Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[N:19]([CH2:20][CH2:21][OH:22])[C:18]3[CH:23]=[CH:24][CH:25]=[CH:26][C:17]=3[N:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC.[F:58][C:59]([F:63])([F:62])[CH2:60]O>C1(C)C=CC=CC=1.C(OCC)(=O)C.CCCCCC.CCCCCC>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[N:19]([CH2:20][CH2:21][O:22][CH2:60][C:59]([F:63])([F:62])[F:58])[C:18]3[CH:23]=[CH:24][CH:25]=[CH:26][C:17]=3[N:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: OCC(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCCN(c2nc3ccccc3n2CCO)CC1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCCN(c2nc3ccccc3n2CCOCC(F)(F)F)CC1
Temperature: 55 °C
Reaction time: 0.17 h

Procedure:
According to the procedure of Tet. Let. 35, 5997-6000 (1994), combine 4-(1-(2-hydroxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane (10 mmol) and di-t-butyl dicarbonate (10 mmol) in tetrahydrofuran (100 mmol). After 18 hours, evaporate in vacuo to give 1-t-butoxycarbonyl-4-(1-(2-hydroxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane. Combine 1-t-butoxycarbonyl-4-(1-(2-hydroxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane (0.66 g, 1.84 mmol) and 1,1'-(azodicarbonyl)dipiperidine (0.50 g, 2 mmol) in toluene (20 mL). Add tributylphosphine (0.5 mL, 2 mmol). After 10 minutes, add 2,2,2-trifluoroethanol (0.7 mL, 10 mmol). Heat to 55° C. After 6 hours, cool to ambient temperature. After 18 hours, concentrate the reaction mixture to give a residue. Chromatograph the residue on silica gel eluting sequentially with hexane and then 30% ethyl acetate/hexane to give 1-t- butoxycarbonyl-4-(1-(2-(2,2,2-trifluoroethoxy)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepane.
Reaction SMILES: [Cl-].[NH2:2][C:3]([NH2:5])=[NH2+:4].CC(C)([O-])C.[K+].[CH2:12]([NH:16][C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH:25]=[C:26]([CH3:32])[C:27](OCC)=[O:28])=[O:18])[CH:13]([CH3:15])[CH3:14]>CN(C)C=O>[CH2:12]([N:16]1[C:17](=[O:18])[C:19]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:25]1[CH:26]([CH3:32])[C:27]([NH:4][C:3]([NH2:5])=[NH:2])=[O:28])[CH:13]([CH3:15])[CH3:14]
Reactant: NC(N)=[NH2+]
Reactant: CCOC(=O)C(C)=Cc1ccccc1C(=O)NCC(C)C
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)CN1C(=O)c2ccccc2C1C(C)C(=O)NC(=N)N
Temperature: 20 °C
Reaction time: 0.75 h
Yield: 73.1 %

Procedure:
N-[2-(2-Isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)propionyl]guanidine is prepared as described in Example 30, starting with 3.73 g (39.0 mmol) of guanidinium chloride in 20 cm3 of dimethylformamide and 3.94 g (35.1 mmol) of potassium tert-butoxide. The mixture is stirred for 45 minutes at a temperature in the region of 20° C., followed by dropwise addition of a solution of 1.13 g (3.90 mmol) of ethyl 3-(2-isobutylcarbamoylphenyl)-2-methylacrylate in 15 cm3 of dimethylformamide, and the mixture is stirred for 3 hours at a temperature in the region of 20° C. After leaving the solution to stand overnight, the solvent is removed and the residue is dissolved in aqueous 2N hydrochloric acid solution. After extracting once with dichloromethane, the organic phase is concentrated and the residue is then taken up in 2N hydrochloric acid solution, filtered and then freeze dried. 862 mg of N-[2-(2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)propionyl]guanidine are thus obtained in the form of a mixture of the diastereomers. The pH of the aqueous phase is adjusted to a value of 12 with potassium hydroxide and the precipitate thus obtained is filtered off*. The solid thus obtained is taken up in aqueous 2N hydrochloric acid solution and, after filtration and a freeze drying procedure, about 255 mg of one of the two diastereomers produced (diastereomer A) are obtained in the form of the hydrochloride enriched in a ratio of 9:1 (MS(ES): M+H: 303.1).
Reaction SMILES: Cl[C:2]1[C:7]2[CH:8]=[N:9][C:10]3[N:14]([CH2:15][CH3:16])[N:13]=[CH:12][C:11]=3[C:6]=2[N:5]2[N:17]=[CH:18][N:19]=[C:4]2[N:3]=1.C(N(CC)CC)C.[F:27][C:28]([F:37])([F:36])[C:29]1[CH:30]=[C:31]([CH:33]=[CH:34][CH:35]=1)[NH2:32]>C(O)CCC>[CH2:15]([N:14]1[C:10]2[N:9]=[CH:8][C:7]3[C:2]([NH:32][C:31]4[CH:33]=[CH:34][CH:35]=[C:29]([C:28]([F:27])([F:36])[F:37])[CH:30]=4)=[N:3][C:4]4[N:5]([N:17]=[CH:18][N:19]=4)[C:6]=3[C:11]=2[CH:12]=[N:13]1)[CH3:16]
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: CCn1ncc2c1ncc1c(Cl)nc3ncnn3c12
Solvent: CCCCO
Solvent: CCN(CC)CC
Product: CCn1ncc2c1ncc1c(Nc3cccc(C(F)(F)F)c3)nc3ncnn3c12

Procedure:
5.8 g. of 5-chloro-8-ethyl-8H-pyrazolo[4',3':5,6]pyrido[3,4-e][1,2,4]triazolo[1,5-a]pyrimidine (0.02 mol.), 3 g. of triethylamine and 3.3 g. of 3-trifluoromethylaniline are refluxed in butyl alcohol for 24 hours with stirring. The solvent is removed in vacuo and the residue treated with 20 ml. of water and filtered off. Recrystallization from alcohol yields 8-ethyl-N-[3-(trifluoromethyl)phenyl]-8H-pyrazolo[4',3':5,6]pyrido[3,4-e][1,2,4]triazolo[1,5-a]pyrimidin-5-amine.
Reaction SMILES: [OH:1][CH2:2][C:3]1[NH:7][N:6]=[C:5]([OH:8])[CH:4]=1.[C:9]1([CH3:19])[CH:14]=[CH:13][C:12]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][CH:10]=1.C(N(CC)CC)C>ClCCl>[OH:1][CH2:2][C:3]1[NH:7][N:6]=[C:5]([O:8][S:15]([C:12]2[CH:13]=[CH:14][C:9]([CH3:19])=[CH:10][CH:11]=2)(=[O:17])=[O:16])[CH:4]=1
Reactant: OCc1cc(O)n[nH]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)Oc2cc(CO)[nH]n2)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 54.2 %

Procedure:
To a stirred suspension of 5-hydroxymethyl-1H-pyrazol-3-ol (J. Heterocycl. Chem., 1979, 16, 505-508) (1.0245 g, 8.98 mmol) in anhydrous dichloromethane (50 ml), under nitrogen, was added p-toluenesulfonyl chloride (1.8825 g, 9.87 mmol), then, dropwise over 5 min, anhydrous triethylamine (1.50 ml, 10.8 mmol). The mixture was stirred at room temperature for 16.5 h under nitrogen, then washed with brine (50 ml). The aqueous layer was further extracted with dichloromethane, and the combined organic extracts were dried (Na2SO4) and evaporated in vacuo. The residue was purified by flash chromatography (silica gel, 5-7% MeOH/CH2Cl2) to afford 1.3067 g (54%) of the title compound as a pale green solid; 1H NMR (360 MHz, d6-DMSO) δ 2.42 (3H, s), 4.38 (2H, d, J=5.7 Hz), 5.32 (1H, t, J=5.7 Hz), 5.82 (1H, d, J=2.2 Hz), 7.47 (2H, d, J=8.3 Hz), 7.77 (2H, d, J=8.3 Hz), 12.55 (1H, s).
Reaction SMILES: [C:1]([NH:11][C@@H:12]([C:14]([OH:16])=[O:15])[CH3:13])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].S(=O)(=O)(O)O.[CH3:22][C:23]1[CH2:27][CH2:26][CH2:25][CH:24]=1>ClCCl>[CH3:22][C:23]1([O:15][C:14](=[O:16])[C@@H:12]([CH3:13])[NH:11][C:1]([O:3][CH2:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)=[O:2])[CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: CC1=CCCC1
Reactant: C[C@@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: C[C@@H](NC(=O)OCc1ccccc1)C(=O)OC1(C)CCCC1
Temperature: 25 °C
Reaction time: 120 h

Procedure:
To a magnetically stirred solution of 22.3 g (0.1 mol) N-Cbz-D-alanine in 50 mls of dry dichloromethane containing 0.5 mls of concentrated sulfuric acid at 0° C., was added dropwise a 10 g (0.1 mol) sample of 1-methylcyclopentene in 50 mls of dichloromethane. After 5 days of stirring at room temperature, the mixture was heated to reflux for 4 hours, after which the reaction was cooled to room temperature, washed with 100 mls of saturated NaHCO3, 100 mls of water and dried over MgSO4. Filtration followed by evaporation of the solvent yielded 1.81 g of the product. NMR(CDCl3): δ1.3-1.4 (d, 3H), 1.5 (s, 3H), 1.5-1.7 (m, 8H), 4.2 (m, 1H), 5.05 (s, 2H), 5.25 (m, 1H), 7.3 (s, 5H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][C:9]1=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:16]([NH2:19])[CH:17]=[CH2:18].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[BH4-].[Na+]>ClCCCl>[NH3:8].[CH2:16]([NH:19][CH:11]1[CH2:12][CH2:13][N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:9](=[O:15])[CH2:10]1)[CH:17]=[CH2:18]
Reactant: C=CCN
Reactant: O=C1CCN(Cc2ccccc2)C(=O)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCCl
Product: C=CCNC1CCN(Cc2ccccc2)C(=O)C1
Product: N
Temperature: 25 °C
Reaction time: 5 h
Yield: 0 %
Yield: 1407.9 %

Procedure:
A mixture of 1-benzyl-piperidine-2,4-dione (508 mg, 0.25 mmol), allylamine (188 μL, 2.50 mmol) and 4 Å molecular sieves (500 mg) in DCE (5 mL) was stirred at ambient temperature for 5 hours, then sodium triacetoxyborohydride (106 mg, 0.50 mmol) was added. The resulting mixture was stirred for 16 hours, filtered through Celite®, and concentrated under vacuum. The resulting residue was dissolved in methanol (4 mL) and sodium borohydride (114 mg, 3.00 mmol) was added. The mixture was stirred for 40 hours and then concentrated under vacuum. The residue was dissolved in DCM and washed with 5% aqueous sodium bicarbonate, and dried over sodium sulfate and concentrated under vacuum. The residue was purified by column chromatography on silica gel (gradient: 0 to 80% methanol in DCM then 0 to 60% 2M NH3 in methanol solution in DCM) to afford 430 mg (70%) of racemic 4-allylamino-1-benzyl-piperidin-2-one. 1H NMR (400 MHz, CDCl3) δ: 7.29 (m, 5H), 5.89-5.85 (m, 1H), 5.20 (m, 2H), 4.85 (s, 1H), 4.61 (m, 2H), 3.95 (s, 1H), 3.68 (m, 1H), 3.29-3.25 (m, 2H), 3.10 (m, 1H), 2.75 (ddd, 1H), 2.33 (t, 1H), 1.99 (m, 1H), 1.70-1.57 (m, 1H).
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([C:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[O:10][N:9]=2)[CH2:4][CH2:3]1.[CH3:17][C:18]1[NH:19][C:20]2[C:25]([C:26]=1[CH2:27][CH2:28][CH2:29]S(C1C=CC=CC=1)(=O)=O)=[CH:24][CH:23]=[CH:22][CH:21]=2.CN(C)C=O.C(=O)([O-])[O-].[K+].[K+]>O>[O:10]1[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:8]([CH:5]2[CH2:4][CH2:3][N:2]([CH2:29][CH2:28][CH2:27][C:26]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[NH:19][C:18]=3[CH3:17])[CH2:7][CH2:6]2)=[N:9]1
Reactant: c1ccc2c(C3CCNCC3)noc2c1
Reactant: Cc1[nH]c2ccccc2c1CCCS(=O)(=O)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1[nH]c2ccccc2c1CCCN1CCC(c2noc3ccccc23)CC1
Reaction time: 4 h
Yield: 61.2 %

Procedure:
A mixture of 1.67 g of 3-(4-piperidyl)-1,2-benzisoxazole hydrochloride, 2.47 g of 2-methyl-3-(phenylsulfonylpropyl)indole, 40 ml of dimethylformamide and 5.0 g of potassium carbonate was stirred under nitrogen at 90° for 4 hrs. The reaction mixture was poured into water. The precipitate was extracted with ethyl acetate and the ethyl acetate was washed with brine, dried over anhydrous magnesium sulfate and the solvent was removed in vacuo to yield an oil. The oil was combined with 1.39 g of previously prepared material and the sample was chromatographed in 120 g of silica gel, using 1% methanol-chloroform as eluent. The eluent was evaporated and the residue was recrystallized two times from ethanol-water to yield 1.60 g (15.4%) of the product, mp 110°-112°.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:29])[CH2:4][O:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([C:13]2[N:17]=[C:16]([C:18]3[S:19][CH:20]=[C:21]([CH2:24][CH:25]([CH3:27])[CH3:26])[C:22]=3[CH3:23])[O:15][N:14]=2)=[CH:8][C:7]=1[CH3:28].[C:30]([N:37]([CH2:39][C:40](O)=[O:41])C)(OC(C)(C)C)=O.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(Cl)Cl>[OH:29][CH:3]([CH2:4][O:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([C:13]2[N:17]=[C:16]([C:18]3[S:19][CH:20]=[C:21]([CH2:24][CH:25]([CH3:27])[CH3:26])[C:22]=3[CH3:23])[O:15][N:14]=2)=[CH:8][C:7]=1[CH3:28])[CH2:2][NH:1][C:40](=[O:41])[CH2:39][NH:37][CH3:30]
Reactant: CN(CC(=O)O)C(=O)OC(C)(C)C
Reactant: Cc1cc(-c2noc(-c3scc(CC(C)C)c3C)n2)cc(C)c1OCC(O)CN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CNCC(=O)NCC(O)COc1c(C)cc(-c2noc(-c3scc(CC(C)C)c3C)n2)cc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.9 %

Procedure:
A solution of rac-1-amino-3-{4-[5-(4-isobutyl-3-methyl-thiophen-2-yl)-[1,2,4]oxadiazol-3-yl]-2,6-dimethyl-phenoxy}-propan-2-ol (100 mg, 0.241 mmol) in DCM (1 mL) is added to a stirred solution of Boc-sarcosine (60 mg, 0.317 mmol), DIPEA (38 mg, 0.292 mmol) and TBTU (85 mg, 0.265 mmol) in DCM (5 mL). The mixture is stirred at rt for 1 h, diluted with DCM (50 mL) and washed with sat. aq. Na2CO3 (2×20 mL). The organic extract is dried (Na2SO4), filtered and evaporated. The residue dissolved in 4M HCl in dioxane (10 mL) and stirred for 1 h. The mixture is diluted with DCM (75 mL) and washed with 1 N aq. NaOH (50 mL). The aq. phase is extracted with DCM (3×30 mL). The combined organic extracts are dried (Na2SO4), filtered and evaporated. The residue is purified on prep. TLC plates with DCM containing 10% of 7 N NH3 in MeOH to give rac-N-(2-hydroxy-3-{4-[5-(4-isobutyl-3-methyl-thiophen-2-yl)-[1,2,4]oxadiazol-3-yl]-2,6-dimethyl-phenoxy}-propyl)-2-methylamino-acetamide (89 mg) as a white powder; LC-MS: tR=0.89 min, [M+1]=487.26; 1H NMR (D6-DMSO): δ 7.85 (t, J=6 Hz, 1H), 7.70 (s, 2H), 7.65 (s, 1H), 5.27 (d br, J=5 Hz, 1H), 3.93-3.85 (m, 1H), 3.76-3.65 (m, 2H), 3.43-3.35 (m, 1H), 3.24-3.14 (m, 1H), 3.02 (s, 2H), 2.54 (s, 3H), 2.45 (d, J=6.4 Hz, 2H), 2.30 (s, 6H), 2.20 (s, 3H), 1.83 (hept, J=7.0 Hz, 1H), 0.88 (d, J=7.0 Hz, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16]3[C:17](=[O:28])[N:18]([CH3:27])[C:19]4[C:24]([C:25]=3[OH:26])=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].C([O-])([O-])=O.[Cs+].[Cs+].Cl[C:36]([F:42])([F:41])C(OC)=O>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16]3[C:17](=[O:28])[N:18]([CH3:27])[C:19]4[C:24]([C:25]=3[O:26][CH:36]([F:42])[F:41])=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: COC(=O)C(F)(F)Cl
Reactant: Cn1c(=O)c(Cc2ccc(-c3ccc(F)c(Cl)c3)cc2)c(O)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1c(=O)c(Cc2ccc(-c3ccc(F)c(Cl)c3)cc2)c(OC(F)F)c2ccccc21
Temperature: 100 °C
Reaction time: 3 h

Procedure:
A solution of example 145, Cs2CO3 (2 eq) in DMF (0.2M) was heated at 100° C. (open flask) then methyl chlorodifluoroacetate (2 eq) was added and the mixture stirred at 90-110° C. for 3 h. After cooling to rt, the mixture was diluted with water, extracted with ethyl acetate and the solvent evaporated. The residue was purified by crystallisation in hexane\ether to give the title compound as a white powder.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:9][O:10][C:11](=[O:16])[CH2:12][C:13](=O)[CH3:14].[CH3:17][O:18][C:19](=[O:22])[C:20]#[CH:21]>CO>[CH3:17][O:18][C:19](=[O:22])[CH:20]=[CH:21][C:12](=[C:13]([NH:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH3:14])[C:11]([O:10][CH3:9])=[O:16]
Reactant: C#CC(=O)OC
Reactant: NCc1ccccc1
Reactant: COC(=O)CC(C)=O
Solvent: CO
Product: COC(=O)C=CC(C(=O)OC)=C(C)NCc1ccccc1
Yield: 68.4 %

Procedure:
Benzyl amine (2.0 mL, 18.7 mmol) was dissolved in MeOH (60 mL). 3-Oxo-butyric acid methyl ester (2.4 mL, 22.4 mmol) was added and the mixture was refluxed for 2 h. The mixture was cooled slightly, and propynoic acid methyl ester (2.5 mL, 28 mmol) was added. The mixture was then refluxed for 48 h. The solvent was evaporated, and the residual oil was recrystallized with MeOH to give 3.7 g of the title compound as a pale yellow solid. 1H NMR (CDCl3, 200 MHz): 8=10.94 (br s, 1H), 7.75 (d, 1H, J=15.4 Hz), 7.20-7.45 (m, 5H), 6.09 (d, 1H, J=15.4 Hz), 4.58 (d, 1H, J=6.2 Hz), 3.78 (s, 3H), 3.74 (s, 3H), 2.27 (s, 3H).
Reaction SMILES: Cl.Cl.Cl.Cl.Cl.[CH3:6][N:7]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[C:17]([N:19]3[CH:28]([CH3:29])[CH2:27][C:26]4[C:21](=[CH:22][C:23]([CH:30]5[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]5)=[CH:24][CH:25]=4)[CH2:20]3)[N:16]=[C:15]([NH2:36])[N:14]=2)[CH2:9][CH2:8]1.[N:37]([CH2:40][CH3:41])=[C:38]=[O:39]>>[NH2:36][C:15]1[N:16]=[C:17]([N:19]2[CH:28]([CH3:29])[CH2:27][C:26]3[C:21](=[CH:22][C:23]([CH:30]4[CH2:31][CH2:32][N:33]([C:38]([NH:37][CH2:40][CH3:41])=[O:39])[CH2:34][CH2:35]4)=[CH:24][CH:25]=3)[CH2:20]2)[CH:18]=[C:13]([N:10]2[CH2:11][CH2:12][N:7]([CH3:6])[CH2:8][CH2:9]2)[N:14]=1
Reactant: CC1Cc2ccc(C3CCNCC3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Reactant: CCN=C=O
Agent: Cl
Product: CCNC(=O)N1CCC(c2ccc3c(c2)CN(c2cc(N4CCN(C)CC4)nc(N)n2)C(C)C3)CC1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 144 starting from 4-(4-methylpiperazin-1-yl)-6-(3-methyl-7-piperidin-4-yl-3,4-dihydroisoquinolin-2(1H)-yl)pyrimidin-2-amine tetrahydrochloride HCl salt (Example 144, Step 3) and isocyanatoethane. LCMS (M+H)+: m/z=493.4.
Reaction SMILES: C(OC(=O)[N:10]([CH:41]1[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]1)[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([CH2:26][N:27]([CH2:35][C:36]3[NH:37][CH:38]=[CH:39][N:40]=3)[CH2:28][C:29]3[N:30]([CH3:34])[CH:31]=[CH:32][N:33]=3)=[CH:22][CH:21]=2)=[CH:14][CH:13]=1)C1C=CC=CC=1.[H][H].C[OH:51]>C(O)C.[C].[Pd]>[CH:41]1([NH:10][CH2:11][C:12]2[CH:13]=[CH:14][C:15]([NH:18][C:19](=[O:51])[C:20]3[CH:21]=[CH:22][C:23]([CH2:26][N:27]([CH2:35][C:36]4[NH:40][CH:39]=[CH:38][N:37]=4)[CH2:28][C:29]4[N:30]([CH3:34])[CH:31]=[CH:32][N:33]=4)=[CH:24][CH:25]=3)=[CH:16][CH:17]=2)[CH2:42][CH2:43][CH2:44][CH2:45][CH2:46]1
Reactant: [H][H]
Reactant: Cn1ccnc1CN(Cc1ccc(CNc2ccc(CN(C(=O)OCc3ccccc3)C3CCCCC3)cc2)cc1)Cc1ncc[nH]1
Reactant: CO
Agent: [Pd]
Solvent: CCO
Product: Cn1ccnc1CN(Cc1ccc(C(=O)Nc2ccc(CNC3CCCCC3)cc2)cc1)Cc1ncc[nH]1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The compound (212 mg) obtained in Example 87-5 was dissolved in methanol (10 ml). After having been cooled with ice, the solution was added with a suspension of 10% palladium-carbon (105 mg) in ethanol (3.0 ml). After having been subjected to hydrogen displacement, the mixture was stirred under a hydrogen atmosphere at room temperature for 3 hours. After the reaction, the solution was filtrated through Celite and the solvent was then distilled off. Then, the residue was purified through silica gel column chromatography (chloroform/methanol) and treated with hydrochloric acid, thereby obtaining hydrochloride (43.1 mg) of the subject compound as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]=[C:7]([C:9]3[CH:10]=[C:11]([OH:15])[CH:12]=[CH:13][CH:14]=3)[O:8][C:4]=2[CH:3]=1.I[CH:19]([CH3:21])[CH3:20].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Br:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]=[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH:19]([CH3:21])[CH3:20])[CH:10]=3)[O:8][C:4]=2[CH:3]=1
Reactant: CC(C)I
Reactant: Oc1cccc(-c2nc3ccc(Br)cc3o2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)Oc1cccc(-c2nc3ccc(Br)cc3o2)c1
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 76.7 %

Procedure:
To a solution of 3-(6-bromobenzoxazol-2-yl)phenol (Compound of Example 272) (1.02 g) in N,N-dimethyl formamide (6 ml) were added 2-iodopropane (0.68 g) and potassium carbonate (0.63 g) at 50° C., and the mixture was stirred at 50° C. for 1.5 hour. To the mixture were further added 2-iodopropane (0.34 g) and potassium carbonate (0.31 g), and the mixture was further stirred at 50° C. for 1 hour. The reaction mixture was poured into water and extracted with ethyl acetate-tetrahydrofuran (3:1, v/v). The organic layer was washed with water and dried over MgSO4. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography. The fraction eluted with ethyl acetate-hexane (1:20 to 1:6, v/v) was concentrated under reduced pressure to isolate 6-bromo-2-(3-isopropoxyphenyl)benzoxazole (896 mg, 77%).
Reaction SMILES: Cl[CH2:2][CH:3]=[O:4].[N:5]1[CH:10]=[CH:9][C:8]([CH2:11][SH:12])=[CH:7][CH:6]=1>>[N:5]1[CH:10]=[CH:9][C:8]([CH2:11][S:12][CH2:2][CH:3]=[O:4])=[CH:7][CH:6]=1
Reactant: SCc1ccncc1
Reactant: O=CCCl
Product: O=CCSCc1ccncc1

Procedure:
By the method of the preceding Example, chloroacetaldehyde is reacted with 4-picolyl mercaptan to yield title product.
Reaction SMILES: Br[C:2]1[C:3]([N:7]2[C:15]3[CH:14]=[CH:13][C:12]([CH3:16])=[CH:11][C:10]=3[C:9]3[CH2:17][N:18]([CH3:21])[CH2:19][CH2:20][C:8]2=3)=[CH:4][S:5][CH:6]=1.[N:22]1[CH:27]=[CH:26][CH:25]=[C:24](B(O)O)[CH:23]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.O.O>[CH3:21][N:18]1[CH2:19][CH2:20][C:8]2[N:7]([C:3]3[C:2]([C:24]4[CH:23]=[N:22][CH:27]=[CH:26][CH:25]=4)=[CH:6][S:5][CH:4]=3)[C:15]3[CH:14]=[CH:13][C:12]([CH3:16])=[CH:11][C:10]=3[C:9]=2[CH2:17]1
Reactant: Cc1ccc2c(c1)c1c(n2-c2cscc2Br)CCN(C)C1
Reactant: OB(O)c1cccnc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)c1c(n2-c2cscc2-c2cccnc2)CCN(C)C1
Temperature: 95 °C
Yield: 25.3 %

Procedure:
To a de-aerated solution of 5-(4-bromo-thiophen-3-yl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (160 mg, 0.44 mmol), 3-pyridinylboronic acid (81.9 mg, 0.66 mmol) and K3PO4 (235 mg, 1.11 mmol) in DMF-water (4.5:0.5 mL) was added dichlorobis(triphenylphosphine) palladium (II) (15.5 mg, 5 mol %). The reaction mixture was heated at 95° C. for 30 min under nitrogen atmosphere. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford crude material, which was purified by reverse phase HPLC to yield 2,8-dimethyl-5-(4-pyridin-3-yl-thiophen-3-yl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (40 mg). 1H NMR (Oxalate salt, CD3OD) δ (ppm): 8.35 (bs, 1H), 8.10 (bs, 1H), 7.95 (s, 1H), 7.8 (s, 1H), 7.45 (bs, 1H), 7.3-7.2 (m, 2H), 6.95 (d, 1H), 6.9 (d, 1H), 4.5 (bs, 2H), 3.6-3.45 (m, 2H), 3.15-3.05 (m, 1H), 3.0 (s, 3H), 2.65-2.59 (m, 1H), 2.4 (s, 3H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH:7]([CH2:11][S:12][C:13](=[O:15])[CH3:14])[C:8]([OH:10])=[O:9])[CH2:3][CH2:2]1.[CH3:16][C:17]([O:20][C:21]([NH:23][CH2:24][C:25](ON1C(=O)CCC1=O)=[O:26])=[O:22])([CH3:19])[CH3:18]>O1CCOCC1>[C:17]([O:20][C:21]([NH:23][CH2:24][C:25]([N:1]1[CH2:2][CH2:3][CH:4]([CH:7]([CH2:11][S:12][C:13](=[O:15])[CH3:14])[C:8]([OH:10])=[O:9])[CH2:5][CH2:6]1)=[O:26])=[O:22])([CH3:19])([CH3:18])[CH3:16]
Reactant: CC(C)(C)OC(=O)NCC(=O)ON1C(=O)CCC1=O
Reactant: CC(=O)SCC(C(=O)O)C1CCNCC1
Solvent: C1COCCO1
Product: CC(=O)SCC(C(=O)O)C1CCN(C(=O)CNC(=O)OC(C)(C)C)CC1

Procedure:
A solution of 2-(piperidin-4-yl)-3-(acetylthio)propanoic acid (0.6 g, 1.72 mmol) and Boc-glycine-N-hydroxysuccinimide ester (0.52 g, 1.9 mmol) was stirred in 15 mL of dioxane for 18 hours. The reaction mixture was concentrated, partitioned between ethyl acetate and 1 M NaHSO4. The organic layer was concentrated to give 2-(1-(t-butoxycarbonylaminomethylcarbonyl)-piperidin-4-yl)-3-(acetylthio)propanoic acid, which was dissolved in 10 mL of 1:1 methylene chloride-TFA for 1 hour. The reaction mixture was then concentrated. The resulting residue was dissolved in water-methanol, cooled to 0° C. and purged with nitrogen gas. Aqueous NH4OH was added and the resulting reaction mixture was stirred for 1 hour and then concentrated to an oil. Purification by prep HPLC afforded 65 mg of 2-(1-(aminomethylcarbonyl)-piperidin-4-yl)-3-mercaptopropanoic acid; NMR (D2O) 1.2-1.21 (m, 2), 1.51-1.82 (m, 3), 2.30-2.40 (m, 1), 2.48-2.71 (m, 2), 2.90-3.00 (m, 1), 3.55 (m, 1), 3.82 (m, 2), 4.21 (m, 1) ppm.