Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=1[NH2:15])(C)(C)C.CCN(C(C)C)C(C)C.Cl[C:27]([O:29][CH2:30][CH:31]=[CH2:32])=[O:28]>C1COCC1>[CH2:30]([O:29][C:27](=[O:28])[NH:15][C:9]1[CH:10]=[C:11]([F:14])[CH:12]=[CH:13][C:8]=1[NH2:7])[CH:31]=[CH2:32]
Reactant: C=CCOC(=O)Cl
Reactant: CC(C)(C)OC(=O)Nc1ccc(F)cc1N
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: C=CCOC(=O)Nc1cc(F)ccc1N
Temperature: 0 °C
Reaction time: 16 h

Procedure:
(2-Amino-4-fluoro-phenyl)-carbamic acid tert-butyl ester (5.0 g, 22 mmol, 1 equiv.) was added to a solution of DIPEA (3.62 ml, 22 mmol, 1 equiv.) in THF (80 ml). The mixture was cooled to 0° C. and allyl chloroformate (2.36 ml, 22 mmol, 1 equiv.) in THF added. The mixture was stirred at room temperature for 16 hours. The solvent was evaporated and the crude extracted from ethylacetate and aq. NaHCO3. The residue was taken up in DCM and trifluoroacetic acid (1:1) for 2 hours. The product was obtained after evaporation of the organic solvents.
Reaction SMILES: Cl.Cl.COC1C=CC(N2CCNCC2)=CC=1.C(Cl)(=O)CC(C)C.[F:24][C:25]1[CH:30]=[C:29]([O:31][CH3:32])[C:28]([F:33])=[CH:27][C:26]=1[N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1.[Cl:40][C:41]1[CH:46]=[CH:45][C:44]([S:47](Cl)(=[O:49])=[O:48])=[CH:43][CH:42]=1>>[Cl:40][C:41]1[CH:46]=[CH:45][C:44]([S:47]([N:37]2[CH2:38][CH2:39][N:34]([C:26]3[CH:27]=[C:28]([F:33])[C:29]([O:31][CH3:32])=[CH:30][C:25]=3[F:24])[CH2:35][CH2:36]2)(=[O:49])=[O:48])=[CH:43][CH:42]=1
Reactant: COc1cc(F)c(N2CCNCC2)cc1F
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Agent: CC(C)CC(=O)Cl
Agent: COc1ccc(N2CCNCC2)cc1
Agent: Cl
Product: COc1cc(F)c(N2CCN(S(=O)(=O)c3ccc(Cl)cc3)CC2)cc1F
Yield: 91.9 %

Procedure:
Production Example 3 was repeated except that 1-(4-methoxyphenyl)piperazine dihydrochloride and isovaleryl chloride were replaced with 1-(2,5-difluoro-4-methoxyphenyl)-piperazine (500 mg) and 4-chlorobenzenesulfonyl chloride (694 mg), respectively, to provide 1-(4-chlorobenzenesulfonyl)-4-(2,5-difluoro-4-methoxyphenyl)piperazine (811 mg).
Reaction SMILES: Br[C:2]1([CH2:15][N:16]2[CH:24]=[C:22]([CH3:23])[C:20](=[O:21])[NH:19][C:17]2=[O:18])[CH2:4][C:3]1([CH2:10][O:11]C(=O)C)[CH2:5][O:6]C(=O)C.C(=O)([O-])[O-].[K+].[K+].CO.O>CN(C)C=O>[OH:6][CH2:5][C:3]1([CH2:10][OH:11])[CH2:4]/[C:2]/1=[CH:15]/[N:16]1[CH:24]=[C:22]([CH3:23])[C:20](=[O:21])[NH:19][C:17]1=[O:18].[OH:6][CH2:5][C:3]1([CH2:10][OH:11])[CH2:4]/[C:2]/1=[CH:15]\[N:16]1[CH:24]=[C:22]([CH3:23])[C:20](=[O:21])[NH:19][C:17]1=[O:18]
Reactant: CC(=O)OCC1(COC(C)=O)CC1(Br)Cn1cc(C)c(=O)[nH]c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cn(/C=C2/CC2(CO)CO)c(=O)[nH]c1=O
Product: Cc1cn(/C=C2\CC2(CO)CO)c(=O)[nH]c1=O
Temperature: 100 °C
Reaction time: 3 h
Yield: 36 %
Yield: 38 %

Procedure:
A mixture of compound 18 (0.60 g, 1.49 mmol) from Example 17 and flame-dried potassium carbonate (616 mg, 4.47 mmol) in N,N-dimethylformamide (50 mL) was stirred at 100° C. under nitrogen for 3 h. After cooling, methanol-water (9:1, 10 mL) was added with stirring which was continued at room temperature for 1 h. The insoluble portion was filtered off and it was washed with N,N-dimethylformamide. The filtrate was evaporated in vacuo and the residue was chromatographed on a silica gel column which was first eluted with ethyl acetate and then dichloromethane-methanol (20:1) to give the Z-isomer 1f (70 mg, 38%) and E-isomer 2f (65 mg, 36%) as white solids.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH:4]([OH:9])[C:5]([O:7][CH3:8])=[O:6].C(N(CC)CC)C.[N+:17]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[S:26](Cl)(=[O:28])=[O:27])([O-:19])=[O:18].O>CN(C)C=O>[OH:9][CH:4]([CH2:3][NH:2][S:26]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[N+:17]([O-:19])=[O:18])(=[O:27])=[O:28])[C:5]([O:7][CH3:8])=[O:6]
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: COC(=O)C(O)CN
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)C(O)CNS(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 2 h
Yield: 72.8 %

Procedure:
To a solution of methyl 3-amino-2-hydroxypropanoate hydrochloride (0.8 g) in N,N-dimethylformamide (10 mL) were added triethylamine (1.1 mL) and 2-nitrobenzenesulfonyl chloride (1.1 g) at 0° C., and the mixture was stirred at 0° C. for 2 hr and then at room temperature overnight. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give the title compound (1.1 g, 89%) as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:14]=[C:13]2[C:8]([C@H:9]([NH:21][CH2:22][C:23]3[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[C:25]([C:33]([F:36])([F:35])[F:34])[CH:24]=3)[CH2:10][C@H:11]([CH3:20])[N:12]2[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:7][C:6]=1[O:37][CH3:38])=[O:4].N1C=CC=CC=1.Cl[C:46]([O:48][CH3:49])=[O:47]>ClCCl>[CH3:1][O:2][C:3]([C:5]1[CH:14]=[C:13]2[C:8]([C@H:9]([N:21]([CH2:22][C:23]3[CH:24]=[C:25]([C:33]([F:34])([F:36])[F:35])[CH:26]=[C:27]([C:29]([F:30])([F:31])[F:32])[CH:28]=3)[C:46]([O:48][CH3:49])=[O:47])[CH2:10][C@H:11]([CH3:20])[N:12]2[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:7][C:6]=1[O:37][CH3:38])=[O:4]
Reactant: COC(=O)Cl
Reactant: CCOC(=O)N1c2cc(C(=O)OC)c(OC)cc2[C@H](NCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C[C@@H]1C
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)N1c2cc(C(=O)OC)c(OC)cc2[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C(=O)OC)C[C@@H]1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 135.1 %

Procedure:
cis-4-(3,5-Bis-trifluoromethyl-benzylamino)-6-methoxy-2-methyl-3,4-dihydro-2H-quinoline-1,7-dicarboxylic acid 1-ethyl ester 7-methyl ester (335 mg, 0.61 mmol) was dissolved in anhydrous dichloromethane (5 mL), and pyridine (0.20 mL, 2.5 mmol) was added. Methyl chloroformate (0.057 mL, 0.73 mmol) was slowly added and the reaction was stirred at room temperature for 3 h. Additional aliquots of reagents were added to drive the reaction to completion. The reaction mixture was then diluted with 35 ml dichloromethane, washed with an aqueous 1N HCl solution (2×7 mL) and with a saturated sodium bicarbonate solution (2×7 mL) saturated NaHCO3. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by silica gel chromatography using 20% acetone/hexanes as eluent afforded the title product (0.50 g, 90%). MS m/z 607 (M++1); 1H NMR (CDCl3) δ 1.5-1.75 (br, 1H), 6.42 (s, 1H).
Reaction SMILES: [CH:1]1[C:10]2[CH2:9][CH2:8][C:7]([C:11]([OH:13])=O)=[CH:6][C:5]=2[CH:4]=[CH:3][N:2]=1.[NH:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16](CC[NH-])=[CH:15]1>>[CH2:15]([NH:14][C:11]([C:7]1[CH2:8][CH2:9][C:10]2[CH:1]=[N:2][CH:3]=[CH:4][C:5]=2[CH:6]=1)=[O:13])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(O)C1=Cc2ccncc2CC1
Reactant: [NH-]CCc1c[nH]c2ccccc12
Product: O=C(NCCc1ccccc1)C1=Cc2ccncc2CC1

Procedure:
Compound #68 7,8-Dihydro-isoquinoline-6-carboxylic acid [2-(1H-indol-3-yl)-ethyl-amide; and
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][N:5]2[C:10]([C:11]=1[CH3:12])=[C:9]([CH:13]1[CH2:15][CH2:14]1)[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6]2=[O:20].[Cl:21][C:22]1[CH:28]=[C:27](B2OC(C)(C)C(C)(C)O2)[CH:26]=[CH:25][C:23]=1[NH2:24]>>[NH2:24][C:23]1[CH:25]=[CH:26][C:27]([C:2]2[CH:3]=[CH:4][N:5]3[C:10]([C:11]=2[CH3:12])=[C:9]([CH:13]2[CH2:15][CH2:14]2)[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6]3=[O:20])=[CH:28][C:22]=1[Cl:21]
Reactant: CC1(C)OB(c2ccc(N)c(Cl)c2)OC1(C)C
Reactant: COC(=O)c1cc(C2CC2)c2c(C)c(Cl)ccn2c1=O
Product: COC(=O)c1cc(C2CC2)c2c(C)c(-c3ccc(N)c(Cl)c3)ccn2c1=O

Procedure:
Methyl 8-(4-amino-3-chloro-phenyl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate was prepared according to General Procedure A from methyl 8-chloro-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (76 mg, 0.26 mmol) and 2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-aniline (78 mg, 0.31 mmol). Purification by flash silica column chromatography (DCM:MeOH) (1:0 to 94:6) afforded the title compound 24 as a yellow solid (63 mg, 62%).
Reaction SMILES: [N:1]1([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:6][CH2:5][C:4]2([C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:9][NH:8][CH2:7]2)[CH2:3][CH2:2]1.[C:23](Cl)(=[O:25])[CH3:24].C(N(CC)CC)C>ClCCl>[C:23]([N:8]1[CH2:7][C:4]2([CH2:3][CH2:2][N:1]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:6][CH2:5]2)[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9]1)(=[O:25])[CH3:24]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CNCc1ccccc12
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1Cc2ccccc2C2(CCN(C(=O)OC(C)(C)C)CC2)C1
Yield: 126.3 %

Procedure:
tert-Butyl 2,3-dihydro-1H-spiro[isoquinoline-4,4′-piperidine]-1′-carboxylate 6a (2.128 g, 6.28 mmol) was dissolved in anhydrous dichloromethane (30 mL), cooled in an ice-H2O bath and treated dropwise with a solution of acetyl chloride (518 mg, 6.59 mmol) in anhydrous dichloromethane (5 mL). The reaction was then treated dropwise with a solution of triethylamine (1.335 g, 13.2 mmol) in anhydrous dichloromethane (5 mL). The reaction was stirred in the ice-H2O bath for 15 minutes, then diluted with dichloromethane (100 mL), washed with H2O, saturated NaHCO3 (3×), saturated brine, dried (Na2SO4) and filtered. The filtrate was concentrated under reduced pressure to afford crude tert-butyl 2-acetyl-2,3-dihydro-1H-spiro[isoquinoline-4,4′-piperidine]-1′-carboxylate 6b as a colorless oil (2.732 g, quantitative yield). LC/MS m/z [M+H]+ 345.2 retention time 2.98 min (10-99% CH3CN—H2O gradient, with 0.05% TFA, 5 min).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][P:6]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])([O:8][CH2:9][CH3:10])=[O:7])[CH3:4].I[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][I:26]>O1CCCC1>[CH2:15]([O:14][C:12](=[O:13])[C:11]([P:6]([O:5][CH2:3][CH3:4])([O:8][CH2:9][CH3:10])=[O:7])([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][I:26])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][I:26])[CH3:16]
Reactant: ICCCCCCCCI
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(CCCCCCCCI)(CCCCCCCCI)P(=O)(OCC)OCC
Temperature: 25 °C
Yield: 41.9 %

Procedure:
0.96 g (0.02 mol) of sodium hydride was added to 40 ml of dry tetrahydrofuran, and to this solution was added dropwise under reflux a mixed solution of 1.34 g (6 mmol) of ethyl diethylphosphonoacetate and 11 g (0.03 mol) of 1,8-diiodooctane, and the solution was refluxed under heating for 4 hours. After distilling off tetrahydrofuran, the residue was cooled to room temperature, added with 1N hydrochloric acid until the litmus paper came to show acidity of the solution and then extracted three times with 50 ml of ether. After drying the extract over anhydrous sodium sulfate, ether was distilled off and the obtained oily residue was refined by passing through a basic alumina(activity II)-packed column using benzene-ethyl acetate (2:1) as eluent to obtain 1.76 g of 2,2-bis(8-iodooctyl)-diethylphosphonoacetic acid ethyl ester, ##STR35## (yield: 42%).
Reaction SMILES: [N:1]([CH2:4][C@@H:5]1[CH2:7][C@H:6]1[C:8]([OH:10])=O)=[N+:2]=[N-:3].C(Cl)(=O)C([Cl:14])=O.CN(C)C=O>ClCCl>[N:1]([CH2:4][C@@H:5]1[CH2:7][C@H:6]1[C:8]([Cl:14])=[O:10])=[N+:2]=[N-:3]
Reactant: O=C(Cl)C(=O)Cl
Reactant: [N-]=[N+]=NC[C@@H]1C[C@H]1C(=O)O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: [N-]=[N+]=NC[C@@H]1C[C@H]1C(=O)Cl
Yield: 97.5 %

Procedure:
A solution of trans-2-azidomethyl-1-cyclopropane carboxylic acid (2.188 g, 15.50 mmol) in dry dichloromethane (25 ml) was treated at room temperature with oxalyl chloride (1.57 ml, 18.60 mmol) and a drop of N,N-dimethylformamide. After the evolution of gas has ceased (2.5 h), the solvent was evaporated under reduced pressure and the residue was distilled under vacuum (bulb to bulb distillation) to give 2.411 g (98%) of a clear oil: bp 70°-75° C./0.8 mm Hg (air bath temperature; ir (film) νmax : 2100 (N3), 1775 cm-1 (C=O); 1Hmr (CDCl3) δ: 3.33 (2H, d, J=6, CH2N3) ~2.2-1.0 ppm (4H, m, cyclopropyl).
Reaction SMILES: C(O[C:6](=[O:32])[NH:7][CH:8]([C:27]1[S:28][CH:29]=[CH:30][CH:31]=1)[C:9]([N:11]1[CH2:16][CH2:15][CH:14]([N:17]2[CH2:21][C:20]3=[CH:22][N:23]=[C:24]([CH3:25])[N:19]3[C:18]2=[O:26])[CH2:13][CH2:12]1)=[O:10])(C)(C)C.[ClH:33].C(O[CH2:38][CH3:39])(=O)C>>[Cl:33][C:39]1[CH:38]=[CH:9][C:8]([NH:7][C:6]([NH:7][CH:8]([C:27]2[S:28][CH:29]=[CH:30][CH:31]=2)[C:9]([N:11]2[CH2:16][CH2:15][CH:14]([N:17]3[CH2:21][C:20]4=[CH:22][N:23]=[C:24]([CH3:25])[N:19]4[C:18]3=[O:26])[CH2:13][CH2:12]2)=[O:10])=[O:32])=[CH:27][CH:31]=1
Reactant: CCOC(C)=O
Reactant: Cl
Reactant: Cc1ncc2n1C(=O)N(C1CCN(C(=O)C(NC(=O)OC(C)(C)C)c3cccs3)CC1)C2
Product: Cc1ncc2n1C(=O)N(C1CCN(C(=O)C(NC(=O)Nc3ccc(Cl)cc3)c3cccs3)CC1)C2
Yield: 42 %

Procedure:
To tert-butyl(2-(4-(5-methyl-3-oxo-1H-imidazo[1,5-c]imidazol-2(3H)-yl)-1-piperidinyl)-2-oxo-1-(2-thienyl)ethyl)carbamate (0.32 g) obtained in Example Sib) was added a 4 N solution of hydrogen chloride in ethyl acetate (2.6 ml), mixed at room temperature for 5 minutes, and then concentrated under reduced pressure. The residue was dissolved in acetonitrile (5 ml), triethylamine (0.14 ml) and 4-chlorophenyl isocyanate (0.08 g) were added thereto, and mixed at room temperature for 3 hours. The solvent was distilled off under reduced pressure, and the residue was dissolved in ethyl acetate. The ethyl acetate solution was washed with an aqueous sodium hydrogen carbonate solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified with basic silica gel column (ethyl acetate to ethyl acetate/methanol=10/1). The product was crystallized from ethyl acetate-diethyl ether to obtain the title compound as colorless powder (0.11 g, 42%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]([OH:12])=O)[CH:8]=2)[CH:3]=[CH:2]1.CN1CCOCC1.[C:20]([O:24][C:25](=[O:34])[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([NH2:33])=[CH:29][CH:28]=1)([CH3:23])([CH3:22])[CH3:21].O>CN(C)C=O>[C:20]([O:24][C:25](=[O:34])[CH2:26][C:27]1[CH:28]=[CH:29][C:30]([NH:33][C:10]([C:7]2[CH:8]=[C:9]3[C:4]([CH:3]=[CH:2][NH:1]3)=[CH:5][CH:6]=2)=[O:12])=[CH:31][CH:32]=1)([CH3:23])([CH3:21])[CH3:22]
Reactant: CC(C)(C)OC(=O)Cc1ccc(N)cc1
Reactant: O=C(O)c1ccc2cc[nH]c2c1
Solvent: O
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Cc1ccc(NC(=O)c2ccc3cc[nH]c3c2)cc1
Temperature: 60 °C
Reaction time: 18 h
Yield: 11.7 %

Procedure:
A solution of indole-6-carboxylic acid (2.00 g, 12.40 mmol) in dimethylformamide (20.00 mL) under argon was treated with N-methyl morpholine (6.82 mL, 62.04 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium-hexaflurophophate (HATU) (7.08 g, 18.62 mmol) and (4-amino-phenyl)-acetic acid tert-butyl ester (2.57 g, 12.40 mmol). The mixture was warmed at 60° C. and stirred for 18 hours. After cooling to room temperature, water (15.00 mL) was added. The resulting slurry was extracted with ethyl acetate and the combined organic phases washed with brine, dried over magnesium sulphate and evaporated. The residue was purified by flash chromatography (heptane/ethyl acetate gradient), to yield pure {4-[(1H-indole-6-carbonyl)-amino]-phenyl}-acetic acid tert-butyl ester (0.51 g) and a mixture of {4-[(1H-indole-6-carbonyl)-amino]-phenyl}-acetic acid tert-butyl ester and 1H-indole-6-carboxylic acid [1,2,3]triazolo[4,5-b]pyridin-3-yl ester (3.41 g). This was dissolved in tetrahydrofuran (34.00 mL) and treated with 1N NaOH. The mixture was stirred at room temperature for 4 hours, then extracted with ethyl acetate. The combined organic phases were washed with brine, dried over magnesium sulphate and evaporated, and the residue triturated in ether to afford {4-[(1H-indole-6-carbonyl)-amino]-phenyl}-acetic acid tert-butyl ester (1.36 g), which was combined with the aliquot obtained by flash chromatography. Total yield of {4-[(1H-indole-6-carbonyl)-amino]-phenyl}-acetic acid tert-butyl ester, 1.87 g (43%), MS (mass spectrometry) (ISP): m/e=351.3 (M+H). As used herein (M+H)=the molecular weight of the compound plus a proton.
Reaction SMILES: [BH4-].[Na+].[C:3]([C:6]1[CH:16]=[CH:15][C:9]([NH:10][S:11]([CH3:14])(=[O:13])=[O:12])=[C:8]([S:17][C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[Cl:25])[CH:7]=1)(=[O:5])[CH3:4].C(O)(=O)C>O1CCCC1.CO>[Cl:25][C:19]1[CH:20]=[C:21]([Cl:24])[CH:22]=[CH:23][C:18]=1[S:17][C:8]1[CH:7]=[C:6]([CH:3]([OH:5])[CH3:4])[CH:16]=[CH:15][C:9]=1[NH:10][S:11]([CH3:14])(=[O:13])=[O:12]
Reactant: CC(=O)c1ccc(NS(C)(=O)=O)c(Sc2ccc(Cl)cc2Cl)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CO
Product: CC(O)c1ccc(NS(C)(=O)=O)c(Sc2ccc(Cl)cc2Cl)c1
Reaction time: 9 h
Yield: 86.2 %

Procedure:
Sodium borohydride (0.22 g) was added portionwise to a solution of 4'-acetyl-2'-(2,4-dichlorophenylthio)methanesulfonanilide (1.5 g) in tetrahydrofuran (20 ml) and methanol (10 ml) at room temperature. The mixture was stirred for 9 hours, treated with acetic acid, and concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed with an aqueous solution of sodium bicarbonate, and dried. The solution was evaporated to dryness and the residue was recrystallized from a mixture of ethanol and water to give colorless needles of 2'-(2,4-dichlorophenylthio)-4'-(1-hydroxyethyl)methanesulfonanilide (1.3 g).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][C:12]#[N:13].Br[CH2:15][CH2:16][CH2:17]Br.[OH-].[K+]>CCOCC.CS(C)=O.C1OCCOCCOCCOCCOCCOC1>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]1([C:12]#[N:13])[CH2:17][CH2:16][CH2:15]1
Reactant: N#CCc1ccc2ccccc2c1
Reactant: BrCCCBr
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CS(C)=O
Product: N#CC1(c2ccc3ccccc3c2)CCC1
Temperature: 15 °C
Yield: 392.9 %

Procedure:
A solution of 2-naphthylacetonitrile (10 g) and 1,3-dibromopropane (144 g) in a mixture of ether (350 ml) and dimethylsulphoxide (150 ml) was added dropwise at 20-25° C. under nitrogen over 2 hours to a stirred mixture of finely-powdered potassium hydroxide (150 g), 18-Crown-6 (1.3 g) and dimethylsulphoxide (570 ml). After the addition was complete, the mixture was cooled to 15° C. and quenched by the slow addition of water (330 ml). Ether (330 ml) was added, and the mixture was filtered through Hyflo Supercel filtration aid. The filter pad was washed well with ether, then the aqueous layer of the filtrate was separated, diluted with water (500 ml), and washed well with ether. All of the ethereal solutions were combined, washed with water (3×100 ml), and the solvents were removed in vacua. The residue was triturated with ethanol (100 ml) and the resulting solid was collected by filtration and dried in vacua to give 1-(2-naphthyl)cyclobutanecarbonitrile as a white solid (48.7 g), which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[N:14]([CH2:23]CO)[N:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:3]=12.[CH2:26]([OH:29])[C:27]#[CH:28].C(N(CC)CC)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCOCC1.[Cu]I.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>[Cl:1][C:2]1[C:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[N:6][N:5]=[C:4]2[N:14]([CH3:23])[N:15]=[C:16]([C:17]3[CH:22]=[C:21]([C:28]#[C:27][CH2:26][OH:29])[CH:20]=[CH:19][CH:18]=3)[C:3]=12
Reactant: OCCn1nc(-c2ccccc2)c2c(Cl)c(-c3ccccc3)nnc21
Reactant: C#CCO
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: Cn1nc(-c2cccc(C#CCO)c2)c2c(Cl)c(-c3ccccc3)nnc21
Temperature: 100 °C
Yield: 38.5 %

Procedure:
A mixture of 4-chloro-3-(3-iodophenyl)-1-methyl-5-phenyl-1H-pyrazolo[3,4-c]pyridazine (Compound 7, Example 32) (80 mg, 0.18 mmol), propargyl alcohol (41 mg, 0.74 mmol), triethylamine (87 μl, 0.63 mmol), CuI (3.5 mg, 0.018 mmol), triphenylphosphine (5 mg, 0.018 mmol) and Pd(PPh3)4 (20 mg, 0.018 mmol) in 1,4-dioxane (1.5 mL) was heated at 100° C. for 4 h in a sealed tube. The reaction mixture was partitioned between CH2Cl2 and water. The organic phase was separated and dried using a phase separating cartridge then concentrated in vacuo. The crude residue was purified by column chromatography (silica gel, 20-30% ethyl acetate/isohexane), yielding Compound 30 as a solid (26 mg).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[CH2:7][CH2:6]1.[CH3:19][N:20]=[C:21]=[O:22]>C(Cl)Cl>[ClH:18].[ClH:18].[Cl:18][C:15]1[CH:14]=[CH:13][C:12]([CH2:11][N:8]2[CH2:9][CH2:10][N:5]([CH2:4][CH2:3][CH2:2][NH:1][C:21]([NH:20][CH3:19])=[O:22])[CH2:6][CH2:7]2)=[CH:17][CH:16]=1
Reactant: NCCCN1CCN(Cc2ccc(Cl)cc2)CC1
Reactant: CN=C=O
Solvent: ClCCl
Product: CNC(=O)NCCCN1CCN(Cc2ccc(Cl)cc2)CC1
Product: Cl
Yield: 31 %

Procedure:
A solution of 1-(3-aminopropyl)-4-(4-chlorobenzyl)-piperazine (2.68 g; 10 mmole) and methyl isocyanate (0.57 g; 10 mmole) in methylene chloride (10 ml) was stirred at room temperature overnight. The reaction mixture was evaporated under reduced pressure, and the residue was chromatographed on a silica gel column (1"×24") using a methanolammonium hydroxide gradient (3-6%) with methylene chloride as the eluant. The product (1.0 g; 31% yield) was dissolved in methylene chloride/ether (1:1; 20 ml), and the solution was treated with anhydrous hydrogen chloride to precipitate the title compound as colorless crystals, m.p. 193°-207° C. (decomp.).
Reaction SMILES: [CH2:1]([C:4]1[N:5]([CH2:17][CH2:18][CH2:19][C:20](OCC)=[O:21])[C:6]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:16]=1)[CH2:2][CH3:3].C1COCC1.[CH3:30][NH2:31]>O>[CH3:30][NH:31][C:20](=[O:21])[CH2:19][CH2:18][CH2:17][N:5]1[C:6]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:16]=[C:4]1[CH2:1][CH2:2][CH3:3]
Reactant: CN
Reactant: CCCc1nc2cnc3ccccc3c2n1CCCC(=O)OCC
Solvent: C1CCOC1
Solvent: O
Product: CCCc1nc2cnc3ccccc3c2n1CCCC(=O)NC
Temperature: 70 °C

Procedure:
A mixture of ethyl 4-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)butanoate (2.0 g, 6.1 mmol), THF (10 mL), and methylamine (available as a 40% solution in water, 4 mL, 52 mmol) was sealed in a high-pressure vessel and heated at 70° C. overnight. An analysis by TLC indicated the presence of starting material, and the reaction was sealed and heated at 80° C. for nine hours. The solvent was removed under reduced pressure, and the residue was dissolved in dichloromethane (100 mL). The resulting solution was washed with 5% aqueous sodium hydroxide (2×25 mL), dried over potassium carbonate, filtered, and concentrated under reduced pressure to provide 1.83 g of N-methyl-4-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)butanamide.