Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[CH:5][C:4]([C:9]2[CH:14]=[CH:13][C:12]([C@@H:15]([N:17]3[CH2:23][CH2:22][CH2:21][C@:20]([CH2:30][C:31]([CH3:33])=[CH2:32])([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[NH:19][C:18]3=[O:34])[CH3:16])=[CH:11][CH:10]=2)=[CH:3]1.C1([SiH3])C=CC=CC=1.C([OH:45])(C)C.C(Cl)Cl>[Co]>[OH:45][C:31]([CH3:33])([CH3:32])[CH2:30][C@:20]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:21][CH2:22][CH2:23][N:17]([C@H:15]([C:12]2[CH:11]=[CH:10][C:9]([C:4]3[CH:5]=[CH:6][C:7](=[O:8])[N:2]([CH3:1])[CH:3]=3)=[CH:14][CH:13]=2)[CH3:16])[C:18](=[O:34])[NH:19]1
Reactant: C=C(C)C[C@]1(c2ccccc2)CCCN([C@@H](C)c2ccc(-c3ccc(=O)n(C)c3)cc2)C(=O)N1
Reactant: CC(C)O
Agent: [Co]
Agent: [SiH3]c1ccccc1
Solvent: ClCCl
Product: C[C@@H](c1ccc(-c2ccc(=O)n(C)c2)cc1)N1CCC[C@](CC(C)(C)O)(c2ccccc2)NC1=O
Reaction time: 1 h
Yield: 34 %

Procedure:
To a solution of (S)-1-((S)-1-(4-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-4-(2-methylallyl)-4-phenyl-1,3-diazepan-2-one (4 mg, 0.0088 mmol) in 2:1 i-Propanol/CH2Cl2 (2 mL) was added the cobalt catalyst A (c.a. 1 mg, cat. amount) and phenylsilane (100 μL, excess). The mixture was stirred vigorously in open air for 1 h. LC-MS found the reaction completed. The mixture was quenched by 1% aq HCl, concentrated and purified by prep HPLC to afford (S)-4-(2-hydroxy-2-methylpropyl)-1-((S)-1-(4-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-4-phenyl-1,3-diazepan-2-one (1.4 mg, 34%). LC-MS Method 1 tR=1.56 min., m/z 473 (M+1); 1H NMR (CD3OD) δ 7.93 (s, 1H), 7.83 (dd, 1H), 7.56 (d, 2H), 7.40-7.34 (m, 4H), 7.27 (t, 1H), 7.16 (d, 2H), 6.62 (d, 1H), 5.46 (q, 1H), 3.63 (s, 3H), 2.93 (m, 1H), 2.76 (m, 1H), 2.39 (d, 1H), 1.52 (d, 3H), 1.17 (s, 3H), 0.59 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[C:10](=[O:11])[N:9]([CH3:12])[C:8]2[C:13]([I:16])=[N:14][NH:15][C:7]=2[CH:6]=1.[O:22](C(OC(C)(C)C)=O)[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=O>O1CCCC1.CN(C1C=CN=CC=1)C.C(OCC)(=O)C.O>[C:26]([O:25][C:23]([N:15]1[C:7]2[CH:6]=[C:5]([O:4][C:3]3[CH:17]=[CH:18][C:19]([F:21])=[CH:20][C:2]=3[F:1])[C:10](=[O:11])[N:9]([CH3:12])[C:8]=2[C:13]([I:16])=[N:14]1)=[O:22])([CH3:29])([CH3:28])[CH3:27]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: Cn1c(=O)c(Oc2ccc(F)cc2F)cc2[nH]nc(I)c21
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: Cn1c(=O)c(Oc2ccc(F)cc2F)cc2c1c(I)nn2C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 120 %

Procedure:
To a solution of 6-(2,4-difluorophenoxy)-3-iodo-4-methyl-1,4-dihydro-pyrazolo[4,3-b]pyridin-5-one (12 mg, 0.0298 mmol) in tetrahydrofuran (5 mL) was added BOC2O (16 mg, 2.5 eq) and DMAP (catalytic). The resulting mixture was heated under reflux for 30 minutes, cooled to room temperature, and diluted with ethyl acetate (35 mL) and water (25 mL). The organic layer was separated, washed successively with water (2×25 mL), 0.5 N HCl (2×20 mL) and brine (1×25 mL), dried over magnesium sulfate, filtered and concentrated to give the title compound as a white powder (18 mg, (M+H)+=504).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1)=[O:5].[CH3:19]I.[Mg].S(=O)(=O)(O)O>C1COCC1.CCOCC.O>[F:18][C:15]1[CH:14]=[CH:13][C:12]([C:9]2[CH:10]=[CH:11][C:6]([C:4]([OH:5])([CH3:19])[CH2:3][CH2:2][NH2:1])=[CH:7][CH:8]=2)=[CH:17][CH:16]=1
Reactant: CI
Reactant: NCCC(=O)c1ccc(-c2ccc(F)cc2)cc1
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: CC(O)(CCN)c1ccc(-c2ccc(F)cc2)cc1

Procedure:
A solution of 24.4 g of 1-amino-3-(4'-fluoro-4-biphenylyl)-propan-3-one [obtainable by reacting 1-chloro-3-(4'-fluoro-4-biphenylyl)-propan-3-one with potassium phthalimide and subsequent hydrolysis] in 200 ml of THF is added dropwise, while stirring, at 20° to a Grignard solution prepared from 30 g of CH3I and 5 g of magnesium in 1000 ml of ether. The mixture is stirred for a further 4 hours, the resulting alcoholate is decomposed by means of water and dilute sulfuric acid, and the mixture is worked up in the customary manner to give 3-(4'-fluoro-4-biphenylyl)-3-hydroxybutylamine, m.p. 144°-146°.
Reaction SMILES: Cl.O1CCOCC1.C(OC([N:15]1[CH2:20][CH2:19][N:18]([S:21]([C:24]2[CH:29]=[CH:28][C:27]([CH:30]3[CH2:32][CH2:31]3)=[CH:26][CH:25]=2)(=[O:23])=[O:22])[C@@H:17]([C:33](=[O:47])[NH:34][CH2:35][C:36]2[CH:41]=[CH:40][C:39]([O:42][C:43]([F:46])([F:45])[F:44])=[CH:38][CH:37]=2)[CH2:16]1)=O)(C)(C)C>>[F:46][C:43]([F:44])([F:45])[O:42][C:39]1[CH:40]=[CH:41][C:36]([CH2:35][NH:34][C:33]([C@H:17]2[CH2:16][NH:15][CH2:20][CH2:19][N:18]2[S:21]([C:24]2[CH:29]=[CH:28][C:27]([CH:30]3[CH2:31][CH2:32]3)=[CH:26][CH:25]=2)(=[O:22])=[O:23])=[O:47])=[CH:37][CH:38]=1
Reactant: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2ccc(C3CC3)cc2)[C@@H](C(=O)NCc2ccc(OC(F)(F)F)cc2)C1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(NCc1ccc(OC(F)(F)F)cc1)[C@H]1CNCCN1S(=O)(=O)c1ccc(C2CC2)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 81.7 %

Procedure:
4N Hydrogen chloride/1,4-dioxane solution (1.3 ml) was added to the compound (130 mg) obtained in Step 3, and the mixture was stirred at room temperature for 6 hr. The reaction mixture was concentrated under reduced pressure, and the residue was partitioned by adding ethyl acetate, saturated aqueous sodium hydrogen carbonate solution and water. The organic layer was dried over anhydrous magnesium sulfate, filtrated, and concentrated under reduced pressure. The residue was purified by thin layer silica gel chromatography (chloroform:methanol=9:1) to give the title compound (88 mg).
Reaction SMILES: C(O[CH:5]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16](OC(=O)C)[CH:15]2[CH:6]1[C:7](=[O:36])[C:8]1[C:9]3([S:35][CH2:34][CH2:33][S:32]3)[CH2:10][CH:11]([C:28]([O:30][CH3:31])=[O:29])[CH2:12][C:13]=1[C:14]2=[O:27])(=O)C.[OH-].[Na+]>CO.O>[O:36]=[C:7]1[C:6]2[C:15](=[CH:16][C:17]3[C:22]([CH:5]=2)=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:14](=[O:27])[C:13]2[CH2:12][CH:11]([C:28]([O:30][CH3:31])=[O:29])[CH2:10][C:9]3([S:32][CH2:33][CH2:34][S:35]3)[C:8]1=2
Reactant: COC(=O)C1CC2=C(C(=O)C3C(OC(C)=O)c4ccccc4C(OC(C)=O)C3C2=O)C2(C1)SCCS2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COC(=O)C1CC2=C(C(=O)c3cc4ccccc4cc3C2=O)C2(C1)SCCS2
Temperature: 20 °C
Reaction time: 1.5 h
Yield: 73.1 %

Procedure:
A mixture of 26.5 mg (0.05 mmol) of methyl rac-1',2',3',4',5',5a',6',11',11a',12'-decahydro-6',11'-diacetoxy-5',12'-dioxospiro[1,3-dithiolane-2,4'-naphthacene]-2'-carboxylate and 5 mg (0.125 mmol) of sodium hydroxide in 2 ml of methanol was stirred at 20° C. for 1.5 hours. The mixture was then diluted with 10 ml of water and extracted with two 10 ml portions of dichloromethane. The combined dichloromethane extracts were washed with 10 ml of water, dried over magnesium sulphate and evaporated to dryness to give 15 mg (73%) of methyl rac-1',2',3',4',5',12'-hexahydro-5',12'-dioxospiro[1,3-dithiolane-2,4'-naphthacene]-2'-carboxylate in the form of a bright yellow solid of melting point 216° C.
Reaction SMILES: S(S([O-])=O)([O-])=O.[Na+].[Na+].[I:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[N+:23]([O-])=O)=[CH:12][CH:11]=1.N>O.C(O)C>[I:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[NH2:23])=[CH:12][CH:11]=1
Reactant: O=[N+]([O-])c1ccccc1Nc1ccc(I)cc1
Agent: N
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Nc1ccccc1Nc1ccc(I)cc1

Procedure:
According to the method of Chem. Abs., 1962, 57, 9840a, a solution of sodium dithionite (85%, 24.74 g, 121 mmol) in water (120 ml) was added to a suspension of (4-iodophenyl)-2-nitroaniline in ethanol (500 ml). The mixture was heated under reflux for 45 minutes, cooled, treated with 300 ml of dilute aqueous ammonia, and concentrated under reduced pressure. The resulting white slurry was treated with 200 ml of dilute aqueous ammonia, filtered and washed with water (200 ml). The solid was dried in a vacuum desiccator at room temperature to give N-(4-iodophenyl)1,2-diaminobenzene, 8.91 g, which gradually darkens on exposure to light, m.p. 122°-123° C.
Reaction SMILES: [CH3:1][N:2]1[C:7]2[CH:8]=[CH:9][C:10]([C:12]3[CH:17]=[CH:16][C:15]([O:18][C:19]([F:22])([F:21])[F:20])=[CH:14][CH:13]=3)=[CH:11][C:6]=2[C:5](=O)[O:4][C:3]1=[O:24].[NH2:25][C@H:26](C(O)=O)[CH2:27][CH2:28][OH:29]>C(O)(=O)C>[OH:29][CH2:28][CH2:27][C@H:26]1[C:3](=[O:24])[N:2]([CH3:1])[C:7]2[CH:8]=[CH:9][C:10]([C:12]3[CH:17]=[CH:16][C:15]([O:18][C:19]([F:22])([F:20])[F:21])=[CH:14][CH:13]=3)=[CH:11][C:6]=2[C:5](=[O:4])[NH:25]1
Reactant: N[C@@H](CCO)C(=O)O
Reactant: Cn1c(=O)oc(=O)c2cc(-c3ccc(OC(F)(F)F)cc3)ccc21
Solvent: CC(=O)O
Product: CN1C(=O)[C@H](CCO)NC(=O)c2cc(-c3ccc(OC(F)(F)F)cc3)ccc21
Temperature: 130 °C
Yield: 10.8 %

Procedure:
1-Methyl-6-(4-(trifluoromethoxy)phenyl)-1H-benzo[d][1,3]oxazine-2,4-dione (60 mg, 0.178 mmol) and L-homoserine (23.3 mg, 0.196 mmol, 1.1 equiv.) were added to a magnetically stirred 0.5-2 mL Smith process vial containing 0.75 mL glacial acetic acid. Reaction mixture was then heated for 2 hours at 130° C. Excess acetic acid was then removed en vacuo, residue was dissolved into a minimal amount of acetonitrile and purified by reverse-phase preparative HPLC to give the title compound (7.6 mg) following removal of solvent as a clear yellow film.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7](O)=[O:8].C(Cl)(=O)C(Cl)=O.C[N:21](C=O)C.[NH4+].[OH-]>C(Cl)Cl.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7]([NH2:21])=[O:8]
Reactant: CN(C)C=O
Reactant: O=C(O)c1cc(F)ccc1[N+](=O)[O-]
Agent: O=C(Cl)C(=O)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: NC(=O)c1cc(F)ccc1[N+](=O)[O-]
Reaction time: 2 h
Yield: 88 %

Procedure:
To 5-Fluoro-2-nitro-benzoic acid (3 g, 16.2 mmol) in 200 mL of methylene chloride was added oxalyl chloride (2.26 g, 17.8 mmol) and a drop of DMF. After stirring for 2 h, the solution was poured into concentrated NH4OH. The partial solution was poured into water, extracted with Ethyl acetate, dried (Na2SO4) and concentrated to give 5-Fluoro-2-nitro-benzamide (2.61 g, 88% yield) used without purification. LCMS m/e 185.1 (M+H) 183.2 (M-H), HPLC tr=2.9 min (100%).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([F:11])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH:12]([CH3:14])[CH3:13].[Cl:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19].CCN(C(C)C)C(C)C>CCCCO>[Cl:15][C:16]1[CH:17]=[C:18]([NH:19][C:2]2[N:10]=[C:9]([F:11])[N:8]=[C:7]3[C:3]=2[N:4]=[CH:5][N:6]3[CH:12]([CH3:14])[CH3:13])[CH:20]=[CH:21][CH:22]=1
Reactant: Nc1cccc(Cl)c1
Reactant: CC(C)n1cnc2c(Cl)nc(F)nc21
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)n1cnc2c(Nc3cccc(Cl)c3)nc(F)nc21
Temperature: 90 °C
Yield: 48.4 %

Procedure:
6-Chloro-2-fluoro-9-isopropyl-9H-purine (214 mg, 1 mmol) was mixed with 3-chloroaniline (127.6 mg, 1 mmol) in 12 mL n-BuOH. DIEA (357.6 mg, 2.8 mmol) was added and the solution was heated at 90° C. overnight. Solvent was removed in vacuo and the residue was chromatographed on silica gel (CH2Cl2/EtOAc 2:2, Rf 0.44) to get the product as a white solid (148 mg, 48%).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][NH:17][CH2:18][CH2:19][CH:20]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1.[H][H]>[Pd].C(O)C>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][CH2:16][NH:17][CH2:18][CH2:19][CH:20]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[CH:13][CH:14]=1
Reactant: [H][H]
Reactant: c1ccc(COc2ccc(CCNCCC(c3ccccc3)c3ccccc3)cc2)cc1
Agent: [Pd]
Solvent: CCO
Product: Oc1ccc(CCNCCC(c2ccccc2)c2ccccc2)cc1
Reaction time: 70 h

Procedure:
The starting material is prepared as follows: The mixture of 7.5 g of N-[2-(4-benzyloxyphenyl)-ethyl]-3,3-diphenylpropylamine, 125 ml of ethanol and 0.25 g of 10% palladium on charcoal is shaken under 3 atmospheres of hydrogen for 20 hours. 4.5 g of fresh catalyst are added and hydrogenolysis continued at 3 atmospheres for 70 hours. The mixture is filtered and evaporated to afford the N-[2-(4-hydroxyphenyl)-ethyl]-3,3-diphenylpropylamine of sufficient purity.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH2:12][C:13]([C:15]2[CH:20]=[CH:19][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:17][CH:16]=2)=O)=[O:10])=[CH:4][CH:3]=1.C(N(CC)CC)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(#N)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](=[O:10])[O:11][CH2:12][C:13]=2[C:15]2[CH:20]=[CH:19][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:17][CH:16]=2)=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)c1ccc(C(=O)COC(=O)Cc2ccc(F)cc2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CS(=O)(=O)c1ccc(C2=C(c3ccc(F)cc3)C(=O)OC2)cc1
Yield: 93.9 %

Procedure:
Under nitrogen, 4.10 g (11.7 mmol) of 2-(4-fluorophenyl)-1-[2-[4-(methylsulfonyl)phenyl]-2-oxoethoxy]ethanone (prepared in Step 4), 6.52 mL (46.8 mmol) of triethylamine, 4.89 g (25.7 mmol) of p-toluenesulfonic acid, and 12 g of 4Å molecular sieves were added to 117 mL of acetonitrile and stirred at reflux for 16 hours. The reaction mixture was concentrated in vacuo and the residue partitioned between dichloromethane and water. The dichloromethane layer was dried (MgSO4) and reconcentrated in vacuo. Recrystallization from hexane/ethyl acetate (2:1) gave 3.65 g (94%) of 3-(4-fluorophenyl)-4-[4-(methylsulfonyl)phenyl]-5H-furan-2-one as a solid: mp 166°-167° C.; NMR (CDCl3) δ3.08 (s, 3H), 5.19 (s, 2H), 7.10 (t, J=9 Hz, 2H), 7.42 (dd, J=6 and 9 Hz, 2H), 7.52 (d, J=9 Hz, 2H), 7.97 (d, J=9 Hz, 2H); HRMS. Calc'd for C17H13FO45 : 332.0519. Found: 332.0501. Anal. Calc'd for C17H13FO45 : C, 61.44; H, 3.94; O, 19.26. Found: C, 61.11; H, 4.06; 0, 19.32.
Reaction SMILES: [CH2:1]=[CH:2][C@@H:3]1[C@@H:8]2[CH2:9][C@@H:10]([C@H:11]([OH:22])[C:12]3[CH:13]=[CH:14][N:15]=[C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=34)[N:5]([CH2:6][CH2:7]2)[CH2:4]1.[OH:23][C:24]([CH:26]([C:28]1[CH:41]=[CH:40][CH:39]=[C:30]([C:31]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[O:32])[CH:29]=1)[CH3:27])=[O:25].C(OCC)(=O)C>CO>[OH:25][C:24]([C@H:26]([C:28]1[CH:41]=[CH:40][CH:39]=[C:30]([C:31]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)=[O:32])[CH:29]=1)[CH3:27])=[O:23].[CH2:1]=[CH:2][C@@H:3]1[C@@H:8]2[CH2:9][C@@H:10]([C@H:11]([OH:22])[C:12]3[CH:13]=[CH:14][N:15]=[C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=34)[N:5]([CH2:6][CH2:7]2)[CH2:4]1
Reactant: CC(C(=O)O)c1cccc(C(=O)c2ccccc2)c1
Agent: C=C[C@H]1CN2CC[C@H]1C[C@H]2[C@H](O)c1ccnc2ccccc12
Solvent: CO
Solvent: CCOC(C)=O
Product: C[C@H](C(=O)O)c1cccc(C(=O)c2ccccc2)c1
Temperature: 35 °C

Procedure:
Cinchonidine (155 g; 0.53 mol) was added to a solution of 115g (0.59 mol) of racemic ketoprofen and 2.8 L of ethyl acetate under vigorous stirring at 50°-60° C. The mixture was diluted with 280 mL of methanol, cooled to 35° C., then seeded with 98% enantiomerically pure S-salt to induce crystallization. After stirring at room temperature for 16 h and 0° C. for 5-6 h, the precipitated diastereomeric salt was filtered under vacuum, washed three times with ethyl acetate and three times with ether, and then dried under vacuum for 16 h [Yield: 127 g (or 44%); enantiomeric purity: 86% S]. One recrystallization from 1.7 L of ethyl acetate/methanol (10:1) afforded 88 g (31% yield) salt of 97% enantiomerically pure S-ketoprofen.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11]/[N:12]=[C:13](\[C:18](=[O:24])[CH2:19][C:20](OC)=[O:21])/[C:14]([O:16][CH3:17])=[O:15])=[CH:7][CH:6]=1)(=[O:4])=[O:3].O>ClC1C=CC=CC=1Cl>[OH:24][C:18]1[C:13]([C:14]([O:16][CH3:17])=[O:15])=[N:12][N:11]([C:8]2[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:6][CH:7]=2)[C:20](=[O:21])[CH:19]=1
Reactant: COC(=O)CC(=O)/C(=N\Nc1ccc(S(C)(=O)=O)cc1)C(=O)OC
Solvent: O
Solvent: Clc1ccccc1Cl
Product: COC(=O)c1nn(-c2ccc(S(C)(=O)=O)cc2)c(=O)cc1O
Temperature: 180 °C
Reaction time: 1 h
Yield: 49.2 %

Procedure:
The mixture of (E)-dimethyl 2-(2-(4-(methylsulfonyl)phenyl) hydrazono)-3-oxopentanedioate (7.0 g, 19.6 mmol) in 1, 2 dichlorobenzene (20 mL) was heated at 180° C. overnight. After cooling the reaction to room temperature, water 50 mL was added to the reaction mixture and stirred for 1 hour. The product was collected by filtration and further washed with water 20 mL and methanol (10 mL×3), then dried overnight under reduced pressure to yield 3.13 g (49.1%) of methyl 4-hydroxy-1-(4-(methylsulfonyl)phenyl)-6-oxo-1,6-dihydropyridazine-3-carboxylate. MS (ESI) 325 (M+H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5](O)=[CH:4][CH:3]=1.C1(=O)[O:13][CH2:12][CH2:11][O:10]1.C(=O)=O>[F-].[K+]>[OH:10][CH2:11][CH2:12][O:13][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1OCCO1
Reactant: Cc1ccc(O)cc1
Agent: O=C=O
Agent: [F-]
Agent: [K+]
Product: OCCOCc1ccccc1
Yield: 93.4 %

Procedure:
The reaction apparatus used in Example 1 was charged with 4-methylphenol (54 grams), ethylene carbonate (45 grams) and a small amount of KF (0.5 grams, 0.5 percent). After thorough mixing the flask was immersed in an oil bath and the temperature adjusted to 160° C.±2°. After a reaction time of 1.1 hours, CO2 evolution ceased and the product, 4-(2-hydroxyethoxy)methylbenzene (71 grams, 94 percent yield) was recovered and purified by recrystallization from acetone.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[C:10]2[CH2:13][CH2:14][NH:15][C:16]([CH:18]2[CH2:20][CH2:19]2)=[O:17])=[CH:5][CH:4]=1.[C:21](Cl)(=[O:23])[CH3:22]>>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[C:8]([C:21](=[O:23])[CH3:22])[CH:9]=[C:10]2[CH2:13][CH2:14][NH:15][C:16]([CH:18]2[CH2:19][CH2:20]2)=[O:17])=[CH:5][CH:4]=1
Reactant: COc1ccc2cccc(CCNC(=O)C3CC3)c2c1
Reactant: CC(=O)Cl
Product: COc1ccc2cc(C(C)=O)cc(CCNC(=O)C3CC3)c2c1
Yield: 31 %

Procedure:
By working as in Example 1, using N-[2-(7-methoxynaphth-1-yl)ethyl]cyclopropylcarboxamide and acetyl chloride as starting materials, the compound of Example 50 is obtained.
Reaction SMILES: C[O:2][C:3](=[O:39])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH2:23][N:24]([C:27]([O:29][CH2:30][C:31]2[CH:36]=[C:35]([Cl:37])[CH:34]=[C:33]([Cl:38])[CH:32]=2)=[O:28])[CH2:25][CH3:26])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.[OH-].[Na+].Cl>C1COCC1.CO>[Cl:37][C:35]1[CH:36]=[C:31]([CH:32]=[C:33]([Cl:38])[CH:34]=1)[CH2:30][O:29][C:27]([N:24]([CH2:23][C:14]1[CH:15]=[C:16]([C:19]([F:21])([F:22])[F:20])[CH:17]=[CH:18][C:13]=1[C:7]1[C:8]([O:11][CH3:12])=[CH:9][CH:10]=[C:5]([CH2:4][C:3]([OH:39])=[O:2])[CH:6]=1)[CH2:25][CH3:26])=[O:28]
Reactant: CCN(Cc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OC)ccc1OC)C(=O)OCc1cc(Cl)cc(Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCN(Cc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)O)ccc1OC)C(=O)OCc1cc(Cl)cc(Cl)c1

Procedure:
(2′-{[(3,5-Dichloro-benzyloxycarbonyl)-ethyl-amino]-methyl}-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid methyl ester (0.088 g, 0.15 mmol) in THF (1 mL) and MeOH (0.8 mL) was hydrolyzed with 1N aqueous NaOH (0.5 mL) for 2.5 hours. The mixture was acidified with 1N aqueous HCl and extracted with CH2Cl2. The combined organic layers were dried over Na2SO4, decanted, and concentrated, and the residue was purified by preparative HPLC to give the title compound.
Reaction SMILES: [N+:1]([CH2:4][CH2:5][CH3:6])([O-:3])=[O:2].C(N(CC)CC)C.[Cl-].[Cl-].C([Al+2])C.[CH:19](=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>ClCCl>[C:20]1([CH:19]([OH:26])[CH:4]([N+:1]([O-:3])=[O:2])[CH2:5][CH3:6])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=Cc1ccccc1
Reactant: CCC[N+](=O)[O-]
Agent: CC[Al+2]
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(C(O)c1ccccc1)[N+](=O)[O-]
Temperature: 25 °C
Yield: 28.7 %

Procedure:
To a solution of nitropropane (0.45 g, 0.005 moles) in dichloromethane (25 mL) at 0° C. was added triethylamine (0.67 mL, 0.005 moles) followed by ethyl aluminum dichloride (1.0 M in hexane, 5 mL, 0.005 moles). After 15 minutes benzaldehyde (0.5 mL 0.005 moles) was added and the solution allowed to warm to room temperature. After a further 3 hours the reaction was cooled in ice to a temperature of 5° C. and quenched with pH 7.0 phosphate buffer. The organic layer was separated, dried and evaporated in vacuo. Flash column chromatography [SiO2, 6:1 hexane, Et2O] gave 1-phenyl-2-nitro-1-butanol (0.28 g, 29%) Erythro:threo ratio 1:1.6.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][O:18][Si:19]([CH:26]([CH3:28])[CH3:27])([CH:23]([CH3:25])[CH3:24])[CH:20]([CH3:22])[CH3:21])[CH:12]=2)=[C:6]([CH:9]=1)[C:7]#[N:8].C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+].[Cl:42][C:43]1[CH:44]=[C:45](B(O)O)[CH:46]=[CH:47][C:48]=1[Cl:49]>CO.O.CCOC(C)=O.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>[Cl:42][C:43]1[CH:44]=[C:45]([C:2]2[CH:3]=[CH:4][C:5]([NH:10][C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][O:18][Si:19]([CH:20]([CH3:21])[CH3:22])([CH:26]([CH3:28])[CH3:27])[CH:23]([CH3:25])[CH3:24])[CH:12]=3)=[C:6]([C:7]#[N:8])[CH:9]=2)[CH:46]=[CH:47][C:48]=1[Cl:49]
Reactant: CC(C)[Si](OCc1cccc(Nc2ccc(Br)cc2C#N)c1)(C(C)C)C(C)C
Reactant: OB(O)c1ccc(Cl)c(Cl)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)[Si](OCc1cccc(Nc2ccc(-c3ccc(Cl)c(Cl)c3)cc2C#N)c1)(C(C)C)C(C)C
Temperature: 25 °C
Yield: 54.2 %

Procedure:
To a suspension of crude 5-bromo-2-(3-((triisopropylsilyloxy)methyl)phenylamino)benzonitrile (3.9 g, 8.49 mmol), tetrakis(triphenylphosphine)palladium(0) (0.438 g, 0.379 mmol), toluene (60 mL), and 2 M aqueous sodium carbonate (9.63 mL, 19.27 mmol) under nitrogen were added a solution of 3,4-dichlorophenylboronic acid (2.203 g, 11.54 mmol) in MeOH (14 mL) at rt. The resulting reaction mixture was heated at reflux for 4 h. After cooling to room temperature, it was diluted with a mixture of water (150 mL) and EtOAc (250 mL) and the two phases were separated. The aqueous phase was extracted with ethyl acetate (2×100 mL), and the combined organic phases were washed with water (2×100 mL), 5% aqueous NH4OH solution (100 mL), and brine (100 mL). The organic phase was dried over Na2SO4 and the solvent removed. The crude material was purified by chromatography on silica gel, eluting with hexane containing 2%-5% EtOAc afforded 2.42 g of 3′,4′-dichloro-4-(3-((triisopropylsilyloxy)methyl)phenylamino)-biphenyl-3-carbonitrile. 1H NMR (CDCl3) δ ppm 7.65 (1H, d, J=1.83 Hz), 7.53-7.58 (2H, m), 7.39 (1H, dd, J=9.00, 2.29 Hz), 7.31 (1H, t, J=7.78 Hz), 7.22 (1H, s), 7.11 (1H, d, J=7.63 Hz), 7.07 (1H, d, J=8.85 Hz), 7.02 (2H, d, J=8.24 Hz), 6.35 (1H, s), 4.82 (2H, s), 1.13-1.22 (3H, m), 1.06-1.11 (18H, m).
Reaction SMILES: C([O:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[C:12]([C:19]([OH:21])=O)[N:13]2[CH3:18])C1C=CC=CC=1.[Cl:22][C:23]1[CH:29]=[CH:28][C:26]([NH2:27])=[CH:25][CH:24]=1>>[Cl:22][C:23]1[CH:29]=[CH:28][C:26]([NH:27][C:19]([C:12]2[N:13]([CH3:18])[C:14]3[C:10]([CH:11]=2)=[C:9]([OH:8])[CH:17]=[CH:16][CH:15]=3)=[O:21])=[CH:25][CH:24]=1
Reactant: Cn1c(C(=O)O)cc2c(OCc3ccccc3)cccc21
Reactant: Nc1ccc(Cl)cc1
Product: Cn1c(C(=O)Nc2ccc(Cl)cc2)cc2c(O)cccc21

Procedure:
From 4-benzyloxy-1-methyl-1H-indole-2-carboxylic acid and 4-chloroaniline the title compound was prepared by a method analogous to that described in Example 11. MS ES (M++H)=301 and 303.