Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:4][CH:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.CCOCC.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[O:1]=[CH:2][C@@H:3]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:16])([CH3:15])[CH3:17])[CH2:4][CH:5]1[CH2:6][CH2:7][O:8][CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N[C@H](CO)CC1CCOCC1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H](C=O)CC1CCOCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.7 %

Procedure:
To a solution of (S)-tert-butyl 1-hydroxy-3-(tetrahydro-2H-pyran-4-yl)propan-2-ylcarbamate (1.7 g, 6.6 mmol) in CH2Cl2 (20 mL) was added Dess-Martin periodionane (3.4 g, 7.9 mmol). The reaction was stirred at r.t. for 1 h. Tlc showed the starting material had disappeared. The mixture was poured into Et2O (100 mL) and K2CO3 (5 g) was added. The organic phase was dried over Na2SO4 and concentrated. The residue was purified by chromatography to give (S)-tert-butyl 1-oxo-3-(tetrahydro-2H-pyran-4-yl)propan-2-ylcarbamate (1.2 g, 71%). 1H NMR (CD3OD) δ 1.45 (s, 9H), 2.07 (m, 2H), 3.90 (m, 3H), 4.30 (b, 1H), 5.0 (b, 1H), 9.55 (s, 1H).
Reaction SMILES: [CH2:1]([O:9][C:10](=[CH:13]N(C)C)[CH:11]=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].Cl.Cl.[C@H:19]1([C:28]([NH2:30])=[NH:29])[CH2:24][CH2:23][C@H:22]([C:25]([NH2:27])=[NH:26])[CH2:21][CH2:20]1.[Na]>C(O)C>[CH2:1]([O:9][C:10]1[CH:11]=[N:26][C:25]([C@H:22]2[CH2:21][CH2:20][C@H:19]([C:28]3[N:30]=[CH:11][C:10]([O:9][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])=[CH:13][N:29]=3)[CH2:24][CH2:23]2)=[N:27][CH:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCOC(C=O)=CN(C)C
Reactant: N=C(N)[C@H]1CC[C@H](C(=N)N)CC1
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: CCCCCCCCOc1cnc([C@H]2CC[C@H](c3ncc(OCCCCCCCC)cn3)CC2)nc1

Procedure:
2.27 g (9.96 mmol) of 2-octyloxy-3-dimethylaminoacrolein in 5 ml of ethanol and 1.0 g (4.15 mmol) of transcyclohexane-1,4-diamidine dihydrochloride are added dropwise at room temperature to 230 mg (9.96 mmol) of sodium, dissolved in 6.3 ml of ethanol, and the mixture is refluxed for 120 hours. After cooling, the reaction solution is adjusted to pH 3 using semiconcentrated HC1 and evaporated, and 30 ml of water are added to the residue. The aqueous solution is extracted several times with dichloromethane. The organic phases are combined, dried over magnesium sulfate and evaporated in vacuo. Chromatographic purification on silica gel and crystallization from hexane gives 380 mg (18%) of the end product. The product has the following phase sequence:
Reaction SMILES: [Cl-:1].[Cl-].[NH3+:3][C:4]1[CH:26]=[CH:25][C:7]([C:8]([NH:10][C:11]2[CH:24]=[CH:23][C:14]([NH:15][C:16]3[CH:21]=[CH:20][N+:19]([CH3:22])=[CH:18][CH:17]=3)=[CH:13][CH:12]=2)=[O:9])=[CH:6][CH:5]=1.[Cl:27][C:28]1[C:37]2[C:32](=[CH:33][C:34]([N+:38]([O-:40])=[O:39])=[CH:35][CH:36]=2)[N:31]=[CH:30][CH:29]=1.Cl>CO>[Cl-:27].[Cl-:1].[CH3:22][N+:19]1[CH:20]=[CH:21][C:16]([NH:15][C:14]2[CH:23]=[CH:24][C:11]([NH:10][C:8](=[O:9])[C:7]3[CH:25]=[CH:26][C:4]([NH:3][C:28]4[C:37]5[C:32](=[CH:33][C:34]([N+:38]([O-:40])=[O:39])=[CH:35][CH:36]=5)[N:31]=[CH:30][CH:29]=4)=[CH:5][CH:6]=3)=[CH:12][CH:13]=2)=[CH:17][CH:18]=1.[CH3:22][N+:19]1[CH:20]=[CH:21][C:16]([NH:15][C:14]2[CH:23]=[CH:24][C:11]([NH:10][C:8](=[O:9])[C:7]3[CH:25]=[CH:26][C:4]([NH:3][C:28]4[C:37]5[C:32](=[CH:33][C:34]([N+:38]([O-:40])=[O:39])=[CH:35][CH:36]=5)[N:31]=[CH:30][CH:29]=4)=[CH:5][CH:6]=3)=[CH:12][CH:13]=2)=[CH:17][CH:18]=1
Reactant: O=[N+]([O-])c1ccc2c(Cl)ccnc2c1
Reactant: C[n+]1ccc(Nc2ccc(NC(=O)c3ccc([NH3+])cc3)cc2)cc1
Agent: Cl
Agent: [Cl-]
Solvent: CO
Product: C[n+]1ccc(Nc2ccc(NC(=O)c3ccc(Nc4ccnc5cc([N+](=O)[O-])ccc45)cc3)cc2)cc1
Reaction time: 65 h

Procedure:
To a solution of amine B7 (1.46 g, 3.73 mmol) in dry MeOH (20 mL) were sequentially added 4-chloro-7-nitroquinoline (S1) (0.78 g, 3.73 mmol) and two drops of c.HCl, and the resulting mixture was refluxed for 4 h. After this time, the temperature was reduced to ˜40° C. and heating was continued for a further 65 h. After this time, solvent was removed under reduced pressure. The residue was re-dissolved in MeOH, and solvent was again removed under reduced pressure. This latter process was repeated once more, and the residue was then re-precipitated twice from MeOH:Et2O. Finally, a portion of the solid thus obtained was re-precipitated from MeOH:EtOAc to afford Cpd. S as an amorphous yellow-orange solid (0.070g, 3%). 1H NMR [(CD3)2SO]: 3.96 [s, 3H, R2N+CH3], 7.14 [m, 3H, ArH], 7.35 [d, J=8.85 Hz, 2H, ArH], 7.68 [d, J=8.57 Hz, 2H, ArH], 7.96 [d, J=8.85 Hz, 2H, ArH], 8.18 [d, J=8.57 Hz, 2H, ArH], 8.26 [d, J=7.37 Hz, 2H, ArH], 8.50 [dd, J=9.28, 2.23 Hz, 1H, ArH], 8.77 [d, J=6.65 Hz, 1H, ArH], 8.94 [d, J=2.23 Hz, 1H, ArH], 9.08 [d, J=9.28 Hz, 1H, ArH], 10.55 [s, 1H, ArNHAr], 10.71 [s, 1H, ArNHAr], 11.21 [br s, 1H, ArC(O)NHAr], 11.21 [v v br s, 1H, quinoline-N+H]; LCMS (APCI+): 492 (100%), 493 (30%). HPLC: 98.1%.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]([N+:14]([O-:16])=[O:15])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH3:17][NH:18][C:19]([C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1)=[O:20].C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:13][O:12][C:10]1[CH:11]=[C:2]([C:24]2[CH:25]=[CH:26][C:21]([C:19](=[O:20])[NH:18][CH3:17])=[CH:22][CH:23]=2)[C:3]([C:4]([O:6][CH3:7])=[O:5])=[CH:8][C:9]=1[N+:14]([O-:16])=[O:15]
Reactant: COC(=O)c1cc([N+](=O)[O-])c(OC)cc1Cl
Reactant: CNC(=O)c1ccc(B(O)O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CNC(=O)c1ccc(-c2cc(OC)c([N+](=O)[O-])cc2C(=O)OC)cc1
Temperature: 40 °C

Procedure:
Under nitrogen, the mixture of methyl 2-chloro-4-methoxy-5-nitrobenzoate (292 mg, 1.19 mmol), 4-(methylcarbamoyl)phenylboronic acid (319 mg, 1.79 mmol), dichlorobis(triphenylphosphine)palladium (II) (41 mg, 0.06 mmol) and sodium carbonate (378 mg, 3.57 mmol) in THF (8 mL) and water (2 mL) is heated at 40° C. overnight. The reaction mixture is cooled to room temperature and then partitioned between EtOAc and brine. The organic extracts are dried (Na2SO4), concentrated in vacuo, and purified by silica gel chromatography (EtOAc/Hexanes:1/3) to afford Methyl 5-methoxy-4′-(methylcarbamoyl)-4-nitrobiphenyl-2-carboxylate; ESMS m/z 345.1 (M+H+).
Reaction SMILES: N1C=CC=CC=1.[Br-:7].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[CH3:28][N:29]([CH3:53])[C:30]1[CH:35]=[CH:34][C:33]([C:36]2[CH:37]=[C:38]3[CH:44]=[CH:43][N:42]([CH2:45][O:46][CH2:47][CH2:48][Si:49]([CH3:52])([CH3:51])[CH3:50])[C:39]3=[N:40][CH:41]=2)=[CH:32][CH:31]=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Br:7][C:44]1[C:38]2[C:39](=[N:40][CH:41]=[C:36]([C:33]3[CH:34]=[CH:35][C:30]([N:29]([CH3:53])[CH3:28])=[CH:31][CH:32]=3)[CH:37]=2)[N:42]([CH2:45][O:46][CH2:47][CH2:48][Si:49]([CH3:51])([CH3:50])[CH3:52])[CH:43]=1
Reactant: CN(C)c1ccc(-c2cnc3c(ccn3COCC[Si](C)(C)C)c2)cc1
Reactant: [Br-]
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CN(C)c1ccc(-c2cnc3c(c2)c(Br)cn3COCC[Si](C)(C)C)cc1
Yield: 70.3 %

Procedure:
Pyridine (0.180 mL, 2.23 mmol) and pyridinium tribromide (0.832 g, 2.34 mmol) were added to a stirred and cooled (−70° C.) solution of 59 (0.820 g, 2.23 mmol) in CH2Cl2 (10 mL). The mixture was stirred at −70° C. for 30 min., poured into saturated aqueous NaHCO3 solution and extracted with CH2Cl2. The organic extract was washed with brine, dried (MgSO4), and concentrated. The residue was purified by means of SGC with hexane:AcOEt as eluent to afford 60 (0.700 g, 70%) as a pale yellow solid. 1H NMR (400 MHz, CDCl3) δ 0.00 (s, 9H), 0.94-1.01 (m, 2H), 3.07 (s, 6H), 3.58-3.64 (m, 2H), 5.71 (s, 2H), 6.88-6.93 (m, 2H), 7.43 (s, 1H), 7.56-7.62 (m, 2H), 8.01 (d, J=0.21 Hz, 1H), 8.62 (d, J=0.21 Hz, 1H).
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([CH:13]([CH3:15])[CH3:14])[C:11]=1[OH:12])[CH:7]=O)([CH3:3])[CH3:2].[C:16]1([S:22]([CH2:25][C:26]#[N:27])(=[O:24])=[O:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH:1]([C:4]1[CH:5]=[C:6](/[CH:7]=[C:25](/[S:22]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)(=[O:23])=[O:24])\[C:26]#[N:27])[CH:9]=[C:10]([CH:13]([CH3:15])[CH3:14])[C:11]=1[OH:12])([CH3:3])[CH3:2]
Reactant: CC(C)c1cc(C=O)cc(C(C)C)c1O
Reactant: N#CCS(=O)(=O)c1ccccc1
Product: CC(C)c1cc(/C=C(\C#N)S(=O)(=O)c2ccccc2)cc(C(C)C)c1O

Procedure:
M30 was prepared with 3,5-diisopropyl-4-hydroxybenzaldehyde and phenylsulfonly acetonitrile under the similar conditions as decribed for M26.
Reaction SMILES: [NH:1]1[C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([C:10]([O:12][CH3:13])=[O:11])[N:3]=[CH:2]1.[Cl:14][C:15]1[CH:34]=[C:33]([O:35][CH3:36])[CH:32]=[CH:31][C:16]=1[O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]SC1SCC(=O)N=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:14][C:15]1[CH:34]=[C:33]([O:35][CH3:36])[CH:32]=[CH:31][C:16]=1[O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][N:1]1[C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([C:10]([O:12][CH3:13])=[O:11])[N:3]=[CH:2]1
Reactant: COc1ccc(OCCCCCCSC2=NC(=O)CS2)c(Cl)c1
Reactant: COC(=O)c1nc[nH]c1C(=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ncn(CCCCCCOc2ccc(OC)cc2Cl)c1C(=O)OC
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Stir for 24 hours at room temperature 3.7 gm. dimethyl 4,5-imidazole dicarboxylate, 3.7 gm. of the iodide prepared in Examples 2 or 3, 25 ml. DMF and 2.8 gm potassium carbonate. Remove the solvent, extract the residue with methylene chloride, filter, wash methylene chloride fractions with water, elute on a silica column with 100% methylene chloride then 10% methanol/methylene chloride to recover the title compound.
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[N:4]=[C:3]1S(C)(=O)=O.[OH:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[C:26]3=[N:27][CH:28]=[CH:29][CH:30]=[C:25]3[N:24]([CH:31]([CH3:33])[CH3:32])[C:23]2=[O:34])=[CH:18][CH:17]=1.[H-].[Na+]>CN(C=O)C.CO>[CH3:33][CH:31]([N:24]1[C:25]2[C:26](=[N:27][CH:28]=[CH:29][CH:30]=2)[N:22]([C:19]2[CH:18]=[CH:17][C:16]([O:15][C:3]3[N:2]([CH3:1])[C:6]4=[N:7][CH:8]=[CH:9][CH:10]=[C:5]4[N:4]=3)=[CH:21][CH:20]=2)[C:23]1=[O:34])[CH3:32]
Reactant: CC(C)n1c(=O)n(-c2ccc(O)cc2)c2ncccc21
Reactant: Cn1c(S(C)(=O)=O)nc2cccnc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: CC(C)n1c(=O)n(-c2ccc(Oc3nc4cccnc4n3C)cc2)c2ncccc21
Temperature: 180 °C
Yield: 30.6 %

Procedure:
3-Methyl-2-(methylsulfonyl)-3H-imidazo[4,5-b]pyridine (270 mg) was added to a solution of 3-(4-hydroxyphenyl)-1-(1-methylethyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (330 mg) and NaH (53.9 mg) in DMF (5 mL) at 100° C. The mixture was heated at 180° C. for 30 min under microwave irradiation. The reaction mixture was diluted with MeOH and concentrated in vacuo. The residue was purified by column chromatography (NH silica gel, eluted with 0%-50% EtOAc in hexane) to give 1-(1-methylethyl)-3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (150 mg) as white crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13]3[CH:14]=[CH:15][C:16]([N:18](S(C)(=O)=O)[S:19]([CH3:22])(=[O:21])=[O:20])=[CH:17][C:12]=3[O:11][C:10]([CH3:28])([CH3:27])[C:9]2=[O:29])=[CH:4][CH:3]=1.[OH-].[Na+].CC1(C)C(=O)NC2C=CC(N(S(C)(=O)=O)S(C)(=O)=O)=CC=2O1.Cl.C(O)(C)C.O>C(O)(C)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:13]3[CH:14]=[CH:15][C:16]([NH:18][S:19]([CH3:22])(=[O:20])=[O:21])=[CH:17][C:12]=3[O:11][C:10]([CH3:27])([CH3:28])[C:9]2=[O:29])=[CH:6][CH:7]=1
Reactant: CC1(C)Oc2cc(N(S(C)(=O)=O)S(C)(=O)=O)ccc2N(c2ccc(F)cc2)C1=O
Agent: CC1(C)Oc2cc(N(S(C)(=O)=O)S(C)(=O)=O)ccc2NC1=O
Agent: Cl
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: CC1(C)Oc2cc(NS(C)(=O)=O)ccc2N(c2ccc(F)cc2)C1=O
Reaction time: 8 h
Yield: 94.7 %

Procedure:
To a suspension of N-[4-(4-fluorophenyl)-2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl]-N-(methylsulfonyl)methanesulfonamide (1 g) in isopropanol (3 mL) was added dropwise an aqueous sodium hydroxide solution (0.18 g/3 mL) at 25° C., then isopropanol/water (1:1.2 mL) was added thereto, and the mixture was stirred overnight at the same temperature. To the reaction mixture was added dropwise concentrated hydrochloric acid/isopropanol/water (0.24 g/0.5 mL/0.35 mL) at 25° C., and the mixture was stirred for 1 hour. The precipitated crystals were collected by filtration, washed with a solution of isopropanol/water (1:1.6 mL), and then dried under reduced pressure at 50° C. to obtain the title compound (0.78 g) as Form D crystals (yield: 94%, purity: 99%).
Reaction SMILES: [OH:1][NH:2][C:3](=[O:23])[CH:4]([OH:22])[CH2:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:11][CH:10]=1)(=[O:8])=[O:7].C1COCC1.NO>CO>[OH:1][NH:2][C:3](=[O:23])[C@@H:4]([OH:22])[CH2:5][S:6]([C:9]1[CH:10]=[CH:11][C:12]([O:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[CH:13][CH:14]=1)(=[O:7])=[O:8]
Reactant: O=C(NO)C(O)CS(=O)(=O)c1ccc(Oc2ccccc2)cc1
Agent: NO
Solvent: CO
Solvent: C1CCOC1
Product: O=C(NO)[C@@H](O)CS(=O)(=O)c1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 67 %

Procedure:
Part F: To a solution of the sulfone of part E (3.9 g, 11.6 mmol) in methanol (20 mL) and THF (20 mL) was added 50% aqueous hydroxylamine (14 mL). The solution was stirred for 18 hours at ambient temperature. The solution was concentrated in vacuo and recrystallization (acetone/H2O) provided (R)-N,2-dihydroxy-3-[(4-phenoxyphenyl)sulfonyl]propanamide as a white solid (2.6 g, 67%). HPLC purity: 99%. HRMS calculated for C15H15NO6S: 338.0698, found: 338.0673.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[S:11]([O-:13])=[O:12].[Na+].C(=O)([O-])O.[Na+].C1(=O)[O:25][C:23](=[O:24])[CH:22]=[CH:21]1>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[S:11]([CH2:21][CH2:22][C:23]([OH:25])=[O:24])(=[O:13])=[O:12]
Reactant: O=C1C=CC(=O)O1
Reactant: O=[N+]([O-])c1ccc(Cl)c(S(=O)[O-])c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: O=C(O)CCS(=O)(=O)c1cc([N+](=O)[O-])ccc1Cl
Temperature: 100 °C
Reaction time: 5 h
Yield: 80.9 %

Procedure:
36 g of sodium 2-chloro-5-nitrobenzenesulphinate, 12.6 g of solid sodium hydrogen carbonate and 22.5 g of maleic anhydride are heated at 100° C. in 250 ml of water for 3 hours. After cooling down, a further 12.6 g of sodium hydrogencarbonate and 22.5 g of maleic anhydride are then added. After a further 5 hours of stirring at 100° C., the cooled, weakly acid reaction mixture is filtered with suction. The filter is cake at 50° C. in 300 ml of water, and the suspension is cooled down to 20° C. and is filtered again with suction. Drying gives 35.1 g of 3-(2-chloro-5-nitrophenylsulphonyl)-propionic acid.
Reaction SMILES: O.C1(C)C=CC(S(O)(=O)=O)=CC=1.N1C=CC=CC=1.[CH3:19][C:20]([C:22]1[CH:30]=[CH:29][C:27](O)=[C:24]([O:25][CH3:26])[CH:23]=1)=[O:21].[O:31]1[CH:36]=[CH:35][CH2:34][CH2:33][CH2:32]1>C(Cl)Cl>[CH3:26][O:25][C:24]1[CH:23]=[C:22]([C:20](=[O:21])[CH3:19])[CH:30]=[CH:29][C:27]=1[CH:32]1[CH2:33][CH2:34][CH2:35][CH2:36][O:31]1
Reactant: COc1cc(C(C)=O)ccc1O
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: O
Solvent: c1ccncc1
Product: COc1cc(C(C)=O)ccc1C1CCCCO1
Yield: 46 %

Procedure:
In an oven-dried, 500 mL round bottom flask equipped with a stir bar and an addition funnel, p-toluenesulfonic acid monohydrate (156 mg, 0.82 mmol), pyridine (66 μL, 0.82 mmol), acetovanillone (6.10 g, 36.7 mmol), and CH2Cl2 (170 mL) were combined and rapidly stirred. Dihydropyran (10 mL, 110 mmol) was diluted with 40 mL of CH2Cl2, poured into the addition funnel, and added drop wise to the acetovanillone solution over a period of 2 h. The reaction was stirred for an additional 12 h at room temperature, after which it was washed with 200 mL of 1.0 N NaOH (2×). The organic phase was dried over Na2SO4, filtered, and concentrated to a clear oil under reduced pressure. The oil crystallized upon standing to afford 4.2 g of THP-C as a white solid (46% yield). The solid was used without further purification. TLC: Rf=0.19 (hexane/EtOAc 4:1); Melting point: 67-69° C.; 1H NMR: (300 MHz, CDCl3) δ 7.52 (s, 1H), 7.50 (d, J=10 Hz, 1H), 7.13 (d, J=8 Hz, 1H), 5.50 (t, J=3 Hz, 1H), 3.90 (s, 3H), 3.89 (m, 1H), 3.59 (m, 1H), 2.54 (s, 3H), 1.95 (m, 3H), 1.63 (m, 1H); 13C NMR: (75 MHz, CDCl3) δ 197.08, 150.92, 150.12, 131.60, 123.18, 115.65, 111.29, 97.14, 62.31, 56.32, 30.33, 26.45, 25.31, 18.79; IR (ATR): 2966, 2936, 2880, 1672, 1585, 1510, 1462, 1442, 1413, 1390, 1352, 1290, 1272, 1243, 1221, 1201, 1172, 1153, 1120, 1110, 1051, 1032, 1020, 959 1046 cm−1; ESI-MS: expected, 250.1; observed, m/z 251.1 [M+H+].
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH2:8][O:9][CH3:10])[CH:5]=[C:4]([F:11])[CH:3]=1.[Li]CCCC.C(O[B:21]1[O:25][C:24]([CH3:27])([CH3:26])[C:23]([CH3:29])([CH3:28])[O:22]1)(C)C>C1COCC1>[F:1][C:2]1[CH:7]=[C:6]([CH2:8][O:9][CH3:10])[CH:5]=[C:4]([F:11])[C:3]=1[B:21]1[O:25][C:24]([CH3:27])([CH3:26])[C:23]([CH3:29])([CH3:28])[O:22]1
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Reactant: COCc1cc(F)cc(F)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COCc1cc(F)c(B2OC(C)(C)C(C)(C)O2)c(F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1,3-difluoro-5-(methoxymethyl)benzene (0.970 g, 6.13 mmol) in THF (24 mL) at −78° C., a solution of n-BuLi in hexanes (1.6 M, 9.58 mL, 15.3 mmol) was slowly added through a dripping funnel. When addition was done, the mixture was kept at −78° C. for 1 h. 2-Isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (3.75 mL, 18.4 mmol) was then added in one portion. The reaction mixture was allowed to warm to room temperature and stirred for 1 h. The mixture was quenched with aq. NaHCO3 and extracted with EtOAc. The combined organic extracts were washed with brine, dried over Na2SO4, and concentrated under reduced pressure to give sub-title compound as a colorless oil. 1H NMR (300 MHz, CDCl3) δ 6.82 (m, 2H), 4.43 (s, 2H), 3.38 (s, 3H), 1.37 (s, 12H) ppm.
Reaction SMILES: [CH3:1][NH2:2].[CH2:3]([O:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[N:17]=[CH:16][C:15]([N+:21]([O-:23])=[O:22])=[C:14]2Cl)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>O>[CH2:3]([O:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[N:17]=[C:16]([CH2:1][NH2:2])[C:15]([N+:21]([O-:23])=[O:22])=[CH:14]2)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1cnc2ccc(OCc3ccccc3)cc2c1Cl
Reactant: CN
Solvent: O
Product: NCc1nc2ccc(OCc3ccccc3)cc2cc1[N+](=O)[O-]
Temperature: 100 °C
Reaction time: 1.5 h

Procedure:
Methylamine (available as a 40% solution in water, 24 mL, 0.28 mol) was added to a solution of 6-benzyloxy-4-chloro-3-nitroquinoline (15.0 g, 48.5 mmol), prepared as described in Parts A-D of Example 2, in distilled water (300 mL), and the reaction was stirred at 100° C. for 1.5 hours. The reaction was allowed to cool to ambient temperature and stirred for four hours. A precipitate formed, which was isolated by filtration and washed with distilled water (3×60 mL). The solid was combined with material from another run and recrystallized from 2-propanol. The crystals were isolated by filtration, washed twice with cold hexanes, and dried for three days under high vacuum to provide 24.10 g of (6-benzyloxy-3-nitroquinolinyl)methylamine as yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8](=O)[CH3:9])=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[NH2:12][NH2:13]>CCOC(C)=O.O>[Cl:1][C:2]1[C:7]2[C:8]([CH3:9])=[N:12][NH:13][C:6]=2[CH:5]=[CH:4][N:3]=1
Reactant: CC(=O)c1c(Cl)ccnc1Cl
Reactant: NN
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1n[nH]c2ccnc(Cl)c12
Yield: 64 %

Procedure:
1-(2,4-Dichloro-pyridin-3-yl)-ethanone (6.2 g, 32.6 mmol) in 65% aqueous hydrazine (45 ml) was stirred at rt overnight. The mixture was diluted with EtOAc and water. The organic extract was washed with brine, dried and concentrated to give a white solid. The crude product was purified by flash column chromatography over silica gel (200 g) eluting with 1:1 petroleum ether:EtOAc to give an off-white solid (3.5 g, 64%). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.64 (s, 3 H), 7.47 (d, J=5.95 Hz, 1 H), 8.06 (d, J=5.95 Hz, 1 H). m/z (ES+APCI)+: 168/170 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[CH:9]([CH2:11][CH2:12][C:13]([NH:15][C:16]1[CH:24]=[CH:23][C:19](C(O)=O)=[CH:18][N:17]=1)=[O:14])[N:8]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1)[C:7]2=[O:33].NC1C=CC([Cl:41])=CN=1>>[Cl:41][C:19]1[CH:23]=[CH:24][C:16]([NH:15][C:13](=[O:14])[CH2:12][CH2:11][CH:9]2[C:10]3[C:6](=[CH:5][CH:4]=[CH:3][C:2]=3[F:1])[C:7](=[O:33])[N:8]2[CH2:25][C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)=[N:17][CH:18]=1
Reactant: O=C(CCC1c2c(F)cccc2C(=O)N1Cc1ccc(F)cc1)Nc1ccc(C(=O)O)cn1
Reactant: Nc1ccc(Cl)cn1
Product: O=C(CCC1c2c(F)cccc2C(=O)N1Cc1ccc(F)cc1)Nc1ccc(Cl)cn1

Procedure:
The product of Example 11, Part D (120 mg, 0.45 mmol) and 2-amino-5-chloropyridine (58 mg, 0.45 mmol) were converted to the title compound in a manner analogous to the method described in Example 27 (85 mg, 49%). 1H NMR (400 MHz, CDCl3) δ 8.12 (s, 1H), 8.09 (d, J=8.7 Hz, 1H), 7.81 (s, 1H); 7.69-7.61 (m, 3H); 7.48-7.43 (m, 1H); 7.35 (m, 2H), 7.26 (t, J=8.8 Hz, 1H); 7.17 (t, J=8.5 Hz, 2H); 5.28 (d, J=15 Hz, 1H), 4.69 (s, 1H), 4.26 (d, J=15 Hz, 1H), 2.59-2.48 (m, 2H); 1.98-1.90 (m, 2H). MS: m/z (MH+) 443.
Reaction SMILES: CO[CH2:3][C:4]([NH:6][C:7]1[S:8][C:9]2[CH:15]=[C:14]([O:16][S:17]([C:20]3[CH:25]=[CH:24][C:23](F)=[CH:22][CH:21]=3)(=[O:19])=[O:18])[CH:13]=[CH:12][C:10]=2[N:11]=1)=[O:5].[CH:27]([NH:30][CH2:31][CH2:32][NH2:33])([CH3:29])[CH3:28].C(=O)([O-])[O-].[Cs+].[Cs+].O>CS(C)=O>[CH:3]1([C:4]([NH:6][C:7]2[S:8][C:9]3[CH:15]=[C:14]([O:16][S:17]([C:20]4[CH:21]=[CH:22][C:23]([NH:33][CH2:32][CH2:31][NH:30][CH:27]([CH3:29])[CH3:28])=[CH:24][CH:25]=4)(=[O:19])=[O:18])[CH:13]=[CH:12][C:10]=3[N:11]=2)=[O:5])[CH2:12][CH2:10][CH2:9][CH2:15]1
Reactant: COCC(=O)Nc1nc2ccc(OS(=O)(=O)c3ccc(F)cc3)cc2s1
Reactant: CC(C)NCCN
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)NCCNc1ccc(S(=O)(=O)Oc2ccc3nc(NC(=O)C4CCCC4)sc3c2)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 48.7 %

Procedure:
A solution of 4-fluorobenzenesulfonic acid 2-(2-methoxyacetylamino)-benzothiazol-6-yl ester (intermediate 68) (90 mg, 0.214 mmol), N-isopropylethylenediamine (65.6 mg, 0.642 mmol) and cesium carbonate (69.7 mg, 0.214 mmol) in 2 ml of dimethyl sulfoxide in a test tube, equipped with a magnetic bar, is stirred overnight at 80° C. 100 ml of water are added and the reaction medium is extracted with ethyl acetate. The organic phase is then washed with water, dried over magnesium sulfate and evaporated. The residue, purified by LC/MS, gives 26.2 mg of 4-(2-isopropylaminoethylamino)benzenesulfonic acid 2-(cyclopentanecarbonyl-amino)benzothiazol-6-yl ester (white powder) in a yield of 24%.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10]2[CH:11]=[C:12]([CH:18]=[CH:19][CH:20]=2)[C:13]([O:15]CC)=[O:14])[CH:6]=[CH:7][CH:8]=1)#[N:2].[OH-].[Na+]>O1CCOCC1.O>[C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10]2[CH:11]=[C:12]([CH:18]=[CH:19][CH:20]=2)[C:13]([OH:15])=[O:14])[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: CCOC(=O)c1cccc(Nc2cccc(C#N)c2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: N#Cc1cccc(Nc2cccc(C(=O)O)c2)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of ethyl 3-(3-cyanophenylamino)benzoate (0.050 g; 0.187 mmol) in dioxane (1 ml) was added a solution of sodium hydroxide (0.022 g; 0.563 mmol) in water (0.6 ml). The mixture was stirred at room temperature for 18 hours and concentrated under reduced pressure to remove the dioxane. The aqueous solution was acidified with 6N hydrochloric acid, extracted with ethyl acetate (2×100 mL), dried and concentrated under reduced pressure to give quantitatively 3-(3-cyanophenylamino)benzoic acid which was directly used in the next step.