Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[Cl:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[C:7]=1[C:8]([NH2:10])=[O:9].[OH-].[Na+]>OS(O)(=O)=O>[Cl:5][C:6]1[C:14]([N+:1]([O-:4])=[O:2])=[CH:13][CH:12]=[C:11]([Cl:15])[C:7]=1[C:8]([NH2:10])=[O:9]
Reactant: NC(=O)c1c(Cl)cccc1Cl
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: NC(=O)c1c(Cl)ccc([N+](=O)[O-])c1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.3 %

Procedure:
A solution of 12 g of fuming HNO3 (d=1.52) in 11 ml of concentrated H2SO4 is added at room temperature over a period of 30 minutes to a solution of 30.4 g of 2,6-dichlorobenzoic acid amide in 60 ml of concentrated H2SO4 (d=1.83). After stirring for 2 hours at room temperature, the reaction mixture is added to ice/H2O and adjusted to a pH of ~ 6 with 30% NaOH and the precipitating crystals are isolated by filtration, affording 28.7 g of 2,6-dichloro-3-nitrobenzoic acid amide (m.p. 163°-165° C.).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[N:5][C:4]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)=[N:3]1.[BH4-].[Na+].[CH4:15]>CO.[Cl-].[Na+].CCOCC>[CH3:1][N:2]1[CH:6]=[N:5][C:4]([C:7]2[CH2:8][N:9]([CH3:15])[CH2:10][CH2:11][CH:12]=2)=[N:3]1
Reactant: C
Reactant: Cn1cnc(-c2cccnc2)n1
Agent: [BH4-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Solvent: CCOCC
Product: CN1CCC=C(c2ncn(C)n2)C1
Temperature: -10 °C
Reaction time: 3 h

Procedure:
A suspension of 6.3 g (0.020 mol) of the methiodide of 57 (prepared from 57 by the procedure described in Example 1) in 75 ml of methanol was cooled to -10° C., and 1.0 g (0.026 mol) of sodium borohydride was added. When the gas evolution had ceased, the mixture was stirred for 3 h at room temperature. Evaporation in vacuo give a red oil which was dissolved in 100 ml of a saturated sodium chloride solution. Extraction with 4×100 ml of dichloromethane, drying of the organic phase over magnesium sulfate, and evaporation in vacuo gave a red oil. The oil was dissolved in 50 ml of ether and stirred with charcoal. Filtration and evaporation gave the base of 59 as a colorless oil, 58. Yield: 1.6 g (0.009 mol, 45%). A 0.5 g portion of 58 was converted to the title compound. M.P. 181°-183° C. Anal. (C11H16N4O2) C, H, N.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12](I)=[CH:11][CH:10]=1)[CH3:2].[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1.C([O-])(O)=O.[Na+]>COCCOC.C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([O:3][C:4](=[O:16])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:22]2[CH:23]=[CH:24][C:19]([O:18][CH3:17])=[CH:20][CH:21]=2)=[CH:11][CH:10]=1)[CH3:2]
Reactant: COc1ccc(B(O)O)cc1
Reactant: CCOC(=O)CCCOc1ccc(I)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: COCCOC
Product: CCOC(=O)CCCOc1ccc(-c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 57.3 %

Procedure:
To a solution in ethylene glycol dimethyl ether (30 mL) of 4-(4-iodophenoxy)butyric acid ethyl ester (0.50 g, 1.5 mmol), prepared as in Example 5, step 1, was added tetrakis(triphenylphosphine)palladium(0) (87 mg, 75 μM), and the mixture was stirred for 15 minutes. A solution in ethanol (9.6 mL) of 4-methoxyphenylboronic acid (0.25 g, 1.64 mmol) was then added. Saturated aqueous NaHCO3 (15 mL) was then poured in quickly and the reaction mixture was warmed to reflux and heated for one hour. The reaction mixture was cooled to ambient temperature and concentrated in vacuo. The residue was partitioned between ethyl acetate and 10% aqueous Na2CO3. The organic phase was washed with 10% aqueous Na2CO3 and brine, dried over Na2SO4, filtered, and concentrated in vacuo. Chromatography on silica gel (20:1, then 10:1, then 5:1 hexane/ethyl acetate) gave 4-[4-(4-methoxyphenyl)phenoxy]butanoic acid ethyl ester (0.27 g, 57%) as white feathery needles.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([OH:8])[CH:7]=1.[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([O:8][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:7]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc(F)cc1OCc1ccccc1
Yield: 90.8 %

Procedure:
In DMF (300 ml), 5-fluoro-2-nitrophenol (10.0 g, 63.7 mmol), benzyl bromide (10.9 g, 63.7 mmol) and potassium carbonate (13.2 g, 95.6 mmol) were stirred at 80° C. for 4 hours. After cooling, the reaction mixture was poured in water (200 ml), followed by extraction with ether (2×200 ml). The extract was washed with saturated brine (200 ml), dried over anhydrous magnesium sulfate and distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column, whereby from hexane-ethyl acetate (4:1) eluate fractions, the title compound (14.3 g, 91.3%) was obtained as a pale yellow amorphous substance.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]3[N:14]=[C:15](S(C)(=O)=O)[N:16]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[C:11]3=[CH:10][C:9]=2[Cl:29])=[CH:4][CH:3]=1.[C:30]1([CH:36]2[O:41][C@H:40]3[CH2:42][C@@H:43]([OH:46])[CH2:44][O:45][C@@H:39]3[CH2:38][O:37]2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]3[N:14]=[C:15]([O:46][C@H:43]4[CH2:44][O:45][C@H:39]5[C@@H:40]([O:41][CH:36]([C:30]6[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=6)[O:37][CH2:38]5)[CH2:42]4)[N:16]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[C:11]3=[CH:10][C:9]=2[Cl:29])=[CH:4][CH:3]=1
Reactant: O[C@H]1CO[C@@H]2COC(c3ccccc3)O[C@H]2C1
Reactant: C[Si](C)(C)CCOCn1c(S(C)(=O)=O)nc2nc(-c3ccc(Br)cc3)c(Cl)cc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C[Si](C)(C)CCOCn1c(O[C@H]2CO[C@@H]3COC(c4ccccc4)O[C@H]3C2)nc2nc(-c3ccc(Br)cc3)c(Cl)cc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-(4-bromophenyl)-6-chloro-2-(methylsulfonyl)-1-((2-(trimethylsilyl)-ethoxy)methyl)-1H-imidazo[4,5-b]pyridine (2.6 g, 5.03 mmol), (4aR,7R,8aS)-2-phenylhexahydropyrano[3,2-d][1,3]dioxin-7-ol (1.307 g, 5.53 mmol), and cesium carbonate (4.92 g, 15.09 mmol) were dissolved in DMF (25.1 mL). The reaction mixture was stirred overnight at rt, then diluted with EtOAc and saturated NH4C/water (50:50). The aqueous phase was extracted with EtOAc (×2) and the combined extracts were washed with sat. NaHCO3 and brine, then dried over Na2SO4, filtered, and concentrated. The resulting residue was purified by column chromatography on a Biotage™ 100 g column by eluting with 10% EtOAc:Hexane to 70% EtOAc:Hexane to yield the desired product. LC-MS: calculated for C31H35BrClN3O5Si 671.12 observed m/e: 671.83 (M+H)+ (Rt 1.37/2 min).
Reaction SMILES: [Br:1][C:2]1[CH:6]=[CH:5][N:4]([CH2:7][CH2:8][OH:9])[N:3]=1.[H-].[Na+].I[CH3:13].O>CN(C)C=O>[Br:1][C:2]1[CH:6]=[CH:5][N:4]([CH2:7][CH2:8][O:9][CH3:13])[N:3]=1
Reactant: CI
Reactant: OCCn1ccc(Br)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COCCn1ccc(Br)n1

Procedure:
To a solution of 2-(3-bromo-1H-pyrazol-1-yl)ethanol obtained in Step D of Example 6 (300 mg) in N,N-dimethylformamide (16 mL) were added sodium hydride (55%, 137 mg) and iodomethane (196 μL) under ice-cooling. The reaction mixture was stirred under ice-cooling for 2 hr, water was added thereto, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (150 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[O:14][CH2:15][CH2:16][CH3:17])[NH:5][C:4](=[O:18])[C:3]=1[C:19]([OH:21])=[O:20].S(=O)(=O)(O)O.[CH3:27]O>>[CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[O:14][CH2:15][CH2:16][CH3:17])[NH:5][C:4](=[O:18])[C:3]=1[C:19]([O:21][CH3:27])=[O:20]
Reactant: CCCOc1ccccc1-c1cc(C)c(C(=O)O)c(=O)[nH]1
Reactant: CO
Agent: O=S(=O)(O)O
Product: CCCOc1ccccc1-c1cc(C)c(C(=O)OC)c(=O)[nH]1

Procedure:
A mixture of 1,2-dihydro-4-methyl-2-oxo-6-(2-propoxyphenyl)pyridine-3-carboxylic acid (0.75 g), methanol (50 ml) and concentrated sulfuric acid (0.5 ml) was heated under reflux for 6 hours. The residue left after evaporation was treated with water (30 ml) and potassium carbonate was added to pH 10. The resultant solid was washed with water and with ether to afford the title compound, 0.6 g, m.p. 167°-169° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([N+:11]([O-:13])=[O:12])=[C:4]([CH3:14])[N:3]=1.[CH3:15]S(C)=O.CN>CN(C)C(=O)C.O>[CH3:15][NH:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([N+:11]([O-:13])=[O:12])=[C:4]([CH3:14])[N:3]=1
Reactant: CS(C)=O
Reactant: Cc1nc(N)c([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: CN
Solvent: CC(=O)N(C)C
Solvent: O
Product: CNc1nc(C)c([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of 2-amino-6-methyl-3,5-dinitropyridine (24.9 g, 0.125 mole) and 175 ml dimethylsulfoxide in a 500 ml Parr bottle was added a solution of methylamine (20 g, 0.65 mole) in 75 ml N,N-dimethylacetamide. The reaction was shaken for 6 hours at ambient temperature and then heated 15 hours at 70° C. Upon cooling, the mixture was diluted with water, filtered, washed with methanol-water (1v/1v) and dried. 2-(methylamino)-6-methyl-3,5-dinitropyridine was obtained as a yellow solid (82% yield). Anal. Calcd. for C7H8N4O4 : C, 39.6; H, 3.8; N, 26.4. Found: C, 39.6; H, 3.9; N, 26.3.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:25]=[O:26])=[C:6]2[C:10]=1[N:9]=[C:8]1[N:11]([C:15]3[C:20]([Br:21])=[CH:19][C:18]([O:22][CH3:23])=[CH:17][C:16]=3[Br:24])[CH2:12][CH2:13][CH2:14][N:7]21.[CH2:27]([Mg]Br)[CH3:28]>O1CCCC1.[Cl-].[NH4+]>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[C:16]([Br:24])=[CH:17][C:18]([O:22][CH3:23])=[CH:19][C:20]=4[Br:21])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:25]([OH:26])[CH2:27][CH3:28])=[CH:4][CH:3]=1
Reactant: COc1cc(Br)c(N2CCCn3c2nc2c(Cl)ccc(C=O)c23)c(Br)c1
Reactant: CC[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCC(O)c1ccc(Cl)c2nc3n(c12)CCCN3c1c(Br)cc(OC)cc1Br
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 91.9 %

Procedure:
To a solution of 9-chloro-1-(2,6-dibromo-4-methoxyphenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole-6-carbaldehyde (80.0 mg, 0.160 mmol) in tetrahydrofuran (3.2 mL) was added dropwise ethylmagnesium bromide (3 M solution in diethyl ether, 0.107 mL, 0.321 mmol) at 0° C., and the mixture was stirred at 0° C. for 5 min. The reaction mixture was diluted with aqueous saturated ammonium chloride, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 10-50% ethyl acetate/n-hexane gradient mixture to give the title compound as a colorless solid (78.0 mg, 0.147 mmol, 92%).
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[C:9]1[N:17]=[CH:16][N:15]=[C:14]2[C:10]=1[NH:11][C:12](=[O:32])[N:13]2[C:18]1[CH:19]=[C:20]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH:21]=[CH:22][CH:23]=1)C1C=CC=CC=1.Cl>CO.[OH-].[OH-].[Pd+2]>[NH2:8][C:9]1[N:17]=[CH:16][N:15]=[C:14]2[C:10]=1[NH:11][C:12](=[O:32])[N:13]2[C:18]1[CH:19]=[C:20]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:28])([CH3:30])[CH3:29])[CH:21]=[CH:22][CH:23]=1
Reactant: CC(C)(C)OC(=O)Nc1cccc(-n2c(=O)[nH]c3c(N(Cc4ccccc4)Cc4ccccc4)ncnc32)c1
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)Nc1cccc(-n2c(=O)[nH]c3c(N)ncnc32)c1
Temperature: 60 °C
Yield: 76.9 %

Procedure:
To a mixture of tert-butyl 3-(6-(dibenzylamino)-8-oxo-7H-purin-9(8H)-yl)phenylcarbamate (4) (3.0 g, 5.7 mmol) in 120 mL MeOH was added 3.0 g Pd(OH)2/C (20 wt %) and 6 drops of con. HCl. After two vacuum/H2 cycles to remove air from the reaction flask, the stirred mixture was heated at 60° C. under hydrogen atmosphere overnight. The reaction mixture was filtered through a Celite pad and the filtrate was concentrated to dryness in vacuo. The residue was purified by column chromatography (silica gel, 0 to 5% methanol in DCM) to give tert-butyl 3-(6-amino-8-oxo-7H-purin-9(8H)-yl)phenylcarbamate (5) (1.5 g, 76%) as a white solid. LC-MS (ESI): m/z (M+1) 343.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:3]=1[C:4]([NH:6][NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[Cl:14])=[O:5].[C:20](Cl)(Cl)=[O:21]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:3]=1[C:4]1[O:5][C:20](=[O:21])[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[Cl:14])[N:6]=1
Reactant: O=C(NNc1ccccc1Cl)c1c(F)cccc1Cl
Reactant: O=C(Cl)Cl
Solvent: Cc1ccccc1
Product: O=c1oc(-c2c(F)cccc2Cl)nn1-c1ccccc1Cl
Temperature: 59 °C

Procedure:
39 g (0.13 mol) of 2-chloro-6-fluoro-N'-(o-chlorophenyl)-benzhydrazide are treated with a solution of 40 g (0.40 mol) of phosgene in 275 ml of toluene and the mixture is heated to reflux temperature (internal temperature 59° C.) for 2.5 hours. A further 13 g (0.13 mol) of phosgene in 70 ml of toluene are added thereto and the reaction mixture is heated to reflux temperature for a further 2.5 hours. The excess phosgene and toluene are distilled off, and the residue is taken up in 500 ml of diethyl ether and the solution is washed with semisaturated sodium chloride solution, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. After recrystallization of the crude product from a mixture of diethyl ether and n-hexane there is obtained pure 5-(2-chloro-6-fluorophenyl)-3-(2-chlorophenyl)-1,3,4-oxadiazol-2(3H)-one, m.p. 92°-95° C.; IR spectrum: 1790 cm-1 ; mass spectrum: 324(12), 280 (10), 125(100).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=1[C:4]#[N:5].[CH3:14][NH:15][NH2:16]>CC(O)C>[CH3:14][N:15]1[C:2]2[C:3](=[CH:6][C:7]([C:10]([F:11])([F:12])[F:13])=[CH:8][CH:9]=2)[C:4]([NH2:5])=[N:16]1
Reactant: N#Cc1cc(C(F)(F)F)ccc1F
Reactant: CNN
Solvent: CC(C)O
Product: Cn1nc(N)c2cc(C(F)(F)F)ccc21

Procedure:
2-Fluoro-5-trifluoromethyl-benzonitrile (Matrix, 6.5 g, 34.4 mmol) and methylhydrazine (Aldrich, 2.72 mL, 51.6 mmol) in IPA (10 mL) were heated to reflux for 2 hours. The solvent was removed to afford the title compound as white solid.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].[N+:11]([C:14]1[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=1)([O-:13])=[O:12].O>CC(N(C)C)=O>[N+:11]([C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:2](=[O:3])[O:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)=[CH:16][CH:15]=1)([O-:13])=[O:12]
Reactant: Nc1ccc([N+](=O)[O-])cc1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: CC(=O)N(C)C
Solvent: O
Product: O=C(Nc1ccc([N+](=O)[O-])cc1)Oc1ccccc1
Reaction time: 8 h

Procedure:
Phenyl chloroformate (1.08 mol) was added dropwise at a temperature <20° C. to a stirring solution of 4-nitrobenzenamine (1.02 mol) in DMA (500 ml) on ice and the mixture was stirred overnight. The mixture was poured into water (1000 ml), stirred till a homogenously suspension and filtered off, yielding phenyl (4-nitrophenyl)carbamate (intermediate 1).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH:27]=O)=[C:5]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N+:19]([O-:21])=[O:20])[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].[CH2:29]([N:31]([CH2:35][CH3:36])[CH2:32][CH2:33][NH2:34])[CH3:30].C1(C)C=CC(S(O)(=O)=O)=CC=1.C(OCC)C>C1C=CC=CC=1>[CH3:1][C:2]1[NH:3][C:4]([CH:27]=[N:34][CH2:33][CH2:32][N:31]([CH2:35][CH3:36])[CH2:29][CH3:30])=[C:5]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N+:19]([O-:21])=[O:20])[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCN(CC)CCN
Reactant: CCOC(=O)C1=C(C)NC(C=O)=C(C(=O)OCC)C1c1ccccc1[N+](=O)[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCC
Solvent: c1ccccc1
Product: CCOC(=O)C1=C(C)NC(C=NCCN(CC)CC)=C(C(=O)OCC)C1c1ccccc1[N+](=O)[O-]
Yield: 96.3 %

Procedure:
A mixture of diethyl 2-methyl-4-(2-nitrophenyl)-6-formyl-1,4-dihydropyridine-3,5-dicarboxylate (970.9 mg), N,N-diethylethylenediamine (290.5 mg) and p-toluenesulfonic acid (catalytic amount) in dried benzene (20 ml) was refluxed under azeotropic dehydration for 4 hours. To the resultant solution was added diethyl ether and the solution was washed with water and dried. The solvent was removed to give red oil (1.1711 g) of diethyl 2-methyl-4-(2-nitrophenyl)-6-[2-(N,N-diethylamino)ethyl]iminomethyl-1,4-dihydropyridine-3,5-dicarboxylate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:33])=[C:14]([C:28](OCC)=[O:29])[C:15](=[O:27])[N:16]3[CH2:19][C:20](=[O:26])[N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[NH2:34][CH:35]([CH3:38])[CH2:36][OH:37]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:33])=[C:14]([C:28]([NH:34][CH:35]([CH3:38])[CH2:36][OH:37])=[O:29])[C:15](=[O:27])[N:16]3[CH2:19][C:20](=[O:26])[N:21]3[CH2:22][CH2:23][CH2:24][CH2:25]3)=[N:11][CH:10]=2)=[CH:6][CH:7]=1
Reactant: CC(N)CO
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC(=O)N2CCCC2)c1=O
Product: CC(CO)NC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC(=O)N2CCCC2)c1=O

Procedure:
This compound was prepared from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1-[2-oxo-2-(1-pyrrolidinyl)ethyl]-1,2-dihydro-1,5-naphthyridine-3-carboxylate and (±)-2-amino-1-propanol employing methods similar to those those described in Example 9 and was purified by reverse phase preparative HPLC (C-18 stationary phase; 10-100% CH3CN/water/0.1% formic acid mobile phase). The product was obtained as a white solid: 1H NMR (CDCl3) δ 10.16 (1H, d, J=8 Hz), 8.54 (1H, s), 7.15 (2H, dd, J=8.5, 5.3 Hz), 7.04 (1H, s), 7.02 (2H, t, J=8.5 Hz), 4.90 (1H, d, J=17 Hz), 4.83 (1H, d, J=17 Hz), 4.27 (1H, m), 4.11 (2H, s), 3.76 (1H, m), 3.66 (1H, m), 3.50-3.44 (4H, m), 2.24 (1H, br), 2.05 (2H, m, J=7 Hz), 1.89 (2H, m, J=7 Hz), 1.29 (3H, d, J=7 Hz); HRMS calcd for C25H27FN4O5+H+: 483.2044. Found: 483.2047.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH:5]([O:18][CH2:19][CH3:20])[CH2:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([OH:17])=[CH:9][CH:8]=1)[CH3:2].Cl[CH2:23][C:24]1[N:25]=[C:26]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[O:27][C:28]=1[CH3:29].[H-].[Na+]>CN(C)C=O>[CH2:1]([O:3][C:4](=[O:21])[CH:5]([O:18][CH2:19][CH3:20])[CH2:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([O:17][CH2:23][C:24]2[N:25]=[C:26]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[O:27][C:28]=2[CH3:29])=[CH:9][CH:8]=1)[CH3:2]
Reactant: CCOC(=O)C(Cc1ccc(O)c2ccccc12)OCC
Reactant: Cc1oc(-c2ccccc2)nc1CCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(Cc1ccc(OCc2nc(-c3ccccc3)oc2C)c2ccccc12)OCC

Procedure:
In analogy to the procedure described in example 108 c], [rac]-2-ethoxy-3-(4-hydroxy-naphthalen-1-yl)-propionic acid ethyl ester was treated with 4-chloromethyl-5-methyl-2-phenyloxazole and sodium hydride in N,N-dimethylformamide to yield [rac]-2-ethoxy-3-[4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-naphthalen-1-yl]-propionic acid ethyl ester, which was further saponified in analogy to the procedure described in example 91 e] to yield [rac]-2-ethoxy-3-[4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-naphthalen-1-yl]-propionic acid as colorless solid.
Reaction SMILES: [N+]([O-])(O)=O.[F:5][C:6]([F:14])([F:13])[CH:7]=[CH:8][C:9]([F:12])([F:11])[F:10].[H][H]>>[F:5][C:6]([F:14])([F:13])[CH2:7][CH2:8][C:9]([F:12])([F:11])[F:10]
Reactant: FC(F)(F)C=CC(F)(F)F
Reactant: [H][H]
Solvent: O=[N+]([O-])O
Product: FC(F)(F)CCC(F)(F)F
Reaction time: 2.5 h
Yield: 99 %

Procedure:
In a 20 1 stainless steel autoclave, which had previously been conditioned using 10% strength nitric acid and was equipped with closed circuit heating and an anchor stirrer, 10.0 kg of 1,1,1,4,4,4-hexafluorobutene were heated from 0 to 30 C. over a period of 10 minutes in the presence of 250 g of catalyst (5% by weight of metallic palladium on activated carbon) at a pressure of 20 bar of hydrogen. After reaching this temperature, the hydrogen consumption was compensated for by repeated pressurization with fresh hydrogen at pressures between 20 and 30 bar. After about 2.5 hours the conversion was 87%. 1,1,1,4,4,4-Hexafluorobutane had been formed in a yield of greater than 99% of theory.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:12]=[N:13][C:14]([O:17][CH2:18][C:19]([OH:21])=[O:20])=[N:15][CH:16]=2)=[O:10])=[CH:4][CH:3]=1.[CH3:22][O:23][C:24]([C:26]1[S:27][CH:28]=[CH:29][C:30]=1O)=[O:25]>CO.ClCCl>[CH3:22][O:23][C:24]([C:26]1[S:27][CH:28]=[CH:29][C:30]=1[O:20][C:19](=[O:21])[CH2:18][O:17][C:14]1[N:13]=[CH:12][C:11]([C:9](=[O:10])[NH:8][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[CH:16][N:15]=1)=[O:25]
Reactant: COC(=O)c1sccc1O
Reactant: O=C(O)COc1ncc(C(=O)Nc2ccc(F)cc2)cn1
Solvent: CO
Solvent: ClCCl
Product: COC(=O)c1sccc1OC(=O)COc1ncc(C(=O)Nc2ccc(F)cc2)cn1
Yield: 44 %

Procedure:
The titled compound was prepared from [5-(4-fluorophenylcarbamoyl)pyrimidin-2-yloxy]acetic acid using 3-hydroxy-thiophene-2-carboxylic acid methyl ester (20 mg, 0.13 mmol) as the source alcohol. Chromatography (5% methanol/dichloromethane) through SiO2 yielded 32 mg (44%) of the titled compound. ESI-MS m/z 432 (MH+), 430 (M−H−).
Reaction SMILES: C[O:2][C:3](=[O:36])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:11]([C:24]2[CH:29]=[CH:28][C:27]([CH:30]3[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]3)=[CH:26][CH:25]=2)[C:12]([NH:14][C@H:15]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[CH3:16])=[O:13])=[CH:6][CH:5]=1.[OH-].[Na+].Cl>C(O)C>[Cl:23][C:20]1[CH:21]=[CH:22][C:17]([C@@H:15]([NH:14][C:12](=[O:13])[N:11]([CH2:10][C:7]2[CH:6]=[CH:5][C:4]([C:3]([OH:36])=[O:2])=[CH:9][CH:8]=2)[C:24]2[CH:29]=[CH:28][C:27]([CH:30]3[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]3)=[CH:26][CH:25]=2)[CH3:16])=[CH:18][CH:19]=1
Reactant: COC(=O)c1ccc(CN(C(=O)N[C@@H](C)c2ccc(Cl)cc2)c2ccc(C3CCCCC3)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: C[C@H](NC(=O)N(Cc1ccc(C(=O)O)cc1)c1ccc(C2CCCCC2)cc1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
4-[3-[1(S)-(4-Chlorophenyl)ethyl]-1-(4-cyclohexylphenyl)ureidomethyl]benzoic acid methyl ester (35.0 g, 69.3 mmol) was dissolved in ethanol (400 mL). 4 N aqueous sodium hydroxide (100 mL) was added and the clear solution was stirred at room temperature for 3 hours. The solution was neutralised with 4 N hydrochloric acid (100 mL), and placed upon an ice bath to initiate crystallization. The crystals were collected, washed extensively with water, and dried in vacuo overnight. Yield: 34.25 g (100%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[C:4]=1[F:25])#[N:2].[CH3:26][O:27][CH2:28][CH2:29][CH2:30][NH:31][CH3:32]>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([N:31]([CH2:30][CH2:29][CH2:28][O:27][CH3:26])[CH3:32])=[O:21])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[C:4]=1[F:25])#[N:2]
Reactant: CNCCCOC
Reactant: Cc1c(-c2cnn(-c3ccc(C(=O)O)cn3)c2O)ccc(C#N)c1F
Product: COCCCN(C)C(=O)c1ccc(-n2ncc(-c3ccc(C#N)c(F)c3C)c2O)nc1

Procedure:
The title compound was prepared in a manner similar to Example 301 using 6-(4-(4-cyano-3-fluoro-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and 3-methoxy-N-methylpropan-1-amine. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.66-1.93 (m, 2H) 2.34 (d, J=2.27 Hz, 3H) 2.98 (s, 3H) 3.07-3.67 (m, 7H) 7.64 (br. s., 1H) 7.70-7.81 (m, 1H) 7.84-8.64 (m, 4H). ESI-MS m/z [M+H]+ 424.3.