Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([N:6]([C:14]1[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][C:15]=1[CH3:21])[NH:7][C:8]([O:10][CH2:11][CH2:12]Cl)=[O:9])=[O:5].C1(C)C(C)=CC=CC=1.[OH-].[Na+]>O>[CH3:1][O:2][CH2:3][C:4]([N:6]([C:14]1[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][C:15]=1[CH3:21])[N:7]1[CH2:12][CH2:11][O:10][C:8]1=[O:9])=[O:5]
Reactant: COCC(=O)N(NC(=O)OCCCl)c1c(C)cccc1C
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1C
Solvent: O
Product: COCC(=O)N(c1c(C)cccc1C)N1CCOC1=O
Reaction time: 2 h

Procedure:
236.1 g (0.75 mol) 2-Chloroethyl 2-(methoxyacetyl)-2-(2,6-dimethylphenyl)-hydrazinecarboxylate, 375 ml xylene and 187 ml water are stirred with external cooling, while 82.5 ml (0.82 mol) of an aqueous solution of sodium hydroxide (containing ~0.4 g NaOH per ml) are added at a rate to maintain the internal temperature at approx. 20°. The mixture is stirred after completion of the addition for 1 hour at 20°, and for 2 hours at 0°. The solid is filtered off, washed with 150 ml water and dried to yield the title compound as a slightly coloured solid, m.p. 102°-103°.
Reaction SMILES: [CH2:1]([N:3]([CH3:14])[C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([CH3:13])[N:12]=1)[C:7]([OH:9])=O)[CH3:2].CCN(C(C)C)C(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[C:57]([O:61][C:62](=[O:78])[CH2:63][CH2:64][C:65]1[C:70]([CH3:71])=[CH:69][C:68]([C:72](=[NH:75])[NH:73]O)=[CH:67][C:66]=1[CH2:76][CH3:77])([CH3:60])([CH3:59])[CH3:58]>CN(C=O)C.O.C([O-])(O)=O.[Na+].O1CCOCC1>[C:57]([O:61][C:62](=[O:78])[CH2:63][CH2:64][C:65]1[C:70]([CH3:71])=[CH:69][C:68]([C:72]2[N:73]=[C:7]([C:6]3[CH:10]=[C:11]([CH3:13])[N:12]=[C:4]([N:3]([CH2:1][CH3:2])[CH3:14])[CH:5]=3)[O:9][N:75]=2)=[CH:67][C:66]=1[CH2:76][CH3:77])([CH3:60])([CH3:59])[CH3:58]
Reactant: CCN(C)c1cc(C(=O)O)cc(C)n1
Reactant: CCc1cc(C(=N)NO)cc(C)c1CCC(=O)OC(C)(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CCc1cc(-c2noc(-c3cc(C)nc(N(C)CC)c3)n2)cc(C)c1CCC(=O)OC(C)(C)C
Reaction time: 1 h

Procedure:
To a solution of 2-(ethyl-methyl-amino)-6-methyl-isonicotinic acid (106 mg, 0.459 mmol) and DIPEA (178 mg, 1.38 mmol) in DMF (2 mL) is added PyBOP (253 mg, 0.486 mmol) at 0° C. The mixture is stirred for 15 min at 0° C. before 3-[2-ethyl-4-(N-hydroxycarbamimidoyl)-6-methyl-phenyl]-propionic acid tert-butyl ester (140 mg, 0.459 mmol) is added. Stirring is continued for 1 h at 0° C. The reaction mixture is diluted with water (2 mL) and sat. aq. NaHCO3-solution and extracted three times with diethyl ether. The combined org. extracts are dried over MgSO4, filtered and concentrated to give the crude hydroxyamidine ester intermediate; LC-MS: tR=0.92 min; [M+1]+=483.22. This material is dissolved in dioxane and then stirred at 80° C. for 15 h. The solvent is removed in vacuo to give crude 3-(2-ethyl-4-{5-[2-(ethyl-methyl-amino)-6-methyl-pyridin-4-yl]-[1,2,4]oxadiazol-3-yl}-6-methyl-phenyl)-propionic acid tert-butyl ester; LC-MS: tR=1.03 min; [M+1]+=463.31. The crude ester is dissolved in 6 N aq. HCl (10 mL) and stirred at 65° C. for 18 h. The mixture is concentrated and the crude product is purified by prep. TLC using DCM containing 11% of methanol as eluent to give 3-(2-ethyl-4-{5-[2-(ethyl-methyl-amino)-6-methyl-pyridin-4-yl]-[1,2,4]oxadiazol-3-yl}-6-methyl-phenyl)-propionic acid (5 mg) as a yellow resin; LC-MS: tR=0.89 min; [M+1]+=409.19.
Reaction SMILES: C[N:2]([CH:4]=[C:5]1[C:10](=O)[CH2:9][CH2:8][N:7]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6]1)C.Cl.[Cl:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[NH:27]N>>[Cl:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N:27]1[C:10]2[CH2:9][CH2:8][N:7]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6][C:5]=2[CH:4]=[N:2]1
Reactant: CN(C)C=C1CN(C(=O)OC(C)(C)C)CCC1=O
Reactant: NNc1ccccc1Cl
Agent: Cl
Product: CC(C)(C)OC(=O)N1CCc2c(cnn2-c2ccccc2Cl)C1

Procedure:
Tert-butyl 3-((dimethylamino)methylene)-4-oxopiperidine-1-carboxylate (Example 32, Step A, 2.0 g) was reacted with 2-chlorophenyl hydrazine hydrochloride as described for Example 32, Step B to yield the title compound a as a yellow oil (1.39 g, 53%). 1H NMR (400 MHz, CDCl3): δ 7.56-7.54 (m, 2H), 7.45-7.40 (m, 3H), 4.54 (s, 2H), 3.72 (br s, 2H), 2.58 (br s, 2H), 1.51 (s, 9H).
Reaction SMILES: [Na].[C:2]1([CH:12]=O)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1>C(OC(=O)C)(=O)C>[C:2]1(/[CH:12]=[CH:12]/[C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:5]=[CH:4][CH:3]=2)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1cccc2ccccc12
Agent: [Na]
Solvent: CC(=O)OC(C)=O
Product: C(=C/c1cccc2ccccc12)\c1cccc2ccccc12

Procedure:
Compound 2 is prepared by the condensation of sodium α-napththylacetate with α-naphthaldehyde in acetic anhydride at 130° C for 8 hours. Some trans-1,2-di(1-naphthyl)ethylene is produced from the reaction and is crystallized from alcohol to yield a yellow crystalline solid, mp. 162°-163° C. Elemental analysis C 94.2, H 5.9, calculated for C22H16, C 94.3, H 5.7. The infrared spectrum of the product is consistent with this product's structure. The principal product of condensation is 2,3-di(1-naphthyl)acrylic acid which is isolated and purified by recrystallization from water as its sodium salt. The free acid (7 percent yield) is recrystallized from acetic acid. A relatively low yield may in part be accounted for by some difficulties in phase separation in the workup. The method used for preparation of compound 2 likely would have provided a higher yield, but this procedure is appropriate to permit isolation of the cis-olefin on decarboxylation of the acrylic acid. The acid is decarboxylated by heating in boiling quinoline with copper chromite catalyst for 1 hour. The resulting product, which appears to be mainly the desired cis-isomer contaminated with a small amount of trans, has mp. 98-105 C; the literature value is 103-104 C (Everett et al, J. Chem. Soc., 601 (1948).
Reaction SMILES: [CH2:1]([O:3][C:4]#[C:5][C:6]1[CH:7]=[C:8]([O:25][C:26]([F:29])([F:28])[F:27])[CH:9]=[C:10]2[C:15]=1[O:14][CH:13]([C:16]([F:19])([F:18])[F:17])[C:12]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:11]2)[CH3:2].[OH:30]S(O)(=O)=O.C([O-])(O)=O.[Na+].C([O-])([O-])=O.[K+].[K+]>CC(C)=O.O>[CH2:1]([O:3][C:4](=[O:30])[CH2:5][C:6]1[CH:7]=[C:8]([O:25][C:26]([F:27])([F:29])[F:28])[CH:9]=[C:10]2[C:15]=1[O:14][CH:13]([C:16]([F:17])([F:18])[F:19])[C:12]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:11]2)[CH3:2]
Reactant: O=S(=O)(O)O
Reactant: CCOC#Cc1cc(OC(F)(F)F)cc2c1OC(C(F)(F)F)C(C(=O)OCC)=C2
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CCOC(=O)Cc1cc(OC(F)(F)F)cc2c1OC(C(F)(F)F)C(C(=O)OCC)=C2
Reaction time: 2.5 h
Yield: 82 %

Procedure:
A solution of ethyl 8-(ethoxyethynyl)-6-(trifluoromethoxy)-2-(trifluoromethyl)-2H-chromene-3-carboxylate prepared as in Step 2 (1.73 g, 4.08 mmole) in a mixture of acetone (32 mL) and H2O (8 mL) was treated with H2SO4 (0.800 g, 8.15 mmole) and the resulting mixture was stiffed at room temperature for 2.5 hrs. Saturated NaHCO3 (200 mL) and then solid K2CO3 were then added and the product was extracted with EtOAc (300 mL). The EtOAc solution was washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The crude product was purified by silica chromatography (0%-15% EtOAc-hexanes gradient) to give 1.47 g (82% yield) of the product as a yellow crystalline solid: EIHRMS m/z 442.0880 (M+, C18H16F6O6, Calc'd 442.0851).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].I[CH2:12][C:13]([NH2:15])=[O:14].C(=O)([O-])[O-].[K+].[K+]>>[C:13]([CH2:12][O:10][C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)(=[O:14])[NH2:15]
Reactant: NC(=O)CI
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: NC(=O)COc1ccc([N+](=O)[O-])cc1
Yield: 33.5 %

Procedure:
A mixture of 4-nitrophenol (2.8 g), iodoacetamide (3.72 g) and potassium carbonate (2.8 g) in DHF (50 ml) was reacted. The product so obtained was recrystallised from a mixture of ethyl acetate and hexane to give 4-(carbamoylmethoxy)nitrobenzene (1.32 g), m.p. 153°-156° C. The product so obtained was dissolved in ethyl acetate and hydrogenated in the presence of a 10% Pd/C catalyst. The product so obtained was recrystallised from a mixture of ethyl acetate and hexane to give 4-(carbamoylmethoxy)aniline (0.58 g), m.p. 125°-127° C.;
Reaction SMILES: [F:1][C:2]1[CH:29]=[CH:28][C:5]([NH:6][C:7]2[CH:19]=[C:18]([C:20]3[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[N:24][CH:25]=3)[CH:17]=[CH:16][C:8]=2[C:9]([O:11]C(C)(C)C)=[O:10])=[CH:4][CH:3]=1.[F:30][C:31]([F:36])([F:35])[C:32]([OH:34])=[O:33]>>[F:30][C:31]([F:36])([F:35])[C:32]([OH:34])=[O:33].[F:1][C:2]1[CH:29]=[CH:28][C:5]([NH:6][C:7]2[CH:19]=[C:18]([C:20]3[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[N:24][CH:25]=3)[CH:17]=[CH:16][C:8]=2[C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1
Reactant: COc1ccc(-c2ccc(C(=O)OC(C)(C)C)c(Nc3ccc(F)cc3)c2)cn1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(-c2ccc(C(=O)O)c(Nc3ccc(F)cc3)c2)cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Trifluoroacetic acid 10 mL was added to the obtained tert-butyl 2-(4-fluoroanilino)-4-(2-methoxypyridin-5-yl)benzoate, and it was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure, the obtained residue was refined by reversed-phase silica gel column chromatography [eluent; 55-90% acetonitrile/0.1% trifluoroacetic acid aqueous solution] to give 2-(4-fluoroanilino)-4-(2-methoxypyridin-5-yl)benzoic acid trifluoroacetate.
Reaction SMILES: Cl[C:2]1[N:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH3:10][O:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16][NH2:17])=[CH:14][CH:13]=1.C(N(CC)C(C)C)(C)C>CC(O)C>[CH3:10][O:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16][NH:17][C:2]2[N:9]=[CH:8][CH:7]=[CH:6][C:3]=2[C:4]#[N:5])=[CH:14][CH:13]=1
Reactant: N#Cc1cccnc1Cl
Reactant: COc1ccc(CN)cc1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CNc2ncccc2C#N)cc1
Temperature: 80 °C
Reaction time: 24 h
Yield: 33.4 %

Procedure:
To a stirred mixture of 2-chloro-nicotinonitrile (Aldrich, 2.20 g, 15.88 mmol) and 4-methoxy-benzylamine (2.27 ml, 17.49 mmol) in 2-propanol (20 ml) was added N,N-diisopropylethylamine (5.53 ml, 31.75 mmol). The reaction mixture was heated to 80° C. and stirred at this temperature for 24 hours. More 4-methoxybenzylamine (0.50 ml, 3.85 mmol) was added and stirring continued at 70° C. for 48 hours. The mixture was cooled to room temperature and the resulting solid material (4-methoxy-benzylamine hydrochloride) removed by filtration. On standing a crystalline product formed in the filtrate, which was isolated by filtration, washed with 2-propanol and dried under reduced pressure affording the title compound as pale yellow crystals (1.27 g). 1H-NMR (DMSO-d6) δ 8.21-8.30 (m, 1H), 7.90 (d, 1H), 7.65 (t, 1H), 7.25 (d, 2H), 6.85 (d, 2H), 6.59-6.68 (m, 1H), 4.50 (d, 2H), 3.75 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][NH2:10].[C:11](OC(=O)C)(=[O:13])[CH3:12]>>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][NH:10][C:11](=[O:13])[CH3:12]
Reactant: CC(=O)OC(C)=O
Reactant: NCCc1ccccc1Br
Product: CC(=O)NCCc1ccccc1Br

Procedure:
In close analogy to the procedure described above, 2-(2-Bromo-phenyl)-ethylamine is reacted with acetic anhydride to provide the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:12])[C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[N+:13]([O-])([OH:15])=[O:14].O>CC(O)=O>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH3:12])[C:9]([OH:11])=[O:10])=[CH:6][C:7]=1[N+:13]([O-:15])=[O:14]
Reactant: O=[N+]([O-])O
Reactant: CC(C(=O)O)c1ccc(O)cc1
Solvent: O
Solvent: CC(=O)O
Product: CC(C(=O)O)c1ccc(O)c([N+](=O)[O-])c1
Reaction time: 1 h

Procedure:
2-(4-Hydroxy-phenyl)-propionic acid (788 mg, 1 mmol) in CH3COOH (10 ml) is added to 60% Nitric acid (552 mg, 1.11 mmol) at room temperature. The reaction mixture is stirred for 1 h. The iced water (50 ml) added to the reaction mixture. The mixture is extracted with ethyl acetate. The extracts are washed with water, dried over magnesium sulfate, filtered and concentrated in vacuo.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]([CH:7]([CH:10]=O)[CH:8]=O)[N:4]=[CH:3][CH:2]=1.Cl.[Br:13][C:14]1[CH:15]=[C:16]([NH:20][NH2:21])[CH:17]=[CH:18][CH:19]=1>C(O)C>[Br:13][C:14]1[CH:15]=[C:16]([N:20]2[CH:10]=[C:7]([C:5]3[CH:6]=[CH:1][CH:2]=[CH:3][N:4]=3)[CH:8]=[N:21]2)[CH:17]=[CH:18][CH:19]=1
Reactant: NNc1cccc(Br)c1
Reactant: O=CC(C=O)c1ccccn1
Agent: Cl
Solvent: CCO
Product: Brc1cccc(-n2cc(-c3ccccn3)cn2)c1
Temperature: 75 °C

Procedure:
2-(2-Pyridyl)malondialdehyde (100 mg, 0.67 mmol) and 3-bromophenylhydrazine hydrochloride (150 mg, 0.67 mmol) were suspended in ethanol (2 mL), and heated to 75° C. for 8 h. The reaction mixture was concentrated in vacuo and the residue was purified by silica gel preparative TLC eluting with hexanes:EtOAc (3:1) to afford 2-[1-(3-bromophenyl)-1H-pyrazol-4-yl]pyridine as a pale yellow solid. 1H-NMR (CDCl3, 300 MHz) δ 8.61 (d, J=4.8 Hz, 1H), 8.51 (s, 1H), 8.18 (s, 1H), 7.99 (s, 1H), 7.73-7.68 (m, 2H), 7.55 (d, J=7.9 Hz, 1H), 7.43 (d, J=8.8 Hz, 1H), 7.35 (t, J=8.1 Hz, 1H), 7.17 (dd, J=4.9, 7.4 Hz, 1H). MS (ESI) 300.0, 302.0 (M++H).
Reaction SMILES: Cl[C:2]1[CH:18]=[CH:17][C:5]([C:6]([C:8]2[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=2[C:10]([OH:12])=[O:11])=[O:7])=[CH:4][C:3]=1[N+:19]([O-:21])=[O:20].Cl.[OH-].[NH4+:24]>>[NH2:24][C:2]1[CH:18]=[CH:17][C:5]([C:6]([C:8]2[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=2[C:10]([OH:12])=[O:11])=[O:7])=[CH:4][C:3]=1[N+:19]([O-:21])=[O:20]
Reactant: [NH4+]
Reactant: O=C(O)c1ccccc1C(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Agent: Cl
Agent: [OH-]
Product: Nc1ccc(C(=O)c2ccccc2C(=O)O)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 24 h
Yield: 95 %

Procedure:
A solution of 2-(4-chloro-3-nitrobenzoyl)benzoic acid (38.5 g, 0.126 mol) in ammonium hydroxide (33% wt, 200 mL) was heated to a gentle reflux and stirred for 24 h. An additional ammonium hydroxide (200 mL) was added every 5 h within the 24 h reaction time period. The reaction mixture was cooled to room temperature and was added 6N aqueous hydrochloric acid until pH reached 2. The precipitated yellow solid was collected by filtration and washed with water then dried in vacuo to provide 2-[(4-amino-3-nitrophenyl)carbonyl]benzoic acid (38.8 g, 95%). 1H NMR (400 MHz, CD3OD): 8.27 (d, 1H), 8.11 (d, 1H), 7.80 (dd, 1H), 7.72 (td, 1H), 7.65 (td, 1H), 7.39 (d, 1H), 7.01 (d, 1H); MS (EI) for C14H10N2O5: 309 (MNa+).
Reaction SMILES: [CH:1]1([NH:4][CH2:5][CH:6]2[CH2:11][CH2:10][CH2:9][CH2:8][O:7]2)[CH2:3][CH2:2]1.C(N(CC)CC)C.[Cl:19][C:20](Cl)([O:22]C(=O)OC(Cl)(Cl)Cl)Cl.O>C1COCC1.CN(C)C1C=CN=CC=1>[CH:1]1([N:4]([CH2:5][CH:6]2[CH2:11][CH2:10][CH2:9][CH2:8][O:7]2)[C:20]([Cl:19])=[O:22])[CH2:3][CH2:2]1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: C1CCC(CNC2CC2)OC1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Cl)N(CC1CCCCO1)C1CC1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a stirred solution of cyclopropyl-(tetrahydro-pyran-2-ylmethyl)-amine (200 mg, 0.74 mmol) in THF (4 mL) is added triethylamine (144 μL, 1.036 mmol) and 4-dimethylaminopyridine (1.81 mg, 0.015 mmol). The mixture is cooled to 0° C., and triphosgene (88 mg, 0.296 mmol) is added in one portion. After stirring for 30 min at 0° C. and overnight at RT, water is cautiously added and the solution is extracted with AcOEt. The combined organic extracts are washed with brine, dried over Na2SO4, filtered and concentrated. TLC, Rf (CH2Cl2/MeOH 95:5)=0.9.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[N:7][C:8]([N:11]2[CH2:24][CH2:23][C:14]3[NH:15][C:16]4[CH:17]=[CH:18][C:19]([CH3:22])=[CH:20][C:21]=4[C:13]=3[CH2:12]2)=[N:9][CH:10]=1)=[O:4].[H-].[Na+].[C:27](Cl)(=[O:29])[CH3:28]>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[N:7][C:8]([N:11]2[CH2:24][CH2:23][C:14]3[N:15]([C:27](=[O:29])[CH3:28])[C:16]4[CH:17]=[CH:18][C:19]([CH3:22])=[CH:20][C:21]=4[C:13]=3[CH2:12]2)=[N:9][CH:10]=1)=[O:4]
Reactant: CC(=O)Cl
Reactant: COC(=O)c1cnc(N2CCc3[nH]c4ccc(C)cc4c3C2)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cnc(N2CCc3c(c4cc(C)ccc4n3C(C)=O)C2)nc1
Reaction time: 0.33 h

Procedure:
From 8-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole and Example 7 was obtained methyl-2-(8-methyl-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl)pyrimidine-5-carboxylate using the method described in Example 12. To a solution of methyl-2-(8-methyl-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl)pyrimidine-5-carboxylate (110 mg) in DMF (5 mL) was added sodium hydride (22 mg) at 0° C. and the mixtue was stirred for 20 min. Acetyl chloride (30 mg) was added and the reaction was allowed to attain room temperature and stirred another 3 hours. The reaction mixtue was partitioned between ethyl acetate and water. The organic layer was separated and washed with water and saturated aqueous sodium bicarbonate. The solvent was dried and evaporated and the residue purified by chromatography to give methyl-2-(5-acetyl-8-methyl-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl)pyrimidine-5-carboxylate.
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:10][C:11]1[CH:12]=[C:13]([C:17]2[CH:22]=[CH:21][C:20]([CH:23]=[C:24]3[S:28][C:27](=[O:29])[NH:26][C:25]3=[O:30])=[CH:19][CH:18]=2)[CH:14]=[CH:15][CH:16]=1.C(N(CC)CC)C>ClCCl>[O:29]=[C:27]1[NH:26][C:25](=[O:30])[C:24](=[CH:23][C:20]2[CH:19]=[CH:18][C:17]([C:13]3[CH:14]=[CH:15][CH:16]=[C:11]([NH:10][C:8]([NH:7][C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)=[O:9])[CH:12]=3)=[CH:22][CH:21]=2)[S:28]1
Reactant: Nc1cccc(-c2ccc(C=C3SC(=O)NC3=O)cc2)c1
Reactant: O=C=Nc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccccc1)Nc1cccc(-c2ccc(C=C3SC(=O)NC3=O)cc2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
500 μl (4.6 mmol) of phenyl isocyanate are added dropwise to a solution of 1.2 g (2.3 mmol) of 5-(3′-aminobiphenyl-4-ylmethylene)thiazolidine-2,4-dione prepared as in Example 33(a) and 0.9 ml (6.4 mmol) of triethylamine in 12 ml of dichloromethane. The reaction medium is stirred at room temperature for 2 hours. It is extracted with dichloromethane and washed with water, and the organic phase is separated out after settling of the phases has taken place. The organic phase is evaporated and the residue obtained is washed with dichloromethane and dried. 950 mg (50%) of the expected product are collected.
Reaction SMILES: [CH3:1][NH2:2].CS([C:7]1[N:12]=[C:11]([O:13][CH:14]([F:16])[F:15])[CH:10]=[C:9]([CH3:17])[N:8]=1)(=O)=O>C(Cl)Cl>[CH3:1][NH:2][C:7]1[N:12]=[C:11]([O:13][CH:14]([F:16])[F:15])[CH:10]=[C:9]([CH3:17])[N:8]=1
Reactant: CN
Reactant: Cc1cc(OC(F)F)nc(S(C)(=O)=O)n1
Solvent: ClCCl
Product: CNc1nc(C)cc(OC(F)F)n1
Yield: 74 %

Procedure:
30 ml of a 40% aqueous methylamine solution are added, at a temperature of between 20° and 25° C., to 2.2 g (0.009 mol) of 2-methylsulfonyl-4-difluoromethoxy-6-methylpyrimidine. The mixture warms up to a temperature of 60° C. The reaction mixture is subsequently stirred for half an hour at the same temperature; it is then cooled and 50 ml of methylene chloride are added. The organic phase is separated, dried over sodium sulfate and concentrated by evaporation. Crystallisation of the residue from a methylene chloride/petroleum ether mixture yields 1.4 g (74% of theory) of 2-methylamino-4-difluoromethoxy-6 -methylpyrimidine, m.p. 129.5°-131° C.
Reaction SMILES: Cl.[F:2][CH2:3][C:4]([C:8]1[CH:9]=[C:10]([NH:20][C:21]([NH:23][C:24]2[C:25]([CH3:36])=[N:26][C:27]([N:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)=[CH:28][CH:29]=2)=[O:22])[N:11]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[N:12]=1)([CH2:6][F:7])[CH3:5].[F:37][C:38]1[CH:46]=[CH:45][CH:44]=[C:43]([F:47])[C:39]=1[C:40](Cl)=[O:41].C(N(CC)CC)C>C(Cl)Cl>[F:37][C:38]1[CH:46]=[CH:45][CH:44]=[C:43]([F:47])[C:39]=1[C:40]([N:33]1[CH2:32][CH2:31][N:30]([C:27]2[N:26]=[C:25]([CH3:36])[C:24]([NH:23][C:21]([NH:20][C:10]3[N:11]([C:13]4[CH:14]=[CH:15][C:16]([CH3:19])=[CH:17][CH:18]=4)[N:12]=[C:8]([C:4]([CH2:6][F:7])([CH3:5])[CH2:3][F:2])[CH:9]=3)=[O:22])=[CH:29][CH:28]=2)[CH2:35][CH2:34]1)=[O:41]
Reactant: Cc1ccc(-n2nc(C(C)(CF)CF)cc2NC(=O)Nc2ccc(N3CCNCC3)nc2C)cc1
Reactant: O=C(Cl)c1c(F)cccc1F
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(-n2nc(C(C)(CF)CF)cc2NC(=O)Nc2ccc(N3CCN(C(=O)c4c(F)cccc4F)CC3)nc2C)cc1

Procedure:
Stir 1-[5-(2-Fluoro-1-fluoromethyl-1-methyl-ethyl)-2-p-tolyl-2H-pyrazol-3-yl]-3-(2-methyl-6-piperazin-1-yl-pyridin-3-yl)-urea hydrochloride (0.85 mmol, 0.5 g), 2,6-difluorobenzoyl chloride (0.85 mmol, 0.1 mL) and triethylamine (2.6 mmol, 0.4 mL) in 5 mL of CH2Cl2 at room temperature overnight. Add water and extract in CH2Cl2. Wash organic layer with saturated aq. sodium chloride solution. Dry over anhydrous sodium sulfate and concentrate under reduced pressure. Subject residue to silica gel chromatography eluting with using hexanes/ethyl acetate (20%-70%). MS(ES): m/z=624 [M+H].
Reaction SMILES: [CH2:1]([O:9][N:10]=[C:11]([C:17](=O)[CH2:18]Cl)[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[NH2:21][C:22]([NH2:24])=[S:23].O.O.O.C([O-])(=O)C.[Na+].O>C(O)C>[NH2:24][C:22]1[S:23][CH:18]=[C:17]([C:11](=[N:10][O:9][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[N:21]=1
Reactant: NC(N)=S
Reactant: CCCCCCCCON=C(C(=O)CCl)C(=O)OCC
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCCCCCCCON=C(C(=O)OCC)c1csc(N)n1
Yield: 35.8 %

Procedure:
Ethyl 2-n-octyloxyimino-4-chloro-3-oxobutyrate (syn isomer, 169.6 g.), thiourea (42.3 g.), sodium acetate trihydrate (75.5 g.), water (420 ml.) and ethanol (1020 ml.) were treated in a similar manner to that of Example F-(3) to give ethyl 2-(2-aminothiazol-4-yl)-2-n-octyloxyiminoacetate (syn isomer, 65 g.), mp. 77° to 78° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([CH3:9])[CH:8]=1)N.CS(O)(=O)=O.[N+]([O-])([O-])=O.[Na+].N.[ClH:21]>C(O)(=O)C>[Cl:21][C:4]1[CH:6]=[C:7]([CH3:9])[CH:8]=[C:2]([CH3:1])[CH:3]=1
Reactant: Cc1cc(C)cc(N)c1
Reactant: Cl
Agent: CS(=O)(=O)O
Agent: N
Agent: O=[N+]([O-])[O-]
Solvent: CC(=O)O
Product: Cc1cc(C)cc(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 3,5-dimethylaniline (36.3 g; 0.3 mole) in glacial acetic acid (200 ml) is treated with methanesulfonic acid (60 g) and the stirred mixture cooled to 0°-5° C. in an ice-salt bath. An ice cold solution of sodium nitrate (21 g in 80 ml H2O) is slowly added over a half hour period and this diazonium solution then added quickly to an ice cold solution of cuprous chloride [from copper sulphate 5 H2O (125 g), sodium chloride (32.5 g) and sodium sulphate (71 g)] in concentrated hydrochloric acid (160 ml). The mixture becomes very thick and is allowed to warm to room temperature. The stirring is continued overnight and the solution heated to 60° C. for 1/2 hour. Concentrated ammonia is added with cooling until the solution is alkaline and the oil extracted with ether. Distillation of the dried ether extract gives 5-chloro-m-xylene, b.p. 70°-73°/12 mm (25.6 g).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2([C:18]3[CH:23]=[CH:22][N:21]=[CH:20][C:19]=3[F:24])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([NH2:17])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[F:25][C:26]1[C:31]([O:32][CH3:33])=[CH:30][CH:29]=[CH:28][C:27]=1B(O)O>>[F:25][C:26]1[C:31]([O:32][CH3:33])=[CH:30][CH:29]=[CH:28][C:27]=1[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2([C:18]3[CH:23]=[CH:22][N:21]=[CH:20][C:19]=3[F:24])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([NH2:17])=[N:9]2)[CH:3]=1
Reactant: NC1=NC(c2cccc(Br)c2)(c2ccncc2F)c2ccccc21
Reactant: COc1cccc(B(O)O)c1F
Product: COc1cccc(-c2cccc(C3(c4ccncc4F)N=C(N)c4ccccc43)c2)c1F
Yield: 69 %

Procedure:
The title compound was synthesized from 1-(3-bromophenyl)-1-(3-fluoropyridin-4-yl)-1H-isoindol-3-amine (Scheme #12, I) as described in Example 67 (Scheme #10, D) in 69% yield using 2-fluoro-3-methoxyphenylboronic acid. 1H NMR (DMSO-d6) δ 8.26 (d, J=2.78 Hz, 1 H), 8.14 (d, J=5.05 Hz, 1 H), 7.67-7.61 (m, 1 H), 7.55-7.50 (m, 1 H), 7.34-7.28 (m, 2 H), 7.21-7.10 (m, 4 H), 7.07-6.92 (m, 3 H), 6.77 (br s, 2 H), 6.74-6.68 (m, 1 H), 3.65 (s, 3 H); MS (ESI) m/z 428 [M+1]+.