Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8]Cl)=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl.Cl.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=1[N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>C(N(CC)CC)C>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=1[N:22]1[CH2:23][CH2:24][N:25]([CH2:8][C:7]2[CH:10]=[CH:11][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[CH2:26][CH2:27]1
Reactant: Clc1ccc(Cl)c(N2CCNCC2)c1
Reactant: O=[N+]([O-])c1ccc(CCl)cc1
Agent: Cl
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccc(CN2CCN(c3cc(Cl)ccc3Cl)CC2)cc1

Procedure:
In the manner given in Example 1A, p-nitrobenzyl chloride is reacted with (2,5-dichlorophenyl)piperazine dihydrochloride in the presence of triethylamine to give 1-(2,5-dichlorophenyl)-4-(p-nitrobenzyl)piperazine.
Reaction SMILES: [OH:1][C:2]1[C:3](=[O:21])[CH:4]=[C:5]([CH2:10][NH:11][S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=[O:14])=[O:13])[O:6][C:7]=1[CH2:8][OH:9].CO.[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH2:24]([O:1][C:2]1[C:3](=[O:21])[CH:4]=[C:5]([CH2:10][NH:11][S:12]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)(=[O:14])=[O:13])[O:6][C:7]=1[CH2:8][OH:9])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=c1cc(CNS(=O)(=O)c2ccccc2)oc(CO)c1O
Reactant: BrCc1ccccc1
Solvent: CO
Product: O=c1cc(CNS(=O)(=O)c2ccccc2)oc(CO)c1OCc1ccccc1
Reaction time: 24 h
Yield: 46.5 %

Procedure:
To a stirred solution of N-(5-hydroxy-6-hydroxymethyl-4-oxo-4H-pyran-2-ylmethyl)-benzene sulfonamide (9-01) (1.7 g, 5.46 mmol) in methanol (30 mL) aqueous NaOH (218.4 mg, 5.46 mmol, 2M) was added. After heating to reflux, benzyl bromide (0.654 mL, 5.46 mmol) was added and heating was continued for 24 h. After completion of the reaction, the mixture was concentrated to remove methanol, then diluted with water and extracted with dichloromethane. The combined organic layer was washed with saturated NaHCO3 solution, water and brine, dried over Na2SO4 and concentrated under reduced pressure. It was then purified using normal column chromatography to get N-(5-benzyloxy-6-hydroxymethyl-4-oxo-4H-pyran-2-ylmethyl)-benzene sulfonamide (10-01) (1.02 gm, 46.48%) as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[C@@H:5]([C@H:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])O)O)[CH3:2].Br[N:16]1C(C)(C)C(=O)[N:19](Br)[C:17]1=O.C=O.C([O-])(=O)C.[NH4+].[OH-].[Na+]>C(OCC)(=O)C.C(O)(=O)C>[NH:16]1[C:5]([C:4]([O:3][CH2:1][CH3:2])=[O:14])=[C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[N:19]=[CH:17]1
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Reactant: CCOC(=O)[C@H](O)[C@@H](O)C(=O)OCC
Agent: C=O
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1nc[nH]c1C(=O)OCC
Temperature: 25 °C
Reaction time: 3 h
Yield: 60.2 %

Procedure:
To a solution of L-tartaric acid diethyl ester (2.0 g) in ethyl acetate (34.2 ml), 1,3-dibromo-5,5-dimethylhydantoin (3.3 g) was added, and the reaction solution was stirred at room temperature for 3 hours. To the reaction solution, acetic acid (17 ml) was added, and subsequently 36% aqueous formaldehyde solution (3.45 ml) was added under ice cooling at an internal temperature of 10° C. or below, followed by addition of ammonium acetate (17.2 g) at an internal temperature of 10° C. or below. The reaction solution was stirred at room temperature for 30 minutes, followed by stirring at 50° C. for 3 hours. To the reaction solution, 5N sodium hydroxide was added, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, and dried over magnesium sulfate. Quantitative analysis of the resulting ethyl acetate solution by HPLC showed that the title compound (1.24 g, yield: 60%) was obtained.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[N:8]2[CH:9]=[C:10]([CH3:13])[CH:11]=[CH:12][C:7]2=[N:6][C:5]=1[C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1.[C:21]1([SH:27])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH3:13][C:10]1[CH:11]=[CH:12][C:7]2[N:8]([C:4]([CH2:3][S:27][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[C:5]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)[N:6]=2)[CH:9]=1
Reactant: Cc1ccc(-c2nc3ccc(C)cn3c2CCl)cc1
Reactant: Sc1ccccc1
Agent: Cl
Product: Cc1ccc(-c2nc3ccc(C)cn3c2CSc2ccccc2)cc1

Procedure:
The title compound was prepared according to Method A and the experimentals described for compound 139 from 3-(chloromethyl)-6-methyl-2-p-tolylimidazo[1,2-a]pyridine hydrochloride and benzenethiol. m/e+ 345 for C22H21N2 (M+H)+; 1H NMR (400 MHz, CDCl3) δ 7.81 (s, 1H), 7.59 (d, J=8.0 Hz, 2H), 7.54 (d, J=9.1 Hz, 1H), 7.35 (d, J=1.8 Hz, 2H), 7.32 (m, 5H), 7.07 (d, J=9.1 Hz, 1H), 4.54 (s, 2H), 2.39 (s, 3H), 2.34 (s, 3H) ppm.
Reaction SMILES: I[C:2]1[N:7]2[N:8]=[C:9]([C:11]3([CH2:14][NH:15][C:16]([N:18]4[CH2:22][CH2:21][CH2:20][CH2:19]4)=[O:17])[CH2:13][CH2:12]3)[N:10]=[C:6]2[C:5]([O:23][CH3:24])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[C:31]([C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][CH:38]=1)#[N:32]>COCCOC.[Cl-].[Na+].O.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>[C:31]([C:33]1[CH:38]=[C:37]([C:2]2[N:7]3[N:8]=[C:9]([C:11]4([CH2:14][NH:15][C:16]([N:18]5[CH2:22][CH2:21][CH2:20][CH2:19]5)=[O:17])[CH2:12][CH2:13]4)[N:10]=[C:6]3[C:5]([O:23][CH3:24])=[CH:4][CH:3]=2)[CH:36]=[CH:35][CH:34]=1)#[N:32]
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: COc1ccc(I)n2nc(C3(CNC(=O)N4CCCC4)CC3)nc12
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: [Cl-]
Solvent: COCCOC
Solvent: O
Product: COc1ccc(-c2cccc(C#N)c2)n2nc(C3(CNC(=O)N4CCCC4)CC3)nc12

Procedure:
In a screw cap vial pyrrolidine-1-carboxylic acid [1-(5-iodo-8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-cyclopropylmethyl]-amide was dissolved in DME (0.45 mL) and 1 M K2CO3 (0.14 mL) under argon. 3-cyanophenyl boronic acid (0.021 g, 0.15 mmol) and Pd(PPh3)4 (4 mg, 0.004 mmol) were added. The suspension was shaken at 80° C. for 17 h after which brine was added, and the aqueous phase was extracted with DCM (×3). The combined organic phases were dried, filtered and concentrated. The crude product was purified by flash chromatography using DCM:MeOH 97:3 as the eluent to afford the amorphous title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13](OS(C(F)(F)F)(=O)=O)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])(=O)C.[K+].B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH:58]1([C:61]2[N:66]=[CH:65][C:64](Br)=[CH:63][N:62]=2)[CH2:60][CH2:59]1.C(=O)(O)[O-].[Na+]>CN(C=O)C.Cl[Pd]Cl.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2]>[C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:64]3[CH:63]=[N:62][C:61]([CH:58]4[CH2:60][CH2:59]4)=[N:66][CH:65]=3)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Brc1cnc(C2CC2)nc1
Reactant: CC(C)(C)OC(=O)N1CCc2cc(OS(=O)(=O)C(F)(F)F)ccc2C1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCc2cc(-c3cnc(C4CC4)nc3)ccc2C1
Temperature: 90 °C
Reaction time: 5 h
Yield: 76.8 %

Procedure:
6-Trifluoromethanesulfonyloxy-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (11.51 g, 30 mmol) was dissolved in DMF (250 mL) and the yellow solution was purged by bubbling argon (g) through the solution. Potassium acetate (8.83 g, 90 mmol), bis(pinacolato)diboron (8.38 g, 33 mmol), PdCl2 dppf (1.22 g, 1.5 mmol) and dppf (0.83 g, 1.5 mmol) were added and the mixture was purged again with argon. The mixture was then heated to 90° C. for 2 h. Tripotassium phosphate monohydrate (18 g, 78 mmol) was added followed by 2-cyclopropyl-5-bromo-pyrimidine (7.76 g, 39 mmol) and stirring was continued for 5 h at 90° C. The reaction mixture was poured onto saturated sodium bicarbonate solution and extracted several times with ethyl acetate. The ethyl acetate solution was dried over magnesium sulphate, the drying agent filtered off and the filtrate was evaporated. The residue was purified by flash chromatography eluting with ethyl acetate:heptane (1:3) to give 8.1 g (76%) of the title compound as a colourless solid.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][NH:6][CH2:5][CH:4]([CH3:8])[NH:3]1.[Li]CCCC.C[Si](Cl)(C)C.[N+:19]([C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1)([O-:21])=[O:20]>C1COCC1>[N+:19]([C:22]1[CH:23]=[CH:24][C:25]([C:26]([N:3]2[CH:4]([CH3:8])[CH2:5][NH:6][CH2:7][CH:2]2[CH3:1])=[O:27])=[CH:29][CH:30]=1)([O-:21])=[O:20]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: CC1CNCC(C)N1
Agent: C[Si](C)(C)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC1CNCC(C)N1C(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
To a stirred solution of 2,6-di-methylpiperazine (LV, 5.0 g, 43.8 mmol) in dry THF (50 mL), maintained at room temperature under an argon atmosphere, was added a solution of 2.5 M n-BuLi in THF (38.54 mL, 96.36 mmol). After the mixture was stirred for 30 min at room temperature, trimethylsilyl chloride (5.5 mL, 43.8 mmol) was added and the reaction mixture stirred for 1 h before the addition of 4-nitrobenzoyl chloride (7.8 gm, 42.05 mmol). After 10 min, the reaction mixture was quenched with MeOH and the solvents were evaporated in vacuo. The residue was purified by silica gel column chromatography to provide product LVI (10.37 gm, 90% 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: Nc1ncnc2nc[nH]c12
Reactant: COC(=O)C1=CCC1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
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)+.
Reaction SMILES: CC1C(=O)N(C(C)(C)C)N=CC=1Cl.[CH2:14]([C:17]1[C:18](=[O:28])[N:19]([C:24]([CH3:27])([CH3:26])[CH3:25])[N:20]=[CH:21][C:22]=1[Cl:23])[CH2:15]C.C(C1C(=O)N(C(C)(C)C)N=CC=1Cl)CCC.C(C1C(=O)N(C(C)(C)C)N=CC=1Cl)CCCC>>[CH2:14]([C:17]1[C:18](=[O:28])[N:19]([C:24]([CH3:27])([CH3:26])[CH3:25])[N:20]=[CH:21][C:22]=1[Cl:23])[CH3:15]
Reactant: CCCc1c(Cl)cnn(C(C)(C)C)c1=O
Agent: CCCCCc1c(Cl)cnn(C(C)(C)C)c1=O
Agent: CCCCc1c(Cl)cnn(C(C)(C)C)c1=O
Agent: Cc1c(Cl)cnn(C(C)(C)C)c1=O
Product: CCc1c(Cl)cnn(C(C)(C)C)c1=O

Procedure:
In the same manner as above, the following compounds were prepared from the corresponding 2-alkyl-4,5-dichloro-3(2H)pyridazinones and alkyl magnesium halides: 4-Methyl-5-chloro-2-t-butyl-3(2H) pyridazinone [oily substance, boiling point: 60°-62° C. (0.22 mmHg)], 4-n-propyl-5-chloro-2-t-butyl-3(2H) pyridazinone (oily substance), 4-n-butyl-5-chloro-2-t-butyl-3(2H)pyridazinone (only substance) and 4-n-pentyl-5-chloro-2-t-butyl-3(2H)pyridazinone (oily substance).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7](Cl)=[O:8])([O-:3])=[O:2].[S:13]1[CH2:17][CH2:16][NH:15][CH2:14]1.C(N(CC)CC)C>C(Cl)Cl.O>[N+:1]([C:4]1[CH:5]=[C:6]([C:7]([N:15]2[CH2:16][CH2:17][S:13][CH2:14]2)=[O:8])[CH:10]=[CH:11][CH:12]=1)([O-:3])=[O:2]
Reactant: C1CSCN1
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: O=C(c1cccc([N+](=O)[O-])c1)N1CCSC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 78 %

Procedure:
To a stirred solution of 3-nitrobenzoyl chloride (5.00 g, 26.9 mmol) in DCM (50 ml), thiazolidine (3.60 g, 40.4 mmol) was added at 0° C. Triethylamine, (7.51 ml, 53.9 mmol) was added dropwise into the reaction mixture over 5 min and the reaction mixture was stirred at RT for 1 hr. Reaction mixture was diluted with cold water. Organic phase was separated and aq. phase was extracted using DCM (3×10.0 ml). Combined organic layer was washed with brine (100 ml), dried over sodium sulphate and the solvent was evaporated under vacuum to afford the title compound (5.0 gm).
Reaction SMILES: [N:1]1[C:6]2[CH:7]=[CH:8][NH:9][C:5]=2[C:4](=[O:10])[NH:3][CH:2]=1.[Br:11]N1C(=O)CCC1=O>CN(C=O)C.O>[Br:11][C:7]1[C:6]2[N:1]=[CH:2][NH:3][C:4](=[O:10])[C:5]=2[NH:9][CH:8]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: O=c1[nH]cnc2cc[nH]c12
Solvent: O
Solvent: CN(C)C=O
Product: O=c1[nH]cnc2c(Br)c[nH]c12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 3,5-dihydropyrrolo[3,2-d]pyrimidin-4-one (200 mg, 1.5 mmol, 1 equiv.) and N-bromosuccinimide (320 mg, 1.8 mmol, 1.2 equiv.) in 10 mL of DMF was stirred for 18 hours at room temperature. The reaction was diluted with water and resulting solid was collected by filtration, dried, suspended in MeOH, and filtered. The filtrate was concentrated in vacuo to provide 7-bromo-3,5-dihydropyrrolo[3,2-d]pyrimidin-4-one as a beige solid which was used without further purification.
Reaction SMILES: C1(CS(O[CH2:12][CH2:13][C@H:14]([NH:16][S:17]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)(=[O:19])=[O:18])[CH3:15])(=O)=O)C=CC=CC=1.[Cl-:27].[Na+].CN(C)C=O>CCOC(C)=O>[Cl:27][CH2:12][CH2:13][C@H:14]([NH:16][S:17]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=[O:19])=[O:18])[CH3:15]
Reactant: C[C@H](CCOS(=O)(=O)Cc1ccccc1)NS(=O)(=O)Cc1ccccc1
Reactant: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C[C@H](CCCl)NS(=O)(=O)Cc1ccccc1
Temperature: 80 °C
Reaction time: 16 h
Yield: 38.9 %

Procedure:
To the crude (R)-3-(phenylmethylsulfonamido)butyl phenylmethanesulfonate (23.6 mmol) was added sodium chloride (984 mg, 16.8 mmol) and dimethylformamide (37 mL) and the reaction was stirred at 80° C. for 16 hours. The reaction was then diluted with EtOAc, washed with water (×2) and brine, dried with MgSO4, concentrated and purified by silica gel column chromatography (0-50% Acetone in Heptane, 216 nM) to give (R)—N-(4-chlorobutan-2-yl)-1-phenylmethanesulfonamide (1.71 g, 6.53 mmol, 58% yield over 2 steps). LCMS (ESI), m/z, 261 [M+H]+.
Reaction SMILES: [C:1]1([N:7]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:8]([O:10][CH2:11][C:12]2([OH:31])[CH2:18][CH2:17][CH2:16][C:15]3[C:19]([O:23][CH2:24][C:25]([O:27]CC)=[O:26])=[CH:20][CH:21]=[CH:22][C:14]=3[CH:13]2[OH:30])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+:39]>CO.O1CCOCC1>[C:32]1([N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8]([O:10][CH2:11][C:12]2([OH:31])[CH2:18][CH2:17][CH2:16][C:15]3[C:19]([O:23][CH2:24][C:25]([O-:27])=[O:26])=[CH:20][CH:21]=[CH:22][C:14]=3[CH:13]2[OH:30])=[O:9])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.[Na+:39]
Reactant: CCOC(=O)COc1cccc2c1CCCC(O)(COC(=O)N(c1ccccc1)c1ccccc1)C2O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Product: O=C([O-])COc1cccc2c1CCCC(O)(COC(=O)N(c1ccccc1)c1ccccc1)C2O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of ethyl {[(5SR,6SR)-6-(N,N -diphenylcarbamoyloxy)methyl-5,6-dihydroxy-6,7,8,9-tetrahydro -5H-benzocyclohepten-1-yl]oxy}acetate (70 mg) in a mixture of MeOH and 1,4-dioxane (1:1, 4 ml) was added 1N sodium hydroxide solution (0.138 ml) at 5° C. The mixture was stirred at room temperature for 1.5 hours. The reaction mixture was evaporated followed by addition of Et2O. The resulting solid was collected by filtration to give sodium {[(5SR,6SR)-6-(N,N -diphenylcarbamoyloxy)methyl-5,6-dihydroxy-6,7,8,9-tetrahydro -5H-benzocyclohepten-1-yl]oxy}acetate (65.8 mg).
Reaction SMILES: [N:1]([CH2:4][CH:5]1[CH2:9][O:8]C(C)(C)[O:6]1)=[N+:2]=[N-:3].Cl.[S:13](Cl)([C:16]1[CH:22]=[CH:21][C:19]([CH3:20])=[CH:18][CH:17]=1)(=[O:15])=[O:14].O>CO.C(OCC)C>[CH3:20][C:19]1[CH:21]=[CH:22][C:16]([S:13]([O:8][CH2:9][CH:5]([OH:6])[CH2:4][N:1]=[N+:2]=[N-:3])(=[O:15])=[O:14])=[CH:17][CH:18]=1
Reactant: CC1(C)OCC(CN=[N+]=[N-])O1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: CO
Solvent: O
Solvent: CCOCC
Product: Cc1ccc(S(=O)(=O)OCC(O)CN=[N+]=[N-])cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49 %

Procedure:
4-(Azidomethyl)-2,2-dimethyl-1,3-dioxolane 13 (2.2 g, 13.99 mmol) was dissolved in methanol (25 mL). To this solution was added a solution of HCl in diethyl ether (2M, 5 mL) at 0° C. The mixture was stirred at room temperature overnight, and then concentrated under reduced pressure to afford a yellow oil which was used for the next step without purification. After drying for 0.5 hr, the residue was dissolved in CH2Cl2 (30 mL) and was treated with Bu2SnO (0.071 mg, 0.3 mmol), followed by TsCl (2.86 g, 15.0 mmol) and TEA (2.2 mL, 16 mmol). After stirring for 3 hr at room temperature, water (30 mL) was added and the organic layer was separated. The aqueous layer was extracted with CH2Cl2 (2×50 mL) and the organic layer was consecutively washed with H2O (50 mL) and brine (50 mL) and dried over MgSO4. The solvent was removed under vacuum and the residue was purified on silica gel using 33% EtOAc/hexanes as the eluent to afford 1.86 g of 14 (48% yield) as a clear, colorless oil. 1H NMR (CDCl3, 400 MHz) δ: 7.77 (d, J=8.0 Hz, 2H), 7.34 (d, J=8.0 Hz, 2H), 3.96-4.09 (m, 3H), 3.31-3.40 (m, 2H), 2.43 (s, 3H). Mass Spec (lo-res): Calc'd for C10H13N3O4S: 271.06. found: 294.1 (M+Na+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([CH:24]([CH3:26])[CH3:25])([CH2:11][CH2:12][CH:13]([N:15]([CH3:23])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)C)[C:9]#[N:10].[ClH:27]>CO>[ClH:27].[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([CH:24]([CH3:26])[CH3:25])([CH2:11][CH2:12][CH2:13][N:15]([CH3:23])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:9]#[N:10]
Reactant: CC(CCC(C#N)(c1ccccc1F)C(C)C)N(C)Cc1ccccc1
Agent: Cl
Solvent: CO
Product: CC(C)C(C#N)(CCCN(C)Cc1ccccc1)c1ccccc1F

Procedure:
A solution of the product of Example 8, Step (c) (470 mg) in methanol (10 mL) was acidified with a solution of hydrochloric acid in methanol. The solvent was evaporated, and the residue was dried by azeotropic distillation with toluene. Crystallization of the residue from ethyl acetate gave the title compound (333 mg) as a white, crystalline solid, m.p. 164° C., characterized as follows: Analysis for C22H28FN2Cl (MW 374.93); Calc'd: C, 70.47; H, 7.53; N, 7.47; Found: C, 70.36; H, 7.54; N, 7.42.
Reaction SMILES: CCCCCC.C([Li])CCC.Br[C:13]1[C:18]([CH3:19])=[CH:17][C:16]([Br:20])=[CH:15][N:14]=1.[CH2:21]1[O:31][C:24]2([CH2:29][CH2:28][C:27](=[O:30])[CH2:26][CH2:25]2)[O:23][CH2:22]1>C1(C)C=CC=CC=1.O>[Br:20][C:16]1[CH:17]=[C:18]([CH3:19])[C:13]([C:27]2([OH:30])[CH2:28][CH2:29][C:24]3([O:31][CH2:21][CH2:22][O:23]3)[CH2:25][CH2:26]2)=[N:14][CH:15]=1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: Cc1cc(Br)cnc1Br
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1cc(Br)cnc1C1(O)CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 2 h
Yield: 55.9 %

Procedure:
1.6M n-Hexane solution of n-butyl lithium (100 ml) was added dropwise under nitrogen atmosphere at −78° C. to a solution of 2,5-dibromo-3-picoline (38.3 g) in toluene (300 ml), and stirred at the same temperature for two hours. Then, a solution of 1,4-cyclohexanedione monoethyleneketal (25 g) in toluene (200 ml) was added slowly dropwise, and after the addition the mixture was stirred at the same temperature for an hour. Then, the reaction solution was warmed up slowly to room temperature under stirring. After completion of the reaction, water was added and extracted with ethyl acetate. The organic layer was washed with water and saturated brine successively, dried over anhydrous sodium sulfate and concentrated. Acetonitrile and water were added to the residue and the precipitate was filtered and dried at 60° C. under air blow to give 8-(5-bromo-3-methylpyridin-2-yl)-1,4-dioxaspiro[4,5]decan-8-ol (28 g) as a light brown solid.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][N:5]=1.F[C:12]1[CH:17]=[C:16]([F:18])[C:15]([N+:19]([O-:21])=[O:20])=[CH:14][C:13]=1[CH3:22]>CN(C=O)C>[Cl:3][C:4]1[CH:9]=[C:8]([O:10][C:12]2[CH:17]=[C:16]([F:18])[C:15]([N+:19]([O-:21])=[O:20])=[CH:14][C:13]=2[CH3:22])[CH:7]=[CH:6][N:5]=1
Reactant: Oc1ccnc(Cl)c1
Reactant: Cc1cc([N+](=O)[O-])c(F)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc([N+](=O)[O-])c(F)cc1Oc1ccnc(Cl)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 62.9 %

Procedure:
To 60% NaH in mineral oil (0.119 g, 2.97 mmol), under an atmosphere of argon, was added anhydrous DMF (3 mL) and the slurry was cooled in an ice bath. To this suspension was added, in portions, a solution of 2-chloropyridin-4-ol (0.35 g, 2.70 mmol) in DMF (2 mL). The reaction mixture was stirred cold for 5 minutes and then allowed to warm to RT and stirred for 20 minutes. 1,5-difluoro-2-methyl-4-nitrobenzene (0.514 g, 2.97 mmol) was added and the reaction mixture heated at 90° C. for 3 hours, cooled to RT, quenched with water and the mixture was extracted with EtOAc (3×). The combined organic phases were washed with brine, dried (Na2SO4), concentrated in vacuo and purified by silica gel column chromatography (EtOAc/hexanes) to obtain 2-chloro-4-(5-fluoro-2-methyl-4-nitrophenoxy)pyridine (0.48 g, 63% yield) MS (ESI) m/z: 283.0 (M+H+).