Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH3:9])=[CH:7][C:6]2[C:10]3([CH2:20][O:21][C:5]=2[CH:4]=1)[C:18]1[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=1)[NH:12][C:11]3=[O:19].Br.Br[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1.BrCC1CCCCO1>>[CH3:1][O:2][C:3]1[C:8]([CH3:9])=[CH:7][C:6]2[C:10]3([CH2:20][O:21][C:5]=2[CH:4]=1)[C:18]1[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=1)[N:12]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1)[C:11]3=[O:19]
Reactant: BrCc1ccccn1
Reactant: COc1cc2c(cc1C)C1(CO2)C(=O)Nc2ccccc21
Agent: Br
Agent: BrCC1CCCCO1
Product: COc1cc2c(cc1C)C1(CO2)C(=O)N(Cc2ccccn2)c2ccccc21

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using 6-methoxy-5-methylspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2″(1′H)-one, and 2-(bromomethyl)pyridine hydrobromide to replace 2-(bromomethyl)tetrahydro-2H-pyran, 6-methoxy-5-methyl-1′-(pyridin-2-ylmethyl)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one was obtained (82%) as a colorless solid: mp 142-144° C.; 1H NMR (300 MHz, CDCl3) δ 8.56 (d, J=4.8 Hz, 1H), 7.67-7.60 (m, 1H), 7.28-7.11 (m, 4H), 7.00 (dd, J=7.5, 7.5 Hz, 1H), 6.90 (d, J=7.8 Hz, 1H), 6.50 (s, 2H), 5.09 (ABq, 2H), 4.84 (ABq, 2H), 3.79 (s, 3H), 2.00 (s, 3H); 13C NMR (75 MHz, CDCl3) δ178.0, 160.3, 159.2, 155.7, 149.5, 142.5, 142.2, 137.1, 132.6, 128.7, 124.3, 123.8, 123.5, 122.8, 121.7, 119.5, 119.2, 109.5, 93.8, 80.3, 58.0, 46.1, 22.6, 16.0; MS (ES+) m/z 373.3 (M+1).
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].[CH3:5][O:6][C:7]([C:9]1[C:12]2[CH:13]=[C:14]([O:17]C)[CH:15]=[CH:16][C:11]=2[CH:10]=1)=[O:8].[CH3:19][C:20]1[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=1[C:22](Cl)=[S:23]>>[CH3:5][O:6][C:7]([C:9]1[C:12]2[CH:13]=[C:14]([OH:17])[C:15]([C:22](=[S:23])[C:21]3[CH:25]=[CH:26][CH:27]=[CH:28][C:20]=3[CH3:19])=[CH:16][C:11]=2[CH:10]=1)=[O:8]
Reactant: Cc1ccccc1C(=S)Cl
Reactant: COC(=O)C1=Cc2ccc(OC)cc21
Agent: [Al+3]
Agent: [Cl-]
Product: COC(=O)C1=Cc2cc(C(=S)c3ccccc3C)c(O)cc21

Procedure:
In a manner analogous to that described in Example 5, starting from 37.12 g of aluminium trichloride, 13.42 g of 5-methoxybenzocyclobutene-1-carboxylic acid methyl ester and 26.05 g of o-methylthiobenzoyl chloride there is obtained 4-(o-methylthiobenzoyl)-5-hydroxybenzocyclobutene-1-carboxylic acid methyl ester in the form of a viscous yellow oil.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]3[CH:25]=[C:24]([N:26]([CH3:28])[CH3:27])[C:23]4[C:18](=[C:19](Br)[CH:20]=[C:21]([O:29][CH3:30])[CH:22]=4)[N:17]=3)=[O:15])=[CH:9][CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH3:32][N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1>[N:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]3[CH:25]=[C:24]([N:26]([CH3:28])[CH3:27])[C:23]4[C:18](=[C:19]([N:36]5[CH2:37][CH2:38][N:33]([CH3:32])[CH2:34][CH2:35]5)[CH:20]=[C:21]([O:29][CH3:30])[CH:22]=4)[N:17]=3)=[O:15])=[CH:9][CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: CN1CCNCC1
Reactant: COc1cc(Br)c2nc(C(=O)Nc3ccc(N4CCOCC4)cc3)cc(N(C)C)c2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Product: COc1cc(N2CCN(C)CC2)c2nc(C(=O)Nc3ccc(N4CCOCC4)cc3)cc(N(C)C)c2c1
Temperature: 25 °C
Yield: 67 %

Procedure:
To a suspension of 8-bromo-4-dimethylamino-6-methoxy-quinoline-2-carboxylic acid (4-morpholin-4-yl-phenyl)-amide Reference Example 28b) (139.9 mg, 0.288 mmol), N-methylpiperazine (48 μL, 0.43 mmol), and 4 Å sieves in 15 mL anhydrous toluene was added Pd2 (dba)2 (15.3 mg, 16.7 μmol), BINAP (63.0 mg, 0.101 mmol) and cesium carbonate (0.436 g, 1.345 mmol). The resulting wine colored mixture was heated at reflux under nitrogen for 20 hours. The reaction mixture was cooled to room temperature and concentrated. The crude mixture was purified by flash chromatography on silica gel using a gradient of 100:0 to 95:5 methylene chloride:methanol to afford the desired product as a yellow solid (96.9 mg, 67%). 1H NMR (300 MHz, DMSO, d6) δ 10.06 (s, 1 H, C(O)NH), 7.69 (d, 2 H, Jo=9.0 Hz, ArH2′& H6′), 7.58 (s, 1 H, ArH3), 7.58 (d, 2 H, Jo=9.0 Hz, ArH3′& H5′), 6.95 (d, 1 H, Jm=2.7 Hz, ArH5), 6.76 (d, 1 H, Jm=2.7 Hz, ArH7), 3.90 (s, 3 H, OCH3), 3.75 (t, 4 H, J=4.8 Hz, OCH2CH2N), 3.37 (bs, 4 H, ArNCH2CH2N), 3.10 (t, 4 H, J=4.8 Hz, OCH2CH2N), 3.01 (s, 6 H, N(CH3)2), 2.71 (bs, 4 H, ArNCH2CH2N), 2.35 (s, 3 H, R2NCH3); Mass Spec.: calc. for [C28H36N6O3+H]+ Theor. m/z=505; Obs.=505.5.
Reaction SMILES: Br[C:2]1[C:10]2[S:9][C:8]([S:11][CH3:12])=[N:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[C:13]([Cu])#[N:14]>CN(C=O)C>[CH3:12][S:11][C:8]1[S:9][C:10]2[C:2]([C:13]#[N:14])=[CH:3][CH:4]=[CH:5][C:6]=2[N:7]=1
Reactant: CSc1nc2cccc(Br)c2s1
Reactant: N#C[Cu]
Solvent: CN(C)C=O
Product: CSc1nc2cccc(C#N)c2s1

Procedure:
The title compound was prepared from 7-bromo-2-methylsulfanyl-1,3-benzothiazole by heating with CuCN (1.0 eq.) in DMF at 160° C. for 12 h.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[N:4](C(OC(C)(C)C)=O)[N:3]=1.C1C(=O)N([Br:25])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[Br:25][CH2:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[NH:4][N:3]=1
Reactant: Cc1nn(C(=O)OC(C)(C)C)c2ncccc12
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1n[nH]c2ncccc12

Procedure:
To a solution of tert-butyl 3-methyl-1H-pyrazolo[3,4-b]pyridine-1-carboxylate (B-4) (699 mg, 3 mmol) in CCl4 (15 mL) were added NBS (641 mg, 3.6 mmol) and AIBN (70 mg, 0.3 mmol). The reaction mixture was stirred under reflux overnight and then filtered. The filtrate was washed with saturated aqueous Na2CO3 (15 mL). The organic layer was dried over Na2SO4 and concentrated to afford the crude product. The crude product was used for next step without further purification. MS (m/z): 212 (M+1)+.
Reaction SMILES: [CH:1]1[CH:9]=[C:8]2[C:4]([CH:5]=[CH:6][S:7]2)=[C:3]([CH2:10][C:11]([OH:13])=O)[CH:2]=1.[CH3:14][NH:15][C@@H:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18][C@H:17]1[N:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1>O1CCCC1>[N:25]1([C@@H:17]2[CH2:18][C:19]3[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=3)[C@H:16]2[N:15]([CH3:14])[C:11](=[O:13])[CH2:10][C:3]2[C:4]3[CH:5]=[CH:6][S:7][C:8]=3[CH:9]=[CH:1][CH:2]=2)[CH2:26][CH2:27][CH2:28][CH2:29]1
Reactant: CN[C@@H]1c2ccccc2C[C@H]1N1CCCC1
Reactant: O=C(O)Cc1cccc2sccc12
Solvent: C1CCOC1
Product: CN(C(=O)Cc1cccc2sccc12)[C@@H]1c2ccccc2C[C@H]1N1CCCC1
Reaction time: 1 h
Yield: 78.2 %

Procedure:
A mixture of 0.5 g of 4-thianaphthene-acetic acid, 0.422 g of carbonyldimmidazole and 20 ml of tetrahydrofuran was stirred for one hour and then a solution of 0.432 g of the product of Step B in 5 ml of tetrahydrofuran was slowly added thereto. The mixture was stirred for 31/2hours and the tetrahydrofuran was distilled off under reduced pressure. The residue was taken up in 100 ml of ether and the solution was washed with aqueous saturated sodium bicarbonate solution, then with aqueous saturated sodium chloride solution, dried and evaporated to dryness under reduced pressure to obtain 0.61 g of trans (±) N-[2,3-dihydro-2-(pyrrolidin-1-yl)-1H-inden-1-yl]-N-methyl-4-benzo[b]thiophene-acetamide in the form of an oil.
Reaction SMILES: [C:1]1([N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9](=O)[C:8]2=[O:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+].O.NN.O.[CH2:24](O)CO>>[CH3:24][C:12]1[CH:11]=[C:10]2[C:15](=[CH:14][CH:13]=1)[N:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:8](=[O:17])[CH2:9]2
Reactant: OCCO
Reactant: O=C1C(=O)N(c2ccccc2)c2ccccc21
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: Cc1ccc2c(c1)CC(=O)N2c1ccccc1

Procedure:
A suspension of 1-phenyl-1H-indole-2,3-dione (1.908 g, 11.83 mmol) in ethylene glycol (30 mL) is treated with powdered potassium hydroxide (1.92 g, 112 mmol), hydrazine hydrate (16.35 mL) and water (4 mL) as described hereinabove. The crude product is purified by flash chromatography eluting with dichloromethane. Product containing fractions are combined, concentrated and the residue is triturated with pentane to afford 5-methyl-1-phenyl-1H-indol-2-one as an off-white solid. MS 224 (M+1)
Reaction SMILES: C([O:8][C:9]1[C:14](=[O:15])[N:13]([CH3:16])[C:12]([NH:17][S:18]([CH2:21][C:22]2[CH:23]=[C:24]([CH3:28])[CH:25]=[CH:26][CH:27]=2)(=[O:20])=[O:19])=[N:11][C:10]=1[C:29]([NH:31][CH3:32])=[O:30])C1C=CC=CC=1>[Pd].C(OCC)(=O)C.CO>[CH3:32][NH:31][C:29]([C:10]1[N:11]=[C:12]([NH:17][S:18]([CH2:21][C:22]2[CH:23]=[C:24]([CH3:28])[CH:25]=[CH:26][CH:27]=2)(=[O:19])=[O:20])[N:13]([CH3:16])[C:14](=[O:15])[C:9]=1[OH:8])=[O:30]
Reactant: CNC(=O)c1nc(NS(=O)(=O)Cc2cccc(C)c2)n(C)c(=O)c1OCc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CNC(=O)c1nc(NS(=O)(=O)Cc2cccc(C)c2)n(C)c(=O)c1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 53.5 %

Procedure:
Palladium on carbon 10% (20 mg, 18.8 μmol) was added to a round-bottomed flask containing a solution of 5-(benzyloxy)-N,1-dimethyl-6-oxo-2-(m-tolylmethylsulfonamido)-1,6-dihydro-pyrimidine-4-carboxamide (0.07 g, 153 μmol) in ethyl acetate (5 ml) and MeOH (5 ml). The resulting mixture was degassed by nitrogen, evacuated and purged with hydrogen. The mixture was stirred at room temperature under an atmosphere of hydrogen for one hour, filtered and evaporated to dryness under reduced pressure. The residue was washed with hexane and DCM, and crystallized from MeOH/Et2O to give the title compound as an off-white solid (0.03 g; 53%). LCMS m/z=367 (MH+).
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[N:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[F:19][C:20]([F:33])([F:32])[C:21]1[CH:26]=[CH:25][C:24](/[CH:27]=[CH:28]/[C:29](O)=[O:30])=[CH:23][CH:22]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[N:17]=[C:16]([NH:18][C:29](=[O:30])/[CH:28]=[CH:27]/[C:24]3[CH:23]=[CH:22][C:21]([C:20]([F:32])([F:33])[F:19])=[CH:26][CH:25]=3)[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: O=C(O)/C=C/c1ccc(C(F)(F)F)cc1
Reactant: CC1(c2ccc(Cn3ncc(N)n3)o2)OCCO1
Product: CC(=O)c1ccc(Cn2ncc(NC(=O)/C=C/c3ccc(C(F)(F)F)cc3)n2)o1

Procedure:
Following general procedure A followed by either B or C, starting from 2-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-2H-[1,2,3]triazol-4-ylamine and (E)-3-(4-trifluoromethyl-phenyl)-acrylic acid.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][C:8]([O:10]CC)=O.[CH3:13][N:14]1[CH2:19][CH2:18][N:17]([CH:20]([CH3:23])[CH2:21][NH2:22])[CH2:16][CH2:15]1>>[CH3:13][N:14]1[CH2:19][CH2:18][N:17]([CH:20]([CH3:23])[CH2:21][NH:22][C:8](=[O:10])[CH2:7][N:3]2[CH2:4][CH2:5][CH2:6][C:2]2=[O:1])[CH2:16][CH2:15]1
Reactant: CC(CN)N1CCN(C)CC1
Reactant: CCOC(=O)CN1CCCC1=O
Product: CC(CNC(=O)CN1CCCC1=O)N1CCN(C)CC1

Procedure:
From 7.0 g. of ethyl 2-oxo-1-pyrrolidineacetate and 6.3 g. of 2-(4-methyl-1-piperazinyl)propylamine, following the procedure of Example 9, there is obtained (±)-N-[2-(4-methyl-1-piperazinyl)propyl]-2-oxo-1-pyrrolidineacetamide; m.p. 84°-85° C. after recrystallization from cyclohexane and from heptane.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:21][CH2:20][C@@:19]2([CH3:22])[C@@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:18]2[CH2:17][CH2:16][C@@:15]2([CH3:23])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:12](=[O:14])[CH3:13])[CH2:3]1.Cl.[C:25](Cl)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[N:28][CH:27]=1.CCOCC>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[C:25]([O:1][C@@H:2]1[CH2:21][CH2:20][C@@:19]2([CH3:22])[C@@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:18]2[CH2:17][CH2:16][C@@:15]2([CH3:23])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:12](=[O:14])[CH3:13])[CH2:3]1)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[N:28][CH:27]=1
Reactant: O=C(Cl)c1cccnc1
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOCC
Product: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](OC(=O)c5cccnc5)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 90 °C
Yield: 95.3 %

Procedure:
To 3α-hydroxy-5α-pregnan-20-one (464 mg, 318.5 g/m, 1.5 mmol) and 4-dimethylaminopyridine (DMAP, 195 mg, 122.17 g/m, 1.6 mmol) dissolved in 10 mL of dry pyridine was added nicotinoyl chloride hydrochloride (285 mg, 178.02 g/m, 1.6 mmol). The reaction mixture was heated at 90° C. for 5 hours and poured into 300 mL of ether. The organic layer was washed twice with saturated sodium bicarbonate, twice with water, dried over magnesium sulfate, and concentrated in vacuo to give the crude product. The crude material was filtered through a bed of silica gel using hexane/ethyl acetate (50:50) elution. The first two fractions gave the titled compound (604 mg, 421 6/m, 1.43 mmol, 96%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([NH2:12])[S:8][C:9]=1[CH2:10][OH:11])=[O:4]>C(Cl)(Cl)Cl.C(OCC)C.[O-2].[O-2].[Mn+4]>[CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([NH2:12])[S:8][C:9]=1[CH:10]=[O:11])=[O:4]
Reactant: COC(=O)c1nc(N)sc1CO
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Product: COC(=O)c1nc(N)sc1C=O
Temperature: 25 °C
Yield: 75.3 %

Procedure:
The compound (1.05 g) obtained in Step 2 was suspended in chloroform (50 ml), manganese dioxide (4.86 g) was added, with stirring at room temperature, and the mixture was stirred at the same temperature for 3 days. The reaction mixture was concentrated, tetrahydrofuran (150 ml) and activated carbon were added, and the mixture was heated under reflux. The insoluble material was filtered off when it was hot, and the insoluble material was washed with a heated mixed solvent (tetrahydrofuran:N,N-dimethylformamide:methanol=8:1:1). The filtrate was concentrated under reduced pressure, and the obtained crude crystals were suspended in diethyl ether, collected by filtration and dried to give the title compound (782 mg).
Reaction SMILES: Cl.Cl.[CH3:3][O:4][C:5](=[O:14])[C@H:6]([CH2:8][C:9]1[N:13]=[CH:12][NH:11][CH:10]=1)[NH2:7].Cl[C:16]1[N:21]=[C:20]([N:22]2[CH:27]=[C:26]([CH:28]3[C:34]4[CH:35]=[CH:36][C:37]([CH3:39])=[CH:38][C:33]=4[CH:32]=[CH:31][C:30]4[CH:40]=[C:41]([CH3:44])[CH:42]=[CH:43][C:29]3=4)[C:25](=[O:45])[NH:24][C:23]2=[O:46])[CH:19]=[CH:18][N:17]=1>>[CH3:39][C:37]1[CH:36]=[CH:35][C:34]2[CH:28]([C:26]3[C:25](=[O:45])[NH:24][C:23](=[O:46])[N:22]([C:20]4[CH:19]=[CH:18][N:17]=[C:16]([NH:7][C@H:6]([C:5]([O:4][CH3:3])=[O:14])[CH2:8][C:9]5[N:13]=[CH:12][NH:11][CH:10]=5)[N:21]=4)[CH:27]=3)[C:29]3[CH:43]=[CH:42][C:41]([CH3:44])=[CH:40][C:30]=3[CH:31]=[CH:32][C:33]=2[CH:38]=1
Reactant: Cc1ccc2c(c1)C=Cc1cc(C)ccc1C2c1cn(-c2ccnc(Cl)n2)c(=O)[nH]c1=O
Reactant: COC(=O)[C@@H](N)Cc1c[nH]cn1
Agent: Cl
Product: COC(=O)[C@H](Cc1c[nH]cn1)Nc1nccc(-n2cc(C3c4ccc(C)cc4C=Cc4cc(C)ccc43)c(=O)[nH]c2=O)n1

Procedure:
The subtitle compound was prepared from L-histidine methyl ester dihydrochloride (1.15 g) and the product of example 8 step (ii) (0.7 g) by the method of example 10 step (ii). Purification was by chromatography eluting with 5-10% methanol in dichloromethane. Yield 0.25 g.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([OH:6])=O.Cl.[CH3:13][O:14][C:15](=[O:26])[CH:16]([NH2:25])[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][CH:19]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>>[CH3:13][O:14][C:15](=[O:26])[CH:16]([NH:25][C:4](=[O:6])[C:3]1[CH:7]=[C:8]([Cl:11])[CH:9]=[CH:10][C:2]=1[NH2:1])[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][CH:19]=1
Reactant: Nc1ccc(Cl)cc1C(=O)O
Reactant: COC(=O)C(N)Cc1ccc(Br)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C(Cc1ccc(Br)cc1)NC(=O)c1cc(Cl)ccc1N
Yield: 60 %

Procedure:
2-Amino-5-chloro-benzoic acid (0.702 g, 4.09 mmol) was coupled with 2-Amino-3-(4-bromo-phenyl)-propionic acid methyl ester hydrochloride (1 g, 4.09 mmol) using HBTU (1.86 g, 4.908 mmol) and diisopropylethylamine (1.32 ml, 10.22 mmol) as per general procedure A to yield the 2-(2-amino-5-chloro-benzoylamino)-3-(4-bromo-phenyl)-propionic acid methyl ester in 60% yield.
Reaction SMILES: [Cl-].[C:2]([C:4]1[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][CH:14]=[CH:13][C:5]=1[O:6][CH2:7][C@H:8]1[CH2:12][CH2:11][CH2:10][NH2+:9]1)#[N:3].CCN(CC)CC.[C:27](Cl)(=[O:31])[CH2:28][CH2:29][CH3:30]>C1COCC1>[C:27]([N:9]1[CH2:10][CH2:11][CH2:12][C@@H:8]1[CH2:7][O:6][C:5]1[CH:13]=[CH:14][CH:15]=[C:16]([N+:17]([O-:19])=[O:18])[C:4]=1[C:2]#[N:3])(=[O:31])[CH2:28][CH2:29][CH3:30]
Reactant: N#Cc1c(OC[C@H]2CCC[NH2+]2)cccc1[N+](=O)[O-]
Reactant: CCCC(=O)Cl
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCC(=O)N1CCC[C@@H]1COc1cccc([N+](=O)[O-])c1C#N
Temperature: 25 °C
Reaction time: 72 h
Yield: 81.7 %

Procedure:
To a suspension of (R)-2-((2-cyano-3-nitrophenoxy)methyl)pyrrolidinium chloride (140 mg, 0.49 mmol) (Example 165c) in THF (3 mL) were added Et3N (143 μL, 1.03 mmol) and butyryl chloride (56 uL, 0.54 mmol). The reaction was stirred for 72 h at rt under N2. Upon completion, the reaction was filtered, and the filtrate was concentrated to provide (R)-2-((1-butyrylpyrrolidin-2-yl)methoxy)-6-nitrobenzonitrile (127 mg, 82%) as a yellow syrup. MS 318 (MH+).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11](/[C:14](/[CH3:18])=[CH:15]/[CH2:16][OH:17])=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH2:19]([O:21][C@@H:22]([CH2:28][C:29]1[CH:34]=[CH:33][C:32](O)=[CH:31][CH:30]=1)[C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH3:20]>>[CH2:19]([O:21][C@@H:22]([CH2:28][C:29]1[CH:30]=[CH:31][C:32]([O:17][CH2:16]/[CH:15]=[C:14](/[C:11]2[CH:12]=[CH:13][C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[CH:3]=3)=[CH:9][CH:10]=2)\[CH3:18])=[CH:33][CH:34]=1)[C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH3:20]
Reactant: C/C(=C\CO)c1ccc(-c2cccc(C)c2)cc1
Reactant: CCOC(=O)[C@H](Cc1ccc(O)cc1)OCC
Product: CCOC(=O)[C@H](Cc1ccc(OC/C=C(\C)c2ccc(-c3cccc(C)c3)cc2)cc1)OCC
Yield: 79.6 %

Procedure:
The title compound (0.365 g, 78% yield) was prepared from (E)-3-(3′-methyl-biphenyl-4-yl)-but-2-en-1-ol (0.238 g, 1.0 mmol) and (S)-ethyl 2-ethoxy-3-(4-hydroxyphenyl)-propionate (0.25 g, 1.05 mmol) by a procedure analogous to that described in example 52 c.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][C:8]1[CH:9]=[CH:10][C:11]([N:19]2[C:23]([CH3:24])=[N:22][N:21]=[N:20]2)=[C:12]([CH:18]=1)[C:13]([O:15][CH2:16][CH3:17])=[O:14].[CH2:25](Br)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CN(C=O)C>[CH2:25]([O:7][C:8]1[CH:9]=[CH:10][C:11]([N:19]2[C:23]([CH3:24])=[N:22][N:21]=[N:20]2)=[C:12]([CH:18]=1)[C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CCOC(=O)c1cc(O)ccc1-n1nnnc1C
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(OCc2ccccc2)ccc1-n1nnnc1C
Reaction time: 0.5 h
Yield: 85.6 %

Procedure:
Potassium carbonate (110 g, 0.793 mol) was added to a solution of ethyl 5-hydroxy-2-(5-methyltetrazol-1-yl)benzoate (98.5 g, 0.397 mol) in 500 mL of DMF. After vigorous stirring for 30 minutes, benzyl bromide (75 g, 0.438) was added and the reaction was stirred overnight. The solution was filtered and then concentrated under reduced pressure (at 50° C.). The resulting solid was slurried in 400 mL of dichloromethane and filtered. The filtrate was concentrated under reduced pressure to give 115 g of ethyl 5-benzyloxy-2-(5-methyltetrazol-1-yl)benzoate as a brown oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[CH2:12][CH2:13][CH2:14][C:15]1([C:29]([O:31]CC)=[O:30])[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][S:23][CH:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)[CH2:17][CH2:16]1)=[CH:9][C:8]([O:34][CH3:35])=[CH:7][CH:6]=2.[ClH:36]>ClCCl.CO>[ClH:1].[ClH:36].[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[CH2:12][CH2:13][CH2:14][C:15]1([C:29]([OH:31])=[O:30])[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][S:23][CH:24]3[CH2:25][CH2:26][CH2:27][CH2:28]3)[CH2:17][CH2:16]1)=[CH:9][C:8]([O:34][CH3:35])=[CH:7][CH:6]=2
Reactant: CCOC(=O)C1(CCCc2c(Cl)cnc3ccc(OC)cc23)CCN(CCSC2CCCC2)CC1
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: COc1ccc2ncc(Cl)c(CCCC3(C(=O)O)CCN(CCSC4CCCC4)CC3)c2c1
Temperature: 100 °C
Reaction time: 5 h

Procedure:
A mixture of 0.55 g of ethyl 4-[3-(3-chloro-6-methoxyquinolin-4-yl)propyl]-1-[2-(cyclopentylthio)ethyl]-piperidine-4-carboxylate in 8 cm3 of aqueous 6 N hydrochloric acid was heated at a temperature in the region of 100° C., with stirring and under an inert atmosphere, for 5 hours. After stirring for 18 hours at a temperature in the region of 20° C., the solution obtained was concentrated under reduced pressure (5 kPa) at a temperature in the region of 40° C. The evaporation residue obtained was taken up in 10 cm3 of a mixture of dichloromethane/methanol (90/10 by volume) and then concentrated under the same conditions as above. 0.59 g of 4-[3-(3-chloro-6-methoxyquinolin-4-yl)propyl]-1-[2-(cyclopentylthio)ethyl]piperidine-4-carboxylic acid dihydrochloride was obtained in the form of a foam melting at 129° C. with softening.
Reaction SMILES: C([O:5][C:6](=[O:38])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][N:18]([C:26]([C:28]2[NH:29][C:30]3[C:35]([CH:36]=2)=[CH:34][C:33]([Cl:37])=[CH:32][CH:31]=3)=[O:27])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[N:15]=1)([CH3:9])[CH3:8])(C)(C)C.Cl.C(OCC)(=O)C>C(O)=O>[Cl:37][C:33]1[CH:34]=[C:35]2[C:30](=[CH:31][CH:32]=1)[NH:29][C:28]([C:26]([N:18]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:17][CH2:16][C:14]1[N:15]=[C:11]([S:10][C:7]([CH3:8])([CH3:9])[C:6]([OH:38])=[O:5])[S:12][CH:13]=1)=[O:27])=[CH:36]2
Reactant: CCCCCCCN(CCc1csc(SC(C)(C)C(=O)OC(C)(C)C)n1)C(=O)c1cc2cc(Cl)ccc2[nH]1
Agent: Cl
Solvent: O=CO
Solvent: CCOC(C)=O
Product: CCCCCCCN(CCc1csc(SC(C)(C)C(=O)O)n1)C(=O)c1cc2cc(Cl)ccc2[nH]1
Temperature: 25 °C
Reaction time: 3 h
Yield: 78.8 %

Procedure:
2-[(4-{2-[[(5-Chloro-1H-indol-2-yl)carbonyl](heptyl)amino]ethyl}-1,3-thiazol-2-yl)thio]-2-methylpropionic acid tert-butyl ester (270 mg) obtained in Example 312-1 was dissolved in formic acid (5 mL), 4N hydrochloric acid/ethyl acetate solution (5 mL) was added, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was concentrated under reduced pressure, and ether was added to the residue to give the title compound (192 mg) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH3:8].OO.C(=O)([O-])[OH:12].[Na+]>C(O)(=O)C>[CH3:1][C:2]1[CH:3]=[N+:4]([O-:12])[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1ccncc1C
Reactant: O=C([O-])O
Agent: OO
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1cc[n+]([O-])cc1C
Temperature: 75 °C
Reaction time: 3 h
Yield: 94 %

Procedure:
Firstly, under an argon gas atmosphere, 27.3 g of 3,4-dimethylpyridine (Aldrich) (255 mmol) in 150 mL acetic acid solution was cooled on ice, and 25 mL of 35% hydrogen peroxide aqueous solution was added thereto, stirred at 75° C. for 3 hours. Then additional 17.5 mL of 35% hydrogen peroxide aqueous solution was added and stirred at 75° C. for 3 hours. The reaction solution was neutralized by adding an aqueous solution of sodium hydrogen carbonate, extracted with methylene dichloride. The extract was dried on salt cake and concentrated to give a solid. The obtained solid was washed with ethyl acetate to give 29.55 g of 3,4-dimethylpyridine-N-oxide (94% yield).