[CH:40][C:35]([O:34][CH3:33])=[CH:36][CH:37]=2
Reactant: COc1ccc(NN)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3ccccc3F)CC2)c1
Agent: Cl
Product: COc1ccc2[nH]c(-c3ccccc3F)c(CCCN3CCC(c4cccc(NC(=O)C(C)C)c4)CC3)c2c1

Procedure:
Prepared by Procedure E and Scheme M using N-(3-{1-[5-(2-fluorophenyl)-5-oxopentyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 4-methoxyphenylhydrazine hydrochloride: ESMS m/e: 528.2 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[NH:13][C:12](=[O:14])[C:11]3=[C:15]([CH2:23][CH3:24])[N:16]=[C:17]([CH:18]4[CH2:22][CH2:21][CH2:20][CH2:19]4)[N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH:25](=O)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[CH2:25]([NH:1][C:2]1[CH:3]=[C:4]([C:8]2[NH:13][C:12](=[O:14])[C:11]3=[C:15]([CH2:23][CH3:24])[N:16]=[C:17]([CH:18]4[CH2:22][CH2:21][CH2:20][CH2:19]4)[N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CCc1nc(C2CCCC2)n2nc(-c3cccc(N)c3)[nH]c(=O)c12
Reactant: O=Cc1ccccc1
Product: CCc1nc(C2CCCC2)n2nc(-c3cccc(NCc4ccccc4)c3)[nH]c(=O)c12

Procedure:
In analogy to the procedure for Example 8, 100 mg (0.31 mmol) 2-(3-aminophenyl)-7-cyclopentyl-5-ethylimidazo[5,1-f][1,2,4]triazin-4(3H)-one (Example 29), 52 mg (0.49 mmol) benzaldehyde and proportionate amounts of the other reagents are used.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])(=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[I-].[K+].Cl[CH2:24][C:25](=[O:27])[CH3:26]>CC(C)=O>[CH2:19]([O:18][C:16](=[O:17])[CH:15]([C:7](=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:24][C:25](=[O:27])[CH3:26])[CH3:20]
Reactant: CCOC(=O)CC(=O)c1ccccc1
Reactant: CC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)C(CC(C)=O)C(=O)c1ccccc1

Procedure:
Potassium carbonate (200 mmol, 27.6 g) was added to a solution of ethyl benzoylacetate (10 mmol, 19.2 g) and potassium iodide (20 mmol, 3.3 g) in dry acetone (100 mL). The resulting solution was refluxed, and chloroacetone (110 mmol, 10.7 g) was added dropwise. Analysis of the reaction mixture by GC/MS indicated the presence of Intermediate 2. Solid material was filtered from the reaction mixture, then washed with 200 mL acetone. The resulting filtrate was concentrated under vacuum, redissolved in ether, then washed three times with water (100 mL). The organic layer was separated from the aqueous layer, and dried over MgSO4. The solids were separated, and the organic solvents removed under vacuum to yield a yellow/orange oil. The crude oil was purified by Kugelrohr distillation (b.p. 175-185 at 0.65 Torr.).