Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li+].C[O-].[CH3:4][C:5]1([CH3:14])[C@H:7]([CH:8]=O)[C@H:6]1[C:10]([O:12][CH3:13])=[O:11].[C:15]1([C:21]2(C3C=CC=CC=3)COC(C3C=CC=CC=3)(CBr)[O:22]2)C=CC=CC=1.CN(C)C=O>CO>[CH3:4][C:5]1([CH3:14])[C@H:7](/[CH:8]=[CH:15]/[CH:21]=[O:22])[C@H:6]1[C:10]([O:12][CH3:13])=[O:11]
Reactant: BrCC1(c2ccccc2)OCC(c2ccccc2)(c2ccccc2)O1
Reactant: COC(=O)[C@@H]1[C@@H](C=O)C1(C)C
Agent: C[O-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CO
Product: COC(=O)[C@@H]1[C@@H](/C=C/C=O)C1(C)C
Temperature: 75 °C
Reaction time: 5 h
Yield: 68.9 %

Procedure:
A solution of 17.1 ml of lithium methylate in methanol was added over 21/2 hours at ≃75° C. to a solution of 46.8 g of methyl (1R,trans) 2,2-dimethyl-3-formyl-cyclopropane-1-carboxylate, 193.2 g of the product of Step A and 750 ml of dimethylformamide and the mixture was stirred at ≃75° C. for 5 hours and then stood overnight at room temperature. The mixture was poured with stirring into an ice-water mixture and the resulting mixture was extracted with ether. The organic phase was washed with aqueous saturated sodium chloride solution and dried under reduced pressure at 50° C. The residue was dissolved in a solution of 750 ml of tetrahydrofuran and 750 ml of N hydrochloric acid and the solution was stirred at room temperature for 3 hours and was poured into water. The mixture was extracted with ether and the organic phase was washed with aqueous solution bicarbonate solution, with aqueous saturated sodium chloride solution, was dried and evaporated to dryness. The residue was taken up in an 8-2 petroleum ether (b.p.=60°-80° C.)-ethyl acetate mixture and the mixture was vacuum filtered. The filtrate was evaporated to dryness and the residue was chromatographed over silica gel. Elution with an 8-2 petroleum ether-ethyl acetate mixture yielded 37.6 g of methyl (1R,trans) 2,2-dimethyl-3[(E)-2-formylethenyl]-cyclopropane-1-carboxylate with a refractive index of nD28 =1.5018.
Reaction SMILES: [F:1][C:2]1[C:3](F)=[C:4]([F:13])[C:5]([F:12])=[C:6]([C:10]#[N:11])[C:7]=1[C:8]#[N:9].[F-].[K+].[Cl:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[SH:24]>CC(=O)CC>[Cl:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[S:24][C:3]1[C:2]([F:1])=[C:7]([C:8]#[N:9])[C:6](=[C:5]([F:12])[C:4]=1[F:13])[C:10]#[N:11]
Reactant: Sc1ccccc1Cl
Reactant: N#Cc1c(F)c(F)c(F)c(F)c1C#N
Agent: [F-]
Agent: [K+]
Solvent: CCC(C)=O
Product: N#Cc1c(F)c(F)c(Sc2ccccc2Cl)c(F)c1C#N
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 70 %

Procedure:
Into a four-neck flask of glass provided with a stirrer, a thermometer, a water separation tube, and a cooling tube and having an inner volume of 100 ml, 30 gr of 2-butanone, 10 gr (0.05 mol) of tetrafluorophthalonitrile, and 3.63 gr (0.062 mol) of potassium fluoride were placed and the flask was dipped in a water bath. The reaction mixture in the reaction vessel was kept stirred at room temperature and 7.6 g (0.053 mol) of 2-chlorobenzene thiol were added thereto over about 20 minutes. The reaction temperature rose to the highest level of 30° C. When the reaction was continued for additional one hour after the completion of this addition, the conversion of tetrafluorophthalonitrile reached 99.0%. The resultant reaction solution was filtered to separate a solid component. The solid component was evaporated under a reduced pressure at 50° C. to obtain about 15 g of 2-butanone by distillation. 100 ml of methanol was added to the resultant residue of the distillation to precipitate crystals. When the crystals consequently precipitated were filtered, 11.4 gr (0.035 mol, yield: 70.2 mol %) of 4-(2-chloro phenylthio)-3,5,6-trifluorophthalonitrile was obtained.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[N+:14]([C:17]1[CH:25]=[CH:24][C:20]([C:21](Cl)=[O:22])=[CH:19][CH:18]=1)([O-])=O.C(N(CC)CC)C>CN(C=O)C>[NH2:14][C:17]1[CH:25]=[CH:24][C:20]([C:21]([N:11]2[CH2:10][CH2:9][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:13][CH2:12]2)=[O:22])=[CH:19][CH:18]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc(N)cc2)CC1

Procedure:
1-Boc-piperazine and 4-nitrobenzoyl chloride were allowed to undergo the reaction in DMF in the presence of triethylamine, and then the nitro group was reduced in the sama manner as the catalytic hydrogenation shown in Reference Example 3 to obtain tert-butyl 4-(4-aminobenzoyl)piperazine-1-carboxylate. ESI: 307.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@:8]12[CH2:16][O:15][C@H:14]([CH3:17])[C@H:13]1[CH2:12][S:11][C:10]([NH2:18])=[N:9]2.FC(F)(F)C(O)=O.S(=O)(=O)(O)O.[Br:31]N1C(=O)CCC1=O>O.[OH-].[Na+]>[Br:31][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([C@:8]23[CH2:16][O:15][C@H:14]([CH3:17])[C@H:13]2[CH2:12][S:11][C:10]([NH2:18])=[N:9]3)[CH:4]=1
Reactant: C[C@H]1OC[C@]2(c3ccccc3F)N=C(N)SC[C@H]12
Reactant: O=C1CCC(=O)N1Br
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: C[C@H]1OC[C@]2(c3cc(Br)ccc3F)N=C(N)SC[C@H]12
Temperature: 57.5 °C
Reaction time: 0.5 h

Procedure:
(4aS,5R,7aS)-7a-(2-Fluorophenyl)-5-methyl-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-amine* (1.0 g, 3.75 mmol) was dissolved in trifluoroacetic acid (3.5 mL, 45.4 mmol). Sulfuric acid (1.2 mL, 22 mmol) was carefully added dropwise, keeping temperature below 30° C. N-Bromosuccinimide (0.74 g, 4.13 mmol) was added portionwise and the reaction was warmed to 55-60° C. After 30 minutes, the reaction was cooled to room temperature and added dropwise to a cooled solution of sodium hydroxide (3.00 g, 75.1 mmol) in water (25 mL). The solution of reaction mixture in sodium hydroxide solution was extracted with EtOAc (×2), checking the pH to ensure the TFA/H2SO4 had all been neutralised. The organic layer was washed with brine and concentrated to leave a brown solid. The solid was recrystalised from IPA (10 mL): heating to 50° C. for 15 minutes on the rotavap under slight vacuum. The suspension was cooled to room temperature, filtered and washed with IPA (2 mL) and heptane (10 mL). The solid was dried overnight to give the title compound (1.30 g). 1H NMR (400 MHz, CDCl3) δ ppm: 7.55 (dd, J=7.2, 2.7 Hz, 1H), 7.36 (ddd, J=8.7, 4.2, 2.5 Hz, 1H), 6.94 (dd, J=11.6, 8.6 Hz, 1H), 4.55 (dd, J=8.8, 1.3 Hz, 1H), 4.35 (q, J=1.0 Hz, 1H), 3.77 (dd, J=8.8, 2.3 Hz, 1H), 3.07 (dd, J=13.4, 3.5 Hz, 1H), 2.71 (dd, J=13.3, 3.9 Hz, 1H), 2.44-2.53 (m, 1H), 1.37 (d, J=6.1 Hz, 3H)
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[C:12]([OH:14])=[O:13].[CH3:15][Si](C=[N+]=[N-])(C)C>C1C=CC=CC=1.CO>[CH3:15][C:11]1[C:2]([NH2:1])=[C:3]([C:12]([OH:14])=[O:13])[C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: Nc1ccc2ccccc2c1C(=O)O
Solvent: c1ccccc1
Solvent: CO
Product: Cc1cc2ccccc2c(C(=O)O)c1N
Reaction time: 2.5 h
Yield: 93.9 %

Procedure:
2-Amino-1-naphthoic acid (3.21 g, 17.2 mmol) in 4:1 benzene/CH3OH (125 mL) was treated with trimethylsilyldiazomethane (9.0 mL, 18.0 mmol, 2.0M solution in hexanes), stirred for 2.5 hours, quenched with acetic acid (0.5 mL), and concentrated. The concentrate was purified by flash column chromatography (4:1 hexanes/ethyl acetate) to provide the desired compound (3.25 g). MS (ESI(+)) m/e 202 (M+H)+; (ESI(−)) m/e 200 (M−H)−.
Reaction SMILES: I[C:2]1[CH:7]=[C:6]([S:8][CH3:9])[N:5]=[C:4]([CH3:10])[N:3]=1.C([Mg]Cl)(C)C.Cl[Sn:17]([CH2:26][CH2:27][CH2:28][CH3:29])([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:18][CH2:19][CH2:20][CH3:21]>C1COCC1>[CH3:10][C:4]1[N:5]=[C:6]([S:8][CH3:9])[CH:7]=[C:2]([Sn:17]([CH2:22][CH2:23][CH2:24][CH3:25])([CH2:26][CH2:27][CH2:28][CH3:29])[CH2:18][CH2:19][CH2:20][CH3:21])[N:3]=1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: CSc1cc(I)nc(C)n1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cc(SC)nc(C)n1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 65.9 %

Procedure:
A solution of 4-iodo-2-methyl-6-(methylthio)pyrimidine (2.35 g, 8.83 mmol) in THF (20 mL) was cooled to −78° C. and treated dropwise with isopropylmagnesium chloride (2 N solution in THF, 2 mL, 4.0 mmol, Aldrich). After 10 min, chlorotributylstannane (2.4 mL, 8.83 mmol, Aldrich) was added. The mixture was stirred at −78° C. for 1 h, then warmed to room temperature and stirred overnight. The mixture was concentrated in vacuo and purified by flash column chromatography with alumina, eluting with a gradient of 0-10% EtOAc in hexane, to give 2-methyl-4-(methylthio)-6-(tributylstannyl)pyrimidine (2.5 g, 5.82 mmol, 65.9% yield) as colorless oil. This was used as such without further purification. m/z (ESI, +ve ion) 430 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH2:4][CH:5]1[CH2:10][CH2:9][CH:8]([C:11]2[N:16]=[CH:15][C:14]([NH:17][C:18](=[O:23])[C:19](OC)=[O:20])=[CH:13][CH:12]=2)[CH2:7][CH2:6]1.O.[NH2:26][NH2:27]>C(O)C>[NH:26]([C:19](=[O:20])[C:18]([NH:17][C:14]1[CH:13]=[CH:12][C:11]([C@H:8]2[CH2:9][CH2:10][C@H:5]([CH2:4][C:3]([O:2][CH3:1])=[O:24])[CH2:6][CH2:7]2)=[N:16][CH:15]=1)=[O:23])[NH2:27]
Reactant: NN
Reactant: COC(=O)CC1CCC(c2ccc(NC(=O)C(=O)OC)cn2)CC1
Solvent: O
Solvent: CCO
Product: COC(=O)C[C@H]1CC[C@H](c2ccc(NC(=O)C(=O)NN)cn2)CC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a suspension of methyl ({6-[4-(2-methoxy-2-oxoethyl)cyclohexyl]pyridin-3-yl}amino)(oxo)acetate, prepared as above, (865 mg, 2.59 mmol) in absolute ethanol (50 mL) was added hydrazine monohydrate (0.15 mL, 3.09 mmol). A thick white suspension formed which was then allowed to stir at ambient temperature for ˜1.5 hrs, filtered, washed with ether (2×20 mL) and then dried to give the title compound (Intermediate 78), 610 mg (1.82 mmol, 70%) as a solid; 1H NMR δ 1.09-1.21 (m, 2H), 1.47-1.56 (m, 2H), 1.71-1.87 (m, 5H), 2.25 (d, 2H), 2.54-2.63 (m, 1H), 3.60 (s, 3H), 4.62 (s, 2H), 7.24 (d, 1H), 8.07 (d, 1H), 8.85 (s, 1H), 10.27 (s, 1H) (not all NH protons seen); MS m/e MH+ 335.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([N:8]2[C:12]([NH2:13])=[N:11][C:10]([NH:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:9]2)[CH:3]=1.[NH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.O>CN1C(=O)CCC1>[C:15]1([NH:14][C:10]2[N:11]=[C:12]([NH2:13])[N:8]([C:4]3[CH:3]=[C:2]([N:21]4[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]4)[N:7]=[CH:6][N:5]=3)[N:9]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Nc1nc(Nc2ccccc2)nn1-c1cc(Cl)ncn1
Reactant: C1CNCCN1
Solvent: O
Solvent: CN1CCCC1=O
Product: Nc1nc(Nc2ccccc2)nn1-c1cc(N2CCNCC2)ncn1
Temperature: 220 °C

Procedure:
To a solution of 200 mg of 1-(6-chloro-pyrimidin-4-yl)-N3-phenyl-1H-[1,2,4]triazole-3,5-diamine (0.69 mMol, 1 equiv) in 5 mL of NMP was added 200 mg of piperazine (2.32 mMol, 3.3 equiv). The reaction vessel was sealed and warmed to 220° C. via microwave irradiation for 6 min and allowed to cool. The resulting solution was poured into 50 mL of water and the precipitate was filtered and washed with water (3×20 mL). The resulting waxy solid (150 mg) was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][C:9]2[CH:10]=[C:11]([CH:14]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:16]=2)[C:12]#[N:13])=[C:6]([F:21])[C:5]([CH3:22])=[CH:4][CH:3]=1.[Br:23]N1C(=O)CCC1=O.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[Br:23][CH2:22][C:5]1[C:6]([F:21])=[C:7]([O:8][C:9]2[CH:10]=[C:11]([CH:14]=[C:15]([C:17]([F:18])([F:19])[F:20])[CH:16]=2)[C:12]#[N:13])[C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: Cc1ccc(Cl)c(Oc2cc(C#N)cc(C(F)(F)F)c2)c1F
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1cc(Oc2c(Cl)ccc(CBr)c2F)cc(C(F)(F)F)c1
Temperature: 75 °C
Reaction time: 4 h
Yield: 48.5 %

Procedure:
To a solution of 3-[(6-chloro-2-fluoro-3-methylphenyl)oxy]-5-(trifluoromethyl)benzonitrile (12.2 g, 37.0 mmol) and N-bromosuccinimide (6.59 g, 37.0 mmol) in carbon tetrachloride (300 mL) was added AIBN (0.304 g, 1.850 mmol) and the mixture was stirred at 75° C. for 4 hours. More AIBN (0.304 g, 1.850 mmol) was added and the reaction mixture was stirred overnight at 75° C. The mixture was filtered through a pad of Celite and the filtrate was concentrated. The crude oil was purified via silica gel chromatography to give 3-{[3-(bromomethyl)-6-chloro-2-fluorophenyl]oxy}-5-(trifluoromethyl)benzonitrile (7.33 g, 17.94 mmol, 49% yield). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.63 (s, 1H), 7.42 (s, 1H), 7.31-7.36 (m, 2H), 7.24 (d, 1H), 4.48 (s, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:7]([Br:10])=[CH:6][C:3]=1[C:4]#[N:5].Cl[C:12]([O:14][CH2:15][CH3:16])=[O:13]>>[CH2:15]([O:14][C:12](=[O:13])[NH:1][C:2]1[CH:9]=[CH:8][C:7]([Br:10])=[CH:6][C:3]=1[C:4]#[N:5])[CH3:16]
Reactant: CCOC(=O)Cl
Reactant: N#Cc1cc(Br)ccc1N
Product: CCOC(=O)Nc1ccc(Br)cc1C#N
Yield: 67.9 %

Procedure:
A suspension of 2-amino-5-bromobenzonitrile (58.5 g, 297 mmol) in ethyl chloroformate (141 mL, 1.48 mol) was heated at reflux for 5 h. The excess ethyl chloroformate (99 mL) was distilled off and toluene (96 mL) was added. Slow addition of cyclohexane (228 mL) induced crystallization. The resulting solid was collected by filtration and rinsed with cyclohexane. Drying in vacuo afforded the title compound (54.3 g, 68%) as an orange solid. MS: m/e=267.1/269.2 [M—H−].
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:20]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:28][CH3:29])=[C:19]([O:30][CH2:31][CH2:32][NH2:33])[N:18]=[C:17]([S:34][CH3:35])[N:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:36]1([CH3:46])[CH:41]=[CH:40][C:39]([S:42](Cl)(=[O:44])=[O:43])=[CH:38][CH:37]=1>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:20]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:28][CH3:29])=[C:19]([O:30][CH2:31][CH2:32][NH:33][S:42]([C:39]3[CH:40]=[CH:41][C:36]([CH3:46])=[CH:37][CH:38]=3)(=[O:44])=[O:43])[N:18]=[C:17]([S:34][CH3:35])[N:16]=2)(=[O:12])=[O:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)nc(SC)nc1OCCN
Product: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)nc(SC)nc1OCCNS(=O)(=O)c1ccc(C)cc1
Yield: 34.7 %

Procedure:
According to Example 36f) 2 g of 4-tert.-butyl-N-[6-(2-aminoethoxy)-5-(o-methoxyphenoxy)-2-methylsulfanyl-pyrimidin-4-yl]-benzenesulfonamide was reacted with 1.19 g p-toluenesulfonylchloride to give 0.9 g 4-tert.-butyl-N-[6-(2-p-toluenesulfonylamino-ethoxy)-5-(o-methoxyphenoxy)-2-methylsulfanyl-pyrimidin-4-yl]-benzenesulfonamide. LC-MS: tR=6.24 min, [M+1]+=673.34.
Reaction SMILES: C([Li])CCC.Br[C:7]1[N:8]=[C:9]([N:17]2[CH2:23][CH2:22][CH2:21][N:20]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:19][CH2:18]2)[C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2.[F:31][C:32]1[N:43]=[CH:42][CH:41]=[CH:40][C:33]=1[C:34](N(OC)C)=[O:35]>O1CCCC1>[F:31][C:32]1[N:43]=[CH:42][CH:41]=[CH:40][C:33]=1[C:34]([C:7]1[N:8]=[C:9]([N:17]2[CH2:23][CH2:22][CH2:21][N:20]([C:24]([O:26][C:27]([CH3:29])([CH3:28])[CH3:30])=[O:25])[CH2:19][CH2:18]2)[C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:35]
Reactant: CC(C)(C)OC(=O)N1CCCN(c2nc(Br)cc3ccccc23)CC1
Reactant: CON(C)C(=O)c1cccnc1F
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCN(c2nc(C(=O)c3cccnc3F)cc3ccccc23)CC1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 45.6 %

Procedure:
A 2.5M n-butyl lithium in tetrahydrofuran solution (0.16 ml, 0.40 mmol) was added dropwise to a solution of tert-butyl 4-(3-bromoisoquinolin-1-yl)-1,4-diazepane-1-carboxylate (155 mg, 0.38 mmol) in tetrahydrofuran (8 ml), cooled to −78° C. The reaction mixture was stirred at that temperature for 10 minutes. A solution of 2-fluoro-N-methoxy-N-methylnicotinamide (70 mg, 0.38 mmol) in tetrahydrofuran (3 ml) was added dropwise. The reaction mixture was allowed to warm up to room temperature and was stirred for 2 hours. The reaction was quenched with a saturated aqueous solution of ammonium chloride and extracted into ethyl acetate. The organic phase was dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified on silica gel by flash column chromatography to afford the title compound as a yellow solid (78 mg, 46% yield).
Reaction SMILES: [C:1](Cl)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[NH:12]1[CH2:18][CH2:17][CH2:16][C@H:13]1[CH2:14][OH:15].C(=O)([O-])O.[Na+]>C(Cl)Cl.O>[C:1]([N:12]1[CH2:18][CH2:17][CH2:16][C@H:13]1[CH2:14][OH:15])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: OC[C@@H]1CCCN1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1CCC[C@H]1CO
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.4 %

Procedure:
A solution of carbobenzoxychloride 7.87 g in methylene chloride 50 ml is dropped to a mixture of L-prolinol 4.9 g in methylene chloride 50 ml and sodium hydrogen carbonate 11.6 g in water 50 ml at 0° C. under vigorously agitation. The mixture is stirred for 1 hour at room temperature. The organic layer is separated, washed, dried and concentrated in vacuo to give N-carbobenzoxy-L-prolinol 10.25 g.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6](=O)[CH2:7][O:8][C:9](=[O:11])[CH3:10])(=[O:3])[CH3:2].Cl.[NH2:14][OH:15]>>[C:1]([O:4][CH2:5][C:6](=[N:14][OH:15])[CH2:7][O:8][C:9](=[O:11])[CH3:10])(=[O:3])[CH3:2]
Reactant: NO
Reactant: CC(=O)OCC(=O)COC(C)=O
Agent: Cl
Product: CC(=O)OCC(COC(C)=O)=NO

Procedure:
3-(Acetyloxy)-2-(hydroxyimino)propyl acetate was prepared from 3-(acetyloxy)-2-oxopropyl acetate (Tetrahedron Lett., 2001; 3331-3334) and hydroxylamine hydrochloride using conditions of General Method 1. 1H NMR (250 MHz, CHLOROFORM-d) δ 8.32 (1H, br. s.), 5.02 (2H, s), 4.75 (2H, s), 2.11 (3H, s), 2.10 (3H, s).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[C:4]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:5]=1[C:6](=[O:12])[NH:7]2.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:33])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:21][CH:20]=1>>[Cl:17][C:15]1[CH:14]=[CH:13][C:5]2[C:6](=[O:12])[NH:7][C:8]3[C:3]([C:4]=2[CH:16]=1)=[C:2]([NH:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:33])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:21][CH:20]=1)[CH:11]=[CH:10][N:9]=3
Reactant: O=c1[nH]c2nccc(Cl)c2c2cc(Cl)ccc12
Reactant: Nc1ccc(NC(=O)c2ccccc2)cc1
Product: O=C(Nc1ccc(Nc2ccnc3[nH]c(=O)c4ccc(Cl)cc4c23)cc1)c1ccccc1

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 267 using 1,9-dichloro-5H-benzo[c][1,8]naphthyridin-6-one and N-(4-aminophenyl)benzamide to provide 293. LC-MS (M+H=442, obsd.=442).
Reaction SMILES: [C:1]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:5][C:4]([S:7]([OH:10])(=[O:9])=[O:8])=[CH:3][CH:2]=1.FC(F)(F)C(O)=O.[N+:24]([O-])([OH:26])=[O:25]>>[N+:24]([C:14]1[CH:15]=[CH:16][C:11]([C:1]2[CH:6]=[CH:5][C:4]([S:7]([OH:10])(=[O:8])=[O:9])=[CH:3][CH:2]=2)=[CH:12][CH:13]=1)([O-:26])=[O:25]
Reactant: O=[N+]([O-])O
Reactant: O=S(=O)(O)c1ccc(-c2ccccc2)cc1
Solvent: O=C(O)C(F)(F)F
Product: O=[N+]([O-])c1ccc(-c2ccc(S(=O)(=O)O)cc2)cc1
Temperature: -5 °C
Reaction time: 2 h

Procedure:
Biphenyl-4-sulfonic acid (30 g) was mixed with trifluoroacetic acid and a suspension was formed. The mixture was cooled to −5° C. Fuming nitric acid (12.8 ml) was added dropwise over 30 min. The reaction mixture was stirred at 0° C. for 2 h. The chloroform was removed in vacuo and the residue was recrystallized from acetic acid to provide 15 g of 4′-nitro-biphenyl-4-sulfonic acid, obtained as white crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH2:10]([N:17]1[CH2:22][CH2:21][C:20](=O)[CH2:19][CH2:18]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C[Si](OS(C(F)(F)F)(=O)=O)(C)C>C(OCC)(=O)C>[NH2:5][C:4]1[C:19]2[CH2:18][N:17]([CH2:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH2:22][CH2:21][C:20]=2[N:1]=[C:2]2[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=12
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: N#Cc1ccccc1N
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CCOC(C)=O
Product: Nc1c2c(nc3ccccc13)CCN(Cc1ccccc1)C2
Yield: 96.8 %

Procedure:
11.55 g (97.80 mmol) of 2-aminobenzonitrile and 24.07 g (127.14 mmol) of N-benzylpiperidine-4-one were dissolved in 200 ml of ethyl acetate, to which 50.00 g (225.00 mmol) of trimethylsilyltrifluoromethane sulfonate was added dropwise at room temperature. After the end of the dropwise addition, the mixture was refluxed under heating for 6 hours. After air cooling, the produced crystals were filtered out and washed with 320 ml of ethyl acetate. The obtained crystals were dried, added to a mixed solution of 400 ml of water and 200 ml of ethanol and dissolved by heating. After air cooling, 250 ml of a 1N sodium hydroxide solution was added thereto and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated saline solution and dried over anhydrous sodium sulfate, and then the drying agent was filtered out. The filtrate was concentrated under reduced pressure and the residue was suspended in a mixed solution of 200 ml of ethyl acetate and 200 ml of hexane. The produced crystals were filtered out and further washed with the above mixed solution to obtain the title compound (27.39 g, 95% yield).
Reaction SMILES: [N:1]1[C:9]([NH2:10])=[C:8]2[C:4]([N:5]=[CH:6][NH:7]2)=[N:3][CH:2]=1.[C:11]1([C:15]([O:17][CH3:18])=[O:16])[CH2:14][CH2:13][CH:12]=1.C1CCN2C(=NCCC2)CC1>C(#N)C>[CH3:18][O:17][C:15]([CH:11]1[CH2:14][CH2:13][CH:12]1[N:5]1[CH:6]=[N:7][C:8]2[C:4]1=[N:3][CH:2]=[N:1][C:9]=2[NH2:10])=[O:16]
Reactant: COC(=O)C1=CCC1
Reactant: Nc1ncnc2nc[nH]c12
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)C1CCC1n1cnc2c(N)ncnc21
Temperature: 25 °C
Reaction time: 66 h
Yield: 61 %

Procedure:
Adenine (486 mg, 3.6 mmol) was combined with an excess of methyl 1-cyclobutene carboxylate (~25 mmol) from Step B of Example 35 and 53 μL (0.36 mmol) of DBU in 75 mL of acetonitrile and the mixture was stirred at ambient temperature, under a nitrogen atmosphere. After 66 h, a second 53 μL aliquot of DBU was added and stirring continued. After a total of 136 h, the reaction was quenched by the addition of 0.28 mL of glacial acetic acid and concentrated in vacuo. The residue was dissolved in approximately 3 mL of methylene chloride and purified on a 1.5×45 cm silica gel column eluted @5-10 psi with a step-wise solvent gradient of methanol in methylene chloride, starting with 100% methylene chloride and increasing in 2% steps to 8% methanol, each step was 200 mL of solvent. The title compound was obtained in 61% yield (542mg) as a mixture of cis and trans isomers and equilibrated to the desired trans isomer by treating the mixture of isomers with 394 μL of DBU in 35 mL of acetonitrile at 45° C., under nitrogen, for 46 h. The reaction mixture was concentrated in vacuo and the residue was dissolved in approximately 2 mL of methylene chloride and purified on a 1.5×45 cm silica gel column eluted @5 psi with a step-wise solvent gradient of 200 mL of methylene chloride followed by 200 mL of 5% methanol in methylene chloride and 200 mL of 7% methanol in methylene chloride to give 502 mg (57% yield) of the desired trans isomer of the title compound; 1H NMR (CD3OD) δ 2.11 (m, 1H), 2.30 (m, 1H), 2.45 (m, 1H), 2.77 (m, 1H), 3.68 (s, 3H), 4.01 (m, 1H), 5.18 (q, 1H), 8.20 (s, 1H), 8.25 (s, 1H); MS DCI-NH3M/Z: 248 (M+H)+.