Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[NH:14][C:13](=[O:15])[CH:12]3[CH:8]([CH2:9][CH2:10][CH2:11]3)[N:7]([CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[C:6]=2[N:21]=1.[CH3:22]N(C)C=O.C(=O)([O-])[O-].[Cs+].[Cs+].IC>C(OCC)(=O)C.O>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[N:14]([CH3:22])[C:13](=[O:15])[CH:12]3[CH:8]([CH2:9][CH2:10][CH2:11]3)[N:7]([CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[C:6]=2[N:21]=1
Reactant: O=C1Nc2cnc(Cl)nc2N(C2CCCC2)C2CCCC12
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CI
Product: CN1C(=O)C2CCCC2N(C2CCCC2)c2nc(Cl)ncc21
Reaction time: 0.33 h

Procedure:
To a mixture of 0.68 g (0.0022 mole) of (rac)-6-chloro-4-cyclopentyl-2,3,3a,4,9,10a-hexahydro-1H-4,5,7,9-tetraaza-benzo[f]azulen-10-one (VI-68), 20 mL of dimethylformamide and 1.83 g (0.0056 mole) of cesium carbonate was added 1.254 g (0.0088 mole) of iodomethane. The mixture was stirred for 20 minutes, then diluted with ethyl acetate and water. The water layer was extracted twice with ethyl acetate and the combined ethyl acetate layers washed successively with water, then brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give 0.580 g of (rac)-6-chloro-4-cyclopentyl-9-methyl-2,3,3a,4,9,10a-hexahydro-1H-4,5,7,9-tetraazabenzo[f]azulen-10-one (VII-68), which was used in the next step without further purification.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([C:12]2[CH2:13][CH2:14][O:15][C:16]3[CH:22]=[CH:21][C:20]([C:23]4[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=4)=[CH:19][C:17]=3[CH:18]=2)=[O:11])=[CH:5][CH:4]=1.[CH:30]([NH:33][CH:34]([CH3:36])[CH3:35])([CH3:32])[CH3:31]>CN(C)C=O>[CH:30]([N:33]([CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([C:12]2[CH2:13][CH2:14][O:15][C:16]3[CH:22]=[CH:21][C:20]([C:23]4[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=4)=[CH:19][C:17]=3[CH:18]=2)=[O:11])=[CH:5][CH:4]=1)[CH:34]([CH3:36])[CH3:35])([CH3:32])[CH3:31]
Reactant: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CCl)cc2)CCO3)cc1
Reactant: CC(C)NC(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C(C)C)C(C)C)cc2)CCO3)cc1

Procedure:
A solution of N-(4-chloromethylphenyl)-7—(4-methylphenyl)-2,3-dihydro-1-benzoxepine-4-carboxamide (0.1 g) and diisopropylamine (0.1 ml) in dimethylformamide (10 ml) was stirred at room temperature over night. The solvent was evaporated, and to the residue was added water. The mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated sodium chloride solution, and, dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated to give crude crystals, which were recrystallized from ethyl acetate-hexane to give N-(4—((diisopropylamino)methyl)phenyl)-7—(4-methylphenyl)-2,3-dihydro-1-benzoxepine-4-carboxamide (Compound 119) (0.11 g) as colorless crystals.
Reaction SMILES: [C:1]([N:5]([CH3:20])[C:6]([C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][Si](C)(C)C)=[CH:10][N:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24](I)[CH:23]=1.CCN(CC)CC.CCCC[N+](CCCC)(CCCC)CCCC.[F-].C1COCC1>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I>[C:1]([N:5]([CH3:20])[C:6]([C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:24]2[CH:25]=[CH:26][CH:27]=[C:22]([F:21])[CH:23]=2)=[CH:10][N:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C(=O)c1ccc(C#C[Si](C)(C)C)cn1)C(C)(C)C
Reactant: Fc1cccc(I)c1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CN(C(=O)c1ccc(C#Cc2cccc(F)c2)cn1)C(C)(C)C
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 103.1 %

Procedure:
5-Trimethylsilanylethynyl-pyridine-2-carboxylic acid tert-butyl-methyl-amide (Example 3, step 2) (60 mg, 0.2 mmol) was dissolved in DMF (1 ml). 1-Fluoro-3-iodobenzene (74 mg, 0.33 mmol, 1.6 equiv.), Et3N (87 μl, 0.62 mmol, 3 equiv.), Bis-(triphenylphosphine)-palladium(II)dichloride (7 mg, 10.4 μmol, 0.05 equiv.) and copper(I)iodide (0.4 mg, 2 μmol, 0.01 equiv.) were added under nitrogen and the mixture was heated to 70° C. TBAF 1M in THF (230 μl, 0.23 mmol, 1.1 equiv.) was added dropwise over a period of 20 minutes at 70° C. The reaction mixture was stirred for 30 minutes at 70° C. and evaporated in presence of Isolute® sorbent to dryness. The crude product was purified by flash chromatography with a 20 g silica gel column eluting with heptane:ethyl acetate 100:0→70:30. The desired 5-(3-fluoro-phenylethynyl)-pyridine-2-carboxylic acid tert-butyl-methyl-amide (64 mg, 99% yield) was obtained as a colorless oil, MS: m/e=311.5 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]2[C:18]3[NH:25][C:24]([C:26]4[CH:34]=[CH:33][C:29]([C:30](O)=[O:31])=[CH:28][CH:27]=4)=[CH:23][C:19]=3[N:20]=[CH:21][N:22]=2)[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:10]=[N:11][C:12]([CH3:15])=[CH:13][CH:14]=1.C(N(CC)CC)C.C(N1C=CN=C1)(N1C=CN=C1)=O.[BH4-].[Na+]>O1CCCC1.O.CO>[CH3:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]2[C:18]3[NH:25][C:24]([C:26]4[CH:27]=[CH:28][C:29]([CH2:30][OH:31])=[CH:33][CH:34]=4)=[CH:23][C:19]=3[N:20]=[CH:21][N:22]=2)[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:10]=[N:11][C:12]([CH3:15])=[CH:13][CH:14]=1
Reactant: Cc1ccc(Oc2ccc(Nc3ncnc4cc(-c5ccc(C(=O)O)cc5)[nH]c34)cc2C)cn1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1ccc(Oc2ccc(Nc3ncnc4cc(-c5ccc(CO)cc5)[nH]c34)cc2C)cn1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 55 %

Procedure:
To a suspension of 4-[4-({3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-6-yl]benzoic acid (122 mg) in tetrahydrofuran (10 mL) was added triethylamine (30.5 mg) and, after stirring at room temperature for 10 min, 1,1′-carbonyldiimidazole (49 mg) was added, and the mixture was stirred at room temperature for 13 hrs. Under ice-cooling, sodium borohydride (28 mg) was added, and methanol (2.5 mL) was further added. After stirring under ice-cooling for 2 hrs, water (1.5 mL) was added, and tetrahydrofuran and methanol were evaporated under reduced pressure. Water (20 mL) was added, and the mixture was extracted with ethyl acetate (30 mL)-tetrahydrofuran (15 mL). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (15 mL)-tetrahydrofuran (5 mL). The organic layers were combined and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography (eluent, ethyl acetate:methanol=99:1→9:1). The object fraction was concentrated under reduced pressure. The residue was recrystallized from methanol-ethyl acetate to give the title compound (65 mg).
Reaction SMILES: [CH2:1]=[CH:2][CH2:3][CH2:4][C:5](=[O:7])[CH3:6].[H][H]>[Hg]>[CH3:1][CH:2]([CH:2]([CH3:1])[CH2:3][CH2:4][C:5](=[O:7])[CH3:6])[CH2:3][CH2:4][C:5](=[O:7])[CH3:6]
Reactant: [H][H]
Reactant: C=CCCC(C)=O
Agent: [Hg]
Product: CC(=O)CCC(C)C(C)CCC(C)=O
Yield: 70 %

Procedure:
25 g. of 1-hexene-5-one were passed in a 15 ml/min flow of hydrogen into the reactor tube while the tube was irradiated for 17.5 hours inside a photoreactor equipped with sixteen 8 W low pressure mercury lamps. During irradiation the temperature inside the quartz tube averaged 65.C. The crude reaction mixture was evaporated under reduced pressure to give 8.2 g. of involatile product containing the title compound, in about 70% yield. 250 MHZ 13 C NMR (CDCl3) 208.4, 41.3, 36.5, 35.7, 29.3, 28.1, 26.2, 15.6, 13.6.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5](=[O:8])[CH2:4][CH2:3]1.[CH2:9]([N:11]([CH2:20][CH3:21])[C:12]1[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=1)[CH3:10].[OH-].[K+]>CO>[CH2:9]([N:11]([CH2:20][CH3:21])[C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[C:4]2[C:5](=[O:8])[C:6](=[CH:16][C:15]3[CH:18]=[CH:19][C:12]([N:11]([CH2:9][CH3:10])[CH2:20][CH3:21])=[CH:13][CH:14]=3)[CH2:7][N:2]([CH3:1])[CH2:3]2)=[CH:14][CH:13]=1)[CH3:10]
Reactant: CCN(CC)c1ccc(C=O)cc1
Reactant: CN1CCC(=O)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CCN(CC)c1ccc(C=C2CN(C)CC(=Cc3ccc(N(CC)CC)cc3)C2=O)cc1
Reaction time: 8 h

Procedure:
1-methyl-4-piperidone (2.25 g) and 7.1 g of p-diethylamino-benzaldehyde were added to a solution of 4 g potassium hydroxide in 50 ml methanol. The reaction mixture was heated at reflex 31/2 hours and allowed to stand at room temperature overnight. The product was collected and recrystallized from 700 ml acetonitrile. The UV spectra of the isolated product was consistent with the structure of the titled compound.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2.[CH3:24][C:25]1([CH3:37])[CH2:29][C:28]2[CH:30]=[CH:31][CH:32]=[C:33]([C:34](O)=[O:35])[C:27]=2[O:26]1>>[CH3:23][C:13]1[S:14][C:15]([C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[C:11]([C:9]([N:8]2[CH2:7][C@H:6]3[C@H:4]([CH2:5]3)[C@H:3]2[CH2:2][NH:1][C:34]([C:33]2[C:27]3[O:26][C:25]([CH3:37])([CH3:24])[CH2:29][C:28]=3[CH:30]=[CH:31][CH:32]=2)=[O:35])=[O:10])[N:12]=1
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CN)c1
Reactant: CC1(C)Cc2cccc(C(=O)O)c2O1
Product: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2cccc3c2OC(C)(C)C3)c1

Procedure:
prepared by reaction of ((1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-(2-methyl-5-m-tolyl-thiazol-4-yl)-methanone with 2,2-Dimethyl-2,3-dihydro-benzofuran-7-carboxylic acid. LC-MS (basic): tR=0.97 min; [M+H]+=502.4.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[CH:10]([NH:12][C:13]1[O:14][CH2:15][C:16]3[CH:22]=[C:21]([NH2:23])[CH:20]=[CH:19][C:17]=3[N:18]=1)[CH2:9][CH2:8]2.[CH:24]1([C:27](Cl)=[O:28])[CH2:26][CH2:25]1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[CH:10]([NH:12][C:13]1[O:14][CH2:15][C:16]3[CH:22]=[C:21]([NH:23][C:27]([CH:24]4[CH2:26][CH2:25]4)=[O:28])[CH:20]=[CH:19][C:17]=3[N:18]=1)[CH2:9][CH2:8]2
Reactant: COc1cccc2c1C(NC1=Nc3ccc(N)cc3CO1)CC2
Reactant: O=C(Cl)C1CC1
Product: COc1cccc2c1C(NC1=Nc3ccc(NC(=O)C4CC4)cc3CO1)CC2
Yield: 73.8 %

Procedure:
Prepared from rac-N2-(7-methoxy-indan-1-yl)-4H-benzo[d][1,3]oxazine-2,6-diamine (Example 10) (100 mg, 0.323 mmol) and cyclopropancarbonyl chloride (32 ul, 0.356 mmol) according to the procedure described for Example 17. Obtained the title compound as a white solid (90 mg, 74%), MS (ISP) m/e=378.3 [(M+H)+].
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]=[C:12]1[NH:16][CH2:15][CH2:14][S:13]1.[C:17](Cl)(=[O:20])[CH2:18][CH3:19].CCN(CC)CC>C(Cl)Cl>[CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]=[C:12]1[N:16]([C:17](=[O:20])[CH2:18][CH3:19])[CH2:15][CH2:14][S:13]1
Reactant: CCC(=O)Cl
Reactant: Cc1cc([N+](=O)[O-])ccc1N=C1NCCS1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(=O)N1CCSC1=Nc1ccc([N+](=O)[O-])cc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 35 %

Procedure:
To a solution of 2-(2-methyl-4-nitrophenylimino)-1,3-thiazolidine (prepared in a manner analogous to that described in Method C1a; 0.084 g, 0.35 mmol) in CH2Cl2 (5 mL) was added propionyl chloride (0.033 g, 0.35 mmol) and Et3N (0.049 mL, 0.35 mmol). The mixture was allowed to stir at room temp for 1 h, then was diluted with CH2Cl2 (40 mL). The resulting solution was sequentially washed with H2O (10 mL) and a saturated NaCl solution (10 mL), dried (Na2SO4), and concentrated under reduced pressure. The residue was purified by preparative TLC (40% EtOAc/hex) to give 2-(2-methyl-4-nitrophenylimino)-3-propanoyl-1,3-thiazolidine (0.036 g, 35%): FAB-MS m/z 294 ((M+H)+).
Reaction SMILES: [S:1]1[C:5]([C@H:6]([O:32][Si:33]([C:46]([CH3:49])([CH3:48])[CH3:47])([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)/[CH:7]=[CH:8]/[C@H:9]2[C:13](=[CH2:14])[CH2:12][C@H:11]([O:15][CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][O:17]3)[C@@H:10]2[CH2:22]/[CH:23]=[CH:24]\[CH2:25][CH2:26][CH2:27][C:28]([O:30]C)=[O:29])=[CH:4][C:3]2[CH:50]=[CH:51][CH:52]=[CH:53][C:2]1=2>CO.[Li+].[OH-].C(OCC)(=O)C>[S:1]1[C:5]([C@H:6]([O:32][Si:33]([C:46]([CH3:48])([CH3:49])[CH3:47])([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)/[CH:7]=[CH:8]/[C@H:9]2[C:13](=[CH2:14])[CH2:12][C@H:11]([O:15][CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][O:17]3)[C@@H:10]2[CH2:22]/[CH:23]=[CH:24]\[CH2:25][CH2:26][CH2:27][C:28]([OH:30])=[O:29])=[CH:4][C:3]2[CH:50]=[CH:51][CH:52]=[CH:53][C:2]1=2
Reactant: C=C1C[C@H](OC2CCCCO2)[C@H](C/C=C\CCCC(=O)OC)[C@H]1/C=C/[C@@H](O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)c1cc2ccccc2s1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: C=C1C[C@H](OC2CCCCO2)[C@H](C/C=C\CCCC(=O)O)[C@H]1/C=C/[C@@H](O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)c1cc2ccccc2s1
Temperature: 4 °C

Procedure:
(Z)-Methyl 7-((1R,2R,5S)-2-((R,E)-3-(benzo[b]thiophen-2-yl)-3-(tert-butyldiphenylsilyloxy)prop-1-enyl)-3-methylene-5-(tetrahydro-2H-pyran-2-yloxy)cyclopentyl)hept-5-enoate (17a, limiting reagent) is dissolved in a 3:1 methanol and 1 N LiOH solution (0.01 M) and stirred at 4° C. Upon completion of the reaction, as judged by TLC, the reaction mixture is diluted with ethyl acetate, washed with 5% aqueous KHSO4 and brine. The organic phase is dried over sodium sulfate, filtered, and the solvent is evaporated. The crude product is purified by flash chromatography on regular silica gel eluted with hexanes-ethyl acetate to afford the title intermediate 19a.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8]/[C:9](=[C:16]2\[C:17](=[O:25])[NH:18][C:19]3[C:24]\2=[CH:23][CH:22]=[CH:21][CH:20]=3)/[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[CH2:26]([N:30]=[C:31]=[O:32])[CH2:27][CH2:28][CH3:29]>C1COCC1>[CH2:26]([NH:30][C:31]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8]/[C:9](=[C:16]2\[C:17](=[O:25])[NH:18][C:19]3[C:24]\2=[CH:23][CH:22]=[CH:21][CH:20]=3)/[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][CH:3]=1)=[O:32])[CH2:27][CH2:28][CH3:29]
Reactant: CCCCN=C=O
Reactant: Nc1ccc(N/C(=C2\C(=O)Nc3ccccc32)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCCNC(=O)Nc1ccc(N/C(=C2\C(=O)Nc3ccccc32)c2ccccc2)cc1

Procedure:
Prepared analogously to Example 45 from (Z)-3-[1-(4-aminophenylamino)-1-phenyl-methylidene]-2-indolinone and butyl isocyanate in THF.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[CH3:29])[C:5]([NH:7][C:8]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[C:10]([CH2:18][N:19]2[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]2)[CH:9]=1)=[O:6].C[Si]([C:34]#[CH:35])(C)C>CC#N.CCN(CC)CC.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.[Cu]I>[C:28]([C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:34]=1[CH3:35])[C:5]([NH:7][C:8]1[CH:13]=[C:12]([C:14]([F:15])([F:16])[F:17])[CH:11]=[C:10]([CH2:18][N:19]2[CH2:20][CH2:21][N:22]([CH3:25])[CH2:23][CH2:24]2)[CH:9]=1)=[O:6])#[CH:29]
Reactant: C#C[Si](C)(C)C
Reactant: Cc1ccc(C(=O)Nc2cc(CN3CCN(C)CC3)cc(C(F)(F)F)c2)cc1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC#N
Solvent: CCN(CC)CC
Product: C#Cc1cc(C(=O)Nc2cc(CN3CCN(C)CC3)cc(C(F)(F)F)c2)ccc1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 3-iodo-4-methyl-N-(3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)benzamide (951 mg, 1.84 mmol), PdCl2(PPh3)2 (65 mg, 0.092 mmol) in MeCN (75 mL) and Et3N (20 mL) at room temperature was added trimethylsilylacetylene (0.8 mL, 5.52 mmol) followed by CuI (18 mg, 0.092 mmol). The resulting mixture was allowed to stir at room temperature for 2 h at which time the reaction mixture was concentrated under reduced pressure followed by reconstitution in MeOH (100 mL). To this mixture was added enough K2CO3 to saturate the mixture and the mixture was allowed to stir for about 1.5 h. The mixture was filtered through a pad of Celite. To the filtrate was added silica gel (˜20 mL) and the mixture was concentrated under reduced pressure, and purified via automated flash chromatography (silica gel, 0% to 15% MeOH in CH2Cl2, gradient elution) to afford 3-ethynyl-4-methyl-N-(3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)benzamide.
Reaction SMILES: [CH:1]1([C:4]2[O:8][N:7]=[C:6]([C:9]3[N:10]=[CH:11][N:12]4[C:21]5[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=5)[N:15]([CH:22]5CC5)[CH2:14][C:13]=34)[N:5]=2)[CH2:3][CH2:2]1.Cl.C1(N2C3C(=CC=CC=3)NC(=[O:39])C2)CC1.C1(C2ON=C(C[N+]#[C-])N=2)CC1>>[CH:1]1([C:4]2[O:8][N:7]=[C:6]([C:9]3[N:10]=[CH:11][N:12]4[C:21]5[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=5)[N:15]([CH3:22])[C:14](=[O:39])[C:13]=34)[N:5]=2)[CH2:3][CH2:2]1
Reactant: c1ccc2c(c1)N(C1CC1)Cc1c(-c3noc(C4CC4)n3)ncn1-2
Reactant: O=C1CN(C2CC2)c2ccccc2N1
Agent: Cl
Agent: [C-]#[N+]Cc1noc(C2CC2)n1
Product: Cn1c(=O)c2c(-c3noc(C4CC4)n3)ncn2c2ccccc21

Procedure:
3-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-4,5-dihydro-5-cyclopropyl imidazo(1,5-a)quinoxaline, M.p. of hydrochloride 290°-300° C., by reaction between 1,2,3,4-tetrahydro-1-cyclopropyl-3-oxo-quinoxaline and 5-cyclopropyl-3-isocyanomethyl-1,2,4-oxadiazole.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[F:11][C:12]1[CH:52]=[CH:51][CH:50]=[C:49]([F:53])[C:13]=1[CH2:14][N:15]1[C:20]2[S:21][C:22]([C:31]3[CH:36]=[CH:35][C:34]([NH:37][C:38]([NH:40][O:41][CH3:42])=[O:39])=[CH:33][CH:32]=3)=[C:23]([CH2:24][N:25]([CH2:27][CH2:28][O:29][CH3:30])[CH3:26])[C:19]=2[C:18](=[O:43])[N:17]([CH2:44][CH:45]([OH:47])[CH3:46])[C:16]1=[O:48].C(N(CC)CC)C.[Cl-].[NH4+]>ClCCl>[F:53][C:49]1[CH:50]=[CH:51][CH:52]=[C:12]([F:11])[C:13]=1[CH2:14][N:15]1[C:20]2[S:21][C:22]([C:31]3[CH:32]=[CH:33][C:34]([NH:37][C:38]([NH:40][O:41][CH3:42])=[O:39])=[CH:35][CH:36]=3)=[C:23]([CH2:24][N:25]([CH2:27][CH2:28][O:29][CH3:30])[CH3:26])[C:19]=2[C:18](=[O:43])[N:17]([CH2:44][C:45](=[O:47])[CH3:46])[C:16]1=[O:48]
Reactant: COCCN(C)Cc1c(-c2ccc(NC(=O)NOC)cc2)sc2c1c(=O)n(CC(C)O)c(=O)n2Cc1c(F)cccc1F
Agent: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCCN(C)Cc1c(-c2ccc(NC(=O)NOC)cc2)sc2c1c(=O)n(CC(C)=O)c(=O)n2Cc1c(F)cccc1F
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 13.2 %

Procedure:
To a solution of oxalyl chloride (0.20 g, 1.58 mmol) in dichloromethane (2 ml) was dropwise added a solution of dimethylsulfoxide (163 mg, 2.09 mmol) in dichloromethane (2 ml) under cooling at −78° C. After stirring for 10 minutes, a solution of the compound (308 mg, 0.5 mmol) obtained in Example 61 in dichloromethane (2 ml) was dropwise added. After stirring for further 30 minutes, triethylamine (0.40 ml, 2.88 mmol) was dropwise added, and the mixture was stirred at 0° C. for 2 hours. To the mixture was added an aqueous solution of ammonium chloride at 0° C., and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated with under reduced pressure. The residue was purified by NH-silica gel (Produced by Fuji Silysia Chemical Ltd.) column chromatography (eluent; ethyl acetate), and the obtained powders was washed with diisopropyl ether and hexane to give the title compound (40.7 mg, 13%) as pale yellow powders.
Reaction SMILES: [C:1]([O:5][C:6](=[O:38])[C:7]([F:37])([F:36])[O:8][C:9]1[CH:35]=[CH:34][C:12]([CH2:13][CH:14]([C:24]2[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:25]=2)[C:15]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)=[O:16])=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C1OCCOCCOCCOCCOCCOC1.CC(C)([O-])C.[K+].Br[CH2:64][C:65]1[CH:70]=[CH:69][C:68]([C:71]([P:74](=[O:85])([O:80][C:81]([CH3:84])([CH3:83])[CH3:82])[O:75][C:76]([CH3:79])([CH3:78])[CH3:77])([F:73])[F:72])=[CH:67][CH:66]=1>C1COCC1>[C:1]([O:5][C:6](=[O:38])[C:7]([F:36])([F:37])[O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:13][C:14]([C:24]2[CH:25]=[CH:26][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:32][CH:33]=2)([CH2:64][C:65]2[CH:70]=[CH:69][C:68]([C:71]([P:74]([O:80][C:81]([CH3:84])([CH3:83])[CH3:82])([O:75][C:76]([CH3:77])([CH3:79])[CH3:78])=[O:85])([F:72])[F:73])=[CH:67][CH:66]=2)[C:15]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)=[O:16])=[CH:34][CH:35]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OP(=O)(OC(C)(C)C)C(F)(F)c1ccc(CBr)cc1
Reactant: COC(=O)c1ccc(C(Cc2ccc(OC(F)(F)C(=O)OC(C)(C)C)cc2)C(=O)c2ccc(F)cc2)cc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C(Cc2ccc(OC(F)(F)C(=O)OC(C)(C)C)cc2)(Cc2ccc(C(F)(F)P(=O)(OC(C)(C)C)OC(C)(C)C)cc2)C(=O)c2ccc(F)cc2)cc1
Temperature: 25 °C
Yield: 48.8 %

Procedure:
To a solution of methyl 4-[1-{4-[2-(tert-butoxy)-1,1-difluoro-2-oxoethoxy]benzyl}-2-(4-fluorophenyl)-2-oxoethyl]benzoate (0.176 g, 0.333 mmol)) in degassed THF (1.7 ml), were added at −20° C. 18-crown-6 (0.15 g) and potassium tert-butoxide 1 M in THE (0.379 ml ). Di(tert-butyl) [4-(bromomethyl)phenyl](difluoro)methylphosphonate (0.156 g, 0.378 mmol) was then added and the reaction mixture was allowed to warm to room temperature. The reaction was quenched with saturated ammonium acetate solution and extracted with ethyl acetate. The organic phase was dried over sodium sulfate, filtered and evaporated to dryness. The residue was purified by flash chromatography using hexane/ethyl acetate 20% giving 0.140 g of the title compound.
Reaction SMILES: [CH2:1]([NH:7][C:8]([NH:10][C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1)=[S:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[C:21]([C:26](O)=[O:27])#[C:22][C:23]([OH:25])=[O:24]>>[CH2:1]([N:7]1[C:26](=[O:27])[C:21](=[CH:22][C:23]([OH:25])=[O:24])[S:9][C:8]1=[N:10][C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: O=C(O)C#CC(=O)O
Reactant: CCCCCCNC(=S)Nc1cccc2ccccc12
Product: CCCCCCN1C(=O)C(=CC(=O)O)SC1=Nc1cccc2ccccc12
Yield: 66.3 %

Procedure:
Prepared by the method described in Example 16 from N-hexyl-N'-1-naphthalenylthiourea (8.0 g, 28 mmoles) and acetylenedicarboxylic acid (3.4 g, 28 mmoles). Recrystallization from acetonitrile gave the product (7.1 g), mp 144°-145° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]#[N:22])[CH:16]=2)[CH:10]([N:12]=[N+]=[N-])[CH3:11])=[CH:4][CH:3]=1>C(OC(C)C)(=O)C.[Pd].CC([O-])=O.CC([O-])=O.[Pb+2]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@@H:9]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]#[N:22])[CH:16]=2)[C@@H:10]([NH2:12])[CH3:11])=[CH:4][CH:3]=1
Reactant: CC(N=[N+]=[N-])C(Cc1ccc(Cl)cc1)c1cccc(C#N)c1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: CC(=O)OC(C)C
Product: C[C@H](N)[C@@H](Cc1ccc(Cl)cc1)c1cccc(C#N)c1
Temperature: 21.5 °C
Reaction time: 48 h

Procedure:
To a solution of 4-(4-chlorophenyl)-3-(3-cyanophenyl)-2-azidobutane (650 g, 2.1 mol) in isopropyl acetate (3.3 L) was added Lindlar's catalyst (130 g), and the mixture was hydrogenated at 40 psi at 45° C. for 24 h and at room temperature for anther 48 h. The reaction mixture was filtered over solka floc, and the cake was washed thoroughly with isopropyl acetate. The filtrate was partially concentrated to approximately 6 L, and was added hydrogen chloride in isopropyl acetate (5-6 N) while maintaining the reaction temperature at 18-25° C. After aging overnight, the precipitate was collected by filtration and washed twice with isopropyl acetate (1 L×2). The precipitate was suspended in isopropyl acetate (5.8 L) and was added aqueous potassium carbonate (1 M, 3.5 L). After stirring for 20 min, the organic layer was separated and concentrated to an oil, which was purified by preparative HPLC eluting on a Chiralpak AD column with heptane/ethanol/diethylamine (70/30/0.1; flow rate: 700 mL/min) to give the title compound.
Reaction SMILES: CO[C:3](=[O:18])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[CH:6][CH:5]=1.[CH3:19][C@@H:20]1[CH2:24][CH2:23][CH2:22][N:21]1[CH2:25][C@@H:26]1[CH2:30][CH2:29][CH2:28][NH:27]1>>[CH3:19][C@@H:20]1[CH2:24][CH2:23][CH2:22][N:21]1[CH2:25][C@@H:26]1[CH2:30][CH2:29][CH2:28][N:27]1[C:3]([C:4]1[CH:5]=[CH:6][C:7]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[CH:8][CH:9]=1)=[O:18]
Reactant: C[C@@H]1CCCN1C[C@@H]1CCCN1
Reactant: COC(=O)c1ccc(OCc2ccccn2)cc1
Product: C[C@@H]1CCCN1C[C@@H]1CCCN1C(=O)c1ccc(OCc2ccccn2)cc1

Procedure:
The title compound is prepared in a manner substantially analogous to Procedure F from 4-(Pyridin-2-ylmethoxy)-benzoic acid methyl ester and 2-(R)-Methyl-1-(2-(S)-pyrrolidinylmethyl)pyrrolidine. MS (ES+) 380.2