Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([Mg]Br)[CH2:3][CH2:2]1.Br[C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][C:14]=1[F:15])[CH:10]=[O:11]>C1COCC1.[Cl-].[Zn+2].[Cl-].CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH:1]1([C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][C:14]=2[F:15])[CH:10]=[O:11])[CH2:3][CH2:2]1
Reactant: O=Cc1ccc(F)c(Br)c1
Reactant: Br[Mg]C1CC1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [Cl-]
Agent: [Zn+2]
Solvent: C1CCOC1
Product: O=Cc1ccc(F)c(C2CC2)c1
Temperature: 50 °C
Reaction time: 0.33 h
Yield: 49.4 %

Procedure:
A flask was charged with cyclopropyl magnesium bromide (29.6 ml, 14.8 mmol) and placed under nitrogen. Zinc chloride (14.8 ml, 14.8 mmol) was added and the reaction was stirred for 20 minutes. 3-Bromo-4-fluorobenzaldehyde (1.0 g, 4.93 mmol) and bis(tri-t-butylphosphine)palladium (0) (0.126 g, 0.246 mmol) were diluted in 600 μL of THF and added to the reaction mixture. After stirring for 4 hours, the reaction was heated to 50° C. and stirred overnight. The reaction was cooled and quenched with saturated NH4Cl and extracted with DCM. The organic layer was dried over MgSO4, filtered and concentrated. The material was purified using a biotage 40M cartridge eluting with hexanes:ethyl acetate (4:1) to yield 3-cyclopropyl-4-fluorobenzaldehyde (400 mg, 49.5% yield)
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([NH2:6])=[O:5].C(Cl)(=O)[C:13](Cl)=[O:14].C(Cl)Cl.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]([F:43])([F:42])[C:29]([F:41])([F:40])[O:30][C:31]2[CH:37]=[CH:36][C:34]([NH2:35])=[CH:33][C:32]=2[O:38][CH3:39])=[CH:24][CH:23]=1>C1(C)C=CC=CC=1.CCCCCCC>[Cl:21][C:22]1[CH:23]=[CH:24][C:25]([C:28]([F:42])([F:43])[C:29]([F:40])([F:41])[O:30][C:31]2[CH:37]=[CH:36][C:34]([NH:35][C:13]([NH:6][C:4](=[O:5])[C:3]3[C:2]([F:1])=[CH:10][CH:9]=[CH:8][C:7]=3[F:11])=[O:14])=[CH:33][C:32]=2[O:38][CH3:39])=[CH:26][CH:27]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: COc1cc(N)ccc1OC(F)(F)C(F)(F)c1ccc(Cl)cc1
Reactant: NC(=O)c1c(F)cccc1F
Solvent: CCCCCCC
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COc1cc(NC(=O)NC(=O)c2c(F)cccc2F)ccc1OC(F)(F)C(F)(F)c1ccc(Cl)cc1
Temperature: 25 °C
Yield: 93.8 %

Procedure:
A stirred mixture of 2,6-difluorobenzamide (0.37 g, 0.027 mole), oxalyl chloride (0.33 g, 0.0026 mole) and methylene chloride (3.0 mL) in toluene (80 mL) was heated at reflux for three hours. Approximately 40 mL of solvent was removed by distillation under reduced pressure. A solution of 4-[2-(4-chlorophenyl)-1,1,2,2-tetrafluoroethoxy]-3-methoxyaniline (0.83 g, 0.0024 mole) in toluene (40 mL) was added to the reaction mixture. The resultant solution was stirred at room temperature for approximately 18 hours. About 40 mL of the solvent was removed by evaporation under reduced pressure, leaving a liquid residue. Approximately 100 mL of n-heptane was added to the residue, and the mixture was stirred at room temperature, slowly forming a precipitate. This solid was collected by filtration to yield 1.2 g of N-[[[4-[2-(4-chlorophenyl)-1,1,2,2-tetrafluoroethoxy]-3-methoxyphenyl]amino]carbonyl]-2,6-difluorobenzamide, m.p. 133°-134.5° C., Compound 10 of Table 1.
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([N+:13]([O-])=O)[CH:5]=[CH:4][CH:3]=1>C(O)(=O)C.C(O)C.O.[Fe]>[NH2:13][C:6]1[CH:5]=[CH:4][CH:3]=[C:2]([CH3:1])[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)c1c(C)cccc1[N+](=O)[O-]
Agent: [Fe]
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)c1c(C)cccc1N

Procedure:
A reaction mixture of 185 g of ethyl 6-methyl-2-nitrobenzoate and 176 g of powdered iron in 343 mL of glacial acetic acid and 2200 mL of ethanol was heated at reflux for 5 hours. The reaction mixture was allowed to cool, diluted with excess water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and concentrated to an orange oil 148.3 g.
Reaction SMILES: [C:1]([OH:22])(=[O:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].[C:23](O)(=O)[CH2:24]CCCCCCCCCCCCCCCC.[OH-].[Na+:44].[N+]([O-])(O)=O>O>[C:1]([O-:22])(=[O:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:23][CH3:24].[Na+:44]
Reactant: CCCCCCCCCCCCCCCCCCCC(=O)O
Reactant: CCCCCCCCCCCCCCCCCC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=[N+]([O-])O
Product: CCCCCCCCCCCCCCCCCCCCCC(=O)[O-]
Temperature: 55 °C

Procedure:
In an amount of 32.4 g of behenic acids, 9.9 g of arachidic acid and 5.6 g of stearic acid were dissolved in 945 mL of pure water at 90° C. Then, the solution was added with 98 mL of 1.5 mol/L sodium hydroxide aqueous solution with stirring at high speed. Subsequently, the solution was added with 0.93 mL of concentrated nitric acid, cooled at 55° C. and stirred for 30 minutes to obtain sodium behenate solution.
Reaction SMILES: [CH:1](=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)O.[ClH:10].C([O:14][CH2:15][CH3:16])(=O)C>>[Cl-:10].[OH:14][C:15]1[C:1]([C:2]2[CH:3]=[CH:5][CH:6]=[CH:7][CH:8]=2)=[O+:9][C:2]2[C:3]([CH:16]=1)=[CH:5][CH:6]=[CH:7][CH:8]=2
Reactant: CCOC(C)=O
Reactant: Cl
Reactant: O=Cc1ccccc1O
Product: Oc1cc2ccccc2[o+]c1-c1ccccc1
Product: [Cl-]
Temperature: 0 °C
Reaction time: 1 h

Procedure:
88 g of salicylaldehyde were dissolved in 300 ml of anhydrous ethyl acetate together with 132 g of omega-acetoxyacethophenone. The solution was cooled to 0° C. and saturation with gaseous HCl commenced, which took about one hour. The mixture was then left at 4° C. for 48 hours and the crystallised solid filtered off, this consisting of 106 g of 3-hydroxyflavylium chloride.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:16]3[CH:15]=[C:14]([C:17]([O:19]C)=[O:18])[NH:13][C:12]=3[CH2:11][CH2:10]2)[CH:5]=[C:6]([CH3:8])[CH:7]=1.O.[OH-].[Li+].C1COCC1>CO>[CH3:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:16]3[CH:15]=[C:14]([C:17]([OH:19])=[O:18])[NH:13][C:12]=3[CH2:11][CH2:10]2)[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: COC(=O)c1cc2c([nH]1)CCC2c1cc(C)cc(C)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(C)cc(C2CCc3[nH]c(C(=O)O)cc32)c1

Procedure:
The title compound was synthesized from methyl 4-(3,5-dimethylphenyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate (150 mg, 0.45 mmol) and lithium hydroxide monohydrate (108 mg, 4.5 mmol), according to General Procedure 7. A 1:1 mixture of THF and methanol (10 mL) was used. The resulting product was purified by chromatography over silica gel (gradient 0 to 100% EtOAc in heptane over 20 min) to give the title compound. 1H NMR (400 MHz, METHANOL-d4) δ ppm 2.16-2.22 (m, 1H), 2.24 (s, 6H), 2.66-2.92 (m, 3H), 4.08 (t, J=7.35 Hz, 1H), 6.51 (s, 1H), 6.78 (s, 2H), 6.80 (s, 1H). LCMS m/e 256 (M+H) and 95% pure by HPLC.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][C:8]1[N:13]=[N:12][C:11]([OH:14])=[CH:10][CH:9]=1.[CH3:15][N:16]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:17](Cl)=[O:18].N12CCN(CC1)CC2.O>CN(C)C=O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][C:8]1[N:13]=[N:12][C:11]([O:14][C:17](=[O:18])[N:16]([CH3:15])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:10][CH:9]=1
Reactant: Oc1ccc(Cc2ccccn2)nn1
Reactant: CN(C(=O)Cl)c1ccccc1
Agent: C1CN2CCN1CC2
Solvent: O
Solvent: CN(C)C=O
Product: CN(C(=O)Oc1ccc(Cc2ccccn2)nn1)c1ccccc1
Yield: 41.2 %

Procedure:
A solution of 6-(2-pyridinylmethyl)-3-pyridazinol (100 mg, 0.53 mmol), N-methyl-N-phenylcarbamoyl chloride (91 mg, 0.53 mmol) and 1,4-diazabicyclo[2.2.2]octane (60 mg, 0.53 mmol) in dimethylformamide (10 ml) was stirred at room temperature for 2 hours. Water was added and the solution was extracted twice with dichloromethane. The combined organic layers were dried over sodium sulphate, filtered and evaporated in vacuo. The residue was purified by flash column chromatography (SiO2, ethyl acetate) yielding the title compound (70 mg, 41% yield) as a yellow oil.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:14]=[CH:13][C:9]([C:10]([OH:12])=O)=[CH:8][CH:7]=2)[CH2:3][CH2:2]1.[C:15]([O:18][CH2:19][CH2:20][NH:21][C:22](=[O:37])[C@@H:23]([NH2:36])[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][C:32]([F:35])([F:34])[F:33])=[CH:27][CH:26]=1)(=[O:17])[CH3:16].P(C#N)(OCC)(OCC)=O.C(N(CC)CC)C>C(OCC)(=O)C.CN(C=O)C>[C:15]([O:18][CH2:19][CH2:20][NH:21][C:22](=[O:37])[C@@H:23]([NH:36][C:10](=[O:12])[C:9]1[CH:8]=[CH:7][C:6]([O:5][CH2:4][CH:1]2[CH2:2][CH2:3]2)=[CH:14][CH:13]=1)[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][C:32]([F:35])([F:33])[F:34])=[CH:27][CH:26]=1)(=[O:17])[CH3:16]
Reactant: CC(=O)OCCNC(=O)[C@@H](N)Cc1ccc(OC(F)(F)F)cc1
Reactant: O=C(O)c1ccc(OCC2CC2)cc1
Agent: CCOP(=O)(C#N)OCC
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(=O)OCCNC(=O)[C@H](Cc1ccc(OC(F)(F)F)cc1)NC(=O)c1ccc(OCC2CC2)cc1
Reaction time: 0.08 h
Yield: 36.6 %

Procedure:
4-(Cyclopropylmethoxy)benzoic acid (1.52 g, 7.90 mmol) prepared in Example 18 (18a) was added to a DMF (53 mL) solution of 2-({(2S)-2-amino-3-[4-(trifluoromethoxy)phenyl]propanoyl}amino)ethyl acetate (2.64 g, 7.90 mmol). To the mixture was added diethyl cyanophosphate (1.54 mL, 9.78 mmol) under ice-cooling with stirring, and then triethylamine (1.32 mL, 9.78 mmol) was dropwise added thereto over 5 minutes. The resulting mixture was stirred at room temperature for 2.5 hours, and to this reaction solution was added ethyl acetate (380 mL). The resulting mixture was washed with water (380 mL, three times) and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated, and the obtained residue was washed with ethyl acetate and dried to give 1.47 g of the title compound. The ethyl acetate used for the washing was also concentrated, and the resulting residue was washed with methanol to give 0.82 g of the title compound. These compound fractions were combined to give 2.29 g of the title compound (white powder, yield: 57%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15]O)=[N:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)[Cl:37]>>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][Cl:37])=[N:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClC(Cl)(Cl)Cl
Reactant: OCc1ccc(OCc2ccccc2)cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: ClCc1ccc(OCc2ccccc2)cn1
Temperature: 25 °C

Procedure:
To a solution of carbon tetrachloride (10 mL) of a known compound (5-benzyloxy-pyridin-2-yl)-methanol (500 mg) was added triphenylphosphine (791 mg) at room temperature, which was heated to reflux for 19 hours and 35 minutes under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, after which the solvent was evaporated under a reduced pressure. The residue was purified by silica gel column chromatography (heptane:ethyl acetate=3:1) to obtain the titled compound (386 mg).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:8][N:7]=1)[CH3:2].C(OC(=O)OCC)C.C([N-]C(C)C)(C)C.[Li+].[N+:36]([C:39]1[CH:46]=[CH:45][C:42]([C:43]#[N:44])=[CH:41][CH:40]=1)([O-:38])=[O:37]>O1CCCC1>[CH2:1]([O:3][C:4](=[O:19])[CH:5]([C:40]1[CH:41]=[C:42]([C:43]#[N:44])[CH:45]=[CH:46][C:39]=1[N+:36]([O-:38])=[O:37])[C:6]1[CH:11]=[CH:10][C:9]([CH2:12][N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:8][N:7]=1)[CH3:2]
Reactant: N#Cc1ccc([N+](=O)[O-])cc1
Reactant: CCOC(=O)Cc1ccc(CN2CCOCC2)cn1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(=O)OCC
Product: CCOC(=O)C(c1ccc(CN2CCOCC2)cn1)c1cc(C#N)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a cold solution of (5-Morpholin-4-ylmethyl-pyridin-2-yl)-acetic acid ethyl ester (25 g, 130 mmol) and diethylcarbonate (33.79 g, 286 mmol) in tetrahydrofuran (62.5 ml) under nitrogen at −10° C. was added lithium diisopropylamide in tetrahydrofuran (158.9 ml, 1.8M, 286 mmol) dropwise over 1 hr 10 min. After stirring for an additional 30 mins at −10° C. a solution of 4-nitrobenzonitrile (29.78 g, 195 mmol) in tetrahydrofuran (175 ml) is added dropwise and stirring continued for 3 hrs. The reaction mixture was poured into a cold aqueous hydrochloric solution (375 ml, 2M) at 0° C.; after warming to room temperature the acidic aqueous layer was separated and washed with tert-butyl methyl ether (200 ml). The acidic aqueous layer was cooled in an ice bath and tert-butyl methyl ether (500 ml) was added. The mixture was then made basic (pH 9) by addition of sodium carbonate solution (55 ml, 25 w/w %). The mixture was then warmed to room temperature and the organic phase separated; the basic aqueous phase was extracted with tert-butyl methyl ether (250 ml). The combined organic layer was treated with Celite® (12.5 g), then filtered and the filtrate concentrated in vacuo to give (5-Cyano-2-nitro-phenyl)-(5-morpholin-4-ylmethyl-pyridin-2-yl)-acetic acid ethyl ester crude (28.58 g, 51% w/w %). The crude material was dissolved in ethanol (300 ml) then heated to 40° C. and a solution of hydrochloric acid in isopropanol (8 ml, 4.95M, 20.7 mmol) was added followed by addition of seeds (90 mg) and the solution cooled to −10° C. over 10 hrs. The crystals were filtered and washed with tert-butyl methyl ether. After drying at 40° C. under vacuum gave 14.51 g, 25% yield of (5-Cyano-2-nitro-phenyl)-(5-morpholin-4-ylmethyl-pyridin-2-yl)-acetic acid ethyl ester hydrochloride salt as red wine crystals. Characterisation data were in accordance with example 7.
Reaction SMILES: Cl.[NH:2]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][NH2:12])=[CH:10][C:5]=2[N:4]=[CH:3]1.[N:13]([C:16]1[S:20][C:19]2[CH2:21][CH2:22][CH2:23][CH2:24][C:18]=2[C:17]=1[C:25]([O:27]CC)=O)=[C:14]=[S:15].C([N:32](CC)CC)C>CN(C=O)C.ClCCl>[NH:2]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][NH2:12])=[CH:10][C:5]=2[N:4]=[CH:3]1.[S:15]=[C:14]1[NH:13][C:16]2[S:20][C:19]3[CH2:21][CH2:22][CH2:23][CH2:24][C:18]=3[C:17]=2[C:25](=[O:27])[NH:32]1
Reactant: CCN(CC)CC
Reactant: CCOC(=O)c1c(N=C=S)sc2c1CCCC2
Agent: Cl
Agent: NCc1ccc2[nH]cnc2c1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=c1[nH]c(=S)[nH]c2sc3c(c12)CCCC3
Temperature: 25 °C
Reaction time: 12 h

Procedure:
(1H-benzo[d]imidazol-5-yl)methanamine (14) (0.08 g, 0.46 mmol) and ethyl 4,5,6,7-tetrahydro-2-isothiocyanatobenzo[b]thiophene-3-carboxylate (0.12 g, 0.46 mmol) were dissolved in 1mL DMF and dichloromethane. Triethylamine (128 μL, 0.92 mmol) was added to the mixture. The mixture was stirred for 12 hours at ambient temperature. The solvent was removed and the resulted residue was dissolved in ethanol. Triethylamine (128 μL, 0.92 mmol) was added and the mixture was heated under reflux for 12 hours. The solvent was removed and the resulted residue was dissolved in ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate. The organic layer was dried over sodium sulfate, filtrated and the solvent was removed. The product was purified by means of flash-chromatographie using silica gel and a CHCl3/MeOH-gradient.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[N:12]=[CH:11][NH:10][C:9]2=O)([O-:3])=[O:2].P(Cl)(Cl)(Cl)(Cl)[Cl:16]>O=P(Cl)(Cl)Cl>[Cl:16][C:9]1[C:8]2[C:13](=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[CH:6][CH:7]=2)[N:12]=[CH:11][N:10]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: O=c1[nH]cnc2c([N+](=O)[O-])cccc12
Solvent: O=P(Cl)(Cl)Cl
Product: O=[N+]([O-])c1cccc2c(Cl)ncnc12
Yield: 91.2 %

Procedure:
A suspension of 8-nitroquinazolin-4(3H)-one (1.0 g, 5.23 mmol) and PCl5 (1.3 g, 6.24 mmol) in POCl3 (5 mL) was heated at reflux for 4 h. Then the reaction mixture was concentrated and the concentrate was diluted with Et2O. The precipitated solid was filtered and dried to afford 1.0 g of the title product. 1H NMR (300 MHz, DMSO d6): δ 9.25 (s, 1H), 8.71 (d, J=7.8 Hz, 1H), 8.59 (d, J=7.8 Hz, 1H), 8.07-8.02 (t, J=7.8 Hz, 1H).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=[O:7])(C)(C)C.[C:19]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:24]=[CH:23][C:22](C(Cl)=O)=[CH:21][CH:20]=1.[O:34]1[CH:38]=[CH:37][CH:36]=[C:35]1[CH2:39][NH2:40]>>[C:28]1([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:29]=[CH:30][C:31]([C:6]([N:8]2[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]2[C:16]([NH:40][CH2:39][C:35]2[O:34][CH:38]=[CH:37][CH:36]=2)=[O:18])=[O:7])=[CH:32][CH:33]=1
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: NCc1ccco1
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Product: CON=C1C[C@@H](C(=O)NCc2ccco2)N(C(=O)c2ccc(-c3ccccc3)cc2)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, [1,1′-biphenyl]-4-carbonyl chloride, and 2-furylmethylamine the title compound was obtained in 75% purity by LC/MS. MS(ESI+): m/z=418.4.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8](=[O:16])[C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:17][C:18]([OH:20])=[O:19].[OH-].[Na+:22]>O1CCCC1>[OH2:16].[NH2:1][C:2]1[C:7]([C:8](=[O:16])[C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:17][C:18]([O-:20])=[O:19].[Na+:22]
Reactant: Nc1c(CC(=O)O)cccc1C(=O)c1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Nc1c(CC(=O)[O-])cccc1C(=O)c1ccc(F)cc1
Product: O

Procedure:
A solution of 1 g. (0.0036 mole) of 2-amino-3-(4-fluorobenzoyl)phenylacetic acid in 10 ml. of tetrahydrofuran was treated with 0.7 g. of a 50% sodium hydroxide solution (0.009 mole) and stirred under nitrogen for 15 min. before a yellow precipitate developed. The stirred mixture was cooled in an ice bath for 2 hr. The precipitate was then filtered off and air-dried. Recrystallization from tetrahydrofuran-water yielded 150 mg. (20%) of product which melted at 240°-250° C. (dec.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:4]=1[O:5][C:6]1[CH:7]=[C:8]([O:19][CH2:20][CH:21]=[CH2:22])[CH:9]=[C:10]([OH:18])[C:11]=1[C:12]2=[O:17].[C:23](=O)([O-])[O-].[K+].[K+].CI>CN(C=O)C.C(OCC)(=O)C.S(=O)(=O)(O)O>[CH3:1][O:2][C:3]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:4]=1[O:5][C:6]1[CH:7]=[C:8]([O:19][CH2:20][CH:21]=[CH2:22])[CH:9]=[C:10]([O:18][CH3:23])[C:11]=1[C:12]2=[O:17]
Reactant: C=CCOc1cc(O)c2c(=O)c3cccc(OC)c3oc2c1
Reactant: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=CCOc1cc(OC)c2c(=O)c3cccc(OC)c3oc2c1
Temperature: 80 °C
Reaction time: 1 h
Yield: 76 %

Procedure:
To a solution of xanthone 2 (150 g, 0.5 mol) in dry DMF (500 mL) was added potassium carbonate (100 g, 0.72 mol) and methyl iodide (180 g, 1.28 mol) and the mixture was heated with constant stirring under argon to 80° C. for 1 hour. The mixture was allowed to cool to room temperature and diluted with 2L ethyl acetate and the remaining potassium carbonate was dissolved in dilute sulfuric acid. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo to afford the xanthone 3 (120 g, 0.38 mol, 77%) as a pale yellow solid.
Reaction SMILES: [C:1]([C:4]1[C:9](=[O:10])[C:8]([O:11][CH3:12])=[CH:7][N:6]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Br:19])[C:14]=2[F:20])[N:5]=1)(=O)[CH3:2].[CH3:21]C(O)=O.[C:25]1([NH:31][NH2:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>COC(OC)N(C)C.Cl>[Br:19][C:15]1[C:14]([F:20])=[C:13]([N:6]2[CH:7]=[C:8]([O:11][CH3:12])[C:9](=[O:10])[C:4]([C:1]3[N:31]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[N:32]=[CH:21][CH:2]=3)=[N:5]2)[CH:18]=[CH:17][CH:16]=1
Reactant: NNc1ccccc1
Reactant: CC(=O)O
Reactant: COc1cn(-c2cccc(Br)c2F)nc(C(C)=O)c1=O
Agent: COC(OC)N(C)C
Agent: Cl
Product: COc1cn(-c2cccc(Br)c2F)nc(-c2ccnn2-c2ccccc2)c1=O
Yield: 59 %

Procedure:
A mixture of 3-acetyl-1-(3-bromo-2-fluorophenyl)-5-methoxypyridazin-4(1H)-one (2.98 g, 8.74 mmol) in N,N-dimethylformamide dimethyl acetal (30 mL) was heated to reflux for 3.5 h. The mixture was concentrated in vacuo. To the residue were added AcOH (30 mL) and phenylhydrazine (1.72 mL, 17.5 mmol). The mixture was heated to reflux for 4 h. The mixture was diluted with 1 M HCl aqueous solution, extracted with AcOEt, washed with saturated NaHCO3 aqueous solution, dried over Na2SO4, filtered, concentrated in vacuo, purified by column chromatography on basic silica gel (hexane/AcOEt=50/50 to 0/100) and recrystallized with EtOH to yield the title compound (2.29 g, 59% yield) as a yellow solid: mp 186-191° C. 1H NMR (DMSO-d6, 300 MHz): δ ppm 3.77 (3H, s), 6.99 (1H, d, J=1.9 Hz), 7.08-7.15 (1H, m), 7.17-7.26 (1H, m), 7.28-7.47 (5H, m), 7.74-7.86 (2H, m), 8.55 (1H, d, J=2.3 Hz). Anal. Calcd for C20H14BrFN4O2: C, 54.44; H, 3.20; N, 12.70. Found: C, 54.70; H, 3.30; N, 12.82.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:5]=[C:6]([NH:10][C:11](=[O:13])[CH3:12])[CH:7]=[CH:8][CH:9]=1.Cl[C:15]1[CH:20]=[C:19]([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:18]([N+:28]([O-:30])=[O:29])=[CH:17][N:16]=1.O>CN(C=O)C>[N+:28]([C:18]1[C:19]([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:20][C:15]([O:3][C:4]2[CH:5]=[C:6]([NH:10][C:11](=[O:13])[CH3:12])[CH:7]=[CH:8][CH:9]=2)=[N:16][CH:17]=1)([O-:30])=[O:29]
Reactant: CC(=O)Nc1cccc(O)c1
Reactant: O=[N+]([O-])c1cnc(Cl)cc1Nc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)Nc1cccc(Oc2cc(Nc3ccccc3)c([N+](=O)[O-])cn2)c1
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 96.9 %

Procedure:
Sodium hydride (60% dispersion in oil, 16.24 g, 406 mmol) was suspended in DMF (800 mL) and solid N-(3-hydroxyphenyl)acetamide (61.0 g, 406 mol) was added portionwise over 1 h (warming and frothing occurs). After the final addition the product from Step 4 (101.2 g, 406 mmol) was added as a solid, portionwise, over 10 min and the resulting mixture was heated to 60° C. overnight. Water (800 mL) was carefully added dropwise to the still warm reaction mixture over 1 h to give a fine yellow precipitate. The mixture was then cooled to 0° C., filtered and the resulting solid was washed with cold H2O and hexane to give the title compound (143.3 g, 97%) as a yellow solid. 1H NMR (400 MHz, DMSO-D6) δ ppm 10.06 (s, 1H), 9.80 (s, 1H), 8.91 (s, 1H), 7.44-7.49 (m, 3H), 7.37 (dd, 2H, 1.26 Hz, 8.6 Hz), 7.29-7.33 (m, 3H), 6.76-6.80 (m, 1H), 6.22 (s, 1H), 2.04 (s, 3H). MS (ES+) m/e 365 [M+H]+.
Reaction SMILES: [Si]([O:8][C@H:9]1[CH2:32][CH2:31][C@@:30]2([CH3:33])[C@@H:11]([CH2:12][CH2:13][C:14]3[C:15]4[C@:26]([CH3:34])([CH2:27][CH2:28][C:29]=32)[C@@H:18]([C@H:19]([CH3:25])[CH2:20][CH2:21][C:22](O)=[O:23])[CH2:17][CH:16]=4)[C:10]1([CH3:36])[CH3:35])(C(C)(C)C)(C)C.[NH3:37].C(O)C.Cl>>[OH:8][C@H:9]1[CH2:32][CH2:31][C@@:30]2([CH3:33])[C@@H:11]([CH2:12][CH2:13][C:14]3[C:15]4[C@:26]([CH3:34])([CH2:27][CH2:28][C:29]=32)[C@@H:18]([C@H:19]([CH3:25])[CH2:20][CH2:21][C:22]([NH2:37])=[O:23])[CH2:17][CH:16]=4)[C:10]1([CH3:36])[CH3:35]
Reactant: C[C@H](CCC(=O)O)[C@H]1CC=C2C3=C(CC[C@@]21C)[C@@]1(C)CC[C@H](O[Si](C)(C)C(C)(C)C)C(C)(C)[C@@H]1CC3
Reactant: N
Agent: Cl
Solvent: CCO
Product: C[C@H](CCC(N)=O)[C@H]1CC=C2C3=C(CC[C@@]21C)[C@@]1(C)CC[C@H](O)C(C)(C)[C@@H]1CC3

Procedure:
3β-tert-Butyldimethylsilyloxy-4,4-dimethyl-5α-chola-8,14-dien-24 oic acid (1.0 g) is reacted with ammonia and hydrolysed with ethanol/HCl following the procedure outlined in example 10 to give the title compound (147 mg). Melting point: 233-235° C. 1H-NMR (CDCl3, 400 MHz)): δ=5.36 (1H, s); 5.45-5.2 (2H, broad d); 3.25 (1H, m). MS: Calculated: 399.6. Found 399.3.