Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]2[NH:8][N:7]=[C:6]([C:9]3[N:14]=[C:13]([NH:15][C:16]4[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=4)[C:12]([O:22][CH3:23])=[CH:11][N:10]=3)[C:5]=2[CH3:24])[CH2:3][CH2:2]1.[H-].[Na+].Br[CH2:28][C:29]1[C:34]([F:35])=[CH:33][C:32]([O:36][CH:37]([F:39])[F:38])=[CH:31][C:30]=1[F:40].O>C1COCC1>[CH:1]1([C:4]2[N:8]([CH2:28][C:29]3[C:30]([F:40])=[CH:31][C:32]([O:36][CH:37]([F:38])[F:39])=[CH:33][C:34]=3[F:35])[N:7]=[C:6]([C:9]3[N:14]=[C:13]([NH:15][C:16]4[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=4)[C:12]([O:22][CH3:23])=[CH:11][N:10]=3)[C:5]=2[CH3:24])[CH2:3][CH2:2]1
Reactant: COc1cnc(-c2n[nH]c(C3CC3)c2C)nc1Nc1ccncc1
Reactant: Fc1cc(OC(F)F)cc(F)c1CBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1cnc(-c2nn(Cc3c(F)cc(OC(F)F)cc3F)c(C3CC3)c2C)nc1Nc1ccncc1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
70 mg 2-(5-cyclopropyl-4-methyl-1H-pyrazol-3-yl)-5-methoxy-N-(pyridin-4-yl)pyrimidin-4-amine 1-16-1 (0-217 mmol, 1.0 eq) were dissolved in 0.52 mL THF and cooled to 0° C. 10.4 mg sodiumhydride (60%, 0.261 mmol, 1.2 eq) were added. The mixture stirred for 5 minutes, then the ice bath was removed and 65.2 mg 2-(bromomethyl)-5-(difluoromethoxy)-1,3-difluorobenzene (0.239 mmol, 1.1 eq) were added. The reaction stirred at rt for 4 days. Again 5 mg sodiumhydride (60%, 0.130 mmol, 0.6 eq) and 33 mg 2-(bromomethyl)-5-(difluoromethoxy)-1,3-difluorobenzene (0.120 mmol, 0.55 eq) were added. The reaction stirred at rt for 2 hours. Water was added and the aqueous layer was extracted by ethylacetate twice. The collected organic layers were washed with brine, dried with a silicon filter and concentrated in vacuo The crude product was purified by flashcromatography and HPLC to provide 10 mg (0.02 mmol, 8%) of the analytically pure target compound.
Reaction SMILES: [N+:1]([C:4]1[C:14]([N+:15]([O-])=O)=[CH:13][C:7]2[N:8]([CH3:12])[C:9](=[O:11])[NH:10][C:6]=2[CH:5]=1)([O-])=O.[H][H]>[Pt]=O.CO>[NH2:1][C:4]1[C:14]([NH2:15])=[CH:13][C:7]2[N:8]([CH3:12])[C:9](=[O:11])[NH:10][C:6]=2[CH:5]=1
Reactant: Cn1c(=O)[nH]c2cc([N+](=O)[O-])c([N+](=O)[O-])cc21
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CO
Product: Cn1c(=O)[nH]c2cc(N)c(N)cc21

Procedure:
2.20 g. (9.2 mMole) 5,6-dinitro-1-methylbenzimidazol-2-one is hydrogenated for 3 hours at 60° C. and 100 bar hydrogen pressure in 730 ml. methanol in the presence of 0.44 g. platinum oxide. The solution of 5,6-diamino-1-methyl-benzimidazol-2-one so obtained is, after filtration, used without further purification.
Reaction SMILES: FC(F)(F)C(O)=O.O.C(Cl)Cl.[C:12]([O:18][CH2:19][CH2:20][C@H:21]([CH:34]([CH3:36])[CH3:35])[CH2:22][C@H:23]([OH:33])[C@@H:24]([NH2:32])[CH2:25][CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)(=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14].[NH:37]([C:59]([O:61][C:62]([CH3:65])([CH3:64])[CH3:63])=[O:60])[C@H:38]([C:46]([NH:48][C@H:49]([C:56](O)=[O:57])[CH2:50][C:51]1[N:55]=[CH:54][NH:53][CH:52]=1)=[O:47])[CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>>[CH:26]1([CH2:25][C@H:24]([NH:32][C:56]([CH:49]([NH:48][C:46]([C@@H:38]([NH:37][C:59](=[O:60])[O:61][C:62]([CH3:64])([CH3:63])[CH3:65])[CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=[O:47])[CH2:50][C:51]2[N:55]=[CH:54][NH:53][CH:52]=2)=[O:57])[C@@H:23]([OH:33])[CH2:22][C@@H:21]([CH:34]([CH3:36])[CH3:35])[CH2:20][CH2:19][O:18][C:12](=[O:17])[C:13]([CH3:14])([CH3:16])[CH3:15])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]cn1)C(=O)O
Reactant: CC(C)[C@@H](CCOC(=O)C(C)(C)C)C[C@H](O)[C@@H](N)CC1CCCCC1
Solvent: ClCCl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)[C@@H](CCOC(=O)C(C)(C)C)C[C@H](O)[C@H](CC1CCCCC1)NC(=O)C(Cc1c[nH]cn1)NC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Yield: 37 %

Procedure:
In an analogous manner to that described in Example 9, 635 mg (1.78 mmol) of t-butyl [(4S,5S)-4-(cyclohexylmethyl)-5-(S)-2-isopropyl-4-(pivaloyloxy)butyl]-2,2-dimethyl-3-oxazolidinecarboxylate are treated with trifluoroacetic acid/water/methylene chloride for the cleavage of the Boc protecting group with simultaneous opening of the oxazolidine ring and the resulting 347 mg (76%) of (3S,5S,6S)-6-amino-7-cyclohexyl-5-hydroxy-3-isopropylheptyl pivaloate are reacted without further purification with Boc-Phe-His-OH, whereby there are obtained 280 mg (37%) of t-butyl [(S)-α-[[(RS)-1-[[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-6-(pivaloyloxy)hexyl]carbamoyl]-2-imidazole-4-ylethyl]carbamoyl]phenethyl]carbamate as an amorphous solid, MS: 740 (M+H)+.
Reaction SMILES: [CH:1]1([S:4]([NH:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][CH:10]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1>CO.[Pd]>[CH:1]1([S:4]([NH:7][CH2:8][C:9]2[CH:10]=[CH:11][C:12]([NH2:15])=[CH:13][CH:14]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1ccc(CNS(=O)(=O)C2CC2)cc1
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(CNS(=O)(=O)C2CC2)cc1
Reaction time: 1 h

Procedure:
N-Cyclopropylsulfonyl-4-nitrobenzylamine was dissolved in methanol (50 mL) and to the solution was added 10% Pd—C. The reaction mixture was placed under hydrogen atmosphere (˜40 psi) and shaken for 1 h. The catalyst was filtered off over celite and washed with methanol (1 L) and water (10 mL). The filtrate was evaporated to give N-cyclopropylsulfonyl-4-aminobenzylamine. 1H NMR (DMSO-d6): δ 0.87 (m, 4H), 2.37 (m, 1H), 3.96 (d, J=6.0 Hz, 2H), 4.99 (br, 2H), 6.49 (d, J=8.1 Hz, 2H), 6.96 (d, J=8.4 Hz, 2H), 7.33 (t, J=6.0 Hz, 1H).
Reaction SMILES: [CH:1]1([CH2:4][NH2:5])[CH2:3][CH2:2]1.[C:6]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH2:17][CH2:18][NH:19][C:20](=[O:34])[C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][N:30]=[C:29](Cl)[N:28]=4)=[CH:23][CH:22]=3)[CH:15]=2)[NH:10][CH:9]=1)#[N:7]>>[C:6]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH2:17][CH2:18][NH:19][C:20](=[O:34])[C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][N:30]=[C:29]([NH:5][CH2:4][CH:1]5[CH2:3][CH2:2]5)[N:28]=4)=[CH:23][CH:22]=3)[CH:15]=2)[NH:10][CH:9]=1)#[N:7]
Reactant: NCC1CC1
Reactant: N#Cc1c[nH]c2ccc(CCNC(=O)c3ccc(-c4ccnc(Cl)n4)cc3)cc12
Product: N#Cc1c[nH]c2ccc(CCNC(=O)c3ccc(-c4ccnc(NCC5CC5)n4)cc3)cc12

Procedure:
Using cyclopropylmethyl-amine and N-[2-(3-Cyano-1H-indol-5-yl)-ethyl]-4-[2-chloro-pyrimidin-4-yl]-benzamide (reference example 1az) as substrates. 1H NMR (DMSO) δ 0.26 (m, 2H); 0.44 (m, 2H); 3.00 (bt, 2H, J=7 Hz); 3.25 (bs, 2H); 3.56 (m, 2H); 7.20 (m, 2H); 7.36 (bt, 1H); 7.50 (m, 2H); 7.94 (d, 2H, J=8 Hz); 8.29 (m, 3H); 8.38 (d, 1H, J=5 Hz); 8.69 (bt, 1H); 12.15 (bs, 1H). MS (ion spray) m/z 437 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C@@H:8]([C@@H:16]1[CH2:18][O:17]1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:20][NH:21][CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[C:1]([O:5][C:6](=[O:19])[NH:7][C@H:8]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C@@H:16]([OH:17])[CH2:18][N:21]([CH3:20])[CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)[C@@H]1CO1
Reactant: CNCCc1ccccc1
Product: CN(CCc1ccccc1)C[C@H](O)[C@@H](Cc1ccccc1)NC(=O)OC(C)(C)C

Procedure:
Using general procedure 1 with [(1R)-1-{(2R)-oxiran-2-yl}-2-phenyl-ethyl]carbamic acid tert-butylester (0.30 g, 1.14 mmol) and N-methyl-phenethylamine (0.166 mL, 1.14 mmol) gives the title compound.
Reaction SMILES: [OH:1][NH:2][C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6].C(N(CC)CC)C.Cl[C:18]([O:20][CH3:21])=[O:19]>C(Cl)Cl>[CH3:21][O:20][C:18]([O:1][NH:2][C:3]([O:4][C:5]([CH3:8])([CH3:7])[CH3:6])=[O:9])=[O:19]
Reactant: CC(C)(C)OC(=O)NO
Reactant: COC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)ONC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of tert-butyl N-hydroxycarbamate (1.4 g, 10.6 mmol) in DCM (10 ml) is added triethylamine (1.5 ml, 10.6 mmol) at 0° C. Methyl choroformate (814 μl, 10.6 mmol) is added drop wise. Reaction stirred for 18 hours at room temperature before being washed with water (2×10 ml), NaHCO3 (2×10 ml), dried over magnesium sulfate and concentrated in vacuo to give the title product as an oil. (1.76 g, 87%), 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 7.71 (1H, br. s.), 3.92 (3H, s), 1.50 (9H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]Cl)=[CH:4][CH:3]=1.[CH:10]([S:12]([CH2:15][CH3:16])(=[O:14])=[O:13])=[CH2:11]>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH:11]=[CH:10][S:12]([CH2:15][CH3:16])(=[O:14])=[O:13])=[CH:4][CH:3]=1
Reactant: C=CS(=O)(=O)CC
Reactant: ClSc1ccc(Cl)cc1
Solvent: ClCCl
Product: CCS(=O)(=O)C=CSc1ccc(Cl)cc1
Reaction time: 1 h

Procedure:
4-chlorophenylsulfenyl chloride, 7.5 g was added to 5.0 g of ethyl vinyl sulfone in 20 ml of dichloromethane. There was no exotherm and the system was refluxed for 3 hours. The dichloromethane was removed by stripping and the residue was dissolved in 50 ml of benzene. Triethylamine, 4.2 g, was added dropwise with cooling and after standing for 1 hour, the triethylamine hydrochloride was removed by filtration and the benzene stripped to give a crude product. Purification was carried out by chromatography on a silica gel column. The product, ethyl 2-(4-chlorophenylthio)vinyl sulfone, 4.2 g, was obtained as a clear oil showing one spot by thin-layer chromatography.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH2:5]([C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=1)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].O>C(O)(=O)C>[N+:1]([C:27]1[CH:28]=[C:23]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH:24]=[CH:25][C:26]=1[OH:29])([O-:4])=[O:2]
Reactant: CCCCCCCCCCCCCCCCCCc1ccc(O)cc1
Reactant: O=[N+]([O-])O
Solvent: O
Solvent: CC(=O)O
Product: CCCCCCCCCCCCCCCCCCc1ccc(O)c([N+](=O)[O-])c1
Reaction time: 1 h

Procedure:
40 ml of nitric acid (d=1.18) was added dropwise to a solution of 10 g of p-octadecylphenol dissolved in 300 ml of acetic acid at 10° to 40° C. After one hour, the reaction mixture was poured into water, extracted with ethyl acetate, washed with water, then with aqueous sodium bicarbonate solution, followed by drying. After the solvent was evaporated, the residued crystals were recrystallized from n-hexane. 2-Nitro-4-octadecylphenol of m.p. 71° C. was obtained in an amount of 8.4 g.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[S:10][C:5]=2[C:4](=[O:17])[N:3]1[CH:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]1.Cl[CH2:32][C:33]1[CH:37]=[C:36]([CH3:38])[O:35][N:34]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:38][C:36]1[O:35][N:34]=[C:33]([CH2:32][N:7]2[C:6]3[CH:8]=[C:9]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[S:10][C:5]=3[C:4](=[O:17])[N:3]([CH:18]3[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]3)[C:2]2=[O:1])[CH:37]=1
Reactant: Cc1cc(CCl)no1
Reactant: CC(C)(C)OC(=O)N1CCC(n2c(=O)[nH]c3cc(-c4ccccc4)sc3c2=O)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(Cn2c(=O)n(C3CCN(C(=O)OC(C)(C)C)CC3)c(=O)c3sc(-c4ccccc4)cc32)no1

Procedure:
According to GP1 tert-butyl 4-(2,4-dioxo-6-phenyl-1,4-dihydrothieno[3,2-d]pyrimidin-3(2H)-yl)piperidine-1-carboxylate (750 mg; compound B50) is reacted with 3-(chloromethyl)-5-methylisoxazole (231 mg; compound D6) in the presence of potassium carbonate (242 mg) in DMF (7 ml). Using WU1 the title compound is obtained as a solid.
Reaction SMILES: C[O:2][C:3](=[O:32])[CH2:4][CH2:5][CH2:6][N:7]1[CH2:11][CH2:10][CH2:9][C@@H:8]1[CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]2[CH:26]=[CH:25][C:24]([N:27]3[CH:31]=[CH:30][CH:29]=[N:28]3)=[CH:23][CH:22]=2)=[CH:16][CH:15]=1.O>Cl>[N:27]1([C:24]2[CH:23]=[CH:22][C:21]([O:20][C:17]3[CH:18]=[CH:19][C:14]([O:13][CH2:12][C@H:8]4[CH2:9][CH2:10][CH2:11][N:7]4[CH2:6][CH2:5][CH2:4][C:3]([OH:32])=[O:2])=[CH:15][CH:16]=3)=[CH:26][CH:25]=2)[CH:31]=[CH:30][CH:29]=[N:28]1
Reactant: COC(=O)CCCN1CCC[C@@H]1COc1ccc(Oc2ccc(-n3cccn3)cc2)cc1
Agent: Cl
Solvent: O
Product: O=C(O)CCCN1CCC[C@@H]1COc1ccc(Oc2ccc(-n3cccn3)cc2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 59.3 %

Procedure:
To a 20 mL vial which contained a solution of the product from step 1 (40 mg, 0.1 mmol) in HCl (4 N in dioxane 2 mL) was added water (0.3 mL) at 0° C. The mixture was allowed to warm to rt and stir at rt for 24 h. The solvent was removed to yield the crude, which was purified by recrystallization from THF-ether to afford the title product (25 mg, 75%); LCMS; 94%, ESI−, Calcd: 421.5; Found m/z: 420.6 (M−1); 1H NMR (400 MHz, DMSO-d6); δ 1.74-2.09 (m, 5H), 2.16-2.25 (m, 1H), 2.31-2.40 (m, 2H), 3.03 (br, 2H), 3.45-3.80 (m, 3H), 4.16-4.20 (m, 1H), 4.20-4.23 (m, 1H), 6.52 (t, J=2.0 Hz, 1H), 6.87 (s, 1H), 7.04-7.06 (m, 5H), 7.71 (d, J=1.6 Hz, 1H), 7.80 (d, J=9.2 Hz, 2H), 8.42 (d, J=2.4 Hz, 1H):
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH2:3][CH2:2]1.ClC(Cl)C(Cl)Cl.[Al+3].[Cl-].[Cl-].[Cl-].[CH3:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[O:25][CH3:26].Cl>O.ClCCl>[CH3:26][O:25][C:20]1[CH:21]=[CH:22][C:23]([C:4](=[O:5])[CH2:3][CH2:2][C:1]([OH:6])=[O:7])=[CH:24][C:19]=1[CH3:18]
Reactant: COc1ccccc1C
Reactant: O=C1CCC(=O)O1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Solvent: ClC(Cl)C(Cl)Cl
Product: COc1ccc(C(=O)CCC(=O)O)cc1C
Temperature: 25 °C
Reaction time: 4 h
Yield: 76.1 %

Procedure:
To a solution of succinic anhydride (12.0 g, 122.0 mmol) and 50 mL of 1,1,2,2,-tetrachloroethane at room temperature was added AlCl3 (21.5 g, 161.2 mmol) and 2-methylanisole (Compound 1, 10 mL, 81.0 mmol). The resulting solution was stirred for 4 h at room temperature, then poured into a solution of concentrated HCl (20 mL) in water (50 mL) and ice. Dichloromethane was added, and the bottom layer was separated. The solvents were removed under reduced pressure, and the residue was dissolved in a boiling solution of sodium carbonate (30 g Na2CO3 in 160 mL H2O) for 10 min, and filtered. The filtrate was acidified with concentrated HCl to pH=0-1, and crystallized in a salt ice bath. The solid product was filtered and washed with cold water, and dried in the air to give 13.7 g (76%) of the title compound as an off-white solid.
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[C@H:3]([CH2:5][CH3:6])[CH3:4].[CH2:10](O)[CH2:11][CH2:12]CCCCC>S(=O)(=O)(O)O.O.C1(C)C=CC=CC=1>[C:7]([OH:9])(=[O:8])[CH2:2][CH2:3][CH2:5][CH2:6][CH2:10][CH2:11][CH3:12].[NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[C@H:3]([CH2:5][CH3:6])[CH3:4]
Reactant: CCCCCCCCO
Agent: CC[C@H](C)[C@H](N)C(=O)O
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCCCCC(=O)O
Temperature: 25 °C

Procedure:
13.1 g of isoleucine was dissolved in a solution of 10 g of concentrated sulfuric acid, 20 mL water, 20 mL of octanol, and 200 mL of toluene in a 500 mL round bottom flask equipped with a condenser and a Dean-Stark apparatus placed in an oil bath. The resulting solution was heated at reflux temperature until no more water could be distilled. The resulting solution was then cooled to room temperature, diluted with 120 mL of ethyl acetate and the organic layer washed with saturated aqueous sodium bicarbonate to neutralize acidic impurities, washed with saturated Brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the resulting liquid distilled to provide isoleucine octanoate as a colorless liquid.
Reaction SMILES: [CH3:1][NH:2][S:3]([C:6]1[CH:11]=[CH:10][C:9]([Br:12])=[CH:8][CH:7]=1)(=[O:5])=[O:4].[H-].[Na+].[CH3:15][O:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21]Cl)=[CH:19][CH:18]=1>CN(C=O)C>[CH3:1][N:2]([CH2:21][C:20]1[CH:23]=[CH:24][C:17]([O:16][CH3:15])=[CH:18][CH:19]=1)[S:3]([C:6]1[CH:11]=[CH:10][C:9]([Br:12])=[CH:8][CH:7]=1)(=[O:5])=[O:4]
Reactant: CNS(=O)(=O)c1ccc(Br)cc1
Reactant: COc1ccc(CCl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(CN(C)S(=O)(=O)c2ccc(Br)cc2)cc1
Reaction time: 0.75 h
Yield: 97.2 %

Procedure:
To a solution of N-methyl-4-bromophenylsulfonamide (2.5 g, 10 mmol) in DMF (20 mL) at room temperature was added in portions NaH (264 mg, 11 mmol). The mixture was stirred for 45 minutes and then p-methoxybenzylchloride (1.49 mL, 11 mmol) was added dropwise. The mixture was stirred for 1 hour, quenched with water and the precipitate which formed was collected by filtration and dried in vacuo at 60° C. to afford 3.6 g (97%) of N-methyl-N-(4-methoxybenzyl)-4-bromophenylsulfonamide.
Reaction SMILES: Br[C:2](P(=O)(OCC)OCC)([F:4])[F:3].[OH:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[N:19]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[N:18]=[C:17]2[I:30].[OH-].[K+]>CC#N.O.CCOC(C)=O>[F:3][CH:2]([F:4])[O:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[N:19]([C:23]([O:25][C:26]([CH3:27])([CH3:29])[CH3:28])=[O:24])[N:18]=[C:17]2[I:30]
Reactant: CC(C)(C)OC(=O)n1nc(I)c2cc(O)ccc21
Reactant: CCOP(=O)(OCC)C(F)(F)Br
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)n1nc(I)c2cc(OC(F)F)ccc21
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 47 %

Procedure:
Diethyl bromodifluoromethylphosphonate (1.13 g, 4.22 mmol) was added in one portion to a cooled (−30° C.) solution of tert-butyl 5-hydroxy-3-iodo-1H-indazole-1-carboxylate and KOH (2.36 g, 42.2 mmol) in MeCN/H2O (20 mL/20 mL). The reaction mixture was allowed to warm to room temperature. After 20 min, the reaction mixture was diluted with EtOAc (15 mL), and the organic phase was separated. The water phase was extracted with EtOAc (10 mL). The combined organic layers were dried over Na2SO4. Evaporation of the solvent gave a crude product that was purified by column chromatography on silica gel eluting with petroleum ether/EtOAc (5:1) to give tert-butyl 5-(difluoromethoxy)-3-iodo-1H-indazole-1-carboxylate (0.41 g, 47% over two steps) as a white solid. 1H NMR (300 MHz, CDCl3): δ 8.13 (d, 1H, J=9.0 Hz), 7.39 (dd, 1H, J=9, 2.4 Hz), 7.23 (d, 1H, J=2.4 Hz), 6.57 (t, 1H, J=73.2 Hz), 1.73 (s, 9H).
Reaction SMILES: [OH:1][C:2]1[CH:18]=[CH:17][C:5]2[C:6]([CH3:16])=[C:7]([CH2:11][C:12]([O:14][CH3:15])=[O:13])[C:8](=[O:10])[O:9][C:4]=2[C:3]=1[CH2:19][CH:20]=[CH2:21]>CO.[Pd]>[OH:1][C:2]1[CH:18]=[CH:17][C:5]2[C:6]([CH3:16])=[C:7]([CH2:11][C:12]([O:14][CH3:15])=[O:13])[C:8](=[O:10])[O:9][C:4]=2[C:3]=1[CH2:19][CH2:20][CH3:21]
Reactant: C=CCc1c(O)ccc2c(C)c(CC(=O)OC)c(=O)oc12
Agent: [Pd]
Solvent: CO
Product: CCCc1c(O)ccc2c(C)c(CC(=O)OC)c(=O)oc12

Procedure:
The phenol from Step 3 (23 g) was hydrogenated in methanol (700 ml) under 50 psi H2 pressure in the presence of 5% palladium on charcoal (2 g) for 1 hour. The catalyst was removed by filtration over celite and the solvent was removed to provide the title compound, m.p. 160°-162°.
Reaction SMILES: [CH2:1]([S:8][CH:9]([CH:42]=O)[CH2:10][NH:11][C:12]([C:14]1[NH:15][C:16]2[C:21]([CH:22]=1)=[CH:20][C:19]([O:23][CH2:24][CH2:25][CH2:26][S:27]([CH3:30])(=[O:29])=[O:28])=[CH:18][C:17]=2[N:31]([CH3:41])[S:32]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=1)(=[O:34])=[O:33])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:44]1[CH2:49][CH2:48][S:47][CH2:46][CH2:45]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O.C(=O)([O-])O.[Na+]>ClCCCl>[CH2:1]([S:8][CH:9]([CH2:42][N:44]1[CH2:49][CH2:48][S:47][CH2:46][CH2:45]1)[CH2:10][NH:11][C:12]([C:14]1[NH:15][C:16]2[C:21]([CH:22]=1)=[CH:20][C:19]([O:23][CH2:24][CH2:25][CH2:26][S:27]([CH3:30])(=[O:28])=[O:29])=[CH:18][C:17]=2[N:31]([CH3:41])[S:32]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=1)(=[O:34])=[O:33])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(c1cc(OCCCS(C)(=O)=O)cc2cc(C(=O)NCC(C=O)SCc3ccccc3)[nH]c12)S(=O)(=O)c1ccccn1
Reactant: C1CSCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])O
Solvent: ClCCCl
Product: CN(c1cc(OCCCS(C)(=O)=O)cc2cc(C(=O)NCC(CN3CCSCC3)SCc3ccccc3)[nH]c12)S(=O)(=O)c1ccccn1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 89 %

Procedure:
A mixture of N-[2-(benzylthio)-3-oxopropyl]-7-[methyl(pyridin-2-ylsulfonyl)amino]-5-[3-(methylsulfonyl)propoxy]-1H-indole-2-carboxamide (0.75 g), thiomorpholine (0.24 mL) and 1,2-dichloroethane (20 mL) was stirred at room temperature for 15 min. Sodium triacetoxyborohydride (0.74 g) was added to the reaction solution, and the mixture was stirred at room temperature for 5 hr. The reaction solution was acidified with aqueous citric acid solution, basified with aqueous sodium hydrogencarbonate solution, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ethyl acetate:hexane=5:5-10:0) to give the title compound (0.76 g, yield: 89%) as a colorless amorphous solid. MS: 733 (MH+).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:11]=[C:10]2[C:6]([N:7]=[CH:8][N:9]2[C@H:12]2[C@H:16]([OH:17])[C@H:15]([OH:18])[C@@H:14]([CH2:19][O:20][CH3:21])[O:13]2)=[C:5]([NH:22][CH2:23][CH:24]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:4]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[N:55]1[CH:60]=[CH:59][CH:58]=[CH:57][C:56]=1[N:61]1[CH2:66][CH2:65][C:64](=O)[CH2:63][CH2:62]1>>[C:25]1([CH:24]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:23][NH:22][C:5]2[N:4]=[C:3]([CH2:2][NH:1][CH:64]3[CH2:63][CH2:62][N:61]([C:56]4[CH:57]=[CH:58][CH:59]=[CH:60][N:55]=4)[CH2:66][CH2:65]3)[N:11]=[C:10]3[C:6]=2[N:7]=[CH:8][N:9]3[C@H:12]2[C@H:16]([OH:17])[C@H:15]([OH:18])[C@@H:14]([CH2:19][O:20][CH3:21])[O:13]2)[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: O=C1CCN(c2ccccn2)CC1
Reactant: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CN)nc32)[C@H](O)[C@@H]1O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Product: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CNC4CCN(c5ccccn5)CC4)nc32)[C@H](O)[C@@H]1O
Yield: 51 %

Procedure:
The title compound was prepared by a similar method to example 6 using (2R,3R,4S,5R)-2-{2-(aminomethyl)-6-[(2,2-diphenylethyl)amino]-9H-purin-9-yl}-5-(methoxymethyl)tetrahydro-3,4-furandiol (example 1) (300 mg, 0.6 mmol), acetic acid (45 mg, 0.72 mmol), sodium triacetoxyborohydride (200 mg, 0.91 mmol) and 1-(2-pyridinyl)-4-piperidinone (120 mg, 0.66 mmol) (preparation 37). The product was purified by column chromatography on silica gel eluting with a solvent system of dichloromethane:methanol:ammonia (96:4:0.2) increasing in polarity to (93:7:0.3) to give the title compound (199 mg) as a foam. MS: 653 (MH+).
Reaction SMILES: [Cl-].[NH2:2][N+:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[OH-].[K+].[C:11]([C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1)#[N:12].C(O)C>O>[N:16]1[CH:17]=[CH:18][C:13]([C:11]2[N:12]=[C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][N:3]3[N:2]=2)=[CH:14][CH:15]=1
Reactant: N[n+]1ccccc1
Reactant: N#Cc1ccncc1
Agent: [Cl-]
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: c1ccn2nc(-c3ccncc3)nc2c1
Reaction time: 66 h
Yield: 53.1 %

Procedure:
1-Aminopyridinium chloride (7.9g) was added to potassium hydroxide (6.72g) in water (60 ml). 4-Cyanopyridine (31.2g) was added to ethanol (63 ml). The two solutions were then admixed at room temperature and left for 66 hours. The ethanol was then evaporated off in vacuo, and the residue extracted with chloroform (100 ml). The chloroform extract was dried over magnesium sulphate, filtered, and evaporated in vacuo. Recrystallisation of the product from ethanol gave 2-(4-pyridyl)-s-triazolo[1,5-a]pyridine (6.3g), mp 188°-190° C.
Reaction SMILES: [C:1]([CH:4]=[CH:5][C:6]1[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8]([OH:10])=[O:9])([OH:3])=[O:2]>CO>[C:1]([CH2:4][CH2:5][C:6]1[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8]([OH:10])=[O:9])([OH:3])=[O:2]
Reactant: O=C(O)C=Cc1ccccc1C(=O)O
Solvent: CO
Product: O=C(O)CCc1ccccc1C(=O)O
Yield: 103 %

Procedure:
A mixture of 2-(2-carboxyvinyl)benzoic acid (5 g, 26 mmol) in MeOH (45 mL) was bubbled with H2 (10 psi) at room temperature overnight. The mixture was filtered and the filtrate was concentrated to give 2-(2-carboxyethyl)benzoic acid (5.2 g, 100%). 1H-NMR (CDCl3): 2.61 (m, 2H), 3.21 (m, 2H), 7.22 (m, 2H), 7.38 (m, 1H), 7.88 (m, 1H).