Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:26]=[CH:25][C:7]([C:8]([C:10]2[CH:15]=[C:14]3[O:16][CH2:17][O:18][C:13]3=[CH:12][C:11]=2[CH:19]([CH3:24])[C:20](OC)=[O:21])=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].O.[NH2:28][NH2:29]>COCCO>[CH2:17]1[O:16][C:14]2=[CH:15][C:10]3[C:8]([C:7]4[CH:25]=[CH:26][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=4)=[N:29][NH:28][C:20](=[O:21])[CH:19]([CH3:24])[C:11]=3[CH:12]=[C:13]2[O:18]1
Reactant: COC(=O)C(C)c1cc2c(cc1C(=O)c1ccc([N+](=O)[O-])cc1)OCO2
Reactant: NN
Solvent: O
Solvent: COCCO
Product: CC1C(=O)NN=C(c2ccc([N+](=O)[O-])cc2)c2cc3c(cc21)OCO3

Procedure:
A mixture of methyl 2-(2-(4-nitrobenzoyl)-4,5-methylenedioxyphenyl)propionate (211 mg, 0.59 mmol), hydrazine hydrate (0.15 mL, 2.4 mmol), and 2-methoxyethanol (6 mL) was heated to reflux for 72 h. The solvent was removed in vacuo and the crude product was purified by chromatography to yield 7,8-methylenedioxy-5-methyl-1-(4-nitrophenyl)-3,5-dihydro-2,3-benzodiazepin-4(4H)-one which was treated with excess amount of hydrazine and Raney Ni for 1 h. The reaction was then allowed to settled and liquid phase was decanted. The solvent was then removed and residue obtained was purified by chromatography (10% acetone in CH2Cl2) to yield the product (5 mg). 1H NMR (CDCl3) 8.44 (s, 1H), 7.43 (d, J=8.7, 2H), 6.86 (s, 1H), 6.68 (d, J=8.7, 2H), 6.65 (s, 1H), 6.04 (s, 1H), 6.00 (s, 1H), 4.83 (b, 2H), 3.29 (q, J=6.8, 1H), 1.59 (d, J=6.8, 3H).
Reaction SMILES: Cl.[C:2]([NH:5][CH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)(=[O:4])[CH3:3].Cl.Cl[C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1.C(=O)([O-])O.[Na+]>CC(C)CCO>[C:2]([NH:5][CH:6]1[CH2:11][CH2:10][N:9]([C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)[CH2:8][CH2:7]1)(=[O:4])[CH3:3]
Reactant: CC(=O)NC1CCNCC1
Reactant: Clc1ccncc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)CCO
Product: CC(=O)NC1CCN(c2ccncc2)CC1

Procedure:
A mixture of the product from step (ii) (1.79 g), 4-chloropyridine hydrochloride (1.50 g), sodium hydrogen carbonate (2.86 g) in 3-methyl 1-butanol (25 ml) was heated at reflux temperature for 16 hours. The cooled mixture was filtered and the filtrate concentrated in vacuo. Purification of the residue by flash chromatography on silica, eluting with methanol/dichloromethane (1:2 v/v) gave 4-acetylamino-1-(4-pyridyl)piperidine as a foam, 0.69 g: NMR(d6DMSO) δ 8.10(2H,d), 7.80(1H,bd), 6.80(2H,dd), 3.82(3H,m), 2.93(2H,dt), 1.78(3H,s), 1.77(2H,m), 1.33(2H,dq); m/e 220 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]2[S:9][CH:10]=[CH:11][N:12]=2)[N:5]=[C:4]([OH:13])[CH:3]=1.[C:14]([O-])([O-])=O.[K+].[K+].IC>CN(C=O)C.O>[F:1][C:2]1[CH:3]=[C:4]([O:13][CH3:14])[N:5]=[C:6]([C:8]2[S:9][CH:10]=[CH:11][N:12]=2)[CH:7]=1
Reactant: Oc1cc(F)cc(-c2nccs2)n1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: COc1cc(F)cc(-c2nccs2)n1
Reaction time: 2 h
Yield: 81.9 %

Procedure:
To a 2 dram vial equipped with a stir bar was added 4-fluoro-6-(thiazol-2-yl)pyridin-2-ol (35 mg, 0.18 mmol) as a solution in DMF (1 mL). To the vial was added K2CO3 (49 mg, 0.36 mmol), then iodomethane (25 μL, 0.40 mmol). The vial was capped with a PTFE-lined cap and then placed in a 40° C. heating block with stirring for 2 h. The reaction mixture was transfered to a 125 mL separatory funnel and was diluted with water (25 mL). The mixture was extracted with CH2Cl2 (2×25 mL). The combined organics were dried over MgSO4; filtered; the concentrated in vacuo. The resulting residue was subjected to SiO2 column chromatography (hexanes:EtOAc, 100:0 to 50:50) to afford 2-(4-fluoro-6-methoxypyridin-2-yl)thiazole as a white solid (31 mg, 82%). 1H-NMR (500 MHz, CDCl3) δ 7.92 (d, J=3.2 Hz, 1H), 7.66 (dd, J=1.9, 1.1 Hz, 1H), 7.48 (d, J=3.3 Hz, 1H), 6.44 (d, J=2.0 Hz, 1H), 3.97 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([C:11]2[CH:12]=[N:13][C:14]([N:17]3[CH2:22][CH2:21][C:20]([CH2:28][CH3:29])([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:19][CH2:18]3)=[N:15][CH:16]=2)=[CH:4][C:3]=1Br.C([Sn](CCCC)(CCCC)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=1)CCC>CN(C=O)C.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>[NH2:1][C:2]1[C:3]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=2)=[CH:4][C:5]([C:11]2[CH:16]=[N:15][C:14]([N:17]3[CH2:18][CH2:19][C:20]([CH2:28][CH3:29])([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:21][CH2:22]3)=[N:13][CH:12]=2)=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: CCOC(=O)C1(CC)CCN(c2ncc(-c3cc(Br)c(N)c([N+](=O)[O-])c3)cn2)CC1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CCOC(=O)C1(CC)CCN(c2ncc(-c3cc(-c4ccccn4)c(N)c([N+](=O)[O-])c3)cn2)CC1
Temperature: 120 °C
Yield: 47.6 %

Procedure:
To a solution of ethyl 1-(5-(4-amino-3-bromo-5-nitrophenyl)pyrimidin-2-yl)-4-ethylpiperidine-4-carboxylate (1.5 g, 3.14 mmol) in DMF (10.0 mL) was added 2-(tributylstannyl)pyridine (1.73 g, 4.72 mmol) and the mixture degassed by purging N2 for 15 min followed by addition of tetrakis(triphenylphosphine)palladium(0) (0.36 g, 0.314 mmol). The reaction mixture was again degassed for 10 min then heated up to 120° C. for 5 h. After completion of reaction, 100 mL ice-cold water was added, extracted with EtOAc (4×100 mL) and the combined organic layer washed with ice-cold water, brine solution respectively, dried over Na2SO4, filtered and evaporated under reduced pressure. The crude residue was purified over neutral alumina using 15% EtOAc:Hexane to obtain the desired product (0.712 g, 47%). 1H NMR (CDCl3): δ 8.68-8.69 (m, 1H), 8.63 (s, 2H), 8.38 (s, 1H), 7.89 (s, 1H), 7.84 (s, 1H), 7.69 (d, J=8.4 Hz, 1H), 7.34-7.36 (m, 1H), 4.65-4.67 (m, 2H), 4.20-4.22 (m, 2H), 3.21-3.25 (m, 2H), 2.30-2.34 (m, 2H), 1.58-1.60 (m, 2H), 1.44-1.46 (m, 2H), 1.30 (t, J=7.20 Hz, 3H) and 0.86 (t, J=7.60 Hz, 3H). MS: 477.44 [M+H]+.
Reaction SMILES: [CH:1]([N:4]([CH:9]([CH3:11])[CH3:10])[CH:5]([CH3:8])[C:6]#N)([CH3:3])[CH3:2].[CH2:12]([Mg]Br)C.O>C(OCC)C>[CH:1]([N:4]([CH:5]([CH2:6][CH3:12])[CH3:8])[CH:9]([CH3:11])[CH3:10])([CH3:3])[CH3:2]
Reactant: CC(C)N(C(C)C)C(C)C#N
Reactant: CC[Mg]Br
Solvent: O
Solvent: CCOCC
Product: CCC(C)N(C(C)C)C(C)C

Procedure:
A solution of 2-(diisopropylamino)propionitrile (25.00 g, 0.162 mol) in diethyl ether (20 ml) was added dropwise to a 1M solution of ethyl magnesium bromide in diethyl ether (32.4 ml, 0.324 mol) and the mixture was refluxed for 30 min. Water (25 ml) was added and white precipitate was filtered off and washed with diethyl ether (2×100 ml). The ether solutions were combined, dried over anhydrous magnesium sulfate and the product was isolated by distillation: 13.80 g, 51%, bp 60°-62° C./20 mm Hg. 1H NMR CDCl3 δ ppm, 0.85 (t, J=6.5 Hz, 3H, CH3) , 0.98 (d, J=6.5 Hz, 6H, CH3) 0.99 (d, J=6.5 Hz, 3H, CH3), 1.05 (d, J=6.5 Hz, 6H, CH3) , 1.17-1.44(m, 2H, CH2), 2.70 (m, 1H, CH), 3.08 (sep, J=6.5 Hz, 2H, CH).
Reaction SMILES: [C:1]12([CH:7]3[CH2:8][CH2:9][CH:4]1[CH:5]1[C:13](=[O:14])[O:12][C:10](=[O:11])[CH:6]13)[CH2:3][CH2:2]2.[Cl:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1>C(Cl)(Cl)Cl>[Cl:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:10]([C@@H:6]2[C@H:7]3[C:1]4([CH2:3][CH2:2]4)[C@H:4]([CH2:9][CH2:8]3)[C@@H:5]2[C:13]([OH:12])=[O:14])=[O:11])=[CH:18][CH:17]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: O=C1OC(=O)C2C1C1CCC2C12CC2
Solvent: ClC(Cl)Cl
Product: O=C(O)[C@@H]1[C@H](C(=O)Nc2ccc(Cl)cc2)[C@@H]2CC[C@H]1C21CC1

Procedure:
Following General Procedure A, Compound 2 (0.042 g, 0.22 mmol) and 4-chloroaniline (0.028 g, 0.22 mmol) in chloroform (1.5 mL) were converted into the title compound, which was isolated as a white solid.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:9]1([CH3:14])[O:13][CH2:12][CH2:11][O:10]1)[C:4]([O:6][CH2:7][CH3:8])=[O:5].[N+:15]([C:18]1[CH:19]=[C:20]2[C:25](=O)[O:24][C:22](=[O:23])[C:21]2=[CH:27][CH:28]=1)([O-:17])=[O:16]>C(Cl)(Cl)Cl>[N+:15]([C:18]1[CH:19]=[C:20]2[C:21](=[CH:27][CH:28]=1)[C:22](=[O:23])[N:1]([CH2:2][CH:3]([C:9]1([CH3:14])[O:10][CH2:11][CH2:12][O:13]1)[C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:25]2=[O:24])([O-:17])=[O:16]
Reactant: CCOC(=O)C(CN)C1(C)OCCO1
Reactant: O=C1OC(=O)c2cc([N+](=O)[O-])ccc21
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C(CN1C(=O)c2ccc([N+](=O)[O-])cc2C1=O)C1(C)OCCO1
Temperature: 80 °C
Yield: 83.2 %

Procedure:
Ethyl 3-amino-2-(2-methyl-[1,3]dioxolan-2-yl)propionate (800 mg, 3.94 mmol) was dissolved in 15 mL of chloroform, and 4-nitrophthalic anhydride (988 mg, 4.33 mmol) was added to the obtained solution. The resulting mixture was then refluxed at 80° C. for 5 days. After the reaction was completed, the solvent was evaporated by distilling under a reduced pressure. The residue was purified by performing column chromatography (eluent: n-hexane/ethyl acetate=1/1) to obtain the desired product as a yellow solid (1.24 g, 83%). Rf=0.32 (n-hexane/ethyl acetate=1/1)
Reaction SMILES: [Na].[OH:2][C:3]1[CH:4]=[C:5]([OH:10])[CH:6]=[C:7]([Cl:9])[CH:8]=1.Cl[CH2:12][CH:13]([O:17][CH2:18][CH3:19])[O:14][CH2:15][CH3:16].[Cl-].[NH4+]>O.CN(C)C=O>[CH2:15]([O:14][CH:13]([O:17][CH2:18][CH3:19])[CH2:12][O:2][C:3]1[CH:4]=[C:5]([OH:10])[CH:6]=[C:7]([Cl:9])[CH:8]=1)[CH3:16]
Reactant: CCOC(CCl)OCC
Reactant: Oc1cc(O)cc(Cl)c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(COc1cc(O)cc(Cl)c1)OCC
Temperature: 90 °C

Procedure:
The monosodium salt of 3-hydroxy-5-chlorophenol (0.05 mole) and dimethylformamide (75 ml) are charged under nitrogen gas into a glass reacton vessel equipped with a mechanical stirrer, thermometer and addition funnel. The mixture is stirred until dissolved, and 1-chloro-2,2-diethoxyethane (0.05 mole) is added dropwise over a period of about 20 minutes. After the addition is completed, the reaction mixture is heated at about 90° C. with stirring for a period of about 48 hours. After this time water (200 ml) is added, and the reaction mixture is neutralized with ammonium chloride. The reaction mixture is then extracted with chloroform, and the organic phase is separated from the aqueous phase. The organic phase is then stripped of solvent, leaving an oil. This oil is distilled under reduced pressure to yield the desired product 3-(2,2-diethoxyethoxy)-5-chlorophenol.
Reaction SMILES: [C:1]1([CH:7]=[N:8][N:9]2[CH2:13][CH:12]([CH2:14][CH2:15][CH2:16]O)[O:11][C:10]2=[O:18])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.S(Cl)([Cl:27])=O>>[Cl:27][CH2:16][CH2:15][CH2:14][CH:12]1[O:11][C:10](=[O:18])[N:9]([N:8]=[CH:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:13]1
Reactant: O=S(Cl)Cl
Reactant: O=C1OC(CCCO)CN1N=Cc1ccccc1
Solvent: c1ccncc1
Product: O=C1OC(CCCCl)CN1N=Cc1ccccc1
Temperature: 25 °C
Yield: 95.9 %

Procedure:
A mixture of 3-phenylmethyleneamino-5-(3-hydroxy) propyl-2-oxazolidinone (10.88 g, 0.0438 mole) CHCl3 (200 ml), and pyridine (4.25 ml, 4.16 g, 0.0526 mole, 1.2 eq.) is stirred at ambient temperature. Thionyl chloride (11.2 ml, 18.2 g, 0.1533 mole, 3.5 eq.) is added dropwise over 30-45 minutes while at ambient temperature (slight exotherm observed). After complete addition, the solution is heated to reflux. Reflux is maintained for 2 hours. After cooling, the solution is concentrated under reduced pressure to a solid residue, which is azeotroped with toluene (2×50 ml). The solid is dissolved in CH2Cl2 (250 ml), then washed with H2O (3×100 ml). The CH2Cl2 is dried over MgSO4, filtered, then concentrated under reduced pressure to give 5-(3-chloropropyl)-3-phenylmethyleneamino-2-oxazolidinone (11.2 g, 0.0420 mole) as a solid residue.
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[N+:6]([C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1)([O-:8])=[O:7]>C(Cl)(Cl)Cl>[N+:6]([C:9]1[CH:10]=[CH:11][C:12]([CH3:15])=[C:13]([S:2]([Cl:1])(=[O:5])=[O:3])[CH:14]=1)([O-:8])=[O:7]
Reactant: O=S(=O)(O)Cl
Reactant: Cc1ccc([N+](=O)[O-])cc1
Solvent: ClC(Cl)Cl
Product: Cc1ccc([N+](=O)[O-])cc1S(=O)(=O)Cl
Temperature: 0 °C
Yield: 78.1 %

Procedure:
Chlorosulfonic acid (50 mL, 750 mmol) was added within about 30 min dropwise to a solution of p-nitrotoluene (13.7 g, 100 mmol) in CHCl3 (50 mL) under ice cooling. After addition, the mixture was refluxed for about 6 h, cooled, the mixture poured into ice water (500 mL) and extracted with CHCl3 (3×300 mL). The CHCl3 layer was washed with water (2×200 mL) and dried with Na2SO4. Evaporation of CHCl3 gave 5-nitro-2-methyl-phenylsulfonyl chloride (18.4 g, 78%): 1H NMR (DMSO-d6) δ: 8.92 (d, J=2.4 Hz, 1H), 8.46 (dd, J=2.4 Hz, 1H), 7.66 (s, 1H), 2.92 (s, 3H).
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[C:12]([O:15][C:16]1[CH:17]=[C:18]([CH:35]=[C:36]([O:38][C:39](=[O:41])[CH3:40])[CH:37]=1)[C:19]([N:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH:22]1[CH:27]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[OH:28])=[O:20])(=[O:14])[CH3:13]>ClCCl>[C:27]([CH:22]1[CH2:23][CH2:24][CH2:25][CH2:26][N:21]1[C:19](=[O:20])[C:18]1[CH:17]=[C:16]([O:15][C:12](=[O:14])[CH3:13])[CH:37]=[C:36]([O:38][C:39](=[O:41])[CH3:40])[CH:35]=1)(=[O:28])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CC(=O)Oc1cc(OC(C)=O)cc(C(=O)N2CCCCC2C(O)c2ccccc2)c1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CC(=O)Oc1cc(OC(C)=O)cc(C(=O)N2CCCCC2C(=O)c2ccccc2)c1
Temperature: 23 °C
Reaction time: 4 h

Procedure:
Add pyridinium chlorochromate (2.96 g) and 3Å, 1/16-inch molecular sieves (2.96 g) to a solution of 1-[3,5-bis(acetyloxy)benzoyl]-α-phenyl-2-piperidinemethanol (2.66 g) in dry dichloromethane (60 ml). Stir the resulting mixture at 23° C. for 4 hours. Filter the mixture through diatomaceous earth, and concentrate the filtrate. Chromatograph the residue over silica gel, and elute the column with 10% ethyl acetate in chloroform. Combine appropriate fractions, concentrate them, and crystallize the residue to obtain 2-benzoyl-1-[3,5-bis(acetyloxy)benzoyl]-piperidine, m.p. 77°-79° C. (from ether-pet. eth.).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH2:11])[C:7]([NH2:10])=[CH:8][CH:9]=1)([O-:3])=[O:2].[Br:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]=[C:20]=S)=[CH:15][CH:14]=1.IC>CO>[Br:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:20]2[NH:11][C:6]3[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:9]=[CH:8][C:7]=3[N:10]=2)=[CH:15][CH:14]=1
Reactant: Nc1ccc([N+](=O)[O-])cc1N
Reactant: S=C=Nc1ccc(Br)cc1
Solvent: CO
Solvent: CI
Product: O=[N+]([O-])c1ccc2nc(Nc3ccc(Br)cc3)[nH]c2c1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
A solution of the 4-nitrobenzene-1,2-diamine in methanol was treated with 4-bromo phenyl isothiocyanate (1 eq) and stirred at 60° C. for 2 hours. The reaction mixture was cooled down to room temperature and iodomethane (1 eq) was added and stirred overnight at 60° C. The reaction was concentrated and purified on silica gel to yield (4-bromophenyl)(5-nitrobenzimidazol-2-yl)amine. The product was taken in methanol and hydrogenated with catalytic amount of 10% Pd/C to give ((5-aminobenzimidazol-2-yl)(4-bromophenylamine). MS: MH+=302.
Reaction SMILES: C(NC1C=CC(C2C=C3C(CN([C@@H](C(C)C)C(O)=O)C3=O)=CC=2)=CC=1)(=O)C1C=CC=CC=1.[Cl:33][C:34]1[CH:67]=[CH:66][C:37]([C:38]([NH:40][C:41]2[CH:46]=[CH:45][C:44]([C:47]3[CH:55]=[C:54]4[C:50]([CH2:51][N:52]([C@@H:57]([CH:62]([CH3:64])[CH3:63])[C:58]([O:60]C)=[O:59])[C:53]4=[O:56])=[CH:49][CH:48]=3)=[C:43]([F:65])[CH:42]=2)=[O:39])=[CH:36][CH:35]=1>>[Cl:33][C:34]1[CH:35]=[CH:36][C:37]([C:38]([NH:40][C:41]2[CH:46]=[CH:45][C:44]([C:47]3[CH:55]=[C:54]4[C:50]([CH2:51][N:52]([C@@H:57]([CH:62]([CH3:64])[CH3:63])[C:58]([OH:60])=[O:59])[C:53]4=[O:56])=[CH:49][CH:48]=3)=[C:43]([F:65])[CH:42]=2)=[O:39])=[CH:66][CH:67]=1
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4ccc(Cl)cc4)cc3F)cc2C1=O
Agent: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)c4ccccc4)cc3)cc2C1=O
Product: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)c4ccc(Cl)cc4)cc3F)cc2C1=O
Yield: 87 %

Procedure:
The compound of example 606 was prepared analogous to compound of example 98 by hydrolysis of compound of example 605.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:37])[NH:20][C:21]3[N:26]=[C:25]([C:27]4[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=4)[CH:24]=[CH:23][N:22]=3)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:38]([O:40]CC)=[O:39].[OH-].[Na+].C(O)C>C1COCC1.C(OCC)(=O)C.Cl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:37])[NH:20][C:21]3[N:26]=[C:25]([C:27]4[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=4)[CH:24]=[CH:23][N:22]=3)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:38]([OH:40])=[O:39]
Reactant: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)Nc4nccc(-c5ccc(C(F)(F)F)cc5)n4)cc3)c(Cl)cc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(Nc1nccc(-c2ccc(C(F)(F)F)cc2)n1)c1ccc(Oc2cc3c(cc2Cl)C(C(=O)O)CCO3)cc1
Reaction time: 2 h
Yield: 10.5 %

Procedure:
Ethyl 6-chloro-7-(4-(4-(4-(trifluoromethyl)phenyl)pyrimidin-2-ylcarbamoyl)phenoxy)chroman-4-carboxylate (50 mg, 0.084 mmol) was diluted with THF (1 mL) followed by the addition of NaOH (502 μL, 0.50 mmol) and ethanol (500 μL). After stirring for 2 hours, the reaction was diluted with ethyl acetate and 2N HCl. The layers were separated and the organic layer was dried over MgSO4, filtered and concentrated. The residue was purified using a 0.5 mm preparative TLC plate eluting with 10% methanol/DCM to yield the desired compound (5 mg, 0.0088 mmol, 10% yield). MS (ESI)=570.1 (M+H)
Reaction SMILES: [C:1]1([P:7](Cl)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>O>[C:8]1([PH:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: ClP(c1ccccc1)c1ccccc1
Solvent: O
Product: c1ccc(Pc2ccccc2)cc1
Yield: 70 %

Procedure:
By Hydrolysis of Diphenylphosphinous Chloride. Diphenylphosphinous chloride (700 g, 3.17 mols) is added with rapid stirring to 1400 ml of distilled water. The temperature rises to 70° C. The solution is heated at reflux 1 hour, then cooled. The lower organic layer is separated from the water, dried, and distilled in vacuum giving diphenylphosphine (207 g, 70 percent yield), b.p. 151° C/10 mm. From the residue, 327 g (95 percent yield) of diphenylphosphonic acid is obtained by recrystallization from ethanol.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1.CN(C)C1C=CC=CC=1.Br[CH:20]([CH3:31])[C:21]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1)=O.Cl>CC1C=CC=CC=1C>[CH3:1][O:2][C:3]1[CH:8]=[C:7]2[C:6](=[CH:5][CH:4]=1)[NH:9][C:21]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1)=[C:20]2[CH3:31]
Reactant: COc1ccc(C(=O)C(C)Br)cc1
Reactant: COc1ccc(N)cc1
Agent: Cl
Solvent: CN(C)c1ccccc1
Solvent: Cc1ccccc1C
Product: COc1ccc(-c2[nH]c3ccc(OC)cc3c2C)cc1
Temperature: 170 °C

Procedure:
0.38 mol of p-anisidine is added to 75 ml of N,N-dimethylaniline in a 1 liter reaction flask, heated to 170° C. while being stirred and then a solution of 0.18 mol of 2-bromo-4'-methoxypropiophenone in 240 ml of o-xylene is added in drops at this temperature. The strongly foaming mixture is refluxed for another 3 hours. After the solution is cooled, it is poured onto 600 ml of 2N HCl, stirred thoroughly and extracted three times with ethyl acetate. The organic extracts are washed twice each with 2N HCl and water, dried on magnesium sulfate (MgSO4) and liberated of solvent. For purification, the crude product is chromatographed on silica gel 60 with CH2Cl2 and then recrystallized from 96% ethanol.
Reaction SMILES: C[O:2][C:3]1[C:4]([Cl:16])=[C:5]([Cl:15])[C:6]2[C:12](=[O:13])[CH2:11][CH2:10][CH2:9][CH2:8][C:7]=2[CH:14]=1.Cl.N1C=CC=CC=1.C1C2CCCCC(=O)C=2C=CC=1>O>[OH:2][C:3]1[C:4]([Cl:16])=[C:5]([Cl:15])[C:6]2[C:12](=[O:13])[CH2:11][CH2:10][CH2:9][CH2:8][C:7]=2[CH:14]=1
Reactant: COc1cc2c(c(Cl)c1Cl)C(=O)CCCC2
Agent: Cl
Agent: O=C1CCCCc2ccccc21
Solvent: O
Solvent: c1ccncc1
Product: O=C1CCCCc2cc(O)c(Cl)c(Cl)c21
Temperature: 180 °C

Procedure:
2-Methoxy-3,4-dichloro-6,7,8,9-tetrahydro-5H- benzocyclohepten-5-one (25.9 g., 0.1 mole) intimately mixed with pyridine hydrochloride (250 g.) is heated at 180° C. for 1 hour. The hot mixture is poured into water whereupon 2-hydroxy-3,4-dichloro-,6,7,8,9-tetrahydro-5H-benzocyclohepten- 5-one separates and is isolated in the usual way.
Reaction SMILES: [CH3:1][CH:2]([CH2:14][CH3:15])[CH2:3][O:4][C:5](=[O:13])[C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1.[C:16]([O:26][C:27]1[CH:35]=[CH:34][C:30]([C:31](Cl)=[O:32])=[CH:29][CH:28]=1)([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17].CCOCC>C1COCC1>[CH3:1][CH:2]([CH2:14][CH3:15])[CH2:3][O:4][C:5](=[O:13])[C:6]1[CH:7]=[CH:8][C:9]([O:12][C:31](=[O:32])[C:30]2[CH:29]=[CH:28][C:27]([O:26][C:16]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:17])=[CH:35][CH:34]=2)=[CH:10][CH:11]=1
Reactant: CCC(C)COC(=O)c1ccc(O)cc1
Reactant: O=C(OCc1ccccc1)Oc1ccc(C(=O)Cl)cc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCC(C)COC(=O)c1ccc(OC(=O)c2ccc(OC(=O)OCc3ccccc3)cc2)cc1
Reaction time: 8 h
Yield: 62.9 %

Procedure:
A solution of 16 m moles (3.3 g) of the above 4-hydroxybenzoic acid 2-methylbutyl ester in 20 ml of THF and 40 ml of pyridien was cooled, and a THF solution of 10 m moles (2.9 g) of the above 4-carbobenzoxyoxybenzoyl chloride was added dropwise. The mixture was returned slowly to room temperature, then stirred for 8 hours. After the reaction, the reaction mixture was ether extracted and concentrated, and then purified by column chromatography to obtain 2.9 g of 4-(4'-carbobenzoxyoxybenzoyloxy)benzoic acid 2-methylbutyl ester [m.p. 64.4°-65.4° C⟧ (yield: 63%)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][C@@H:12]2[CH2:16][N:15](C(OC(C)(C)C)=O)[C@H:14]([C:24](=[O:36])[NH:25][C@:26]3([C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:28][C@H:27]3[CH:29]=[CH2:30])[CH2:13]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1>Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][C@@H:12]2[CH2:16][NH:15][C@H:14]([C:24]([NH:25][C@:26]3([C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:28][C@H:27]3[CH:29]=[CH2:30])=[O:36])[CH2:13]2)(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@H](OS(=O)(=O)c2ccc(Br)cc2)CN1C(=O)OC(C)(C)C)C(=O)OCC
Agent: Cl
Product: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@H](OS(=O)(=O)c2ccc(Br)cc2)CN1)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 101.9 %

Procedure:
HCl (4M in dioxane, 300 ml) was added to the product of Step 2 (40 g) and the solution was stirred at room temperature for 30 min. The solvent was evaporated under reduced pressure. The residue was dissolved in ethyl acetate and a saturated sodium bicarbonate solution was added. The phases were separated. The precipitated solid was filtrated from the organic layer to give the desired product (33.8 g) as a white solid. LRMS (ES+) m/z 487.0 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][CH2:6][CH2:5]2.Br[C:14]1[CH:15]=[N:16][CH:17]=[CH:18][C:19]=1[C:20]([F:23])([F:22])[F:21].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([C:14]1[CH:15]=[N:16][CH:17]=[CH:18][C:19]=1[C:20]([F:23])([F:22])[F:21])[CH2:6][CH2:5]2
Reactant: O=C1NCCc2cc(F)ccc21
Reactant: FC(F)(F)c1ccncc1Br
Agent: I[Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: O=C1c2ccc(F)cc2CCN1c1cnccc1C(F)(F)F
Yield: 63.8 %

Procedure:
6-Fluoro-3,4-dihydroisoquinolin-1(2H)-one (I-78d: 500 mg, 3.029 mmol) was reacted with 3-bromo-4-(trifluoromethyl)-pyridine (890 mg, 3.93 mmol), 1,4-dioxane (15 mL), copper iodide (57.5 mg, 0.30 mmol), trans-N,N′-dimethyl-cyclohexyl-1,2-diamine (43 mg, 0.302 mmol) and potassium phosphate (1.92 g, 9.08 mmol) for 36 hours at 120° C. to afford the crude product. Purification by column chromatography on silica gel (2% methanol in CHCl3), afforded 600 mg of the product (64.5% yield).