Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([F:9])[C:3]=1[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12].C([N-]C(C)C)(C)C.[Li+].[CH:24]1([C:31](Cl)=[O:32])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1.Cl>O1CCCC1>[CH:24]1([C:31](=[O:32])[CH:10]([C:3]2[C:2]([F:1])=[CH:7][C:6]([F:8])=[CH:5][C:4]=2[F:9])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: CCOC(=O)Cc1c(F)cc(F)cc1F
Reactant: O=C(Cl)C1CCCCCC1
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C(C(=O)C1CCCCCC1)c1c(F)cc(F)cc1F
Temperature: 25 °C
Yield: 59.9 %

Procedure:
A solution of ethyl 2,4,6-trifluorophenylacetate (436 mg, 2.0 mmol) in 3 mL of tetrahydrofuran is cooled to −78° C., and lithium diisopropylamide (2.0 M in heptane/tetrahydrofuran/ethylbenzene, 1.0 mL, 2.0 mmol) is added dropwise with stirring. The mixture is stirred at −78° C. for 1 h, and cycloheptanecarboxylic acid chloride (321 mg, 2.0 mmol) is added dropwise. The mixture is warmed to room temperature and acidified with 2 mL of 1.0 N hydrochloric acid. The product is extracted with ethyl acetate. The organic layer is washed with saturated sodium chloride, dried over magnesium sulfate, and concentrated to a residue. The residue is chromatographed over silica gel, eluting with a gradient of hexanes to 10% ethyl acetate in hexanes. Concentration provides ethyl 3-cycloheptyl-3-oxo-2-(2,4,6-trifluorophenyl)propanoate as a colorless oil (410 mg). MS: m/z 341.2 (M−H).
Reaction SMILES: O.[N-:2]=[N+]=[N-].[Na+].[C:6](Cl)(=[O:17])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH:15]=[CH2:16].C[C:20](C)=[O:21]>>[C:6]([N:2]=[C:20]=[O:21])(=[O:17])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH:15]=[CH2:16]
Reactant: C=CCCCCCCCCC(=O)Cl
Reactant: CC(C)=O
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Product: C=CCCCCCCCCC(=O)N=C=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
150 g of purified water was added to 45.5 g of sodium azide and a completely homogeneous solution was prepared by stirring while cooling with ice water. To this was added dropwise in small portions a solution prepared by mixing 101.4 g of 10-undecenoyl chloride with 150 mL of acetone; this addition was carried out so as to keep the solution temperature in the range from 10 to 15° C. Stirring at around 12° C. was continued for 1 hour after the completion of addition. The solution was then transferred to a separatory funnel and the aqueous and organic layers were separated. The organic layer was slowly added to 500 mL of toluene held at 60° C., followed by stirring for 3 hours in the temperature range from 50 to 60° C. The toluene was distilled off and distillation in vacuo was thereafter carried out to obtain 73.2 g of 10-undecenoyl isocyanate.
Reaction SMILES: [OH:1][C:2]1[C:3]([Cl:12])=[C:4]([C:7]([Cl:11])=[CH:8][C:9]=1[Cl:10])[C:5]#[N:6].[Na].Br[CH2:15][C:16]([O:18][CH2:19]C)=[O:17]>CO>[CH3:19][O:18][C:16](=[O:17])[CH2:15][O:1][C:2]1[C:9]([Cl:10])=[CH:8][C:7]([Cl:11])=[C:4]([C:5]#[N:6])[C:3]=1[Cl:12]
Reactant: CCOC(=O)CBr
Reactant: N#Cc1c(Cl)cc(Cl)c(O)c1Cl
Agent: [Na]
Solvent: CO
Product: COC(=O)COc1c(Cl)cc(Cl)c(C#N)c1Cl
Yield: 64.5 %

Procedure:
22.5 g (0.1 mol) of 3-hydroxy-2,4,6-trichlorobenzonitrile are dissolved in 240 ml of methanol with the addition of 2.3 g (0.1 mol) of metallic sodium. To the resultant suspension of the sodium salt is added 12.15 ml (0.11 mol) of ethyl bromoacetate, and the reaction mixture is heated to reflux until solution is complete. After filtration over active carbon, the solution is cooled and stirred for several hours in an ice bath. The resultant crystalline precipitate is vacuum-filtered, washed with a little ice-cold methanol and dried at 50° C., to produce 19 g (64.5% of theory) of 3-cyano-2,4,6-trichlorophenoxyacetic acid methyl ester as a white powder, mp 110°-112° C.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][C:4]([C:9]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[CH:19]=3)([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[CH:12]=3)[OH:10])([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[C:25]1([CH2:31][O:32][CH2:33][CH2:34][Br:35])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CC#N>[Br-:35].[OH:10][C:9]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[CH:19]=1)([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[CH:12]=1)[C:4]12[CH2:5][CH2:6][N+:1]([CH2:34][CH2:33][O:32][CH2:31][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)([CH2:8][CH2:7]1)[CH2:2][CH2:3]2
Reactant: BrCCOCc1ccccc1
Reactant: Cc1cccc(C(O)(c2cccc(C)c2)C23CCN(CC2)CC3)c1
Solvent: CC#N
Product: Cc1cccc(C(O)(c2cccc(C)c2)C23CC[N+](CCOCc4ccccc4)(CC2)CC3)c1
Product: [Br-]
Yield: 11 %

Procedure:
Following the general procedure outlined in Example 4, 1-azabicyclo[2.2.2]oct-4yl[bis(3-methylphenyl)]methanol (0.0496 g, 0.154 mmol) and 2-bromoethyl phenylmethyl ether (0.0364 mL, 0.230 mmol) in 2 CH3CN/3 CHCl3 (4.0 mL) were reacted to give the desired product (0.0091 g, 11.0%). EI-MS m/z 456(M+) Rt (2.20 min).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8](Cl)=[O:9])[C:5]2[C:11]([O:33][CH3:34])=[N:12][N:13]([C:14]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:4]=2[CH:3]=1.[NH2:35][NH2:36]>C(#N)C>[Cl:1][C:2]1[N:7]=[C:6]([C:8]([NH:35][NH2:36])=[O:9])[C:5]2[C:11]([O:33][CH3:34])=[N:12][N:13]([C:14]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:4]=2[CH:3]=1
Reactant: NN
Reactant: COc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(Cl)nc(C(=O)Cl)c12
Solvent: CC#N
Product: COc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(Cl)nc(C(=O)NN)c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
6-chloro-3-methoxy-1-trityl-1H-pyrazolo[4,3-c]pyridine-4-carbonyl chloride (240 mg, 0.491 mmol) was taken up in acetonitrile (4 ml). TEA (0.205 ml, 1.474 mmol) was added followed by the dropwise addition of hydrazine (0.046 ml, 1.474 mmol). The reaction was allowed to stir at rt overnight. The reaction mixture was concentrated in vacuo. The mixture was then resuspended in EtOAc and saturated NH4Cl was added. The products were extracted into EtOAc (3×) and the combined organics were washed with brine, dried over MgSO4, and concentrated in vacuo to give 6-chloro-3-methoxy-1-trityl-1H-pyrazolo[4,3-c]pyridine-4-carbohydrazide. The products were carried forward without further purification. MS: [M+H]+ m/z 484.
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[CH3:13][N:14]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:15](Cl)=[O:16]>>[N:1]1([C:6]2[CH:11]=[CH:10][C:9]([O:12][C:15](=[O:16])[N:14]([CH3:13])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: Oc1ccc(-n2ccnc2)cc1
Reactant: CN(C(=O)Cl)c1ccccc1
Product: CN(C(=O)Oc1ccc(-n2ccnc2)cc1)c1ccccc1

Procedure:
The title compound was prepared from 4-imidazol-1-yl-phenol and N-methyl-N-phenylcarbamoyl chloride. The crude product was subjected to preparative HPLC (4%, clear oil). HPLC-MS m/z=294.1 (M+1), Rt: 2.25 min.
Reaction SMILES: [C:1]([C:4]1[C:9]([NH:10][C:11]([C:13]2[S:14][CH:15]=[C:16]([C:18]#[C:19][Si](C)(C)C)[N:17]=2)=O)=[C:8]([CH3:24])[C:7]([O:25][CH3:26])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].CC(C)([O-])C.[K+]>C(O)(C)(C)C>[CH3:26][O:25][C:7]1[C:8]([CH3:24])=[C:9]2[C:4]([C:1]([OH:3])=[CH:2][C:11]([C:13]3[S:14][CH:15]=[C:16]([C:18]#[CH:19])[N:17]=3)=[N:10]2)=[CH:5][CH:6]=1
Reactant: COc1ccc(C(C)=O)c(NC(=O)c2nc(C#C[Si](C)(C)C)cs2)c1C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: C#Cc1csc(-c2cc(O)c3ccc(OC)c(C)c3n2)n1
Temperature: 80 °C
Yield: 52 %

Procedure:
To a suspension of compound 208b (8.71 g, 1 eq.) in tert-butanol (240 mL) was added potassium tert-butoxide (5.32 g, 2.1 eq.). The heterogeneous mixture was stirred and heated to 80° C. The solvent was then evaporated and water was added to the resulting black residue. The pH of the mixture was brought to 6 with 1N HCl. The mixture was extracted with dichloromethane. The organic layer was dried over Na2SO4, filtered, and concentrated under vacuo. The solid was purified by chromatography on silica gel to give compound 209b as an orange solid in 52% yield. 1H NMR (CDCl3, 400 MHz) δ (ppm) 2.45 (s, 3H), 3.25 (s, 1H), 3.99 (s, 3H), 6.89 (br s, 1H), 7.06 (d, J=9.09 Hz, 1H), 7.72 (s, 1H), 8.26 (d, J=9.09 Hz, 1H), 9.50 (br s, 1H); MS (ESI, EI+): m/z=297 (MH+).
Reaction SMILES: P(Br)(Br)([Br:3])=O.[CH3:6][C:7]1[CH:8]=[C:9](O)[C:10]2[CH:15]=[N:14][N:13]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:11]=2[N:12]=1.C1(C)C=CC=CC=1>CN(C=O)C>[Br:3][C:9]1[CH:8]=[C:7]([CH3:6])[N:12]=[C:11]2[N:13]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:14]=[CH:15][C:10]=12
Reactant: Cc1cc(O)c2cnn(Cc3ccccc3)c2n1
Reactant: O=P(Br)(Br)Br
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: Cc1cc(Br)c2cnn(Cc3ccccc3)c2n1

Procedure:
Phosphorus oxybromide (5.31 g, 18.54 mmol) was added to a suspension of 6-methyl-1-(phenylmethyl)-1H-pyrazolo[3,4-b]pyridin-4-ol (3.08 g, 12.87 mmol) and toluene (25 mL). The contents were heated to reflux for 1 h, wherein 10 mL DMF were added during this process. The solvent was removed under reduced pressure. The crude residue was suspended in 30 mL water containing ice. The contents were adjusted to pH=10 by addition of sat. NaHCO3. The solid product was filtered and dried under hi-vacuum. The final product was collected as 3.55 g (91%). LCMS E-S (M+H)=302.1/304.0. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.61 (s, 3 H), 5.65 (s, 2 H), 7.16-7.35 (m, 5 H), 7.48 (s, 1 H), 8.12 s, 1 H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[OH:9].[H-].[Na+].I[CH3:13]>CN(C=O)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[O:9][CH3:13]
Reactant: CI
Reactant: Oc1cc(F)ccc1Br
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc(F)ccc1Br
Temperature: 60 °C
Reaction time: 16 h

Procedure:
A mixture of 2-bromo-5-fluorophenol (2 mL, 17.8 mmol)), sodium hydride (0.5 g, 20.8 mmol) and iodomethane (5 mL, 82 mmol) in DMF (20 mL) was heated to 60° C., stirred for 16 hours, diluted with ethyl acetate (100 mL), washed sequentially with 1M HCl, water, and brine, dried (MgSO4), filtered, and concentrated to provide the desired product.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:9]([NH:10][C:11](=[O:21])[CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17](Br)=[CH:16][N:15]=2)=[CH:8][S:7][CH:6]=1)=[O:4].[CH3:22][O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1B(O)O.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCCC1.O.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:2][C:3]([C:5]1[C:9]([NH:10][C:11](=[O:21])[CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=3[O:23][CH3:22])=[CH:16][N:15]=2)=[CH:8][S:7][CH:6]=1)=[O:4]
Reactant: COc1ccccc1B(O)O
Reactant: COC(=O)c1cscc1NC(=O)COc1ccc(Br)cn1
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: [Cs+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)c1cscc1NC(=O)COc1ccc(-c2ccccc2OC)cn1
Temperature: 80 °C
Reaction time: 8 h
Yield: 79 %

Procedure:
To a solution of 4-[2-(5-bromo-pyridin-2-yloxy)-acetylamino]-thiophene-3-carboxylic acid methyl ester (50 g, 0.135 mmol) in a mixture of tetrahydrofuran (10.5 mL) and water (2.5 mL) was added 2-methoxyphenylboronic acid (24.5 mg, 0.162 mmol) and cesium carbonate (175.3 mg, 0.54 mmol). The solution was then degassed by bubbling a flux of argon for 20 minutes before adding tetrakis(triphenylphosphine)palladium (4.24 mg, 0.0034 mmol). The reaction mixture was then stirred overnight at 80° C. under argon atmosphere before allowing to cool down to room temperature and diluting with ethyl acetate. The reaction mixture was then filtered; the filtrate was then washed twice with water and dried over sodium sulfate before being concentrated in vacuo. The residue was then purified by column chromatography (SiO2, EtOAc/Heptane, 0-60%) to yield the title compound as a light yellow solid (42.5 mg, 79%).
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[CH:17]=[C:16]3[C:11]([CH:12]=[CH:13][CH:14]=[N:15]3)=[C:10]([O:18][CH2:19][C@:20]3([F:33])[CH2:25][CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21]3)[N:9]=2)[CH:5]=[N:4]1)[CH3:2].FC(F)(F)C(O)=O>C(Cl)Cl.CO>[CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[CH:17]=[C:16]3[C:11]([CH:12]=[CH:13][CH:14]=[N:15]3)=[C:10]([O:18][CH2:19][C@:20]3([F:33])[CH2:25][CH2:24][CH2:23][NH:22][CH2:21]3)[N:9]=2)[CH:5]=[N:4]1)[CH3:2]
Reactant: CCn1cc(-c2cc3ncccc3c(OC[C@]3(F)CCCN(C(=O)OC(C)(C)C)C3)n2)cn1
Solvent: ClCCl
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: CCn1cc(-c2cc3ncccc3c(OC[C@]3(F)CCCNC3)n2)cn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 72.2 %

Procedure:
To a solution of 1,1-dimethylethyl (3S)-3-({[7-(1-ethyl-1H-pyrazol-4-yl)-1,6-naphthyridin-5-yl]oxy}methyl)-3-fluoro-1-piperidinecarboxylate (1.1 g, 2.415 mmol) in DCM (3 ml) was added trifluoroacetic acid (3 ml, 38.9 mmol) and this was stirred at room temp for 3 h. The reaction had gone to completion and so was concentrated in vacuo to yield the crude product. The TFA salt was dissolved in methanol and loaded onto an SCX cartridge (20 g). The impurities were eluted with methanol, and the product was eluted with 2M ammonia in methanol. The filtrate was concentrated in vacuo to yield a cream gummy solid (620 mg). This was purified by large-scale MDAP (Method C). The appropriate vials were combined and concentrated in vacuo to give the product as the TFA salt. To form the free base, this was dissolved in methanol and purified through an SCX cartridge (20 g) eluting with methanol. The product was eluted with 2M ammonia in methanol. The filtrate was concentrated in vacuo to yield the title compound as a clear glass (500 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11]Br)=[CH:7][CH:6]=1.C(=O)([O-])[O-:15].[Ca+2].O>O1CCOCC1>[CH3:1][O:2][C:3](=[O:13])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][OH:15])=[CH:7][CH:6]=1
Reactant: O=C([O-])[O-]
Reactant: COC(=O)Cc1ccc(CBr)cc1
Agent: [Ca+2]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)Cc1ccc(CO)cc1

Procedure:
To a stirring solution of 15 in dioxane (0.4 M) at room temperature under nitrogen was added calcium carbonate (5.5 eq) and H2O (0.8 M). The reaction was refluxed overnight then vacuum filtered. The dioxane was removed under reduced pressure. The reaction mixture was diluted with H2O then extracted with dichloromethane (3×). The organic phases were combined, dried over sodium sulfate, filtered and concentrated in vacuo to afford the product. (77%) 1H NMR (400 MHz, CDCl3) δ 7.33 (d, 2H), 7.27 (d, 2H), 4.67 (s, 2H), 3.69 (s, 3H), 3.63 (s, 2H), 1.78 (br s, 1H).
Reaction SMILES: [CH:1]([OH:3])=O.[C:4]([O:7][C:8](=O)[CH3:9])(=O)[CH3:5].C(O[NH:19][C:20]1[CH:25]=[C:24]([CH2:26][CH2:27][N:28]([CH2:32][CH2:33][CH3:34])[CH2:29][CH2:30][CH3:31])[CH:23]=CC=1)C1C=CC=CC=1>C(Cl)(Cl)Cl>[CH2:4]([O:7][C:8]1[CH:9]=[CH:23][C:24]([CH2:26][CH2:27][N:28]([CH2:29][CH2:30][CH3:31])[CH2:32][CH2:33][CH3:34])=[CH:25][C:20]=1[NH:19][CH:1]=[O:3])[C:5]1[CH:27]=[CH:26][CH:24]=[CH:25][CH:20]=1
Reactant: CCCN(CCC)CCc1cccc(NOCc2ccccc2)c1
Reactant: O=CO
Reactant: CC(=O)OC(C)=O
Solvent: ClC(Cl)Cl
Product: CCCN(CCC)CCc1ccc(OCc2ccccc2)c(NC=O)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Under ice cooling, 4 ml of a mixture of formic acid and acetic anhydride (ratio 3:5) is added dropwise to 3.2 g of 2-(benzyloxy-5-(2-dipropylaminoethyl)aniline in 10 ml of chloroform, then the mixture is stirred for 2 hours at room temperature. The solution is washed with aqueous NaHCO3 solution, concentrated, and the residue chromatographed on silica gel with methylene chloride/acetone (1:1), yielding 1.8 g of N-[2-benzyloxy-5-(2-dipropylaminoethyl)phenyl]formamide as an oil.
Reaction SMILES: [CH3:1][CH:2]([N:18]([CH3:20])[CH3:19])[CH2:3][N:4]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[S:11][C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]1=2.Cl.[S:22]([O:27]C)([O:25][CH3:26])(=[O:24])=[O:23]>CC(C)=O>[CH3:26][O:25][S:22]([O-:27])(=[O:24])=[O:23].[CH3:20][N+:18]([CH3:26])([CH3:19])[CH:2]([CH3:1])[CH2:3][N:4]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=2[S:11][C:12]2[C:13]1=[CH:14][CH:15]=[CH:16][CH:17]=2
Reactant: CC(CN1c2ccccc2Sc2ccccc21)N(C)C
Reactant: COS(=O)(=O)OC
Agent: Cl
Solvent: CC(C)=O
Product: CC(CN1c2ccccc2Sc2ccccc21)[N+](C)(C)C
Product: COS(=O)(=O)[O-]
Reaction time: 8 h

Procedure:
dl-Promethazine hydrochloride (30 g.) was converted to the free base and was dissolved in absolute acetone and dimethyl sulfate (10 g.) was added (this is less than are equivalent of dimethyl sulfate due to its hazardous nature). After standing overnight, the solution was heated on a steam bath and cooled. The precipitated solid was filtered, washed with tetrahydrofuran and ether to provide dl-trimethyl[1-methyl-2-(phenothiazine-10-yl)ethyl]ammonium methyl sulfate, 27.6 g., m.p. 170°-173° C.
Reaction SMILES: [C:1]([NH:4][CH:5]([CH2:29][NH:30][S:31]([CH2:34][CH2:35][CH2:36]Cl)(=[O:33])=[O:32])[CH2:6][O:7][C:8](=[O:28])[NH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])(=[O:3])[CH3:2].C(SCC(OC)CNS(CCC[I:65])(=O)=O)CCCCCCCCCCCCCCC>>[C:1]([NH:4][CH:5]([CH2:29][NH:30][S:31]([CH2:34][CH2:35][CH2:36][I:65])(=[O:33])=[O:32])[CH2:6][O:7][C:8](=[O:28])[NH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])(=[O:3])[CH3:2]
Reactant: CCCCCCCCCCCCCCCCCCNC(=O)OCC(CNS(=O)(=O)CCCCl)NC(C)=O
Reactant: CCCCCCCCCCCCCCCCSCC(CNS(=O)(=O)CCCI)OC
Product: CCCCCCCCCCCCCCCCCCNC(=O)OCC(CNS(=O)(=O)CCCI)NC(C)=O

Procedure:
2-acetamido-3-(3-chloropropylsulfonylamino)-1-octadecylcarbamoyloxypropane IIIg1 is allowed to react and worked up by the same procedure as described in (5). m.p. 101°-102° C. The summary of the experimental condition and the physical data of the product are listed in Table 8.
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[C:6]([Cl:13])[N:5]=[C:4]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)[N:3]=1.[CH3:24][O:25][CH:26]([O:29][CH3:30])[CH2:27][NH2:28].C(N(C(C)C)CC)(C)C>O1CCOCC1>[Cl:13][C:6]1[C:7]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[C:2]([NH:28][CH2:27][CH:26]([O:29][CH3:30])[O:25][CH3:24])[N:3]=[C:4]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)[N:5]=1
Reactant: COC(CN)OC
Reactant: COC(=O)Cc1c(Cl)nc(Cc2ccc([N+](=O)[O-])cc2)nc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: COC(=O)Cc1c(Cl)nc(Cc2ccc([N+](=O)[O-])cc2)nc1NCC(OC)OC
Temperature: 80 °C
Reaction time: 2 h
Yield: 79.4 %

Procedure:
A mixture of methyl [4,6-dichloro-2-(4-nitrobenzyl)pyrimidin-5-yl]acetate (2.0 g, 5.6 mmol), aminoacetaldehyde dimethylacetal (0.68 g, 6.5 mmol) and diisopropylethylamine (1.5 mL, 8.4 mmol) in 1,4-dioxane (50 mL) was stirred at 80° C. for 2 hours. The mixture was concentrated under reduced pressure. The residue was extracted with ethyl acetate. The extracts were washed with aq NaHCO3 and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by preparative MPLC (silica gel, hexane:ethyl acetate, 2/1) to give methyl [4-chloro-6-[(2,2-dimethoxyethyl)amino]-2-(4-nitrobenzyl)pyrimidin-5-yl]-acetate (1.89 g, 79%) as a gray solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([C:10]2[C:15]([CH3:16])=[CH:14][N:13](O)[CH2:12][C:11]=2[CH3:18])=[C:5]([CH3:19])[CH:4]=1.O.[PH2]([O-])=O.[Na+]>C(O)(=O)C.[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH3:19])[C:6]([C:10]2[C:15]([CH3:16])=[CH:14][N:13]=[CH:12][C:11]=2[CH3:18])=[C:7]([CH3:9])[CH:8]=1
Reactant: COc1cc(C)c(C2=C(C)CN(O)C=C2C)c(C)c1
Agent: [Pd]
Agent: O=[PH2][O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COc1cc(C)c(-c2c(C)cncc2C)c(C)c1
Temperature: 80 °C
Reaction time: 12 h
Yield: 97.7 %

Procedure:
To a mixture of 3 (6.55 g, 25.5 mmol) and palladium (10 wt. % on activated carbon; 3.05 g, 2.8 mmol) in acetic acid (150 mL) was added sodium hypophosphite hydrate (6.7 g, 63 mmol) in a single portion at 80° C. The reaction mixture was stirred at 80° C. under N2 for 12 h, then filtered and concentrated in vacuo. The resulting light-yellow oil was dissolved in chloroform (250 mL) and washed successively with saturated NaHCO3 (aq.), water, and brine. The organic layer was then separated, dried over MgSO4, filtered, and concentrated in vacuo. The resulting pale-yellow solid was purified by flash chromatography on silica gel eluting with 1:1 hexane: ethyl acetate, to give 6.01 g (97.9%) of the title compound as colorless solid: mp 87-88° C.; 1H NMR (400 MHz, CD2Cl2): δ 8.334 (s, 2H), 6.707 (s, 2H), 3.804 (s, 3H), 1.892 (s, 6H), 1.851 (s, 6H); 13C NMR (100 MHz, CD2Cl2): δ 159.330, 148.939, 148.420, 136.373, 131.905, 129.958, 113.489, 55.556, 20.188, 16.831; MS (APCI): m/z 242.2 [(M+H)+, 100]; Anal. Calcd. For C16H19NO: C, 79.63; H, 7.94; N, 5.80. Found: C, 79.39; H, 7.94; N, 5.75.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)[CH:5]=[CH:6][C:7]=1[N+:8]([O-])=O.[H][H]>[Pd].CO>[NH2:1][C:2]1[CH:3]=[C:4]([N:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)[CH:5]=[CH:6][C:7]=1[NH2:8]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc([N+](=O)[O-])c(N)c2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(N)c(N)c2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.8 %

Procedure:
A 500 ml Parr hydrogenation flask was charged with tert-butyl 4-(3-amino-4-nitrophenyl)piperazine-1-carboxylate (9.0 g), methanol (250 mL) and 10% palladium on carbon (50% w/w water, 2.0 g). The atmosphere of the vessel was replaced by hydrogen gas. The reaction was shaken under a hydrogen atmosphere at 40 psi at room temperature for 1 hour. The reaction mixture was filtered through a plug of Celite, which was washed with additional methanol. The filtrate was concentrated at reduced pressure and the residue was triturated with ether to give 7.0 g of tert-butyl 4-(3,4-diaminophenyl)piperazine-1-carboxylate (yield 85%). 1H-NMR (400 MHz, MeOH-d4): δ 6.65 (d, 1H), 6.47 (s, 1H), 6.30 (d, 1H), 3.52 (s, 4H) 2.90 (s, 4H), 1.48 (s, 9H). MS (EI) for: 293 (MH+).
Reaction SMILES: [CH3:1][CH2:2][CH2:3]CCCC.C1(C)C=CC=CC=1.C1C=C2C=C[C:23]([OH:36])=[C:24]([C:25]3C4C(=CC=CC=4)C=C[C:26]=3[OH:35])C2=CC=1.[OH2:37]>CC(C)[O-].CC(C)[O-].CC(C)[O-].CC(C)[O-].[Ti+4]>[CH3:1][C:2]1([CH3:3])[O:36][CH2:23][CH:24]2[CH:25]([O:37]2)[CH2:26][O:35]1
Reactant: O
Reactant: Oc1ccc2ccccc2c1-c1c(O)ccc2ccccc12
Reactant: CCCCCCC
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: Cc1ccccc1
Product: CC1(C)OCC2OC2CO1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Heptane-toluene (9:1, volume ratio, 350 ml) was added to (S)-1,1′-bi-2-naphthol (1.89 g), and titanium tetraisopropoxide (Ti(OPri)4, 1.95 ml) was added under a nitrogen atmosphere, which was followed by stirring for 10 min at room temperature. (R)-1-Phenethylamine (compound [2], 85 ml), water (0.5 ml) and 4,4-dimethyl-3,5,8-trioxabicyclo[5.1.0]octane (compound [1′], 100 g) obtained by a known method were successively added with stirring, and the mixture was stirred at 40° C. for 24 hr. Toluene was added to the reaction mixture and the mixture was stirred at 40° C. for 1 hr. Then, the mixture was cooled to 10° C. or less over one hour and stirred for one more hour. The crystals in the reaction mixture were collected by filtration and washed with heptane-toluene (2:1, volume ratio) to give (5R,6S)-2,2-dimethyl-6-[(R)-1-phenethylamino]-1,3-dioxepan-5-ol (compound [3′], 159 g, yield 91%) as yellow crystals. mp. 108-109° C.