Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=O)[C@@H:4]1[CH2:8][CH2:7][C:6](=[CH:9][N+:10]([O-])=O)[N:5]1[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[H][H]>[Pd].CO>[CH2:13]([N:5]1[C@@H:6]2[CH2:7][CH2:8][C@H:4]1[C:3](=[O:2])[NH:10][CH2:9]2)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: [H][H]
Reactant: COC(=O)[C@@H]1CCC(=C[N+](=O)[O-])N1Cc1ccccc1
Agent: [Pd]
Solvent: CO
Product: O=C1NC[C@H]2CC[C@@H]1N2Cc1ccccc1
Yield: 59.4 %

Procedure:
(S)-1-Benzyl-5-nitromethylene proline methyl ester (3.22 g, 11.6 mmol) was added to a suspension of 10% palladium on carbon (1.35 g) in methanol (75 mL) and the mixture was hydrogenated under 30 psi of hydrogen for 20 h. The catalyst was removed by filtration through a pad of celite and the solvent was removed under reduced pressure. The crude product was purified by silica gel chromatography, eluting with 5% methanol/methylene chloride, to yield the desired product (1.49 g, 60%). 1H NMR (300 MHz, CDCl3): δ 1.78 (m, 1 H), 2.08 (m, 1 H), 2.22 (m, 2 H), 2.99 (dd, 1 H, J=2.0, 11.3), 3.38 (m, 1 H), 3.49 (d, 1 H, J=6.1), 3.67 (dd, 1 H, J=3.9, 11.3), 3.78 (s, 2 H), 5.66 (s, 1 H), 7.33 (m, 5 H). MS ESI+: m/z 217 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[N:9][N:10]2[CH:13]([CH3:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:6][CH:5]=1)([O-])=O.O.Cl>C(O)(C)C>[NH2:1][C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[N:9][N:10]2[CH:13]([CH3:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:6][CH:5]=1
Reactant: CCOC(=O)C(C)n1ncc2ccc([N+](=O)[O-])cc21
Agent: Cl
Solvent: CC(C)O
Solvent: O
Product: CCOC(=O)C(C)n1ncc2ccc(N)cc21

Procedure:
Ethyl 2-(6-nitroindazol-1-yl)propionate (1 g), water (3.7cm3) and reduced iron (2.3 g) were stirred in isopropanol (17cm3) at room temperature. Concentrated hydrochloric acid (0.14cm3) was added and the mixture stirred and heated under reflux for 20 minutes. The mixture was filtered through hyflo whilst hot and filter pad washed with ethanol. The combined filtrate was concentrated under vacuum and the residue purified by chromatography (SiO2 ; CHCl3 : ether, 3:1) to give ethyl 2-(6 aminoindazol-1-yl)propionate (0.649). M+ =233
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[O:12][CH2:13][CH3:14])[C:7]#[N:8])[CH3:2].C(N)(=S)C.Cl.CN(C)C=[O:23]>>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[O:12][CH2:13][CH3:14])[C:7]([NH2:8])=[O:23])[CH3:2]
Reactant: CN(C)C=O
Reactant: CCOc1ccc(C#N)cc1OCC
Agent: CC(N)=S
Agent: Cl
Product: CCOc1ccc(C(N)=O)cc1OCC
Temperature: 130 °C

Procedure:
In 120 ml of 10% hydrochloric acid-dimethylformamide were dissolved 29 g of 3,4-diethoxybenzonitrile and 23 g of thioacetamide. The solution was heated at 90° C. for 3 hours and further at 130° C. for 5 hours to conduct a reaction. The reaction mixture was subjected to distillation to remove the solvent. The residue was washed twice with 100 ml of diethyl ether, followed by washing with 100 ml of water. The resulting crystals were collected by filtration and dried to obtain 21.7 g of 3,4-diethoxybenzamide.
Reaction SMILES: [F:1][C:2]([F:18])([C:9]([F:17])([F:16])[C:10]([F:15])([F:14])[CH:11]([F:13])[F:12])[CH2:3][CH:4]([C:7]#[N:8])[C:5]#[N:6].FC(F)(F)S(O[CH2:25][C:26]([F:31])([F:30])[CH:27]([F:29])[F:28])(=O)=O.C(=O)([O-])[O-].[K+].[K+].Cl>COCCOC>[F:1][C:2]([F:18])([C:9]([F:16])([F:17])[C:10]([F:14])([F:15])[CH:11]([F:13])[F:12])[CH2:3][C:4]([CH2:25][C:26]([F:31])([F:30])[CH:27]([F:29])[F:28])([C:7]#[N:8])[C:5]#[N:6]
Reactant: N#CC(C#N)CC(F)(F)C(F)(F)C(F)(F)C(F)F
Reactant: O=S(=O)(OCC(F)(F)C(F)F)C(F)(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: N#CC(C#N)(CC(F)(F)C(F)F)CC(F)(F)C(F)(F)C(F)(F)C(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 18.3 %

Procedure:
1.4 g of 2-(2,2,3,3,4,4,5,5-octafluoropentyl)malononitrile and 4.0 g of 2,2,3,3-tetrafluoropropyl trifluoromethanesulfonate were dissolved in 10 ml of ethylene glycol dimethyl ether, 1.4 g of potassium carbonate was added, and the mixture was stirred at room temperature for 8 hours. Thereafter, dilute hydrochloric acid was added to the reaction mixture, followed by extraction with methyl tert-butyl ether. The organic layer was washed successively with water, aqueous saturated sodium hydrogen carbonate and aqueous saturated sodium chloride, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.36 g of 2-(2,2,3,3,4,4,5,5-octafluoropentyl)-2-(2,2,3,3-tetrafluoropropyl)malononitrile (hereinafter, referred to as the present compound (61)).
Reaction SMILES: [OH:1][C:2]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=O.[N:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:24]([NH:26][NH2:27])=[O:25].O>CN1CCCC1=O>[N:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:24]([NH:26][N:27]=[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3]1[CH:12]=[CH:13][C:14]([O:16][CH3:17])=[CH:15][C:2]=1[OH:1])=[O:25]
Reactant: COc1ccc(C(=O)c2ccccc2)c(O)c1
Reactant: NNC(=O)c1ccccn1
Solvent: O
Solvent: CN1CCCC1=O
Product: COc1ccc(C(=NNC(=O)c2ccccn2)c2ccccc2)c(O)c1
Temperature: 25 °C
Yield: 81.8 %

Procedure:
47.0 g of 2-hydroxy-4-methoxybenzophenone and 27.7 g of picolinic acid hydrazide are stirred in 150 ml of N-methylpyrrolidone for 18 hours at 140° C. After the reaction mixture has cooled to room temperature, the brownish yellow solution is treated with 200 ml of water. The precipitate produced is isolated by filtration and washed with isopropanol and then with water. After the product has been dried under vacuum at 50°-60° C., 57.4 g of 2-hydroxy-4-methoxybenzophenone picolinoylhydrazone are obtained.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Br:13])=[C:4]([CH:9]=[C:10]([Cl:12])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[O:14]1[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClCCCl.O>[Br:13][C:3]1[C:2]([NH:1][CH:17]2[CH2:18][CH2:19][O:14][CH2:15][CH2:16]2)=[CH:11][C:10]([Cl:12])=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cc(Cl)cc(N)c1Br
Reactant: O=C1CCOCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Solvent: O
Product: COC(=O)c1cc(Cl)cc(NC2CCOCC2)c1Br
Reaction time: 21 h
Yield: 68.2 %

Procedure:
To a solution of methyl 3-amino-2-bromo-5-chlorobenzoate (1.0 g, 3.8 mmol) in 1,2-dichloroethane (15 ml) at room temperature under nitrogen was added oxan-4-one (0.7 ml, 7.6 mmol) followed by acetic acid (1.3 ml, 23 mmol). This solution was stirred for 5 minutes before the addition of sodium triacetoxyborohydride (2.4 g, 11 mmol) at room temperature. After 21 h, additional oxan-4-one (0.7 ml, 7.6 mmol) was added to the reaction mixture, with stirring for 10 minutes before adding sodium triacetoxyborohydride (2.4 g, 11 mmol). After stirring for 20 h, deionized water (30 ml) was added and the mixture was neutralised with solid NaHCO3. The phases were separated and the aqueous layer was extracted with EtOAc (2×30 ml). The combined organic extracts were dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by FCC (25 g silica, Isolute cartridge, gradient of eluents; 9:1 Heptane:EtOAc to 8:2 Heptane:EtOAc) to give 903 mg (68%) of the title compound as a white solid. LC-MS 92%, 2.11 min (3 minute LC-MS method), m/z=348.2/350.2/351.9, 1H NMR (500 MHz, Chloroform-d) δ 6.94-7.07 (1H, m), 6.70 (1H, d, J=2.36 Hz), 4.72 (1H, d, J=7.57 Hz), 3.96-4.15 (2H, m), 3.87-3.96 (3H, m), 3.40-3.67 (3H, m), 2.05 (2H, d, J=13.08 Hz), 1.49-1.69 (2H, m).
Reaction SMILES: C([O:5][C:6](=[O:40])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([F:17])=[CH:14][CH:15]=2)[C:10]([C:18]2[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[S:21](=[O:29])(=[O:28])[N:20]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=3)[N:19]=2)=[C:9]1[CH3:39])(C)(C)C.C(O)(C(F)(F)F)=O>>[CH3:38][O:37][C:34]1[CH:35]=[CH:36][C:31]([CH2:30][N:20]2[N:19]=[C:18]([C:10]3[C:11]4[C:16](=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=4)[N:8]([CH2:7][C:6]([OH:40])=[O:5])[C:9]=3[CH3:39])[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[S:21]2(=[O:28])=[O:29])=[CH:32][CH:33]=1
Reactant: COc1ccc(CN2N=C(c3c(C)n(CC(=O)OC(C)(C)C)c4ccc(F)cc34)c3ccccc3S2(=O)=O)cc1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(CN2N=C(c3c(C)n(CC(=O)O)c4ccc(F)cc34)c3ccccc3S2(=O)=O)cc1

Procedure:
{3-[2-(4-Methoxy-benzyl)-1,1-dioxo-1,2-dihydro-1λ6-benzo[e][1,2,3]thiadiazin-4-yl]-5-fluoro-2-methyl-indol-1-yl}-acetic acid tert-butyl ester (61 μmol) was treated with TFA (2 mL) for 2 hours, concentrated, and purified by preparative LCMS to give the title compound. 1H NMR (d6-DMSO) δ 8.12 (d, 1H), 7.91 (t, 1H), 7.81 (t, 1H), 7.44 (d, 1H), 7.32 (m, 3H), 6.92 (m, 3H), 6.62 (dd, 1H), 4.99 (bs, 2H), 4.51 (s, 2H), 3.73 (s, 3H), 2.09 (s, 3H) ppm. MS calculated for C26H22FN3O5S—H: 506, observed: 506.
Reaction SMILES: [C:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([CH2:12]O)[CH:4]=1)#[N:2].S(Cl)([Cl:16])=O>ClCCl>[Cl:16][CH2:12][N:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:3]([C:1]#[N:2])=[CH:4]1
Reactant: N#Cc1cn(CO)c2ccccc12
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: N#Cc1cn(CCl)c2ccccc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1.69 g of 3-cyano-1H-indole-1-ylmethanol was dissolved to 30 ml of dichloromethane. 1.4 ml of thionyl chloride was added to the solution, followed by stirring at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure to obtain 1.70 g of 1-(chloromethyl)-3-cyano-1H-indole.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:26]#[N:27])[CH2:13][CH2:12][C:11]([N:14]3[CH2:19][CH2:18][N:17]([C:20]4[N:21]=[N:22][CH:23]=[CH:24][CH:25]=4)[CH2:16][CH2:15]3)=[CH:10][CH2:9]2)=[CH:4][CH:3]=1.C[O-].[Na+].[BH4-].[Na+]>CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:26]#[N:27])[CH2:9][CH2:10][CH:11]([N:14]3[CH2:15][CH2:16][N:17]([C:20]4[N:21]=[N:22][CH:23]=[CH:24][CH:25]=4)[CH2:18][CH2:19]3)[CH2:12][CH2:13]2)=[CH:4][CH:3]=1
Reactant: N#CC1(c2ccc(F)cc2)CC=C(N2CCN(c3cccnn3)CC2)CC1
Agent: C[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: N#CC1(c2ccc(F)cc2)CCC(N2CCN(c3cccnn3)CC2)CC1
Reaction time: 8 h
Yield: 61.5 %

Procedure:
To a stirred mixture of 7.3 parts of 1-(4-fluorophenyl)-4-[4-(3-pyridazinyl)-1-piperazinyl]-3-cyclohexenecarbonitrile, 1 part of sodium methoxide solution 30% and 240 parts of methanol were added portionwise 0.8 parts of sodium borohydride. Upon completion, stirring was continued overnight at room temperature. The reaction mixture was poured onto ice water and the product was extracted with trichloromethane. The extract was dried, filtered and evaporated. The residue was crystallized from 2-propanol. Yielding 4.5 parts (61.5%) of 1-(4-fluorophenyl)-4-[4-(3-pyridazinyl)-1-piperazinyl]cyclohexanecarbonitrile; mp. 188.7° C. (compound 8).
Reaction SMILES: C(O[C:4](=[O:22])[CH2:5][N:6]1[CH2:10][C@H:9]([O:11][CH3:12])[C@@H:8]([NH:13][C:14]([C:16]2[S:17][C:18]([Cl:21])=[CH:19][CH:20]=2)=[O:15])[CH2:7]1)C.[NH2:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]2[CH2:35][CH2:34][O:33][CH2:32][C:31]2=[O:36])=[CH:26][CH:25]=1>>[CH3:12][O:11][C@H:9]1[CH2:10][N:6]([CH2:5][C:4](=[O:22])[NH:23][C:24]2[CH:25]=[CH:26][C:27]([N:30]3[CH2:35][CH2:34][O:33][CH2:32][C:31]3=[O:36])=[CH:28][CH:29]=2)[CH2:7][C@@H:8]1[NH:13][C:14]([C:16]1[S:17][C:18]([Cl:21])=[CH:19][CH:20]=1)=[O:15]
Reactant: Nc1ccc(N2CCOCC2=O)cc1
Reactant: CCOC(=O)CN1C[C@H](NC(=O)c2ccc(Cl)s2)[C@@H](OC)C1
Product: CO[C@H]1CN(CC(=O)Nc2ccc(N3CCOCC3=O)cc2)C[C@@H]1NC(=O)c1ccc(Cl)s1

Procedure:
Using general procedure F {(3S,4S)-3-[(5-chloro-thiophene-2-carbonyl)-amino]-4-methoxy-pyrrolidin-1-yl}-acetic acid ethyl ester (example 25.2) was reacted with 4-(4-aminophenyl)-morpholin-3-one (CAS 438056-69-0) to give 5-chloro-thiophene-2-carboxylic acid ((3S,4S)-4-methoxy-1-{[4-(3-oxo-morpholin-4-yl)-phenylcarbamoyl]-methyl}-pyrrolidin-3-yl)-amide. Yellow solid. MS 493.0 ([M+H]+)
Reaction SMILES: C[Si]([C:5]#[C:6][C:7]1[C:15]2[C:11](=[N:12][S:13][N:14]=2)[CH:10]=[CH:9][CH:8]=1)(C)C.C([O-])([O-])=O.[K+].[K+].C1COCC1>CO>[C:6]([C:7]1[C:15]2[C:11](=[N:12][S:13][N:14]=2)[CH:10]=[CH:9][CH:8]=1)#[CH:5]
Reactant: C[Si](C)(C)C#Cc1cccc2nsnc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CO
Product: C#Cc1cccc2nsnc12
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
4-(Trimethylsilyl)ethynylbenzo[c][1,2,5]-thiadiazole (0.100 g, 4.30×10−4 mol), K2CO3 (78.6 mg, 5.71×10−4 mol), THF (3 ml), and MeOH (2 ml) were added to a 25-ml Schlenk tube. The mixture was purged with N2 for 5 min, following which the reaction was stirred at room temperature for 1.5 h. The reaction mixture was then filtered, evaporated, and chromatographed on silica gel using 5:1 hexanes:THF as the eluent. Yield=63 g (91.4% based on 0.100 g of 4-(trimethylsilyl)ethynylbenzothiadiazole). 1H NMR (500 MHz, CDCl3): δ 8.01 (m, 1H, Ph-H), 7.78 (m, 1H, Ph-H), 7.56 (m, 1H, Ph-H), 3.56 (s, 1H, —CC—H).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[C:15]([NH2:17])[N:14]4[N:18]=[CH:19][CH:20]=[C:13]4[N:12]=3)[CH2:7]C2)[O:4][CH2:3][CH2:2]1.ClC1N2N=CC=C2N=C(C2CCC3(OCCO3)C2)C=1.ClC1N2N=CC=C2N=C(C2CCC3(OCCO3)CC2)C=1>>[O:4]1[C:5]2([CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[C:15]([NH2:17])[N:14]4[N:18]=[CH:19][CH:20]=[C:13]4[N:12]=3)[CH2:7]2)[O:1][CH2:2][CH2:3]1
Reactant: Nc1cc(C2CCC3(CC2)OCCO3)nc2ccnn12
Agent: Clc1cc(C2CCC3(C2)OCCO3)nc2ccnn12
Agent: Clc1cc(C2CCC3(CC2)OCCO3)nc2ccnn12
Product: Nc1cc(C2CCC3(C2)OCCO3)nc2ccnn12

Procedure:
5-(1,4-Dioxaspiro[4.4]nonan-7-yl)pyrazolo[1,5-a]pyrimidin-7-amine was synthesized in a manner similar to the synthesis of 5-(1,4-dioxaspiro[4.5]decan-8-yl)pyrazolo[1,5-a]pyrimidin-7-amine, but with 7-chloro-5-(1,4-dioxaspiro[4.4]nonan-7-yl)pyrazolo[1,5-a]pyrimidine substituted for 7-chloro-5-(1,4-dioxaspiro[4.5]decan-8-yl)pyrazolo[1,5-a]pyrimidine.
Reaction SMILES: C1(C[O:8][CH2:9][C@H:10]2[O:30][C@H:29]([C@@H:31]([CH2:40][O:41]CC3C=CC=CC=3)[O:32][CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C@@H:20]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C@@H:11]2[O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)C=CC=CC=1.B(F)(F)F.CCOCC>C(OC(=O)C)(=O)C>[C:14]1([CH2:13][O:12][C@H:11]2[C@H:20]([O:21][CH2:22][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[C@@H:29]([C@@H:31]([CH2:40][OH:41])[O:32][CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[O:30][C@@H:10]2[CH2:9][OH:8])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: c1ccc(COC[C@@H](OCc2ccccc2)[C@H]2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@@H]2OCc2ccccc2)cc1
Agent: FB(F)F
Solvent: CCOCC
Solvent: CC(=O)OC(C)=O
Product: OC[C@@H](OCc1ccccc1)[C@H]1O[C@H](CO)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1

Procedure:
In accordance with Flowchart D, 2,5-anhydro-D-mannose 26 is treated with acetyl chloride in methanol at reflux, then neutralized with lead carbonate, giving 2,5-anhydro-D-mannose, dimethyl acetal 27. which is treated with sodium hydride and benzyl bromide in dimethylformamide, giving 2,5-anhydro-3,4,6-tris-O-(phenylmethyl)-D-mannose, dimethyl acetal 28. Compound 28 is then treated with tetrafluoroboric acid in acetonitrile, giving 2,5-anhydro-3,4,6-tris-O-(phenylmethyl)-D-mannose 29 which is then treated with Tebbe's reagent in ether at -40° C., then neutralized with sodium hydroxide, giving 3,6-anhydro-1,2-dideoxy-4,5,7-tris-O-(phenylmethyl)-D-manno-hept-1-enitol 30. Compound 30 is treated with osmium tetroxide in pyridine, giving 2,5-anhydro-1,3,4-tris-O-(phenylmethyl)-D-glycero-D-manno-heptitol 31, which is treated with sodium hydride in dimethylformamide, followed by treatment with benzyl bromide, giving 2,5-anhydro-1,3,4,6,7-pentakis-O-(phenylmethyl)-D-glycero-D-manno-heptitol 32. Compound 32 is treated with borontrifluoride etherate in acetic anhydride, giving 2,5-anhydro-3,4,6-tris-O-(phenylmethyl)D-glycero-D-manno-heptitol, 1,7-diacetate 33, which is treated with sodium ethoxide in ethanol, giving 2,5-anhydro-3,4,6-tris-O-(phenylmethyl)-D-glycero-D-manno-heptitol 34. Compound 34 is treated with diethyl phosphorochloridate in pyridine at reduced temperature, giving 2,5-anhydro-3,4,6-tris-O-(phenylmethyl)-D-glycero-D-manno-heptitol, 1,7-bis(diethyl phosphate) 35. Substituting other esterifying agents as described in Flowchart A will result in the corresponding tetraesters. Compound 35 is treated with bromotrimethyl silane in chloroform at reduced temperature, under an inert atmosphere, giving 2,5-anhydro-3,4,6-tris-O-(phenylmethyl)-D-glycero-D-manno-heptitol, 1,7-bis(dihydrogen phosphate) 36, which is then hydrogenated over palladium on carbon in methanol, giving the product of Formula I, where R', R", R'" and R"" are hydrogen,
Reaction SMILES: [Br:1][C:2]([Br:5])(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH:31]=O)[CH:26]=1>C(Cl)Cl>[Br:1][C:2]([Br:5])=[CH:31][C:27]1[CH:26]=[N:25][CH:30]=[CH:29][CH:28]=1
Reactant: BrC(Br)(Br)Br
Reactant: O=Cc1cccnc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: BrC(Br)=Cc1cccnc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 51 %

Procedure:
Tetrabromomethane (24.82 g, 0.747 mole) and triphenylphosphine (39.17 g, 0.149 mole) were stirred together in dry methylene chloride (100 mL) for 5 min. at 0° C. under a nitrogen atmosphere. To this mixture was added dropwise pyridine 3-carboxaldehyde (4 g, 0.0373 mole). The solution was then stirred for 45 min. at ambient temperature. The reaction mixture was extracted with aqueous 6N hydrochloric acid (3×25 mL), the aqueous layer basified with solid sodium bicarbonate to pH 8-9 and extracted with chloroform (4×25 mL). The combined organic liquours were dried over anhydrous sodium sulfate, filtered and concentrated on a rotary evaporator to give a dark colored syrup. The crude product was chromatographed on silica gel (70-230 mesh) with chloroform:methanol (95:5) as eluant, to afford a light yellow solid (5.0 g, 70%) which rapidly turned dark on standing.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@@H:3]1[C:8]([NH:10][C@H:11]([C:13]1[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=1)[CH3:12])=[O:9].[F:23][C:24]1[CH:33]=[CH:32][C:27]([O:28][CH2:29][CH:30]=O)=[CH:26][CH:25]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[F:23][C:24]1[CH:33]=[CH:32][C:27]([O:28][CH2:29][CH2:30][N:2]2[CH2:7][CH2:6][CH2:5][CH2:4][C@@H:3]2[C:8]([NH:10][C@H:11]([C:13]2[CH:14]=[CH:15][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:21][CH:22]=2)[CH3:12])=[O:9])=[CH:26][CH:25]=1
Reactant: O=CCOc1ccc(F)cc1
Reactant: COC(=O)c1ccc([C@H](C)NC(=O)[C@H]2CCCCN2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: COC(=O)c1ccc([C@H](C)NC(=O)[C@H]2CCCCN2CCOc2ccc(F)cc2)cc1
Yield: 70.4 %

Procedure:
Stir a mixture of methyl 4-[(1S)-1-[[(2R)-piperidine-2-carbonyl]amino]ethyl]benzoate hydrochloride (650 mg, 1.99 mmol) and 2-(4-fluorophenoxy)acetaldehyde (337 mg, 2.19 mmol) in DCE (9.9 mL) at room temperature for 30 min. Add acetic acid (0.113 mL, 1.99 mmol) and sodium triacetoxyborohydride (590 mg, 2.78 mmol) and stir at room temperature for three days. Quench the reaction with saturated aqueous NaHCO3 (25 mL) and extract the aqueous layer with EtOAc (2×25 mL). Wash the combined organic layers with saturated aqueous NaCl (25 mL), then dry the organic phase over MgSO4, filter, and concentrate under reduced pressure. Subject the resulting oil to flash chromatography on silica gel, eluting with a gradient of 0% to 100% EtOAc/hexanes. Concentrate the fractions containing the desired product under reduced pressure to provide the title compound as a white solid (600 mg, 70% yield). Mass spectrum (m/z) 429 (M+H)+, 451 (M+Na)+.
Reaction SMILES: [CH2:1]([N:4]([CH2:27][CH2:28][CH3:29])[C:5](=[O:26])[CH:6]([NH:13][C:14](=[O:25])[C:15](=[C:20]1[S:24][CH:23]=[CH:22][S:21]1)[C:16]([O:18]C)=[O:17])[CH2:7][CH2:8][C:9]([O:11]C)=[O:10])[CH2:2][CH3:3].[OH-].[K+]>CO>[C:16]([C:15](=[C:20]1[S:21][CH:22]=[CH:23][S:24]1)[C:14]([NH:13][CH:6]([C:5]([N:4]([CH2:27][CH2:28][CH3:29])[CH2:1][CH2:2][CH3:3])=[O:26])[CH2:7][CH2:8][C:9]([OH:11])=[O:10])=[O:25])([OH:18])=[O:17]
Reactant: CCCN(CCC)C(=O)C(CCC(=O)OC)NC(=O)C(C(=O)OC)=C1SC=CS1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CCCN(CCC)C(=O)C(CCC(=O)O)NC(=O)C(C(=O)O)=C1SC=CS1

Procedure:
Methyl 5-(dipropylamino)-4-((2-(1,3-dithiol-2-ylidene)-3-methoxy-3-oxopropanoyl)amino)-5-oxopentanoate (5) (111 g) was dissolved in methanol (1 l), followed by the addition of 2.5 N potassium hydroxide solution (300 ml). The resulting mixture was heated under reflux for 2 hours. The solvent was removed under reduced pressure. The resulting residue was washed several times with water, whereby 4-((2-carboxy-2-(1,3-dithiol-2-ylidene)acetyl)amino)-5-(dipropylamino)-5-oxopentanoic acid (6) was obtained as a waxy substance. Without purification, the reaction product was provided for use in the next example.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([CH3:10])[CH:3]=1.[CH2:11]([SH:13])[CH3:12]>>[CH2:11]([S:13][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([CH3:10])[CH:3]=1)[CH3:12]
Reactant: CCS
Reactant: Cc1cc(Br)ccc1C#N
Product: CCSc1ccc(C#N)c(C)c1

Procedure:
4 g of 4-bromo-2-methylbenzonitrile was used in Procedure Q with ethanethiol to afford 4-(ethylthio)-2-methylbenzonitrile. 2 g of 4-(ethylthio)-2-methylbenzonitrile was reacted via Procedure R to give 4-(ethylsulfonyl)-2-methylbenzonitrile. 2.5 g of 4-(ethylsulfonyl)-2-methylbenzonitrile was reacted via Procedure T to give 4-(ethylsulfonyl)-2-methylbenzoic acid. 75 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 4-(ethylsulfonyl)-2-methylbenzoic acid via Procedure G. The product was purified on reverse phase HPLC to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(ethylsulfonyl)-2-methylbenzamide. MS (Q1) 415.0 (M)+.
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[CH:16]([O:20][CH2:21][C:22]([NH:24][CH3:25])=O)[CH2:15][CH2:14][CH2:13]3)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.B.[ClH:27]>C1COCC1>[ClH:27].[C:1]1([S:7]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[CH:16]([O:20][CH2:21][CH2:22][NH:24][CH3:25])[CH2:15][CH2:14][CH2:13]3)(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CNC(=O)COC1CCCc2cc(S(=O)(=O)c3ccccc3)ccc21
Agent: B
Agent: Cl
Solvent: C1CCOC1
Product: CNCCOC1CCCc2cc(S(=O)(=O)c3ccccc3)ccc21
Yield: 58 %

Procedure:
(2-(6-Benzenesulfonyl-1,2,3,4-tetrahydro-naphthalen-1-yloxy)-N-methyl-acetamide (0.7 g, 1.9 mmol) was dissolved in 25 mL of dry THF. Borane (10 mL of 1N THF solution) was added, and the reaction mixture was refluxed for three hours under nitrogen. The reaction mixture was cooled and 25 mL of 25% aqueous HCl was added. The reaction mixture was refluxed for 10 minutes, cooled, and solvent was removed under reduced pressure. The aqueous residue was basified by dropwise addition of 1N aqueous NaOH, and the aqueous mix was extracted three times with 50 mL of EtOAc. The combined organic layers were washed with water, brine, and dried over MgSO4. The residue was recrystallized from Et2O/MeOH/HCl to give 380 mg (1.1 mmol, 58%) of [2-(6-benzenesulfonyl-1,2,3,4-tetrahydro-naphthalen-1-yloxy)-ethyl]-methyl-amine hydrochloride. MS: 346 (M+H)+.