Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:13]=[C:12]([NH:14][CH:15]2[CH2:20][CH2:19][CH:18]([N:21]([CH3:23])[CH3:22])[CH2:17][CH2:16]2)[C:11]2[C:10]3[CH2:9][CH2:8][CH2:7][C:6]=3[S:5][C:4]=2[N:3]=1.[NH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:22][N:21]([CH3:23])[CH:18]1[CH2:19][CH2:20][CH:15]([NH:14][C:12]2[C:11]3[C:10]4[CH2:9][CH2:8][CH2:7][C:6]=4[S:5][C:4]=3[N:3]=[C:2]([NH:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:13]=2)[CH2:16][CH2:17]1
Reactant: CN(C)C1CCC(Nc2nc(Cl)nc3sc4c(c23)CCC4)CC1
Reactant: Nc1ccccc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CN(C)C1CCC(Nc2nc(Nc3ccccc3)nc3sc4c(c23)CCC4)CC1
Temperature: 110 °C
Reaction time: 8 h
Yield: 14.4 %

Procedure:
A solution of 4-N-[10-chloro-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yl]-1-N,1-N-dimethylcyclohexane-1,4-diamine (120 mg, 0.34 mmol, 1.00 equiv) in dioxane (5 mL), was added aniline (60 mg, 0.72 mmol, 2.00 equiv), XantPhos (20 mg, 0.03 mmol, 0.10 equiv) and Pd2(dba)3 (20 mg, 0.02 mmol, 0.06 equiv) subsequently under nitrogen. The resulting solution was stirred overnight at 110° C. After completion of the reaction, the solids were filtered out and the filtrate was diluted with DCM, washed with brine. The organic layer was concentrated under vacuum and the crude product (80 mg) was purified by Prep-HPLC with the following conditions (SHIMADZU): Column, SunFire Prep C18, 19*150 mm 5 um; mobile phase, water with 0.05% NH4HCO3 and CH3CN (25% CH3CN up to 100% in 15 min); Flow rate, 20 mL/min; UV detection at 254/220 nm. The product-containing fractions were collected and partially evaporated to remove water and CH3CN under reduced pressure. The residue was lyophilized overnight to give the 12-N-[4-(dimethylamino)cyclohexyl]-10-N-phenyl-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraene-10,12-diamine (20 mg) as a grey solid. LCMS (ES, m/z): 408 [M+H]+;
Reaction SMILES: [CH:1]([N:4]([CH2:8][C:9]1[CH:14]=[C:13]([N:15](C(=O)C)C(=O)C)[C:12]([F:22])=[CH:11][C:10]=1[Cl:23])[CH:5]([CH3:7])[CH3:6])([CH3:3])[CH3:2].[OH-].[K+].CO.O>C(OCC)C>[Cl:23][C:10]1[C:9]([CH2:8][N:4]([CH:5]([CH3:7])[CH3:6])[CH:1]([CH3:2])[CH3:3])=[CH:14][C:13]([NH2:15])=[C:12]([F:22])[CH:11]=1
Reactant: CC(=O)N(C(C)=O)c1cc(CN(C(C)C)C(C)C)c(Cl)cc1F
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: CCOCC
Solvent: O
Product: CC(C)N(Cc1cc(N)c(F)cc1Cl)C(C)C
Temperature: 25 °C
Yield: 92 %

Procedure:
A mixture of 0.72 g (0.0021 mole) of N,N-diiso-propyl-2-chloro-4-fluoro-5-diacetylaminobenzylamine, 1 g (0.018 mole) of potassium hydroxide, 20 ml of methanol, and 5 ml of water was refluxed for six hours. After cooling to room temperature, the reaction mixture was diluted with diethyl ether and was washed with water. The aqueous washes were combined and extracted with methylene chloride. These extracts were combined with the diethyl ether solution. This mixture was dried, filtered, and the solvents were evaporated under reduced pressure, yielding 0.50 g of 4-chloro-2-fluoro-5-(diisopropylaminomethyl)aniline. The nmr and ir spectra were consistent with the proposed structure.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:21])[NH:4][C:5](=[S:20])[N:6]([CH:9]([C:11]2[NH:15][C:14]3[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=3[N:12]=2)[CH3:10])[C:7]=1[NH2:8].[C:22](O)(=O)C.C(N)=N>CS(C)=O>[NH:12]1[C:13]2[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=2[N:15]=[C:11]1[CH:9]([N:6]1[C:7]2[N:8]=[CH:22][NH:1][C:2]=2[C:3](=[O:21])[NH:4][C:5]1=[S:20])[CH3:10]
Reactant: CC(=O)O
Reactant: CC(c1nc2ccccc2[nH]1)n1c(N)c(N)c(=O)[nH]c1=S
Agent: N=CN
Solvent: CS(C)=O
Product: CC(c1nc2ccccc2[nH]1)n1c(=S)[nH]c(=O)c2[nH]cnc21
Temperature: 80 °C
Yield: 11 %

Procedure:
To 5,6-diamino-1-[1-(1H-benzimidazol-2-yl)ethyl]-2-thioxo-2,3-dihydropyrimidin-4(1H)-one (obtained from Example 9(c)) in DMSO (2 mL) was added formamidine acetate (0.058 g, 0.56 mmol) and the reaction was heated to 80° C. for 2 h and 10 min. Purification of the crude product using preparative HPLC gave the title compound (0.025 g, 11%) as a solid.
Reaction SMILES: [C:1]([NH2:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N+:17]([O-:19])=[O:18]>>[N+:17]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[NH:9][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)([O-:19])=[O:18]
Reactant: O=[N+]([O-])c1ccccc1I
Reactant: NC(=O)c1ccccc1
Product: O=C(Nc1ccccc1[N+](=O)[O-])c1ccccc1
Yield: 70.3 %

Procedure:
Using general procedure A, benzamide (150 mg, 1.24 mmol) was coupled with 1-iodo-2-nitrobenzene (260 mg, 1.04 mmol). The crude product was purified by flash chromatography on silica gel (2×15 cm; hexane-ethyl acetate 8:1; 15 mL fractions). Fractions 8-14 provided 177 mg (70% yield) of the product as bright yellow needles. The 1H NMR spectrum was in accord with that reported by Murphy et al. Murphy, J. A.; Rasheed, F.; Gastaldi, S.; Ravishanker, T.; Lewis, N. J. Chem. Soc., Perkin Trans 1 1997, 1549.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[C:6]([CH3:8])([CH3:7])[O:5][B:4](C2CC3(CC(C(OC)=O)C3)C=2)[O:3]1.[C:21]([NH:24][C:25]1([C:39]([O:41][CH3:42])=[O:40])[CH2:30][CH2:29][C:28](OS(C(F)(F)F)(=O)=O)=[CH:27][CH2:26]1)(=[O:23])[CH3:22]>>[C:21]([NH:24][C:25]1([C:39]([O:41][CH3:42])=[O:40])[CH2:30][CH2:29][C:28]([B:4]2[O:5][C:6]([CH3:8])([CH3:7])[C:2]([CH3:20])([CH3:1])[O:3]2)=[CH:27][CH2:26]1)(=[O:23])[CH3:22]
Reactant: COC(=O)C1CC2(C=C(B3OC(C)(C)C(C)(C)O3)C2)C1
Reactant: COC(=O)C1(NC(C)=O)CC=C(OS(=O)(=O)C(F)(F)F)CC1
Product: COC(=O)C1(NC(C)=O)CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Yield: 48.4 %

Procedure:
The title compound was prepared following the method described in step 2 for the preparation of methyl 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[3.3]hept-5-ene-2-carboxylate, using methyl 1-acetamido-4-(((trifluoromethyl)sulfonyl)oxy)cyclohex-3-enecarboxylate as the reactant. (48.4% yield). MS: m/e 325.25 (M+H)+, 2.126 min (method 8). 1H NMR (400 MHz, CHLOROFORM-d) δ 6.42 (br. s., 1H), 5.90 (s, 1H), 3.83-3.59 (m, 3H), 2.65 (d, J=18.8 Hz, 1H), 2.35 (d, J=18.1 Hz, 1H), 2.25 (d, J=11.0 Hz, 2H), 2.13-2.03 (m, 1H), 1.98-1.90 (m, 3H), 1.88-1.75 (m, 1H), 1.36-1.18 (m, 12H).
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]([CH3:21])=[C:9]([CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=2)[CH:10]=1)=[O:5])C.[OH-].[Na+]>CCO>[CH3:20][O:19][C:15]1[CH:14]=[C:13]([CH2:12][CH2:11][C:9]2[CH:10]=[C:6]([C:4]([OH:5])=[O:3])[NH:7][C:8]=2[CH3:21])[CH:18]=[CH:17][CH:16]=1
Reactant: CCOC(=O)c1cc(CCc2cccc(OC)c2)c(C)[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1cccc(CCc2cc(C(=O)O)[nH]c2C)c1
Temperature: 80 °C

Procedure:
To a solution of 4-[2-(3-methoxy-phenyl)-ethyl]-5-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (127) in EtOH, 3 equiv of NaOH aq (3 M) was added then the mixture was heated at 80° C. for 1 hour. When the reaction is judged complete, the solvent was removed under vacuum, H2O was added and an equal volume of Et2O was added. The organic layer was removed then the aqueous layer was made acidic with HCl (1M). If the product precipitated out at this point, it was filtered off, washed with H2O, and dried to obtain pure desired product. If the product didn't crash out when the aqueous layer is made acidic, Et2O was added, and the organic layer was removed (2×). The organic layer was dried with Na2SO4, filtered, and concentrated to obtain desired product. Purification: Extraction. Amount: 37 mg. 1H (CDCl3, 400 MHz): δ 8.90 (NH, broad s), 7.19 (1H, dd), 6.88 (1H, s), 6.75 (2H, m), 6.94 (1H, s), 3.78 (3H, s), 2.80 (2H, dd), 2.68 (2H, dd), 2.08 (3H, s) ppm. 13C (CDCl3, 100 MHz): δ 165.5, 159.6, 143.5, 132.3, 129.3, 122.6, 121.0, 118.7, 117.8, 114.2, 111.2, 55.2, 37.3, 27.8, 11.3 ppm. HPLC (20 min): 91.6%. LC/MS: 97%.
Reaction SMILES: Br[CH:2]1[C:7]([CH3:8])=[C:6]([C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:10])[N:5]2[C:17](=[O:21])[C@H:18]([O:19][CH3:20])[C@H:4]2[S:3]1(=[O:23])=[O:22].CC[O:26][C:27]([CH3:29])=[O:28]>C(#N)C.C([O-])(=O)C1C=CC=CC=1.[Ag+]>[C:27]([O:26][CH:2]1[C:7]([CH3:8])=[C:6]([C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:10])[N:5]2[C:17](=[O:21])[C@H:18]([O:19][CH3:20])[C@H:4]2[S:3]1(=[O:23])=[O:22])(=[O:28])[C:29]1[CH:11]=[CH:9][CH:6]=[CH:7][CH:2]=1
Reactant: CCOC(C)=O
Reactant: CO[C@H]1C(=O)N2C(C(=O)c3ccccc3)=C(C)C(Br)S(=O)(=O)[C@H]12
Agent: [Ag+]
Agent: O=C([O-])c1ccccc1
Solvent: CC#N
Product: CO[C@H]1C(=O)N2C(C(=O)c3ccccc3)=C(C)C(OC(=O)c3ccccc3)S(=O)(=O)[C@H]12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 2-bromo-7α-methoxy-3-methyl-4-phenylcarbonyl-3-cephem 1,1-dioxide (130 mg) and silver benzoate (115 mg) in acetonitrile (10 ml) was stirred at room temperature for 30 minutes. The reaction mixture was diluted with EtOAc, then filtered and the filtrate was rotoevaporated. The residue was purified by flash chromatography (eluting with n-hexane/EtOAc mixtures) affording the title product as a white powder (85 mg) IR (KBr) 1805, 1740, 1675.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH:14]2[CH2:19][CH2:18][N:17](C(OCC3C4C(=CC=CC=4)C4C3=CC=CC=4)=O)[CH2:16][CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1CCCCC1>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(C2CCN(C(=O)OCC3c4ccccc4-c4ccccc43)CC2)CC1
Solvent: C1CCNCC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(C2CCNCC2)CC1

Procedure:
4-(1-Fmoc-piperidin-4-yl)-piperazine-1-carboxylic acid tert-butyl ester (0.3 g, 0.61 mmol) was stirred with 20% piperidine in methylene chloride for 40 min. The mixture was concentrated to dryness to give 4-piperidin-4-yl-piperazine-1-carboxylic acid tert-butyl ester. It was then dissolved in tetrahydrofuran (5 mL), and triethylamine (308 mg, 3.05 mmol) and acetic anhydride (86 mg, 0.9 mmol) were added, respectively. After the reaction mixture was stirred for 2 h, water and ethyl acetate were added. The layers were separated, and the aqueous layer was extracted with ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulfate. The solids were filtered off, and the filtrate was concentrated to give 4-(1-acetyl-piperidin-4-yl)-piperazine-1-carboxylic acid tert-butyl ester. It was dissolved in methylene chloride (7 mL), cooled with an ice bath and trifluoroacetic acid was added. The reaction mixture was stirred for 30 min, and the solvent was removed. The residue was triturated with diethyl ether and the solvent was removed to give 1-(4-piperazin-1-yl-piperidin-1-yl)-ethanone trifluoroacetate as a light-yellow foam (151 mg, 76%). LR-MS: 212 [(M+H)+]
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([CH2:9][C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[N:15]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH:14]=[CH:13]3)[CH2:5][CH2:4]1.N1C=CN=C1.[Si:31](Cl)([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32]>CN(C=O)C>[Si:31]([O:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([CH2:9][C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[N:15]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH:14]=[CH:13]3)[CH2:5][CH2:4]1)([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(C)(C)OC(=O)n1ccc2cc(CN3CCC(CO)CC3)ccc21
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)n1ccc2cc(CN3CCC(CO[Si](C)(C)C(C)(C)C)CC3)ccc21
Yield: 76.4 %

Procedure:
In a similar manner to Step 1 of Reference Example 18, 5-(4-hydroxymethylpiperidinomethyl)-1-(tert-butoxycarbonyl)indole (2.85 g, 8.27 mmol) was dissolved in DMF (50 mL), and the solution was treated with imidazole (619 mg, 9.09 mmol and tert-butyldimethylsilyl chloride (1.37 g, 9.09 mmol), followed by purification by flash column chromatography (hexane/ethyl acetate=95/5 to 80/20) to obtain 5-[4-(tert-butyldimethylsilyloxy)methylpiperidinomethyl]-1-(tert-butoxycarbonyl)indole (2.90 g, yield 76%).
Reaction SMILES: [C:1]([O:9]CC)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.[CH2:12]([NH2:15])[CH2:13][NH2:14]>>[NH2:14][CH2:13][CH2:12][NH:15][C:1]([C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1)=[O:9]
Reactant: NCCN
Reactant: CCOC(=O)c1cccnc1
Product: NCCNC(=O)c1cccnc1
Temperature: 100 °C

Procedure:
A mixture of ethyl nicotinate (21.9 g.) and ethylenediamine (30 ml.) was heated to 100° C. for 16 hours under an atmosphere of argon. Excess ethylenediamine was removed by distillation in vacuo and the residue was dissolved in water (100 ml.) The insoluble material [bis(carboxamido)derivative] was removed by filtration. Evaporation of the filtrate, addition of toluene (50 ml.) followed by re-evaporation gave crude N-(2-aminoethyl)pyridine-3-carboxamide (26.5 g.) as its oily free base, essentially pure by TLC (Si02 : 10% MeOH/CHCl3) and which was used without purification.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:11]([NH:13][C@@H:14]([C:29](=[O:31])[NH2:30])[CH2:15][CH2:16][C:17]([NH:19][C@H:20]([C:26]([OH:28])=[O:27])[CH2:21][CH2:22][CH2:23][CH2:24][NH2:25])=[O:18])=[O:12])[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:32](O)(=[O:36])[CH2:33][CH2:34][CH3:35]>>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:11]([NH:13][C@@H:14]([C:29](=[O:31])[NH2:30])[CH2:15][CH2:16][C:17]([NH:19][C@H:20]([C:26]([OH:28])=[O:27])[CH2:21][CH2:22][CH2:23][CH2:24][NH:25][C:32](=[O:36])[CH2:33][CH2:34][CH3:35])=[O:18])=[O:12])[CH3:10])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCCC(=O)O
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@H](CCC(=O)N[C@@H](CCCCN)C(=O)O)C(N)=O
Product: CCCC(=O)NCCCC[C@H](NC(=O)CC[C@@H](NC(=O)[C@H](C)NC(=O)OC(C)(C)C)C(N)=O)C(=O)O

Procedure:
In the same manner as described in Example 1-(2), 1.50 g of Nα -(t-butyloxycarbonyl-alanyl-D-isoglutaminyl)-lysine and 1.01 g of an N-hydroxy-5-norbornene-2,3-dicarboxyimide active ester of butyric acid were reacted to obtain 1.57 g of Nα -(t-butyloxycarbonyl-alanyl-D-isoglutaminyl)-Nε -butyryl-lysine; melting point: 84°-87° C. (decomp.); [α]D25 -12.2° (c 0.9, methanol).
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[CH3:6][C:7]([OH:12])([CH2:10][CH3:11])[CH2:8][CH3:9].C(N(CC)CC)C>ClCCl>[C:1]([O:12][C:7]([CH2:10][CH3:11])([CH3:6])[CH2:8][CH3:9])(=[O:4])[CH:2]=[CH2:3]
Reactant: CCC(C)(O)CC
Reactant: C=CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CC(=O)OC(C)(CC)CC
Temperature: 25 °C
Reaction time: 14 h
Yield: 63.2 %

Procedure:
To a solution of acryloyl chloride (5.0 g, 55.2 mmol) and 3-methyl-3-pentanol (7.6 ml, 60.8 mmol) in dichloromethane, triethylamine (23 ml, 166 mmol) was added at room temperature under a nitrogen atmosphere. After stirring at room temperature for 14 hours, the reaction mixture was diluted with dichloromethane and washed with water and saturated aqueous sodium chloride. The organic layer was dried over anhydrous sodium sulfate. After evaporation under reduced pressure to remove the solvent, the resulting residue was purified by column chromatography (hexane:ethyl acetate=10:1) to give the titled compound (5.45 g, 63%) as a colorless oil.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[C:12]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[C:6]2[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:16][CH2:17][C:5]1=2.C(N(CC)CC)C.[CH3:32][S:33](Cl)(=[O:35])=[O:34]>C(Cl)Cl.CCOC(C)=O>[CH3:32][S:33]([O:1][CH2:2][CH2:3][N:4]1[C:12]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[C:6]2[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:16][CH2:17][C:5]1=2)(=[O:35])=[O:34]
Reactant: CC(C)(C)OC(=O)N1CCc2c(n(CCO)c3ccccc23)CC1
Reactant: CS(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCc2c(n(CCOS(C)(=O)=O)c3ccccc23)CC1
Reaction time: 0.5 h

Procedure:
tert-Butyl 6-(2-hydroxyethyl)-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate (0.181 g, 0.549 mmol) and triethylamine (0.115 mL, 0.0833 g, 0.824 mmol, 1.5 equiv.) were dissolved in CH2Cl2 at −10° C. under N2. MsCl (0.0510 mL, 0.0755 g, 0.659 mmol, 1.2 equiv.) was added and the reaction mixture was stirred for 30 min. The reaction mixture was taken up in EtOAc (25 mL) and was washed sequentially with 10% citric acid (10 mL), 5% NaHCO3 (10 mL), and brine (10 mL). The organic layer was dried over MgSO4, filtered, and concentrated. The crude tert-butyl 6-{2-[(methylsulfonyl)oxy]ethyl}-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate was used directly in the next reaction.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:25])[C:5]([CH3:24])=[C:6]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][C:21]([OH:23])=O)=[CH:15][CH:14]=2)[C:7](=[O:11])[C:8]=1[O:9][CH3:10].[NH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1>>[CH3:1][O:2][C:3]1[C:4](=[O:25])[C:5]([CH3:24])=[C:6]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([CH2:19][CH2:20][C:21]([N:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)=[O:23])=[CH:17][CH:18]=2)[C:7](=[O:11])[C:8]=1[O:9][CH3:10]
Reactant: C1CCNCC1
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(CCC(=O)O)cc2)=C(C)C1=O
Product: COC1=C(OC)C(=O)C(Cc2ccc(CCC(=O)N3CCCCC3)cc2)=C(C)C1=O
Yield: 136.2 %

Procedure:
3-[4-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-ylmethyl)phenyl]propionic acid (200 mg, 0.58 mmol) obtained in Example 1 and piperidine (64 mg, 0.75 mmol) were used, and a method similar to that described in Example 3 was employed to obtain the title compound (118 mg, 0.79 mmol, yield 50%).
Reaction SMILES: CC(C)(C)C([NH:5][C:6]1[N:11]=[CH:10][C:9]2[CH:12]([C:15]([O-:17])=[O:16])[CH2:13][CH2:14][C:8]=2[CH:7]=1)=O>Cl>[NH2:5][C:6]1[N:11]=[CH:10][C:9]2[CH:12]([C:15]([OH:17])=[O:16])[CH2:13][CH2:14][C:8]=2[CH:7]=1
Reactant: CC(C)(C)C(=O)Nc1cc2c(cn1)C(C(=O)[O-])CC2
Agent: Cl
Product: Nc1cc2c(cn1)C(C(=O)O)CC2

Procedure:
A solution of 3-[(2,2-dimethylpropanoyl)amino]-6,7-dihydro-5H-cyclopenta[c]pyridine-7-carboxylate (0.624 mg, 1.96 mmol) in 6N hydrochloric acid (25 mL) was heated to reflux for 24 h. The solution was cooled and concentrated to provide 3-amino-6,7-dihydro-5H-cyclopenta[c]pyridine-7-carboxylic acid which was used without further purification in the next step. LC/MS (M+1)+=179.0;
Reaction SMILES: [N:1]1([C:12](=[O:13])[C:11]2[NH:10][CH:9]=[N:8][C:7]=2[N:5]([CH3:6])[C:3]1=[O:4])[CH3:2].[OH-].[K+].[CH2:16](Br)[CH2:17][CH3:18]>CN(C)C=O>[CH3:2][N:1]1[C:12](=[O:13])[C:11]2[N:10]([CH2:16][CH2:17][CH3:18])[CH:9]=[N:8][C:7]=2[N:5]([CH3:6])[C:3]1=[O:4]
Reactant: CCCBr
Reactant: Cn1c(=O)c2[nH]cnc2n(C)c1=O
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CCCn1cnc2c1c(=O)n(C)c(=O)n2C
Temperature: 90 °C
Yield: 88.8 %

Procedure:
600 g of theophylline (a product of Katayama Kagaku Kogyo K.K.) was dissolved in 180 ml of an aqueous solution containing 263.4 g of potassium hydroxide, and the solution was evaporated to dryness under reduced pressure to prepare a potassium salt of theophylline. The resulting salt was suspended in 3600 ml of dimethylformamide, and 436.5 ml of propyl bromide was added thereto, followed by heating at 90° C. for 8 hours while stirring. Dimethylformamide was removed by distillation under reduced pressure, and to the residue was added 1800 ml of dichloromethane. The mixture was washed three times with 300 ml portions of a 1N potassium hydroxide aqueous solution and then once with 300 ml of water and dried over 54 g of anhydrous magnesium sulfate. The desiccant was removed by filtration, and the mother liquor was dried under reduced pressure and then in vacuo (85° C., 5 hours) to obtain 657 g (yield: 88.8%) of 1,3-dimethyl-7-propylxanthine.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[CH3:19][O:20][C:21](=[O:61])[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][C:32]([C:35]([CH2:58][CH3:59])([C:38]3[CH:43]=[CH:42][C:41]([C:44]#[C:45][C:46]4([O:52][Si](C)(C)C)[CH2:51][CH2:50][O:49][CH2:48][CH2:47]4)=[C:40]([CH3:57])[CH:39]=3)[CH2:36][CH3:37])=[CH:31][C:30]=2[CH3:60])=[CH:25][CH:24]=1>O1CCCC1.C(OCC)(=O)C>[CH3:19][O:20][C:21](=[O:61])[CH2:22][C:23]1[CH:24]=[CH:25][C:26]([C:29]2[CH:34]=[CH:33][C:32]([C:35]([CH2:36][CH3:37])([C:38]3[CH:43]=[CH:42][C:41]([C:44]#[C:45][C:46]4([OH:52])[CH2:51][CH2:50][O:49][CH2:48][CH2:47]4)=[C:40]([CH3:57])[CH:39]=3)[CH2:58][CH3:59])=[CH:31][C:30]=2[CH3:60])=[CH:27][CH:28]=1
Reactant: CCC(CC)(c1ccc(C#CC2(O[Si](C)(C)C)CCOCC2)c(C)c1)c1ccc(-c2ccc(CC(=O)OC)cc2)c(C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCC(CC)(c1ccc(C#CC2(O)CCOCC2)c(C)c1)c1ccc(-c2ccc(CC(=O)OC)cc2)c(C)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 89.8 %

Procedure:
Tetrabutylammonium fluoride (1 M solution in tetrahydrofuran, 0.364 mL, 0.364 mmol) was added to a solution of (4′-{1-ethyl-1-[3-methyl-4-(4-trimethylsilanyloxytetrahydro-pyran-4-ylethynyl)-phenyl]-propyl}-2′-methyl-biphenyl-4-yl)-acetic acid methyl ester (Example 130-(5); 43.5 mg, 0.073 mmol) in tetrahydrofuran (3 mL), and the mixture was stirred at room temperature for 15 minutes. Then, the reaction mixture was diluted with ethyl acetate and was washed with brine. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (hexane:ethyl acetate=1:1) to give the target compound as a colorless oil (34.4 mg, 90%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:38])[CH:4]=[C:5]1[CH2:10][N:9](C(OCC2C=CC=CC=2)=O)[C@H:8]([C:21]([O:23]CC2C=CC=CC=2)=[O:22])[C@@H:7]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:6]1.[H][H]>CO.[Pd]>[C:34]([O:33][C:31]([C@H:7]1[CH2:6][CH:5]([CH2:4][C:3]([O:2][CH3:1])=[O:38])[CH2:10][NH:9][C@@H:8]1[C:21]([OH:23])=[O:22])=[O:32])([CH3:37])([CH3:35])[CH3:36]
Reactant: [H][H]
Reactant: COC(=O)C=C1C[C@H](C(=O)OC(C)(C)C)[C@@H](C(=O)OCc2ccccc2)N(C(=O)OCc2ccccc2)C1
Agent: [Pd]
Solvent: CO
Product: COC(=O)CC1CN[C@H](C(=O)O)[C@@H](C(=O)OC(C)(C)C)C1
Yield: 88.6 %

Procedure:
A solution of 1,2-dibenzyl 3-tert-butyl (2S,3S)-5-(2-methoxy-2-oxoethylidene)piperidine-1,2,3-tricarboxylate (98 mg, 0.188) in methanol (5 mL) was hydrogenated in the presence of 10% palladium on carbon (100 mg, 0.094), under balloon pressure of hydrogen, overnight. The resulting reaction mixture was filtered through a pad of celite and the precipitate was washed with methanol (2×5 mL). The volatiles were removed in-vacuo to afford 50 mg (88%) of (2S,3S)-3-(tert-butoxycarbonyl)-5-(2-methoxy-2-oxoethyl)piperidine-2-carboxylic acid as a sticky amorphous solid, which was used directly in the following coupling without further purification. LCMS (ESI): 246 (M−t-Bu+H+), 302 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([N:8]=[CH:9][C:10]=2[C:11]([OH:13])=O)[CH:7]=1.S(Cl)(Cl)=O.[NH2:18][C:19]1[CH:20]=[C:21]([CH:39]=[CH:40][C:41]=1[CH3:42])[C:22]([NH:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[N:32]1[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]1)=[O:23].N1C=CC=CC=1>CO.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([N:8]=[CH:9][C:10]=2[C:11]([NH:18][C:19]2[CH:20]=[C:21]([C:22](=[O:23])[NH:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[N:32]3[CH2:33][CH2:34][N:35]([CH3:38])[CH2:36][CH2:37]3)[CH:39]=[CH:40][C:41]=2[CH3:42])=[O:13])[CH:7]=1
Reactant: O=C(O)c1cnn2cc(Br)ccc12
Reactant: Cc1ccc(C(=O)NCc2ccccc2N2CCN(C)CC2)cc1N
Solvent: CO
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: Cc1ccc(C(=O)NCc2ccccc2N2CCN(C)CC2)cc1NC(=O)c1cnn2cc(Br)ccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture comprising 6-bromopyrazolo[1,5-a]pyridine-3-carboxylic acid (commercially available) (196 mg, 0.813 mmol) and thionyl chloride (2 ml, 27.4 mmol) was heated at 60° C. for 1 hr and concentrated in vacuo. To this was added 3-amino-4-methyl-N-(2-(4-methylpiperazin-1-yl)benzyl)benzamide (step 1) (220 mg, 0.651 mmol) and pyridine (5 ml). The reaction was stirred under nitrogen at room temperature for 2 hrs. The mixture was diluted with 10% MeOH in EtOAc and washed with water, sat NaHCO3, brine and concentrated in vacuo. The crude product was purified by chromatography on silica eluting with 0-20% 2M NH3 in MeOH/DCM to afford the title compound;