Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)(C(F)(F)F)=O.[Cl:8][C:9]1[C:14]([O:15][CH3:16])=[CH:13][C:12]([O:17][CH3:18])=[C:11]([Cl:19])[C:10]=1[C:20]1[N:25]=[C:24]2[NH:26][N:27]=[C:28](I)[C:23]2=[CH:22][N:21]=1.[O:30]1[C:34]2[CH:35]=[CH:36][C:37](B(O)O)=[CH:38][C:33]=2[CH2:32][CH2:31]1>>[Cl:8][C:9]1[C:14]([O:15][CH3:16])=[CH:13][C:12]([O:17][CH3:18])=[C:11]([Cl:19])[C:10]=1[C:20]1[N:25]=[C:24]2[NH:26][N:27]=[C:28]([C:37]3[CH:36]=[CH:35][C:34]4[O:30][CH2:31][CH2:32][C:33]=4[CH:38]=3)[C:23]2=[CH:22][N:21]=1
Reactant: OB(O)c1ccc2c(c1)CCO2
Reactant: COc1cc(OC)c(Cl)c(-c2ncc3c(I)n[nH]c3n2)c1Cl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(OC)c(Cl)c(-c2ncc3c(-c4ccc5c(c4)CCO5)n[nH]c3n2)c1Cl

Procedure:
This compound was prepared as TFA salt by using procedures analogous to those described for the synthesis of Example 7, Step 3 starting from 6-(2,6-dichloro-3,5-dimethoxyphenyl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidine and 2,3-dihydro-1-benzofuran-5-ylboronic acid. LCMS (M+H)+=443.0/445.0.
Reaction SMILES: [Mg].BrBr.C([O:11][C:12]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:16][C:13]=1[CH:14]=[O:15])C1C=CC=CC=1>C(OCC)C.C1(C)C=CC=CC=1>[CH2:21]([O:20][C:17]1[CH:18]=[CH:19][C:12]([OH:11])=[C:13]([CH:16]=1)[CH:14]=[O:15])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: O=Cc1cc(OCc2ccccc2)ccc1OCc1ccccc1
Agent: BrBr
Agent: [Mg]
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: O=Cc1cc(OCc2ccccc2)ccc1O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 57.9 %

Procedure:
To a mixed suspension of magnesium (305 mg, 12.6 mmol) in diethyl ether (7.5 mL) and toluene (7.5 mL) was added bromine (354 μL, 6.91 mmol) at 0° C., which was stirred at room temperature for 5 minutes under nitrogen atmosphere and was refluxed while heating for 5 minutes. After the reaction mixture was cooled to room temperature, a toluene (20 mL) solution of 2,5-bis-benzyloxy-benzaldehyde (2.00 g, 6.28 mmol) described in Production Example 7-1-1 were added followed by stirring at room temperature for 24 hours under nitrogen atmosphere. Moreover, after stirring for 6 hours while refluxing while heating, the reaction mixture was cooled to room temperature. The precipitated solid was filtered out and washed with toluene. 1 N aqueous hydrochloric acid solution (20 mL) was added to the filtered solid followed by stirring for 1 hour while refluxing and heating. The reaction solution was allowed to cool to room temperature followed by extraction with ethyl acetate. The organic layer was washed with sat. NaCl followed by drying over anhydrous magnesium sulfate and filtering. The filtrate was concentrated under a reduced pressure and the residue was purified by silica gel column chromatography (heptane:ethyl acetate=1:1) to obtain the title compound (830 mg, 58%) as a pale yellow solid.
Reaction SMILES: C([O:5][C:6](=[O:20])[CH2:7][C@@:8]([OH:19])([CH2:12][CH2:13][C:14]1[CH:18]=[CH:17][S:16][CH:15]=1)[CH:9]([CH3:11])[CH3:10])(C)(C)C.[Li+].[OH-].O>CO>[OH:19][C@:8]([CH2:12][CH2:13][C:14]1[CH:18]=[CH:17][S:16][CH:15]=1)([CH:9]([CH3:10])[CH3:11])[CH2:7][C:6]([OH:20])=[O:5]
Reactant: CC(C)[C@](O)(CCc1ccsc1)CC(=O)OC(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)[C@](O)(CCc1ccsc1)CC(=O)O

Procedure:
The title compound was prepared as described in General Method 10 using (S)-3-hydroxy-4-methyl-3-(2-thiophen-3-yl-ethyl)-pentanoic acid tert-butyl ester (Example F-1 (S); 8 mmol), LiOH (16 mmol), H2O (5 mL), and MeOH (15 mL).
Reaction SMILES: [Br:1][C:2]1[C:10]([C:11](N(OC)C)=[O:12])=[CH:9][C:8]([Br:17])=[C:7]2[C:3]=1[CH2:4][CH2:5][CH2:6]2.[CH2:18]([C:20]1[CH:25]=[CH:24][C:23]([Mg]Br)=[CH:22][CH:21]=1)[CH3:19]>C1COCC1>[Br:1][C:2]1[C:10]([C:11]([C:23]2[CH:24]=[CH:25][C:20]([CH2:18][CH3:19])=[CH:21][CH:22]=2)=[O:12])=[CH:9][C:8]([Br:17])=[C:7]2[C:3]=1[CH2:4][CH2:5][CH2:6]2
Reactant: CON(C)C(=O)c1cc(Br)c2c(c1Br)CCC2
Reactant: CCc1ccc([Mg]Br)cc1
Solvent: C1CCOC1
Product: CCc1ccc(C(=O)c2cc(Br)c3c(c2Br)CCC3)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 84.9 %

Procedure:
To a solution of amide 9 (0.27 g, 0.73 mmol) in anhydrous THF (2.7 mL) was added dropwise 4-ethylphenylmagnesium bromide (3.65 mL of 0.5M in THF, 1.83 mol) at 0° C. under nitrogen atmosphere. The mixture was warmed up to room temperature slowly and stirred at room temperature for 15 h. The reaction mixture was quenched with 1M HCl solution (10 mL) and extracted with EtOAc (20 mL). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography to provide the compound 10 (0.25 g, 0.62 mmol, 85%).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:8])=[N:4][O:5][C:6]=1[NH2:7].[H-].[Na+].[CH3:11][N:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[C:13]1[S:21](Cl)(=[O:23])=[O:22]>C1COCC1>[Br:1][C:2]1[C:3]([CH3:8])=[N:4][O:5][C:6]=1[NH:7][S:21]([C:13]1[N:12]([CH3:11])[C:20]2[C:15]([CH:14]=1)=[CH:16][CH:17]=[CH:18][CH:19]=2)(=[O:22])=[O:23]
Reactant: Cn1c(S(=O)(=O)Cl)cc2ccccc21
Reactant: Cc1noc(N)c1Br
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1noc(NS(=O)(=O)c2cc3ccccc3n2C)c1Br

Procedure:
N-(4-bromo-3-methyl-5-isoxazolyl)-1-methylindole-2-sulfonamide was prepared by the method of Example 41 with 4-bromo-3-methyl-5-aminoisoxazole (1.0 mmols, 0.18 g), NaH (2.5 mmols, 60 mg), 1-methylindole-2-sulfonyl chloride (1.2 mmols, 0.26 g) and THF (7 ml). Recrystallization from chloroform and hexane provided 0.28 g (77%) of a brown solid, m.p. 132-134° C.
Reaction SMILES: [OH-:1].[K+].O.Cl[C:5]([O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[O:6].[Cl-].O[NH3+:19]>CCOCC>[CH2:8]([O:7][C:5](=[O:6])[NH:19][OH:1])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: [OH-]
Reactant: [NH3+]O
Reactant: CCCCCCCCCOC(=O)Cl
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: CCOCC
Product: CCCCCCCCCOC(=O)NO
Reaction time: 3 h

Procedure:
A solution of 112 parts of potassium hydroxide in 1000 parts of water and 206.5 parts of nonyl chloroformate were added at equivalent rates over 2 hours to a stirred suspension of 69.5 parts of ground hydroxyl ammonium chloride in 1000 parts of ether at 0° C. to 5° C. The reaction mixture was stirred for a further 3 hours at 0°-5° C. followed by 18 hours at 25° C. and was then filtered to remove potassium chloride. The ether layer was separated, washed with water, dried, filtered and evaporated to constant weight at 40° C. under reduced pressure to give 190 parts of nonyl-N-hydroxycarbamate as a colourless oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[CH:4]([CH:5]=[C:6]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[C:7]([O:9][CH3:10])=[O:8])[CH:3]1[C:16]([O-:18])=[O:17].CO.CC(C)=O.Cl>O>[CH3:1][C:2]1([CH3:19])[CH:4]([CH:5]=[C:6]([O:11][C:12]([CH3:13])([CH3:14])[CH3:15])[C:7]([O:9][CH3:10])=[O:8])[CH:3]1[C:16]([OH:18])=[O:17]
Reactant: COC(=O)C(=CC1C(C(=O)[O-])C1(C)C)OC(C)(C)C
Agent: Cl
Solvent: CC(C)=O
Solvent: CO
Solvent: O
Product: COC(=O)C(=CC1C(C(=O)O)C1(C)C)OC(C)(C)C
Temperature: 20 °C
Reaction time: 6 h

Procedure:
A mixture of 410 mg of methoxymethyl (1R,trans,ΔE) 2,2-dimethyl-3-[2-tert.-butoxy-2-methoxy carbonyl-ethenyl]cyclopropane-carboxylate, 8 ml of methanol, 8 ml of acetone and 16 ml of aqueous N hydrochloric acid was stirred at 20° C. for 6 hours and was poured into water. The mixture was extracted with ether and the organic phase was evaporated to dryness under reduced pressure to obtain 300 mg of (1R,trans,ΔE) 2,2-dimethyl-3-[2-tert.-butoxy-2-methoxy carbonyl-ethenyl]cyclopropane-carboxylic acid.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[S:4][CH:5]=[C:6]([CH2:8]O)[N:7]=1.S(Cl)(Cl)=O.[CH3:16][S-:17].[Na+].O>C(Cl)(Cl)Cl>[F:1][C:2]([F:11])([F:10])[C:3]1[S:4][CH:5]=[C:6]([CH2:8][S:17][CH3:16])[N:7]=1
Reactant: OCc1csc(C(F)(F)F)n1
Reactant: C[S-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: O=S(Cl)Cl
Product: CSCc1csc(C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.4 %

Procedure:
2-(Trifluoromethyl)4-thiazolemethanol (EP 402246; 1.5 g, 8.3 mmol) was dissolved in 15 ml chloroform, treated with thionyl chloride(1.8 ml, 2.4 g, 21 mmol) and heated to reflux. After 1h, the mixture was cooled and volatiles were removed under vacuum. The residue was taken up in 25 ml ethyl acetate and washed with 10 ml sat. NaHCO3, 10 ml sat. NaCl, dried(Na2SO4) and evaporated. The residue was taken up in 5 ml ethanol and treated in portions with sodium thiomethoxide (800 mg, 12 mmol) and stirred for 1 h at 25° C. The mixture was poured into 15 ml water and extracted 2× 15 ml ethyl acetate. The combined extracts were washed with sat. NaCl, dried(Na2SO4) and evaporated to obtain 1.3 g of 2-(Trifluoro-methyl)-4(methylthio)methyl thiazole (A).
Reaction SMILES: [CH3:1][O:2][NH:3][CH2:4][CH2:5][CH2:6][C:7]1[C:12]([Cl:13])=[CH:11][C:10]([Cl:14])=[CH:9][C:8]=1[Cl:15].C(N(CC)CC)C.[F:23][CH:24]([F:34])[C:25]1[C:29]([C:30](Cl)=[O:31])=[CH:28][N:27]([CH3:33])[N:26]=1>ClCCl.O>[CH3:1][O:2][N:3]([CH2:4][CH2:5][CH2:6][C:7]1[C:8]([Cl:15])=[CH:9][C:10]([Cl:14])=[CH:11][C:12]=1[Cl:13])[C:30]([C:29]1[C:25]([CH:24]([F:34])[F:23])=[N:26][N:27]([CH3:33])[CH:28]=1)=[O:31]
Reactant: CONCCCc1c(Cl)cc(Cl)cc1Cl
Reactant: Cn1cc(C(=O)Cl)c(C(F)F)n1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CON(CCCc1c(Cl)cc(Cl)cc1Cl)C(=O)c1cn(C)nc1C(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 91 %

Procedure:
To a stirred solution of O-methyl-N-[3-(2,4,6-trichloro-phenyl)-propyl]-hydroxylamine (0.35 g, 1.3 mmol) prepared as described in example P24c in dichloromethane (5 ml), triethylamine (0.55 ml, 3.9 mmol) and a solution of 3-difluoromethyl-1-methyl-1H-pyrazole-4-carbonyl chloride acid in dichloromethane (2 ml) was added slowly at a temperature of 0° C. After complete addition of the acid chloride the mixture was stirred at ambient temperature for the next 3 hours. When the TLC confirmed the completion of the reaction, the reaction mass was diluted with water and extracted with dichloromethane (3×60 ml). The combined dichloromethane layer was washed with 2N HCl followed by saturated NaHCO3 solution, water and finally brine. The organic layer was then dried over anhydrous sodium sulphate and concentrated under reduced pressure. The resulting crude mass was purified over column chromatography (silica gel 60-120 mesh, 26% ethylacetate in hexane) to afford 3-Difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid methoxy-[3-(2,4,6-trichloro-phenyl)-propyl]-amide (0.5 g, 91%) as white crystalline solid. m.p-95-96° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:31])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([CH:18]([OH:29])[C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=4)=[C:13]([C:15]([OH:17])=O)[N:14]=[C:7]3[C:6]=2[CH:30]=1.[Cl-].[NH4+:33]>>[Br:1][C:2]1[C:3]([F:31])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([CH:18]([OH:29])[C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:26])([F:28])[F:27])[CH:20]=4)=[C:13]([C:15]([NH2:33])=[O:17])[N:14]=[C:7]3[C:6]=2[CH:30]=1
Reactant: [NH4+]
Reactant: O=C(O)c1nc2n(c1C(O)c1cccc(C(F)(F)F)c1)CCOc1cc(F)c(Br)cc1-2
Agent: [Cl-]
Product: NC(=O)c1nc2n(c1C(O)c1cccc(C(F)(F)F)c1)CCOc1cc(F)c(Br)cc1-2

Procedure:
The title compound was prepared similarly according to the procedure described in Example 2. 10-bromo-9-fluoro-3-(hydroxy(3-(trifluoromethyl)phenyl)methyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxylic acid was reacted with ammonium chloride to give the titled compound which was used in subsequent steps without purification.
Reaction SMILES: [ClH:1].Cl.[CH3:3][N:4]1[CH2:9][CH2:8][N:7]([CH2:10][C:11]2[CH:19]=[CH:18][C:14]([C:15](O)=[O:16])=[CH:13][CH:12]=2)[CH2:6][CH2:5]1.S(Cl)([Cl:22])=O.CN(C)C=O>ClCCl>[ClH:22].[ClH:1].[CH3:3][N:4]1[CH2:9][CH2:8][N:7]([CH2:10][C:11]2[CH:19]=[CH:18][C:14]([C:15]([Cl:22])=[O:16])=[CH:13][CH:12]=2)[CH2:6][CH2:5]1
Reactant: CN1CCN(Cc2ccc(C(=O)O)cc2)CC1
Reactant: O=S(Cl)Cl
Agent: Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CN1CCN(Cc2ccc(C(=O)Cl)cc2)CC1

Procedure:
A mixture of 4-(4-methylpiperzin-1-ylmethyl)benzoic acid dihydrochloride (2.5 kg), thionyl chloride (16.2 kg) and N,N-dimethylformamide (0.62 L) was refluxed for 20 hours. After completion of reaction, the reaction mass was distilled out completely under vacuum to give residue which was diluted with dichloromethane (5.0 L). Solid thus precipitated was filtered and washed to give 4-(4-methylpiperzin-1-ylmethyl)benzoyl chloride dihydrochloride. Dichloromethane (25.0 L), potassium carbonate (4 kg) was added to the above product and stirred for 30 minutes. The reaction mass was cooled to 0-5° C. and 4-methyl-N-(4-pyridin-3-yl-pyridin-2-yl)benzene-1,3-diamine (1.0 kg) was added to the reaction mixture. The reaction mass was refluxed for 10 hours. After completion of reaction, the reaction mass was quenched with dilute hydrochloric acid (21.0 L) up to pH 2.5-3.0 and layers were separated. Aqueous layer was washed with dichloromethane, diluted with tetrahydrofuran (6.0 L) and basified up to pH 8.0-8.5 with aqueous sodium hydroxide solution (20%, 10.0 L). Solid thus precipitated was filtered, washed with sodium hydroxide solution and demineralised water to give title compound having amine intermediate 29 ppm. Resulting solid was dissolved in a mixture of dichloromethane and methanol (8.0 L+2.0 L), washed with water and concentrated to give residue: Methanol (20.0 L) was added to the resulting residue, refluxed and charcoalized. Methanol was partially distilled out and resulting reaction mass was cooled down to 25-30° C. Reaction mixture was stirred for 1.0 hour. Reaction mixture was filtered, washed and dried to give 1.3 kg (yield: 73%) of title compound having purity 99.8% by HPLC and amine intermediate: 9.0 ppm.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[CH:7]=[C:6]2[C:13]1[N:26](COCC[Si](C)(C)C)[C:16]2=[N:17][CH:18]=[C:19]([CH2:21][NH:22][C:23](=[O:25])[CH3:24])[N:20]=[C:15]2[CH:14]=1.C(N)CN.CCCC[N+](CCCC)(CCCC)CCCC.[F-].CCOC(C)=O>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[CH:7]=[C:6]2[C:13]1[NH:26][C:16]2=[N:17][CH:18]=[C:19]([CH2:21][NH:22][C:23](=[O:25])[CH3:24])[N:20]=[C:15]2[CH:14]=1
Reactant: COc1ccc2c(c1)c(-c1cc3nc(CNC(C)=O)cnc3n1COCC[Si](C)(C)C)cn2C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CN(C)C=O
Solvent: NCCN
Solvent: CCOC(C)=O
Product: COc1ccc2c(c1)c(-c1cc3nc(CNC(C)=O)cnc3[nH]1)cn2C
Temperature: 85 °C
Reaction time: 16 h
Yield: 74.1 %

Procedure:
N-((6-(5-Methoxy-1-methyl-1H-indol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)methyl)acetamide (0.200 g, 0.417 mmol) in DMF (10 mL) was treated with ethylenediamine (0.90 mL, 13 mmol) and TBAF (1 M in THF, 1.7 mL, 1.7 mmol). The mixture was heated to about 85° C. for about 90 min then cooled and concentrated under reduced pressure. The material was stirred with water (20 mL) for about 16 h, Et2O (10 mL) was added, and stirring was continued for about 15 min. The slurry was filtered and the solid collected was dried. The filtrate was extracted with EtOAc (2×25 mL) then the combined organic solutions were dried over anhydrous MgSO4, filtered, and concentrated to give material, which was combined with the previously collected solid. The material was triturated with EtOAc (5 mL) and filtered to give a solid. The filtrate was purified by silica gel chromatography eluting with DCM/MeOH (9:1) to give an additional amount of product which was combined with the solid obtained from the EtOAc trituration to give N-((6-(5-methoxy-1-methyl-1H-indol-3-yl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)methyl)acetamide (0.108 g, 74%): LC/MS (Table 2, Method a) Rt=1.91 min; MS m/z: 350.2 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11](OS(C(F)(F)F)(=O)=O)[C:12]([NH:23][C:24]([OH:26])=[O:25])=[C:13](OS(C(F)(F)F)(=O)=O)[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[P:35]([O-:42])([O:39][CH2:40][CH3:41])[O:36][CH2:37][CH3:38].C(N([CH2:48][CH3:49])CC)C>C(#N)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([P:35]([O:42][CH2:48][CH3:49])([O:36][CH2:37][CH3:38])=[O:39])[C:12]([NH:23][C:24]([OH:26])=[O:25])=[C:13]([P:35]([O:39][CH2:40][CH3:41])([O:36][CH2:37][CH3:38])=[O:42])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOP([O-])OCC
Reactant: O=C(O)Nc1c(OS(=O)(=O)C(F)(F)F)cc(OCc2ccccc2)cc1OS(=O)(=O)C(F)(F)F
Reactant: CCN(CC)CC
Solvent: CC#N
Product: CCOP(=O)(OCC)c1cc(OCc2ccccc2)cc(P(=O)(OCC)OCC)c1NC(=O)O

Procedure:
To a solution of 5-benzyloxycarboxyamino-1,3-bis(trifluoromethylsulphonyloxy)benzene (5 g, 9.78 mmole) in anhydrous acetonitrile(320 ml) under argon was added diethyl phosphite (5.9 g, 42.7 mmole), triethylamine (5.95 g, 58.9 mmole) and tetrakis(triphenylphosphine)palladium[0] (870 mg, 0.75 mmole) and the stirred mixture was heated to relux. The light yellow solution was refluxed for 3.5 hours then cooled and solvent removed in vacuo. The residue was partitioned between ethyl acetate and water and the organic layer washed with 1M hydrochloric acid, water and saturated sodium bicarbonate solution then dried over magnesium sulphate and evaporated. The residue was crystallised from ethyl acetate/petroleum ether bp 40°-60° C. to give white crystals
Reaction SMILES: C1(=O)O[C:4](=[O:5])[CH:3]=[CH:2]1.O.O.O.[C:11]([O-:14])(=[O:13])[CH3:12].[Na+].[C:16](O)(=O)C>C1(NC2C=CC=CN=2)C=CC=CC=1>[CH3:2][C:3]1=[C:12]([CH3:16])[C:11]([O:14][C:4]1=[O:5])=[O:13]
Reactant: CC(=O)[O-]
Reactant: O=C1C=CC(=O)O1
Reactant: CC(=O)O
Agent: [Na+]
Agent: c1ccc(Nc2ccccn2)cc1
Solvent: O
Product: CC1=C(C)C(=O)OC1=O
Yield: 44.3 %

Procedure:
A solution of 98.0 g (1 mol) of maleic anhydride in 200 ml of glacial acetic acid is added dropwise over 1 hour to a boiling mixture of 1.7 g (0.01 mol) of 2-phenylaminopyridine and 22.8 g of sodium acetate trihydrate in 100 ml of glacial acetic acid. The mixture is subsequently boiled under reflux for 18 hours. Working up as in Example 1 affords 27.9 g (44.3%) of dimethylmaleic anhydride with a melting point of 91°-93° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([C:13]([OH:15])=O)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH2:16]([O:18][C:19](=[O:29])[CH2:20][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([NH2:28])[CH:23]=1)[CH3:17]>>[CH2:16]([O:18][C:19](=[O:29])[CH2:20][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([NH:28][C:13]([C:11]2[O:12][C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[CH:9][CH:10]=2)=[O:15])[CH:23]=1)[CH3:17]
Reactant: O=C(O)c1ccc(-c2ccc(F)cc2)o1
Reactant: CCOC(=O)COc1cccc(N)c1
Product: CCOC(=O)COc1cccc(NC(=O)c2ccc(-c3ccc(F)cc3)o2)c1

Procedure:
Carboxylic acid (76) (53 mg, 0.26 mmol) was coupled to aniline (64) (56 mg, 0.26 mmol) using Method C to give the title compound.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH2:9][C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=O)[CH:6]=[CH:7][CH:8]=1)[CH3:2].[CH2:18]([O:20][C:21]1[CH:22]=[C:23]([CH:26]=[C:27]([N+:30]([O-:32])=[O:31])[C:28]=1[OH:29])[CH:24]=O)[CH3:19].[NH2:33][C:34]([NH2:36])=[O:35].Cl>C(O)C>[CH2:18]([O:20][C:21]1[CH:22]=[C:23]([CH:24]2[C:9]([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([CH2:1][CH3:2])[CH:4]=3)=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[NH:36][C:34](=[O:35])[NH:33]2)[CH:26]=[C:27]([N+:30]([O-:32])=[O:31])[C:28]=1[OH:29])[CH3:19]
Reactant: CCc1cccc(CC(=O)c2ccccc2)c1
Reactant: NC(N)=O
Reactant: CCOc1cc(C=O)cc([N+](=O)[O-])c1O
Agent: Cl
Solvent: CCO
Product: CCOc1cc(C2NC(=O)NC(c3ccccc3)=C2c2cccc(CC)c2)cc([N+](=O)[O-])c1O
Temperature: 115 °C
Reaction time: 6 h
Yield: 25.2 %

Procedure:
A mixture of 2-(3-ethylphenyl)-1-phenylethanone (Intermediate 74) (90 mg, 0.40 mmol), 3-ethoxy-4-hydroxy-5-nitrobenzaldehyde (84.5 mg, 0.40 mmol), urea (72 mg, 1.2 mmol), conc. HCl (0.2 mL) in ethanol (1 mL) was stirred at 115° C. for 6 h. Solvent was removed in vacuo and purification by prep-HPLC (0.1% TFA as additive) gave Compound 141 (46.3 mg, yield 25%). 1H NMR (DMSO 400 MHz): δ 10.29 (brs, 1H), 8.71 (s, 1H), 7.54 (s, 1H), 7.46 (s, 1H), 7.28-7.20 (m, 5H), 6.97-6.91 (m, 1H), 7.43 (d, J=7.6 Hz, 1H), 6.71-6.61 (m, 2H), 5.22 (d, J=2.8 Hz, 1H), 4.04 (q, J=6.8 Hz, 2H), 2.29 (q, J=7.6 Hz, 2H) 1.33 (t, J=6.8 Hz, 3H), 0.85 (t, J=7.6 Hz, 3H), MS (ESI): m/z 460.3 [M+H]+.
Reaction SMILES: [CH3:1][C:2]([C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)[CH3:3].[OH-:18].[Na+].C(C1C=C[C:27]([OH:30])=CC=1)(C)(C)C.C(Cl)(Cl)=[O:32]>C(Cl)Cl.O>[CH3:3][C:2]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([C:11]1[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=1)[CH3:1].[C:27]([OH:30])([OH:32])=[O:18]
Reactant: CC(C)(C)c1ccc(O)cc1
Reactant: [OH-]
Reactant: O=C(Cl)Cl
Agent: CC(C)(c1ccc(O)cc1)c1ccc(O)cc1
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: O=C(O)O
Temperature: 25 °C

Procedure:
Into a mixture of 272.4 parts by weight of 4,4'-dihydroxy diphenyl-2,2-propane (bisphenol A), 145 parts by weight of sodium hydroxide, 1045 parts by weight of deionized water, 1330 parts by weight (1.0 liter) of methylene chloride and 5.55 parts by weight p-tertbutylphenol, 150 parts by weight of carbonyl chloride were added over a period of 0.5 hour with stirring and at a temperature of 25° C. This resulted in solution of bisphenol A polycarbonate oligomers in methylene chloride at a concentration of about 23 percent by weight in the organic phase
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.Cl.[NH2:19][C@@H:20]1[CH2:25][CH2:24][CH2:23][CH2:22][C@H:21]1[OH:26].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)C(C)C)C>CN(C)C=O>[Cl:1][C:2]1[C:10]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)=[CH:9][C:5]([C:6]([NH:19][C@@H:20]2[CH2:25][CH2:24][CH2:23][CH2:22][C@H:21]2[OH:26])=[O:8])=[CH:4][N:3]=1
Reactant: N[C@@H]1CCCC[C@H]1O
Reactant: O=C(O)c1cnc(Cl)c(-c2ccc(Cl)cc2)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(N[C@@H]1CCCC[C@H]1O)c1cnc(Cl)c(-c2ccc(Cl)cc2)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 73 %

Procedure:
6-Chloro-5-(4-chloro-phenyl)-nicotinic acid (1.4 g, 5 mmol) was dissolved in N,N-dimethylformamide (30 mL). To this solution was added sequentially (1R,2R)-2-amino-cyclohexanol hydrochloride (0.87 g, 6 mmol), TBTU (1.84 g, 6 mmol), and N-ethyldiisopropylamine (4.47 mL, 26 mmol). The reaction mixture was stirred at room temperature for 72 hours then concentrated in vacuo. The residue was then dissolved in ethyl acetate (100 mL) and washed with 0.5 N HCl (100 mL), saturated sodium bicarbonate (100 mL) and water (100 mL). The aqueous phases were extracted with ethyl acetate (2×100 mL), the organics were combined and the whole was dried over MgSO4 and concentrated in vacuo. The solid residue was purified by stirring with (ethylacetate/heptane 1:2, 50 mL) to give 6-chloro-5-(4-chloro-phenyl)-N-((1R,2R)-2-hydroxy-cyclohexyl)-nicotinamide as a colorless solid, 1.4 g (73% yield). m/z (ISP+): 364.9, 366.9 (M+H).