Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH3:24])[C:4](=[O:23])[C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13](Br)[CH:14]=3)[O:9][CH:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:7]2)[N:6]=1.[CH3:25][N:26]([CH3:38])[C:27]([C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][CH:34]=1)=[O:28]>O1CCOCC1.C([O-])([O-])=O.[Cs+].[Cs+].Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:1][C:2]1[N:3]([CH3:24])[C:4](=[O:23])[C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:33]4[CH:34]=[C:29]([CH:30]=[CH:31][CH:32]=4)[C:27]([N:26]([CH3:38])[CH3:25])=[O:28])[CH:14]=3)[O:9][CH:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:7]2)[N:6]=1
Reactant: CN(C)C(=O)c1cccc(B(O)O)c1
Reactant: CN1C(=O)C2(CC(c3ccccc3)Oc3ccc(Br)cc32)N=C1N
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CN(C)C(=O)c1cccc(-c2ccc3c(c2)C2(CC(c4ccccc4)O3)N=C(N)N(C)C2=O)c1
Temperature: 120 °C
Yield: 6.1 %

Procedure:
Pd(PPh3)2Cl2 (10 mg, 0.01 mmol) in a 10 mL flask under Ar was treated sequentially with 2′-amino-6-bromo-1′-methyl-2-phenylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (20 mg, 0.052 mmol) in 1,4-dioxane (1 mL), Cs2CO3 (2 N, 0.3 mL) and 3-(dimethylcarbamoyl)phenylboronic acid (20 mg, 0.104 mmol). The mixture was heated at 120° C. under Ar in a microwave reactor for 30 minutes. The reaction mixture was concentrated in vacuo to give the residue, which was purified by preparative TLC to give 3-(2′-amino-1′-methyl-5′-oxo-2-phenyl-1′,5′-dihydrospiro[chroman-4,4′-imidazole]-6-yl)-N,N-dimethylbenzamide (1.44 mg, 6%). 1H-NMR (MeOD): 2.44 (m, 1H), 2.62 (m, 1H), 3.14 (s, 3H), 3.13 (s, 1H), 5.24 (m, 0.3H), 5.88 (m, 0.7H), 7.15 (m, 1H), 7.41 (m, 3H), 7.45 (m, 1H), 7.53 (m, 4H), 7.18 (m, 3H).
Reaction SMILES: CC1C=CC(S([NH:11][NH:12][C:13]2[CH2:18][CH:17]([C:19]3[CH:23]=[CH:22][S:21][CH:20]=3)[CH2:16][C:15](=[O:24])[CH:14]=2)(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:32][C:33](=O)[CH3:34].[I-].[Na+]>COCCOC.C(O)C>[CH3:34][C:33]1[C:14]2[C:15](=[O:24])[CH2:16][CH:17]([C:19]3[CH:23]=[CH:22][S:21][CH:20]=3)[CH2:18][C:13]=2[N:12]=[N:11][CH:32]=1
Reactant: CC(=O)CCl
Reactant: Cc1ccc(S(=O)(=O)NNC2=CC(=O)CC(c3ccsc3)C2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCO
Solvent: COCCOC
Product: Cc1cnnc2c1C(=O)CC(c1ccsc1)C2
Temperature: 80 °C
Reaction time: 1 h
Yield: 32.8 %

Procedure:
A mixture of 1-[2-(4-methylphenylsulfonyl)hydrazino]-5-(thiophen-3-yl)cyclohexen-3-one (3.62 g), anhydrous potassium carbonate (3.45 g), chloroacetone (1.15 g), sodium iodide (1 g), ethanol (50 ml) and 1,2-dimethoxyethane (20 ml) was stirred at 80° C. for 1 hour. Under reduced pressure, the solvent was evaporated, and the residue was extracted with ethyl acetate. The organic layer was concentrated, and the residue was purified with silica gel column chromatography. The resulting crystals were recrystallized from ethyl acetate-hexane to give 4-methyl-7-(thiophen-3-yl)-5,6,7,8-tetrahydrocinnolin-5-one (0.8 g) as yellow crystals.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[S:13][C:14]1[C:15]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]3[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=3)=[CH:24][C:16]=2[S:17][C:18]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20].C(N(CC)C(C)C)(C)C>ClCCl>[CH3:1][S:2]([N:6]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[S:13][C:14]1[C:15]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]3[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=3)=[CH:24][C:16]=2[S:17][C:18]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20])[S:2]([CH3:1])(=[O:4])=[O:3])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)c1sc2cc(OCc3cccnc3)ccc2c1Sc1ccccc1N
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1sc2cc(OCc3cccnc3)ccc2c1Sc1ccccc1N(S(C)(=O)=O)S(C)(=O)=O
Reaction time: 20 h
Yield: 78.3 %

Procedure:
Methanesulfonyl chloride (0.86 ml, 1.1 mmol) was added to a stirred solution of ethyl 3-[(2-aminophenyl)sulfanyl]-6-(3-pyridylmethoxy)benzo[b]thiophene-2-carboxylate (Example 12 220 mg, 0.5 mmol) and N,N-diisopropylethylamine (0.2 ml, 1.1 mmol) in dichloromethane (3 ml). The mixture was left at ambient temperature for 20 hours and then diluted with dichloromethane and washed with water. The organics were dried (magnesium sulfate), and evaporated under reduced pressure. The residue was flash chromatographed on silica gel using diethyl ether, and then ethyl acetate, as eluant. The title product was crystallised from diethyl ether to give a colourless solid (232 mg).
Reaction SMILES: [CH2:1]1[CH2:6][C@H:5]([C:7]([OH:9])=[O:8])[CH2:4][CH2:3][C@H:2]1[CH2:10][NH2:11].[CH3:12][CH:13]([CH3:30])[CH2:14][C:15]([O:17][CH2:18][O:19][C:20](ON1C(=O)CCC1=O)=[O:21])=[O:16]>CC(OC)(C)C.CC(C)=O.O>[CH3:12][CH:13]([CH3:30])[CH2:14][C:15]([O:17][CH2:18][O:19][C:20]([NH:11][CH2:10][C@H:2]1[CH2:3][CH2:4][C@H:5]([C:7]([OH:9])=[O:8])[CH2:6][CH2:1]1)=[O:21])=[O:16]
Reactant: CC(C)CC(=O)OCOC(=O)ON1C(=O)CCC1=O
Reactant: NC[C@H]1CC[C@H](C(=O)O)CC1
Solvent: COC(C)(C)C
Solvent: O
Solvent: CC(C)=O
Product: CC(C)CC(=O)OCOC(=O)NC[C@H]1CC[C@H](C(=O)O)CC1

Procedure:
Following the general nucleophilic carbamoylation procedure, tranexamic acid (472 mg, 3.0 mmol) and 1-[(2,5-dioxopyrrolidinyl)oxycarbonyloxy]methyl 3-methylbutanoate (547 mg, 2.0 mmol) were reacted in the MTBE/acetone/water mixture (16 mL) to yield the title compound 5 (310 mg, 49% yield) as a white powder after work-up and mass-guided preparative HPLC purification. 1H NMR (400 MHz, DMSO-d6): δ=0.86-0.94 (br. m, 8H), 1.17-1.38 (br. m, 3H), 1.64-1.72 (br. m, 2H), 1.83-1.91 (br. m, 2H), 1.96 (hept., J=7.2 Hz, 1H), 2.09 (tt, J=12.4, 3.6 Hz, 1H), 2.21 (d, J=6.8 Hz, 2H), 2.78-2.86 (br. m, 2H), 5.61 (s, 2H), 7.55 (t, J=5.6 Hz, 1H), 11.99 (br. s, 1H). MS (ESI) m/z 316.11 (M+H)+; 314.07 (M−H)−.
Reaction SMILES: C[O:2][C:3](=[O:32])[CH2:4][CH2:5][NH:6][C:7](=[O:31])[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([O:21][C:22]2[CH:27]=[C:26]([CH3:28])[C:25](Br)=[C:24]([CH3:30])[CH:23]=2)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:10][CH:9]=1.[F-].[K+].[F:35][C:36]([F:48])([F:47])[O:37][C:38]1[CH:43]=[CH:42][C:41](B(O)O)=[CH:40][CH:39]=1>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>[CH3:28][C:26]1[CH:27]=[C:22]([O:21][CH:14]([C:11]2[CH:10]=[CH:9][C:8]([C:7]([NH:6][CH2:5][CH2:4][C:3]([OH:2])=[O:32])=[O:31])=[CH:13][CH:12]=2)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH:23]=[C:24]([CH3:30])[C:25]=1[C:41]1[CH:40]=[CH:39][C:38]([O:37][C:36]([F:35])([F:47])[F:48])=[CH:43][CH:42]=1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Reactant: CCCCCCC(Oc1cc(C)c(Br)c(C)c1)c1ccc(C(=O)NCCC(=O)OC)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [F-]
Agent: [K+]
Product: CCCCCCC(Oc1cc(C)c(-c2ccc(OC(F)(F)F)cc2)c(C)c1)c1ccc(C(=O)NCCC(=O)O)cc1
Yield: 91.8 %

Procedure:
3-{4-[1-(4-Bromo-3,5-dimethyl-phenoxyl)-heptyl]-benzoylamino}-propionic acid methyl ester (isomer 1, 100 mg, 0.2 mmol), potassium fluoride (35 mg, 0.6 mmol), 4-triflouromethoxylphenyl boronic acid (83 mg, 0.4 mmol) and tetrakis(triphenylphosphine)palladium (23 mg, 0.02 mmol) are place in a flask. After the reaction is purged with N2 for several times, Toluene/H2O (20 ml/5 ml) is added. The resulting solution is refluxed overnight, loaded on silica gel, eluted with hexane and ethyl acetate to give 3-{4-[1-(2,6-Dimethyl-4′-trifluoromethoxy-biphenyl-4-yloxy)-heptyl]-benzoylamino}-propionic acid, (105 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([C:9]2[C:14](Cl)=[C:13]([Cl:16])[N:12]=[C:11]([Cl:17])[N:10]=2)[CH:3]=1.Cl>S1C=CC=C1C([O-])=O.[Cu+].CN1CCCC1=O>[Cl:17][C:11]1[N:12]=[C:13]([Cl:16])[C:14]2[O:8][C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=3[C:9]=2[N:10]=1
Reactant: Oc1ccc(Cl)cc1-c1nc(Cl)nc(Cl)c1Cl
Agent: [Cu+]
Agent: Cl
Agent: O=C([O-])c1cccs1
Solvent: CN1CCCC1=O
Product: Clc1ccc2oc3c(Cl)nc(Cl)nc3c2c1
Temperature: 100 °C
Reaction time: 0.25 h
Yield: 83.8 %

Procedure:
A 10 mL flask was charged with 4-chloro-2-(2,5,6-trichloro-pyrimidin-4-yl)-phenol (75 mg, 0.24 mmol) and N-methylpyrrolidinone (3.0 mL) under a N2 atmosphere. The solution was purged with N2 for, 10 min. Copper (I) thiophene-2-carboxylate (60 mg, 0.32 mmol, 1.3 equiv.) was added and the mixture was heated to 100° C. for 2 h. The reaction mixture was cooled to rt and added to aq. HCl (0.1 M, 6.0 mL) slowly and stirred for 15 min. Additional aq. HCl (0.1 M, 3.0 mL) was added and the mixture was stirred for 20 min. The resulting solid was collected by filtration, rinsed with water, and dried to give a tan solid (55 mg, 83%). GC-MS (CI): mass calcd. for C10H3Cl3N2O, 271.9; m/z found, 272.0. 1H NMR (CDCl3): 8.22 (d, J=2.1 Hz, 1H), 7.75 (dd, J=8.9, 2.1 Hz, 1H), 7.69 (d, J=9.0 Hz, 1H).
Reaction SMILES: [CH:1](=[N+:8]([O-:16])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:17]([S:19]([CH:22]=[CH2:23])(=[O:21])=[O:20])=[CH2:18]>C1(C)C=CC=CC=1>[CH2:1]([N:8]1[CH:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:18][CH:17]([S:19]([CH:22]2[O:16][N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH2:23]2)(=[O:21])=[O:20])[O:16]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [O-][N+](=Cc1ccccc1)Cc1ccccc1
Reactant: C=CS(=O)(=O)C=C
Solvent: Cc1ccccc1
Product: O=S(=O)(C1CC(c2ccccc2)N(Cc2ccccc2)O1)C1CC(c2ccccc2)N(Cc2ccccc2)O1
Yield: 25.9 %

Procedure:
A solution of 2.11 g (10 mmol) of N-benzylidenebenzylamine N-oxide and 1.09 g (5 mmol) of divinyl sulfone in 30 ml of toluene under a nitrogen atmosphere is heated at reflux temperature for 8 hours. The solvent is removed under reduced pressure to give 4.1 g of crude product which is then purified by preparative HPLC (Waters Prep 500A, silica gel, 3:1 heptane:ethyl acetate eluent) to give 0.70 g (26% yield) of a yellow amorphous solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][OH:12])=[CH:4][CH:3]=1.Cl[CH2:14][C:15]1[N:16]=[C:17](/[CH:20]=[CH:21]/[C:22]2[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][CH:23]=2)[O:18][CH:19]=1>>[Br:28][C:25]1[CH:26]=[CH:27][C:22](/[CH:21]=[CH:20]/[C:17]2[O:18][CH:19]=[C:15]([CH2:14][O:1][C:2]3[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][OH:12])=[CH:6][CH:7]=3)[N:16]=2)=[CH:23][CH:24]=1
Reactant: ClCc1coc(/C=C/c2ccc(Br)cc2)n1
Reactant: OCCCCc1ccc(O)cc1
Product: OCCCCc1ccc(OCc2coc(/C=C/c3ccc(Br)cc3)n2)cc1
Yield: 91 %

Procedure:
Using 4-(4-hydroxyphenyl)-1-butanol (4.99 g) and (E)-4-chloromethyl-2-[2-(4-bromophenyl)ethenyl]oxazole (7.43 g), the same reaction as Reference Example 17-(i) was carried out to yield 4-[4-[2-(E)-[2-(4-bromophenyl)ethenyl]-1,3-oxazol-4-yl]methoxyphenyl]-1-butanol (9.70 g). Using the compound obtained (4.28 g), the same reaction as Reference Example 17-(ii) was carried out to yield the titled compound (4.47 g) as a white powder.
Reaction SMILES: Cl.[NH2:2][CH:3]([CH2:7][NH2:8])[C:4]([OH:6])=[O:5].[OH-].[Na+].[C:11]([C:14]([CH3:16])=O)([CH3:13])=O>CO>[CH3:13][C:11]1[N:8]=[CH:7][C:3]([C:4]([OH:6])=[O:5])=[N:2][C:14]=1[CH3:16]
Reactant: NCC(N)C(=O)O
Reactant: CC(=O)C(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1ncc(C(=O)O)nc1C
Reaction time: 0.5 h

Procedure:
To a solution of 2,3-diaminopropanoic acid hydrochloride (1 g, 7.11 mmol) in methanol (63 mL) was added sodium hydroxide (1.42 g, 28.4 mmol) at 10° C., and then the mixture was degassed with N2. After 30 min, biacetyl (612 mg, 7.11 mmol) was added and the reaction mixture was stirred at the same temperature for 3 h. Dry air was passed through the reaction mixture for 16 h. The solvent was then removed under reduced pressure, the residue was dissolved in water (7 mL), and the solution was adjusted to pH 2 with concentrated HCl slowly at 0° C., and the mixture was filtered. The yellow solid (580 mg) was used in the next step without further purification. MS (ESI): m/z 153.1 [M+H]+.
Reaction SMILES: [O:1]=[C:2]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:6][C:5](=[O:15])[N:4]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:3]1[C:23]1([OH:34])[CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24]1.Cl.O1CCOCC1>CO>[OH:34][C:23]1([CH:3]2[N:4]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:5](=[O:15])[CH2:6][N:7]([CH2:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:2]2=[O:1])[CH2:26][NH:25][CH2:24]1
Reactant: CC(C)(C)OC(=O)N1CC(O)(C2C(=O)N(Cc3ccccc3)CC(=O)N2Cc2ccccc2)C1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: O=C1C(C2(O)CNC2)N(Cc2ccccc2)C(=O)CN1Cc1ccccc1
Temperature: 25 °C
Yield: 61 %

Procedure:
A solution of 1,1-dimethylethyl 3-[3,6-dioxo-1,4-bis(phenylmethyl)piperazin-2-yl]-3-hydroxyazetidine-1-carboxylate (1.04 g, 2.2 mmol) in methanol (10 mL) was treated with hydrogen chloride in dioxane (4 N, 5.5 mL, 22 mmol) at 60° C. for 25 min. After cooling to room temperature the solution was concentrated. Ethyl acetate and 2 N hydrochloric acid were added to the residue and the phases were separated. The organic phase was discarded. The aqueous phase was basified with 5 M sodium hydroxide and the resulting solution was extracted 4 times with ethyl acetate. The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography (85% dichloromethane: 14% methanol: 1% aqueous ammonium hydroxide) to provide 3-(3-hydroxyazetidin-3-yl)-1,4-bis(phenylmethyl)piperazine-2,5-dione as a colorless film (493 mg, 1.35 mmol, 61% yield). 1H NMR (400 MHz, CDCl3): 7.39-7.28 (m, 6H), 7.25-7.20 (m, 4H), 5.39 (d, 1H), 4.80 (d, 1H), 4.44 (d, 1H), 4.36 (d, 1H), 4.26 (d, 1H), 4.11 (s, 1H), 3.97 (d, 1H), 3.83 (d, 1H), 3.71 (d, 1H), 3.27 (m, 2H); MS (EI) for C21H23N3O3: 366 (MH+).
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([O:14][CH3:15])=[O:13])[CH:10]=2)[CH:5]=[CH:4][N:3]1[CH2:16][CH:17]=O.[CH3:19][O:20][C:21]1[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][CH:22]=1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO.O>[CH3:19][O:20][C:21]1[CH:27]=[CH:26][C:24]([NH:25][CH2:17][CH2:16][N:3]2[CH:4]=[CH:5][C:6]3[C:11](=[CH:10][C:9]([C:12]([O:14][CH3:15])=[O:13])=[CH:8][CH:7]=3)[C:2]2=[O:1])=[CH:23][CH:22]=1
Reactant: COC(=O)c1ccc2ccn(CC=O)c(=O)c2c1
Reactant: COc1ccc(N)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)c1ccc2ccn(CCNc3ccc(OC)cc3)c(=O)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.1 %

Procedure:
A solution of methyl 1-oxo-2-(2-oxoethyl)-1,2-dihydroisoquinoline-7-carboxylate (0.10 g, 0.41 mmol) and 4-methoxyaniline (65 mg, 0.53 mmol) in methanol (2 mL) was stirred at rt for 30 mins. Then acetic acid (2.3 μL, 0.04 mmol) and sodium cyanoborohydride (64 mg, 1.0 mmol) was added and the reaction mixture was stirred at rt overnight. The mixture was diluted with water and extracted with DCM (2×). The combined organic phases were then washed with water, and brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by flash silica gel chromatography (20% to 70% EtOAc/hexanes) to afford methyl 2-{2-[(4-methoxyphenyl)amino]ethyl}-1-oxo-1,2-dihydroisoquinoline-7-carboxylate (0.12 g, 83%). LC-MS: (FA) ES+ 353.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:17][CH3:18])=[CH:5][C:6]2[CH2:12][CH2:11][CH2:10][C:9]([C:13](Cl)=[O:14])=[CH:8][C:7]=2[CH:16]=1.Cl.[NH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH:21]1[C:26]([O:28][CH2:29][CH3:30])=[O:27].C(N(CC)CC)C>ClCCl>[CH3:1][O:2][C:3]1[C:4]([O:17][CH3:18])=[CH:5][C:6]2[CH2:12][CH2:11][CH2:10][C:9]([C:13]([N:23]3[CH2:24][CH2:25][NH:20][CH:21]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:22]3)=[O:14])=[CH:8][C:7]=2[CH:16]=1
Reactant: COc1cc2c(cc1OC)CCCC(C(=O)Cl)=C2
Reactant: CCOC(=O)C1CNCCN1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C1CN(C(=O)C2=Cc3cc(OC)c(OC)cc3CCC2)CCN1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 74.9 %

Procedure:
A solution of 2,3-dimethoxy-6,7-dihydro-5H-benzocycloheptene-8-carbonylchloride (1.1 g) in dichloromethane (12 ml) is added dropwise, taking 30 minutes while stirring under ice-cooling, to a mixture of ethyl piperazine-2-carboxylate hydrochloride (1.0 g), triethylamine (0.5 g) and dichloromethane (20 ml). The reaction mixture is stirred for one hour at 0 ° C, and then poured into ice-water, followed by extraction with dichloromethane. The organic layer is washed with water and dried, then the solvent is distilled off under reduced pressure. The residue is purified by means of a silica gel column chromatography (hexane:ethyl acetate:acetone=1:1:1) to afford ethyl 4-(2,3-dimethoxy-6,7-dihydro-5H-benzocyclohepten-8-ylcarbonyl)piperazine-2-carboxylate as crystals (1.2 g). This product is recrystallized form ethyl acetate and hexane to give colorless prisms, m.p. 105-106° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH2:10])[C:5]=1[NH2:11])([O-])=O>CO.[Pd]>[C:6]1([NH2:10])[CH:7]=[CH:8][CH:9]=[C:4]([NH2:1])[C:5]=1[NH2:11]
Reactant: Nc1cccc([N+](=O)[O-])c1N
Agent: [Pd]
Solvent: CO
Product: Nc1cccc(N)c1N
Yield: 100 %

Procedure:
A solution of 3-nitrobenzene-1,2-diamine at 0.05 mol/1 in methanol was passed through an H-Cube reactor on a cartridge of palladium on carbon with a flow rate of 1 ml/min. After one and a half hours, the product was completely hydrogenated. The solvent was concentrated. 450.7 g of benzene-1,2,3-triamine were obtained in the form of a green oil. Yield>100%.
Reaction SMILES: [C:1]([C:4]12[CH2:11][CH2:10][C:7]([NH:12][CH2:13][C:14]([N:16]3[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]3[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]1)[CH2:6][CH2:5]2)([OH:3])=O.Cl.[CH:25]1([CH2:30][NH2:31])[CH2:29][CH2:28][CH2:27][CH2:26]1>>[CH:25]1([CH2:30][NH:31][C:1]([C:4]23[CH2:9][CH2:8][C:7]([NH:12][CH2:13][C:14]([N:16]4[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]4[C:22]#[N:23])=[O:15])([CH2:10][CH2:11]2)[CH2:6][CH2:5]3)=[O:3])[CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)O)(CC1)CC2
Reactant: NCC1CCCC1
Agent: Cl
Product: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)NCC3CCCC3)(CC1)CC2
Yield: 22.2 %

Procedure:
In a similar manner to Example 87, (2S,4S)-1-[[N-(4-carboxybicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (70.0 mg) and cyclopentylmethylamine hydrochloride (72.2 mg) were used to obtain (2S,4S)-1-[[N-[4-(N-cyclopentylmethylamino)carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (19.4 mg).
Reaction SMILES: [N:1]([CH2:4][C:5]1[N:6]=[C:7]([N:10]2[CH2:13][CH:12]([O:14][Si:15]([C:28]([CH3:31])([CH3:30])[CH3:29])([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:11]2)[S:8][CH:9]=1)=[N+]=[N-].[O:32]1[CH:36]=[CH:35][CH:34]=[C:33]1[C:37](Cl)=[O:38].C(N(CC)CC)C>CO.[OH-].[Pd+2].[OH-]>[Si:15]([O:14][CH:12]1[CH2:13][N:10]([C:7]2[S:8][CH:9]=[C:5]([CH2:4][NH:1][C:37]([C:33]3[O:32][CH:36]=[CH:35][CH:34]=3)=[O:38])[N:6]=2)[CH2:11]1)([C:28]([CH3:31])([CH3:30])[CH3:29])([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)(C)[Si](OC1CN(c2nc(CN=[N+]=[N-])cs2)C1)(c1ccccc1)c1ccccc1
Reactant: O=C(Cl)c1ccco1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CO
Product: CC(C)(C)[Si](OC1CN(c2nc(CNC(=O)c3ccco3)cs2)C1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 56.2 %

Procedure:
1-(4-Azidomethyl-1,3-thiazol-2-yl)-3-t-butyldiphenylsilyloxyazetidine (2.47 g, 5.50 mmol) (obtained as described in Reference Example 62(1)) in methanol (120 ml) was subjected to catalytic reduction in the presence of 20% palladium hydroxide (2.47 g) at room temperature. After checking the completion of the reaction, the reaction mixture was filtered in order to remove the catalyst and the filtrate concentrated under reduced pressure. The residue was dissolved in methylene chloride (115 ml). To the mixture were added 2-furoyl chloride (0.65 ml, 6.60 mmol) and triethylamine (0.92 ml, 6.60 mmol), and the mixture was stirred at room temperature for 1 hour. After checking the completion of the reaction, the mixture was distilled under reduced pressure. The residue was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using hexane:ethyl acetate (1:1) as the eluant to afford 3-t-butyldiphenylsilyloxy-1-[4-(furan-2-carbonylamino)methyl-1,3-thiazol-2-yl]azetidine (1.60 g, yield 60%) as a pale yellow oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[CH:3]=1.C([O-])([O-])=O.[K+].[K+].[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][SH:23])=[CH:18][CH:17]=1>C(Cl)Cl>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][S:23][C:2]2[CH:7]=[CH:6][NH:5][C:4](=[O:8])[CH:3]=2)=[CH:18][CH:17]=1
Reactant: O=c1cc(Cl)cc[nH]1
Reactant: SCc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: O=c1cc(SCc2ccc(Cl)cc2)cc[nH]1
Temperature: 100 °C
Reaction time: 18 h

Procedure:
A mixture of 4-chloropyridin-2(1H)-one (100 mg, 0.77 mmol), K2CO3 (320 mg, 2.32 mmol) and (4-chlorophenyl)methanethiol (612 mg, 3.86 mmol) was stirred at 100° C. for 18 hours. After cooling the reaction to RT and was dilution with CH2Cl2 (5 mL), the crude product was subjected to flash chromatography (silica gel/hexane-EtOAc 100:0 to 0:100 gradient, employing LC-MS to identify the fractions containing the desired product) to afford 4-(4-chlorobenzylthio)pyridin-2(1H)-one 8A (96 mg, 46.9% yield). 1H NMR (400 MHz, Chloroform-D) δ ppm 12.30 (1H, br. s.), 7.28-7.43 (4H, m), 7.15 (1H, d, J=7.03 Hz), 6.28 (1H, d, J=1.51 Hz), 6.11 (1H, dd, J=6.90, 1.88 Hz), 4.11 (2H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[C:13]([N+:15]([O-])=O)[CH:12]=[CH:11][C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.[H][H]>[Ni].C1COCC1>[Cl:1][C:2]1[CH:14]=[C:13]([NH2:15])[CH:12]=[CH:11][C:3]=1[CH2:4][N:5]1[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc(CN2CCCCC2)c(Cl)c1
Agent: [Ni]
Solvent: C1CCOC1
Product: Nc1ccc(CN2CCCCC2)c(Cl)c1

Procedure:
0.4 g of Raney nickel is added to a solution of 2.37 g (9.31 mmol) of 1-(2-chloro-4-nitrobenzyl)piperidine in 100 mL of THF and hydrogenated at ambient temperature and 3 bar hydrogen. After hydrogen uptake has ended, the catalyst is filtered off and the filtrate is evaporated down. Yield: 1.88 g (90% of theory); C12H17ClN2 (M=224.73); calc.: molecular ion peak (M+H)+: 255/7 (Cl); found: molecular ion peak (M+H)+: 255/7 (Cl); Rf value: 0.20 (silica gel, dichloromethane/methanol (90:10)).
Reaction SMILES: [CH2:1]([N:9]([CH3:25])[C:10]([C@@H:12]1[CH2:16][C@@H:15]([OH:17])[CH2:14][N:13]1C(OC(C)(C)C)=O)=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]=[CH:7][CH3:8].C(N(C)C([C@@H]1C[C@@H](O)CN1)=O)CCCC=C>>[CH2:1]([N:9]([CH3:25])[C:10]([C@@H:12]1[CH2:16][C@@H:15]([OH:17])[CH2:14][NH:13]1)=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]=[CH:7][CH3:8]
Reactant: CC=CCCCCCN(C)C(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Agent: C=CCCCCN(C)C(=O)[C@@H]1C[C@@H](O)CN1
Product: CC=CCCCCCN(C)C(=O)[C@@H]1C[C@@H](O)CN1
Yield: 51 %

Procedure:
Compound 71b was synthesized from compound 70b as yellow oil in 51% yield, following the procedure as described for compound 49.