Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=C(C)[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[K+].[K+].S(=O)(=O)(O)O.[C:28]([OH:31])(=[O:30])[CH3:29]>>[F:1][C:2]1[CH:7]=[C:29]([CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10])[C:28]([OH:31])=[O:30]
Reactant: Cc1ccc([N+](=O)[O-])c(F)c1
Reactant: CC(=O)O
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=C(O)c1ccc([N+](=O)[O-])c(F)c1
Temperature: 120 °C
Yield: 83 %

Procedure:
2-Fluoro-4-methyl-1-nitro-benzene (1.0 g, 12.9 mmol) was added portion-wise to a suspension of potassium dichromate (5.04 g, 17.16 mmol) in glacial acetic acid (8 mL) follow by concentrated sulfuric acid (3.6 mL). The reaction mixture was heated to 120° C. for 2 h and then allowed to cool to ambient temperature. The reaction was quenched with crushed ice and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to afford 3-fluoro-4-nitro-benzoic acid (1.9 g, 83%) as a white solid.
Reaction SMILES: [F:1][C:2]1[C:11]([F:12])=[C:10]2[C:5]([C:6]([OH:16])=[C:7]([C:13]([OH:15])=O)[CH:8]=[N:9]2)=[CH:4][CH:3]=1.CN(C)C=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[Cl:34][C:35]1[CH:42]=[CH:41][C:38]([CH2:39][NH2:40])=[CH:37][CH:36]=1>O>[Cl:34][C:35]1[CH:42]=[CH:41][C:38]([CH2:39][NH:40][C:13]([C:7]2[CH:8]=[N:9][C:10]3[C:5]([C:6]=2[OH:16])=[CH:4][CH:3]=[C:2]([F:1])[C:11]=3[F:12])=[O:15])=[CH:37][CH:36]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: O=C(O)c1cnc2c(F)c(F)ccc2c1O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NCc1ccc(Cl)cc1)c1cnc2c(F)c(F)ccc2c1O
Temperature: 50 °C
Reaction time: 18 h

Procedure:
To a mixture of 0.25 g of 7,8-difluoro-4-hydroxy-3-quinolinecarboxylic acid and 10 mL of dimethyformamide is added 0.20 g of carbonyldiimidazole. The mixture is stirred 18 h at 50° C. and then it is cooled to 25° C. The mixture is treated with 0.10 mL of distilled water and stirred for 5 min. To the resulting solution is added 0.15 mL of 4-chlorobenzylamine. After stirring for 18 hours the solvent is evaporated at reduced pressure and the residue is dissolved in 10 mL of refluxing glacial acetic acid. Hot (100° C.) water is added dropwise until the solution becomes cloudy, and the mixture is allowed to cool to 25° C. The precipitate is collected by filtration and it is washed with two successive 5 mL portions of 50% aqueous acetic acid. It is dried for 18 h at 20 torr and 90° C. This procedure yields the title compound as 280 mg of a white powder.
Reaction SMILES: S(Cl)([Cl:3])=O.O[CH:6]([C:10]1[CH:11]=[CH:12][C:13]2[O:17][CH2:16][CH2:15][C:14]=2[CH:18]=1)[CH:7]([CH3:9])[CH3:8].O>ClCCl>[Cl:3][CH:6]([C:10]1[CH:11]=[CH:12][C:13]2[O:17][CH2:16][CH2:15][C:14]=2[CH:18]=1)[CH:7]([CH3:9])[CH3:8]
Reactant: O=S(Cl)Cl
Reactant: CC(C)C(O)c1ccc2c(c1)CCO2
Solvent: O
Solvent: ClCCl
Product: CC(C)C(Cl)c1ccc2c(c1)CCO2

Procedure:
Thionyl chloride (2.02 cm3, 0.265 mol) was added dropwise to a stirred solution of 2,3-dihydro-5-(1-hydroxy-2-methyl-1-propyl)benzofuran (5.10 g, 0.0265 mol) pyridine (2.16 cm3, 0.0265 mol) in dichloromethane (45 cm3) at 0°-5° C., and the mixture was heated to reflux for 3 hr. The mixture was poured into water and separated. The organic layer was washed with hydrochloric acid (2 N, 20 cm3), water, dried (Na2SO4), filtered and the solvent was removed. The residue was subjected to column chromatography on silica using toluene as the eluant. The appropriate fractions were combined and the solvent was removed to give 5-(1-chloro-2-methyl-1-propyl)-2,3-dihydrobenzofuran. (5.43 g, 0.028 mol, 97.2%) RF 0.68.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[CH:10][C:11]3[N:12]=[CH:13][N:14]=[C:15]([NH2:18])[C:16]=3[N:17]=2)[CH:5]=[CH:4][N:3]=1.Cl.[OH-:20].[Na+]>O1CCOCC1>[NH2:18][C:15]1[C:16]2[N:17]=[C:8]([C:6]3[CH:5]=[CH:4][NH:3][C:2](=[O:20])[CH:7]=3)[CH:9]=[CH:10][C:11]=2[N:12]=[CH:13][N:14]=1
Reactant: Nc1ncnc2ccc(-c3ccnc(F)c3)nc12
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Product: Nc1ncnc2ccc(-c3cc[nH]c(=O)c3)nc12
Temperature: 80 °C
Yield: 60 %

Procedure:
6-(2-fluoro-4-pyridyl)pyrido[3,2-d]pyrimidin-4-amine (50 mg, 0.21 mmol) 1 was treated with hydrogen chloride (4 mol/L) in 1,4-dioxane. The mixture was heated to 80° C. for 1 hour. Cooled to room temperature and basified with 4 N NaOH. Yellow precipitate was collected, and purified with Prep HPLC, 30 mg of 4-(4-aminopyrido[3,2-d]pyrimidin-6-yl)pyridin-2(1H)-one 2 was obtained (yield 60%). LC/MS (ESI+): m/z 240 (M+H). 1H NMR (400 MHz, DMSO) δ 8.39 (d, J=8.7 Hz, 1H), 8.18 (s, 1H), 8.15 (d, J=8.6 Hz, 1H), 7.52 (d, J=6.9 Hz, 1H), 7.11 (d, J=1.6 Hz, 1H), 7.00 (dd, J=6.9, 1.8 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5](Cl)=[CH:4][C:3]=1[Cl:12].[NH2:13][CH2:14][CH2:15][CH2:16][OH:17].[K]>C(O)CCC>[Cl:1][C:2]1[C:3]([Cl:12])=[CH:4][C:5]([NH:13][CH2:14][CH2:15][CH2:16][OH:17])=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1
Reactant: NCCCO
Reactant: O=[N+]([O-])c1cc(Cl)c(Cl)cc1Cl
Agent: [K]
Solvent: CCCCO
Product: O=[N+]([O-])c1cc(Cl)c(Cl)cc1NCCCO

Procedure:
A mixture of 113.2 parts of 1,2,4-trichloro-5-nitrobenzene, 75 parts of 3-amino-1-propanol, 0.2 parts of potassium iodic and 200 parts of butanol is stirred and refluxed overnight. The butanol is removed be evaporated in vacuo and water is added to the residue. The product is extracted with 4-methyl-2-pentanone. The extract is washed a few times with water, dried, filtered and evaporated. The oily residue is purified by column-chromatography over silica gel using a mixture of trichoromethane and 5% of methanol as elluent. The pure fractions are collected and the eluent is evaporated. The residue is triturated in 2,2'-oxybispropane. The product is filtered off and crystallized from a mixture of 2,2'-oxybispropane and 2-propanol, yielding 31.7 parts of 3-[(4,5-dichloro-2-nitrophenyl)amino]-1-propanol; mp. 97° C.
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[CH:4]=[CH:5][C:6]([OH:8])=O.[F:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)=[CH:16][C:15]=1[CH:26]([NH2:28])[CH3:27].CCN=C=NCCCN(C)C.Cl.CCN(CC)CC>CN(C1C=CN=CC=1)C.C(Cl)Cl>[F:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)=[CH:16][C:15]=1[CH:26]([NH:28][C:6](=[O:8])[CH:5]=[CH:4][C:3]1[CH:9]=[CH:10][CH:11]=[CH:12][C:2]=1[F:1])[CH3:27]
Reactant: O=C(O)C=Cc1ccccc1F
Reactant: CC(N)c1cc(N2CCOCC2)ccc1F
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(NC(=O)C=Cc1ccccc1F)c1cc(N2CCOCC2)ccc1F
Reaction time: 16 h

Procedure:
A mixture of 2-fluoro-cinnamic acid (83 mg), 1-(2-fluoro-5-morpholin-4-yl-phenyl)ethylamine, Preparation 25(112 mg), DMAP (61 mg), EDC.HCl (190 mg), and Et3N (202 mg) in CH2Cl2 (4 mL) was stirred for 16 hours. The crude product was purified by flash chromatography over silica gel (elution with 50% ethyl acetate in hexane) to give 150 mg of the title compound as a solid.
Reaction SMILES: [NH2:1][CH:2]([CH2:5][OH:6])[CH2:3][OH:4].Cl[CH2:8][C:9]([OH:11])=[O:10].[OH-].[Na+]>O>[OH:4][CH2:3][CH:2]([CH2:5][OH:6])[NH:1][CH2:8][C:9]([OH:11])=[O:10]
Reactant: NC(CO)CO
Reactant: O=C(O)CCl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)CNC(CO)CO
Temperature: 25 °C
Reaction time: 16 h
Yield: 51.6 %

Procedure:
Serinol (2.5 g, 26 mMol), chloroacetic acid (2.41 g, 26 mMol) and NaOH (3.2 ml 10N, 52 mMol) were dissolved in 25 ml water and stirred at room temperature for 16 h. The solution was concentrated on a rotoevaporator, and the resulting glass was redissolved in methanol. Addition of acetone gave a white solid (2 g, 51%) which was recrystallised from methanol/ethyl acetate. Mass spec calculated for C5H11NO4 : 149; found: 150 (M+1); 1H NMR in D2O (0.75% TMS): 3.85 (m, 4H), 3.80 (s, 2H), 3.45 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[O:9][C:10](=[CH2:15])[C:11]([O:13]C)=[O:12].O.[OH-].[Li+]>C1COCC1.O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[O:9][C:10](=[CH2:15])[C:11]([OH:13])=[O:12]
Reactant: C=C(Oc1ccccc1OC)C(=O)OC
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: C=C(Oc1ccccc1OC)C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 2-(2-methoxyphenyloxy)propenoate (0.30 g, 1.4 mmol) in THF (30 mL) and water (30 mL) was added lithium hydroxide monohydrate 0.17 g, 4.0 mmol). After stirring at room temperature overnight, the reaction was quenched by addition of concentrated hydrochloric acid (final pH=2), and the product was extracted with EtOAc (3×100 mL). The combined extracts were dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to give the title compound. 1H NMR (500 MHz, CD3OD): δ 7.42 (ddd, 1H), 7.22 (dd, 1H), 7.10 (dd, 1H), 6.97 (ddd, 1H), 5.48 (d, 1H), 4.51 (d, 1H), 3.64 (s, 3H).
Reaction SMILES: [N:1]([CH:4]1[CH2:23][N:8]2[C:9]3[C:14]([C:15]([CH2:16][C:17]([O:19]CCC)=[O:18])=[C:7]2[CH2:6][CH2:5]1)=[CH:13][CH:12]=[CH:11][CH:10]=3)=[N+:2]=[N-:3].[C:24]([C:26]1[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=1)#[CH:25]>>[F:33][C:32]([F:34])([F:35])[C:29]1[CH:28]=[CH:27][C:26]([C:24]2[N:3]=[N:2][N:1]([CH:4]3[CH2:23][N:8]4[C:9]5[C:14]([C:15]([CH2:16][C:17]([OH:19])=[O:18])=[C:7]4[CH2:6][CH2:5]3)=[CH:13][CH:12]=[CH:11][CH:10]=5)[CH:25]=2)=[CH:31][CH:30]=1
Reactant: C#Cc1ccc(C(F)(F)F)cc1
Reactant: CCCOC(=O)Cc1c2n(c3ccccc13)CC(N=[N+]=[N-])CC2
Product: O=C(O)Cc1c2n(c3ccccc13)CC(n1cc(-c3ccc(C(F)(F)F)cc3)nn1)CC2

Procedure:
The title compound was prepared using procedures described in EXAMPLE 1 from propyl (7-azido-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl)acetate and 1-ethynyl-4-(trifluoromethyl)benzene. MS (+ESI) m/z: 441.1.
Reaction SMILES: [NH:1]=[C:2]1[NH:6][C:5]([C:11]([F:14])([F:13])[F:12])([C:7]([F:10])([F:9])[F:8])[C:4](=[C:15]([F:20])[C:16]([F:19])([F:18])[F:17])[S:3]1.[N+:21]([C:24]1[CH:34]=[CH:33][CH:32]=[CH:31][C:25]=1[C:26]([N:28]=[C:29]=[O:30])=[O:27])([O-:23])=[O:22]>C1(C)C=CC=CC=1>[F:14][C:11]([F:12])([F:13])[C:5]1([C:7]([F:10])([F:9])[F:8])[C:4](=[C:15]([F:20])[C:16]([F:17])([F:18])[F:19])[S:3][C:2]([NH:1][C:29]([NH:28][C:26](=[O:27])[C:25]2[CH:31]=[CH:32][CH:33]=[CH:34][C:24]=2[N+:21]([O-:23])=[O:22])=[O:30])=[N:6]1
Reactant: O=C=NC(=O)c1ccccc1[N+](=O)[O-]
Reactant: N=C1NC(C(F)(F)F)(C(F)(F)F)C(=C(F)C(F)(F)F)S1
Solvent: Cc1ccccc1
Product: O=C(NC(=O)c1ccccc1[N+](=O)[O-])NC1=NC(C(F)(F)F)(C(F)(F)F)C(=C(F)C(F)(F)F)S1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
In toluene (10 ml) was dissolved 2-imino-4,4-bis(trifluoromethyl)-5-(tetrafluoroethylidene)-1,3-thiazolidine (1.0 g), and 2-nitrobenzoylisocyanate (0.4 g) which is a starting compound was added thereto and the mixture was stirred at room temperature for 3 hours.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.[CH3:11][C:12]1[C:16](I)=[C:15]([CH3:18])[O:14][N:13]=1.C([O-])(O)=O.[Na+]>COCCOC.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:16]2[C:12]([CH3:11])=[N:13][O:14][C:15]=2[CH3:18])=[CH:4][CH:3]=1
Reactant: Cc1noc(C)c1I
Reactant: OB(O)c1ccc(Br)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cc1noc(C)c1-c1ccc(Br)cc1
Temperature: 80 °C
Yield: 85 %

Procedure:
A mixture of 4-bromophenylboronic acid (1 g, 5 mmol), 3,5-dimethyl-4-iodoisoxazole (0.93 g, 4.2 mmol), bis(triphenylphospine)palladium(II) chloride (59 mg, 2 mol %), NaHCO3 (1.06 g, 12.6 mmol) in DME (5 mL) and H2O (5 mL) was heated to 80° C. under N2 for 18 h. The reaction mixture was partitioned between 1 N HCl and EtOAc. The organic layer was washed with saturated NaHCO3, brine, dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography (5% EtOAc in hexanes) to give the title compound as a white solid (0.9 g, 86%).
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:14][C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)=[C:7]([C:12]#[N:13])[CH:8]=[N:9]2)=[CH:4][C:3]=1[N+:27]([O-:29])=[O:28].[N-:30]=[N+:31]=[N-:32].[Na+]>CS(C)=O>[N:30]([C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:14][C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)=[C:7]([C:12]#[N:13])[CH:8]=[N:9]2)=[CH:4][C:3]=1[N+:27]([O-:29])=[O:28])=[N+:31]=[N-:32]
Reactant: COc1cc(Nc2c(C#N)cnc3cc(Cl)c([N+](=O)[O-])cc23)cc(OC)c1OC
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1cc(Nc2c(C#N)cnc3cc(N=[N+]=[N-])c([N+](=O)[O-])cc23)cc(OC)c1OC
Temperature: 0 °C
Reaction time: 15 h
Yield: 97.6 %

Procedure:
A mixture of 506.1 mg (1.2 mmol) of 7-chloro-6-nitro-4-(3,4,5-trimethoxyanilino)-3-quinolinecarbonitrile and 390.0 mg (6.0 mmol) of sodium azide in 10.0 mL of DMSO is heated at 40–50° C. for 5 hours, and then at room temperature for 15 hours. The mixture is poured into ice water and extracted with ethyl acetate. The organic phase is washed with brine and dried over sodium sulfate. Removal of the solvent yields 493.4 mg (97.7%) of 7-azido-6-nitro-4-(3,4,5-trimethoxyanilino)-3-quinolinecarbonitrile as a yellow solid which is used in the next reaction without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:21])[O:4][C:5]2[CH:18]=[C:17]([CH3:19])[C:16]([Cl:20])=[CH:15][C:6]=2[C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH3:14].[F:22][C:23]([F:34])([F:33])[C:24]1[CH:25]=[C:26]([N:30]=[C:31]=[O:32])[CH:27]=[CH:28][CH:29]=1>C1C=CC=CC=1>[Cl:20][C:16]1[C:17]([CH3:19])=[CH:18][C:5]2[O:4][C:3](=[O:21])[C:2]([NH:1][C:31]([NH:30][C:26]3[CH:27]=[CH:28][CH:29]=[C:24]([C:23]([F:22])([F:33])[F:34])[CH:25]=3)=[O:32])=[C:7]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[CH3:14])[C:6]=2[CH:15]=1
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Reactant: Cc1cc2oc(=O)c(N)c(-c3ccccc3C)c2cc1Cl
Solvent: c1ccccc1
Product: Cc1cc2oc(=O)c(NC(=O)Nc3cccc(C(F)(F)F)c3)c(-c3ccccc3C)c2cc1Cl

Procedure:
A mixture of 3-amino-6-chloro-7-methyl-4-(2-methylphenyl)-2H-benzopyran-2- one (297 mg), 3-trifluoromethylphenylisocyanate (374 mg) and benzene (4 ml) was refluxed for 2 hours and then distilled to remove the solvent. The residue was crystallized from ethyl ether. The resulting crystals were recrystallized from ethanol to obtain colorless needles of N-[6-chloro-7-methyl-4-(2-methylphenyl)-2-oxo- 2H-1-benzopyran-3-yl]-N'-(3-trifluoromethylphenyl) urea.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[C:5]([C:9]1[S:13][C:12]([NH2:14])=[N:11][N:10]=1)([CH3:8])([CH3:7])[CH3:6]>C(OCC)(=O)C>[C:5]([C:9]1[S:13][C:12]([N:14]=[C:1]=[O:2])=[N:11][N:10]=1)([CH3:8])([CH3:7])[CH3:6]
Reactant: O=C(Cl)Cl
Reactant: CC(C)(C)c1nnc(N)s1
Solvent: CCOC(C)=O
Product: CC(C)(C)c1nnc(N=C=O)s1
Reaction time: 16 h

Procedure:
A saturated solution of phosgene in ethyl acetate (100 ml) was charged into a glass reaction vessel equipped with a mechanical stirrer. A slurry of 5-t-butyl-2-amino-1,3,4-thiadiazole (10 grams) in ethyl acetate (300 ml) was added to the reaction vessel, and the resulting mixture was stirred for a period of about 16 hours, resulting in the formation of a precipitate. The reaction mixture was then purged with nitrogen gas to remove unreacted phosgene. The purged mixture was then filtered to recover the desired product 5-t-butyl-1,3,4-thiadiazol-2-yl isocyanate dimer as a solid having a melting point of 261° to 263° C.
Reaction SMILES: [CH3:1][N:2]1[C:9](=[O:10])[CH:8]([C:11]([O:13]CC)=O)[C:6](=[O:7])[N:5]([CH3:16])[C:3]1=[O:4].[F:17][C:18]([F:34])([F:33])[C:19]1[CH:20]=[CH:21][C:22]([O:25][C:26]2[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][CH:27]=2)=[N:23][CH:24]=1.C(O)C>C1(C)C=CC=CC=1>[CH3:16][N:5]1[C:6](=[O:7])[CH:8]([C:11](=[O:13])[NH:30][C:29]2[CH:31]=[CH:32][C:26]([O:25][C:22]3[CH:21]=[CH:20][C:19]([C:18]([F:34])([F:17])[F:33])=[CH:24][N:23]=3)=[CH:27][CH:28]=2)[C:9](=[O:10])[N:2]([CH3:1])[C:3]1=[O:4]
Reactant: Nc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Reactant: CCOC(=O)C1C(=O)N(C)C(=O)N(C)C1=O
Solvent: CCO
Solvent: Cc1ccccc1
Product: CN1C(=O)C(C(=O)Nc2ccc(Oc3ccc(C(F)(F)F)cn3)cc2)C(=O)N(C)C1=O

Procedure:
1.60 g (0.007 mol) of 1,3-dimethyl-5-ethoxycarbonylbarbituric acid and 1.78 g (0.007 mol) of 4-(5-trifluoromethylpyrid-2-yloxy)aniline are suspended in 20 ml of toluene. The suspension is heated to reflux for 16 hours, during which time ethanol escapes. After cooling, the precipitate is isolated by filtration, washed with toluene and dried, affording 1,3-dimethyl-5-[4-(5-trifluoromethylpyrid-2-yloxy)phenylcarbamoyl]barbituric acid of the formula ##STR24## with a melting point of 180°-181° C.
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]([CH:11]([CH3:13])[CH3:12])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C([O-])([O-])=O.[K+].[K+].[C:20]1([CH:27]=[CH:26][C:24]([OH:25])=[CH:23][CH:22]=1)[OH:21]>CN(C=O)C>[CH:11]([N:4]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:3][CH2:2][O:21][C:20]1[CH:27]=[CH:26][C:24]([OH:25])=[CH:23][CH:22]=1)([CH3:13])[CH3:12]
Reactant: CC(C)N(CCCl)c1ccccc1
Reactant: Oc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)N(CCOc1ccc(O)cc1)c1ccccc1
Temperature: 80 °C
Reaction time: 6 h
Yield: 38.5 %

Procedure:
A mixture of compound 4c (400 mg, 2 mmol), K2CO3 (558 mg, 4 mmol), and KI (720 mg, 4 mmol) in DMF (50 mL) was bubbled with argon for 10 min Hydroquinone (440 mg, 4 mmol) was added to the mixture under argon. The reaction mixture was heated and stirred at 80° C. for 6 hr. After cooling to room temperature, the solvent was evaporated and the residue was quenched with 100 mL water. The mixture was adjusted pH to ˜7 with diluted hydrochloric acid. The mixture was then extracted with CH2Cl2 and the combined organic layer was washed with water and then brine and was dried over Na2SO4. The solvent was evaporated and the residue was purified by silica gel column chromatography to provide compound 4 (210 mg, 0.77 mmol, 38.3% yield) as a brown oil. HRMS (ESI, positive) m/z calcd. for C17H22N1O2 [M+H]+: 272.16451, found: 272.16455. 1H NMR (400 MHz, CDCl3) δ 7.16-7.05 (m, 2H), 6.75-6.56 (m, 7H), 4.08-3.83 (m, 4H), 3.50-3.42 (t, J=7.1 Hz, 1H), 1.19-1.06 (m, 6H).
Reaction SMILES: [N+:1]([C:4]1[C:9]([CH:10]=O)=[CH:8][C:7]([O:12][CH3:13])=[C:6]([O:14][CH3:15])[CH:5]=1)([O-:3])=[O:2].[C:16]([CH2:18][C:19]([O:21][CH3:22])=[O:20])#[N:17].N1CCCCC1>CO>[C:16]([C:18](=[CH:10][C:9]1[CH:8]=[C:7]([O:12][CH3:13])[C:6]([O:14][CH3:15])=[CH:5][C:4]=1[N+:1]([O-:3])=[O:2])[C:19]([O:21][CH3:22])=[O:20])#[N:17]
Reactant: COC(=O)CC#N
Reactant: COc1cc(C=O)c([N+](=O)[O-])cc1OC
Solvent: C1CCNCC1
Solvent: CO
Product: COC(=O)C(C#N)=Cc1cc(OC)c(OC)cc1[N+](=O)[O-]
Yield: 78.1 %

Procedure:
To a mixture of 7.00 g (33.15 mmol) of 6-nitroveratraldehyde (80%) and 3.4 mL (38.42 mmol) of methyl cyanoacetate in 70 mL of methanol is added 0.7 mL of piperidine. An additional 100 mL of methanol is added and the thick suspension is warmed slightly until the mixture stirred freely. After stirring at room temperature for 1 hour, the solids are collected by filtration washing with methanol followed by diethyl ether to give 7.57 g (78%) of methyl 2-cyano-3-(4,5-dimethoxy-2-nitrophenyl)-2-propenoate as a pale yellow solid, mp 162-164° C.
Reaction SMILES: [NH2:1][NH2:2].[CH2:3]([O:10][C@@H:11]([C@@H:14]([C@@H:23]([CH2:25][O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[OH:24])[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:12]=[O:13])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>CO.O1CCCC1>[NH:1]([C:12]([C@H:11]([C@@H:14]([C@@H:23]([CH2:25][O:26][CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[OH:24])[O:15][CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[O:10][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:13])[NH2:2]
Reactant: O=C[C@@H](OCc1ccccc1)[C@H](OCc1ccccc1)[C@H](O)COCc1ccccc1
Reactant: NN
Solvent: C1CCOC1
Solvent: CO
Product: NNC(=O)[C@@H](OCc1ccccc1)[C@H](OCc1ccccc1)[C@H](O)COCc1ccccc1

Procedure:
To a solution of 3.8 g (119 mmoles) of anhydrous hydrazine in 10 ml of absolute methanol a solution of 5 g (11.9 mmoles) of 2,3,5-tri-O-benzyl-D-arabinose in 10 ml of absolute tetrahydrofuran (THF) is added dropwise while stirring and cooling in an ice bath at a moderate speed. After 10 minutes the ice bath is removed and the solution is stirred for 6 hours at room temperature. Then the solvent is removed with the superfluous hydrazine, and the remaining yellowish oil is dried for removal of the last traces of hydrazine for one day under a continuous oil pump vacuum.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:10])[CH:9]=1)[CH:5]=O.[CH:11]1([NH2:14])[CH2:13][CH2:12]1>>[CH:11]1([NH:14][CH2:5][C:4]2[CH:3]=[C:2]([F:1])[CH:9]=[C:8]([F:10])[CH:7]=2)[CH2:13][CH2:12]1
Reactant: NC1CC1
Reactant: O=Cc1cc(F)cc(F)c1
Product: Fc1cc(F)cc(CNC2CC2)c1

Procedure:
Synthesized according to typical procedure J from 3,5difluorobenzaldehyde and cyclopropylamine.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=2)=[CH:10][CH:9]=1)=[O:6].[CH3:38][N:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1>>[F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21]([N:42]3[CH2:43][CH2:44][N:39]([CH3:38])[CH2:40][CH2:41]3)[N:20]=2)=[CH:10][CH:9]=1)=[O:6]
Reactant: CN1CCNCC1
Reactant: CS(=O)(=O)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCCCC4)c3)c3ccccc23)n1
Product: CN1CCN(c2nccc(Oc3ccc(NC(=O)c4cc(F)cc(N5CCCCC5)c4)c4ccccc34)n2)CC1

Procedure:
Compound is prepared from 3-fluoro-N-[4-(2-methanesulfonyl-pyrimidin-4-yloxy)-naphthalen-1-yl]-5-piperidin-1-yl-benzamide and N-methylpiperazine according to conditions described in general procedure C. Mp: 182-184° C.;
Reaction SMILES: [CH3:1][NH:2][C:3]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[CH:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH2:16]=[C:17]1O[C:19](=[O:20])[CH2:18]1.C(Cl)Cl>CCOCC>[CH3:1][N:2]1[C:17]([CH3:16])=[CH:18][C:19](=[O:20])[C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])=[C:3]1[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: CCOC(=O)C=C(NC)c1ccccc1
Reactant: C=C1CC(=O)O1
Solvent: ClCCl
Solvent: CCOCC
Product: CCOC(=O)c1c(-c2ccccc2)n(C)c(C)cc1=O
Reaction time: 117 h

Procedure:
10.25 gms of ethyl beta-methylaminocinnamate, 9.4 gms of technical grade diketene and 25 mls dry methylene chloride are mixed in a flask fitted with a calcium chloride drying tube. The reaction mixture is stored at room temperature for 117 hours. Approximately 75 ml of dry ether is added and the resulting crystalline solid is filtered to yield 8.5 gms of ethyl 1,6-dimethyl-2-phenyl-4-oxonicotinate. mp (toluene)=244-8.
Reaction SMILES: S(CO[CH:7]1[C:15]2[CH:14]=[CH:13][C:12]3[C:16]4[C:21]([CH:22]=[CH:23][C:11]=3[C:10]=2[NH:9][CH2:8]1)=CC=CC=4)(O)(=O)=O.C1CS(=O)(=O)[O:26][CH2:25]1>>[CH:25]([N:9]1[C:10]2[C:15](=[CH:14][CH:13]=[C:12]3[CH:16]=[CH:21][CH:22]=[CH:23][C:11]3=2)[CH2:7][CH2:8]1)=[O:26]
Reactant: O=S1(=O)CCCO1
Reactant: O=S(=O)(O)COC1CNc2c1ccc1c2ccc2ccccc21
Product: O=CN1CCc2ccc3ccccc3c21

Procedure:
N-propylsulfonate naphthoindoline 102 (FIG. 19) was prepared by alkylation of 93 (FIG. 17) with 1,3-propane sultone with heating. Formyl-benzoindoline derivative 107 (FIG. 20) was prepared by formylation of 95 (FIG. 18) by the procedures of Example 17.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:4][N:3]=1.[BH4-].[Na+]>CO>[NH2:1][C:2]1[CH:7]=[C:6]([CH:8]([OH:10])[CH3:9])[CH:5]=[CH:4][N:3]=1
Reactant: CC(=O)c1ccnc(N)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(O)c1ccnc(N)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 45.2 %

Procedure:
To a mixture of 1-(2-aminopyridin-4-yl)ethanone (21) (168 mg, 1.234 mmol) in MeOH (10 mL), under nitrogen at 0° C., was added sodium borohydride (46.7 mg, 1.234 mmol). The resulting reaction mixture was stirred at RT for 2 hr, and then the solvents were removed under reduced pressure. The residue was taken up into EtOAc (25 mL), and extracted with saturated aq NaHCO3 solution (30 mL) and the layers separated. The aqueous layer was extracted with EtOAc (20 mL×2), and the combined organic extracts were washed with brine (30 mL), dried and the solvents removed under reduced pressure, to give 1-(2-aminopyridin-4-yl)ethanol (22) (77 mg, 45%) as a yellow oil: m/z 139 (M+H)+ (ES+).