Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-])=O)[CH:15]=3)[N:9]=2)[CH:5]=[C:4]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=2)[CH:3]=1.[H][H]>C1COCC1.CCO.[Pd]>[CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[CH:15]=[C:16]([NH2:20])[CH:17]=[CH:18][CH:19]=3)[N:9]=2)[CH:5]=[C:4]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:31])([F:30])[F:32])=[CH:25][CH:24]=2)[CH:3]=1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(-c3cccc([N+](=O)[O-])c3)n2)n1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(-c3cccc(N)c3)n2)n1
Yield: 80.5 %

Procedure:
A mixture of the above prepared 6-methyl-6′-(3-nitro-phenyl)-4-(4-trifluoromethylphenyl)-[2,2′]bipyridinyl (3.4 g, 7.81 mmol) in THF-EtOH 1:1 (100 mL) and 10% palladium on carbon (1 mol %) was hydrogenated (1 bar hydrogen) at 23° C. for 2 h. The catalyst was filtered off, washed with EtOH and the filtrate was completely evaporated totally to leave a crude product, which was purified by silica gel column chromatography with heptane/EtOAc, followed by trituration with diethyl ether to give the title compound as a white solid (2.55 g, 80%). MS (ISP) 406.3 [(M+H)+]; mp 167° C.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[N:9]([CH3:11])[C:8]3[CH2:12][CH2:13][N:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:15][C:7]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1.B(O)(O)[C:22]1[CH:23]=[CH:24][C:25]([CH3:28])=[CH:26][CH:27]=1.C(N(CC)CC)C>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:11][N:9]1[C:10]2[C:2]([NH:1][C:22]3[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=3)=[CH:3][CH:4]=[CH:5][C:6]=2[C:7]2[CH2:15][N:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:13][CH2:12][C:8]1=2
Reactant: CCOC(=O)N1CCc2c(c3cccc(N)c3n2C)C1
Reactant: Cc1ccc(B(O)O)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)N1CCc2c(c3cccc(Nc4ccc(C)cc4)c3n2C)C1
Reaction time: 36 h
Yield: 54.3 %

Procedure:
Ethyl 6-amino-5-methyl-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indole-2-carboxylate (103 mg, 0.37 mmol) was combined with p-tolylboronic acid (100 mg, 0.74 mmol), triethylamine (75 mg, 0.74 mmol), and copper (II) acetate (68 mg, 0.37 mmol) in CH2Cl2 (2 mL) and allowed to stir for 36 h. The solvent was evaporated and the residue purified by silica gel column chromatography (20% EtOAc-Hex) affording ethyl 5-methyl-6-(4-toluidino)-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indole-2-carboxylate as a green semi-solid (73 mg, 73%) yield. 1H NMR (CDCl3, 300 MHz) δ 7.32 (d, 1H, J=7.7 Hz), 7.03 (t, 1H, J=7.7 Hz), 6.97 (d, 2H, J=8.0 Hz), 6.92 (d, 1H, J=6.9 Hz), 6.54 (d, 2H, J=8.4 Hz), 5.37 (s, 1H), 4.70 (s, 2H), 4.21 (q, 2H, J=7.0 Hz), 3.88 (br. s, 2H), 3.71 (s, 3H), 2.76 (t, 2H, J=5.5 Hz), 2.24 (s, 3H), 1.30 (t, 3H, J=7.3 Hz) ppm.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:10]([NH:12][C:13](=[NH:16])SC)=[O:11])=[N:4][C:5]([Cl:9])=[C:6]([NH2:8])[N:7]=1.C(N(CC)CC)C.N[CH2:25][C:26]([NH2:29])([CH3:28])[CH3:27]>CCO>[CH3:25][C:26]1([CH3:28])[CH2:27][NH:16]/[C:13](=[N:12]/[C:10]([C:3]2[C:2]([NH2:1])=[N:7][C:6]([NH2:8])=[C:5]([Cl:9])[N:4]=2)=[O:11])/[NH:29]1
Reactant: CSC(=N)NC(=O)c1nc(Cl)c(N)nc1N
Reactant: CC(C)(N)CN
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC1(C)CN/C(=N/C(=O)c2nc(Cl)c(N)nc2N)N1

Procedure:
A suspension of 1-(3,5-diamino-6-chloro-pyrazine-2-carbonyl)-2-methyl-isothiourea (Intermediate A) (0.2 g, 0.517 mmol) in EtOH (2 ml) is treated with triethylamine (0.029 ml, 0.258 mmol) followed by 1,2-diamino-2-methylpropane (0.07 ml, 0.672 mmol) and stirred at reflux overnight. The resulting suspension is filtered under vacuum to afford the title compound as a pale yellow solid; [M+H]+ 284
Reaction SMILES: Br[CH2:2][C:3]1[C:14](=[O:15])[N:13]([CH:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[C:6]2[N:7]=[C:8]([S:11][CH3:12])[N:9]=[CH:10][C:5]=2[CH:4]=1.[C:21]([OH:24])(=[O:23])[CH3:22]>C([O-])(=O)C.[Ag+]>[CH:16]1([N:13]2[C:6]3[N:7]=[C:8]([S:11][CH3:12])[N:9]=[CH:10][C:5]=3[CH:4]=[C:3]([CH2:2][O:24][C:21](=[O:23])[CH3:22])[C:14]2=[O:15])[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: CSc1ncc2cc(CBr)c(=O)n(C3CCCC3)c2n1
Reactant: CC(=O)O
Agent: [Ag+]
Agent: CC(=O)[O-]
Product: CSc1ncc2cc(COC(C)=O)c(=O)n(C3CCCC3)c2n1
Temperature: 110 °C
Yield: 71 %

Procedure:
6-Bromomethyl-8-cyclopentyl-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one (1.33 g, 3.75 mmol), prepared as in Example 25, and silver acetate (1.03 g, 6.2 mmol) were added to glacial acetic acid (10 ml) and heated to 110° C. for 5 hours. The solvents then were evaporated at reduced pressure and the resulting residue was suspended in ethyl acetate and filtered. The solid obtained was recrystallized from ethyl acetate to provide acetic acid 8-cyclopentyl-2-methylsulfanyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-6-ylmethyl ester as a solid (0.89 g, 71%). MS (APCI) M++1; Calc'd 334.11. Found 334.2.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.Cl.[OH:11][NH2:12].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6](=[N:12][OH:11])[NH2:7])=[CH:4][CH:3]=1
Reactant: NO
Reactant: N#Cc1ccc(Cl)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: NC(=NO)c1ccc(Cl)cc1
Yield: 40.4 %

Procedure:
To a solution of 4-chloro benzonitrile (1.000 g, 7.26 mmol) in ethanol (20 mL) was added hydroxyl amine HCl (0.752 g, 10.90 mmol) and potassium carbonate (3.00 g, 21.80 mmol). The reaction mass was refluxed for 10-12 h. Excess of solvent was removed under vacuum and the residue was diluted with water, acidified with dilute HCl. Precipitate obtained was filtered off and sucked dried to afford 0.500 g of desired product. 1H NMR (300 MHz, DMSO d6): δ 5.88 (br s, 2H), 7.42 (d, J=8.1 Hz, 2H), 7.68 (d, J=8.4 Hz, 2H), 9.70 (br s, 1H); MS (m/z): 171.13 (M+H)+.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([N:19]3[CH2:30][CH2:29][C:22]4[N:23]=[C:24]([S:27][CH3:28])[N:25]=[CH:26][C:21]=4[CH2:20]3)[N:14]=2)=[O:12])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[OH:31]OS([O-])=O.[K+]>C1COCC1.O>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([NH:10][C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([N:19]3[CH2:30][CH2:29][C:22]4[N:23]=[C:24]([S:27]([CH3:28])=[O:31])[N:25]=[CH:26][C:21]=4[CH2:20]3)[N:14]=2)=[O:12])=[CH:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: CSc1ncc2c(n1)CCN(c1cccc(C(=O)Nc3ccc(C(C)C)cc3)n1)C2
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)c1ccc(NC(=O)c2cccc(N3CCc4nc(S(C)=O)ncc4C3)n2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred mixture of N-(4-isopropylphenyl)-6-[2-(methylthio)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl]pyridine-2-carboxamide (400 mg, 0.953 mmol) in THF (40 ml) and water (16 ml) was added oxone (potassium peroxomonosulfate, 586 mg, 0.953 mmol). After stirring at room temperature for 3 hours, the reaction mixture was quenched by addition of 10% NaHSO3(aq.) (20 ml) and neutralized with sat'd NaHCO3(aq.) (16 ml). The solution was stirred for 20 minutes before extraction with ethyl acetate (2×60 ml). The combined organic extracts were dried (MgSO4), filtered, and concentrated to give the title compound as a light yellow, amorphous solid which was used without further purification (405 mg, 98%).
Reaction SMILES: [CH2:1]([C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19]([O:21]CC)=[O:20])=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[OH-].[Na+].Cl>CO.O1CCCC1>[CH2:1]([C:12]1[CH:13]=[CH:14][C:15]([CH2:18][C:19]([OH:21])=[O:20])=[CH:16][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCCCCCCCCCc1ccc(CC(=O)OCC)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCCCCCCCCCCc1ccc(CC(=O)O)cc1
Temperature: 50 °C
Reaction time: 0.33 h
Yield: 26.9 %

Procedure:
To the solution of ethyl 4-undecylphenylacetate (7.2 g, 0.023 mol) in a mixture of methanol (40 ml) and tetrahydrofuran (40 ml) was added sodium hydroxide (2.2 g, 0.055 mol) and stirred at 50° C. for 20 minutes. The reaction mixture was adjusted to pH 4 with 2N hydrochloric acid after concentration. The resultant mixture was extracted with ethyl acetate, and the organic layer was washed with water, dried and concentrated under reduced pressure. The resulting crude crystals were recrystallized from hexane to obtain 4-undecylphenylacetic acid (3-x, 1.8 g, 27%). m.p. 83°-84° C.
Reaction SMILES: [CH3:1][C:2]([CH3:8])=[C:3]1[CH:7]=[CH:6][CH:5]=[CH:4]1.Cl[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12].CC(C)([O-])C.[K+].C(O)(C)(C)C>C(Cl)(Cl)(Cl)Cl>[CH3:1][C:2]1([CH3:8])[C:3]2([CH:7]=[CH:6][CH:5]=[CH:4]2)[CH:10]1[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CC(C)=C1C=CC=C1
Reactant: CCOC(=O)CCl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)C1C(C)(C)C12C=CC=C2

Procedure:
A well stirred, 10°-15° C. nitrogen blanketed mixture of 10.6 g. of 6,6-dimethylfulvene, prepared above, and 12.2 g. of ethyl chloroacetate was treated dropwise over 1.5 hr. with a solution of 11.7 g. of potassium t-butoxide in 75 ml. of dry t-butyl alcohol. The reaction was stirred an additional 1.5 hr. at 10° C. and most of the alcohol was then removed at reduced pressure. Ether extraction of an aqueous solution of the residual semisolid afforded 15.2 g. of yellow oil. Subsequent distillation afforded 2.5 g. (13%) of yellow ester, b.p. 75°-80° C. (0.25 mm.). Gas chromatographically purified ester exhibited the following spectral properties: ir (film) 5.77, 8.33, 8.69, 9.24, 12.0, 12.7 μ; nmr (CCl4) τ 3.38, 3.69, 3.99 (3m, 4, --CH=CH--CH=CH--), 5.99 (q, 2, J = 7 Hz, OCH2CH3), 7.41 (s, 1, CHCO2Et), 8.47, 8.60 (6, CH3 's), 8.80 (t, 3, J = 7 Hz, OCH2CH3).
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:11][C:12]1[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:19].[CH2:20]([NH2:23])[CH:21]=[CH2:22]>CO>[CH2:20]([NH:23][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:11][C:12]1[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:19])[CH:21]=[CH2:22]
Reactant: Clc1cccc(Cl)c1Cn1cnc2c(Cl)ncnc21
Reactant: C=CCN
Solvent: CO
Product: C=CCNc1ncnc2c1ncn2Cc1c(Cl)cccc1Cl
Yield: 81 %

Procedure:
6-Chloro-9-(2,6-dichlorobenzyl)purine (314 mg), 286 mg of allylamine and 25 ml of methanol were treated in the same manner as Example 2, whereby 271 mg (yield 81%) of 6-allylamino-9-(2,6-dichlorobenzyl)purine was obtained as colorless prisms melting at 202.5°-204° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@:9]1([CH2:22][CH:23]2[CH2:28][CH2:27][N:26]([C:29]([O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])=[O:30])[CH2:25][CH2:24]2)[C:16](=[O:17])[N:15]2[C@@H:11]([S:12][CH2:13][C@H:14]2[C:18]([O:20]C)=O)[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH3:38]>>[C:1]([O:5][C:6]([NH:8][C@@:9]1([CH2:22][CH:23]2[CH2:28][CH2:27][N:26]([C:29]([O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])=[O:30])[CH2:25][CH2:24]2)[C:16](=[O:17])[N:15]2[C@@H:11]([S:12][CH2:13][C@H:14]2[C:18](=[O:20])[NH2:38])[CH2:10]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)[C@@H]1CS[C@H]2C[C@@](CC3CCN(C(=O)OCC[Si](C)(C)C)CC3)(NC(=O)OC(C)(C)C)C(=O)N21
Reactant: N
Product: CC(C)(C)OC(=O)N[C@]1(CC2CCN(C(=O)OCC[Si](C)(C)C)CC2)C[C@@H]2SC[C@@H](C(N)=O)N2C1=O

Procedure:
340 mg of methyl (3R,6R,7aS)-6-tert-butoxycarbonylamino-5-oxo-6-[1-(2-trimethylsilanylethoxycarbonyl)piperidin-4-ylmethyl]hexahydropyrrolo[2,1-b]thiazole-3-carboxylate were dissolved at 0° C. in 35 ml of an ammonia-saturated methanol solution. The mixture was allowed to reach room temperature in the course of 4 h, and then the solvents were removed in vacuo. The residue was employed without further purification in the next reaction.
Reaction SMILES: CN1CCOCC1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.ON1C2C=CC=CC=2N=N1.[C:42]([O:46][C:47]([NH:49][C@@H:50]([C:54]([CH3:57])([CH3:56])[CH3:55])[C:51]([OH:53])=O)=[O:48])([CH3:45])([CH3:44])[CH3:43].[CH3:58][C@@H:59]1[CH2:63][NH:62][C@@H:61]2[C@@H:64]([OH:67])[CH2:65][O:66][C@H:60]12>CN(C)C=O>[OH:67][C@@H:64]1[C@H:61]2[N:62]([C:51](=[O:53])[C@@H:50]([NH:49][C:47](=[O:48])[O:46][C:42]([CH3:43])([CH3:44])[CH3:45])[C:54]([CH3:57])([CH3:56])[CH3:55])[CH2:63][C@@H:59]([CH3:58])[C@H:60]2[O:66][CH2:65]1
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)O)C(C)(C)C
Reactant: C[C@@H]1CN[C@H]2[C@@H]1OC[C@@H]2O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: C[C@@H]1CN(C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)C)[C@H]2[C@@H]1OC[C@@H]2O
Reaction time: 0.08 h
Yield: 133.6 %

Procedure:
4-Methylmorpholine (1.062 mL, 9.7 mmol) was added to a suspension of 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU, 1839 mg, 4.85 mmol), 1-hydroxybenzotriazole (654 mg, 4.85 mmol) and (S)-2-(tert-butoxycarbonylamino)-3,3-dimethylbutanoic acid (1.125 g, 4.85 mmol) in dimethylformamide (5 mL). The mixture was stirred for 5 minutes before adding to (3R,3aR,6R,6aR)-6-methylhexahydro-2H-furo[3,2-b]pyrrol-3-ol (107) (prepared as above with appropriate scaling of quantities, assume 4.62 mmol). The mixture was stirred for 16 hours then the solvents removed in vacuo. The crude product was dissolved in DCM (75 mL) then washed with (75 ML each) sat. NaHCO3, 0.01N HCl, brine and the organic layer dried over Na2SO4. The mixture was filtered to leave a tan oil (2.20 g). Flash chromatography over silica, eluting with ethyl acetate:pentane mixtures 15:85 to 50:50 gave desired alcohol as a white solid (1.45 g, contaminated with tetramethylurea). Analytical HPLC main peak, Rt=11.94 min., HPLC-MS 301.2 [M+2H−tBu]+, 357.2 [M+H]+, 379.2 [M+Na]+, 735.5 [2M+Na]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13](B3OC(C)(C)C(C)(C)O3)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].I[C:27]1[S:28][C:29]([CH3:32])=[CH:30][N:31]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:27]3[S:28][C:29]([CH3:32])=[CH:30][N:31]=3)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1cnc(I)s1
Reactant: CC(C)(C)OC(=O)N1Cc2ccc(B3OC(C)(C)C(C)(C)O3)cc2C1
Product: Cc1cnc(-c2ccc3c(c2)CN(C(=O)OC(C)(C)C)C3)s1

Procedure:
Prepared in analogy to Example A23(b) from 5-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester and 2-Iodo-5-methyl-thiazole (CAS: 847547-16-4). Yellow solid. MS (m/e): 317.0 ([M]+, 100%)
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:13])=[C:4]([C:9]([Cl:12])=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].Cl[C:15](OC(Cl)(Cl)Cl)=[O:16]>C1(C)C=CC=CC=1>[Cl:12][C:9]1[C:4]([C:5]([O:7][CH3:8])=[O:6])=[C:3]([CH3:13])[C:2]([N:1]=[C:15]=[O:16])=[CH:11][CH:10]=1
Reactant: COC(=O)c1c(Cl)ccc(N)c1C
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: COC(=O)c1c(Cl)ccc(N=C=O)c1C
Reaction time: 18 h
Yield: 100 %

Procedure:
A solution of 14.7 grams (0.074 mole) of methyl 3-amino-6-chloro-2-methylbenzoate in 1000 mL of toluene was stirred and 14.6 grams (0.074 mole) of trichloromethyl chloroformate was added dropwise thereto. Upon completion of the addition, the reaction mixture was warmed to reflux where it stirred for about 18 hours. After this time the reaction mixture was concentrated under reduced pressure to a residue, which was assumed to be a theoretical yield (16.7 grams) of the subject compound. The subject compound was taken directly to the next reaction in the sequence.
Reaction SMILES: [C@@H:1]12[C:10](=[O:11])O[C:7](=O)[C@H:2]1[CH2:3][CH2:4][CH2:5][CH2:6]2.[OH-].[NH4+:13]>>[C:10]1(=[O:11])[C@H:1]2[C@@H:2]([CH2:3][CH2:4][CH2:5][CH2:6]2)[CH2:7][NH:13]1
Reactant: O=C1OC(=O)[C@H]2CCCC[C@H]12
Reactant: [NH4+]
Agent: [OH-]
Product: O=C1NC[C@@H]2CCCC[C@@H]12
Yield: 80 %

Procedure:
A solution of trans-1,2-cyclohexanedicarboxylic anhydride (10 g, 65 mmol) in ammonium hydroxide (conc., 30 mL) was hydrogenated by the method of EXAMPLE 168 to yield 7.4 g (80%) of the title material.
Reaction SMILES: [O:1]=[S:2]1(=[O:25])[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[N:20]4[N:21]=[C:22]([NH2:24])[N:23]=[C:19]4[CH:18]=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:4][CH2:3]1.Br[C:27]1[CH:28]=[C:29]([N:33]2[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]2)[CH:30]=[CH:31][CH:32]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[O:25]=[S:2]1(=[O:1])[CH2:3][CH2:4][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[N:20]4[N:21]=[C:22]([NH:24][C:27]5[CH:32]=[CH:31][CH:30]=[C:29]([N:33]6[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]6)[CH:28]=5)[N:23]=[C:19]4[CH:18]=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:6][CH2:7]1
Reactant: Nc1nc2cccc(-c3ccc(CN4CCS(=O)(=O)CC4)cc3)n2n1
Reactant: CN1CCN(c2cccc(Br)c2)CC1
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CN1CCN(c2cccc(Nc3nc4cccc(-c5ccc(CN6CCS(=O)(=O)CC6)cc5)n4n3)c2)CC1

Procedure:
5-{4-[(1,1-dioxidothiomorpholin-4-yl)methyl]phenyl}-N-[3-(4-methylpiperazin-1-yl)phenyl][1,2,4]triazolo[1,5-a]pyridin-2-amine was prepared from 5-{4-[(1,1-dioxidothiomorpholin-4-yl)methyl]phenyl}[1,2,4]triazolo[1,5-a]pyridin-2-amine (75.0 mg, 0.210 mmol) and 1-(3-bromo-phenyl)-4-methyl-piperazine (65.0 mg, 0.255 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (22.0 mg, 0.0402 mmol) as the ligand in a manner analogous to Step 2d and was isolated as an off-white solid (0.052 g, 47%). MP=150-152° C. 1H NMR (400 MHz, CDCl3, δ, ppm): 8.02 (d, J=7.7 Hz, 2H), 7.55-7.42 (m, 5H), 7.17 (t, J=7.8 Hz, 1H), 6.97 (d, J=7.0 Hz, 1H), 6.87-6.80 (m, 2H), 6.55 (d, J=8.3 Hz, 1H), 3.76 (s, 2H), 3.24-3.19 (m, 4H), 3.14-3.03 (m, 8H), 2.58-2.53 (m, 4H), 2.36 (s, 3H). MS=532 (MH)+.
Reaction SMILES: [CH:1]([N:4]=[C:5]=[O:6])([CH3:3])[CH3:2].[CH2:7]([O:9][CH2:10][C:11]1[N:12]([CH2:32][CH2:33][CH3:34])[C:13]2[C:22]3[CH:21]=[C:20]([O:23][CH:24]4[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]4)[CH:19]=[CH:18][C:17]=3[N:16]=[C:15]([NH2:30])[C:14]=2[N:31]=1)[CH3:8]>ClCCl>[NH2:30][C:15]1[C:14]2[N:31]=[C:11]([CH2:10][O:9][CH2:7][CH3:8])[N:12]([CH2:32][CH2:33][CH3:34])[C:13]=2[C:22]2[CH:21]=[C:20]([O:23][CH:24]3[CH2:25][CH2:26][N:27]([C:5]([NH:4][CH:1]([CH3:3])[CH3:2])=[O:6])[CH2:28][CH2:29]3)[CH:19]=[CH:18][C:17]=2[N:16]=1
Reactant: CCCn1c(COCC)nc2c(N)nc3ccc(OC4CCNCC4)cc3c21
Reactant: CC(C)N=C=O
Solvent: ClCCl
Product: CCCn1c(COCC)nc2c(N)nc3ccc(OC4CCN(C(=O)NC(C)C)CC4)cc3c21
Yield: 83.5 %

Procedure:
Isopropyl isocyanate (0.190 mL, 1.90 mmol) was added dropwise to a solution of 2-(ethoxymethyl)-8-(piperidin-4-yloxy)-1-propyl-1H-imidazo[4,5-c]quinolin-4-amine (prepared as described in Example 411, 0.730 g, 1.90 mmol) in dichloromethane (15 mL) at room temperature. The reaction was diluted with dichloromethane and stirred vigorously. A precipitate formed that was isolated by filtration to afford 0.743 g of 4-{[4-amino-2-(ethoxymethyl)-1-propyl-1H-imidazo[4,5-c]quinolin-8-yl]oxy}-N-isopropylpiperidine-1-carboxamide as a white solid, mp 236.5-239° C.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([NH2:9])[CH:6]=[CH:7][CH:8]=1.[Cl:12][CH2:13][CH2:14][N:15]=[C:16]=[O:17]>C1(C)C=CC=CC=1>[Cl:12][CH2:13][CH2:14][NH:15][C:16]([NH:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:10])([F:11])[F:1])[CH:4]=1)=[O:17]
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: O=C=NCCCl
Solvent: Cc1ccccc1
Product: O=C(NCCCl)Nc1cccc(C(F)(F)F)c1
Yield: 96 %

Procedure:
Using analogous reagents and reaction conditions as described in Example 1 above, 3-trifluoromethyl-phenylamine (2.0 g, 12.412 mmol) in toluene (20 mL) was reacted with 1-chloro-2-isocyanatoethane (1.96 g, 18.618 mmol to give 3.2 g of pure product (96%)
Reaction SMILES: [CH2:1]([Mg]Cl)[CH2:2][CH3:3].[CH2:6]([C:8]1[N:13]=[C:12]2[S:14][C:15]3[CH2:20][CH2:19][CH2:18][CH2:17][C:16]=3[C:11]2=[C:10]([C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=2)[C:9]=1[CH:28]=[C:29]1[S:33][C:32](=[O:34])[NH:31][C:30]1=[O:35])[CH3:7].C(OCC)C.O1CCCC1>C(OCC)C.[Cu]I>[CH2:6]([C:8]1[N:13]=[C:12]2[S:14][C:15]3[CH2:20][CH2:19][CH2:18][CH2:17][C:16]=3[C:11]2=[C:10]([C:21]2[CH:22]=[CH:23][C:24]([CH3:27])=[CH:25][CH:26]=2)[C:9]=1[CH:28]([CH:29]1[S:33][C:32](=[O:34])[NH:31][C:30]1=[O:35])[CH2:1][CH2:2][CH3:3])[CH3:7]
Reactant: CCc1nc2sc3c(c2c(-c2ccc(C)cc2)c1C=C1SC(=O)NC1=O)CCCC3
Reactant: CCC[Mg]Cl
Agent: [Cu]I
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCCC(c1c(CC)nc2sc3c(c2c1-c1ccc(C)cc1)CCCC3)C1SC(=O)NC1=O
Reaction time: 0.33 h
Yield: 9 %

Procedure:
To a cold (−15° C.) solution of copper(I)iodide (0.200 g; 1.05 mmol) in anhydrous diethyl ether (5 mL) was added a 2M solution of n-propylmagnesium chloride in diethyl ether (1.0 mL; 2.0 mmol). The mixture was stirred for 20 min and a solution of 5-[1-(2-ethyl-4-(p-tolyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl)methylene]thiazolidine-2,4-dione (0.083 g; 0.197 mmol) in a mixture diethyl ether-tetrahydrofurane (2/1, 3 mL) was added dropwise and stirring was carried on for 2 h at −15° C. and 18 h at room temperature. The reaction was quenched with a saturated solution of ammonium chloride (50 mL) and diluted with diethyl ether (20 mL). Both phases were separated, the aqueous layer was extracted with diethyl ether, the combined organic phases were washed with a saturated solution of ammonium chloride, dried over magnesium sulphate, filtered and concentrated under reduced pressure. Purification by preparative HPLC (HPLC method 1) furnished 0.008 g (9%) of the title compound.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[NH:10]1[CH:14]=[CH:13][CH:12]=[N:11]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[N:10]1([C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=2)[CH:14]=[CH:13][CH:12]=[N:11]1
Reactant: N#Cc1ccc(F)cc1
Reactant: c1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc(-n2cccn2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 86 %

Procedure:
4-Fluorobenzonitrile (204.2 g), pyrazole (138.6 g, 1.22 eq) and potassium carbonate (281.5 g, 1.22 eq) in DMF (1110 ml) were heated at 120° C. for 7 hours. The suspension was cooled to 25° C. and water (2920 ml) added. The reaction was extracted with MTBE (3×1460 ml) and the combined extracts were washed with water (3×1460 ml) and saturated aqueous sodium chloride (1460 ml). The organic phase was concentrated at atmospheric pressure until the pot temperature rose to 65° C. Heptane (1700 ml) was added over 30 minutes at 60-65° C., and then a further 300 ml of distillate was collected. The solution was stirred at 60-65° C. for 15 minutes and then cooled to <5° C. The slurry was filtered and washed with heptane (2×200 ml), and dried under vacuum to constant weight to give the title compound as a solid (245.3 g, 87%).
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3][SH:4].[N+:7]([C:10]1[N:14]=[C:13]([C:15]2[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[C:17](F)[CH:16]=2)[NH:12][N:11]=1)([O-:9])=[O:8].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[N+:7]([C:10]1[N:14]=[C:13]([C:15]2[CH:16]=[CH:17][C:18]([CH:19]=[O:20])=[C:21]([S:4][CH2:3][C:2]([F:6])([F:5])[F:1])[CH:22]=2)[NH:12][N:11]=1)([O-:9])=[O:8]
Reactant: O=Cc1ccc(-c2nc([N+](=O)[O-])n[nH]2)cc1F
Reactant: FC(F)(F)CS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1ccc(-c2nc([N+](=O)[O-])n[nH]2)cc1SCC(F)(F)F
Temperature: 5 °C
Reaction time: 4 h
Yield: 80 %

Procedure:
0.8 g of 2,2,2-trifluoroethylmercaptan was added dropwise under cooling with ice to a mixture of 1.6 g of 4-(3-nitro-1,2,4-triazolyl)-2-fluorobenzaldehyde, 1.3 g of potassium carbonate and 50 ml of N,N-dimethylformamide, followed by stirring at from 0 to 10° C. for 4 hours. The mixture was concentrated under reduced pressure, 200 ml of water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 1.8 g of 4-(3-nitro-1,2,4-triazolyl)-2-(2,2,2-trifluoroethylthio)benzaldehyde.