Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][CH3:9])[CH:5]=[C:4]([Cl:10])[N:3]=1.ClC1C=CC=C(C(OO)=[O:19])C=1>C(O)C>[NH2:1][C:2]1[N+:7]([O-:19])=[C:6]([NH:8][CH3:9])[CH:5]=[C:4]([Cl:10])[N:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CNc1cc(Cl)nc(N)n1
Solvent: CCO
Product: CNc1cc(Cl)nc(N)[n+]1[O-]
Temperature: 10 °C
Reaction time: 3 h
Yield: 36.3 %

Procedure:
4 g of 2-amino-4-methylamino-6-chloropyrimidine are suspended in 50 ml of ethanol. After having cooled to 10° C., 11.9 g of meta-chloroperbenzoic acid are added dropwise as a solution in 100 ml of ethanol. At the end of addition, room temperature is regained and stirring is continued for 3 hours. The reaction mixture is cooled to 5° C. and then filtered on sintered glass. The precipitate obtained is recrystallized from 160 ml of a 2/3-1/3 ethanol-water mixture. 1.60 g of 2-amino-4-methylamino-6-chloropyrimidine 3-oxide are obtained.
Reaction SMILES: [CH:1]1[C:2]2[C:17](=[O:18])[C:16]([C:19]([OH:21])=[O:20])=[CH:15][N:14]([CH:22]3[CH2:24][CH2:23]3)[C:3]=2[CH:4]=[C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[C:6]=1[F:7].[P:25](Cl)([O:30][CH2:31][CH3:32])([O:27][CH2:28][CH3:29])=[O:26]>C(Cl)Cl>[CH:22]1([N:14]2[C:3]3[C:2](=[CH:1][C:6]([F:7])=[C:5]([N:8]4[CH2:9][CH2:10][N:11]([P:25]([O:30][CH2:31][CH3:32])([O:27][CH2:28][CH3:29])=[O:26])[CH2:12][CH2:13]4)[CH:4]=3)[C:17](=[O:18])[C:16]([C:19]([OH:21])=[O:20])=[CH:15]2)[CH2:23][CH2:24]1
Reactant: CCOP(=O)(Cl)OCC
Reactant: O=C(O)c1cn(C2CC2)c2cc(N3CCNCC3)c(F)cc2c1=O
Solvent: ClCCl
Product: CCOP(=O)(OCC)N1CCN(c2cc3c(cc2F)c(=O)c(C(=O)O)cn3C2CC2)CC1
Reaction time: 0.17 h

Procedure:
A suspension of 2.816 g (8.5 mmol) of ciprofloxacin base in 100 ml of dry CH2Cl2 was stirred under argon as 3.46 g (17 mmol) of N,O-bis(trimethylsilyl)-acetamide was added. After the solid had dissolved (2-3 hours), 1.47 g (8.5 mmol) of diethyl chlorophosphate was added. After 24 hours at approximately 23° the solution was evaporated, finally at 0.03 mm for 15 hours. Washing of the solid residue with water gave a white solid which was dried and then recrystallized from CH2Cl2 -toluene, boiling out te CH2Cl2 within 10 minutes to avoid thermal degradation. The product was 3.74 g (94%) of cream-colored solid, m.p. 192°-193° C.; NMR (CDCl3, 80 MHz) δ 1.36 (t, CH3), 3.30 (s, CH2N), 4.06 (5 peaks, OCH2); IR (KBr) 1028(P=O), 1630 (--COOH), 1724 cm-1 (C=O).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[OH:13][CH2:14][C@H:15]1[S:19][C@H:18]([OH:20])[CH2:17][S:16]1.[OH2:21]>N1C=CC=CC=1>[N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([O:13][CH2:14][C@H:15]2[S:19][C@H:18]([O:20][C:8](=[O:9])[C:7]3[CH:11]=[CH:12][C:4]([N+:1]([O-:2])=[O:21])=[CH:5][CH:6]=3)[CH2:17][S:16]2)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: OC[C@@H]1SC[C@@H](O)S1
Solvent: c1ccncc1
Product: O=C(OC[C@@H]1SC[C@@H](OC(=O)c2ccc([N+](=O)[O-])cc2)S1)c1ccc([N+](=O)[O-])cc1
Reaction time: 18 h

Procedure:
p-Nitrobenzoyl chloride (4.72 g, 25.42 mmol) was added to a solution of cis and trans-2-hydroxymethyl-4-hydroxy-1,3-dithiolane (1.38 g, 9.08 mmol) in dry pyridine (50 mL) at 0° C. the reaction mixture was then placed in the refrigerator for 18 h. The reaction mixture was then poured into water and extracted with methylene chloride (3X). The combined organic extracts were washed with water, brine, dried and concentrated to give a yellow solid, 3.68 g (90%). 1H NMR (CDCl3) (300 MHz) δ: (8.27 (m, 8H, Ar-H), 6.86+6.81 (dd's, 1H, 3Hz, 2Hz, C4-H), 4.96+4.87 (t's, 1H, 7Hz, C2--H), 4.47 (m, 2H, CH2OAr), 3.5 (m, 2H, C5--H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[O:13]1[C:18]2[CH:19]=[CH:20][C:21]([CH:23]=O)=[CH:22][C:17]=2[O:16][CH2:15][CH2:14]1.C(O)(C(F)(F)F)=O>>[O:13]1[C:18]2[CH:19]=[CH:20][C:21]([CH:23]3[C:5]4[NH:6][C:7]5[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=5)[C:4]=4[CH2:3][CH2:2][NH:1]3)=[CH:22][C:17]=2[O:16][CH2:15][CH2:14]1
Reactant: NCCc1c[nH]c2ccccc12
Reactant: O=Cc1ccc2c(c1)OCCO2
Solvent: O=C(O)C(F)(F)F
Product: c1ccc2c3c([nH]c2c1)C(c1ccc2c(c1)OCCO2)NCC3
Yield: 75 %

Procedure:
This product was prepared using the same procedure as for Intermediate 1 with tryptamine (4.92 g, 30.7 mmol), 2,3-dihydrobenzo[1,4]dioxin-6-carboxaldehyde (5.05 g, 1.0 equiv.) and TFA (5.0 mL, 2 equiv.) to give the title compound (7.05 g, 75%) as white crystals after recrystallization from iPr2O.
Reaction SMILES: Br.[N:2]1([C:8](=[NH:10])[NH2:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[Cl:11][C:12]([SH:15])(Cl)Cl.[OH-].[Na+]>C(Cl)Cl.O>[Cl:11][C:12]1[S:15][N:9]=[C:8]([N:2]2[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]2)[N:10]=1
Reactant: N=C(N)N1CCCCC1
Reactant: SC(Cl)(Cl)Cl
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: Clc1nc(N2CCCCC2)ns1
Temperature: 25 °C
Yield: 25.5 %

Procedure:
To a solution of piperidine-1-carboximidamide hydrobromide (2.00 g, 9.61 mmol) and perchloromethyl mercaptan (1.04 ml, 9.61 mmol) in methylene chloride (10 ml) was added dropwise a solution of sodium hydroxide (1.54 g, 38.4 mmol) in water (4 ml) under ice-cooling. The mixture was stirred under ice-cooling for 1 hour and at room temperature for 1 hour. The reaction mixture was poured to water, and the organic layer was separated and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate=4:1) to give 500 mg (25.6%) of the desired product as a solid.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]/[CH:19]=[CH:20]/[CH:21]=O.C(OC(=O)C)(=O)C.[F:30][C:31](Cl)(Cl)[C:32]([O:34][CH3:35])=[O:33]>O1CCCC1.C(OCC)C.[Zn]>[F:30]/[C:31](=[CH:21]\[CH:20]=[CH:19]\[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][O:11][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:1]=1)/[C:32]([O:34][CH3:35])=[O:33]
Reactant: COC(=O)C(F)(Cl)Cl
Reactant: O=C/C=C/CCCCCCCOc1ccc2ccccc2n1
Agent: [Zn]
Solvent: CCOCC
Solvent: CC(=O)OC(C)=O
Solvent: C1CCOC1
Product: COC(=O)/C(F)=C/C=C/CCCCCCCOc1ccc2ccccc2n1
Reaction time: 0.5 h

Procedure:
Activated zinc powder (496 mg), powdered molecular sieve 4A (1.25 g) (ex. BDH) and cuprous chloride (84 mg) were suspended in anhydrous tetrahydrofuran (10 ml). (2E)-10-(2-Quinolinyloxy)dec-2-enal (1 g) was added followed by acetic anhydride (320 μl). The mixture was warmed to 50° under nitrogen and methyl fluorodichloroacetate (328 μl) was added. The mixture was warmed at 50-5° for 4 hours, additional zinc (0.2 g) was added and warming continued for 30 minutes. Upon cooling the reaction mixture was diluted with diethyl ether, filtered through celite and filtrate worked-up in standard fashion. Purification by column chromatography (silica; 4;1, hexane: ether) gave (2Z,4E) methyl 2-fluoro-12-(2-quinolinyloxy)dodeca-2,4-dienoate (0.26 g).
Reaction SMILES: C([O-])(O)=O.[Na+].[Cl:6][C:7]1[N:8]=[N:9][C:10](Cl)=[CH:11][CH:12]=1.CC1(C)C(C)(C)OB([C:22]2[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH:23]=2)O1>COCCOC.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>[Cl:6][C:7]1[N:8]=[N:9][C:10]([C:22]2[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH:23]=2)=[CH:11][CH:12]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: Clc1ccc(Cl)nn1
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: COCCOC
Product: CC(C)(C)OC(=O)N1CC=C(c2ccc(Cl)nn2)CC1
Temperature: 80 °C
Yield: 48.3 %

Procedure:
Saturated aqueous NaHCO3 solution (10 mL) was added to a stirred solution of 3,6-dichloropyridazine (0.968 g, 6.5 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (2.010 g, 6.50 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.376 g, 0.33 mmol) in DME (20 mL). The vessel was flushed with nitrogen and the initial suspension was heated at 80° C. for 9 hours. The reaction mixture was diluted with DCM and washed with water. The organic phase was dried over MgSO4 and evaporated. The crude product was purified by MPLC silica chromatography, elution gradient 35 to 45% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford tert-butyl 4-(6-chloropyridazin-3-yl)-5,6-dihydropyridine-1(2H)-carboxylate (0.929 g, 48.3%) as a colourless crystalline solid.
Reaction SMILES: [CH3:1][C:2]([CH3:4])=[O:3].O=[CH:6][C@@H:7]([C@H:9]([C@@H:11]([CH2:13][OH:14])[OH:12])[OH:10])[OH:8].[Sb](Cl)(Cl)(Cl)(Cl)Cl.N1C=C[CH:24]=[CH:23][CH:22]=1>>[CH3:1][C:2]1([CH3:4])[O:10][C@@H:9]2[C@H:11]3[O:12][C:23]([CH3:24])([CH3:22])[O:14][C@H:13]3[O:8][C@@H:7]2[CH2:6][O:3]1
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)CO
Reactant: CC(C)=O
Reactant: c1ccncc1
Agent: Cl[Sb](Cl)(Cl)(Cl)Cl
Product: CC1(C)OC[C@H]2O[C@@H]3OC(C)(C)O[C@@H]3[C@H]2O1
Temperature: 60 °C
Reaction time: 5 h
Yield: 89.2 %

Procedure:
To 200 ml of acetone were added 10.0 g of D-xylose and 89.7 mg of antimony pentachloride, and the mixture was refluxed with stirring in a water bath of 60° C. for 5 hours. During this reaction, the refluxing solvent was dried with 20 g of Molecular Sieves 3A interposed between the reaction vessel and the condenser. After completion of the reaction, a small amount of pyridine was added to the reaction solution, and the acetone was distilled off under reduced pressure. The residue was dissolved in benzene, and the benzene solution was washed with aqueous sodium bicarbonate solution and water successively, and dried over anhydrous magnesium sulfate. The benzene was distilled off under reduced pressure, and the resulting residue was distilled under reduced pressure to give 13.7 g (89.2%) of 1,2:3,5-di-O-isopropylidene-α-D-xylofuranose as a fraction of 94 to 97° C./3 mmHg.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:15]([O-])=O)=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[CH:7]=1>CCOC(C)=O>[F:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[C:5]([NH2:15])=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1Nc1ccccn1
Solvent: CCOC(C)=O
Product: Nc1ccc(F)cc1Nc1ccccn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 101.3 %

Procedure:
A mixture of (5-fluoro-2-nitrophenyl)pyridin-2-yl-amine (3.92 g, 17 mmol) in EtOAc (150 mL) was degassed with a stream of nitrogen prior to addition of 10% Pd/C (500 mg) and was stirred at RT under a hydrogen atmosphere for 18 h. The suspension was filtered through a phase separator and the filtrate concentrated in vacuo to afford the title compound as a black solid (3.5 g, quantitative).
Reaction SMILES: C([O:3][C:4]([C:6]1[S:7][C:8]2[CH2:9][CH2:10][O:11][C:12]3[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][C:13]=3[C:14]=2[N:15]=1)=O)C.O.[NH2:22][NH2:23]>C(O)C>[Br:20][C:17]1[CH:18]=[CH:19][C:12]2[O:11][CH2:10][CH2:9][C:8]3[S:7][C:6]([C:4]([NH:22][NH2:23])=[O:3])=[N:15][C:14]=3[C:13]=2[CH:16]=1
Reactant: NN
Reactant: CCOC(=O)c1nc2c(s1)CCOc1ccc(Br)cc1-2
Solvent: CCO
Solvent: O
Product: NNC(=O)c1nc2c(s1)CCOc1ccc(Br)cc1-2
Temperature: 25 °C

Procedure:
Alternatively, to a suspension of 9-bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid ethyl ester (4.55 g) in ethanol (50 mL) was added hydrazine monohydrate (5 mL) and the reaction heated at reflux for 16 h. After cooling to room temperature, the solid was filtered, washed with diethyl ether and air-dried to give 9-bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid hydrazide.
Reaction SMILES: CN(C)C=O.[OH:6][C:7]1[CH:14]=[CH:13][C:10]([CH:11]=[O:12])=[CH:9][CH:8]=1.[N:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH2:21]Cl.C(=O)([O-])[O-].[K+].[K+]>O.C(OCC)(=O)C>[N:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH2:21][O:6][C:7]1[CH:14]=[CH:13][C:10]([CH:11]=[O:12])=[CH:9][CH:8]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: ClCc1ccccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1ccc(OCc2ccccn2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 82.9 %

Procedure:
To an N,N-dimethylformamide (250 mL) solution of 4-hydroxybenzaldehyde (20 g, 164 mmol) and 2-picolyl chloride (27 g, 165 mmol) was added potassium carbonate (68 g, 492 mmol), which was stirred for 3 days at room temperature. This mixture was partitoned into ethyl acetate and water. The organic layer was separated, washed with water, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure to obtain the title compound (29 g, 83%). The title compound was not purified but used for the next reaction.
Reaction SMILES: CC(C)([O-])C.[K+].C(O)(C)(C)C.[CH2:12]([O:14][C:15](=[O:21])[CH2:16][C:17](=[O:20])[CH2:18][CH3:19])[CH3:13].Br[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][CH:25]=1>O1CCCC1.O>[CH2:12]([O:14][C:15](=[O:21])[CH:16]([CH2:23][C:24]1[CH:25]=[CH:26][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:28][CH:29]=1)[C:17](=[O:20])[CH2:18][CH3:19])[CH3:13]
Reactant: CCOC(=O)CC(=O)CC
Reactant: CS(=O)(=O)c1ccc(CBr)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C(Cc1ccc(S(C)(=O)=O)cc1)C(=O)CC
Temperature: 70 °C

Procedure:
A suspension of potassium tert-butoxide (3.9 g) in anhydrous tetrahydrofuran (60 mL) at 0° C. was treated with a mixture of tert-butanol (0.15 mL) and 3-oxopentanoic acid ethyl ester (5.0 g). The mixture was warmed to room temperature and after 30 minutes a solution of 1-bromomethyl-4-methanesulfonylbenzene (8.6 g) in tetrahydrofuran (20 mL) was added and the resulting mixture heated at 70° C. for 17 hours. The mixture was cooled to room temperature and diluted with water (20 mL) and this mixture was extracted with ethyl acetate. The combined extracts were washed with saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solvent was removed under reduced pressure and the residue purified, by column chromatography on silica gel, eluting with a mixture of dichloromethane and ethyl acetate (1:0 to 4:1 by volume) to afford title compound as a white solid, 3.6 g.
Reaction SMILES: C([O:8][C:9]([C@@H:11]([CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH2:12][C@H:13]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:14]([O:16][CH2:17][O:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])=[O:15])=[O:10])C1C=CC=CC=1>C(O)C.[Pd]>[C:19]([O:18][CH2:17][O:16][C:14]([C@@H:13]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:12][C@H:11]([CH2:32][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[C:9]([OH:10])=[O:8])=[O:15])(=[O:24])[C:20]([CH3:22])([CH3:23])[CH3:21]
Reactant: CC(C)(C)C(=O)OCOC(=O)[C@@H](Cc1ccccc1)C[C@H](Cc1ccccc1)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)C(=O)OCOC(=O)[C@@H](Cc1ccccc1)C[C@H](Cc1ccccc1)C(=O)O

Procedure:
A solution of 2.5 g of pivaloyloxymethyl 4-(benzyloxycarbonyl)-(R*,R*)-2,4-dibenzylbutyrate in 75 ml of ethanol is hydrogenated at atmospheric pressure in the presence of 0.2 g of 5% palladium on carbon. The reaction is filtered and evaporated to give 4-(pivaloyloxymethoxycarbonyl)-2,4-(R*,R*)-dibenzylbutyric acid.
Reaction SMILES: [CH:1](=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[C:10]1(=[O:16])[O:15][CH:13]([CH3:14])[CH2:12][CH2:11]1>C1(C)C=CC=CC=1>[OH:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[CH:1]=[C:11]1[CH2:12][CH:13]([CH3:14])[O:15][C:10]1=[O:16]
Reactant: O=Cc1ccccc1O
Reactant: CC1CCC(=O)O1
Solvent: Cc1ccccc1
Product: CC1CC(=Cc2ccccc2O)C(=O)O1
Yield: 66.9 %

Procedure:
Salicylaldehyde (15.2 g) and γ-valerolactone (25 g) were dissolved in toluene (150 ml). By the reactions as in the same manner as in Example 307, the title compound (17 g) was obtained, melting point 112–114° C.
Reaction SMILES: C[Mg+].[Br-].CCOCC.CO[C:11]([C:13]1[C:14]2[N:15]([CH:19]=[C:20]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[N:21]=2)[CH:16]=[CH:17][N:18]=1)=O.C1COCC1>CN1C(=O)CCC1>[F:28][C:25]1[CH:24]=[CH:23][C:22]([C:20]2[N:21]=[C:14]3[C:13]([CH3:11])=[N:18][CH:17]=[CH:16][N:15]3[CH:19]=2)=[CH:27][CH:26]=1
Reactant: COC(=O)c1nccn2cc(-c3ccc(F)cc3)nc12
Agent: C[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CN1CCCC1=O
Product: Cc1nccn2cc(-c3ccc(F)cc3)nc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 104.1 %

Procedure:
A solution of 3M MeMgBr in Et2O (16.1 mL, 48.3 mmol) was added drop-wise to a mixture of 8-chloro-2-(4-fluorophenyl)-imidazo[1,2-a]pyrazine (prepared using general procedure B using 3-chloropyrazin-2-ylamine and 2-bromo-1-(4-fluorophenyl)-ethanone; 10.0 g, 40.6 mmol), ferric acetylacetonate (0.71 g, 2.0 mmol), THF (240 mL), and NMP (23 mL) at about 0° C. The mixture was warmed to ambient temperature over about 1 hour. After about 1 hour, the reaction was cooled to about 0° C. and treated with additional 3 M MeMgBr in Et2O (4 mL, 12 mmol). The mixture was allowed to warm to ambient temperature over about 1 h. After about an additional 1 h, the mixture was quenched with water and extracted with EtOAc. The organic layers were combined and dried with Na2SO4. After concentration, the crude material was purified by FCC on silica gel using EtOAc as an eluent to afford the expected product as an off-white solid (9.6 g, 100%): LC/MS (Table 1, Method b) Rt=1.8 min; MS m/z: 228.2 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][OH:4].[Cl:5][C:6]1[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][C:12]([N+:18]([O-:20])=[O:19])=[CH:11][C:7]=1[C:8](Cl)=[O:9].Cl>O>[Cl:5][C:6]1[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][C:12]([N+:18]([O-:20])=[O:19])=[CH:11][C:7]=1[C:8]([NH:1][CH2:2][CH2:3][OH:4])=[O:9]
Reactant: NCCO
Reactant: O=C(Cl)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1Cl
Agent: Cl
Solvent: O
Product: O=C(NCCO)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1Cl
Reaction time: 0.5 h
Yield: 56.6 %

Procedure:
2-Aminoethanol (2.9 g, 47 mmol) in 5 mL of water was added in one portion to a solution of crude 2-chloro-3,5-dinitrobenzoic acid chloride [prepared from 2-chloro-3,5-dinitrobenzoic acid 11 (5.0 g, 18.3 mmol) with SOCl2] in Me2CO (50 mL) while cooling in an ice-bath. The mixture was stirred for 30 min, then acidified with 1N HCl to pH4-5 and concentrated under reduced pressure to remove the Me2CO. EtOAc (100 mL) was added, and after 2 h a white solid was collected, washed with EtOAc and air-dried to give 2-chloro-3,5-dinitro-N-(2-hydroxyethyl)benzamide (12b) (3.0 g, 36%):
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][O:14][C:13]3[N:17]=[CH:18][C:19]([C:21](Cl)=[O:22])=[CH:20][C:12]2=3)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH2:24][C:25]1[C:30](O)=[CH:29][CH:28]=[CH:27][N:26]=1.CCN(C(C)C)C(C)C.CC[N+](S(N=C(OC)[O-])(=O)=O)(CC)CC>C1COCC1.C(Cl)Cl.C(=O)(O)[O-].[Na+]>[O:22]1[C:30]2[C:25](=[N:26][CH:27]=[CH:28][CH:29]=2)[N:24]=[C:21]1[C:19]1[CH:18]=[N:17][C:13]2[O:14][CH2:15][CH2:16][N:11]([S:8]([C:5]3[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=3)(=[O:10])=[O:9])[C:12]=2[CH:20]=1
Reactant: O=C(Cl)c1cnc2c(c1)N(S(=O)(=O)c1ccc(F)cc1)CCO2
Reactant: Nc1ncccc1O
Agent: CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=S(=O)(c1ccccc1)N1CCOc2ncc(-c3nc4ncccc4o3)cc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1-(4-fluorophenylsulfonyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-7-carbonyl chloride (25 mg, 70 μmol) was dissolved in THF (0.5 mL) and placed in a 2 mL microwave vial. To this solution was added 2-aminopyridin-3-ol (8.5 mg, 77 μmol), DIPEA (26 μL, 150 μmol) and a magnetic stirrer bar and the reaction was capped. After stirring at room temperature for 1 hour, conversion to the amide was complete as shown by LCMS. To the crude reaction mixture was added Burgess reagent (83 mg, 350 μmol) and the reaction was heated for 5 minutes at 150° C. on a Biotage Initiator. The reaction mixture was diluted with DCM (3 mL) and saturated aqueous sodium bicarbonate (3 mL). The organic layer was removed and the aqueous layer extracted with DCM (2 mL). The organic layers were combined, dried with sodium sulfate, filtered and evaporated to produce a brown oil that was purified by flash column chromatography on an ISCO HPLC using a 4 gram SiO2 cartridge and a gradient of 25-100% hexanes in EtOAc. This yielded 15 mg (52%) of a yellow oil. LCMS (+ESI) m/z=413.0 [M+H]+; 1H-NMR (CDCl3) δ 9.05 (dd, 2H), 8.60 (d, 1H), 7.95 (dd, 1H), 7.82 (d, 1H), 7.78 (d, 1H), 7.35 (dd, 1H), 7.20 (dd, 2H), 4.12 (t, 2H), 3.96 (t, 2H).
Reaction SMILES: [Br-].C(OC[N+:10]1[CH:14]=[C:13]([CH2:15][CH2:16][N:17]2C(=O)C3=CC=CC=C3[C:18]2=O)[N:12](CC2C=CC(C#N)=CC=2)[CH:11]=1)(=O)C(C)(C)C.[NH2:37]N.C(OC)(=O)[C:40]1[C:41](=[CH:46][CH:47]=[CH:48][CH:49]=1)[C:42](OC)=O>C(O)C>[C:42]([C:41]1[CH:40]=[CH:49][C:48]([CH2:18][NH:17][CH2:16][CH2:15][C:13]2[N:12]=[CH:11][NH:10][CH:14]=2)=[CH:47][CH:46]=1)#[N:37]
Reactant: CC(C)(C)C(=O)OC[n+]1cc(CCN2C(=O)c3ccccc3C2=O)n(Cc2ccc(C#N)cc2)c1
Reactant: COC(=O)c1ccccc1C(=O)OC
Reactant: NN
Agent: [Br-]
Solvent: CCO
Product: N#Cc1ccc(CNCCc2c[nH]cn2)cc1
Reaction time: 6 h

Procedure:
1-Pivaloyloxymethyl-3-(4-cyanobenzyl)-4-(2-phthalimidoethyl) imidazolium bromide (1.00 g, 1.81 mmol) was dissolved in ethanol (50 mL), treated with hydrazine (0.287 mL, 9.06 mmol), and heated at reflux for 16 h. Dimethyl phthalate (2.22 mL, 13.57 mmol) was added and reflux was continued for 6 h. The reaction mixture was cooled in an ice-H2O bath, the solid precipitate filtered off, the filtrate concentrated to dryness, and the residue chromatographed (SiO2, CH2Cl2 (NH4OH): 3-8% CH3OH) to give the title compound. 1H NMR (CD3OD) δ 7.76 (s, 1H), 7.74 (d, 2H, J=8 Hz), 7.27 (d, 2H, J=8 Hz), 6.88 (s, 1H), 5.35 (s, 2H), 2.76 (t, 2H, J=6 Hz), 2.60 (t, 2 H, J=6 Hz).
Reaction SMILES: C([Li])CCC.[CH3:6][CH2:7][CH2:8][CH2:9][CH2:10]C.[Cl:12][C:13]1[CH:18]=[CH:17][N:16]=[CH:15][C:14]=1[CH2:19][S:20]([C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=1)(=[O:22])=[O:21].ICCCCCI>O.C(COC)OC>[Cl:12][C:13]1[CH:18]=[CH:17][N:16]=[CH:15][C:14]=1[C:19]1([S:20]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)(=[O:21])=[O:22])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: CCCCCC
Reactant: O=S(=O)(Cc1cnccc1Cl)c1ccc(Cl)cc1
Agent: ICCCCCI
Agent: [Li]CCCC
Solvent: O
Solvent: COCCOC
Product: O=S(=O)(c1ccc(Cl)cc1)C1(c2cnccc2Cl)CCCCC1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 18 %

Procedure:
At −78° C., butyl lithium (a 1.57M hexane solution; 0.58 ml, 0.913 mmol) was added dropwise to a dimethoxyethane (5 ml) solution of the 4-chloro-3-(4-chlorophenylsulfonylmethyl)pyridine (138 mg, 0.457 mmol) obtained in Example 104. At −78° C., the resulting mixture was stirred for 20 minutes and then 1,5-diiodopentane (0.068 ml, 0.457 mmol) was added thereto. The temperature of the reaction mixture was gradually raised to room temperature, at which stirring was performed for 17 hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with brine and then dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was subjected to flash chromatography on a silica gel column, and the fraction obtained from the hexane:ethyl acetate (=2:1) eluate was concentrated under reduced pressure. The residue thus obtained was purified by high performance liquid chromatography (using a mixed solvent of water/acetonitrile/formic acid) to give the title compound (30 mg, 18%) as a white solid. The resulting solid was washed with ether and then collected by filtration, whereby the title compound was obtained as a white powder.