Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][CH2:5][O:6][C:7]1[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=1[C:9]([OH:11])=[O:10])(=[O:3])[CH3:2].[C:16]1([C:22]([O:24]O)=[O:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C1(N=C=NC2CCCCC2)CCCCC1>C(OCC)C.ClCCl.C(OCC)C>[C:1]([O:4][CH2:5][O:6][C:7]1[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=1[C:9]([O:11][O:24][C:22](=[O:23])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:10])(=[O:3])[CH3:2]
Reactant: CC(=O)OCOc1ccccc1C(=O)O
Reactant: O=C(OO)c1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCOCC
Solvent: ClCCl
Product: CC(=O)OCOc1ccccc1C(=O)OOC(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 63.1 %

Procedure:
5 g (24 mmol) of 2-acetoxymethoxy-benzoic acid (prepared as described in example 1-2) and 3.3 g (24 mmol) of benzenecarboperoxoic acid are dissolved in 150 mL of diethyl ether/dichloromethane mixture, 6/4. The solution is cooled to 0° C., then 4.9 g (24 mmol) of N,N′-dicyclohexylcarbodiimide dissolved in 85 ml of diethyl ether is added dropwise. After stirring for 3 hours at 0° C., the reaction mixture is filtered and then concentrated. The residue is precipitated in diethyl ether and the filtrate is concentrated under reduced pressure. 5 g of (2-acetoxymethoxy-benzoyl)benzoyl peroxide is obtained in the form of white solid at a yield of 63%.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32](Cl)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:38]1[CH2:44][CH2:43][C:42](=[O:45])[NH:41][CH2:40][CH2:39]1>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:38]3[CH2:44][CH2:43][C:42](=[O:45])[NH:41][CH2:40][CH2:39]3)=[O:33])[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[C@@:14]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: O=C1CCNCCN1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCNC(=O)CC1

Procedure:
In a manner analogous to the method described in examples 8, (4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride (example 51) was coupled with [1,4]-diazepan-5-one (Oakwood) to give the title compound. HR-MS (ES, m/z) calculated for C34H40Cl2N5O3 [(M+H)+] 636.2503, observed 636.2504.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][CH:15]([N:18]3[CH2:22][CH2:21][C@H:20]([O:23][C:24]4[CH:32]=[CH:31][C:27]([C:28](O)=[O:29])=[CH:26][C:25]=4[F:33])[C:19]3=[O:34])[CH2:14][CH2:13]2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[NH:35]1[CH2:39][CH2:38][CH2:37][CH2:36]1>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[C:3]([N:12]2[CH2:13][CH2:14][CH:15]([N:18]3[CH2:22][CH2:21][C@H:20]([O:23][C:24]4[CH:32]=[CH:31][C:27]([C:28]([N:35]5[CH2:39][CH2:38][CH2:37][CH2:36]5)=[O:29])=[CH:26][C:25]=4[F:33])[C:19]3=[O:34])[CH2:16][CH2:17]2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1
Reactant: C1CCNC1
Reactant: O=C(O)c1ccc(O[C@H]2CCN(C3CCN(c4ncc(C(F)(F)F)cc4Cl)CC3)C2=O)c(F)c1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(c1ccc(O[C@H]2CCN(C3CCN(c4ncc(C(F)(F)F)cc4Cl)CC3)C2=O)c(F)c1)N1CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 6.3 %

Procedure:
To a solution of (S)-4-(1-(1-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)piperidin-4-yl)-2-oxopyrrolidin-3-yloxy)-3-fluorobenzoic acid (0.040 g, 0.080 mmol) and pyrrolidine (0.028 g, 0.40 mmol) in DMF (1 mL) was added HTBU (0.060 g, 0.16 mmol) and the reaction was stirred overnight at ambient temperature. The reaction was diluted with EtOAc (20 mL) and washed with 1 N HCl (5 mL), 1 N NaOH (5 mL), and brine (5 mL), and the combined organic phases were dried over MgSO4, and concentrated under vacuum. The material was purified on silica, using EtOAc as eluent to yield (S)-1-(1-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)piperidin-4-yl)-3-(2-fluoro-4-(pyrrolidine-1-carbonyl)phenoxy)pyrrolidin-2-one (0.0026 g, 0.005 mmol, 6% yield). Mass spectrum (apci) m/z=555.0 (M+H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[Li]CCCC.[N:13]1([CH2:18][C:19](OCC)=[O:20])[CH:17]=[CH:16][CH:15]=[CH:14]1.[NH4+].[Cl-]>C1COCC1>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:19](=[O:20])[CH2:18][N:13]1[CH:17]=[CH:16][CH:15]=[CH:14]1
Reactant: CCOC(=O)Cn1cccc1
Reactant: Brc1ccccn1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: O=C(Cn1cccc1)c1ccccn1
Temperature: -78 °C
Reaction time: 0.67 h
Yield: 63.1 %

Procedure:
To a solution of 2-bromopyridine (380 μL, 4.0 mmol) in dry THF (15 mL) was added n-BuLi (1.6 M in hexanes, 2.5 mL, 4.0 mmol) at −78° C. The dark brown mixture was stirred for 30 minutes before a solution of ethyl 1H-pyrrol-1-ylacetate (720 mg, 4.7 mmol) in THF (5 mL) was added. The brown solution was stirred at −78° C. for 40 minutes and then at room temperature for 2 hours. The solution was poured into a saturated aqueous solution of NH4Cl (30 mL) and extracted with EtOAc (3×20 mL). The organic layers were dried (MgSO4), filtered and concentrated in vacuo to give a dark yellow oil that was purified by flash chromatography (Biotage SP4, 40 g cartridge, gradient 0-60% EtOAc in hexanes). To give 1-(Pyridine-2-yl)-2-(1H-pyrrol-1-yl)ethanone as a oil (470 mg, yield 63%). 1H-NMR (400 MHz, CDCl3): δ 5.60 (s, 2H), 6.23-6.27 (m, 2H), 6.69-6.72 (m, 2H), 7.54 (ddd, 1H, J 7.5, 4.8, 1.1 Hz), 7.88 (dt, 1H, J 7.7, 1.7 Hz), 8.06-8.10 (m, 1H), 8.69-8.73 (m, 1H).
Reaction SMILES: [CH:1]1[C:6]([NH2:7])=[CH:5][CH:4]=[C:3]([OH:8])[CH:2]=1.[OH-].[Na+].[CH2:11]([O:13][C:14](Cl)=[O:15])[CH3:12].S(S([O-])=O)([O-])=O.[Na+].[Na+]>O>[CH2:11]([O:13][C:14]([NH:7][C:6]1[CH:5]=[CH:4][C:3]([OH:8])=[CH:2][CH:1]=1)=[O:15])[CH3:12]
Reactant: Nc1ccc(O)cc1
Reactant: CCOC(=O)Cl
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCOC(=O)Nc1ccc(O)cc1

Procedure:
p-aminophenol 33.36 g (0.3 mole) and 12 g NaOH were dissolved in 120 ml water and cooled to ice salt bath temperature. To the stirring solution, 24 ml ethylchloroformate were slowly added. A white precipitate was found. One gram sodium dithionite was added and mixed. The solid was filtered by suction and washed with cold water (50 ml). Recrystallization from hot water gave a crystalline powder, 48.3 g (89%), MP 120-123°.
Reaction SMILES: [Cl-].[NH4+].[CH:3]1([O:9][C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][C:11]=2[NH:19][S:20]([CH3:23])(=[O:22])=[O:21])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.C(OCC)(=O)C>[Fe].O>[NH2:16][C:13]1[CH:14]=[CH:15][C:10]([O:9][CH:3]2[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]2)=[C:11]([NH:19][S:20]([CH3:23])(=[O:22])=[O:21])[CH:12]=1
Reactant: CS(=O)(=O)Nc1cc([N+](=O)[O-])ccc1OC1CCCCC1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: O
Product: CS(=O)(=O)Nc1cc(N)ccc1OC1CCCCC1
Temperature: 80 °C
Yield: 80.9 %

Procedure:
To 100 ml of an aqueous solution containing 5.0 g of ammonium chloride were added 98.0 g of N-(2-cyclohexyloxy-5-nitrophenyl)methanesulfonamide and 78.0 g of an iron powder with heating at 80° C. with stirring, followed by stirring for 2 hours. The reaction solution was cooled back to room temperature, and then ethyl acetate and water were added thereto. After extraction, the organic layer was successively washed with water and a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. After evaporation of the solvent, the residue was recrystallized from ethanol to give 71.7 g of N-(5-amino-2-cyclohexyloxyphenyl)methanesulfonamide as colorless prisms.
Reaction SMILES: [NH2:1][C:2]1[O:3][C:4]2[C:9]([C@@H:10]([C:14]3[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([Br:24])[CH:15]=3)[C:11]=1[C:12]#[N:13])=[CH:8][CH:7]=[C:6]([NH:25][C:26]([C@@H:28]([NH:30]C(=O)OCC1C3C=CC=CC=3C3C1=CC=CC=3)[CH3:29])=[O:27])[C:5]=2[NH2:48].C(Cl)Cl.[OH-].[Na+]>CO>[NH2:30][C@@H:28]([CH3:29])[C:26]([NH:25][C:6]1[C:5]([NH2:48])=[C:4]2[C:9]([C@@H:10]([C:14]3[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([Br:24])[CH:15]=3)[C:11]([C:12]#[N:13])=[C:2]([NH2:1])[O:3]2)=[CH:8][CH:7]=1)=[O:27]
Reactant: COc1cc([C@H]2C(C#N)=C(N)Oc3c2ccc(NC(=O)[C@H](C)NC(=O)OCC2c4ccccc4-c4ccccc42)c3N)cc(Br)c1OC
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: COc1cc([C@H]2C(C#N)=C(N)Oc3c2ccc(NC(=O)[C@H](C)N)c3N)cc(Br)c1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 16.3 %

Procedure:
To an oven-dried one-neck round bottom reaction flask charged with a magnetic stir bar at room temperature under argon was added (9H-fluoren-9-yl)methyl(S)-1-((R)-2,8-diamino-3-cyano-4-(3-bromo-4,5-dimethoxyphenyl)-4H-chromen-7-ylcarbamoyl)-ethylcarbamate (0.045 g, 0.063 mmol), CH2Cl2:MeOH, 1:1 (2.11 mL) and 2N NaOH (0.063 mL, 0.13 mmol). The orange suspension was stirred at room temperature overnight. The suspension was concentrated leaving a brown residue. The residue was extracted with CHCl3 (3×40 mL), dried over MgSO4, filtered and concentrated to give the crude product. Purification by flash column chromatography (silica gel 4 g pre-packed column, elution with CH2Cl2:MeOH, 1:1) gave 0.005 g (16%) of the title compound as a yellow solid: 1H-NMR (DMSO-d6): δ 8.32 (s, 1H), 7.02 (d, J=8.2 Hz, 1H), 6.98 (d, J=1.9 Hz, 1H), 6.91 (br s, 2H), 6.86 (d, J=1.9 Hz, 1H), 6.33 (d, J=8.5 Hz, 1H), 4.78 (br s, 2H), 4.69 (s, 1H), 3.80 (s, 3H), 3.70 (s, 3H), 1.22 (d, J=6.9 Hz, 3H). ESI-MS (C21H22BrN5O4) 487.09 m/z (%): 488 [M+H]+ (100%), 490 [M+H]+ (90%).
Reaction SMILES: N12CCCN=C1CCCCC2.Cl.[NH2:13][CH2:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[C:17](=[O:33])[N:18]([CH:25]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:26]1=[O:32])[C:19]2=[O:24].[CH:34]1([C:39](Cl)=[O:40])[CH2:38][CH2:37][CH2:36][CH2:35]1>CC#N>[O:32]=[C:26]1[CH:25]([N:18]2[C:17](=[O:33])[C:16]3[C:20](=[CH:21][CH:22]=[CH:23][C:15]=3[CH2:14][NH:13][C:39]([CH:34]3[CH2:38][CH2:37][CH2:36][CH2:35]3)=[O:40])[C:19]2=[O:24])[CH2:30][CH2:29][C:28](=[O:31])[NH:27]1
Reactant: O=C(Cl)C1CCCC1
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: O=C1CCC(N2C(=O)c3cccc(CNC(=O)C4CCCC4)c3C2=O)C(=O)N1
Reaction time: 0.33 h
Yield: 83.2 %

Procedure:
1,8-Diazabicyclo[5,4,0]undec-7-ene (0.62 g, 4.08 mmol) was added to a stirred suspension of 4-(aminomethyl)-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione hydrochloride (0.60 g, 1.85 mmol) in CH3CN (50 mL). After stirring for 20 min, cyclopentanecarbonyl chloride (0.29 g, 2.22 mmol) was added. The mixture was stirred at room temperature for 17 hours. The solvent was removed in vacuo and the residue was dissolved in CH2Cl2 (70 mL). The CH2Cl2 solution was washed with 1N HCl (30 mL), H2O (30 mL), brine (30 mL) and dried (MgSO4). The solvent was removed in vacuo and the solid was stirred with ether (20 mL) to give N-{[2-(2,6-dioxo(3-piperidyl))-1,3-dioxoisoindolin-4-yl]methyl}cyclopentylcarboxamide (0.59 g, 83%) as a white solid: mp 175-177° C.; 1H NMR (DMSO-d6) δ 11.13 (s, 1H), 8.41 (t, J=5.7 Hz, 1H), 7.87-7.78 (m, 2H), 7.66-7.63 (m, 1H), 5.19-5.12 (dd, J=5.3 and 12.5 Hz, 1H), 4.72 (d, J=5.8 Hz, 2H), 2.98-2.83 (m, 1H), 2.73-2.51 (m, 3H), 2.08-2.04 (m, 1H), 1.81-1.51 (m, 8H); 13C NMR (DMSO-d6) δ 175.71, 172.75, 169.82, 167.49, 166.95, 139.68, 134.76, 132.91, 131.50, 127.01, 121.77, 48.84, 44.20, 37.60, 30.93, 29.96, 25.60, 21.97; Anal. Calcd. For C20H21N3O5: C, 62.65; H, 5.52; N, 10.96. Found: C, 62.52; H, 5.55; N, 10.81.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:28])[C@@H:4]([NH:14][C:15](=[O:27])[C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=1[C:23]([F:26])([F:25])[F:24])[C@H:5]([OH:13])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH3:12].C(N(CC)CC)C.[C:36]1([N:42]([CH3:46])[C:43](Cl)=[O:44])[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:1][NH:2][C:3](=[O:28])[C@@H:4]([NH:14][C:15](=[O:27])[C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=1[C:23]([F:24])([F:25])[F:26])[C@H:5]([O:13][C:43]([N:42]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[CH3:46])=[O:44])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH3:12]
Reactant: CN(C(=O)Cl)c1ccccc1
Reactant: CNC(=O)[C@@H](NC(=O)c1ccc(F)cc1C(F)(F)F)[C@H](O)c1ccccc1C
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CNC(=O)[C@@H](NC(=O)c1ccc(F)cc1C(F)(F)F)[C@H](OC(=O)N(C)c1ccccc1)c1ccccc1C
Reaction time: 15 h
Yield: 52.7 %

Procedure:
0.4 g (0.001 mol) of (2S,3R)—N-methyl-2-(4-fluoro-2-trifluoromethylbenzoylamino)-3-hydroxy-3-o-tolylpropionamide was dissolved in methylene chloride, 0.13 g (0.0013 mol) of triethylamine and a spatula-tip of 4-dimethylaminopyridine were added, and 0.22 g of N-phenyl-N-methylcarbamoyl chloride in methylene chloride was added dropwise. The suspension was stirred for 15 hours and then extracted with 5% strength hydrochloric acid and NaHCO3 solution and dried. Chromatographic purification (silica gel column, cyclohexane/ethyl acetate) gave 0.28 g of the title compound as a colorless oil.
Reaction SMILES: [CH3:1][N:2]([CH:4]=O)[CH3:3].[CH2:6]([O:10][CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:21]=[CH:22][C:23]3[N:29]([CH2:30][C:31]4[O:32][CH:33]=[CH:34][CH:35]=4)[CH2:28][CH2:27][C:26]([C:36](O)=[O:37])=[CH:25][C:24]=3[CH:39]=2)=[CH:16][CH:15]=1)[CH2:7][CH2:8][CH3:9].S(Cl)(Cl)=O>O1CCCC1>[CH2:6]([O:10][CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:21]=[CH:22][C:23]3[N:29]([CH2:30][C:31]4[O:32][CH:33]=[CH:34][CH:35]=4)[CH2:28][CH2:27][C:26]([C:36]([NH:29][C:23]4[CH:24]=[CH:39][C:20]([CH2:4][N:2]([CH3:1])[CH:3]5[CH2:12][CH2:11][O:10][CH2:6][CH2:7]5)=[CH:21][CH:22]=4)=[O:37])=[CH:25][C:24]=3[CH:39]=2)=[CH:16][CH:15]=1)[CH2:7][CH2:8][CH3:9]
Reactant: CN(C)C=O
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3Cc2ccco2)cc1
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCN3Cc2ccco2)cc1
Reaction time: 1 h

Procedure:
One droplet of DMF was added to a solution of 7-(4-butoxyethoxyphenyl)-1-(2-furylmethyl)-2,3-dihydro-1-benzazepine-4-carboxylic acid (200 mg) in tetrahydrofuran (10 ml). Then, thionyl chloride (155 mg) was added at 0° C., the temperature was returned to room temperature, and the mixture was stirred under nitrogen atmosphere for 1 hour. Then, the solvent and excess thionyl chloride were evaporated, and the resulting residue was suspended in tetrahydrofuran (15 ml) and added to a solution of 4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]aniline (115 mg) and triethylamine (1.1 g) in tetrahydrofuran (10 ml) at 0° C. The mixture was stirred under nitrogen atmosphere at room temperature for 2.5 hours, to the mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried with magnesium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was separated and purified with silica gel column chromatography (methanol:ethyl acetate=1:8), which was recrystallized from hexane-ethyl acetate to give 7-(4-butoxyethoxyphenyl)-1-(2-furylmethyl)-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 72) (199 mg) as yellow crystals.
Reaction SMILES: [F:1][C:2]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:3]=1[CH2:4][O:5][C:6]1[CH:11]=[CH:10][N+:9]([O-])=[CH:8][CH:7]=1.C(OC(=O)C)(=[O:20])C>>[F:1][C:2]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:3]=1[CH2:4][O:5][C:6]1[CH:11]=[CH:10][NH:9][C:8](=[O:20])[CH:7]=1
Reactant: [O-][n+]1ccc(OCc2ccc(F)cc2F)cc1
Reactant: CC(=O)OC(C)=O
Product: O=c1cc(OCc2ccc(F)cc2F)cc[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 31 %

Procedure:
A solution of 4-(2,4-difluorobenzyloxy)pyridine-1-oxide (13.4 g, 57 mmol) in acetic anhydride (30 mL) was stirred at reflux for 4 h. The solvent was removed under reduced pressure, the residue was diluted with 1:1 MeOH/water (60 mL), and the mixture was stirred at room temperature for 1 h. The solvent was removed under reduced pressure. Purification by flash column chromatography (silica, eluent methylene chloride to 9:1 methylene chloride/methanol) provided 4-(2,4-difluorobenzyloxy)-1H-pyridin-2-one as a light brown solid (4.2 g, 31%): 1H NMR (300 MHz, CDCl3) δ 7.43 (q, J=8 Hz, 1H), 7.23 (d, J=7 Hz, 1H), 6.91-6.87 (m, 2H), 6.02 (dd, J=8, 2 Hz, 1H), 5.97 (d, J=2 Hz, 1H), 5.03 (s, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:16][O:17][C:18](=[O:27])[C:19]1[CH:24]=[CH:23][C:22]([CH2:25]Br)=[CH:21][CH:20]=1>CN(C=O)C>[CH:6]([C:5]1[CH:8]=[CH:9][C:2]([O:1][CH2:25][C:22]2[CH:23]=[CH:24][C:19]([C:18]([O:17][CH3:16])=[O:27])=[CH:20][CH:21]=2)=[CH:3][CH:4]=1)=[O:7]
Reactant: O=Cc1ccc(O)cc1
Reactant: COC(=O)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(COc2ccc(C=O)cc2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 96.2 %

Procedure:
To a suspension of 4-hydroxybenzaldehyde (244.2 mg, 2 mmol) and cesium carbonate (445 mg, 1.36 mmol) in anhydrous DMF (8 mL) was added methyl-4-(bromomethyl)benzoate (481 mg, 2.1 mmol). The resulting mixture was stirred for 24 hours at room temperature, after which time the mixture was concentrated under reduced pressure. The resulting crude was partitioned between dichloromethane (30 mL) and water (10 mL). The mixture was filtered through a phase separator, washed with dichloromethane and the solvent was removed in vacuo to yield the title compound as an off-white solid (520 mg, 96%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[C:5]([CH2:13][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)([CH2:11][OH:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].C(N(CC)CC)C.[CH3:28][S:29](Cl)(=[O:31])=[O:30].Cl>C(Cl)Cl>[CH2:9]([O:8][C:6](=[O:7])[C:5]([CH2:13][CH:14]1[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]1)([CH2:11][O:12][S:29]([CH3:28])(=[O:31])=[O:30])[C:4]([O:3][CH2:1][CH3:2])=[O:20])[CH3:10]
Reactant: CCOC(=O)C(CO)(CC1CCCCC1)C(=O)OCC
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C(COS(C)(=O)=O)(CC1CCCCC1)C(=O)OCC
Temperature: -10 °C
Yield: 100 %

Procedure:
A solution of 2-cyclohexylmethyl-2-hydroxymethyl-malonic acid diethyl ester (1.31 g, 4.13 mmol) in methylene chloride (20 mL) and triethyl amine (1.16 mL, 8.00 mmol) was cooled to −40° C. A solution of methylsulfonyl chloride (0.402 mL, 5.2 mmol) in methylene chloride (4 mL) was added to the reaction mixture over 5 minutes. The reaction mixture was warmed to −10° C. over 1 hour and then poured into cold dilute aqueous HCl. The product was extracted with ethyl acetate, the extracts were washed with saturated aqueous sodium chloride and then dried over magnesium sulfate. The solvent was removed by rotary evaporation at reduced pressure to give 2-cyclohexylmethyl-2-methylsulfonyloxymethyl-malonic acid diethyl ester (1.505 g).
Reaction SMILES: [CH3:1][N:2]([CH3:16])[CH:3]=[C:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N+:13]([O-:15])=[O:14])[CH:5]=O.[N+:17]([CH2:20][C:21]([O:23][CH3:24])=[O:22])([O-:19])=[O:18].C(OC(=O)C)(=O)C>>[CH3:24][O:23][C:21](=[O:22])[C:20]([N+:17]([O-:19])=[O:18])=[CH:5][C:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N+:13]([O-:15])=[O:14])=[CH:3][N:2]([CH3:16])[CH3:1]
Reactant: COC(=O)C[N+](=O)[O-]
Reactant: CN(C)C=C(C=O)c1ccccc1[N+](=O)[O-]
Solvent: CC(=O)OC(C)=O
Product: COC(=O)C(=CC(=CN(C)C)c1ccccc1[N+](=O)[O-])[N+](=O)[O-]
Yield: 80.4 %

Procedure:
A mixture of 63.0 g (0.29 mol) of the compound of Example 14 and 35.7 g (0.30 mol) of methyl nitroacetate in 600 ml. of acetic anhydride was heated at 85° for 2 hours. The resulting product was worked up and recrystallized from benzene-DMF (2:1) affording 74.9 g (81%) of product as red orange crystals, m.p. 211-214°.
Reaction SMILES: [CH:1]1[C:11]2[C:10](=[O:12])[NH:9][C:8]3[CH:13]=[CH:14][CH:15]=[CH:16][C:7]=3[NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.Cl.[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1.N1C=CC=CC=1.Cl>O1CCOCC1>[N:22]1[CH:23]=[CH:24][C:19]([C:18]([N:6]2[C:5]3[CH:4]=[CH:3][CH:2]=[CH:1][C:11]=3[C:10](=[O:12])[NH:9][C:8]3[CH:13]=[CH:14][CH:15]=[CH:16][C:7]2=3)=[O:25])=[CH:20][CH:21]=1
Reactant: O=C(Cl)c1ccncc1
Reactant: O=C1Nc2ccccc2Nc2ccccc21
Agent: Cl
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: O=C1Nc2ccccc2N(C(=O)c2ccncc2)c2ccccc21
Temperature: 0 °C

Procedure:
A mixture of 21.0 g (0.1 mol) of 5,10-dihydro-11H-dibenzo[b,e][1,4]diazepin-11-one, 23.0 g (0.129 mol) of isonicotinic acid chloride hydrochloride, 21 ml (0.26 mol) of pyridine and 300 ml of anhydrous dioxan was refluxed for 3 hours. After cooling, the mixture was poured into 1 liter of ice-cold water, acidified with conc. hydrochloric acid and extracted twice, each time with 200 ml of dichloromethane. The aqueous phase was made alkaline with methylene chloride. The combined methylene chloride extracts were washed with water, dried over sodium sulphate and the solvent was removed in vacuo. The residue was recrystallized from hot methanol. After washing with ether, the beige crystals melted at 277°-279° C. Yield 16.0 g (51% of theory).
Reaction SMILES: [CH3:1][N:2]([CH3:6])[C:3](Cl)=[O:4].[NH2:7][CH2:8][CH2:9][CH2:10][CH2:11][N:12]1[C:20]2[C:19]([CH3:21])=[CH:18][N:17]=[C:16]([NH2:22])[C:15]=2[N:14]=[C:13]1[CH2:23][O:24][CH2:25][CH3:26]>>[NH2:22][C:16]1[C:15]2[N:14]=[C:13]([CH2:23][O:24][CH2:25][CH3:26])[N:12]([CH2:11][CH2:10][CH2:9][CH2:8][NH:7][C:3](=[O:4])[N:2]([CH3:6])[CH3:1])[C:20]=2[C:19]([CH3:21])=[CH:18][N:17]=1
Reactant: CCOCc1nc2c(N)ncc(C)c2n1CCCCN
Reactant: CN(C)C(=O)Cl
Product: CCOCc1nc2c(N)ncc(C)c2n1CCCCNC(=O)N(C)C

Procedure:
Using the method of Examples 147-164, dimethylcarbamyl chloride was reacted with 1-(4-aminobutyl)-2-(ethoxymethyl)-7-methyl-1H-imidazo[4,5-c]pyridin-4-amine to provide the desired compound. The observed accurate mass was 349.2334.
Reaction SMILES: [N+:1]([C:4]1[CH:20]=[CH:19][C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][C:10]=2[N+:16]([O-:18])=[O:17])=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl[C:22]([O:24][CH2:25][CH3:26])=[O:23]>N1C=CC=CC=1>[N+:1]([C:4]1[CH:20]=[CH:19][C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:22](=[O:23])[O:24][CH2:25][CH3:26])=[CH:11][C:10]=2[N+:16]([O-:18])=[O:17])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CCOC(=O)Cl
Reactant: Nc1ccc(Oc2ccc([N+](=O)[O-])cc2)c([N+](=O)[O-])c1
Solvent: c1ccncc1
Product: CCOC(=O)Nc1ccc(Oc2ccc([N+](=O)[O-])cc2)c([N+](=O)[O-])c1
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
4-(4-Nitrophenoxy)-3-nitrobenzenamine (0.1 mole) and pyridine (50 ml) are charged into a glass reaction vessel fitted with a mechanical stirrer and thermometer and are cooled to about 5° C. Ethyl chloroformate (0.125 mole) is added, with stirring, at about 5° C. Stirring is continued for a period of about 30 minutes at about 5° C., then for an additional 16 hours at room temperature. The mixture is then washed with 2 portions of water (50 ml), dried and the solvent is then removed to yield the desired product ethyl [4-(4-nitrophenoxy)-3-nitrophenyl]carbamate.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([CH3:21])([CH3:20])[C:8](=[O:19])[C:9](C(OCC)=O)=[C:10]2[OH:13])=[CH:5][CH:4]=1>C(O)(C(F)(F)F)=O>[Br:2][C:3]1[CH:12]=[C:11]2[C:6](=[CH:5][CH:4]=1)[C:7]([CH3:21])([CH3:20])[C:8](=[O:19])[CH:9]=[C:10]2[OH:13]
Reactant: CCOC(=O)C1=C(O)c2cc(Br)ccc2C(C)(C)C1=O
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)C(=O)C=C(O)c2cc(Br)ccc21
Temperature: 80 °C
Yield: 70 %

Procedure:
Concentrated aqueous HCl (36.5-37.5%, 10 mL) was added to a solution of ethyl 7-bromo-1-hydroxy-4,4-dimethyl-3-oxo-3,4-dihydronaphthalene-2-carboxylate (1.40 g, 4 mmol) in TFA (10 mL). The mixture was heated to 80° C. for 18 hours. The solvent was then removed under reduced pressure, and the residue was rinsed with water and diethyl ether. The remaining solids were dried in vacuo at 50° C. to afford the title compound in 70% yield. 1H-NMR (300 MHz, DMSO-d6) δ ppm 7.98 (1H, d, J=1.9 Hz), 7.75 (1H, dd, J=2.0, 8.5 Hz), 7.67 (1H, br. d, J˜8.0 Hz), 5.64 (1H, s), 2.51 (6H, m). MS (m/z not observed).