Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:23])[C@@H:5]([O:20][CH2:21][CH3:22])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]([C:17]([OH:19])=O)([CH3:16])[CH3:15])=[CH:9][CH:8]=1)C.[C:24]1([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:29]=[CH:28][CH:27]=[C:26]([CH2:30][NH2:31])[CH:25]=1.C(O[C@@H](CC1C=CC(O[C@@H](C(=O)NCCC2C=CC(OC3C=CC=CC=3)=CC=2)C)=CC=1)C(O)=O)C>>[C:24]1([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:29]=[CH:28][CH:27]=[C:26]([CH2:30][NH:31][C:17]([C:14]([CH3:15])([O:13][C:10]2[CH:9]=[CH:8][C:7]([CH2:6][C@H:5]([O:20][CH2:21][CH3:22])[C:4]([OH:3])=[O:23])=[CH:12][CH:11]=2)[CH3:16])=[O:19])[CH:25]=1
Reactant: CCOC(=O)[C@H](Cc1ccc(OC(C)(C)C(=O)O)cc1)OCC
Reactant: NCc1cccc(-c2ccccc2)c1
Agent: CCO[C@@H](Cc1ccc(O[C@H](C)C(=O)NCCc2ccc(Oc3ccccc3)cc2)cc1)C(=O)O
Product: CCO[C@@H](Cc1ccc(OC(C)(C)C(=O)NCc2cccc(-c3ccccc3)c2)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-[4-(1-carboxy-1-methyl-ethoxy)-phenyl]-2-ethoxy-propionic acid ethyl ester (EXAMPLE 49, step 2) and C-biphenyl-3-yl-methylamine via the same procedure used for the preparation of (2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionic acid (Example 1, step 3) to produce a colorless oil. MS (ES) for C28H31NO5 [M−H]−: 462.
Reaction SMILES: [CH2:1]([CH:3]([CH2:13][CH3:14])[C:4]([NH:6][CH2:7][C:8]([O:10]CC)=[O:9])=[O:5])[CH3:2].[OH-].[Na+:16]>CO>[CH2:13]([CH:3]([CH2:1][CH3:2])[C:4]([NH:6][CH2:7][C:8]([O-:10])=[O:9])=[O:5])[CH3:14].[Na+:16]
Reactant: CCOC(=O)CNC(=O)C(CC)CC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCC(CC)C(=O)NCC(=O)[O-]
Reaction time: 1.5 h

Procedure:
To a solution of ethyl N-(2-ethylbutyryl)glycinate (33.73 g) in 100 mL of methanol was added 167.6 mL of 1N sodium hydroxide, and the solution stirred for 1.5 hr. Solvents were evaporated in vacuo, and then fresh methanol was added and evaporated to give 32.6 g of a pale yellow oil.
Reaction SMILES: [CH2:1]([CH:4]1[CH2:9][C:8](=[O:10])[CH2:7][C:6](=[O:11])[CH2:5]1)[CH2:2][CH3:3].[Br:12]Br>CC(O)=O>[Br:12][CH:7]1[C:6](=[O:11])[CH2:5][CH:4]([CH2:1][CH2:2][CH3:3])[CH2:9][C:8]1=[O:10]
Reactant: BrBr
Reactant: CCCC1CC(=O)CC(=O)C1
Solvent: CC(=O)O
Product: CCCC1CC(=O)C(Br)C(=O)C1

Procedure:
To a stirred solution of 5-propylcyclohexane-1,3-dione (1.54 g, 10 mmol) in AcOH (20 mL) at r.t. was added bromine (1.6 g, 0.51 mL, 1 mmol) dropwise. The reaction was carried out according to Method A to give the title compound in quantitative yield as a light brown solid, which was used without further purification. LCMS (ES+) 232.9 (M+H)+.
Reaction SMILES: S(=O)(=O)(O)O.[CH3:6][S:7]([O:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:23])[C:19](C)(C)C)=[C:13]([CH3:24])[C:12]=1[O:25][CH3:26])(=[O:9])=[O:8].[OH-].[Na+].N1C=CC=CC=1.C(OC(=O)C)(=O)C>C(O)CCC.C(OCC)(=O)C>[CH3:6][S:7]([O:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:23])[CH3:19])=[C:13]([CH3:24])[C:12]=1[O:25][CH3:26])(=[O:9])=[O:8]
Reactant: COc1c(OS(C)(=O)=O)ccc(NC(=O)C(C)(C)C)c1C
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: COc1c(OS(C)(=O)=O)ccc(NC(C)=O)c1C
Temperature: 100 °C
Reaction time: 14 h
Yield: 79.7 %

Procedure:
A 20%-aqueous sulfuric acid solution (4 ml) was added dropwise to a solution of 4-[(2,2-dimethylpropanoyl)amino]-2-methoxy-3-methylphenyl methanesulfonate (223 mg, 0.707 mmol) in n-butanol (2 ml) at room temperature, and the resulting mixture was heated to 100° C. After 14 hours, the reaction solution was poured onto ice (50 ml) and adjusted to pH 11 with an aqueous sodium hydroxide solution. The resulting mixture was extracted with ethyl acetate (50 ml×3) and the organic layer was dried over anhydrous magnesium sulfate. The organic layer dried was concentrated under reduced pressure, and to a solution of the resulting residue in ethyl acetate (5 ml) were added pyridine (0.069 ml, 0.848 mmol) and acetic anhydride (0.073 ml, 0.778 mmol) at room temperature. The resulting mixture was heated to 60° C. After 2 hours, the reaction solution was concentrated under reduced pressure and the resulting residue was purified by a silica gel column chromatography (eluent: hexane/ethyl acetate→chloroform/ethyl acetate) to obtain 4-(acetylamino)-2-methoxy-3-methylphenyl methanesulfonate (154 mg, 79%).
Reaction SMILES: [CH3:1][S:2][CH2:3][CH2:4][CH2:5][NH:6][C:7]1[C:16]2[C:11](=[CH:12][C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:14][CH:15]=2)[N:10]=[CH:9][C:8]=1[N+:23]([O-])=O>C1(C)C=CC=CC=1.[Pt]>[CH3:1][S:2][CH2:3][CH2:4][CH2:5][NH:6][C:7]1[C:16]2[C:11](=[CH:12][C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:14][CH:15]=2)[N:10]=[CH:9][C:8]=1[NH2:23]
Reactant: CSCCCNc1c([N+](=O)[O-])cnc2cc(-c3ccccc3)ccc12
Agent: [Pt]
Solvent: Cc1ccccc1
Product: CSCCCNc1c(N)cnc2cc(-c3ccccc3)ccc12
Yield: 100 %

Procedure:
(3-Methylsulfanylpropyl)-(3-nitro-7-phenylquinolin-4-yl)amine (3.0 g, 8.5 mmol) was hydrogenated in a Parr bottle over Pt/C (0.3 g of 5%) in 42 mL of toluene for 1 h. The reaction mixture was filtered through CELITE filter agent, washed with methanol (100 mL) and CHCl3 (50 mL), and then concentrated to afford 2.75 g of N4-(3-methylsulfanylpropyl)-7-phenylquinoline-3,4-diamine as a brown oil.
Reaction SMILES: [CH2:1]([NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:15]([OH:17])=O)[CH:13]=2)[CH:8]=[CH:7][N:6]=1)[CH2:2][CH3:3].C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:51][C@@H:52]([CH2:66][C:67]1[CH:72]=[C:71]([F:73])[CH:70]=[C:69]([F:74])[CH:68]=1)[C@H:53]([OH:65])[CH2:54][NH:55][CH2:56][C:57]1[CH:62]=[CH:61][CH:60]=[C:59]([CH2:63][CH3:64])[CH:58]=1>C(Cl)Cl>[F:73][C:71]1[CH:72]=[C:67]([CH:68]=[C:69]([F:74])[CH:70]=1)[CH2:66][C@H:52]([NH:51][C:15]([C:12]1[CH:13]=[C:14]2[C:9]([CH:8]=[CH:7][N:6]=[C:5]2[NH:4][CH2:1][CH2:2][CH3:3])=[CH:10][CH:11]=1)=[O:17])[C@H:53]([OH:65])[CH2:54][NH:55][CH2:56][C:57]1[CH:62]=[CH:61][CH:60]=[C:59]([CH2:63][CH3:64])[CH:58]=1
Reactant: CCCNc1nccc2ccc(C(=O)O)cc12
Reactant: CCc1cccc(CNC[C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCNc1nccc2ccc(C(=O)N[C@@H](Cc3cc(F)cc(F)c3)[C@H](O)CNCc3cccc(CC)c3)cc12
Reaction time: 18 h
Yield: 34 %

Procedure:
To a stirred solution of 1-(propylamino)isoquinoline-7-carboxylic acid (81 mg, 0.396 mmol) and N,N-diisopropyl ethylamine (3.75 μL, 2.16 mmol) in methylene chloride (5.0 mL) was added HBTU (152 mg, 0.396 mmol) and the reaction stirred for 0.5 h. (2R,3S)-3-Amino-4-(3,5-difluorophenyl)-1-[(3-ethylbenzyl)amino]butan-2-ol (150 mg, 0.36 mmol) was added in one portion and the reaction mixture was stirred under nitrogen for 18 h. The reaction mixture was then diluted with additional methylene chloride and washed with saturated sodium bicarbonate, saturated sodium chloride, dried (sodium sulfate), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica, 0-5% methanol/methylene chloride) gave N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-1-(propylamino)isoquinoline-7-carboxamide (67 mg) which was characterized as its bis-HCl salt: mp 262° C. dec; ESI MS m/z 547 [M+H]+
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C:11]1[CH2:12][CH2:13][N:14]([CH3:17])[CH2:15][CH:16]=1.[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.Cl>>[ClH:1].[C:18]([N:7]1[C:8]2[C:4](=[CH:3][C:2]([Cl:1])=[CH:10][CH:9]=2)[C:5]([C:11]2[CH2:12][CH2:13][N:14]([CH3:17])[CH2:15][CH:16]=2)=[CH:6]1)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CN1CC=C(c2c[nH]c3ccc(Cl)cc23)CC1
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Product: CN1CC=C(c2cn(C(=O)c3ccccc3)c3ccc(Cl)cc23)CC1

Procedure:
(20 mg, 59%) from 5-chloro-3-(1-methyl-1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole (Example 4d, 25 mg, 0.1 mmol) and benzoyl chloride (21.1 mg, 0.15 mmol), m.p 256-7° C., HRMS-FAB+ for C21H19N2OCl.HCl, calculated MH+ (--HCl): 351.1264; found: 351.12595.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2O[C:10](/[CH:13]=[CH:14]/[C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH:25]=[C:24]([CH3:26])[N:23]=[CH:22]4)=[C:17]([O:27][CH3:28])[CH:16]=3)=[N:11][N:12]=2)[CH:5]=[CH:6][CH:7]=1.C([O-])(=O)C.[NH4+:33]>C(O)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[NH:33][C:10](/[CH:13]=[CH:14]/[C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH:25]=[C:24]([CH3:26])[N:23]=[CH:22]4)=[C:17]([O:27][CH3:28])[CH:16]=3)=[N:11][N:12]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(/C=C/c2nnc(-c3cccc(F)c3)o2)ccc1-n1cnc(C)c1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Product: COc1cc(/C=C/c2nnc(-c3cccc(F)c3)[nH]2)ccc1-n1cnc(C)c1
Temperature: 150 °C
Yield: 58.2 %

Procedure:
A solution of 2-(3-fluorophenyl)-5-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-[1,3,4]oxadiazole (50 mg) and ammonium acetate (205 mg) in acetic acid (3 mL) was heated under reflux at 150° C. for 1.5 hours. The reaction solution was left to cool to room temperature and concentrated under reduced pressure. Ethyl acetate and saturated sodium bicarbonate water were added to the residue, and the organic layer was separated. The resulting organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate->ethyl acetate:methanol=5:1) to obtain 29 mg of the title compound. The property value of the compound is as follows.
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[CH:8][C:7]([N:10]3[CH2:14][CH2:13][C:12]4([CH2:19][CH2:18][N:17]([CH2:20][C:21](O)=[O:22])[CH2:16][CH2:15]4)[C:11]3=[O:24])=[CH:6][CH:5]=2)[CH2:3][CH2:2]1.CN(C(O[N:33]1N=N[C:35]2C=CC=C[C:34]1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(CC)CC.C(N)C>CN(C=O)C>[CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([N:10]3[CH2:14][CH2:13][C:12]4([CH2:15][CH2:16][N:17]([CH2:20][C:21]([NH:33][CH2:34][CH3:35])=[O:22])[CH2:18][CH2:19]4)[C:11]3=[O:24])=[CH:8][CH:9]=2)[CH2:2][CH2:3]1
Reactant: O=C(O)CN1CCC2(CC1)CCN(c1ccc(C3CC3)cc1)C2=O
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CCN
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCNC(=O)CN1CCC2(CC1)CCN(c1ccc(C3CC3)cc1)C2=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 35.1 %

Procedure:
A mixture of mg 42.7 mg (0.13 mmol) [2-(4-Cyclopropyl-phenyl)-1-oxo-2,8-diaza-spiro[4.5]dec-8-yl]-acetic acid, 54.2 mg (0.195 mmol) TBTU, 26 mg (0.26 mmol) NEt3 and 8.7 mg (0.195 mmol) ethylamine in 2 mL DMF was stirred at room temperature for 16 h and evaporated to dryness. The residue was taken up in DMF and subjected to purification by preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile, water and NEt3. The product containing fractions were evaporated to yield 16.2 mg (35%) of the title compound. MS m/e: 356.3 [M+H]+.
Reaction SMILES: [N:1]1([C:6]([C@@H:8]([NH:11]C(=O)OCC2C=CC=CC=2)[CH2:9][CH3:10])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.CO>[OH-].[OH-].[Pd+2]>[N:1]1([C:6]([C@@H:8]([NH2:11])[CH2:9][CH3:10])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC[C@H](NC(=O)OCc1ccccc1)C(=O)N1CCCC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC[C@H](N)C(=O)N1CCCC1
Yield: 97 %

Procedure:
Phenylmethyl [(1S)-1-(1-pyrrolidinylcarbonyl)propyl]carbamate (J. Med. Chem., 1991, 34, 3149-58) was dissolved in methanol (20 mL) (559 mg, 1.9 mmol). Pd(OH)2 (140 mg) was added, and the resulting suspension was stirred under a hydrogen balloon until the deprotection was complete. Filtration of the catalyst and evaporation of the solvent yielded [(1S)-1-(1-pyrrolidinylcarbonyl)propyl]amine (291 mg, 97%).
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[S:27])[C:12]3[CH:19]=[C:18]([CH2:20][N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[S:17][C:13]=3[N:14]([CH3:16])[CH:15]=2)=[S:9])=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].C[O:41]C1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=S)=CC=1.C1(C)C=CC=CC=1>ClC(Cl)C.ClCCl>[Cl:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[S:27])[C:12]3[CH:19]=[C:18]([CH2:20][N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[S:17][C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:41])=[CH:4][CH:3]=1.[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[S:27])[C:12]3[CH:19]=[C:18]([CH2:20][N:21]4[CH2:22][CH2:23][O:24][CH2:25][CH2:26]4)[S:17][C:13]=3[N:14]([CH3:16])[CH:15]=2)=[S:9])=[CH:28][CH:29]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cn1cc(C(=S)NCc2ccc(Cl)cc2)c(=S)c2cc(CN3CCOCC3)sc21
Agent: [K+]
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: CC(Cl)Cl
Product: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=S)c2cc(CN3CCOCC3)sc21
Temperature: 25 °C

Procedure:
Preparation of N-(4-Chlorobenzyl)-7-methyl-2-(4-morpholinylmethyl)-4-thioxo-4,7-dihydrothieno[2,3-b]pyridine-5-carbothioamide, (A-2 of Chart A) A-1 (570 mg, 1.32 mmol) was dissolved in dichloroethane (80 mL) followed by the addition of KHMDS (0.5 M, 2.64 mL, 1.32 mmol, 1 equiv.). Then Lawesson's reagent (1.1 g, 2.64 mmol, 2.0 equiv.) and toluene (80 mL) was added and the resulting mixture was heated at reflux for 6 h. The reaction was cooled to rt, diluted with dichloromethane, washed with water, Na2CO3, brine, dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (heptane/EtOAc 1/1, ¼, 0/1 then DCM/MeOH 19/1) to afford 248 mg of crude N-(4-chlorobenzyl)-7-methyl-2-(4-morpholinylmethyl)-4-thioxo-4,7-dihydrothieno[2,3-b]pyridine-5-carboamide and 139 mg of crude N-(4-chlorobenzyl)-7-methyl-2-(4-morpholinylmethyl)-4-thioxo-4,7-dihydrothieno[2,3-b]pyridine-5-carbothioamide A-2. The crude A-2 was purified by multiple silica gel chromatography (heptane/EtOAc 1/1, ¼, 0/1 then DCM/MeOH 1/0, 50/1, 19/1) to afford 55 mg (9%) of pure tan solid.
Reaction SMILES: COC1C=CC(C(O[C:10]2[C:15]([NH:16][C:17](=[O:26])[C:18]3[CH:23]=[CH:22][C:21]([O:24]C)=[CH:20][CH:19]=3)=[CH:14][C:13]([O:27]C)=[CH:12][C:11]=2[Br:29])=O)=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.CC1C=CC(C)=CC=1>O>[Br:29][C:11]1[C:10]2[O:26][C:17]([C:18]3[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=3)=[N:16][C:15]=2[CH:14]=[C:13]([OH:27])[CH:12]=1
Reactant: COc1ccc(C(=O)Nc2cc(OC)cc(Br)c2OC(=O)c2ccc(OC)cc2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccc(C)cc1
Solvent: O
Product: Oc1ccc(-c2nc3cc(O)cc(Br)c3o2)cc1
Temperature: 25 °C
Yield: 88.9 %

Procedure:
A suspension of 2-bromo-4-methoxy-6-[(4-methoxybenzoyl)amino]phenyl 4-methoxybenzoate (42.0 g, 86.4 mmol), p-toluenesulfonic acid monohydrate (32.8 g, 172.8 mmol) and anhydrous p-xylene (800 mL) was refluxed for 1 h with continuous water removal (Dean-Stark Trap). The initial suspension turned into a brown solution at refluxing temperature. The mixture was cooled to room temperature and washed with NaOH (2N). The organic layer was dried over MgSO4. Evaporation and crystallization from acetone/ethyl ether gave an off-white solid (23.5 g, 82% yield, m.p. 139-141° C.); MS m/e 334 (M+H)+.
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][CH:16]=[CH:15][C:14]=2[CH2:19][CH2:20][C:21]([OH:23])=O)[C:7](=[O:11])[C:8]=1[O:9][CH3:10].[CH:26]([NH2:29])([CH3:28])[CH3:27]>>[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][CH:16]=[CH:15][C:14]=2[CH2:19][CH2:20][C:21]([NH:29][CH:26]([CH3:28])[CH3:27])=[O:23])[C:7](=[O:11])[C:8]=1[O:9][CH3:10]
Reactant: CC(C)N
Reactant: COC1=C(OC)C(=O)C(Cc2ccccc2CCC(=O)O)=C(C)C1=O
Product: COC1=C(OC)C(=O)C(Cc2ccccc2CCC(=O)NC(C)C)=C(C)C1=O
Yield: 27.3 %

Procedure:
3-[2-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-ylmethyl)phenyl]propionic acid (15 mg, 0.044 mmol) obtained in Example 69 and isopropylamine (0.005 ml, 0.066 mmol) were used, and a method similar to that described in Example 46 was employed to obtain the title compound (4.7 mg, 0.012 mmol, yield 27%).
Reaction SMILES: [N:1]([C:4]1[CH:5]=[C:6]([CH:19]=[C:20]([N:22]([S:26]([CH3:29])(=[O:28])=[O:27])[CH2:23][CH2:24][CH3:25])[CH:21]=1)[C:7]([NH:9][C@@H:10]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)[CH3:11])=[O:8])=[N+:2]=[N-:3].O.O=[C:32]1O[C@H:37]([C@H](CO)O)[C:35]([O-])=[C:33]1[OH:34].[Na+]>CC(O)(C)C.O.S([O-])([O-])(=O)=O.[Cu+2]>[C:33]([C:35]1[N:3]=[N:2][N:1]([C:4]2[CH:5]=[C:6]([CH:19]=[C:20]([N:22]([S:26]([CH3:29])(=[O:27])=[O:28])[CH2:23][CH2:24][CH3:25])[CH:21]=2)[C:7]([NH:9][C@@H:10]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[CH3:11])=[O:8])[CH:37]=1)(=[O:34])[CH3:32]
Reactant: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Reactant: CCCN(c1cc(N=[N+]=[N-])cc(C(=O)N[C@H](C)c2ccc(F)cc2)c1)S(C)(=O)=O
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Product: CCCN(c1cc(C(=O)N[C@H](C)c2ccc(F)cc2)cc(-n2cc(C(C)=O)nn2)c1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 1025.5 %

Procedure:
To a solution of 0.15 g (0.36 mmol) 3-azido-N-[(1R)-1-(4-fluorophenyl)ethyl]-5-[(methylsulfonyl)(propyl)amino]benzamide in 2 mL t-BuOH was added 1 mL water and 0.004 g (0.018 mmol) copper(II) sulfate hydrate and 0.007 g (0.036 mmol) sodium ascorbate. The heterogeneous reaction mixture was stirred at rt for 24 h, then diluted w. 75 mL EtOAc, washed with 50 mL water, 50 mL brine, dried over MgSO4, filtered, and concentrated. Purification by automated flash chromatography (40 g silica gel cartridge 20-100% EtAOc/hex over 15 min) afforded 0.18 g (100%) 3-(4-acetyl-1H-1,2,3-triazol-1-yl)-N-[(1R)-1-(4-fluorophenyl)ethyl]-5-[(methylsulfonyl) (propyl)amino]benzamide as a foam. 1H NMR (CDCl3, 400 MHz) δ 8.57 (s, 1H), 8.11 (br t, J=1.83 Hz, 1H), 7.93 (t, J=2.02 Hz, 1H), 7.89 (br t, J=1.64 Hz, 1H), 7.38 (m, 2H) 7.06 (m, 2H), 6.52 (br d, J=7.50 Hz, 1H), 5.32 (quint, J=7.15 Hz, 1H), 3.74 (t, J=7.14 Hz, 2H), 2.93 (s, 3H), 2.76 (s, 3H), 1.64 (d, J=6.96 Hz, 3H), 1.54 (m, 2H), 0.93 (t, J=7.32 Hz, 3H). LCMS [M+H]+=488.1
Reaction SMILES: C(OCC)(=O)C.O.O.[Cl:9][C:10]1[CH:29]=[CH:28][C:13]([C:14]([NH:16][C:17]([CH2:24][CH2:25][C:26]#[N:27])([C:21]([O-:23])=[O:22])[C:18]([O-:20])=[O:19])=[O:15])=[CH:12][CH:11]=1.[Na+].[Na+].Cl>O>[Cl:9][C:10]1[CH:11]=[CH:12][C:13]([C:14]([NH:16][C:17]([CH2:24][CH2:25][C:26]#[N:27])([C:21]([OH:23])=[O:22])[C:18]([OH:20])=[O:19])=[O:15])=[CH:28][CH:29]=1
Reactant: N#CCCC(NC(=O)c1ccc(Cl)cc1)(C(=O)[O-])C(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: N#CCCC(NC(=O)c1ccc(Cl)cc1)(C(=O)O)C(=O)O
Yield: 100.6 %

Procedure:
Fifty milliliters of ethyl acetate were added to a solution of 4.0 g of disodium 2-(p-chlorobenzoylamino)-2-(2-cyanoethyl)malonate dihydrate in water (50 ml), and the resulting solution was adjusted to pH 2.0 by adding 1N hydrochloric acid at 0°-5° C. The organic layer was separated off and dried over magnesium sulphate. The solvent was distilled off and the resulting residue was recrystallized from diethyl ether, to give 3.2 g of the desired acid (b) as a colourless powder melting at 103°-105° C. (with decomposition).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH2:6][C:7]([OH:9])=O)=[CH:2]1.[CH3:10][NH:11][C@H:12]1[CH2:31][N:16]2[C:17]3[C:22]([C:23]([CH2:24][C:25]([O:27]CCC)=[O:26])=[C:15]2[CH2:14][CH2:13]1)=[CH:21][CH:20]=[CH:19][CH:18]=3>>[CH3:10][N:11]([C:7](=[O:9])[CH2:6][C:3]1[CH:4]=[CH:5][S:1][CH:2]=1)[C@H:12]1[CH2:31][N:16]2[C:17]3[C:22]([C:23]([CH2:24][C:25]([OH:27])=[O:26])=[C:15]2[CH2:14][CH2:13]1)=[CH:21][CH:20]=[CH:19][CH:18]=3
Reactant: CCCOC(=O)Cc1c2n(c3ccccc13)C[C@H](NC)CC2
Reactant: O=C(O)Cc1ccsc1
Product: CN(C(=O)Cc1ccsc1)[C@@H]1CCc2c(CC(=O)O)c3ccccc3n2C1

Procedure:
The title compound was prepared using analogous procedures described in Example 1 (Method A) from thiophen-3-yl acetic acid and propyl [(7R)-7-(methylamino)-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl]acetate. MS (+ESI) m/z: 383.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[CH:4][C:3]=1[OH:11].[CH2:12]1[CH2:17][O:16][CH:15]=[CH:14][CH2:13]1.CS(O)(=O)=O>C1COCC1>[Br:1][C:2]1[C:3]([OH:11])=[CH:4][C:5]2[C:9]([CH:10]=1)=[N:8][N:7]([CH:15]1[CH2:14][CH2:13][CH2:12][CH2:17][O:16]1)[CH:6]=2
Reactant: Oc1cc2cn[nH]c2cc1Br
Reactant: C1=COCCC1
Agent: CS(=O)(=O)O
Solvent: C1CCOC1
Product: Oc1cc2cn(C3CCCCO3)nc2cc1Br
Temperature: 25 °C
Reaction time: 22 h
Yield: 162.3 %

Procedure:
To a solution of 6-bromo-5-hydroxy-1H-indazole (725.0 g, 3.4 mol) in THF (10.2 L) is added DHP (336.5 mL, 3.57 mol) and CH3SO3H (65.4 g, 0.68 mol) at RT. The resulting mixture is stirred at RT for 22 hours. The reaction mixture is quenched with distilled water (6 L) and extracted with EtOAc (6 L). Saturated aqueous NaHCO3 solution (1100 mL) is added to adjust the pH to 8. After phase separation, the organic phase is washed with water (4 L) and then saturated aqueous sodium chloride (3 L), dried over anhydrous Na2SO4, filtered, and concentrated to give the product as a solid (1.64 kg, 99.3% yield). MS (m/z): 299.0 (M+H).
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.[C:6](#[N:9])[CH:7]=[CH2:8]>>[N:1]1([CH2:8][CH2:7][C:6]#[N:9])[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: c1nc[nH]n1
Reactant: C=CC#N
Product: N#CCCn1cncn1
Temperature: 80 °C

Procedure:
A mixture of 1,2,4-triazole (25 g, 0.362 mol) and acrylonitrile (100 mL, 4 w/v) was heated up to 80° C. under nitrogen for 16 h. The reaction mixture was then concentrated under reduced pressure to remove the excess of acrylonitrile affording 41 g of the title compound as a colourless liquid (93%). It was used in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[C:12]([O:16][CH3:17])[C:13]=1[O:14][CH3:15])[CH:6]=[CH:7][C:8]([OH:10])=O.S(Cl)(Cl)=O.[NH2:22][CH:23]([C:31]1[CH:39]=[CH:38][C:34]([C:35]([OH:37])=[O:36])=[CH:33][CH:32]=1)CC1C=CC=CC=1.[OH-].[Na+]>ClCCl>[CH3:17][O:16][C:12]1[CH:11]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[C:13]=1[O:14][CH3:15])[CH:6]=[CH:7][C:8]([NH:22][CH2:23][C:31]1[CH:32]=[CH:33][C:34]([C:35]([OH:37])=[O:36])=[CH:38][CH:39]=1)=[O:10]
Reactant: COc1cc(C=CC(=O)O)cc(OC)c1OC
Reactant: NC(Cc1ccccc1)c1ccc(C(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: COc1cc(C=CC(=O)NCc2ccc(C(=O)O)cc2)cc(OC)c1OC
Yield: 113.1 %

Procedure:
3,4,5-trimethoxycinnamic acid (2.38 g, 10 mmol), thionylchloride (4.72 g, 40 mmol), dichloromethane (10 ml), 4-(1-amino-2-phenylethyl)benzoic acid (2.41 g, 10 mmol), and 10 ml of 1 mol/L sodium hydroxide are used according to the method for the production of compound III in Method one to obtain 4.20 g of 4-[(3,4,5-trimethoxycinnamoyl)aminomethyl]benzoic acid (intermediate M-42) as a white solid, with a yield of 91.2%.