Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:14]=[CH:13][C:12](=[O:15])[N:11]([C:16]3[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=3[F:23])[C:4]=2[N:5]=[C:6](S(C)=O)[N:7]=1.[CH2:24]([N:26]([CH2:31][CH3:32])[CH2:27][CH2:28][CH2:29][NH2:30])[CH3:25].C(N(CC)CC)C>ClCCl>[Cl:1][C:2]1[C:3]2[CH:14]=[CH:13][C:12](=[O:15])[N:11]([C:16]3[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=3[F:23])[C:4]=2[N:5]=[C:6]([NH:30][CH2:29][CH2:28][CH2:27][N:26]([CH2:31][CH3:32])[CH2:24][CH3:25])[N:7]=1
Reactant: CCN(CC)CCCN
Reactant: CS(=O)c1nc(Cl)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCN(CC)CCCNc1nc(Cl)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.5 %

Procedure:
To the compound 4-chloro-8-(2,6-difluorophenyl)-2-(methylsulfinyl)-pyrido[2,3-d]pyrimidin-7(8H)-one (1.59 g, 4.47 mmol) in dichloromethane (89.4 mL) were added N,N-diethyl-1,3-propanediamine (0.845 mL, 5.36 mol) and triethylamine (1.26 uL, 8.94 mmol). The mixture was stirred at rt overnight. Some white precipitate was formed during the reaction. Filtration followed by wash with ethyl acetate/dichoromethane/methnol afforded the title compound (1.028 g, 60%).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]2[CH:10]=[CH:11][S:12][C:3]=12.[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[SH:21]>CN(C)C=O>[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[S:21][C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]2[CH:10]=[CH:11][S:12][C:3]=12
Reactant: Sc1ccc(Cl)cc1Cl
Reactant: N#Cc1cnc2ccsc2c1Cl
Solvent: CN(C)C=O
Product: N#Cc1cnc2ccsc2c1Sc1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.7 %

Procedure:
A mixture of 7-chlorothieno[3,2-b]pyridine-6-carbonitrile (200 mg, 1.03 mmol) and 2,4-dichlorothiophenol (202.9 mg, 1.13 mmol) in 5 mL of N,N-dimethylformamide is stirred at room temperature for 1 hour, and then concentrated in vacuo. The resulting residue is treated with water and stirred for 1 hour. The precipitate is filtered, washed with water, air dried, and then purified by flash column chromatography eluting with a gradient of 5% ethyl acetate in hexane to 20% ethyl acetate in hexane to provide 249.0 mg of 7-[(2,4-dichlorophenyl)thio]thieno[3,2-b]pyridine-6-carbonitrile as a white solid, mp 126–128° C.; 1H NMR (DMSO-d6) δ 7.47 (dd, J=6,2 Hz, 1H), 7.54 (d, J=6 Hz, 1H), 7.73 (d, J=4 Hz, 1H), 7.88 (d, J=2 Hz, 1 H), 8.43 (d, J=4 Hz, 1H), 9.09 (s, 1H); MS 336.9, 339.0 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]3[CH2:11][CH2:12][CH:13]([CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:6]3=[CH:5][C:4]=2[CH:3]=1.Cl[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([CH:30]2[CH2:34][CH2:33][CH2:32][CH2:31]2)=[C:26]([C:35]([F:38])([F:37])[F:36])[CH:25]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH:30]1([C:27]2[CH:28]=[CH:29][C:24]([CH2:23][O:1][C:2]3[CH:10]=[CH:9][C:8]4[N:7]5[CH2:11][CH2:12][CH:13]([CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:6]5=[CH:5][C:4]=4[CH:3]=3)=[CH:25][C:26]=2[C:35]([F:36])([F:37])[F:38])[CH2:31][CH2:32][CH2:33][CH2:34]1
Reactant: CC(C)(C)OC(=O)CC1CCn2c1cc1cc(O)ccc12
Reactant: FC(F)(F)c1cc(CCl)ccc1C1CCCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CC1CCn2c1cc1cc(OCc3ccc(C4CCCC4)c(C(F)(F)F)c3)ccc12
Yield: 62.3 %

Procedure:
tert-Butyl 2-(7-hydroxy-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate (0.563 g, 1.960 mmol), 4-(chloromethyl)-1-cyclopentyl-2-(trifluoromethyl)benzene (0.515 g, 1.960 mmol) and cesium carbonate (0.703 g, 2.156 mmol) in DMF (4 mL) were heated to 50° C. for 16 h in a 20 mL sealed scintillation vial. The reaction mixture was filtered by vacuum filtration through Celite® and washed with EtOAc (3×10 mL). The filtrate was concentrated under reduced pressure. The residue was taken up in EtOAc (25 mL), washed with water (2×25 mL), saturated NaCl (20 mL), dried over MgSO4 and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography to give a yellow sticky oil. A precipitate, formed by addition of hexanes to the oil, was collected by filtration, was washed with hexanes (3×20 mL) and dried (vacuum oven) to provide the title compound as a white solid (0.6273 g). LCMS m/z=514.4 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.44 (s, 9H), 1.57-1.72 (m, 4H), 1.81-1.87 (m, 2H), 1.95-2.04 (m, 2H), 2.15-2.24 (m, 1H), 2.53-2.67 (m, 2H), 2.71-2.81 (m, 1H), 3.20-3.27 (m, 1H), 3.57 (quintet, J=7.75 Hz, 1H), 3.91-3.99 (m, 1H), 4.06-4.13 (m, 1H), 5.13 (s, 2H), 5.99 (s, 1H), 6.77 (dd, J=8.65, 2.08 Hz, 1H), 7.07 (d, J=2.27 Hz, 1H), 7.19 (d, J=8.72 Hz, 1H), 7.62 (d, J=8.72 Hz, 1H) 7.68-7.70 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=1)[C:5]([NH:7][CH3:8])=[O:6].[Li+].CC([N-]C(C)C)C.C1C(=O)N([Cl:27])C(=O)C1>C1COCC1>[Cl:1][C:2]1[C:3]([Cl:27])=[C:4]([CH:9]=[CH:10][N:11]=1)[C:5]([NH:7][CH3:8])=[O:6]
Reactant: CNC(=O)c1ccnc(Cl)c1
Reactant: O=C1CCC(=O)N1Cl
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CNC(=O)c1ccnc(Cl)c1Cl
Temperature: -78 °C
Reaction time: 1 h

Procedure:
2-Chloro-N-methyl-isonicotinamide (12-2, 1.19 g, 6.98 mmol) was dissolved in 20 mL anhydrous THF and the solution was cooled to −78° C. LDA (2M, 7.33 mL, 14.7 mmol) was added dropwise and the reaction turns orange. After 15 min NCS (1.02 g, 7.67 mmol) was added and the reaction was allowed to warm to RT. After 1 h at RT HPLC shows ˜3:1 starting material/product. The reaction was quenched with water, extracted 3× w/ EtOAc, and the organic phases were dried over Na2SO4, filtered, and concentrated. The residue vias purified by preparative reverse phase HPLC to afford the pure titled compound. 1H NMR (CDCl3) δ8.36 (d, 1H, J=4.8 Hz), 7.41 (d, 1H, J=4.8 Hz), 6.10 (bs, 1H), 3.05 (d, 3H, J=4.9 Hz).
Reaction SMILES: [Cl-].[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([CH:13]3[C:22]4[C:17](=[CH:18][CH:19]=[C:20]([O:23][CH2:24][CH2:25][NH:26][S:27]([CH2:30][CH2:31][CH3:32])(=[O:29])=[O:28])[CH:21]=4)[CH2:16][CH2:15][NH2+:14]3)[CH2:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[H][H]>CO.[Pd]>[Cl-:2].[C:6]1([C:9]2([CH:13]3[C:22]4[C:17](=[CH:18][CH:19]=[C:20]([O:23][CH2:24][CH2:25][NH:26][S:27]([CH2:30][CH2:31][CH3:32])(=[O:29])=[O:28])[CH:21]=4)[CH2:16][CH2:15][NH2+:14]3)[CH2:12][CH2:11][CH2:10]2)[CH:5]=[CH:4][CH:3]=[CH:8][CH:7]=1
Reactant: CCCS(=O)(=O)NCCOc1ccc2c(c1)C(C1(c3ccc(Cl)cc3)CCC1)[NH2+]CC2
Reactant: [H][H]
Agent: [Pd]
Agent: [Cl-]
Solvent: CO
Solvent: CCN(CC)CC
Product: CCCS(=O)(=O)NCCOc1ccc2c(c1)C(C1(c3ccccc3)CCC1)[NH2+]CC2

Procedure:
1-(1-(4-Chlorophenyl)cyclobutyl)-7-(2-(propylsulfonamido)ethoxy)-1,2,3,4-tetrahydroisoquinolinium chloride (187 mg, 0.374 mmol, example 4), triethylamine (91 mg, 0.897 mmol), Pd/C (11.95 mg, 0.011 mmol) were suspended in dry MeOH (5 ml) and treated with hydrogen gas at ambient pressure for 14 h. The solvent was removed and the residue was purified by column chromatography using silica gel dichloromethane/methanol (97:3->95:5) as the eluent. The product was transferred into the hydrochloride with isopropylether and HCl dissolved in isopropanol (6%). The product was obtained as a white powder (68.0 mg, 0.146 mmol, 39%.)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:20][CH2:19][C:11]2([C:15](=[O:16])[N:14]([OH:17])[C:13](=[O:18])[CH2:12]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Cl[CH2:24][C:25]#[N:26].C(OCC)(=O)C>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:20][CH2:19][C:11]2([C:15](=[O:16])[N:14]([O:17][CH2:24][C:25]#[N:26])[C:13](=[O:18])[CH2:12]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: N#CCCl
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CC(=O)N(O)C2=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CC(=O)N(OCC#N)C2=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 8-tert-butyloxycarbonyl-2-hydroxy-2,8-diazaspiro[4,5]decane-1,3-dione (0.56 g) in dimethylformamide (5 ml) was added 88 mg of sodium hydride (60% in oil), and the mixture was stirred for one hour at room temperature. To the mixture was added chloroacetonitrile (140 μl). The whole mixture was stirred for 2 hours at room temperature, to which was added ethyl acetate (30 ml), followed by washing with a saturated aqueous solution of sodium hydrogencarbonate and then with a 10% aqueous solution of citric acid. The organic layer was dried over anhydrous magnesium sulfate, then the solvent was evaporated off. The residue was recrystallized from ethyl acetate-diethyl ether to obtain 0.53 g of a colorless solid, m.p. 138° to 139° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][N:15]=[N:14][CH:13]=2)[N:3]=1.[F:18][C:19]1[CH:20]=[C:21]([NH2:26])[CH:22]=[CH:23][C:24]=1[F:25]>CC(O)C>[F:18][C:19]1[CH:20]=[C:21]([NH:26][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=[C:4]([C:12]3[CH:17]=[CH:16][N:15]=[N:14][CH:13]=3)[N:3]=2)[CH:22]=[CH:23][C:24]=1[F:25]
Reactant: Clc1nc(-c2ccnnc2)nc2ccccc12
Reactant: Nc1ccc(F)c(F)c1
Solvent: CC(C)O
Product: Fc1ccc(Nc2nc(-c3ccnnc3)nc3ccccc23)cc1F
Temperature: 85 °C
Yield: 53.1 %

Procedure:
(This method is representative of method G1, G2, and G3. These three methods can be implemented in a similar way except for substitution of the appropriate solvent and temperature) The mixture of 4-chloro-2-(pyridazin-4-yl)quinazoline (10 mg, 0.041 mmol, 1 eq.) and 3,4-difluorobenzenamine (11 mg, 0.082 mmol, 2 eq.) was suspended in i-PrOH. The mixture was heated at 85° C. overnight. After cooling, the resulting precipitate was filtered and purified on HPLC (Condition C). 7.3 mg of N-(3,4-difluorophenyl)-2-(pyridazin-4-yl)quinazolin-4-amine was obtained (yield 53%). LCMS m/z=336.0 (M+1) (Method B) (retention time=1.731 min). 1H-NMR (400 MHz, DMSO-d6): δ 10.23 (s, 1H), 10.00 (dd, J=2.2, 1.3 Hz, 1H), 9.44 (dd, J=5.4, 1.2 Hz, 1H), 8.59 (d, J=8.1 Hz, 1H), 8.39 (dd, J=5.4, 2.4 Hz, 1H), 8.05-8.13 (m, 1H), 7.99 (s, 1H), 7.97 (d, J=3.6 Hz, 1H), 7.72-7.79 (m, 2H), 7.51-7.61 (m, 1H).
Reaction SMILES: [CH3:1][C:2]1([CH2:6][S:7][CH2:8][C:9]2([CH3:13])[CH2:12][O:11][CH2:10]2)[CH2:5][O:4][CH2:3]1.C[OH:15]>O>[S:7]([CH2:6][C:2]1([CH3:1])[CH2:5][O:4][CH2:3]1)([CH2:8][C:9]1([CH3:13])[CH2:10][O:11][CH2:12]1)=[O:15]
Reactant: CC1(CSCC2(C)COC2)COC1
Reactant: CO
Solvent: O
Product: CC1(CS(=O)CC2(C)COC2)COC1
Temperature: 0 °C
Reaction time: 12 h

Procedure:
A 1-L round-bottom flask was charged with a solution of 6 (14.9 g, 73.6 mmol) in MeOH (240 mL) and cooled to 0° C. A solution of NaIO4 (16.5 g, 77.3 mmol) in water (180 mL) was added via addition funnel over ˜15 min. The ice bath was removed and the slurry was warmed to rt. MeOH (2×50 mL, added 20 min apart) was added, and the mixture was stirred for 12 h at rt. The mixture was filtered through a fritted funnel, and the white precipitate was washed with MeOH. The combined filtrate and washings were concentrated in vacuo, and the concentrate was coevaporated with toluene (200 mL). CH2Cl2 (400 mL) was added to the residue, followed by MgSO4. The mixture was filtered, and the filtrate was concentrated in vacuo to afford crude 3 (15.82 g) as a yellow solid. To the flask containing the crude solid was added toluene (200 mL), and the slurry was heated to 60° C. to affect complete dissolution. Decolorizing carbon was added, and the mixture was filtered by gravity into a 1-L Erlenmeyer flask. To the colorless solution was slowly added distilled hexanes (˜100 mL total) until cloudiness/precipitation occurred. The mixture was allowed to stand at rt overnight. Upon filtration and drying under high vacuum, 3 (10.49 g) was collected as a white solid. Material recovered from the mother liquor was recrystallized to afford an additional 2.68 g of 3 as white solid for a total yield of 82%. Reported analytical data refer to that of the first crop: Mp 92.8-94.1° C.; IR (ATR) 2939, 2863, 1451, 1381, 1227, 1026, 971 cm−1; H NMR (400 MHz, CDCl3) δ 4.80 (d, J=6.0 Hz, 2H), 4.61 (d, J=5.6 Hz, 2H), 4.50 (d, J=5.4 Hz, 2H), 4.45 (d, J=6.0 Hz, 2H), 3.38 (d, J=12.9 Hz, 2H), 2.75 (d, J=12.9 Hz, 2H), 1.61 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 82.4, 82.0, 61.9, 38.4, 23.4; HRMS (ES) m/z calc for C10H18O3NaS (M+Na) 241.0874. found 241.0885.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([Si:8]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)([CH3:15])[CH2:9][N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:30][C:31]([SH:34])([Cl:33])[Cl:32]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([Si:8]([C:16]2[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=2)([CH3:15])[CH2:9][N:10]2[C:14]([S:34][C:31]([Cl:33])([Cl:32])[Cl:30])=[N:13][CH:12]=[N:11]2)=[CH:6][CH:7]=1
Reactant: SC(Cl)(Cl)Cl
Reactant: C[Si](Cn1cncn1)(c1ccc(F)cc1)c1ccc(F)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[Si](Cn1ncnc1SC(Cl)(Cl)Cl)(c1ccc(F)cc1)c1ccc(F)cc1
Reaction time: 2 h
Yield: 59.6 %

Procedure:
To a solution of 4.0 g (0.013 mol) of bis(4-fluorophenyl)methyl(1H-1,2,4-triazol-1-ylmethyl)silane and 2.0 mL (0.014 mol) of triethylamine in 50 mL of methylene chloride at 6° was added 1.4 mL (0.013 mol) of perchloromethylmercaptan over 2 minutes. The reaction temperature rose 6°. The dark solution was stirred at 25° for 2 hours, then diluted with methylene chloride, washed with water and brine, and evaporated to give 3.6 g of the title compound as an oil: ir (neat) 3100, 3020, 2960, 1590, 1500; nmr (CDCl3) δ 0.7 (3H, s), 4.4 (2H, s), 7.1 (4H, t), 7.5 (4H, dd), 8.1 (1H, s); mass spectrum: m/e 464.
Reaction SMILES: [NH2:1][N:2]1[CH:6]=[CH:5][C:4]([Cl:7])=[C:3]1[C:8]([O:10]CC1C=CC=CC=1)=[O:9].Cl.C(OCC)C>CO.[Pd]>[NH2:1][N:2]1[CH:6]=[CH:5][C:4]([Cl:7])=[C:3]1[C:8]([OH:10])=[O:9]
Reactant: Nn1ccc(Cl)c1C(=O)OCc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: Nn1ccc(Cl)c1C(=O)O
Reaction time: 21 h
Yield: 103.7 %

Procedure:
To a solution of benzyl 1-amino-3-chloro-1H-pyrrole-2-carboxylate (20.56 g, 0.08 mol) in methanol (205 mL) was added 32.1 mL of a 3M methanolic solution of HCl (0.1 mol) and 7.7 g (0.07 mol) of 10% palladium on charcoal and this mixture was submitted to hydrogenation in a Parr apparatus working at 25 psi and room temperature during 21 hours. At the end of this period, the reaction was stopped filtering palladium catalyst through a pad of Celite® and the filtrate was concentrated in vacuum to give a light brown solid that was macerated with 40 mL of diethyl ether. This solid was filtrated and washed with petroleum ether to yield 13.32 g of the title compound with a purity of 55% (59% yield) being the dehalogenated compound the main impurity. No further purifications were done proceeding to the next step.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH:17]3[CH2:20][N:19]([CH2:21][CH3:22])[CH2:18]3)=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[C:23]([O:26][CH2:27][C:28]1[C:33]([N:34]2[CH2:46][CH2:45][N:37]3[C:38]4[CH2:39][CH2:40][CH2:41][CH2:42][C:43]=4[CH:44]=[C:36]3[C:35]2=[O:47])=[CH:32][C:31]([F:48])=[CH:30][C:29]=1B1OC(C)(C)C(C)(C)O1)(=[O:25])[CH3:24]>>[C:23]([O:26][CH2:27][C:28]1[C:33]([N:34]2[CH2:46][CH2:45][N:37]3[C:38]4[CH2:39][CH2:40][CH2:41][CH2:42][C:43]=4[CH:44]=[C:36]3[C:35]2=[O:47])=[CH:32][C:31]([F:48])=[CH:30][C:29]=1[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH:17]3[CH2:20][N:19]([CH2:21][CH3:22])[CH2:18]3)=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1)(=[O:25])[CH3:24]
Reactant: CCN1CC(c2ccc(Nc3cc(Br)cn(C)c3=O)nc2)C1
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cc(F)cc1N1CCn2c(cc3c2CCCC3)C1=O
Product: CCN1CC(c2ccc(Nc3cc(-c4cc(F)cc(N5CCn6c(cc7c6CCCC7)C5=O)c4COC(C)=O)cn(C)c3=O)nc2)C1
Yield: 65 %

Procedure:
Following Example 136e, starting with 250a and 4-fluoro-2-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl acetate 210d, a 65% yield of 250b was obtained. LCMS: (M+H)+ 639
Reaction SMILES: CC1(C)OC(CO[C:9]2[C:18](C)=[CH:17][C:12]([C:13]([NH:15][OH:16])=[NH:14])=[CH:11][C:10]=2C)CO1.[OH:22][CH2:23]C1C=CC(C#N)=CC=1>C(N(CC)CC)C>[OH:16][NH:15][C:13](=[NH:14])[C:12]1[CH:11]=[CH:10][C:9]([CH2:23][OH:22])=[CH:18][CH:17]=1
Reactant: Cc1cc(C(=N)NO)cc(C)c1OCC1COC(C)(C)O1
Reactant: N#Cc1ccc(CO)cc1
Solvent: CCN(CC)CC
Product: N=C(NO)c1ccc(CO)cc1

Procedure:
The title compound is prepared in analogy to rac-4-(2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-N-hydroxy-3,5-dimethyl-benzamidine (step b) starting from 4-hydroxymethyl-benzonitrile and using triethylamine as base; LC-MS: tR=0.21 min, [M+1]+=167.04.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Cl:7][C:8]1[N:17]=[C:16]2[C:11]([CH:12]=[CH:13][C:14]([N:18]3[CH:26]([O:27][C:28](OC4C=CC=CC=4)=[O:29])[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[C:19]3=[O:37])=[N:15]2)=[CH:10][CH:9]=1.C(OC(C)C)(C)C>C(#N)C>[Cl:7][C:8]1[N:17]=[C:16]2[C:11]([CH:12]=[CH:13][C:14]([N:18]3[CH:26]([O:27][C:28]([N:1]4[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]4)=[O:29])[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[C:19]3=[O:37])=[N:15]2)=[CH:10][CH:9]=1
Reactant: O=C(Oc1ccccc1)OC1c2ccccc2C(=O)N1c1ccc2ccc(Cl)nc2n1
Reactant: C1CNCCN1
Solvent: CC(C)OC(C)C
Solvent: CC#N
Product: O=C(OC1c2ccccc2C(=O)N1c1ccc2ccc(Cl)nc2n1)N1CCNCC1
Yield: 47 %

Procedure:
Anhydrous piperazine (5.15 g.) is added to a suspension of 2-(7-chloro-1,8-naphthyridin-2-yl)-3-phenoxycarbonyloxy-isoindolin-1-one (5.2 g.) in acetonitrile (32 cc.). The reaction mixture is stirred for 1 hour at a temperature of about 20° C. and diisopropyl ether (150 cc.) is then added. The insoluble product is filtered off and washed with a mixture (20 cc.) of acetonitrile and diisopropyl ether (50--50 by volume) and then with diisopropyl ether (50 cc.). After recrystallisation of the product thus obtained from a mixture (160 cc.) of acetonitrile and methanol (90--10 by volume), 2-(7-chloro-1,8-naphthyridin-2-yl)-3-(piperazin-1-yl)carbonyloxy-isoindolin-1-one (2.4 g.), melting with decomposition at 245° C., is obtained.
Reaction SMILES: Br[C:2]1[S:3][C:4]([Cl:7])=[CH:5][CH:6]=1.[CH:8]([C:10]1[S:14][C:13](B(O)O)=[CH:12][CH:11]=1)=[O:9].C([O-])([O-])=O.[Na+].[Na+]>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.CCO>[Cl:7][C:4]1[S:3][C:2]([C:13]2[S:14][C:10]([CH:8]=[O:9])=[CH:11][CH:12]=2)=[CH:6][CH:5]=1
Reactant: Clc1ccc(Br)s1
Reactant: O=Cc1ccc(B(O)O)s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: O=Cc1ccc(-c2ccc(Cl)s2)s1
Temperature: 85 °C
Reaction time: 0.17 h
Yield: 23.6 %

Procedure:
In a flask are placed 2-bromo-5-chlorothiophene (0.55 mL, 5.0 mmol) and Pd(PPh3)4 (0.17 g, 0.15 mmol), and the flask is vacuum purged and nitrogen filled (3×). THF (10 mL) is added by syringe and stirred 10 min. In a separate flask is placed 5-formyl-2-thiopheneboronic acid (0.94 g, 6.0 mmol) and EtOH (2 mL) and stirred until dissolved. This mixture is added by syringe to the first flask followed by vacuum purge and nitrogen fill (3×). A solution of Na2CO3 (2M, 5.0 mL, 10.0 mmol) is added by syringe followed by vacuum purge and nitrogen fill (3×). The reaction mixture is heated at 85° C. for 20 h. The reaction is cooled to rt and diluted with water. The aqueous solution is extracted with ether (3×). The combined ether layers are washed with water (3×) then brine (2×). The ether is dried over MgSO4, filtered, and concentrated. The crude product is purified over silica gel (5% EtOAc-heptane) to provide the product as an orange solid (0.27 g, 24%). 1H NMR (400 MHz, CDCl3) δ 9.89, 7.69, 7.20, 7.16, 6.93.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:15]([OH:17])=O)=[C:7]2[C:11]=1[O:10][C:9]([CH2:12][O:13][CH3:14])=[CH:8]2.[CH3:18][C:19]1[C:23]([NH2:24])=[C:22]([CH3:25])[O:21][N:20]=1>>[CH3:18][C:19]1[C:23]([NH:24][C:15]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[C:11]3[O:10][C:9]([CH2:12][O:13][CH3:14])=[CH:8][C:7]=23)=[O:17])=[C:22]([CH3:25])[O:21][N:20]=1
Reactant: COCc1cc2c(C(=O)O)ccc(OC)c2o1
Reactant: Cc1noc(C)c1N
Product: COCc1cc2c(C(=O)Nc3c(C)noc3C)ccc(OC)c2o1
Yield: 69.4 %

Procedure:
Starting from 7-methoxy-2-methoxymethylbenzofuran-4-carboxylic acid (0.19 g) and 3,5-dimethylisoxazol-4-ylamine (88 mg). Purification by column chromatography on silica eluting with ethyl acetate afforded the title compound as a cream solid (0.18 g).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][CH2:12][CH2:13][CH3:14])[CH:8]=[CH:7][C:5]=2[N:6]=1.Cl[C:16]([O:18][CH2:19][CH3:20])=[O:17]>N1C=CC=CC=1>[CH2:19]([O:18][C:16](=[O:17])[NH:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][CH2:12][CH2:13][CH3:14])[CH:8]=[CH:7][C:5]=2[N:6]=1)[CH3:20]
Reactant: CCOC(=O)Cl
Reactant: CCCOc1ccc2nc(N)sc2c1
Solvent: c1ccncc1
Product: CCCOc1ccc2nc(NC(=O)OCC)sc2c1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a chilled solution of 10.4 g. 2-amino-6-n-propoxybenzothiazole in 50 ml dry pyridine is dropwise added 6 g. ethyl chloroformate with stirring. The mixture is then allowed to stand at room temperature for 8 hrs. It is poured in 200 g. of ice water and stirred for 30 mins. The white solid product is separated by filtration and dried. Crystallization from ethanol gave 12 g. of the product. m.p. 175°-177° C.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5](B2OC(C)(C)C(C)(C)O2)=[CH:4][C:3]=1[CH3:18].Br[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[N:21]=1>>[Br:1][C:2]1[C:3]([CH3:18])=[CH:4][C:5]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[N:21]=2)=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1cccc(Br)n1
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)cc(C)c1Br
Product: Cc1cccc(-c2cc(C)c(Br)c(C)c2)n1

Procedure:
The title compound is prepared from 2-bromo-1,3-dimethyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzene and 2-bromo-6-methyl-pyridine following a procedure analogous to that described in Step 1 of Intermediate 56. LC (method 7): tR=0.88 min; Mass spectrum (ESI+): m/z=276/278 (Br) [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][NH:8][CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10]1)([CH3:4])([CH3:3])[CH3:2].[C:19]([O:23][C:24]([NH:26][C@H:27]([C:43](O)=[O:44])[CH2:28][CH2:29][CH2:30][CH2:31][NH:32][C:33]([O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:34])=[O:25])([CH3:22])([CH3:21])[CH3:20]>>[C:1]([O:5][C:6](=[O:18])[CH2:7][N:8]([C:43](=[O:44])[C@H:27]([CH2:28][CH2:29][CH2:30][CH2:31][NH:32][C:33]([O:35][CH2:36][C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)=[O:34])[NH:26][C:24]([O:23][C:19]([CH3:22])([CH3:20])[CH3:21])=[O:25])[CH:9]1[CH2:10][C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:17]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)O
Reactant: CC(C)(C)OC(=O)CNC1Cc2ccccc2C1
Product: CC(C)(C)OC(=O)CN(C(=O)[C@H](CCCCNC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C)C1Cc2ccccc2C1
Yield: 69.3 %

Procedure:
By reacting 8.2 g of N-(indan-2-yl)glycine tert-butyl ester with 13 g of Nα -tert-butoxycarbonyl-Nε -carbobenzoxy-L-lysine as in Reference Example 5, there is obtained 14 g of Nα -tert-butoxycarbonyl-Nε -carbobenzoxy-L-lysyl-N-(indan-2-yl)glycine tert-butyl ester as a colorless oil.