Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2]/[CH:3]=[CH:4]/[CH:5]1[CH2:9][C:8]2[CH:10]=[C:11]([C:14]3[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=3)[CH:12]=[CH:13][C:7]=2[O:6]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)=O.C(Cl)Cl>[O:2]=[CH:3][CH2:4][CH:5]1[CH2:9][C:8]2[CH:10]=[C:11]([C:14]3[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=3)[CH:12]=[CH:13][C:7]=2[O:6]1
Reactant: CO/C=C/C1Cc2cc(-c3ccc(C#N)cc3)ccc2O1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: ClCCl
Solvent: CC(C)=O
Product: N#Cc1ccc(-c2ccc3c(c2)CC(CC=O)O3)cc1
Yield: 86.5 %

Procedure:
A solution of Example 67A (0.5 g, 1.8 mmol) in acetone (10 mL) and p-toluenesulfonic acid monohydrate (0.51 g, 2.7 mmol) was stirred for 45 minutes, diluted with CH2Cl2 (150 mL), washed with cold aqueous sodium bicarbonate (2×100 mL, 10% solution), water (2×100 mL), dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified on silica using CH2Cl2 to give the titled compound (0.41 g, 87%). 1H NMR (CDCl3): 2.95 (m, 2H), 3.65 (m, 3H), 6.82 (d, J=7 Hz, 1H), 7.40 (m, 2H), 7.62 (m, 4H), 9.55(d, J=7 Hz, 1H); MS (DCI) 263 (M+), 281 (M+NH4+).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][NH2:11])=[CH:6][CH:5]=1.C(N(CC)CC)C.[C:19]([CH2:25][C:26]#[N:27])(=O)[C:20]([CH3:23])([CH3:22])[CH3:21]>C1(C)C=CC=CC=1>[C:20]([C:19]1[CH:25]=[C:26]([NH2:27])[N:10]([C:7]2[CH:8]=[CH:9][C:4]([O:3][CH3:2])=[CH:5][CH:6]=2)[N:11]=1)([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)C(=O)CC#N
Reactant: COc1ccc(NN)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COc1ccc(-n2nc(C(C)(C)C)cc2N)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70.9 %

Procedure:
Solid 4-methoxyphenylhydrazine hydrochloride (25.3 g) was suspended in toluene (100 mL) and treated with triethylamine (20.2 g). The mixture was stirred at RT for 30 min and treated with pivaloylacetonitrile (18 g). The reaction was heated to reflux and stirred overnight. The hot mixture was filtered, the solids washed with hexane and dried in vacuo to afford 3-tert-butyl-1-(4-methoxyphenyl)-1H-pyrazol-5-amine (25 g, 70%). 1H NMR (DMSO-d6): δ 7.5 (d, 2H); 7.0 (d, 1H), 6.4 (s, 1H), 6.1 (s, 2H), 3.9 (s, 3H), 1.3 (s, 9H).
Reaction SMILES: [C:1]([N:11]1[CH2:18][CH2:17][CH2:16][C@H:12]1[C:13](O)=[O:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].B.CSC.O>C1COCC1>[C:1]([N:11]1[CH2:18][CH2:17][CH2:16][CH:12]1[CH2:13][OH:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2]
Reactant: O=C(O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Agent: B
Solvent: CSC
Solvent: C1CCOC1
Solvent: O
Product: O=C(OCc1ccccc1)N1CCCC1CO
Temperature: 0 °C
Reaction time: 16 h
Yield: 91.2 %

Procedure:
N-Carbobenzyloxy-L-proline (0.048 moles, 12.0 g) was dissolved in 50 ml THF and cooled to 0° C. Borane-methyl sulfide complex (0.05 moles, 25 ml of 2M in THF) was added dropwise. The reaction was stirred for 16 hours at room temperature and then cooled to 0° C. Water (50 ml) was added dropwise. The solution was filtered. The solid was washed with ethyl acetate. The organic solutions were combined, washed with water, dried over sodium sulfate and concentrated to yield 10.3 g of N-carbobenzyloxy-2-hydroxymethyl pyrrolidine. N-carbobenzyloxy-2-hydroxymethyl pyrrolidine (0.038 moles, 9.0 g) and triethylamine (0.076 mole) were dissolved in 150 ml of chloroform. Tosyl chloride (0.0475 moles, 9.05 g) was added portionwise followed by dimethylaminopyridine (200 mg). The solution was stirred overnight at room temperature. Chloroform was added. The solution was washed with water, dried over sodium sulfate, and concentrated. The resulting tosylate (0.0385 moles, 15.0 g) and sodium cyanide (0.048 moles, 2.35 g) were dissolved in 150 ml DMSO. The reaction was heated to reflux until completion as measured by thin layer chromatography. The reaction was cooled; water was added. The intermediate was extracted with ethyl acetate and concentrated to yield 9.56 g of 2-pyrrolidineacetonitrile. The nitrile was hydrolyzed by dissolving in 150 ml ethanolic HCl and slowing adding water to the solution. The solution was then concentrated in vacuo. Ethyl acetate and sodium bicarbonate were added. The ethyl acetate solution was concentrated. The residue dissolved in ethyl acetate, filtered and concentrated. The resulting acetate was chromatographed on silica gel eluted with a gradient of 50-100% ethyl acetate in hexane followed by a gradient of 0-20% ethanol in ethyl acetate to yield 4.35 g of ethyl 2-pyrrolidineacetate. (MS)
Reaction SMILES: [S:1]([C:4]1[S:8][C:7]([NH2:9])=[N:6][CH:5]=1)[C:2]#[N:3].[CH:10]1([NH:16][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.C1C[O:26][CH2:25]C1>CN(C1C=CN=CC=1)C>[CH:17]1([N:16]([CH:10]2[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]2)[C:25]([NH:9][C:7]2[S:8][C:4]([S:1][C:2]#[N:3])=[CH:5][N:6]=2)=[O:26])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]1
Reactant: C1CCC(NC2CCCCC2)CC1
Reactant: N#CSc1cnc(N)s1
Reactant: C1CCOC1
Agent: CN(C)c1ccncc1
Product: N#CSc1cnc(NC(=O)N(C2CCCCC2)C2CCCCC2)s1
Temperature: 65 °C
Reaction time: 8 h

Procedure:
An equimolar mixture of 1,1-carbonyldiimidazole, 5-thiocyanato-thiazol-2-ylamine (commercial available or prepared as described in J. Am. Chem. Soc 71, 4007, 1949 or J. Med. Chem., 20, 572, 1977) and DMAP (5 mol %) in THF was heated for 2 h at 60-70° C. and then cooled to room temperature. Dicyclohexyl amine (1 equivalent) was added and the reaction is stirred overnight at room temperature. The reaction mixture was quenched with water. The organic phase was isolated and the aqueous phase was extracted with CH2Cl2, and the combined organic phases were dried and concentrated in vacuo. The crude product was purified by flash chromatography (heptane:EtOAc 100:0 50:50) affording 1,1-dicyclohexyl-3-(5-thiocyanato-thiazol-2-yl)-urea as an oil.
Reaction SMILES: C([O:3][C:4](=[O:26])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2([C:19]3[CH:24]=[CH:23][C:22](Br)=[CH:21][CH:20]=3)[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[CH:9][CH:8]=1)C.CC1(C)C(C)(C)OB([C:35]2[CH:36]=[N:37][NH:38][CH:39]=2)O1>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>[NH:37]1[CH:36]=[C:35]([C:22]2[CH:21]=[CH:20][C:19]([C:13]3([C:10]4[CH:9]=[CH:8][C:7]([O:6][CH2:5][C:4]([OH:3])=[O:26])=[CH:12][CH:11]=4)[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[CH:24][CH:23]=2)[CH:39]=[N:38]1
Reactant: CCOC(=O)COc1ccc(C2(c3ccc(Br)cc3)CCNCC2)cc1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: O=C(O)COc1ccc(C2(c3ccc(-c4cn[nH]c4)cc3)CCNCC2)cc1
Temperature: 80 °C
Yield: 5 %

Procedure:
{4-[4-(4-bromo-phenyl)-piperidin-4-yl]-phenoxy}-acetic acid ethyl ester was reacted with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole following the procedure set out in Example 1, but using tetrakis(triphenylphosphine)palladium (0) as the catalyst and heating at 80° C. for 30 minutes, to yield a mixture of the title compounds. On work up the basic aqueous extract was neutralised with hydrochloric acid and extracted with ethyl acetate (×2), then these organic extracts were combined and washed with brine, dried (MgSO4), filtered and concentrated to give a crude product that was recrystallised from water to afford (4-{4-[4-(1H-pyrazol-4-yl)-phenyl]-piperidin-4-yl}-phenoxy)-acetic acid (12 mg, 5%); LCMS (PS-A3) Rt 5.33 min [M+H]+ 378. 1H NMR (DMSO-d6) δ 2.22-2.26 (4H, m), 2.67-2.71 (4H, m), 4.65 (2H, s) 6.67 (2H, d), 7.11 (2H, d), 7.24 (2H, d), 7.46 (2H, d), 7.96 (2H, br.s).
Reaction SMILES: [CH:1]#[CH:2].[N+:3]([C:6]1[CH:19]=[CH:18][C:9]([C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:11])=[CH:8][CH:7]=1)([O-:5])=[O:4].Cl>O1CCCC1>[N+:3]([C:6]1[CH:7]=[CH:8][C:9]([C:10]([C:1]#[CH:2])([OH:11])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:18][CH:19]=1)([O-:5])=[O:4]
Reactant: C#C
Reactant: O=C(c1ccccc1)c1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: C1CCOC1
Product: C#CC(O)(c1ccccc1)c1ccc([N+](=O)[O-])cc1
Yield: 91 %

Procedure:
Acetylene is introduced for 30 minutes into a 20°-22° C mixture of 118 ml. of tetrahydrofuran and 16.8 g. of potassium-tert.butylate, and thereafter 22.7 g. of 4-nitro-benzophenone are added to the mixture. The introduction of acetylene is continued at 20° to 22° C for an additional 30 minutes, then the mixture is neutralized with 5 n hydrochloric acid under nitrogen atmosphere. The organic phase is separated, dried over anhydrous sodium sulfate, and the solvent is distilled off in vacuo. 23.1 g. (91%) of 4-nitro-α-ethynyl-benzhydrol are obtained; m.p.: 88°-89° C.
Reaction SMILES: [O:1]=[C:2]1[CH:7]([N:8]2[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([CH2:17][NH:18][C:19](=[O:38])[NH:20][C:21]4[CH:22]=[C:23]5[C:28](=[CH:29][CH:30]=4)[CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][CH2:24]5)[CH:14]=3)[C:9]2=[O:39])[CH2:6][CH2:5][C:4](=[O:40])[NH:3]1.Cl>C(Cl)Cl.C(OCC)C>[O:1]=[C:2]1[CH:7]([N:8]2[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([CH2:17][NH:18][C:19]([NH:20][C:21]4[CH:22]=[C:23]5[C:28](=[CH:29][CH:30]=4)[CH2:27][NH:26][CH2:25][CH2:24]5)=[O:38])[CH:14]=3)[C:9]2=[O:39])[CH2:6][CH2:5][C:4](=[O:40])[NH:3]1
Reactant: CC(C)(C)OC(=O)N1CCc2cc(NC(=O)NCc3ccc4c(c3)CN(C3CCC(=O)NC3=O)C4=O)ccc2C1
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: O=C1CCC(N2Cc3cc(CNC(=O)Nc4ccc5c(c4)CCNC5)ccc3C2=O)C(=O)N1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of tert-butyl 6-(3-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)ureido)-3,4-dihydroisoquinoline-2(1H)-carboxylate (0.55 g, 1.0 mmol) in methylene chloride (100 mL) is treated with HCl (5 mL of a 2N solution in diethyl ether), and stirred at ambient temperature for 48 hours. The mixture is evaporated under vacuum, and triturated in ethyl acetate (10 mL), filtered, and dried under vacuum.
Reaction SMILES: [C:1]([NH:4][CH:5]1[CH2:20][CH2:19][C:8]2=[C:9]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[S:10][C:11]([S:12][CH3:13])=[C:7]2[C:6]1=[O:21])(=O)[CH3:2].P(Cl)(Cl)(Cl)=O>C1(C)C=CC=CC=1>[CH3:2][C:1]1[O:21][C:6]2[C:7]3=[C:11]([S:12][CH3:13])[S:10][C:9]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:8]3[CH2:19][CH2:20][C:5]=2[N:4]=1
Reactant: CCOC(=O)c1sc(SC)c2c1CCC(NC(C)=O)C2=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: CCOC(=O)c1sc(SC)c2c1CCc1nc(C)oc1-2
Yield: 93.8 %

Procedure:
A mixture of ethyl 5-acetylamino-4,5,6,7-tetrahydro-3-methylthio-4-oxobenzo[c]thiophene-1-carboxylate (2.46 g), phosphorus oxychloride (3.46 g) and toluene (80 ml) was refluxed under heating for 1.5 hours; the solution obtained was concentrated under reduced pressure, diluted with a saturated aqueous solution of sodium hydrogen carbonate (200 ml) and extracted with ethyl acetate. The organic layer was washed with water and dried (MgSO4), after which the solvent was distilled off to yield ethyl 4,5-dihydro-2-methyl-8-methylthiothieno[3,4-g]benzoxazole-6-carboxylate (2.18 g, 94.0%), which was then recrystallized from ethyl acetate-hexane. Light-yellow needles. Melting point 131-132° C.
Reaction SMILES: [C:1]1([C:7]2[CH:16]=[CH:15][C:14]3[C:9](=[CH:10][C:11]([C:17]4[N:18]=[C:19]([CH2:27][CH:28]5[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]5)[N:20]5[CH:25]=[CH:24][N:23]=[C:22]([NH2:26])[C:21]=45)=[CH:12][CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.[C:43](OC(=O)C)(=[O:45])[CH3:44]>C(Cl)Cl>[NH2:26][C:22]1[C:21]2[N:20]([C:19]([CH2:27][CH:28]3[CH2:33][CH2:32][N:31]([C:43](=[O:45])[CH3:44])[CH2:30][CH2:29]3)=[N:18][C:17]=2[C:11]2[CH:10]=[C:9]3[C:14]([CH:15]=[CH:16][C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)=[N:8]3)=[CH:13][CH:12]=2)[CH:25]=[CH:24][N:23]=1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1nccn2c(CC3CCNCC3)nc(-c3ccc4ccc(-c5ccccc5)nc4c3)c12
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)N1CCC(Cc2nc(-c3ccc4ccc(-c5ccccc5)nc4c3)c3c(N)nccn23)CC1
Reaction time: 0.25 h

Procedure:
1-(2-Phenyl-quinolin-7-yl)-3-piperidin-4-ylmethyl-imidazo[1,5-a]pyrazin-8-ylamine (100.00 mg, 0.23 mmol) in a dried 10 mL round-bottom flask was dissolved in 1.7 mL of methylene chloride and was charged with PS-DIEA (117.95 mg, 0.46 mmol). Acetic anhydride (Ac2O) (11 μL, 0.51 equiv) was added in one portion. After 15 min., another 5.5 μL of Ac2O (0.25 equiv) was added. After another 15 min., another 2.64 μL of Ac2O (0.12 equiv) was added. After another 15 min., another 11 μL of Ac2O (0.51 equiv) was added. The reaction was filtered through a fritted funnel, and the resins were rinsed multiple times with methylene chloride. The crude product was purified by silica gel flash chromatography (wetted with 100% EtOAc, eluted with 5% (7N NH3) in MeOH/EtOAc) and afforded the desired product; 1H NMR (400 MHz, CHLOROFORM-d) δ 8.41 (1H, d, J=1.68), 8.28 (1H, d, J=8.20), 8.19 (2H, dd, J=1.51 Hz, J=1.18), 7.93 (3H, m), 7.53 (3H, m), 7.23 (1H, d, J=5.10), 7.12 (1H, d, J=5.76), 5.55 (2H, m), 4.67 (1H, d, J=13.28), 3.83 (1H, d, J=12.26), 3.06 (1H, m), 2.96 (2H, m), 2.56 (1H, m), 2.27 (1H, m), 2.10 (3H, s), 1.85 (2H, t), 1.31 (2 H, m); MS (ES+): m/z 477.11/478.08 (40/20) [MH+]; HPLC: tR=2.11 min (OpenLynx, polar—5 min).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[O:10][C:9]([CH2:12][CH2:13][NH2:14])=[CH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.Cl[C:23]([O:25][CH2:26][CH3:27])=[O:24]>C1COCC1>[CH3:1][O:2][C:3]1[C:11]2[O:10][C:9]([CH2:12][CH2:13][NH:14][C:23](=[O:24])[O:25][CH2:26][CH3:27])=[CH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: CCOC(=O)Cl
Reactant: COc1cccc2cc(CCN)oc12
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)NCCc1cc2cccc(OC)c2o1
Temperature: 25 °C
Reaction time: 5 h
Yield: 21.8 %

Procedure:
2-(7-methoxy-1-benzofuran-2-yl)ethanamine (from step 5) (100 mg, 0.523 mmol) was dissolved in THF (4 ml). To this solution triethylamine (0.211 g, 2.09 mmol) and ethyl chloroformate (0.085 g, 0.784 mmol) was added at 0° C. and then stirred at room temperature for 5 h. THF was evaporated and the residue was purified by column chromatography using 100-200 mesh silica gel and eluted in 5% ethyl acetate-petroleum ether to obtain 30 mg of yellow thick liquid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:34]=[CH:33][C:9]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]#[C:20][CH2:21][CH2:22][CH2:23][CH2:24][O:25][C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)=[CH:8][CH:7]=1)=[O:5])[CH3:2].[H][H]>C(O)(=O)C.O=[Pt]=O>[CH2:1]([O:3][C:4]([C:6]1[CH:34]=[CH:33][C:9]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][O:25][C:26]2[CH:27]=[CH:28][C:29]([Cl:32])=[CH:30][CH:31]=2)=[CH:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc(OCCCCCCCCC#CCCCCOc2ccc(Cl)cc2)cc1
Reactant: [H][H]
Agent: O=[Pt]=O
Solvent: CC(=O)O
Product: CCOC(=O)c1ccc(OCCCCCCCCCCCCCCOc2ccc(Cl)cc2)cc1
Yield: 80.3 %

Procedure:
1-(4-ethoxycarbonylphenoxy)-14-(4-chlorophenoxy)-tetradec 9-yne (2.00 g.; 0.0041 M.) in acetic acid (15 ml.) was reduced in the presence of hydrogen and PtO2 (0.05 g.) at 60° C. and atmospheric pressure. When hydrogen absorption was complete the solution was filtered, the catalyst washed well with ethanol and the solvents evaporated under reduced pressure to yield a colourless oil. 1-(4-ethoxycarbonylphenoxy)-14-(4-chlorophenoxy)-tetradecane (1.62 g.; 80%) M.P. 72.5°-73.5° C. was obtained as a pure crystalline compound by chromatography of this oil on silica-gel (100 g.).
Reaction SMILES: [C:1]([C:5]1[CH:26]=[CH:25][C:8]([CH2:9][NH:10][C:11]([C:13]2[C:14]([CH3:24])=[N:15][C:16]3[C:21]([CH:22]=2)=[CH:20][C:19](I)=[CH:18][N:17]=3)=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:27]([O-:30])([O-])=O.[Cs+].[Cs+].CC1C=N[C:37]2[C:46](C=1C)=[CH:45][CH:44]=[C:43]1[C:38]=2N=CC(C)=C1C>C(O)C1C=CC=CC=1.[Cu]I>[CH2:27]([O:30][C:19]1[CH:20]=[C:21]2[C:16](=[N:17][CH:18]=1)[N:15]=[C:14]([CH3:24])[C:13]([C:11]([NH:10][CH2:9][C:8]1[CH:25]=[CH:26][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:6][CH:7]=1)=[O:12])=[CH:22]2)[C:37]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:38]=1
Reactant: Cc1cnc2c(ccc3c(C)c(C)cnc32)c1C
Reactant: Cc1nc2ncc(I)cc2cc1C(=O)NCc1ccc(C(C)(C)C)cc1
Reactant: O=C([O-])[O-]
Agent: [Cu]I
Agent: [Cs+]
Solvent: OCc1ccccc1
Product: Cc1nc2ncc(OCc3ccccc3)cc2cc1C(=O)NCc1ccc(C(C)(C)C)cc1
Temperature: 120 °C
Yield: 235.1 %

Procedure:
In a screw cap pressure tube were N-(4-tert-butylbenzyl)-6-iodo-2-methyl-1,8-naphthyridine-3-carboxamide (135 mg, 0.30 mmol), Cs2CO3 (191.5 mg, 0.6 mmol), CuI (5.6 mg, 0.03 mmol) and 3,4,7,8-tetramethyl-1,10-phenantroline (14.0 mg, 0.06 mmol)) suspended in benzyl alcohol (4.5 ml). N2 was bubbled through the suspension for 5 min. The tube was sealed and the mixture heated to 120° C. overnight. The mixture was allowed to cool. CH2Cl2 was added and the mixture washed with H2O, dried (MgSO4), filtered and concentrated. The crude mixture was purified by flash chromatography (CH2Cl2/MeOH 98:2→97:3) yielding 62 mg of the title compound (47%).
Reaction SMILES: Cl[C:2](OC1C=CC([N+]([O-])=O)=CC=1)=[O:3].[Cl:14][C:15]1[C:20]([CH3:21])=[CH:19][C:18]([CH2:22][C@@H:23]([OH:28])[C:24]([O:26][CH3:27])=[O:25])=[CH:17][C:16]=1[CH3:29].[NH:30]1[CH2:35][CH2:34][CH:33]([N:36]2[CH2:42][CH2:41][C:40]3[CH:43]=[CH:44][CH:45]=[CH:46][C:39]=3[NH:38][C:37]2=[O:47])[CH2:32][CH2:31]1>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[O:47]=[C:37]1[N:36]([CH:33]2[CH2:32][CH2:31][N:30]([C:2]([O:28][C@@H:23]([C:24]([O:26][CH3:27])=[O:25])[CH2:22][C:18]3[CH:17]=[C:16]([CH3:29])[C:15]([Cl:14])=[C:20]([CH3:21])[CH:19]=3)=[O:3])[CH2:35][CH2:34]2)[CH2:42][CH2:41][C:40]2[CH:43]=[CH:44][CH:45]=[CH:46][C:39]=2[NH:38]1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: O=C1Nc2ccccc2CCN1C1CCNCC1
Reactant: COC(=O)[C@H](O)Cc1cc(C)c(Cl)c(C)c1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: COC(=O)[C@@H](Cc1cc(C)c(Cl)c(C)c1)OC(=O)N1CCC(N2CCc3ccccc3NC2=O)CC1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
Under a nitrogen atmosphere 1.0 g (8.2 mmol) 4-dimethylaminopyridine in 30 mL pyridine were combined with 1.7 g (8.2 mmol) 4-nitrophenyl chloroformate, stirred for 40 min at RT, then 2.0 g (8.2 mmol) methyl (R)-3-(4-chloro-3,5-dimethyl-phenyl)-2-hydroxy-propionate were added, the mixture was again stirred for 20 min at RT and then combined with 2.0 g (8.2 mmol) 3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one and the reaction mixture was stirred for 20 h at RT. The mixture was evaporated down i.vac., the residue was taken up in EtOAc, washed with 10% KHSO4 and saturated NaHCO3 solution and the organic phase was dried over. After the desiccant and solvent had been eliminated the residue was purified by chromatography (silica gel, cyc/EtOAc 1:1 to 1:2).
Reaction SMILES: C1(C[O:8][C:9]2[CH:33]=[CH:32][C:12]([CH2:13][CH:14]3[C:23]4[C:18](=[CH:19][C:20]([O:24][CH3:25])=[CH:21][CH:22]=4)[CH2:17][CH2:16][N:15]3[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[CH:11][CH:10]=2)C=CC=CC=1>C(O)(=O)C.C(O)C.[Pd]>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:13][CH:14]2[C:23]3[C:18](=[CH:19][C:20]([O:24][CH3:25])=[CH:21][CH:22]=3)[CH2:17][CH2:16][N:15]2[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[CH:32][CH:33]=1
Reactant: COc1ccc2c(c1)CCN(c1ccccc1)C2Cc1ccc(OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: COc1ccc2c(c1)CCN(c1ccccc1)C2Cc1ccc(O)cc1
Yield: 62.9 %

Procedure:
A solution of 1-{4-(phenylmethoxy)benzyl}-6-methoxy-2-phenyl-1,2,3,4-tetrahydroisoquinoline (0.60 g, 1.38 mmol), palladium (5% wt. on activated carbon, 0.06 g), and glacial acetic acid (3 drops) in ethanol (30 mL) was stirred under hydrogen for 15 hours. The reaction was filtered and concentrated to provide the title compound (0.30 g, 63% yield): ES-MS (m/z) 346 [M+H]+.
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1.[CH3:13][NH:14][CH2:15][CH2:16][NH:17][CH3:18].C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>O1CCCC1>[CH3:13][N:14]([CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1)[CH2:15][CH2:16][NH:17][CH3:18]
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: CNCCNC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CNCCN(C)Cc1ccc(C(=O)OC)cc1
Yield: 62 %

Procedure:
A mixture of methyl 4-(bromomethyl)benzoate (2 g, 8.73 mmol) and N,N′-dimethylethan-1,2-diamine (7.5 mL, 70 mmol) was heated with triethylamine (9.8 mL, 70 mmol) in tetrahydrofuran (80 mL) to reflux for two hours. After cooling, the mixture was treated with saturated sodium bicarbonate solution. The mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. Flash chromatography gave 1.28 g of methyl 4-[(methyl(2-(methylamino)ethyl)amino)methyl]benzoate, 1H NMR (300 MHz, CD3OD) δ 7.97 (d, 2H), 7.45 (d, 2H), 3.59 (s, 2H), 2.67 (m, 2H), 2.54 (m, 2H), 2.35 (s, 3H), 2.22 (s, 3H) ppm.
Reaction SMILES: [H-].[K+].[Br:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[CH:13]1[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]1.FC(F)(F)S(O[Si:26]([CH:33]([CH3:35])[CH3:34])([CH:30]([CH3:32])[CH3:31])[CH:27]([CH3:29])[CH3:28])(=O)=O>O1CCCC1>[Br:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([Si:26]([CH:33]([CH3:35])[CH3:34])([CH:30]([CH3:32])[CH3:31])[CH:27]([CH3:29])[CH3:28])[CH:8]=[C:7]2[CH:13]1[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]1
Reactant: CC(C)[Si](OS(=O)(=O)C(F)(F)F)(C(C)C)C(C)C
Reactant: CN1CCC(c2c[nH]c3ccc(Br)cc23)CC1
Agent: [H-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)[Si](C(C)C)(C(C)C)n1cc(C2CCN(C)CC2)c2cc(Br)ccc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 173.3 %

Procedure:
To a 10° C. slurry of potassium hydride (1.6 g, 14.3 mmol, 35% in mineral oil) in tetrahydrofuran (40 mL) was added neat 5-bromo-3-(1-methyl-4-piperidinyl)indole (2.8 g, 9.5 mmol) portionwise over 30 minutes. The resulting reaction mixture was stirred at 0° C. for 1 hour. Triisopropylsilyl trifluoromethanesulfonate (3.1 mL, 11.4 mmol) was added dropwise over 20 minutes and a slight exotherm was observed. After stirring 2 hours at 0° C., the reaction was quenched with ice chips then diluted with water and methylene chloride. The layers were separated and the aqueous layer was extracted with methylene chloride. The organic extracts were combined, washed with brine, dried over sodium sulfate, and concentrated in vacuo to give 7.4 g of a clear colorless oil. Purification by chromatography (florisil, 50:50 methylene chloride:hexanes, then 100% methylene chloride, then 95:5 methylene chloride:methanol) provided 3.6 g (84.1%) of the title compound. MS(FD) 448, 450 (M+).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=1)[C:3]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[NH:17][S:18]([CH3:21])(=[O:20])=[O:19])[CH2:7][CH2:6]1)=[O:4].[N:30]1([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:39][C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH2:32][C@H:31]1[C:40](O)=[O:41].CCN=C=NCCCN(C)C.CI.C1C=NC2N(O)N=NC=2C=1>CN(C=O)C>[Cl:29][C:26]1[CH:25]=[CH:24][C:23]([CH2:22][C@H:2]([NH:1][C:40]([C@@H:31]2[CH2:32][C:33]3[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH2:39][N:30]2[C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])=[O:41])[C:3]([N:5]2[CH2:6][CH2:7][N:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[NH:17][S:18]([CH3:21])(=[O:19])=[O:20])[CH2:9][CH2:10]2)=[O:4])=[CH:28][CH:27]=1
Reactant: CS(=O)(=O)Nc1ccccc1N1CCN(C(=O)[C@@H](N)Cc2ccc(Cl)cc2)CC1
Reactant: CC(C)(C)OC(=O)N1Cc2ccccc2C[C@H]1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CI
Product: CC(C)(C)OC(=O)N1Cc2ccccc2C[C@H]1C(=O)N[C@@H](Cc1ccc(Cl)cc1)C(=O)N1CCN(c2ccccc2NS(C)(=O)=O)CC1

Procedure:
tert-Butyl (3S)-3-(N-[(1S)-1-[(4-chlorophenyl)methyl]-2-(4-{2-[(methylsulfonyl)amino]phenyl}piperazinyl)-2-oxoethyl]carbamoyl)-1,2,3,4-tetrahydroisoquinoline-2-carboxylate was prepared from (2S)-2-amino-3-(4-chlorophenyl)-1-(4-{2-[(methylsulfonyl)amino]phenyl}-piperazinyl)propan-1-one (Step 2) (380 mg, 0.87 mmol), according to the procedure for Preparation XIX using Boc-L-Tic-OH (250 mg, 0.91 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide methiodide (540 mg, 1.8 mmol), HOAT (140 mg, 1.0 mmol), and DMF (25 mL). Crude material was obtained in a quantitative yield and used without further purification. MS (ESI, pos. ion) m/z: 696 (M+H), (ESI, neg. ion) m/z: 694 (M−H). Calc'd for C35H42ClN5O6S: 695.25.