Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][N:7]([CH2:14][C:15]1[CH:28]=[CH:27][C:18]([C:19]([NH:21][CH2:22][CH2:23][CH2:24][CH2:25][NH2:26])=[O:20])=[CH:17][CH:16]=1)[CH2:8][C:9]1[NH:10][CH:11]=[CH:12][N:13]=1.[C:29]1(=O)[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1.C([BH3-])#N.[Na+].C(O)(=O)C>CO>[NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][N:7]([CH2:14][C:15]1[CH:28]=[CH:27][C:18]([C:19]([NH:21][CH2:22][CH2:23][CH2:24][CH2:25][NH:26][CH:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)=[O:20])=[CH:17][CH:16]=1)[CH2:8][C:9]1[NH:13][CH:12]=[CH:11][N:10]=1
Reactant: O=C1CCCCC1
Reactant: NCCCCNC(=O)c1ccc(CN(Cc2ncc[nH]2)Cc2ncc[nH]2)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: O=C(NCCCCNC1CCCCC1)c1ccc(CN(Cc2ncc[nH]2)Cc2ncc[nH]2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
The compound (28.8 mg) obtained in Example 3-2 was dissolved in methanol (0.5 ml). The solution was added with cyclohexanone (8.80 μl) and sodium cyanoborohydride (4.40 mg) and then adjusted to approximately pH 5 with acetic acid, followed by stirring at room temperature for 16 hours. After completion of the reaction, the solvent was distilled off. Then, the residue was dissolved in chloroform and washed with a 1 mol/l sodium hydroxide aqueous solution and saturated saline solution, followed by the addition of 1 mol/l hydrochloric acid to extract the objective substance. Subsequently, the aqueous layer was concentrated under reduced pressure and then the residue was purified through a solid-phase extraction column (Bond Elut® C18 (manufactured by Varian Inc.), 200 mg), thereby obtaining hydrochloride (17.6 mg) of the subject compound as a white solid.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:9])[CH2:6][NH:7][CH3:8])[CH3:3].C(N(CC)CC)C.[S:17](Cl)([C:20]1[CH:26]=[CH:25][C:23]([CH3:24])=[CH:22][CH:21]=1)(=[O:19])=[O:18]>C(Cl)Cl>[CH3:8][N:7]([S:17]([C:20]1[CH:26]=[CH:25][C:23]([CH3:24])=[CH:22][CH:21]=1)(=[O:19])=[O:18])[CH2:6][C:5]([O:4][CH2:2][CH3:3])=[O:9]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCOC(=O)CNC
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CN(C)S(=O)(=O)c1ccc(C)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 105 %

Procedure:
An ice cold suspension of sarcosine ethyl ester hydrochloride salt (3.1 g, 20 mmol) in CH2Cl2 (150 mL) was sequentially treated with triethyl amine (4.45 g, 44 mmol) and tosyl chloride (4.19 g, 22 mmol) and stirred for 1 h, after which time the ice bath was removed, and the reaction was allowed to stir for an additional 1 h. The reaction mixture was then partitioned between water and CH2Cl2 and the organic extract was washed with brine, dried, filtered, and concentrated to give 5.7 g of the title compound as a white solid.
Reaction SMILES: [C:1]1([CH2:7][NH:8][C@@H:9]2[CH2:14][CH2:13][NH:12][CH2:11][C@H:10]2[OH:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(C)C=O.Cl[CH2:22][C:23]#[N:24]>C(N(CC)CC)C>[OH:15][C@H:10]1[C@H:9]([NH:8][CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:14][CH2:13][N:12]([CH2:22][C:23]#[N:24])[CH2:11]1
Reactant: O[C@@H]1CNCC[C@H]1NCc1ccccc1
Reactant: N#CCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: N#CCN1CC[C@@H](NCc2ccccc2)[C@H](O)C1
Reaction time: 8 h
Yield: 76.2 %

Procedure:
To a stirred and heated (±70° C.) solution of 14.44 parts of trans-4-[(phenylmethyl)amino]-3-piperidinol in 189 parts of N,N-dimethylformamide were added 5.81 parts of chloroacetonitrile. After the addition of 9.7 parts of N,N-diethylethanamine, stirring was continued overnight at 70° C. After evaporation, the residue was taken up in dichloromethane. The organic layer was washed with a sodium carbonate solution in water, dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (90:10 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was suspended in 2,2'-oxybispropane. The product was filtered off and dried, yielding 13.1 parts (76.2%) of trans-3-hydroxy-4-[(phenylmethyl)amino]-1-piperidineacetonitrile; mp. 113.2° C. (interm. 16).
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][NH:14][C@H:15]([CH2:36][C:37]1[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][CH:38]=1)[C:16]([NH:18][N:19]1[CH2:23][CH2:22][C@H:21]([N:24]([CH:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)[C:25](=[O:29])[CH:26]([CH3:28])[CH3:27])[CH2:20]1)=[O:17])(OC(C)(C)C)=O.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][NH:14][C@H:15]([CH2:36][C:37]1[CH:38]=[CH:39][C:40]([Cl:43])=[CH:41][CH:42]=1)[C:16]([NH:18][N:19]1[CH2:23][CH2:22][C@H:21]([N:24]([CH:30]2[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]2)[C:25](=[O:29])[CH:26]([CH3:27])[CH3:28])[CH2:20]1)=[O:17]
Reactant: CC(C)C(=O)N(C1CCCCC1)[C@H]1CCN(NC(=O)[C@@H](Cc2ccc(Cl)cc2)NC[C@H]2CCCN2C(=O)OC(C)(C)C)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)C(=O)N(C1CCCCC1)[C@H]1CCN(NC(=O)[C@@H](Cc2ccc(Cl)cc2)NC[C@H]2CCCN2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 136.6 %

Procedure:
To a solution of (2R)-2-{[(2R)-1-(BOC)pyrrolidine-2-yl]methyl}amino-N-{(3S)-3-[cyclohexyl(isobutyryl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide(50 mg, 0.0831 mmol), prepared in Step A, in DCM (2 mL) was added TFA (2 mL). After being stirred at rt for 1 h, the reaction solution was concentrated in vacuo, and the residue was purified by HPLC to give the title compound (58.8 mg, 97.1%).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][C:7]([N:11]3[C:19]4[CH:18]=[CH:17][C:16]([CH3:20])=[CH:15][C:14]=4[C:13]4[CH2:21][N:22]([CH3:25])[CH2:23][CH2:24][C:12]3=4)=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.[CH:26]([O-])=[O:27].[NH4+]>CO.[Pd]>[CH3:25][N:22]1[CH2:23][CH2:24][C:12]2[N:11]([C:7]3[CH:6]=[C:5]4[C:10](=[CH:9][CH:8]=3)[CH2:1][N:2]([CH:26]=[O:27])[CH2:3][CH2:4]4)[C:19]3[CH:18]=[CH:17][C:16]([CH3:20])=[CH:15][C:14]=3[C:13]=2[CH2:21]1
Reactant: O=C[O-]
Reactant: Cc1ccc2c(c1)c1c(n2-c2ccc3cnccc3c2)CCN(C)C1
Agent: [Pd]
Agent: [NH4+]
Solvent: CO
Product: Cc1ccc2c(c1)c1c(n2-c2ccc3c(c2)CCN(C=O)C3)CCN(C)C1
Yield: 27.8 %

Procedure:
To a de-aerated solution of 5-isoquinolin-6-yl-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (35 mg, 0.10 mmol) in MeOH (5 mL) were added 10% Pd—C (18 mg) and ammonium formate (68 mg, 1.07 mmol). The reaction mixture was refluxed for 15 h and filtered through Celite. The filtrate was concentrated under reduced pressure to afford crude material, which was purified by column chromatography using silica (100:200) and 3% MeOH-DCM to yield 6-(2,8-dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-3,4-dihydro-1H-isoquinoline-2-carbaldehyde (10 mg). 1H NMR (HCl salt, CD3OD) d (ppm): 8.2 (s, 1H), 7.41 (s, 1H), 7.3 (s, 1H), 7.25 (m, 2H), 7.1 (d, 1H), 7.03 (d, 1H), 4.7 (d, 1H), 4.4 (d, 1H), 3.8 (m, 3H), 3.57 (m, 3H), 3.17 (s, 3H), 3.0 (m, 4H), 2.4 (s, 3H).
Reaction SMILES: COC1C=CC(C[N:8]([C@@H:12]([C@H:27]([O:35][Si:36]([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:38])[CH3:37])[C:28]2[CH:29]=[N:30][C:31]([Cl:34])=[CH:32][CH:33]=2)[CH2:13][CH2:14][C:15](=O)[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=2)C(=O)[O-])=CC=1.FC(F)(F)C(O)=O>ClCCl>[Si:36]([O:35][C@@H:27]([C@H:12]1[CH2:13][CH2:14][C:15]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=2)=[N:8]1)[C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[N:30][CH:29]=1)([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:37])[CH3:38]
Reactant: COc1ccc(CN(C(=O)[O-])[C@H](CCC(=O)Cc2ccc([N+](=O)[O-])cc2)[C@H](O[Si](C)(C)C(C)(C)C)c2ccc(Cl)nc2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)O[C@H](c1ccc(Cl)nc1)[C@H]1CCC(Cc2ccc([N+](=O)[O-])cc2)=N1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.9 %

Procedure:
To a stirred solution of 18 g (28 mmol) of 4-methoxybenzyl[(1R)-1-[(R)-{[tert-butyl(dimethyl)silyl]oxy}(6-chloropyridin-3-yl)methyl]-5-(4-nitrophenyl)-4-oxopentyl]carbamate from Step B in 75 mL of anhydrous dichloromethane was added 75 ml of trifluoroacetic acid. The resulting mixture was stirred at ambient temperature for 2 h during which time the reaction became dark red in color. All volatiles were removed in vacuo and the residue dissolved in 300 mL of dichloromethane. The solution was washed with a saturated aqueous sodium bicarbonate solution (2×100 mL), brine (100 ml) and then dried over magnesium sulfate and filtered. All volatiles were evaporated in vacuo to afford the title compound as a dark red gum (13 g, >99%) that was used immediately without further purification. LC-MS: m/z (ES) 460.4 (MH)+.
Reaction SMILES: [CH2:1]1[NH:6][C:4](=[O:5])[NH:3][CH2:2]1.[N:7]1([S:13](Cl)(=[O:15])=[O:14])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1>CO.C(O)(C)C>[N:7]1([S:13]([N:3]2[CH2:2][CH2:1][NH:6][C:4]2=[O:5])(=[O:15])=[O:14])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: O=C1NCCN1
Reactant: O=S(=O)(Cl)N1CCCCC1
Solvent: CO
Solvent: CC(C)O
Product: O=C1NCCN1S(=O)(=O)N1CCCCC1
Reaction time: 3 h

Procedure:
To 17.4 of ethyleneurea is added with shaking 36 g of piperidinosulfonyl chloride (b.p. 130°/11m) and the mixture kept under nitrogen at 100° for 3 hrs. The mixture is cooled and the gummy material treated with methanol-isopropanol (1:1) to give a granular product of 1-piperidinosulfonyl-2-oxo-tetrahydroimidazole which melts at 201° on recrystallization from methanol.
Reaction SMILES: N.O.S[C:4]1[N:5]([CH:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH3:13])[C:6]([C:9]([NH2:11])=[O:10])=[CH:7][N:8]=1>[Ni].C(O)C>[C:14]1([CH:12]([N:5]2[C:6]([C:9]([NH2:11])=[O:10])=[CH:7][N:8]=[CH:4]2)[CH3:13])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC(c1ccccc1)n1c(C(N)=O)cnc1S
Agent: [Ni]
Agent: N
Solvent: O
Solvent: CCO
Product: CC(c1ccccc1)n1cncc1C(N)=O
Temperature: 25 °C

Procedure:
To 80 parts of ethanol, previously saturated with gaseous ammonia, are added 2.3 parts of (+) -2-mercapto-1-(1-phenylethyl)-1H-imidazole-5-carboxamide hydrate and 6 parts of Raney-nickel. The mixture is stirred and refluxed for 2 hours and thereafter allowed to cool to room temperature. The Raney-nickel is filered off and the filter-cake is washed with ethanol. The filtrate is evaporated in vacuo and the residue is purified by column-chromatography over silica gel using a mixture of trichloromethane 5% of methanol as eluent. The pure fractions are collected and the eluent is evaporated, yielding (+)-1-(1-phenylethyl)-1H-imidazole-5-carboxamide, essentially free of its (-)-isomer, as a residue.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1.[CH:15]([NH:17][NH2:18])=O>C(O)CCC>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]([C:5]2[CH:6]=[CH:7][C:2]3[N:3]([CH:15]=[N:17][N:18]=3)[N:4]=2)=[CH:9][CH:10]=1
Reactant: Clc1ccc(-c2ccc(Cl)nn2)cc1
Reactant: NNC=O
Solvent: CCCCO
Product: Clc1ccc(-c2ccc3nncn3n2)cc1

Procedure:
A mixture of 9.0 g. of 3-chloro-6-(p-chlorophenyl)pyridazine (prepared as in Example 12), 5.1 g. of formylhydrazine and 60 ml. of butyl alcohol is heated at reflux temperature for 40 hours. The reaction mixture is cooled, filtered and the solid washed with petroleum ether and with water. The material is then heated with 125 ml. of ethanol and the insoluble material is collected by filtration. The filtrate is cooled and the precipitate is collected and combined with the insoluble material collected above. The combined solids are recrystallized from 130 ml. of ethyl alcohol to provide the product of the example as crystals, m.p. 216°-218° C.
Reaction SMILES: [OH:1][CH:2]1[C:14]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.C(N(CC)CC)C.[C:22](Cl)(=[O:25])[CH:23]=[CH2:24]>C1C=CC=CC=1>[CH:13]1[C:14]2[CH:2]([O:1][C:22](=[O:25])[CH:23]=[CH2:24])[C:3]3[C:8](=[CH:7][CH:6]=[CH:5][CH:4]=3)[C:9]=2[CH:10]=[CH:11][CH:12]=1
Reactant: C=CC(=O)Cl
Reactant: OC1c2ccccc2-c2ccccc21
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: C=CC(=O)OC1c2ccccc2-c2ccccc21
Temperature: 8 °C
Reaction time: 8 h
Yield: 73 %

Procedure:
To a 250 mL round-bottomed flask was added 9-hydroxyfluorene (5 g, 27.4 mmol) and triethylamine (3.86 ml, 27.4 mmol) in benzene (150 mL) to give a colorless solution. The solution was cooled to 8° C. with an ice bath. Next, acryloyl chloride (2.229 mL, 27.4 mmol) was dissolved in 25 mL of benzene, placed in a dropping funnel, and added over 1 hour with vigorous stirring. The reaction formed a white precipitate. The ice bath was removed and the viscous sludge was stirred overnight at room temperature. The resulting cloudy white suspension was washed with 50 mL water, followed by 50 mL 5% NaOH solution, and 50 mL water. The benzene layer was collected and dried with MgSO4, filtered, and rotovapped to give the 9-fluorenylacrylate as a viscous beige oil which crystallized on cooling to 4° C. (4.73 g, 20.02 mmol, 73.0% yield).
Reaction SMILES: [N:1]1([C:6]2[CH:23]=[CH:22][C:9]([C:10]([C:12]3[C:13]([C:18](OC)=[O:19])=[N:14][CH:15]=[CH:16][CH:17]=3)=O)=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.O.[NH2:25][NH2:26]>CCO>[N:1]1([C:6]2[CH:23]=[CH:22][C:9]([C:10]3[C:12]4[CH:17]=[CH:16][CH:15]=[N:14][C:13]=4[C:18](=[O:19])[NH:25][N:26]=3)=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: NN
Reactant: COC(=O)c1ncccc1C(=O)c1ccc(-n2ccnc2)cc1
Solvent: O
Solvent: CCO
Product: O=c1[nH]nc(-c2ccc(-n3ccnc3)cc2)c2cccnc12

Procedure:
A mixture of 3-[4-(1H-imidazol-1-yl)benzoyl]-2-carbomethoxypyridine (1.21 g, 3.94 mmol) in 50 mL of EtOH is treated with 0.22 g (4.33 mmol) of hydrazine monohydrate and heated to reflux for 1 day. The white solid which precipitates from the reaction mixture is filtered and recrystallized from DMF-H2O to give 5-[4-(1H-imidazol-1-yl)phenyl]-8-oxo-7,8-dihydropyrido[2,3-d]pyridazine. M.P. 359°-361° C.
Reaction SMILES: Cl.[CH3:2][N:3]1[CH2:7][CH2:6][CH2:5][C@H:4]1[CH2:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][N:10]1[CH2:15][C:16]([OH:18])=O.[NH2:19][C@@H:20]([CH2:38][O:39][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C:21]([NH:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)=[CH:26][CH:25]=1)=[O:22]>>[CH2:40]([O:39][CH2:38][C@H:20]([NH:19][C:16](=[O:18])[CH2:15][N:10]1[CH2:11][CH2:12][CH2:13][CH2:14][CH:9]1[CH2:8][C@@H:4]1[CH2:5][CH2:6][CH2:7][N:3]1[CH3:2])[C:21]([NH:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)=[CH:26][CH:25]=1)=[O:22])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: CN1CCC[C@H]1CC1CCCCN1CC(=O)O
Reactant: N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Agent: Cl
Product: CN1CCC[C@H]1CC1CCCCN1CC(=O)N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Yield: 43.3 %

Procedure:
Proceeding as in Example 1, but substituting 2-(2-(((S)-1-methylpyrrolidin-2-yl)methyl)piperidin-1-yl)acetic acid hydrochloride and (S)-2-amino-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)propanamide, gave Compound 113, (2S)-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)-2-(2-(2-(((S)-1-methylpyrrolidin-2-yl)methyl)piperidin-1-yl)acetamido)propanamide (20.9 mg, 43.3%). Major isomer: 1H-NMR (400 MHz, DMSO-D6): σ 10.27 (d, 1H), 8.51 (s, 1H), 7.67-7.64 (m, 2H), 7.31 (m, 5H), 7.21 (t, 2H), 7.03-6.98 (m, 4H), 4.72 (m, 1H), 4.52 (d, 2H), 4.16 (m, 1H), 4.04 (m, 1H), 3.77-3.73 (m, 4H), 3.38 (s, 2H), 2.99 (s, 2H), 2.79 (m, 1H), 2.43 (m, 2H), 2.32 (m, 2H), 2.18 (m, 1H), 1.99 (m, 2H), 1.75 (m, 1H), 1.51 (m, 4H), 1.37 (m, 2H). MS (EI) for C35H43FN4O4. found 603.7 (MH+).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]([CH:9]=[O:10])[NH:7][CH:8]=1.[C:11]1([CH3:21])[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=1>C1COCC1>[CH3:21][C:11]1[CH:16]=[CH:15][C:14]([S:17]([N:7]2[C:6]([CH:9]=[O:10])=[CH:5][C:4]([Br:3])=[CH:8]2)(=[O:19])=[O:18])=[CH:13][CH:12]=1
Reactant: O=Cc1cc(Br)c[nH]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2cc(Br)cc2C=O)cc1
Reaction time: 1 h
Yield: 68.6 %

Procedure:
Following a reported procedure (Tietze, L. F. et al., Synthesis 1996, 851-857), a stirred suspension of NaH (865 mg, 36.0 mmol) in THF (200 mL) was treated with 17 (5.22 g, 30.0 mmol) at room temperature. When the evolution of gas had ceased, the mixture was stirred for 1 h before treating with p-toluenesulfonyl chloride (6.30 g, 33.0 mmol). After 16 h, the conversion was complete as monitored by TLC. The reaction mixture was quenched by adding aqueous NH4Cl. Ethyl acetate was added and the organic layer was separated. The organic layer was washed with water, brine and dried (Na2SO4). Concentration followed by crystallization (ethyl acetate/hexanes) afforded pale yellow crystals (6.75 g, 68%): mp 83-85° C.; 1H NMR δ 2.43 (s, 3H), 7.09 (d, J=2.0 Hz, 1H), 7.35 (d, J=8.3 Hz, 2H), 7.57 (d, J=2.0 Hz, 1H), 7.81 (d, J=8.3 Hz, 2H), 9.94 (s, 1H); 13C NMR δ 22.0, 101.8, 125.4, 127.8, 127.9, 130.6, 133.5, 134.7, 146.7, 178.5. Anal. Calcd or C12H10BrNO3S: C, 43.92; H, 3.07; N, 4.27; S, 9.77. Found: C, 43.92; H, 3.02; N, 4.26; S, 9.84.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[C@H:9]([OH:10])[CH2:8][CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4].[Li+].[CH3:19]C([N-]C(C)C)C.IC>C1COCC1>[CH3:1][O:2][C:3]([C@:5]1([CH3:19])[C@H:9]([OH:10])[CH2:8][CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4]
Reactant: CC(C)[N-]C(C)C
Reactant: COC(=O)[C@@H]1[C@H](O)CCN1C(=O)OC(C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: COC(=O)[C@]1(C)[C@H](O)CCN1C(=O)OC(C)(C)C
Temperature: -20 °C
Reaction time: 1 h
Yield: 30.3 %

Procedure:
To a solution of (2S,3R)—N-tert-butyloxycarbonyl-3-hydroxy-2 pyrrolidinecarboxylic acid methyl ester (1D) (1.13 g, 4.61 mmol) in THF (73 mL) at −78° C. was slowly added a 1.8 M solution of LDA (7.70 mL, 13.86 mmol). After stirring for 1 h, iodomethane (2.87 mL, 46.10 mmol) was added, and the reaction was stirred for 1 h at −78° C., before warming gradually to −20° C. for 3 h, and then was stored at −40° C. overnight. After quenching with saturated aqueous NH4Cl, water and EtOAc were added and the layers were separated. The organic layer was washed with brine, and the aqueous layer was extracted with EtOAc. The combined organics were dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified using preparative HPLC (Luna C-18, 21.2×250 mm, eluting with 50-90% solvent B (A=90% H2O—10% MeOH and B=10% H2O—90% MeOH) over 30 min; Flow rate at 10 mL/min. UV detection at 220 nm) to provide a mixture of the starting material and its epimer as a yellow oil (490 mg) and the title compound as a yellow oil (362 mg); LC/MS m/z 260 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C@@H:3]1[C@H:18]([OH:19])[C@H:17]([CH3:20])[O:16][C@H:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][CH:8]=2)[C@H:4]1[OH:21].[H][H].ClCCl.CO>CO.[Pt](=O)=O>[CH3:1][O:2][C@@H:3]1[C@H:18]([OH:19])[C@H:17]([CH3:20])[O:16][C@H:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]([NH2:13])=[CH:11][CH:12]=2)[C@H:4]1[OH:21]
Reactant: CO[C@H]1[C@H](O)[C@@H](Oc2ccc([N+](=O)[O-])cc2)O[C@@H](C)[C@H]1O
Reactant: [H][H]
Agent: O=[Pt]=O
Solvent: CO
Solvent: ClCCl
Product: CO[C@H]1[C@H](O)[C@@H](Oc2ccc(N)cc2)O[C@@H](C)[C@H]1O

Procedure:
3.81 g (12.73 nmmol) of p-nitrophenyl 3-O-methyl-β-L-fucopyranoside are dissolved in methanol and, after addition of platinum dioxide, hydrogenated in a hydrogen atmosphere at a slight overpressure. After filtering off the catalyst and precipitating with ether, 3 g (88%) of the target product are obtained. [TLC: dichloromethane/methanol 9:1 Rf =0.53].
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.[F:12][C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=1>CS(C)=O>[Br:1][C:2]1[C:3]([NH:17][C:16]2[CH:18]=[CH:19][C:13]([F:12])=[CH:14][CH:15]=2)=[N:4][CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1
Reactant: O=[N+]([O-])c1cnc(Cl)c(Br)c1
Reactant: Nc1ccc(F)cc1
Solvent: CS(C)=O
Product: O=[N+]([O-])c1cnc(Nc2ccc(F)cc2)c(Br)c1
Temperature: 120 °C
Reaction time: 1 h
Yield: 81.2 %

Procedure:
3-Bromo-2-chloro-5-nitropyridine (3.936 g, 16.58 mmol), 4-fluoroaniline (5.53 g, 49.7 mmol) and dimethylsulfoxide (33.2 mL) were combined and stirred at 120° C. for 1 hour. The reaction mixture was cooled to ambient temperature producing a solid. Precipitation was induced further by the addition of 150 mL of water. The solid was collected by filtration and rinsed with 600 mL of water. The solid was purified by flash chromatography (silica gel, 0 to 20% ethyl acetate in heptanes) and then triturated in 15% ethyl acetate in heptanes to give 4.2 g (81%) of the title compound.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH:9]2[CH2:14][C:13]([CH3:16])([CH3:15])[NH:12][C:11]([CH3:18])([CH3:17])[CH2:10]2)[C:5]([F:19])=[CH:4][N:3]=1.[CH:20]1([C:23]2[CH:24]=[C:25]([NH2:35])[CH:26]=[C:27]([C:29]3[N:33]([CH3:34])[N:32]=[N:31][N:30]=3)[CH:28]=2)[CH2:22][CH2:21]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)(C)C>[CH:20]1([C:23]2[CH:24]=[C:25]([NH:35][C:2]3[N:7]=[C:6]([NH:8][CH:9]4[CH2:14][C:13]([CH3:16])([CH3:15])[NH:12][C:11]([CH3:18])([CH3:17])[CH2:10]4)[C:5]([F:19])=[CH:4][N:3]=3)[CH:26]=[C:27]([C:29]3[N:33]([CH3:34])[N:32]=[N:31][N:30]=3)[CH:28]=2)[CH2:22][CH2:21]1
Reactant: Cn1nnnc1-c1cc(N)cc(C2CC2)c1
Reactant: CC1(C)CC(Nc2nc(Cl)ncc2F)CC(C)(C)N1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)O
Solvent: O
Product: Cn1nnnc1-c1cc(Nc2ncc(F)c(NC3CC(C)(C)NC(C)(C)C3)n2)cc(C2CC2)c1
Yield: 41.6 %

Procedure:
2-Chloro-5-fluoro-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyrimidin-4-amine (90 mg, 0.31 mmol) was treated with 3-cyclopropyl-5-(1-methyl-1H-tetrazol-5-yl)benzenamine (80 mg, 0.37 mmol) and p-toluenesulfonic acid monohydrate (48 mg, 0.25 mmol) in isopropanol (5 mL) and heated at reflux, in a loosely capped vial, overnight. The solvent evaporated, over the course of the reaction. 2-Chloro-5-fluoro-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyrimidin-4-amine remained in the reaction mixture. An additional equivalent of 3-cyclopropyl-5-(1-methyl-1H-tetrazol-5-yl)benzenamine was added, along with more isopropanol. The reaction was allowed to heat at reflux for an additional 8 hours. This process was repeated until the 2-chloro-5-fluoro-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyrimidin-4-amine was consumed, 4 days later. The resulting residue was purified by column chromatography, on silica gel, eluting with methanol:methylene chloride (1:99) followed by 2M ammonia in methanol:methylene chloride (2:98), to yield N2-(3-cyclopropyl-5-(1-methyl-1H-tetrazol-5-yl)phenyl)-5-fluoro-N4-(2,2,6,6-tetramethylpiperidin-4-yl)pyrimidine-2,4-diamine (60 mg, 42% yield) as an off-white solid.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[NH:15]1[CH2:21][CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.C(N(CC)CC)C>ClCCl>[F:1][C:2]([F:14])([F:13])[C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:15]2[CH2:21][CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Reactant: C1CNCCNC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=S(=O)(c1ccc(C(F)(F)F)cc1)N1CCCNCC1
Reaction time: 8 h
Yield: 95.2 %

Procedure:
The 1-(4-trifluoromethylphenylsulphonyl)homopiperazine was prepared as follows. 4-Trifluoromethylphenylsulphonylchloride (1.5 g) in 20 ml dichloromethane was added dropwise to 5 g homopiperazine and 1.8 ml triethylamine in 55 ml dichloromethane and left stirring overnight. Washed with water and brine, dried (MgSO4), and evaporated to give 1-(4-trifluoromethylphenylsulphonyl)homopiperazine (1.80 g) as a colourless solid; NMR (CDCl3) 1.75 (1H,br), 1.78-1.9 (2H,m), 2.9-3.0 (4H,m), 3.3-3.44 (4H,m), 7.78 (2H,d),