Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[C:14](Cl)(=O)C(Cl)=O>CO.C(Cl)Cl>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:14])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: O=C(O)c1ccc(F)c([N+](=O)[O-])c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CO
Product: COC(=O)c1ccc(F)c([N+](=O)[O-])c1
Reaction time: 2 h
Yield: 63 %

Procedure:
4-fluoro-3-nitrobenzoic acid (2.5 g, 14 mmol, 1.0 eq) was dissolved in MeOH (68 mL) and heated to reflux. 2.0M oxalyl chloride in CH2Cl2 (14 mL) was added to the refluxing solution slowly and stirred for 2 h at reflux. The reaction was concentrated in vacuo, crystallized at 0° C., and filtered to give 1.7 g (63%) of crude methyl 4-fluoro-3-nitrobenzoate as a white solid. The product was confirmed by LCMS (>98% @ 220 nm and 254 nm) and carried forward without purification. Methyl 4-fluoro-3-nitrobenzoate (1.7 g, 8.4 mmol, 1.0 eq) and 5% palladium on carbon (89 mg, 0.84 mmol, 0.10 eq) were dissolved in EtOH (40 mL) and stirred under H2 atmosphere (1 atm) for 24 h. The mixture was filtered through celite and concentrated in vacuo affording 1.4 g (97%) of crude methyl 3-amino-4-fluorobenzoate as a brown solid. The product was confirmed by LCMS (>98% @ 220 nm and 254 nm) and carried forward without purification. Methyl 3-amino-4-fluorobenzoate (1.4 g, 8.2 mmol, 1.2 eq), 5-bromopyrimidine (1.1 g, 6.8 mmol, 1.0 eq), cesium carbonate (3.1 g, 9.6 mmol, 1.4 eq), Bis(dibenzylideneacetone)palladium (0.50 g, 0.55 mmol, 0.080 eq), and 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene (0.47 g, 0.82 mmol, 0.12 eq) were dissolved in Dioxane (17 mL) and stirred under argon at 100° C. overnight. The mixture cooled to rt and was filtered through celite and washed with 5% MeOH in CH2Cl2. The filtrate was collected, concentrated in vacuo, and purified by flash chromatography on silica gel afforded 1.5 g (90%) of the title compound as an orange solid: 1H NMR (400 MHz, DMSO-d6) δ 8.73 (s, 1H), 8.63 (s, 1H), 8.50 (s, 2H), 7.84 (dd, J=8.1, 2.1 Hz, 1H), 7.63 (ddd, J=8.5, 4.7, 2.1 Hz, 1H), 7.42 (dd, J=11.2, 8.6 Hz, 1H), 3.83 (s, 3H); ES-MS [M+1]+:248.1.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([N:14]2[CH2:18][CH:17]([CH2:19][O:20][CH3:21])[O:16][C:15]2=[O:22])[CH:5]=[CH:6][C:7]=1[CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.S(=O)(=O)(O)[OH:24].N([O-])=O.[Na+]>O>[CH:8]1([C:7]2[CH:6]=[CH:5][C:4]([N:14]3[CH2:18][CH:17]([CH2:19][O:20][CH3:21])[O:16][C:15]3=[O:22])=[CH:3][C:2]=2[OH:24])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: O=S(=O)(O)O
Reactant: COCC1CN(c2ccc(C3CCCCC3)c(N)c2)C(=O)O1
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: COCC1CN(c2ccc(C3CCCCC3)c(O)c2)C(=O)O1
Temperature: 0 °C
Yield: 60 %

Procedure:
200 mg (0.7 mmol) of (RS)-3-(3-amino-4-cyclohexyl-phenyl)-5-methoxymethyl-oxazolidin-2-one were suspended in a mixture of 0.86 ml of water, 0.72 g of ice and 0.235 ml of conc. sulfuric acid and treated at 0°-50 with a solution of 45 mg (0.66 mmol) of sodium nitrite in 0.4 ml of water. After boiling under reflux for 3 hours the mixture was extracted with dichloromethane, dried with sodium sulfate and the solvent was distilled off. Chromatography over silica gel with ethyl acetate/hexane 1:2 gave 120 mg (60%) of white crystals with m.p. 207°-208°.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13](=[O:15])[CH3:14])=[CH:10][CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[Br-:16].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>C1COCC1.[Br-].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13](=[O:15])[CH2:14][Br:16])=[CH:10][CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc2c(c1)CCN2C(C)=O
Reactant: [Br-]
Agent: c1cc[nH+]cc1
Solvent: C1CCOC1
Product: CC(=O)N1CCc2cc(C(=O)CBr)ccc21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 92.9 %

Procedure:
To a suspension of 1,5-diacetylindoline (10.0 g, 49.2 mmol) in 90 mL of THF at rt was added pyridinium tribromide (16.52 g, 51.7 mmol, 1 equiv) as solids portionwise over a period of 10 min. When there was still about 1.5 g of pyridinium tribromide left, the mixture solidified. Added another 30 mL of THF to make the mixture stirrable again. The remaining 1.5 g tribromide was added in one portion. The mixture was stirred at rt (no exotherm as checked by a thermometer). After 1.5 h, LCMS showed conversion complete. The suspension was filtered. The cake was washed with THF (2×30 mL), and then water (2×50 mL). The wet cake was sucked under house vacuum at rt for 2 days to give 1-(1-acetyl-2,3-dihydro-1H-indol-5-yl)-2-bromoethanone (12.89 g) as light grey solids. LC-MS (ES) m/z=281.9, 283.9.
Reaction SMILES: [O-:1][N+:2]1[O:6][N:5]=[C:4]([O:7][CH2:8][CH2:9][C:10]([O:12]C(C)(C)C)=[O:11])[C:3]=1[S:17]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)(=[O:19])=[O:18].C(O)(C(F)(F)F)=O>ClCCl>[O-:1][N+:2]1[O:6][N:5]=[C:4]([O:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])[C:3]=1[S:17]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)(=[O:18])=[O:19]
Reactant: CC(C)(C)OC(=O)CCOc1no[n+]([O-])c1S(=O)(=O)c1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CCOc1no[n+]([O-])c1S(=O)(=O)c1ccccc1
Reaction time: 6 h

Procedure:
14 g of the compound obtained in Step A dissolved in 100 ml of dichloromethane are placed under argon, 10 ml of TFA are added, and then stirring is carried out for 6 hours at ambient temperature.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1.[H-].[Na+].Cl[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([CH:27]=[C:28]([CH3:34])[C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:23][CH:22]=1>CN(C=O)C.O>[CH2:32]([O:31][C:29]([C:28]([CH3:34])=[CH:27][C:24]1[CH:25]=[CH:26][C:21]([CH2:20][N:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[C:2]([CH3:1])=[C:3]2[C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[CH:22][CH:23]=1)=[O:30])[CH3:33]
Reactant: Cc1c(-c2cccnc2)[nH]c2ccccc12
Reactant: CCOC(=O)C(C)=Cc1ccc(CCl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(C)=Cc1ccc(Cn2c(-c3cccnc3)c(C)c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 3-methyl-2-(3-pyridyl)indole (2.08 g) in 12 ml of DMF is added to a suspension of 0.528 g of 50% sodium hydride (dispersion in mineral oil) in 6 ml of DMF under nitrogen at 10°-15°. After complete addition the mixture is stirred at room temperature for 0.5 hour and is treated with a solution of 2.39 g of ethyl 3-(p-chloromethylphenyl)-2-methylacrylate in 5 ml of DMF dropwise. The resulting mixture is stirred at room temperature overnight and poured in 100 ml of water. The resulting mixture is extracted with ethyl acetate (2×50 ml) and the organic layer is washed with 100 ml of brine, dried over magnesium sulfate and evaporated to yield 1-[p-(2-ethoxycarbonylpropen-1-yl)benzyl]-3-methyl-2-(3-pyridyl)indole.
Reaction SMILES: [CH3:1][CH:2]([S:4]([NH:7][CH:8]1[CH2:12][CH2:11][CH2:10][C:9]1=[O:13])(=[O:6])=[O:5])[CH3:3].[F:14][C:15]1[CH:20]=[CH:19][C:18]([Mg]Br)=[CH:17][CH:16]=1.[Cl-].[NH4+]>C1COCC1.O>[F:14][C:15]1[CH:20]=[CH:19][C:18]([C:9]2([OH:13])[CH2:10][CH2:11][CH2:12][CH:8]2[NH:7][S:4]([CH:2]([CH3:1])[CH3:3])(=[O:6])=[O:5])=[CH:17][CH:16]=1
Reactant: CC(C)S(=O)(=O)NC1CCCC1=O
Reactant: Fc1ccc([Mg]Br)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)S(=O)(=O)NC1CCCC1(O)c1ccc(F)cc1
Temperature: 25 °C

Procedure:
Scheme IA, step D: Into a flame dried 100 mL 3 neck flask that was fitted with a thermometer and condenser, 2-{[(methylethyl)sulfonyl]amino}cyclopentan-1-one (1.10 g, 5.36 mmol) in THF (25 mL) was added dropwise to 4-fluorophenylmagnesium bromide (3 mL, 2M solution in diethyl ether) while stirring at room temperature under a nitrogen atmosphere and keeping the temperature above 25° C. After the addition was complete, the reaction was refluxed for 2 hours and then stirred overnight at room temperature. In the morning, enough saturated ammonium chloride in water was added to precipitate the salts and the organic layer was decanted off. The remaining salts were washed two times with ether and the combined organic layers were concentrated under reduced vacuum. The resulting material was taken into ethyl acetate, washed once with water, dried over potassium carbonate, filtered, and concentrated under reduced vacuum to yield 930 mg of a dark oil. This isomeric mixture was purified via silica gel chromatography employing the Chromatotron® and using a 4000 micron rotor while eluting with a solvent of hexane/ethyl acetate 7:3 to provide the title compound (787 mg, 49%) as an oil. Ion Spray M.S. 300.1 (M*−1). Calculated for C14H20NO3SF—½H2O: Theory: C, 54.16; H, 6.82; N, 4.51. Found: C, 54.39; H, 6.61; N, 4.69.
Reaction SMILES: [C:1]([C:4]1[CH:34]=[CH:33][C:7]([O:8][CH2:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][CH:15]([O:18][CH:19]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=3)[CH2:14][CH2:13]2)=[CH:6][CH:5]=1)(O)=[O:2].C(Cl)(=O)C(Cl)=O.[NH2:41][C:42]1[NH:46][N:45]=[N:44][N:43]=1.N1C=CC=CC=1>ClCCl>[NH:43]1[C:42]([NH:41][C:1]([C:4]2[CH:34]=[CH:33][C:7]([O:8][CH2:9][CH2:10][CH2:11][N:12]3[CH2:17][CH2:16][CH:15]([O:18][CH:19]([C:26]4[CH:27]=[CH:28][C:29]([Cl:32])=[CH:30][CH:31]=4)[C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=4)[CH2:14][CH2:13]3)=[CH:6][CH:5]=2)=[O:2])=[N:46][N:45]=[N:44]1
Reactant: O=C(O)c1ccc(OCCCN2CCC(OC(c3ccc(Cl)cc3)c3ccccn3)CC2)cc1
Reactant: Nc1nnn[nH]1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Nc1nnn[nH]1)c1ccc(OCCCN2CCC(OC(c3ccc(Cl)cc3)c3ccccn3)CC2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 56.3 %

Procedure:
To 0.84 g (1.75 mmol) of 1-[3-(4-carboxyphenoxy)propyl]-4[(4-chlorophenyl)-2-pyridylmethoxy]piperidine dissolved in 8 ml of dichloromethane was added dropwise 1.5 ml of oxalyl chloride under cooling in an ice bath. The mixture was stirred at 0° C. for 0.5 hour and then at room temperature for 0.5 hour, and concentrated under reduced pressure. The residue was added dropwise to a mixed solution of 0.15 g (1.76 mmol) of 5-amino-1,2,3,4-tetrazole dissolved in 10 ml of dichloromethane and 5 ml of pyridine under cooling in an ice bath. After completion of the dropwise addition, the mixture was stirred at 0° C. for 2 hours and then at room temperature for 2 hours, and concentrated under reduced pressure. The residue was applied to silica gel column chromatography using a mixed solvent of chloroform and methanol in a volume ratio of 20:1 and then using a mixed solvent of chloroform, methanol and 28% aqueous ammonia in a volume ratio of 100:10:1 as eluents to obtain 0.54 g (yield: 57%) of 1-{3-{4-[N-(1,2,3,4-tetrazol-5-yl)carbamoyl]phenoxy}propyl}-4-[(4-chlorophenyl)-2-pyridylmethoxy]piperidine as an orange foamy product.
Reaction SMILES: O=[C:2]([CH2:8][C:9](=O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH3:17][CH:18]([N:20]1[C:24]([NH2:25])=[CH:23][CH:22]=[N:21]1)[CH3:19].C1C=CC=CC=1>C(O)(=O)C>[CH3:17][CH:18]([N:20]1[C:24]2[N:25]=[C:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:8]=[C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:23]=2[CH:22]=[N:21]1)[CH3:19]
Reactant: CC(C)n1nccc1N
Reactant: CCOC(=O)C(=O)CC(=O)c1ccccc1
Solvent: c1ccccc1
Solvent: CC(=O)O
Product: CCOC(=O)c1cc(-c2ccccc2)nc2c1cnn2C(C)C

Procedure:
The title compound was prepared in the same manner as described for intermediate 61 using ethyl 2,4-dioxo-4-phenylbutanoate (5 g, 22.7 mmol), 1-(1-methylethyl)-1H-pyrazol-5-amine (2.84 g, 22.7 mmol), benzene (70 mL), and acetic Acid (44 mL) The crude product was purified by silica gel chromatography (eluent: 0 to 100% EtOAc/hexanes) to give 6.72 g (95%) as a pale yellow solid. LCMS E-S (M+H)=310.5. 1H NMR (400 MHz, DMSO-d6) δ 8.39 (s, 1H), 8.17-8.28 (m, 3H), 7.49-7.64 (m, 3H), 5.38 (quin, J=6.69 Hz, 1H), 4.49 (q, J=7.07 Hz, 2H), 1.57 (d, J=6.57 Hz, 6H), 1.44 (t, 3H).
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=1[O:19][CH3:20])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9]C)=O.[C:21]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:22]([CH:27]=O)=[CH:23][CH:24]=[CH:25][CH:26]=1>>[C:21]1([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH2:27][N:1]1[CH:2]([C:11]2[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=2[O:19][CH3:20])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]1=[O:9]
Reactant: O=Cc1ccccc1-c1ccccc1
Reactant: COC(=O)CCCCC(N)c1c(OC)cccc1OC
Product: COc1cccc(OC)c1C1CCCCC(=O)N1Cc1ccccc1-c1ccccc1

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 6-amino-6-(2,6-dimethoxyphenyl)hexanoate with commercially available [1,1′-biphenyl]-2-carbaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.98 min.; [M+H]+: 416.24 g/mol.
Reaction SMILES: [CH:1]([C:3]1[CH:7]=[CH:6][N:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[OH:14])[CH:4]=1)=O.C([N:17](CC)CC)C.Cl.NO>C(OC(=O)C)(=O)C>[C:1]([C:3]1[CH:7]=[CH:6][N:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[OH:14])[CH:4]=1)#[N:17]
Reactant: CCN(CC)CC
Reactant: O=Cc1ccn(-c2ccccc2O)c1
Agent: Cl
Agent: NO
Solvent: CC(=O)OC(C)=O
Product: N#Cc1ccn(-c2ccccc2O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.4 %

Procedure:
2-(3-Formyl-1-pyrrolyl)phenol (3 g, 16 mmol) and triethylamine (17.6 mmol) are added to a suspension of hydroxylamine hydrochloride (1.22 g, 17.6 mmol) in acetic anhydride (7.7 ml), and the mixture is allowed to stir overnight at ambient temperature. The mixture is refluxed for 5 hours, concentrated, dissolved in 50 ml ethanol and stirred for 10 min with 50 ml 2 M aqueous sodium hydroxide. After neutralisation with aqueous hydrochloric acid, and extraction with ethyl acetate, the organic layer is dried and concentrated. The residue is purified by chromatography (toluene/ethanol 9:1) to yield 2-(3-cyano-1-pyrrolyl)phenol (2.4 g, 92%). This phenolic product is reacted with (2S)-glycidyl 3-nitrobenzenesulfonate substantially as described for Epoxide 1 to yield the title epoxide.
Reaction SMILES: [Si:1]([O:8][CH:9]([C:11]1[O:15][N:14]=[C:13]([CH2:16][OH:17])[CH:12]=1)[CH3:10])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].N12CCN(CC1)CC2.[C:26]1([CH3:36])[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1.O>COC(C)(C)C>[CH3:36][C:26]1[CH:31]=[CH:30][C:29]([S:32]([O:17][CH2:16][C:13]2[CH:12]=[C:11]([CH:9]([O:8][Si:1]([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3])[CH3:10])[O:15][N:14]=2)(=[O:34])=[O:33])=[CH:28][CH:27]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(O[Si](C)(C)C(C)(C)C)c1cc(CO)no1
Agent: C1CN2CCN1CC2
Solvent: O
Solvent: COC(C)(C)C
Product: Cc1ccc(S(=O)(=O)OCc2cc(C(C)O[Si](C)(C)C(C)(C)C)on2)cc1
Reaction time: 10 h
Yield: 30.6 %

Procedure:
7.35 g of {5-[1-(t-butyldimethylsilanyloxy)ethyl]isoxazol-3-yl}methanol was dissolved in 50 ml of methyl-t-butyl ether, and 3.36 g of 1,4-diazabicyclo[2.2.2]octane and 5.72 g of 4-toluenesulfonyl chloride were then added under ice-cooling. The mixture was stirred for 10 hours under ice-cooling. After water was added, the reaction mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, filtered and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 3.60 g of {5-[1-(t-butyldimethylsilanyloxy)ethyl]isoxazol-3-yl}methyl 4-methylbenzenesulfonate.
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[NH:7][CH2:8][CH2:9][CH2:10][NH:11][CH:12]([C:15]1[N:16]([CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:17](=[O:28])[C:18]2[C:23]([C:24]([F:27])([F:26])[F:25])=[N:22][O:21][C:19]=2[N:20]=1)[CH2:13][CH3:14])([CH3:4])([CH3:3])[CH3:2].[CH3:37][C:38]1[CH:46]=[CH:45][C:41]([C:42](Cl)=[O:43])=[CH:40][CH:39]=1.CCN(CC)CC>C(Cl)Cl>[C:1]([O:5][C:6](=[O:36])[NH:7][CH2:8][CH2:9][CH2:10][N:11]([CH:12]([C:15]1[N:16]([CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:17](=[O:28])[C:18]2[C:23]([C:24]([F:26])([F:25])[F:27])=[N:22][O:21][C:19]=2[N:20]=1)[CH2:13][CH3:14])[C:42](=[O:43])[C:41]1[CH:45]=[CH:46][C:38]([CH3:37])=[CH:39][CH:40]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: CCC(NCCCNC(=O)OC(C)(C)C)c1nc2onc(C(F)(F)F)c2c(=O)n1Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(c1nc2onc(C(F)(F)F)c2c(=O)n1Cc1ccccc1)N(CCCNC(=O)OC(C)(C)C)C(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.2 %

Procedure:
To a solution of 11 (60 mg, 0.118 mmol) in CH2Cl2 (2.0 mL) stirred at room temperature was added 4-methyl-benzoyl chloride (24.1 mg, 0.153 mmol), followed by Et3N (18 mg, 0.117 mmol). The reaction mixture was stirred at room temperature for 1 h. More 4-methyl-benzoyl chloride (24 mg, 0.153 mmol), and Et3N (18 mg, 0.117 mmol) were added. After another hour, the reaction mixture was purified by SiO2 chromatography directly (EtOAc:heaxanes/1:4) to afford 12 (52 mg, 70%). MS (ESI): 628 (M+H)+.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]=[C:14]([CH3:17])[CH:13]=[C:12]2[NH:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=1.[N:28]1[CH:33]=[CH:32][CH:31]=[C:30]([S:34](Cl)(=[O:36])=[O:35])[CH:29]=1>>[Cl:27][C:22]1[CH:21]=[C:20]([CH:25]=[CH:24][C:23]=1[Cl:26])[CH2:19][NH:18][C:12]1[C:11]2[C:16](=[C:7]([O:6][CH2:5][CH2:4][NH:3][S:34]([C:30]3[CH:29]=[N:28][CH:33]=[CH:32][CH:31]=3)(=[O:36])=[O:35])[CH:8]=[CH:9][CH:10]=2)[N:15]=[C:14]([CH3:17])[CH:13]=1
Reactant: Cc1cc(NCc2ccc(Cl)c(Cl)c2)c2cccc(OCCN)c2n1
Reactant: O=S(=O)(Cl)c1cccnc1
Agent: Cl
Product: Cc1cc(NCc2ccc(Cl)c(Cl)c2)c2cccc(OCCNS(=O)(=O)c3cccnc3)c2n1

Procedure:
Preparation was made using a similar procedure as described in example 21. Starting materials were [8-(2-aminoethoxy)-2-methylquinolin-4-yl]-(3,4-dichlorobenzyl)-amine dihydrochloride and pyridine-3-sulfonyl chloride.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([N:15]2[C:20](=[O:21])[C:19]3[CH2:22][S:23][CH2:24][C:18]=3[NH:17][C:16]2=[O:25])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5].[CH3:26]N(C)C=O>>[Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([N:15]2[C:20](=[O:21])[C:19]3[CH2:22][S:23][CH2:24][C:18]=3[N:17]([CH3:26])[C:16]2=[O:25])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5]
Reactant: CN(C)C=O
Reactant: CC(C)OC(=O)c1cc(-n2c(=O)[nH]c3c(c2=O)CSC3)c(F)cc1Cl
Product: CC(C)OC(=O)c1cc(-n2c(=O)c3c(n(C)c2=O)CSC3)c(F)cc1Cl

Procedure:
using isopropyl 2-chloro-4-fluoro-5-{1,2,5,7-tetrahydro-2,4-dioxo-thieno[3,4-d]pyrimidin-3(4H)-yl}-benzoate in dimethylformamide there is obtained isopropyl 2-chloro-4-fluoro-5-{1,2,5,7-tetrahydro-1-methyl-2,4-dioxo-thieno[3,4-d]pyrimidin-3(4H)-yl}-benzoate, 1H-NMR (CDCl3, 400 MHz) 7.82 ppm (d, 1H), 7.35 ppm (d, 1H), 5.23 ppm (m, 1H), 4.24 ppm (m, 2H), 4.09 ppm (m, 2H), 3.45 ppm (s, 3H), 1.36 ppm (d, 6H),
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:5]=[C:6]([NH:10][C:11]([C:13]2[O:14][C:15]([Br:18])=[CH:16][CH:17]=2)=[O:12])[CH:7]=[CH:8][CH:9]=1)#[N:2].[Sn]([N:23]=[N+:24]=[N-:25])(C)(C)C>>[NH:23]1[C:1]([CH2:3][C:4]2[CH:5]=[C:6]([NH:10][C:11]([C:13]3[O:14][C:15]([Br:18])=[CH:16][CH:17]=3)=[O:12])[CH:7]=[CH:8][CH:9]=2)=[N:2][N:25]=[N:24]1
Reactant: N#CCc1cccc(NC(=O)c2ccc(Br)o2)c1
Reactant: C[Sn](C)(C)N=[N+]=[N-]
Product: O=C(Nc1cccc(Cc2nnn[nH]2)c1)c1ccc(Br)o1

Procedure:
Nitrile (83) (162 mg, 0.53 mmol) was treated with Me3SnN3 using Method K. The residue was purified by column chromatography, flushing with heptane (200 ml) and eluting with 50% EtOAc in heptane to give the title compound.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[C:5]([N+:23]([O-:25])=[O:24])=[C:6]2[C:11](=[C:12]([O:15][CH3:16])[C:13]=1[F:14])[NH:10][CH:9]=[C:8]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:7]2=[O:22].[CH2:26](Br)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CN(C=O)C>[CH2:26]([N:10]1[C:11]2[C:6](=[C:5]([N+:23]([O-:25])=[O:24])[C:4]([F:3])=[C:13]([F:14])[C:12]=2[O:15][CH3:16])[C:7](=[O:22])[C:8]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:9]1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)c1c[nH]c2c(OC)c(F)c(F)c([N+](=O)[O-])c2c1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(Cc2ccccc2)c2c(OC)c(F)c(F)c([N+](=O)[O-])c2c1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 26.8 %

Procedure:
A solution of NaH (1.17 g, 29.3 mmol, 60% in oil) in DMF (50 mL) was cooled to 0° C. and treated dropwise with ethyl 6,7-difluoro-1,4-dihydro-8-methoxy-5-nitro-4-oxoquinoline-3-carboxylate (8.0 g, 24.4 mmol) in DMF (50 mL). The reaction mixture was stirred at 0° C. for 30 min and at room temperature for 30 min. To the solution was added benzyl bromide (4.4 mL, 36.9 mmol) and stirred over night. The reaction mixture was poured into ice-water and extract with CH2Cl2. The organic layer washed with water, brine, and then dried. The solvent was removed and the crude product was purified by column chromatography (Hexane:EtOAc 3:1 →1:1) to yield ethyl 1-benzyl-6,7-difluoro-1,4-dihydro-8-methoxy-5-nitro-4-oxoquinoline-3-carboxylate (2.74 g, 27%) as a pale yellow solid.
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:25][C:11]3[CH:12]=[N:13][C:14]([NH:16][C:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=4)=[O:18])=[CH:15][C:10]=3[N:9]=2)=[CH:4][CH:3]=1.[CH:26]1([C:32](Cl)=[O:33])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1>C1COCC1.N1C=CC=CC=1>[CH:26]1([C:32]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[NH:25][C:11]4[CH:12]=[N:13][C:14]([NH:16][C:17]([C:19]5[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=5)=[O:18])=[CH:15][C:10]=4[N:9]=3)=[CH:4][CH:3]=2)=[O:33])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: O=C(Cl)C1CCCCC1
Reactant: Nc1ccc(-c2nc3cc(NC(=O)c4ccccn4)ncc3[nH]2)cc1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: O=C(Nc1cc2nc(-c3ccc(C(=O)C4CCCCC4)cc3)[nH]c2cn1)c1ccccn1
Yield: 49 %

Procedure:
A solution of amine 22 (0.040 g, 0.12 mmol) and cyclohexane carbonyl chloride (0.100 ml, 0.68 mmol) in dry THF-Pyridine (10 ml/0.300 ml) was stirred at room temperature overnight. A usual work-up as described earlier afforded the diamide 23 (0.025 g, 47%). M.p. 258° C.; 1H NMR (DMSO-d6, 500 MHz): δ 13.5 (1H, brs, NH), 10.60 (1H, brs, NH), 10.13 (1H, brs, NH), 8.78 (1H, d, J=5.0 Hz), 8.74 (1H, brs), 8.46 (1H, brs), 8.24 (1H, d, J=12.5 Hz), 8.115 (2H, d, J=8.0 Hz), 7.81 (2H, d, J=8.0 Hz), 7.74 (1H, dt, J=10.0 and 13.5 Hz), 2.37 (1H, m), 1.84-1.18 (10H, m); EIMS m/z: 441.4 (M+1), 439.6 (M−1); Anal (C25H24N6O2×1.10 H2O) C, H, N.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]#[N:10])[CH:5]=[CH:6][CH:7]=1.C[O-].[Na+].[F:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]=[CH:22][C:23]([O:25][CH3:26])=[O:24])=[CH:17][CH:16]=1>C1(C)C=CC=CC=1>[C:9]([CH:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=1)[CH:21]([C:18]1[CH:17]=[CH:16][C:15]([F:14])=[CH:20][CH:19]=1)[CH2:22][C:23]([O:25][CH3:26])=[O:24])#[N:10]
Reactant: COC(=O)C=Cc1ccc(F)cc1
Reactant: N#CCc1cccc(F)c1
Agent: C[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COC(=O)CC(c1ccc(F)cc1)C(C#N)c1cccc(F)c1
Temperature: 65 °C
Reaction time: 15 h
Yield: 66.2 %

Procedure:
Under protective gas (Ar), 0.767 g (5.0 mmol) of (3-fluorophenyl)acetonitrile and 0.1 ml of sodium methoxide solution (30% in methanol) were added to 0.820 g (4.55 mmol) of methyl 3-(4-fluorophenyl)acrylate in 15.0 ml of toluene, and the mixture was stirred in a closed vessel at 65° C. for 15 h. The solvent was removed under reduced pressure, the residue was taken up in ethyl acetate and the mixture was washed twice with in each case 25 ml of water. The combined organic phases were dried over sodium sulphate and the solvent was removed under reduced pressure. Chromatography of the residue on silica gel (ethyl acetate/heptane=20:80) gave 0.950 g (57% of theory) of the diastereomeric methyl 4-cyano-4-(3-fluorophenyl)-3-(4-fluorophenyl)butanoate (erythro:threo=54:46 according to integration of the methyl singlets in the 1H-NMR in CDCl3 at 3.66 and 3.56 ppm).