Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([S:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([OH:25])=O)[NH:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.ON1C2C=CC=CC=2N=N1.[CH2:37]([NH2:44])[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O>[C:1]1([C:7]2[N:8]=[C:9]([S:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([NH:44][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])=[O:25])[NH:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)CCCCSc1nc(-c2ccccc2)c(-c2ccccc2)[nH]1
Reactant: CCCCCCCN
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCCNC(=O)CCCCSc1nc(-c2ccccc2)c(-c2ccccc2)[nH]1
Reaction time: 2 h
Yield: 86 %

Procedure:
Part C, Method 1. To a solution of 5-(4,5-diphenyl-1H-imidazol-2-ylthio)pentanoic acid (2.0 g, 0.0057 mol) in N,N-dimethylformamide (25 mL) was added 1-hydroxybenzotriazole hydrate (0.93 g, 0.0069 mol) followed by a solution of heptylamine (1.10 mL, 0.86 g, 0.0074 mol) in N,N-dimethylformamide (10 mL). The reaction mixture was cooled to 0° and dicyclohexylcarbodiimide (1.42 g, 0.0069 mol) was added portionwise as a solid. The reaction mixture was stirred for 2 hours at 0° and then stirred for 48 hours at ambient temperature. The solids were filtered and washed with N,N-dimethylformamide. The filtrate was concentrated and the residue was chromatographed with 1:1 hexane-ethyl acetate. The resulting solid was recrystallized from acetonitrile and triturated with hexane to give 5-(4,5-diphenyl-1H-imidazol-2-ylthio)-N-heptylpentanamide (2.21 g, 0.0049 mol) as a white solid, mp 104°-106°. 1H NMR (CDCl3) δ 11.6(s,1H) , 7.6-7.1(m,10H), 6.1-6.0(m,1H), 3.1-2.8(m,4H), 2.2(t,2H,J=7 Hz), 1.9-1.7(m,2H), 1.7-1.5(m,2H), 1.4-1.1(m,10H), 0.9(t,3H,J=8 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([C:6]([C:22]#[CH:23])([OH:21])[C:7]2[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][N:16]([CH2:19][CH3:20])[CH2:17][CH3:18])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[H][H]>[Pd].C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([CH2:22][CH3:23])([OH:21])[C:7]2[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][N:16]([CH2:17][CH3:18])[CH2:19][CH3:20])=[CH:9][CH:8]=2)=[CH:24][CH:25]=1
Reactant: C#CC(O)(c1ccc(Cl)cc1)c1ccc(OCCN(CC)CC)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: c1ccccc1
Product: CCN(CC)CCOc1ccc(C(O)(CC)c2ccc(Cl)cc2)cc1

Procedure:
17.9 g. of 4-chloro-4'-[2-(diethylamino)ethoxy]-α-ethinyl-benzhydrol are dissolved in 180 ml. of benzene, and the reaction mixture is hydrogenated in the presence of 0.9 g. of a 10% palladium-on-charcoal catalyst. As soon as the uptake of the calculated amount of hydrogen is complete, the catalyst is filtered off, and benzene is distilled off under reduced pressure. The solid residue is crystallized from n-hexane to yield 14.2 g. of the title compound, melting at 50° to 51° C.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:17][CH:16]=3)=[CH:13][C:12]([C:25](OCC)=[O:26])=[N:11]2)=[CH:6][CH:5]=1)([OH:3])=[O:2].C[O-].[Na+].Cl.C([NH2:36])=O>>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([S:21]([CH3:24])(=[O:22])=[O:23])=[CH:17][CH:16]=3)=[CH:13][C:12]([C:25]([NH2:36])=[O:26])=[N:11]2)=[CH:8][CH:9]=1)([OH:3])=[O:2]
Reactant: NC=O
Reactant: CCOC(=O)c1cc(-c2ccc(S(C)(=O)=O)cc2)n(-c2ccc(C(=O)O)cc2)n1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Product: CS(=O)(=O)c1ccc(-c2cc(C(N)=O)nn2-c2ccc(C(=O)O)cc2)cc1
Temperature: 45 °C
Reaction time: 3 h

Procedure:
A mixture of ethyl 1-(4-carboxyphenyl)-5-[4-(methylsulfonyl)phenyl]pyrazole-3-carboxylate (3.9 g) and sodium methoxide (3 g) in formamide (40 ml) was stirred at 45° C. for 3 hours. The mixture was poured into a mixture of ice-water and hydrochloric acid. The precipitates were collected, washed with water, and dried to give crystals of 1-(4-carboxyphenyl)-5-[4-(methylsulfonyl)phenyl]pyrazole-3-carboxamide (3.2 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]([CH2:18]O)=[CH:16][C:15]3[C:10](=[C:11]([O:20][CH3:21])[CH:12]=[CH:13][CH:14]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.C(Cl)(Cl)[Cl:23].S(Cl)([Cl:28])=O>>[ClH:23].[Cl:28][CH2:18][C:17]1[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)=[N:9][C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[CH:12][C:11]=2[O:20][CH3:21]
Reactant: O=S(Cl)Cl
Reactant: COc1cccc2cc(CO)c(-c3cccc(F)c3)nc12
Reactant: ClC(Cl)Cl
Product: COc1cccc2cc(CCl)c(-c3cccc(F)c3)nc12
Product: Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of (2-(3-fluorophenyl)-8-methoxyquinolin-3-yl)methanol (2.2330 g, 7.882 mmol) in chloroform (26.27 mL, 7.882 mmol) was treated with thionyl chloride (2.868 mL, 39.41 mmol) dropwise, and the reaction mixture was stirred at room temperature. After 3 h, the mixture was concentrated under reduced pressure and co-evaporated three times with CH2Cl2 to give 3-(chloromethyl)-2-(3-fluorophenyl)-8-methoxyquinoline hydrochloride as a yellow solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 8.59 (1H, s), 7.55-7.65 (3H, m), 7.44-7.52 (2H, m), 7.33-7.41 (1H, m), 7.23-7.30 (1H, m), 4.91 (2H, s); LC-MS (ESI) m/z 302.0 [M+H]+ (Exact Mass of neutral form: 301.067). The yellow solid was carried on crude without purification for the next step.
Reaction SMILES: [CH:1]([NH:14][C:15]([C:17]1[C:18]([OH:25])=[N:19][C:20]([CH:23]=[O:24])=[N:21][CH:22]=1)=[O:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[O-:27]Cl=O.[Na+]>CC(O)(C)C>[CH:1]([NH:14][C:15]([C:17]1[C:18]([OH:25])=[N:19][C:20]([C:23]([OH:27])=[O:24])=[N:21][CH:22]=1)=[O:16])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ncc(C(=O)NC(c2ccccc2)c2ccccc2)c(O)n1
Reactant: [O-][Cl+][O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)(C)O
Product: O=C(O)c1ncc(C(=O)NC(c2ccccc2)c2ccccc2)c(O)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of step G product (2-h, 0.7 g) in t-BuOH (35 mL) was added NaH2PO4.12H2O (0.6 g, 1.7 mmol) followed by H2O (6 mL) and NaClO2 (0.95 g, 10.5 mmol). After being allowed to stir at the ambient temperature overnight, the reaction mixture was evaporated under vacuum to remove t-BuOH, diluted with H2O, treated with aq. HCl to pH 2 and the solid was filtered and the cake was washed with water and dried under vacuum to afford compound 2-i as a crude (0.35 g), which was directly used for next step without further purification.
Reaction SMILES: O.[C:2]1([OH:10])[CH:9]=[C:7]([CH3:8])[CH:6]=[C:4]([OH:5])[CH:3]=1.[CH3:11][O:12][C:13]1[C:18]([S:19](Cl)(=[O:21])=[O:20])=[CH:17][CH:16]=[CH:15][C:14]=1C.[C:24]([O-])(O)=O.[Na+]>C(OCC)C>[CH3:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([CH3:24])=[CH:17][C:18]=1[S:19]([O:5][C:4]1[CH:3]=[C:2]([OH:10])[CH:9]=[C:7]([CH3:8])[CH:6]=1)(=[O:20])=[O:21]
Reactant: O=C([O-])O
Reactant: COc1c(C)cccc1S(=O)(=O)Cl
Reactant: Cc1cc(O)cc(O)c1
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: COc1ccc(C)cc1S(=O)(=O)Oc1cc(C)cc(O)c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 1.00 g (8.05 mmol) of orcinol monohydrate and 1.63 g (7.38 mmol) of 2-methoxy-m-toluenesulfonyl chloride in 20 mL of diethyl ether was added 20 mL of saturated aqueous NaHCO3 and the biphasic mixture stirred vigorously at ambient temperature for 3 days. The layers were separated and the aqueous layer extracted with 2×30 mL of ethyl acetate. The combined organic layers were washed with 50 mL of brine, dried (Na2SO4) and concentrated to give 2.2 g of an orange syrup. Crystallization from dichloromethane-hexane (two crops) afforded 1.24 g (54%) of the title compound as a light orange powder: 1H-NMR (300 MHz; CDCl3) δ 7.62 (d, 1 H, J=2.0 Hz), 7.40 (m, 1 H), 6.96 (d, 1 H, J=8.5 Hz), 6.52 (m, 2 H), 6.42 (t, 1 H, J=2.1 Hz), 5.13 (s, 1 H), 3.96 (s, 3 H), 2.29 (s, 3 H) and 2.23 (s, 3 H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:16]O)=[N:13][C:14]=1[CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[Br:22][C:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][C:30]=2[N+:32]([O-:34])=[O:33])[NH:25][N:24]=1.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl.CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:16][N:25]2[C:26]3[C:31](=[C:30]([N+:32]([O-:34])=[O:33])[CH:29]=[CH:28][CH:27]=3)[C:23]([Br:22])=[N:24]2)=[N:13][C:14]=1[CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1cccc2[nH]nc(Br)c12
Reactant: Cc1nc(CO)ccc1OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1nc(Cn2nc(Br)c3c([N+](=O)[O-])cccc32)ccc1OCc1ccccc1
Reaction time: 3 h
Yield: 87 %

Procedure:
To (5-(benzyloxy)-6-methylpyridin-2-yl)methanol (3.51 g, 15.3 mmol, Prepared as described in U.S. Pat. No. 3,952,101) in DCM (10 mL) was added sulfurous dichloride (10.9 g, 91.9 mmol). The reaction mixture was stirred for 3 hours, and then solvent was removed under reduced pressure. To the resulting solid was added 3-bromo-4-nitro-1H-indazole (3.71 g, 15.3 mmol), K2CO3 (6.35 g, 45.9 mmol) and anhydrous DMF (20 mL). The reaction mixture was stirred for 18 hours. The solvent was removed under reduced pressure. The residue was diluted with water (50 mL) and extracted with EtOAc. The combined organic extracts were dried (Na2SO4), and concentrated, and the residue was purified by silica gel flash chromatography (1:3 EtOAc/hexanes) to give desired product (87%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[SH:12])=[CH:9][CH:8]=[CH:7][CH:6]=2.[C:13](O)(=O)[CH2:14][CH3:15]>>[CH2:14]([C:15]1[S:12][C:11]2[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]=[CH:3][C:2]=2[N:1]=1)[CH3:13]
Reactant: CCC(=O)O
Reactant: Nc1cnc2ccccc2c1S
Product: CCc1nc2cnc3ccccc3c2s1

Procedure:
Propionyl anhydride (20 mL) was added to a suspension of 3-amino-quinoline4-thiol (15 g) in propionic acid (100 mL). The reaction mixture was heated at reflux overnight and then filtered to remove a precipitate. The filtrate was concentrated under vacuum. The residue was taken up in dichloromethane (200 mL), washed with sodium bicarbonate then with water, and then dried over magnesium sulfate. The solution was filtered through a layer of silica gel eluting first with 1:1 ethyl acetate:hexane and then with ethyl acetate. The filtrate was evaporated to provide 2.6 g of 2-ethylthiazolo[4,5-c]quinoline as a yellow oil.
Reaction SMILES: C=O.[CH:3]([C:6]1[S:15][C:14]2[NH:13][C:12]3[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=3[N:10]=[C:9]([N:20]3[CH2:25][CH2:24][NH:23][C@@H:22]([CH2:26][C@@H:27]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[OH:28])[CH2:21]3)[C:8]=2[N:7]=1)([CH3:5])[CH3:4].[C:35](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C.C(=O)(O)[O-].[Na+]>[CH:3]([C:6]1[S:15][C:14]2[NH:13][C:12]3[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=3[N:10]=[C:9]([N:20]3[CH2:25][CH2:24][N:23]([CH3:35])[C@@H:22]([CH2:26][C@@H:27]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[OH:28])[CH2:21]3)[C:8]=2[N:7]=1)([CH3:5])[CH3:4]
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: CC(C)c1nc2c(s1)Nc1ccccc1N=C2N1CCN[C@@H](C[C@H](O)c2ccccc2)C1
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: CC(C)c1nc2c(s1)Nc1ccccc1N=C2N1CCN(C)[C@@H](C[C@H](O)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 56.7 %

Procedure:
Add formaldehyde (23 μL, 0.29 mmol, 37% in water) to a solution of (S,S)-2-[4-(2-isopropyl-4H-3-thia-1,4,9-triaza-benzo[f]azulen-10-yl)-piperazin-2-yl]-1-phenyl-ethanol (117 mg, 0.26 mmol) in dichloroethane (5 mL). Stir 15 min at ambient temperature. Add sodium triacetoxyborohydride (83 mg, 0.39 mmol) and stir 2 h at ambient temperature. Dilute with saturated sodium bicarbonate solution and extract with methylene chloride. Dry the extracts with sodium sulfate, filter and concentrate the filtrate. Purify by radial silica gel chromatography using a 2 mm plate and 2N ammonia in methanol-methylene chloride (1%–4%) as the eluent to give 68 mg (56%) of the title compound: mass spectrum (ion spray): m/z=462 (M+1), 460 (M−1). HR-MS calculated for C26H32N5OS: 462.2328. Found 462.2322. 1H NMR (DMSO-d6): δ 7.82 (s, 1H), 7.35–7.18 (m, 5H), 6.91–6.76 (m, 3H), 6.69 (br d, 1H), 5.29 (s, 1H), 4.58–4.46 (m, 1H), 4.14–3.77 (m, 2H), 3.02–3.17 (m, 2), 2.90 (dd, 1H), 2.74–2.65 (m, 1H), 2.28–2.11 (m, 1H), 2.14 (s, 3H), 2.03–1.84 (m, 2H) 1.70–1.54 (m, 1H), 1.26 (d, 6H).
Reaction SMILES: C([S:8][C:9]1[C:14]([Cl:15])=[CH:13][CH:12]=[CH:11][C:10]=1[NH2:16])C1C=CC=CC=1.[Al+3].[Cl-].[Cl-].[Cl-].CCOC(C)=O>C1C=CC=CC=1>[ClH:15].[NH2:16][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]([Cl:15])[C:9]=1[SH:8]
Reactant: Nc1cccc(Cl)c1SCc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Product: Cl
Product: Nc1cccc(Cl)c1S
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-benzylsulfanyl-3-chloro-phenylamine (204) in 140 mL of benzene at 0° C. was added AlCl3 (Aldrich, 23.8 g, 179 mmol) in portion. The mixture turned to purple. After stirred at ambient temperature overnight, the mixture was poured to ice and EtOAc and stirred for 20 min. The mixture was extracted 3× with EtOAc (500 mL). The organic layers were washed twice with a brine solution (400 mL), dried over Na2SO4, and concentrated under vacuum. The crude product was treated with 145 mL of 1N HCl in ether. The product (13.6 g) was collected by filtration and washed with hexanes. 1H NMR (400 MHz, DMSO) δ 7.05 (t, J=8.2 Hz, 1H), 6.70 (d, J=8.2 Hz, 1H), 6.61 (d, J=7.8 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:16])=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7]2.[Cl:17][C:18]1[C:23]([S:24](Cl)(=[O:26])=[O:25])=[CH:22][CH:21]=[CH:20][N:19]=1>N1C=CC=CC=1>[Cl:17][C:18]1[C:23]([S:24]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([CH3:16])=[C:6]3[C:10]=2[NH:9][C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7]3)(=[O:26])=[O:25])=[CH:22][CH:21]=[CH:20][N:19]=1
Reactant: O=S(=O)(Cl)c1cccnc1Cl
Reactant: CCOC(=O)c1cc2c(C)ccc(N)c2[nH]1
Solvent: c1ccncc1
Product: CCOC(=O)c1cc2c(C)ccc(NS(=O)(=O)c3cccnc3Cl)c2[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.1 %

Procedure:
To a solution of ethyl 7-amino-4-methyl-1H-indole-2-carboxylate (1.00 g) in pyridine (10 mL) was added 2-chloropyridine-3-sulfonyl chloride (1.99 g) at 0° C., and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated, 10% aqueous citric acid solution was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed successively with 10% aqueous citric acid solution and saturated brine, dried (MgSO4), and concentrated to give ethyl 7-{[(2-chloropyridin-3-yl)sulfonyl]amino}-4-methyl-1H-indole-2-carboxylate (1.32 g) as a crude oil.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[S:12]([O-:18])([O:15][CH2:16][CH3:17])(=[O:14])=[O:13]>CC(N(C)C)=O>[CH2:16]([O:15][S:12]([O-:18])(=[O:14])=[O:13])[CH3:17].[CH2:16]([N+:10]1[C:11]2[C:6](=[CH:5][CH:4]=[CH:3][C:2]=2[OH:1])[CH:7]=[CH:8][CH:9]=1)[CH3:17]
Reactant: Oc1cccc2cccnc12
Agent: CCOS(=O)(=O)[O-]
Solvent: CC(=O)N(C)C
Product: CC[n+]1cccc2cccc(O)c21
Temperature: 0 °C
Yield: 78.6 %

Procedure:
Into a 2-liter three-neck flask, provided with a mechanical agitator, with a reflux condenser and calcium chloride tube, and with a dropping funnel, one introduces 580 g of 8-hydroxyquinoline (i.e. 4 moles) and 800 ml of dimethylacetamide. After dissolution of the 8-hydroxyquinoline one adds, drop by drop, 616 g of freshly distilled ethyl sulfate, and then cools the reaction mixture with a bath of ice water. After heating on a steam bath for 2 hours, the solution becomes orange-yellow. One removes the dimethylformamide by means of distillation in a water-jet pump vacuum. The yellow residue is washed with anhydrous ether. The quaternary salt crystallizes after scraping. One recrystallizes the quaternary salt by dissolution in isopropanol at the rate of 1 g of quaternary salt per 1.5 ml of isopropanol. One obtains 920 g of yellow crystals which are washed thoroughly with ethyl ether.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[OH:9].[C:10](O)(=[O:13])[CH2:11][CH3:12]>FC(F)(F)S(O)(=O)=O>[Cl:1][C:2]1[CH:7]=[C:6]([C:10](=[O:13])[CH2:11][CH3:12])[CH:5]=[C:4]([Cl:8])[C:3]=1[OH:9]
Reactant: Oc1c(Cl)cccc1Cl
Reactant: CCC(=O)O
Agent: O=S(=O)(O)C(F)(F)F
Product: CCC(=O)c1cc(Cl)c(O)c(Cl)c1
Temperature: 80 °C
Yield: 65.6 %

Procedure:
A mixture of 2,6-dichlorophenol (10.10 g, 61.96 mmol) and propionic acid (3.34 mL, 62.58 mmol) in trifluoromethanesulfonic acid (50 g) was heated to 80° C. for 24 h. The reaction was cooled to ambient temperature, poured onto ice and extracted with chloroform (3×). The combined organic layer was washed with aqueous bicarbonate and brine, dried, and concentrated to give 8.90 g (66%) of 2,6-dichloro-4-propionylphenol as a tan solid which had: mp 50-52° C.; NMR δ 7.89 (s, 2 H), 6.29 (s, 1 H), 2.91 (q, J=7 Hz, 2 H), 1.20 (t, J=7 Hz, 3 H). This material was used without further purification.
Reaction SMILES: [C:1]1([C:7]2[N:12]=[CH:11][C:10]([NH:13][C:14](=[O:19])[CH2:15][C:16]([OH:18])=O)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.Cl.[Br:53][C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][C:55]=1[NH:60][CH:61]1[CH2:66][CH2:65][NH:64][CH2:63][CH2:62]1>CN(C=O)C.O>[Br:53][C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][C:55]=1[NH:60][CH:61]1[CH2:66][CH2:65][N:64]([C:16](=[O:18])[CH2:15][C:14]([NH:13][C:10]2[CH:11]=[N:12][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:8][CH:9]=2)=[O:19])[CH2:63][CH2:62]1
Reactant: Brc1ccccc1NC1CCNCC1
Reactant: O=C(O)CC(=O)Nc1ccc(-c2ccccc2)nc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C(CC(=O)N1CCC(Nc2ccccc2Br)CC1)Nc1ccc(-c2ccccc2)nc1
Reaction time: 8 h
Yield: 65.8 %

Procedure:
To a stirred solution of N-(6-phenyl-pyridin-3-yl)-malonamic acid (0.07 g, 0.00024 mole) in DMF (2 mL) was added DIPEA (0.153 g, 0.00120 mole), HOBt (0.039 g, 0.00029 mole) and EDCI.HCl (0.055 g, 0.00029 mole). After 2 minutes (2-bromo-phenyl)-piperidin-4-yl-amine dihydrochloride (0.093 g, 0.00029 mole) was added and the resulting mixture was stirred overnight. The reaction mixture was then diluted with cold water and the product was extracted with ethyl acetate. The organic layer was washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure to afford 77.9 mg (66%) of 3-[4-(2-bromo-phenylamino)-piperidin-1-yl]-3-oxo-N-(6-phenyl-pyridin-3-yl)-propionamide. LC-MS purity: 493.12 (M+1)+, 99.22%, 1H NMR (DMSO-d6): δ 10.5 (s, 1H), 8.8 (d, 1H), 8.2 (dd, 1H), 8.1 (d, 1H), 8.0 (d, 1H), 7.6-7.4 (m, 4H), 7.2 (t, 1H), 6.9 (d, 1H), 6.6 (t, 1H), 4.7 (d, 1H), 4.4 (d, 1H), 4.0 (d, 1H), 3.7-3.6 (m, 3H), 3.3-3.2 (m, 1H), 2.0 (t, 2H), 1.6-1.5 (m, 1H), 1.4-1.3 (m, 1H).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:23]3[C:18](=[CH:19][C:20]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[C:21]([F:24])[CH:22]=3)[N:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])(C)(C)C.Cl.[N+](C1C=CC(OC(=O)[NH:43][C:44]2[CH:49]=[CH:48][C:47]([N:50]3[CH2:54][CH2:53][CH2:52][CH2:51]3)=[CH:46][CH:45]=2)=CC=1)([O-])=O>>[N:50]1([C:47]2[CH:48]=[CH:49][C:44]([NH:43][C:6]([N:8]3[CH2:9][CH2:10][CH:11]([C:14]4[C:23]5[C:18](=[CH:19][C:20]([N:25]6[CH2:30][CH2:29][O:28][CH2:27][CH2:26]6)=[C:21]([F:24])[CH:22]=5)[N:17]=[CH:16][N:15]=4)[CH2:12][CH2:13]3)=[O:7])=[CH:45][CH:46]=2)[CH2:51][CH2:52][CH2:53][CH2:54]1
Reactant: O=C(Nc1ccc(N2CCCC2)cc1)Oc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ncnc3cc(N4CCOCC4)c(F)cc23)CC1
Agent: Cl
Product: O=C(Nc1ccc(N2CCCC2)cc1)N1CCC(c2ncnc3cc(N4CCOCC4)c(F)cc23)CC1

Procedure:
The title compound was prepared from 4-(6-Fluoro-7-morpholin-4-yl-quinazolin-4-yl)-piperidine-1-carboxylic acid tert-butyl ester, prepared as described in Example 210a, and (4-pyrrolidin-1-yl-phenyl)-carbamic acid 4-nitro-phenyl ester hydrochloride, prepared as described in Example 74a, using essentially the protocol given for Example 170c. 1H-NMR (400 MHz, CDCl3) δ 9.12 (s, 1H), 7.70 (d, 1H), 7.38 (d, 1H), 7.18 (m, 2H), 6.52 (m, 2H), 6.24 (s, 1H), 4.26 (m, 2H), 3.93 (m, 4H), 3.51 (tt, 1H), 3.31 (m, 4H), 3.26 (m, 4H), 3.11 (td, 2H), 2.17-2.05 (m, 2H), 2.03-1.90 (m, 6H). LC/MS (ESI): calcd mass 504.3, found 505.3.
Reaction SMILES: [Br:1][C:2]1[C:11]([OH:12])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[C:7]2Cl.Cl.C[OH:16]>>[Br:1][C:2]1[C:11]([OH:12])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][NH:6][C:7]2=[O:16]
Reactant: Oc1ccc2c(Cl)nccc2c1Br
Reactant: CO
Agent: Cl
Product: O=c1[nH]ccc2c(Br)c(O)ccc12
Temperature: 150 °C

Procedure:
5-Bromo-1-chloro-6-hydroxyisoquinoline (108 mg, 0.42 mmol) was mixed with hydrochloric acid (5M, 2 ml) and heated under microwave conditions at 150° C. for 40 minutes. The cooled residue was mixed with methanol and azeotroped to dryness under reduced pressure to give 5-bromo-6-hydroxy-2H-isoquinolin-1-one El-MS: m/z=240 and 242[M+H]+.
Reaction SMILES: C([NH:6][O:7][CH2:8][CH2:9][CH2:10][CH:11]1[NH:15]C(=O)N[C:12]1=[O:17])(OCC)=O.[OH2:18].O.O.O.O.O.O.O.[OH-].[Ba+2].[OH-]>O>[NH2:15][CH:11]([CH2:10][CH2:9][CH2:8][O:7][NH2:6])[C:12]([OH:17])=[O:18]
Reactant: CCOC(=O)NOCCCC1NC(=O)NC1=O
Reactant: O
Agent: [Ba+2]
Agent: [OH-]
Product: NOCCCC(N)C(=O)O

Procedure:
Mix 5-[3-(carbethoxyaminooxy)-propyl]-hydantoin (2.45 g, 10 mmol), barium hydroxide octahydrate (18.15 g, 10 mmol) and water (55 mL). Reflux for 12 hours, remove the white solid by filtration, extract the filter cake with boiling water (25 ml) and finally wash with hot water (25 mL). Combine the filtrate and washings, treat with ammonium carbonate (5.7 g) and heat with stirring. Filter off the barium carbonate, wash the filter cake with hot water and evaporate the filtrate and washings in vacuo to give 2-amino-5-aminooxy-pentanoic acid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:22]=[C:23]([C:25]([O:27][CH3:28])=[O:26])[CH:24]=1)[O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([OH:19])=O)=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[C:35]([NH:38][NH2:39])(=[O:37])[CH3:36].N1C=CC=CC=1>C(Cl)Cl.CN(C=O)C.Cl>[C:35]([NH:38][NH:39][C:17]([C:16]1[CH:20]=[CH:21][C:13]([O:12][C:11]2[CH:22]=[C:23]([CH:24]=[C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:10]=2)[C:25]([O:27][CH3:28])=[O:26])=[CH:14][CH:15]=1)=[O:19])(=[O:37])[CH3:36]
Reactant: COC(=O)c1cc(OCc2ccccc2)cc(Oc2ccc(C(=O)O)cc2)c1
Reactant: CC(=O)NN
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)c1cc(OCc2ccccc2)cc(Oc2ccc(C(=O)NNC(C)=O)cc2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirring solution of 4-[3-(benzyloxy)-5-(methoxycarbonyl)phenoxy]benzoic acid (Intermediate 11) (34 g, 82.87 mmol, 1 equiv) in dry DCM (50 mL), DMF (1.5 mL, catalytic) was added followed by oxalyl chloride (20.1 g, 158.7 mmol, 2 equiv.) dropwise at 0-5° C. The reaction mixture was stirred at room temperature for 2 h. After 2 h, a mixture of acetic hydrazide (8.8 g, 119 mmol, 1.5 equiv.) and dry pyridine (12.4 mL, 158.7 mmol, 2 equiv.) in dry DCM (50 mL) was added to the above prepared acid chloride at 0° C. The reaction mixture was allowed to warm to room temperature and stirred for 15 min. The reaction was monitored by TLC. After completion, the reaction mixture was diluted with dil. HCl and extracted with DCM. The organic layer was washed with water, brine and dried over sodium sulphate and concentrated to afford white solid. (32 g).