Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH:9]([C:12]1[S:13][CH:14]=[CH:15][C:16]=1[CH3:17])[NH:10][CH3:11].[Cl:18]N1C(=O)CCC1=O>CN(C)C=O.C(OCC)C>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:18])=[CH:4][C:3]=1[CH2:8][CH:9]([C:12]1[S:13][CH:14]=[CH:15][C:16]=1[CH3:17])[NH:10][CH3:11]
Reactant: CNC(Cc1ccccc1N)c1sccc1C
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CNC(Cc1cc(Cl)ccc1N)c1sccc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 11.5 %

Procedure:
A stirred solution of 8 g of 2-amino-N-methyl-α-(3-methyl-2-thienyl)benzeneethanamine in 40 ml of N,N-dimethylformamide was treated with a solution of 6.41 g of N-chlorosuccinimide in 40 ml of N,N-dimethylformamide and then stirred at room temperature for 8 hours. Evaporation of the volatiles afforded an oil which was decanted into 100 ml of water, basified with 30 ml of 10% aqueous sodium hydroxide and extracted with dichloromethane (2×100 ml). The extract was washed with water (2×100 ml), dried over anhydrous sodium sulfate and concentrated. Thin layer chromatography of the resultant oil indicated a multicomponent mixture. Purification of the mixture was accomplished by successive HPLC separations (Water's Associates Prep LC/System 500, silica gel, elution with methanol). Concentration of the appropriate fractions afforded a residue which was dissolved in diethyl ether, filtered free of insolubles and concentrated. The resultant oil crystallized upon standing to yield 1.05 g of 2-amino-5-chloro-N-methyl-α-(3-methyl-2-thienyl)benzeneethanamine, mp 59°-61° C.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C@H:5]([C:7]([OH:9])=O)[CH2:4][S:3]1.Cl.[CH3:11][C@H:12]([NH2:18])[CH2:13][O:14][N+:15]([O-:17])=[O:16].C(N(CC)CC)C.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1>O1CCCC1>[CH3:11][C@H:12]([NH:18][C:7]([C@@H:5]1[CH2:4][S:3][C:2](=[O:1])[NH:6]1)=[O:9])[CH2:13][O:14][N+:15]([O-:17])=[O:16]
Reactant: O=C1N[C@H](C(=O)O)CS1
Reactant: C[C@H](N)CO[N+](=O)[O-]
Agent: Cl
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C[C@@H](CO[N+](=O)[O-])NC(=O)[C@@H]1CSC(=O)N1
Yield: 94.2 %

Procedure:
In 60 ml of dry tetrahydrofuran were suspended 2.06 g of (4R)-2-oxothiazolidine-4-carboxylic acid and 2.00 g of (1S)-1-methyl-2-nitroxyethylamine hydrochloride, 4.5 ml of triethylamine and 3.00 ml of diphenylphosphoryl azide were added thereto with stirring under ice-cooling, and the mixture was stirred at room temperature for 5 hours. Then, the solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography employing cyclohexane-ethyl acetate (1:4) as an eluent to obtain 3.00 g of colorless crystals. The crystals were recrystallized from ethyl acetate to obtain 0.964 g of the desired compound as colorless needle crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH2:9])=[S:8])=[CH:5][CH:4]=1.[CH2:12]([O:14][C:15](=[O:21])[CH:16](Cl)[C:17](=O)[CH3:18])[CH3:13]>C(O)C>[CH2:12]([O:14][C:15]([C:16]1[S:8][C:7]([C:6]2[CH:10]=[CH:11][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[N:9][C:17]=1[CH3:18])=[O:21])[CH3:13]
Reactant: CCOC(=O)C(Cl)C(C)=O
Reactant: COc1ccc(C(N)=S)cc1
Solvent: CCO
Product: CCOC(=O)c1sc(-c2ccc(OC)cc2)nc1C
Yield: 69.7 %

Procedure:
A mixture of 4-methoxy-thiobenzamide (5 g, 30 mmol) and 2-chloro-3-oxo-butyric acid ethyl ester (4.6 mL, 33 mmol) in ethanol is stirred under reflux overnight. The reaction is concentrated and the residue is triturated with ether to give 2-(4-methoxy-phenyl)-4-methyl-thiazole-5-carboxylic acid ethyl ester as a yellow solid (5.8 g, 70%).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][NH:9]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C=O)C>[CH2:18]([N:9]1[C:10]2[C:5](=[CH:4][CH:3]=[C:2]([Br:1])[CH:11]=2)[CH2:6][CH2:7][CH2:8]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: BrCc1ccccc1
Reactant: Brc1ccc2c(c1)NCCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Brc1ccc2c(c1)N(Cc1ccccc1)CCC2
Temperature: 60 °C
Yield: 71.2 %

Procedure:
To a stirred solution of 7-bromo-1,2,3,4-tetrahydroquinoline (7.0 g, 33.0 mmol) in DMF (50 mL) was added potassium carbonate (13.6 g, 99.0 mmol), and benzyl bromide (4.33 mL, 36.3 mmol), and the mixture was heated to 60° C. for 12 h, then cooled to room temperature and quenched by the addition of ice-cold water (150 mL). The resulting mixture was extracted with ethyl acetate (3×50 mL), and the organic layers were combined and washed with water (50 mL) and brine (50 mL), then dried over sodium sulfate, concentrated and purified by silica gel column chromatography to furnish 1-benzyl-7-bromo-1,2,3,4-tetrahydro-quinoline (7.1 g).
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7](=[O:19])[N:8]([CH2:11][CH2:12][N:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[CH2:9][CH2:10][C:5]=2[NH:4][C:3]=1[CH:20]=O.[CH3:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:24]=1[CH2:25][C:26](=[O:32])[NH:27]2>>[CH3:1][C:2]1[C:6]2[C:7](=[O:19])[N:8]([CH2:11][CH2:12][N:13]3[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]3)[CH2:9][CH2:10][C:5]=2[NH:4][C:3]=1[CH:20]=[C:25]1[C:24]2[C:28](=[CH:29][CH:30]=[CH:31][C:23]=2[CH3:22])[NH:27][C:26]1=[O:32]
Reactant: Cc1cccc2c1CC(=O)N2
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN1CCCCC1)CC2
Product: Cc1cccc2c1C(=Cc1[nH]c3c(c1C)C(=O)N(CCN1CCCCC1)CC3)C(=O)N2
Yield: 75.9 %

Procedure:
The title compound was prepared under the same conditions as described in Example 25 with 3-methyl-4-oxo-5-(2-piperidin-1-yl-ethyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde and 4-methyl-1,3-dihydro-indol-2-one (prepared according to U.S. Pat. No. 6,114,371) as starting materials to give 3-methyl-2-(4-methyl-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-5-(2-piperidin-1-yl-ethyl)-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one (41 mg, 75.9%) as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([CH:15]([CH3:19])[C:16]([OH:18])=[O:17])=[CH:11][CH:10]=1.S(=O)(=O)(O)O.[CH3:25]O>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([CH:15]([CH3:19])[C:16]([O:18][CH3:25])=[O:17])=[CH:11][CH:10]=1
Reactant: CO
Reactant: CC(C(=O)O)c1ccc(-c2ccc(F)cc2F)cc1
Agent: O=S(=O)(O)O
Product: COC(=O)C(C)c1ccc(-c2ccc(F)cc2F)cc1

Procedure:
2-(2',4'-Difluoro-4-biphenylyl)propionic acid (2 g.), methanol (20 ml.) and concentrated sulphuric acid (0.6 ml.) were refluxed for 16 hours. Excess methanol was distilled in vacuo, the residue was diluted with water and the oil isolated in ether. Distillation gave methyl 2-(2',4'-difluoro-4-biphenylyl)propionate, b.p. 118°-120°C./0.2 mm.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:18])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[OH:17].[C:19](=O)([O-])[O-].[K+].[K+].IC>CC(C)=O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:18])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[O:17][CH3:19]
Reactant: O=C(Nc1ccc(F)cc1F)c1ccccc1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COc1ccccc1C(=O)Nc1ccc(F)cc1F
Temperature: 25 °C

Procedure:
To a solution of compound 3a (0.50 g, 2 mmole) in anhydrous acetone (10 mL) were added potassium carbonate (0.69 g, 5 mmole) and iodomethane (0.28 mL, 4.4 mmol) and refluxed 8 hr. After cooled to room temperature, the reaction mixture was filtered through Celite and concentrated. The residue was extracted with ethyl acetate and dried over anhydrous magnesium sulfate, then concentrated and recrystallized with hot methanol.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl[C:8]1[CH:13]=[CH:12][C:11](/[CH:14]=[CH:15]/[C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=2)=[CH:10][N:9]=1.[CH2:25]([OH:34])[CH2:26][O:27][CH2:28][CH2:29][O:30][CH2:31][CH2:32][OH:33].O>CN(C=O)C>[OH:34][CH2:25][CH2:26][O:27][CH2:28][CH2:29][O:30][CH2:31][CH2:32][O:33][C:8]1[CH:13]=[CH:12][C:11](/[CH:14]=[CH:15]/[C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=2)=[CH:10][N:9]=1
Reactant: OCCOCCOCCO
Reactant: O=[N+]([O-])c1ccc(/C=C/c2ccc(Cl)nc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc(/C=C/c2ccc(OCCOCCOCCO)nc2)cc1
Temperature: 25 °C
Yield: 77.3 %

Procedure:
The mixture of potassium carbonate (158.7 mg, 1.15 mmol), compound 3 (100 mg, 0.38 mmol) and triethylene glycol (576 mg, 3.8 mmol) in anhydrous DMF (5.0 ml) was sealed in a microwavable vial (from Biotage) and subjected to microwave irradiation (Biotage Initiator system) at 180° C. for 25 min. After cooling to room temperature, water was added and reaction mixture was extracted with ethyl acetate. Organic layer was separated, washed with brine, dried over anhydrous sodium sulfate and evaporated. The residue was purified with PTLC (4% MeOH in DCM as developing solvent) gave product 7 (110 mg, Yield: 77%): 1H NMR (200 MHz, CDCl3): δ.8.20 (3H, m), 7.83 (1H, d, d, J1=8.6 Hz, J2=2.4 Hz), 7.61 (2H, d, J=8.8 Hz), 7.10 (2H, m) 6.84 (1H, d, J=8.6 Hz), 4.53 (2H, t, J=4.8 Hz), 3.88 (2H, t, J=4.8 Hz), 3.71 (6H, m), 3.61 (2H, m), 2.10 (1H, b), HRMS (EI) m/z calcd. for [C19H22N2O6]+ 374.1478.
Reaction SMILES: [CH2:1]([C:4]12[CH2:10][CH:7]([CH:8]=[CH:9]1)[CH:6]1[C:11]([O:13][C:14](=[O:15])[CH:5]21)=[O:12])[CH:2]=[CH2:3].[OH:16][CH:17]([CH2:20][OH:21])[CH2:18][NH2:19]>>[OH:16][CH:17]([CH2:20][OH:21])[CH2:18][N:19]=[C:14]([CH:5]1[CH:6]([C:11]([OH:13])=[O:12])[CH:7]2[CH2:10][C:4]1([CH2:1][CH:2]=[CH2:3])[CH:9]=[CH:8]2)[OH:15]
Reactant: C=CCC12C=CC(C1)C1C(=O)OC(=O)C12
Reactant: NCC(O)CO
Product: C=CCC12C=CC(C1)C(C(=O)O)C2C(O)=NCC(O)CO

Procedure:
102 g of allylbicyclo[2.2.1]hept-5-ene-2,3-dicarboxylic anhydride are heated with 45.55 g of 2,3-dihydroxypropylamine to 200° C., and the pressure is lowered to 47 Pa. The yield is 138 g (96.5% of theory) of a highly viscous product having η80 =605 mPa.s and n25D =1.5380.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[N:12][C:13]([N:17](C(OC(C)(C)C)=O)[NH:18][C:19](OC(C)(C)C)=O)=[CH:14][CH:15]=2)[CH:10]=[C:9]1[CH2:33][O:34][Si](C(C)(C)C)(C)C)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[CH3:44]C(O)=O>C1COCC1.O>[CH2:1]([N:8]1[C:16]2[CH:15]=[CH:14][C:13]3[N:12]([C:19]([CH3:44])=[N:18][N:17]=3)[C:11]=2[CH:10]=[C:9]1[CH2:33][OH:34])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)O
Reactant: CC(C)(C)OC(=O)NN(C(=O)OC(C)(C)C)c1ccc2c(cc(CO[Si](C)(C)C(C)(C)C)n2Cc2ccccc2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1nnc2ccc3c(cc(CO)n3Cc3ccccc3)n12

Procedure:
di-tert-Butyl 1-[1-benzyl-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)-1H-pyrrolo[3,2-b]pyridin-5-yl]hydrazine-1,2-dicarboxylate (0.20 g, 0.34 mmol, from Step 4) in AcOH (2.7 mL) was heated in the microwave to a temperature of 180° C. for 5 minutes. Acetic acid was removed in vacuo and the residue was then stirred with NaOH (69 mg, 1.7 mmol) in THF (2.0 mL) and water (2 mL) for 20 minutes. The product was purified by preparative HPLC-MS (C18 eluting with a gradient of MeCN and H2O containing 0.15% NH4OH). Yield: (38 mg, 38%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:12]2[O:13][C:14]3[CH:20]=[CH:19][C:18](Br)=[CH:17][C:15]=3[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])([O-:3])=[O:2].[F:22][C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1>>[N+:1]([C:4]1[CH:5]=[C:6]([C:12]2[O:13][C:14]3[CH:20]=[CH:19][C:18]([C:26]4[CH:27]=[CH:28][C:23]([F:22])=[CH:24][CH:25]=4)=[CH:17][C:15]=3[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])([O-:3])=[O:2]
Reactant: OB(O)c1ccc(F)cc1
Reactant: COc1ccc(-c2nc3cc(Br)ccc3o2)cc1[N+](=O)[O-]
Product: COc1ccc(-c2nc3cc(-c4ccc(F)cc4)ccc3o2)cc1[N+](=O)[O-]

Procedure:
Prepared by the method of Example 15d), from 2-(3-nitro-4-methoxyphenyl)-5-bromobenzoxazole (200 mg, 0.57 mmol) and 4-fluorophenylboronic acid (120 mg, 0.86 mmol) the subtitle compound was obtained, (135 mg, 65%). 1H NMR (DMSO) δ 8.64(d, 1H), 8.45(dd, 1H), 8.05(d, 1H), 7.87(d, 2H), 7.78(dd, 1H), 7.72(dd, 1H), 7.62(d, 2H), 7.33(t, 1H), 4.08(s, 3H).
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[CH2:3][CH:2]2[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][N:14]=[CH:15][C:16]1[CH:25]=[CH:24][C:23]([OH:26])=[C:22]2[C:17]=1[CH:18]=[CH:19][CH:20]=[N:21]2.[BH4-].[Na+]>CO.O>[CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[CH2:3][CH:2]2[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH:14][CH2:15][C:16]1[CH:25]=[CH:24][C:23]([OH:26])=[C:22]2[C:17]=1[CH:18]=[CH:19][CH:20]=[N:21]2
Reactant: Oc1ccc(C=NCCCCCCC2CC3C=CC2C3)c2cccnc12
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Oc1ccc(CNCCCCCCC2CC3C=CC2C3)c2cccnc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 50 %

Procedure:
Imine 7 was dissolved in 50 mL of dry methanol and 1 equivalent of NaBH4 (0.136 g, 0.0036 mol) was added in small increments. After the addition was complete, the solution was allowed to stir for 10 minutes at room temperature. The solution was diluted with water and extracted three times with 20 mL of methylene chloride. The combined organic layers were washed with water, NaHCO3, brine, and dried over Na2SO4. The solvent was removed under reduced pressure to yield a brown liquid. Purification by column chromatography (silica gel, 4:1 hexanes/ethyl acetate, then pure ethyl acetate, then 5% methanol in ethyl acetate) gave the product as a pale yellow solid (0.658 g, 50%). 1H NMR (300 MHz, CDCl3) δ8.75 (1H, dd, J=1.09, 4.39); 8.51 (1H, dd, J=1.09, 8.24); 7.46 (1H, dd, J=4.39, 8.24); 7.38 (1H, d, J=7.69); 7.08 (1H, d, J=7.69); 6.11 (1H endo, dd, J=2.74, 5.49); 6.06–5.99 (2H exo, m); 5.90 (1H endo, dd, J=2.74, 5.49); 4.10 (1H, s); 2.73 (2H, s); 2.71 (2H, t, J=7.14); 1.99–1.02 (12H, m); 0.49–0.43 (1H, m). 13C NMR (75 MHz, CDCl3) δ151.8; 147.6; 137.0; 136.3; 133.4; 132.6; 128.0; 127.4; 126.8; 121.8; 109.2; 51.2; 50.0; 49.7; 45.5; 42.7; 38.9; 34.9; 32.6; 30.2; 29.9; 28.8; 27.5. Anal. Calcd for C23H30N2O: C, 78.88; H, 8.63; N, 8.00. Found C: 78.79, H: 8.72, N: 8.00.
Reaction SMILES: [H-].[Na+].[O:3]1[CH2:7][CH2:6][NH:5][C:4]1=[O:8].[CH:9]1([C:12]2[C:13]([N:21]3[CH2:26][CH2:25][N:24]([C:27]([C:29]4[CH:30]=[N:31][C:32](F)=[CH:33][C:34]=4[CH3:35])=[O:28])[CH2:23][CH2:22]3)=[N:14][CH:15]=[C:16]([CH:18]3[CH2:20][CH2:19]3)[CH:17]=2)[CH2:11][CH2:10]1.O>CN(C)C=O>[CH:9]1([C:12]2[C:13]([N:21]3[CH2:22][CH2:23][N:24]([C:27]([C:29]4[C:34]([CH3:35])=[CH:33][C:32]([N:5]5[CH2:6][CH2:7][O:3][C:4]5=[O:8])=[N:31][CH:30]=4)=[O:28])[CH2:25][CH2:26]3)=[N:14][CH:15]=[C:16]([CH:18]3[CH2:20][CH2:19]3)[CH:17]=2)[CH2:10][CH2:11]1
Reactant: O=C1NCCO1
Reactant: Cc1cc(F)ncc1C(=O)N1CCN(c2ncc(C3CC3)cc2C2CC2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(N2CCOC2=O)ncc1C(=O)N1CCN(c2ncc(C3CC3)cc2C2CC2)CC1
Temperature: 25 °C
Yield: 45.7 %

Procedure:
To a solution of sodium hydride (168 mg, 60% in oil) in N,N-dimethylformamide (10 mL) was added oxazolidin-2-one (367 mg) under ice-cooling, and the mixture was stirred at room temperature. Thereto was added a solution of [4-(3,5-dicyclopropylpyridin-2-yl)piperazin-1-yl](6-fluoro-4-methylpyridin-3-yl)methanone (400 mg) described in Preparation Example 139 in N,N-dimethylformamide (5 mL) and the mixture was stirred at 90° C. for 5 hr. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed twice with water, washed with saturated brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography (ethyl acetate:hexane). Then, diethyl ether was added and the mixture was stirred at room temperature. The solid was collected by filtration to give the title compound (215 mg).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([OH:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[OH-].[Na+:13].Br[CH2:15][CH2:16][CH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1>O.C(O)(C)C>[CH:17]1([CH2:16][CH2:15][O:1][C:2]2[CH:7]=[CH:6][C:5]([S:8]([O-:11])(=[O:9])=[O:10])=[CH:4][CH:3]=2)[CH2:21][CH2:20][CH2:19][CH2:18]1.[Na+:13]
Reactant: O=S(=O)(O)c1ccc(O)cc1
Reactant: BrCCC1CCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: O=S(=O)([O-])c1ccc(OCCC2CCCC2)cc1

Procedure:
A solution of 4-hydroxybenzenesulfonic acid (6.5 grams, 28.2 mmole) and sodium hydroxide (2.2 grams, 55 mmole) in water (15 mL) was mixed with a solution of 2-(bromoethyl)cyclopentane (15.0 grams, 84.7 mmole) in isopropanol (40 mL) and the resulting mixture was heated at reflux for 2 days. The isopropanol was removed by evaporation under vaccuum. The titled compound, 4.7 grams (57%), was collected by filtration washing with isopropanol.
Reaction SMILES: C(OC([NH:11][C@@H:12]1[C:15](=[O:16])[NH:14][C@@H:13]1[CH2:17][N:18]1[CH:22]=[CH:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C:19]1=[O:30])=O)C1C=CC=CC=1>[Pd]>[NH2:11][C@@H:12]1[C:15](=[O:16])[NH:14][C@@H:13]1[CH2:17][N:18]1[CH:22]=[CH:21][N:20]([C:23]([O:25][C:26]([CH3:28])([CH3:27])[CH3:29])=[O:24])[C:19]1=[O:30]
Reactant: CC(C)(C)OC(=O)n1ccn(C[C@H]2NC(=O)[C@H]2NC(=O)OCc2ccccc2)c1=O
Agent: [Pd]
Product: CC(C)(C)OC(=O)n1ccn(C[C@H]2NC(=O)[C@H]2N)c1=O
Reaction time: 2 h
Yield: 15 %

Procedure:
A mixture of tert-Butyl 3-(((2R,3S)-3-(((benzyloxy)carbonyl)amino)-4-oxoazetidin-2-yl)methyl)-2-oxo-2,3-dihydro-1H-imidazole-1-carboxylate (490 mg, 1.18 mmol) and Palladium on carbon (10% wt, 140 mg) in MeOH (60 mL) was evacuated and backfilled with H2 (3×), bringing the final pressure up to 30 psi. After 2 h of stirring, the mixture was filtered through celite and concentrated in vacuo. The crude residue was purified via silica gel chromatography (MeOH-DCM, 6%), affording the title compound (50 mg, 25%).
Reaction SMILES: CO[C:3](=O)[CH2:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH:7]=[CH:8][C:9]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[N:10]2.[H-].[Al+3].[Li+].[H-].[H-].[H-].CC[O:32]CC>>[CH2:16]([O:15][C:9]1[CH:8]=[CH:7][C:6]2[C:11](=[CH:12][CH:13]=[CH:14][C:5]=2[CH:4]([OH:32])[CH3:3])[N:10]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CCOCC
Reactant: COC(=O)Cc1cccc2nc(OCc3ccccc3)ccc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CC(O)c1cccc2nc(OCc3ccccc3)ccc12
Temperature: -10 °C
Reaction time: 1 h

Procedure:
(2-Benzyloxy-quinolin-5-yl)-acetic acid methyl ester (0.198 g, 0.64 mmol) was dissolved in 10 mL of anhydrous ether, and cooled to −10° C. Lithium aluminum hydride (1.0M solution in ether, 0.5 mL, 0.5 mmol) was added and stirred at −10° C. for 1 h. The reaction was quenched with 0.5 mL water, then 0.5 mL 15% NaOH, then 1.5 mL water. A solution of Na, K tartrate was added to help solublized the salts. Ethyl acetate was added and the layers were separated. The aqueous layer was washed with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered, and rotovapped. (2-Benzyloxy-quinolin-5-yl)-ethanol (0.140 g, 78%) was used without further purification. MS m/z 280 (M+1).
Reaction SMILES: [Cl:1][CH:2]=[CH:3][CH2:4][NH:5][CH2:6][CH:7]=[CH:8][Cl:9].[CH:10](O)=[O:11]>>[Cl:1][CH:2]=[CH:3][CH2:4][N:5]([CH2:6][CH:7]=[CH:8][Cl:9])[CH:10]=[O:11]
Reactant: ClC=CCNCC=CCl
Reactant: O=CO
Product: O=CN(CC=CCl)CC=CCl

Procedure:
Bis-(3-chloroallyl)amine (2.5 g, 0.015 mol) and 25 ml formic acid were combined and refluxed for 5 hours. The mixture was stripped under a vacuum from a hot-water bath. The yield was 2.6 g of the above-named product.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:9][CH3:10])=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.[Br:11]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C1C=CC=CC=1.O>[Br:1][C:2]1[C:3]([O:9][CH3:10])=[N:4][CH:5]=[C:6]([CH2:8][Br:11])[CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ncc(C)cc1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: O
Solvent: c1ccccc1
Product: COc1ncc(CBr)cc1Br
Temperature: 80 °C
Reaction time: 8 h

Procedure:
3-Bromo-2-methoxy-5-methyl-pyridine (4.0 g, 19.8 mmol), N-bromosuccinimide (4.45 g, 23.8 mmol), and azobisisobutyronitrile (0.163 g, 0.99 mmol) were combined in benzene (40 mL) and stirred overnight at 80° C. The reaction was stirred for another 24 hours at 80° C., and then additional N-bromosuccinimide (1.8 g, 10.1 mmol), and azobisisobutyronitrile (catalytic) were added. After stirring for another 2 hours at 80° C., the mixture was diluted with H2O and extracted with CH2Cl2. The residue was purified by silica gel chromatography to give 3-bromo-5-bromomethyl-2-methoxy-pyridine.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10](=O)[C:11]([F:17])([F:16])[C:12]([F:15])([F:14])[F:13])[CH:5]=[CH:6][CH:7]=1.Cl.[F:20][C:21]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=1[NH:28][NH2:29].Cl>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]2[N:28]([C:22]3[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=3[F:20])[N:29]=[C:10]([C:11]([F:17])([F:16])[C:12]([F:15])([F:14])[F:13])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: NNc1ccc(F)cc1F
Reactant: O=C(C=Cc1cccc(Br)c1)C(F)(F)C(F)(F)F
Agent: Cl
Solvent: CCO
Product: Fc1ccc(N2N=C(C(F)(F)C(F)(F)F)CC2c2cccc(Br)c2)c(F)c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 95.3 %

Procedure:
1-(3-Bromo-phenyl)-4,4,5,5,5-pentafluoro-pent-1-en-3-one (1.8 g, 5.3 mmol) prepared in Step 1, 2,4-difluorophenylhydrazine hydrochloride (1.2 g, 6.4 mmol) and conc. hydrochloric acid (100.0 uL) were added to ethanol (15.0 mL). The reaction mixture was stirred at 100° C. for 8 hours, quenched with a saturated solution of sodium hydrogen carbonate, and then extracted with ethyl acetate three times. The combined extract was washed with brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/60) to give 2.3 g of the titled compound as a yellow liquid.
Reaction SMILES: Br[C:2]1[CH:18]=[CH:17][C:5]([O:6][CH:7]([CH3:16])[CH2:8][NH:9][S:10]([CH:13]([CH3:15])[CH3:14])(=[O:12])=[O:11])=[CH:4][CH:3]=1.O.[NH2:20][C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][CH:26]=1.C(=O)([O-])[O-].[Na+].[Na+]>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.O1CCOCC1>[NH2:20][C:21]1[CH:26]=[C:25]([C:2]2[CH:18]=[CH:17][C:5]([O:6][CH:7]([CH3:16])[CH2:8][NH:9][S:10]([CH:13]([CH3:15])[CH3:14])(=[O:12])=[O:11])=[CH:4][CH:3]=2)[CH:24]=[CH:23][CH:22]=1
Reactant: Nc1cccc(B(O)O)c1
Reactant: CC(CNS(=O)(=O)C(C)C)Oc1ccc(Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(CNS(=O)(=O)C(C)C)Oc1ccc(-c2cccc(N)c2)cc1
Yield: 82.2 %

Procedure:
The title compound (230 mg, 82%) was prepared from [2-(4-bromophenoxy)propyl][(methylethyl)sulfonyl]amine (270 mg, 0.803 mmol, prepared in example 1), 3-aminobenzeneboronic acid monohydrate (150 mg, 0.968 mmol), tetrakis(triphenylphosphine)palladium(0) (5 mg, 0.004 mmol), 2 M sodium carbonate (290 mg in 1.4 mL water) and 1,4-dioxane (5.5 mL) in a manner analogous to the procedure described in Example 2.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([Cl:9])[N:5]=[C:4]([C:10]([O:12]C)=[O:11])[CH:3]=1.[OH-].[Na+]>O1CCOCC1.O>[Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([Cl:9])[N:5]=[C:4]([C:10]([OH:12])=[O:11])[CH:3]=1
Reactant: COC(=O)c1cc(Cl)c(Cl)c(Cl)n1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)c1cc(Cl)c(Cl)c(Cl)n1
Temperature: 25 °C
Reaction time: 72 h
Yield: 94.3 %

Procedure:
Methyl 4,5,6-trichloropyridine-2-carboxylate (10.11 g, 42 mmol) was suspended in dioxane (200 mL) and water (200 mL). To this mixture was added 1 N NaOH (42 mL, 42 mmol), and the reaction mixture was stirred at 25° C. After 72 h, 2 N NaOH (15 mL, 30 mmol) was added to drive the reaction to completion. The dioxane was removed by rotary evaporation, and the aqueous residue was acidified with concentrated hydrochloric acid. The precipitate was collected by suction filtration, washed with water and dried to provide 4,5,6-trichloropyridine-2-carboxylic acid (8.92 g, 39.6 mmol), mp 115-120° C.