Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:11]2[CH2:16][CH:15]([C:17]([O:19]C)=[O:18])[CH2:14][CH2:13][N:12]2[C:21]([O:23][CH3:24])=[O:22])[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[Br-].[Li+].C(N(CC)CC)C.CC(OC)(C)C>C(#N)C.O>[C:1]([C:5]1[CH:6]=[C:7]([CH:11]2[CH2:16][CH:15]([C:17]([OH:19])=[O:18])[CH2:14][CH2:13][N:12]2[C:21]([O:23][CH3:24])=[O:22])[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)C1CCN(C(=O)OC)C(c2cccc(C(C)(C)C)c2)C1
Agent: [Br-]
Agent: [Li+]
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: O
Product: COC(=O)N1CCC(C(=O)O)CC1c1cccc(C(C)(C)C)c1
Yield: 89.9 %

Procedure:
Dimethyl 2-(3-tert-butylphenyl)piperidine-1,4-dicarboxylate (3.17 g, 9.51 mmol) was dissolved in acetonitrile (60 mL) and water (1.200 mL), then lithium bromide (6.61 g, 76.06 mmol) was added in one portion. Triethylamine (5.27 mL, 38.03 mmol) was added and the resulting brown suspension was heated under reflux for 1.5 h. Water (120 mL) and MTBE (120 mL) were added. The organic phase was extracted with water (2×25 mL). The pooled aqueous layer was acidified to pH 1 with 0.5 M HCl (30 mL) and extracted with MTBE (2×150 mL). The combined organic layer was washed with water (25 mL), dried over Na2SO4 and evaporated. 2-(3-tert-Butylphenyl)-1-(methoxycarbonyl)piperidine-4-carboxylic acid (2.73 g, 90%) was isolated as a foam.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]1[CH2:10][CH2:9][C:8]2[C:11](=[O:20])[C:12]([O:18][CH3:19])=[C:13]([O:16][CH3:17])[C:14](=[O:15])[C:7]=2[CH2:6][CH2:5]1.[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26](O)=[CH:25][CH:24]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[CH3:17][O:16][C:13]1[C:14](=[O:15])[C:7]2[CH2:6][CH2:5][CH:4]([CH2:3][CH2:2][O:1][C:26]3[CH:27]=[CH:28][C:23]([O:22][CH3:21])=[CH:24][CH:25]=3)[CH2:10][CH2:9][C:8]=2[C:11](=[O:20])[C:12]=1[O:18][CH3:19]
Reactant: COC1=C(OC)C(=O)C2=C(CCC(CCO)CC2)C1=O
Reactant: COc1ccc(O)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC1=C(OC)C(=O)C2=C(CCC(CCOc3ccc(OC)cc3)CC2)C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.1 %

Procedure:
To a solution of 7-(2-hydroxyethyl)-2,3-dimethoxy-4,5,6,7,8,9-hexahydro-1H-benzo[a]cycloheptene-1,4-dione (56 mg), p-methoxyphenol (78 mg), and triphenylphosphine (69 mg) in THF (1 ml) was added a solution of diethyl azodicarboxylate (45, mg) in THF (1 ml) at room temperature. The reaction mixture was stirred at room temperature for 2 hr and then concentrated in vacuo. The residue was purified by alumina column chromatography (ethyl acetate:hexane=1:4) and then recrystallized from ethyl acetate-hexane to obtain the entitled compound (68 mg).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([C:11]([F:14])([F:13])[F:12])[CH:5]=1.Cl[CH2:16][O:17][CH2:18][CH2:19][O:20][CH3:21]>C1COCC1>[Br:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:16][O:17][CH2:18][CH2:19][O:20][CH3:21])=[C:6]([C:11]([F:12])([F:13])[F:14])[CH:5]=1
Reactant: Oc1ccc(Br)cc1C(F)(F)F
Reactant: COCCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCCOCOc1ccc(Br)cc1C(F)(F)F
Reaction time: 0.5 h

Procedure:
Sodium hydride (60% w/w dispersion in mineral oil, 0.96 g) was added to a solution of 4-bromo-2-trifluoromethyl-phenol (5.0 g) in dry THF (200 ml) and the mixture was stirred for 30 minutes. 1-Chloromethoxy-2-methoxy-ethane (2.85 ml) was then added and the mixture was stirred for 1 hour at room temperature. The solvent was removed under reduced pressure. The residue was taken into water and tert-butyl methyl ether, the organic layer was washed with brine, dried over sodium sulphate and concentrated under reduced pressure to afford 4-bromo-1-(2-methoxy-ethoxymethoxy)-2-trifluoromethyl-benzene (6.4 g) as an oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]=[O:9])=[CH:4][N:3]=1.[CH3:10][O:11][C:12]1[N:17]=[CH:16][C:15]([CH:18]=O)=[CH:14][CH:13]=1.FC(F)(F)C(O)=O.C([SiH](CC)CC)C>C(#N)C>[CH3:10][O:11][C:12]1[N:17]=[CH:16][C:15]([CH2:18][NH:1][C:2]2[N:7]=[CH:6][C:5]([CH:8]=[O:9])=[CH:4][N:3]=2)=[CH:14][CH:13]=1
Reactant: Nc1ncc(C=O)cn1
Reactant: COc1ccc(C=O)cn1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: COc1ccc(CNc2ncc(C=O)cn2)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a round bottom flask, 2-amino-pyrimidine-5-carbaldehyde (70, 0.750 g, 6.09 mmol), 6-methoxy-pyridine-3-carbaldehyde (64, 1.67 g, 12.2 mmol), trifluoroacetic acid (2.5 mL, 32.0 mmol), and triethylsilane (5.00 mL, 31.3 mmol) were combined with 10 mL of acetonitrile. The reaction was stirred at room temperature overnight, then concentrated under vacuum and combined with aqueous potassium carbonate and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material was purified by silica gel flash column chromatography, eluting with 15-100% ethyl acetate in hexane. Appropriate fractions were combined and concentrated under vacuum to provide the desired compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][NH2:11])[CH:6]=[CH:7][CH:8]=1.CCN(CC)CC.Cl[C:20]([O:22][CH2:23][CH3:24])=[O:21].O>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][CH:8]=1)[CH2:9][CH2:10][NH:11][C:20](=[O:21])[O:22][CH2:23][CH3:24]
Reactant: COc1cccc(CCN)c1
Reactant: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)NCCc1cccc(OC)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.1 %

Procedure:
To an ice-cold solution of 2-(3-methoxyphenyl)-1-ethanamine (5.00 g, 33.1 mmol) and Et3N (5.10 mL, 3.70 g, 36.6 mmol) in CH2Cl2 (100 mL) was added ethyl chloroformate (3.50 mL, 3.62 g, 33.4 mmol). The resulting solution was allowed to warm to RT and was stirred for 2 h. Water (100 mL) was added and the mixture was extracted with CH2Cl2 (3×50 mL), dried (MgSO4) and concentrated to yield ethyl 3-methoxyphenethylcarbamate (7.32 g, 99% yield) as a pale yellow oil. 1H NMR (400 MHz, CDCl3): δ 7.22 (t, J=7.8 Hz, 1H), 6.78 (d, J=8.0 Hz, 1H), 6.77 (d, J=8.0 Hz; 1H), 6.74 (s, 1H), 4.65 (brs, 1H), 4.11 (q, J=7.2 Hz, 2H), 3.80 (s, 3H), 3.44 (q, J=6.4 Hz, 2H), 2.79 (t, J=7.0 Hz, 2H), 1.23 (t, J=7.0 Hz, 3H); MS (ESI) m/z: 224.2 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][N:11]2[C:15]3[CH:16]=[C:17]([F:21])[C:18]([F:20])=[CH:19][C:14]=3[N:13]=[C:12]2[C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=2[OH:29])[CH:5]=1.Br[CH2:32][CH:33]1[CH2:37][CH2:36][CH2:35][CH2:34]1>>[CH3:1][O:2][C:3](=[O:30])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][N:11]2[C:15]3[CH:16]=[C:17]([F:21])[C:18]([F:20])=[CH:19][C:14]=3[N:13]=[C:12]2[C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=2[O:29][CH2:32][CH:33]2[CH2:37][CH2:36][CH2:35][CH2:34]2)[CH:5]=1
Reactant: COC(=O)c1cccc(Cn2c(-c3ccc(Cl)cc3O)nc3cc(F)c(F)cc32)c1
Reactant: BrCC1CCCC1
Product: COC(=O)c1cccc(Cn2c(-c3ccc(Cl)cc3OCC3CCCC3)nc3cc(F)c(F)cc32)c1

Procedure:
The title compound was prepared in analogy to Example 5, intermediate a, from 3-[2-(4-chloro-2-hydroxy-phenyl)-5,6-difluoro-benzoimidazol-1-ylmethyl]-benzoic acid methyl ester and bromomethyl-cyclopentane (CAS Reg. No. 3814-30-0). Brown sticky solid (72%). MS (Turbo Spray): m/z=511.2 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:14])=[CH:4][C:5]2[C:9]([CH3:10])=[C:8]([CH3:11])[S:7][C:6]=2[C:12]=1[Cl:13].Br[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>CC(=O)CC>[CH2:20]([O:19][C:17](=[O:18])[CH2:16][O:14][C:3]1[C:2]([Cl:1])=[C:12]([Cl:13])[C:6]2[S:7][C:8]([CH3:11])=[C:9]([CH3:10])[C:5]=2[CH:4]=1)[CH3:21]
Reactant: CCOC(=O)CBr
Reactant: Cc1sc2c(Cl)c(Cl)c(O)cc2c1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCC(C)=O
Product: CCOC(=O)COc1cc2c(C)c(C)sc2c(Cl)c1Cl
Reaction time: 2 h
Yield: 85.4 %

Procedure:
To a mixture of 22.4 g of 6,7-dichloro-5-hydroxy-2,3-dimethylbenzo[b]thiophene is added a mixture of 18.23 g of ethyl bromoacetate in 100 ml of 2-butanone, followed by 15 g of potassium carbonate and 7.5 ml of sieve-dried dimethylformamide. The reaction mixture is stirred at 95°-100° for 21/2 hrs, allowed to cool and filtered. To the filtrate is added 100 ml of water and the mixture is extracted with ethyl ether. The organic layers are separated, washed, dried over anhydrous magnesium sulfate, filtered and the solvent is removed to give a solid. The solid is recrystallized from acetone-hexane to give 25.8 g of ethyl[(6,7-dichloro-2,3-dimethylbenzo[b]thien-5-yl)oxy]acetate, mp 102°-104°.
Reaction SMILES: C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.C(NC(C)C)(C)C.[C:21]([O:25][C:26](=[O:56])[NH:27][C:28]1([C:32]2[CH:37]=[CH:36][C:35]([C:38]3[C:47](=[O:48])[C:46]4[C:41](=[C:42](Br)[CH:43]=[CH:44][CH:45]=4)[O:40][C:39]=3[C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)=[CH:34][CH:33]=2)[CH2:31][CH2:30][CH2:29]1)([CH3:24])([CH3:23])[CH3:22].[CH3:57][Si:58]([C:61]#[CH:62])([CH3:60])[CH3:59]>C1(C)C=CC=CC=1.[Cu]I.C1C=CC(C#N)=CC=1.C1C=CC(C#N)=CC=1.Cl[Pd]Cl>[C:21]([O:25][C:26](=[O:56])[NH:27][C:28]1([C:32]2[CH:37]=[CH:36][C:35]([C:38]3[C:47](=[O:48])[C:46]4[C:41](=[C:42]([C:62]#[C:61][Si:58]([CH3:60])([CH3:59])[CH3:57])[CH:43]=[CH:44][CH:45]=4)[O:40][C:39]=3[C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)=[CH:34][CH:33]=2)[CH2:31][CH2:30][CH2:29]1)([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4c(Br)cccc4c3=O)cc2)CCC1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Solvent: CC(C)NC(C)C
Solvent: N#Cc1ccccc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4c(C#C[Si](C)(C)C)cccc4c3=O)cc2)CCC1
Yield: 99.4 %

Procedure:
Copper(I) iodide (1 mg, 0.005 mmol) and bis(benzonitrile)dichloro palladium(II) (2 mg, 0.005 mmol) were dissolved in toluene (1 mL) with stirring. Tri-tert-butylphosphine (2 mg, 0.01 mmol), diisopropylamine (0.017 ml, 0.118 mmol), {1-[4-(8-bromo-4-oxo-2-phenyl-4H-chromen-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester (50 mg, 0.091 mmol) and (trimethylsilyl)acetylene (0.015 mL, 0.109 mmol) were added, the vial was sealed, and reaction mixture was stirred at RT under an atmosphere of argon for 3 h. The mixture was concentrated in vacuo and the resultant residue subjected to flash chromatography (SiO2, gradient 0 to 10% ethyl acetate in DCM) to afford the title compound as a white solid (51 mg, 100%). LCMS (Method G): RT=5.30 min, [M+H]+=564.
Reaction SMILES: O1CCCC1.[CH2:6]([SH:8])[CH3:7].C(=O)([O-])[O-].[K+].[K+].Br[CH2:16][C:17]1[C:18]([Cl:31])=[C:19]([CH:24]=[CH:25][C:26]=1[S:27]([CH3:30])(=[O:29])=[O:28])[C:20]([O:22][CH3:23])=[O:21]>C(Cl)(Cl)Cl>[Cl:31][C:18]1[C:17]([CH2:16][S:8][CH2:6][CH3:7])=[C:26]([S:27]([CH3:30])(=[O:29])=[O:28])[CH:25]=[CH:24][C:19]=1[C:20]([O:22][CH3:23])=[O:21]
Reactant: CCS
Reactant: COC(=O)c1ccc(S(C)(=O)=O)c(CBr)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: CCSCc1c(S(C)(=O)=O)ccc(C(=O)OC)c1Cl
Temperature: 25 °C
Reaction time: 24 h
Yield: 98.6 %

Procedure:
To 100 ml of tetrahydrofuran, 1.3 g of ethanethiol and 1.5 g of potassium carbonate and then 4.4 g of methyl 3-bromomethyl-2-chloro-4-methanesulfonylbenzoate were added, and the mixture was stirred for 1 day at room temperature. Then, the mixture was stirred further for 1 hour at a temperature of from 50° to 60° C. After cooling, chloroform was added thereto, and the mixture was washed with a dilute potassium carbonate aqueous solution. The chloroform layer was separated and dried. Then, the solvent was distilled off to obtain 4.1 g of methyl 2-chloro-3-ethylthiomethyl-4-methanesulfonylbenzoate as an oily substance.
Reaction SMILES: [C:1]([N:4]1[CH:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:8]([CH2:16][OH:17])[C:7](=[O:18])[CH2:6][O:5]1)(=[O:3])[CH3:2].[O:19]1CC[CH2:21][CH2:20]1.C(Cl)(=O)C>C(N(CC)CC)C>[C:1]([N:4]1[CH:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:8]([CH2:16][O:17][C:20](=[O:19])[CH3:21])[C:7](=[O:18])[CH2:6][O:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1OCC(=O)N(CO)C1c1ccccc1
Reactant: C1CCOC1
Solvent: CC(=O)Cl
Solvent: CCN(CC)CC
Product: CC(=O)OCN1C(=O)CON(C(C)=O)C1c1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 77 %

Procedure:
To a solution of 1.0 g. (4 mmoles) of 2-acetyl-3-phenyl-4-hydroxymethyl-tetrahydro-1,2,4-oxadiazin-5-one in 10 ml. of dry tetrahydrofurane 0.72 ml. of dry triethyl amine are added. The solution is cooled to 0° C. and 0.36 ml. (0.40 g., 5 mmoles) of acetyl chloride are added dropwise at this temperature. The mixture is stirred at room temperature for two hours, the precipitated triethyl amine hydrochloride is filtered off and the filtrate is evaporated to dryness. The residue is dissolved in 10 ml. of ethyl acetate, the solution is shaken with 3 ml. of a 1 N aqueous sodium hydrocarbonate solution, 3 ml. of a 1 N aqueous hydrochloric acid solution and finally with two 3-ml. portions of water, whereupon it is dried with anhydrous sodium sulfate and evaporated to dryness. The residue is recrystallized from a mixture of 3 ml. of diethyl ether and 6 ml. of n-hexane. 0.90 g. (77%) of 2-acetyl- 3-phenyl-4-acetoxymethyl-tetrahydro-1,2,4-oxadiazin-5-one are obtained, melting at 75° C. to 76° C. RfA =0.7.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]2[NH:10][C:11]3[C:16]([CH:17]=2)=[CH:15][C:14]([C:18]([NH:20][CH2:21][CH2:22][CH2:23][N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[O:19])=[CH:13][CH:12]=3)=[CH:7][CH:6]=[CH:5][N:4]=1.[Br:30]N1C(=O)CCC1=O>C1COCC1>[Br:30][C:17]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:18]([NH:20][CH2:21][CH2:22][CH2:23][N:24]3[CH2:25][CH2:26][O:27][CH2:28][CH2:29]3)=[O:19])[CH:15]=2)[NH:10][C:9]=1[C:8]1[C:3]([O:2][CH3:1])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ncccc1-c1cc2cc(C(=O)NCCCN3CCOCC3)ccc2[nH]1
Reactant: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Product: COc1ncccc1-c1[nH]c2ccc(C(=O)NCCCN3CCOCC3)cc2c1Br
Temperature: 60 °C
Reaction time: 1.5 h

Procedure:
A suspension of 2-(2-methoxypyridin-3-yl)-N-(3-morpholinopropyl)-1H-indole-5-carboxamide (0.850 g, 0.215 mmol) in 100 ml THF was heated to 60° C. until dissolved. To the solution was added N-bromosuccinimide (0.406 g, 0.263 mmol) and the reaction was allowed to stir for 1.5 hours. The reaction was not complete, so more N-bromosuccinimide (0.062 g, 0.35 mmol; 0.040 g, 0.022 mmol) was added sequentially and the reaction stirred for 10 more minutes after each addition. Upon completion, the reaction was concentrated and to the residue was added 50 ml EtOAC and 100 ml water. The organics were separated, washed with water (50 ml) and brine (25 ml) and concentrated. The crude product was used with no further purification. LCMS: 473 [M+H].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:17]([OH:19])=O)[C:5]2[O:9][C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[N:7][C:6]=2[CH:16]=1.Cl.Cl.[NH2:22][CH:23]1[CH:28]2[CH2:29][CH2:30][N:25]([CH2:26][CH2:27]2)[CH2:24]1>>[N:25]12[CH2:30][CH2:29][CH:28]([CH2:27][CH2:26]1)[CH:23]([NH:22][C:17]([C:4]1[C:5]3[O:9][C:8]([C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=4)=[N:7][C:6]=3[CH:16]=[C:2]([Cl:1])[CH:3]=1)=[O:19])[CH2:24]2
Reactant: O=C(O)c1cc(Cl)cc2nc(-c3ccccc3)oc12
Reactant: NC1CN2CCC1CC2
Agent: Cl
Product: O=C(NC1CN2CCC1CC2)c1cc(Cl)cc2nc(-c3ccccc3)oc12
Yield: 56 %

Procedure:
N-(1-Azabicyclo[2.2.2]oct-3-yl)-5-chloro-2-phenylbenzoxazole-7-carboxamide was prepared from 5-chloro-2-phenyl-benzoxazole-7-carboxylic acid and 3-aminoquinuclidine dihydrochloride using the method outlined in Step C of Example 7. This compound was obtained in 56% yield as a white solid: mp 283-285° C.; 1H NMR (300 MHz, CH3OD) δ 8.22 (dd, J=8.1, 1.5 Hz, 2H), 7.86 (d, J=2.1 Hz, 1H), 7.70 (d, J=2.1 Hz, 1H), 7.64-7.56 (m, 3H), 4.27-4.24 (m, 1H), 3.50-3.42 (m, 1H), 3.12-2.86 (m, 5H), 2.17 (q, J=3.0 Hz, 1H), 2.11-2.06 (m, 1H), 1.85-1.73 (m, 2H), 1.74-1.67 (m, 1H); MS (ESI) m/z 382[M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:10]=2[C:11]([OH:13])=[O:12])=[C:4]([F:19])[CH:3]=1.[CH3:20][Si](C=[N+]=[N-])(C)C>CO.C1C=CC=CC=1>[CH3:20][O:12][C:11](=[O:13])[C:10]1[CH:14]=[CH:15][C:16]([Cl:18])=[N:17][C:9]=1[NH:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=1[F:19]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: O=C(O)c1ccc(Cl)nc1Nc1ccc(Br)cc1F
Solvent: CO
Solvent: c1ccccc1
Product: COC(=O)c1ccc(Cl)nc1Nc1ccc(Br)cc1F
Reaction time: 1 h
Yield: 93 %

Procedure:
To a suspension of 2-(4-bromo-2-fluorophenylamino)-6-chloro-nicotinic acid (5.00 g, 14.5 mmol) in methanol/benzene (1:1, 100 mL) under N2 was added (trimethylsilyl)diazomethane (2.0 M solution in hexanes) dropwise until the bubbling caused by gas evolution ceased. Solids precipitated out of solution. The reaction was allowed to stir for 1 hour. Excess (trimethylsilyl)diazomethane was quenched by the dropwise addition of glacial acetic acid. The precipitated solids were filtered and washed with methanol. The filtrate was concentrated to a smaller volume and additional solids precipitated out of solution that were filtered and washed with methanol. The solids were combined and dried under vacuum to yield 4.82 g (93%) of pure desired product as a dark pink solid.
Reaction SMILES: [CH3:1][C:2]([O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:6])[C:3]([OH:5])=O.[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]2[C:27](=[O:28])[CH2:26][C:25](=[O:29])[NH:24][C:23]3[C:30]4[C:35]([CH:36]=[CH:37][C:22]2=3)=[CH:34][CH:33]=[CH:32][CH:31]=4)=[CH:17][CH:16]=1.CC(OC1C=CC=CC=1)(C)C(Cl)=O>>[CH3:6][C:2]([O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:1])[C:3]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]2[C:27](=[O:28])[CH2:26][C:25](=[O:29])[NH:24][C:23]3[C:30]4[C:35]([CH:36]=[CH:37][C:22]2=3)=[CH:34][CH:33]=[CH:32][CH:31]=4)=[CH:17][CH:16]=1)=[O:5]
Reactant: Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Reactant: CC(C)(Oc1ccccc1)C(=O)O
Agent: CC(C)(Oc1ccccc1)C(=O)Cl
Product: CC(C)(Oc1ccccc1)C(=O)Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Yield: 101 %

Procedure:
2-Methyl-2-phenoxypropionic acid (34 mg, 0.189 mmol) was made into acid chloride in a conventional manner. By using 5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (30 mg, 0.095 mmol) obtained in Example 1, (3), and 2-methyl-2-phenoxypropionic acid chloride mentioned above, the title compound (46 mg, yield 100%) was obtained in the same manner as that of Example 1.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][O:18][C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:29][S:30]([C:33]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:36]=[CH:35][CH:34]=1)(=[O:32])=[O:31].CC(C)([O-])C.[K+].Cl>C1COCC1>[CH2:1]([O:8][C:9]([N:11]1[CH2:12][CH2:13][CH:14]([CH2:17][O:18][C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[C:21]([CH2:29][S:30]([C:33]3[C:42]4[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=4)[CH:36]=[CH:35][CH:34]=3)(=[O:31])=[O:32])[CH:20]=2)[CH2:15][CH2:16]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(=O)(CCl)c1cccc2ccccc12
Reactant: O=C(OCc1ccccc1)N1CCC(COc2ccc([N+](=O)[O-])cc2)CC1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)N1CCC(COc2ccc([N+](=O)[O-])c(CS(=O)(=O)c3cccc4ccccc34)c2)CC1
Temperature: -40 °C
Reaction time: 5 h
Yield: 74.1 %

Procedure:
A mixture of 4-(4-nitrophenoxymethyl)piperidine-1-carboxylic acid benzyl ester (0.8 g, 2.16 mmoles) and 1-chloromethanesulfonylnaphthalene (1.03 g, 4.3 mmoles) in THF (50 ml) at −78° C., under nitrogen, was treated dropwise with a solution of 1M potassium t-butoxide (6.5 ml, 6.5 mmoles) over a 30 minute period, allowed to warm to −40° C., stirred at −40° C. for 5 hours, poured into cold 2N HCl and extracted with EtOAc. The extracts were combined, dried over Na2SO4, and concentrated under vacuum. The resultant was purified by normal phase HPLC on a silica column, using as eluent 40% EtOAc/hexane, to afford the title compound as an off-white solid (0.9 g, 1.6 mmoles).
Reaction SMILES: [CH3:1][N:2]([CH3:22])[S:3]([N:6]1[C:10]2[CH:11]=[C:12]([Cl:20])[C:13]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:14][C:9]=2[N:8]=[C:7]1Cl)(=[O:5])=[O:4].[CH2:23]([O:25][C:26]([C:28]1[CH:29]=[N:30][NH:31][CH:32]=1)=[O:27])[CH3:24].C([O-])([O-])=O.[K+].[K+]>>[CH2:23]([O:25][C:26]([C:28]1[CH:29]=[N:30][N:31]([C:7]2[N:6]([S:3](=[O:5])(=[O:4])[N:2]([CH3:22])[CH3:1])[C:10]3[CH:11]=[C:12]([Cl:20])[C:13]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:14][C:9]=3[N:8]=2)[CH:32]=1)=[O:27])[CH3:24]
Reactant: CCOC(=O)c1cn[nH]c1
Reactant: CN(C)S(=O)(=O)n1c(Cl)nc2cc(OC(F)(F)F)c(Cl)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)c1cnn(-c2nc3cc(OC(F)(F)F)c(Cl)cc3n2S(=O)(=O)N(C)C)c1
Temperature: 70 °C
Reaction time: 10 h

Procedure:
2,6-Dichloro-5-trifluoromethoxy-1H-benzoimidazole (160 g, 0.59 mol, 1.0 equiv.) was dissolved in dry DMF (1.5 L) and then K2CO3 (98 g, 0.71 mol, 1.2 equiv.) and dimethylsulfamoyl chloride (85 g, 0.59 mol, 1.0 equiv.) were added sequentially. The reaction mixture was stirred at room temperature for 16 hours to afford 2,6-dichloro-5-trifluoromethoxy-benzoimidazole-1-sulfonic acid dimethylamide. Without isolation of 2,6-dichloro-5-trifluoromethoxy-benzoimidazole-1-sulfonic acid dimethylamide, 1H-pyrazole-4-carboxylic acid ethyl ester (91 g, 0.65 mol, 1.1 equiv.) and K2CO3 (98 g, 0.71 mol, 1.2 equiv.) were added to the reaction mixture. The reaction mixture was stirred at 70° C. for 10 hours and cooled to room temperature, to afford 1-(6-chloro-1-dimethylsulfamoyl-5-trifluoromethoxy-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid ethyl ester. To crude reaction mixture was added LiOH H2O (124 g, 2.95 mol, 5.0 equiv.) in 2.5 L water. The reaction solution was heated at 70° C. for 6 hours and then cooled to room temperature. Concentrated HCl was added to adjust pH=4.0. The precipitated solid was collected by filtration, washed with water and dried. The solid was recrystallized from hot EtOAc (˜3 L). After cooling to room temperature and filtration, the pure compound was obtained as a white solid (109 g, 0.31 mol, 54% over 3 steps). MS (ESI/CI): mass calcd. for C12H6ClF3N4O2, 346.0; m/z found, 347.0 [M+H]+. 1H NMR (500 MHz, DMSO-d6): 13.79 (s, 1H), 13.06 (s, 1H), 8.91 (s, 1H), 8.33 (s, 1H), 7.79 (br d, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([O:7][C:8]2[C:13]([CH3:14])=[CH:12][C:11]([N+:15]([O-:17])=[O:16])=[CH:10][C:9]=2[CH3:18])=[CH:5][CH:4]=1.C1N2CN3CN(C2)CN1C3.FC(F)(F)[C:33](O)=[O:34]>>[CH3:18][C:9]1[CH:10]=[C:11]([N+:15]([O-:17])=[O:16])[CH:12]=[C:13]([CH3:14])[C:8]=1[O:7][C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[C:20]([CH:19]=1)[CH:33]=[O:34]
Reactant: O=C(O)C(F)(F)F
Reactant: COc1ccc(Oc2c(C)cc([N+](=O)[O-])cc2C)cc1
Agent: C1N2CN3CN1CN(C2)C3
Product: COc1ccc(Oc2c(C)cc([N+](=O)[O-])cc2C)cc1C=O
Temperature: 75 °C
Reaction time: 6 h

Procedure:
To a solution of 4-(4-methoxy-phenoxy)-3,5-dimethyl-nitrobenzene (7.0 g, 25.6 mmol) in trifluoroacetic acid (60 mL) at room temperature was added hexamethylenetetramine (5.75 g, 41.0 mmol). The resulting mixture was stirred at 75° C. for 6 hours and then concentrated. To the residue was added water (150 mL), stirred at room temperature for 19 hours, extracted with 10% methanol in methylene chloride (4 times 50 mL) and ethyl acetate (75 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated. The product (6.56 g) was crystalized from dissolving in a minimum amount of Et2O. 1H NMR (400 MHz, CDCl3) δ10.40 (s, 1H), 8.00 (s, 2H), 7.07-7.04 (s+d, 2H), 6.95 (d, 1H), 3.90 (s, 3H), 2.18 (s, 6H). MS (APCI−) Calc: 301.0, Found: 300.0 (M−1).
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([C:6]([C:8]2[CH:9]=[C:10]([C:17]([OH:19])=[O:18])[C:11](=[CH:15][CH:16]=2)[C:12](O)=[O:13])=[O:7])=[CH:4][CH:3]=1.C(OC(=O)C)(=O)C>C(O)(=O)C>[Cl:1][C:2]1[CH:21]=[CH:20][C:5]([C:6]([C:8]2[CH:9]=[C:10]3[C:17](=[O:19])[O:18][C:12](=[O:13])[C:11]3=[CH:15][CH:16]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(C(=O)O)c(C(=O)O)c1
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: O=C(c1ccc(Cl)cc1)c1ccc2c(c1)C(=O)OC2=O
Yield: 96.7 %

Procedure:
To 10 ml of acetic acid were added 1.00 g of 4-(4-chlorobenzoyl)phthalic acid and 1.34 g of acetic anhydride, and the resultant mixture was refluxed under heating for 3.5 hours. After finishing the reaction, the acetic acid was evaporated in vacuo and the resultant residue was mixed with hexane. The precipitated solid was filtered, washed with hexane and dried to give 0.91 g of the titled compound.