Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH2:2][C@@H:3]([NH2:8])[CH2:4][CH:5]([CH3:7])[CH3:6].COC(=O)[C@H](CC(C)C)N.OCCN.[F:23][C:24]([F:38])([F:37])[C:25]1[CH:30]=[C:29]([N+:31]([O-:33])=[O:32])[CH:28]=[CH:27][C:26]=1[N:34]=[C:35]=[S:36]>>[F:38][C:24]([F:37])([F:23])[C:25]1[CH:30]=[C:29]([N+:31]([O-:33])=[O:32])[CH:28]=[CH:27][C:26]=1[N:34]=[C:35]1[NH:8][C@@H:3]([CH2:4][CH:5]([CH3:7])[CH3:6])[CH2:2][S:36]1
Reactant: CC(C)C[C@H](N)CO
Reactant: O=[N+]([O-])c1ccc(N=C=S)c(C(F)(F)F)c1
Agent: COC(=O)[C@@H](N)CC(C)C
Solvent: NCCO
Product: CC(C)C[C@H]1CSC(=Nc2ccc([N+](=O)[O-])cc2C(F)(F)F)N1

Procedure:
(1S)-1-(Hydroxymethyl)-3-methylbutylamine was made from (L)-leucine methyl ester as described in Method B1b. The 2-hydroxyethylamine was converted to (1S)-1-(chloromethyl)-3-methylbutanammonium chloride as described in Method B7a. 2-(Trifluoromethyl)4-nitrophenyl isothiocyanate was reacted with (1S)-1-(chloromethyl)-3-methylbutanammonium chloride according to Method C1c to give (4S)-2-(2-(trifluoromethyl)-4-nitrophenylimino)-4-isobutyl-1,3-thiazolidine. The thiazolidine was reacted with isobutyl bromide according to Method D2f to afford (4S)-2-(2-(trifluoromethyl)-4-nitrophenylimino)-3,4-diisobutyl-1,3-thiazolidine trifluoroacetate salt.
Reaction SMILES: [CH2:1]([N:3]([C:29](=O)[C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[C:32]([F:37])[CH:31]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[C@@H:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22]C(=O)C(C)(C)C)[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2].Cl[CH2:40][C:41]([N:43]1[CH2:48][CH2:47][CH:46]([CH3:49])[CH2:45][CH2:44]1)=O>>[CH2:1]([N:3]([CH2:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][CH2:40][CH2:41][N:43]2[CH2:48][CH2:47][CH:46]([CH3:49])[CH2:45][CH2:44]2)=[C:32]([F:37])[CH:31]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[C@@H:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2]
Reactant: CCN(C(=O)c1ccc(O)c(F)c1)c1cc(OC)ccc1[C@@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Reactant: CC1CCN(C(=O)CCl)CC1
Product: CCN(Cc1ccc(OCCN2CCC(C)CC2)c(F)c1)c1cc(OC)ccc1[C@@H]1CCc2cc(O)ccc2C1
Yield: 43.1 %

Procedure:
Synthesized from pivalic acid (R)-6-{2-[ethyl(3-fluoro-4-hydroxybenzoyl)amino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (15 mg) and 2-chloro-1-(4-methylpiperidin-1-yl)ethanone (10 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (6.8 mg) was obtained.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.[NH2:9][C:10]1[CH:11]=[CH:12][C:13]([O:16][CH3:17])=[N:14][CH:15]=1.CC(O)C.C([O-])([O-])=O.[Na+].[Na+]>C(OCC)(=O)C>[CH3:17][O:16][C:13]1[N:14]=[CH:15][C:10]([NH:9][C:2]2[CH:3]=[C:4]([NH2:8])[N:5]=[CH:6][N:7]=2)=[CH:11][CH:12]=1
Reactant: COc1ccc(N)cn1
Reactant: Nc1cc(Cl)ncn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: COc1ccc(Nc2cc(N)ncn2)cn1
Temperature: 90 °C
Reaction time: 36 h

Procedure:
A mixture of 6-chloro-pyrimidin-4-ylamine (0.65 g, 5 mmol), 5-amino-2-methoxypyridine (0.62 g, 5 mmol) and 2-propanol (5 mL) is shaken for 36 h at 90° C. After cooling to room temperature, the reaction mixture is distributed between half-saturated Na2CO3-solution and ethyl acetate. The organic layer is dried over Na2SO4 and evaporated. The solid residue is washed consecutively with CH3OH, ethyl acetate and CH2Cl2 and dried in vacuo.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][C:9]([O:10][C:11]3[CH:12]=[C:13]4[C:18](=[CH:19][CH:20]=3)[C:17]([NH2:21])=[CH:16][CH:15]=[CH:14]4)=[C:4]2[CH:3]=[N:2]1.[Cl:22][C:23]1[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][CH:24]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([NH:21][C:17]2[C:18]3[C:13](=[CH:12][C:11]([O:10][C:9]4[CH:8]=[CH:7][N:6]=[C:5]5[NH:1][N:2]=[CH:3][C:4]=45)=[CH:20][CH:19]=3)[CH:14]=[CH:15][CH:16]=2)=[O:28])=[CH:25][CH:24]=1
Reactant: O=C(O)c1ccc(Cl)cc1
Reactant: Nc1cccc2cc(Oc3ccnc4[nH]ncc34)ccc12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cccc2cc(Oc3ccnc4[nH]ncc34)ccc12)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
6-(1H-Pyrazolo[3,4-b]pyridin-4-yloxy)naphthalen-1-amine (25 mg, 0.09 mmol), 4-chlorobenzoic acid (16 mg, 0.10 mmol) and TBTU (35 mg, 0.108 mmol) were dissolved in DMF (0.75 mL). Hunig's base (18 mg, 0.14 mmol) was then added and the reaction mixture was stirred at RT for 16 h. Additional 4-chlorobenzoic acid (6 mg, 0.036 mmol) and TBTU (12 mg, 0.036 mmol) were added to the reaction and stirring was continued for 3 days. The reaction mixture was concentrated in vacuo. The remaining dark brown residue was purified by silica gel chromatography (0% to 2% MeOH in DCM) to yield 4-chloro-N-(6-(1H-pyrazolo[3,4-b]pyridin-4-yloxy)-1-naphthalenyl)benzamide as an off-white solid. MS (ESI, pos. ion) m/z: 415.0 (M+1). MS (ESI pos. ion) m/z: 415.0 (M+H). Calc'd for C23H15ClN4O2-414.85.
Reaction SMILES: N=[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]1[NH:8][C:9]([N:11]1C=CN=C1)=[S:10].Cl[CH2:17][C:18]1[N:19]=[C:20]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:22][N:21]2[CH:29]=1>C(O)CC>[N:11]1[C:9]([S:10][CH2:17][C:18]2[N:19]=[C:20]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH2:22][N:21]3[CH:29]=2)=[N:8][N:3]2[CH:2]=[CH:7][CH:6]=[CH:5][C:4]=12
Reactant: ClCc1cn2c(n1)-c1ccccc1C2
Reactant: N=c1ccccn1NC(=S)n1ccnc1
Solvent: CCCO
Product: c1ccc2c(c1)Cn1cc(CSc3nc4ccccn4n3)nc1-2
Yield: 62.4 %

Procedure:
An adaptation of the method described in WO 96/01826 was used. Imidazole-1-carbothioic acid (2-imino-2H-pyridin-1-yl)-amide (200 mg, 1.37 mmol) and 2-Chloromethyl-5H-imidazo[2,1-a]isoindole (300 mg, 1.46 mmol) were dissolved in 1-propanol (25 mL) and the mixture was heated to reflux for 2 hours. The solvent was removed under reduced pressure and the residue dissolved in dichloromethane. The solution was washed with water and the organic layer was dried over Na2SO4 and concentrated. The residue was purified by chromatography on silica gel to afford the title compound (273 mg, 62%) as a yellow solid. LC-MS: m/z=321.1 (MH+). tR=1.40 min, method B.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]([N:11]2[C:15](=[O:16])[CH2:14][C@@H:13]([C:17]([OH:19])=O)[CH2:12]2)[CH3:10])=[CH:5][CH:4]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.C(N(C(C)C)CC)(C)C.[CH3:41][NH:42][O:43][CH3:44].Cl>CC1OCCC1>[CH3:44][O:43][N:42]([CH3:41])[C:17]([C@@H:13]1[CH2:14][C:15](=[O:16])[N:11]([C@@H:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[CH3:10])[CH2:12]1)=[O:19]
Reactant: COc1ccc([C@@H](C)N2C[C@H](C(=O)O)CC2=O)cc1
Reactant: CNOC
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CC1CCCO1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc([C@@H](C)N2C[C@H](C(=O)N(C)OC)CC2=O)cc1
Reaction time: 1.25 h

Procedure:
To a suspension of (R)-1-((R)-1-(4-methoxyphenyl)ethyl)-5-oxopyrrolidine-3-carboxylic acid 1.01 (1.0 g, 3.80 mmol) in 2-MeTHF (5 mL) was added CDI (925 mg, 5.70 mmol) and the mixture was stirred for 75 minutes over which time the reaction became homogenous. Diisopropylethyl amine (800 μL, 4.56 mmol) and N,O-dimethylhydroxylamine (445 mg, 4.56 mmol) were added and the reaction was stirred for 3 hours. 3M HCl (4 mL, 12 mmol) was added and the mixture was stirred for 5 minutes. The layers were separated, and the aqueous layer was extracted with EtOAc (2×20 mL). The combined organics were dried (MgSO4), filtered and concentrated to afford (R)-N-methoxy-1-((R)-1-(4-methoxyphenyl)ethyl)-N-methyl-5-oxopyrrolidine-3-carboxamide 1.02.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]2[N:13]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=3)[C:12]3[CH:22]=[C:23]([F:27])[C:24]([F:26])=[CH:25][C:11]=3[N:10]=2)=[C:6]([OH:8])[CH:7]=1.[CH3:28][O:29][C:30](=[O:39])[C:31]1[CH:36]=[CH:35][C:34]([CH2:37]Br)=[CH:33][CH:32]=1>>[CH3:28][O:29][C:30](=[O:39])[C:31]1[CH:36]=[CH:35][C:34]([CH2:37][O:8][C:6]2[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[C:9]2[N:13]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=3)[C:12]3[CH:22]=[C:23]([F:27])[C:24]([F:26])=[CH:25][C:11]=3[N:10]=2)=[CH:33][CH:32]=1
Reactant: Oc1cc(Cl)ccc1-c1nc2cc(F)c(F)cc2n1Cc1cccc(Cl)c1
Reactant: COC(=O)c1ccc(CBr)cc1
Product: COC(=O)c1ccc(COc2cc(Cl)ccc2-c2nc3cc(F)c(F)cc3n2Cc2cccc(Cl)c2)cc1

Procedure:
The title compound was prepared in analogy to Example 5, intermediate a, from 5-chloro-2-[1-(3-chloro-benzyl)-5,6-difluoro-1H-benzoimidazol-2-yl]-phenol (Example 53, intermediate a) and 4-bromomethyl-benzoic acid methyl ester (CAS Reg. No. 2417-72-3). Colorless sticky solid (56%). MS (Turbo Spray): m/z=553.1 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].[C:12]1([C@@H:18](O)[CH3:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CCN=C=NCCCN(C)C>CN(C1C=CN=CC=1)C.C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([O:11][C@H:18]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:19])=[O:10]
Reactant: O=C(O)Cc1ccccc1F
Reactant: C[C@H](O)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: C[C@H](OC(=O)Cc1ccccc1F)c1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 91.7 %

Procedure:
A mixture of 2-fluorophenylacetic acid (5.45 g, 35.4 mmol), (S)-1-phenylethanol (5.62 g, 46.0 mmol), EDCI (8.82 g, 46.0 mmol) and DMAP (0.561 g, 4.60 mmol) in CH2Cl2 (100 mL) was stirred at room temperature for 12 hours. The solvent was then concentrated and the residue partitioned with H2O-ethyl acetate. The phases were separated and the aqueous layer back-extracted with ethyl acetate (2×). The combined organic phases were washed (H2O, brine), dried Na2SO4), filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (Biotage/0-20% ethyl acetate-hexane) to provide the title compound as a colorless oil (8.38 g, 92%). 1H NMR (400 MHz, CD3OD) δ 7.32-7.23 (m, 7H), 7.10-7.04 (m, 2), 5.85 (q, J=6.5 Hz, 1H), 3.71 (s, 2H), 1.48 (d, J=6.5 Hz, 3H).
Reaction SMILES: [N:1]1[S:5][N:4]=[C:3]2[C:6]([S:10]([NH:13][C:14]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:15]=3[C:16]([OH:18])=O)(=[O:12])=[O:11])=[CH:7][CH:8]=[CH:9][C:2]=12.Cl.[Cl:25][C:26]1[CH:27]=[C:28]([CH:33]([CH3:36])[CH2:34][NH2:35])[CH:29]=[CH:30][C:31]=1[Cl:32]>>[N:1]1[S:5][N:4]=[C:3]2[C:6]([S:10]([NH:13][C:14]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:15]=3[C:16]([NH:35][CH2:34][CH:33]([C:28]3[CH:29]=[CH:30][C:31]([Cl:32])=[C:26]([Cl:25])[CH:27]=3)[CH3:36])=[O:18])(=[O:12])=[O:11])=[CH:7][CH:8]=[CH:9][C:2]=12
Reactant: CC(CN)c1ccc(Cl)c(Cl)c1
Reactant: O=C(O)c1cc(Cl)ccc1NS(=O)(=O)c1cccc2nsnc12
Agent: Cl
Product: CC(CNC(=O)c1cc(Cl)ccc1NS(=O)(=O)c1cccc2nsnc12)c1ccc(Cl)c(Cl)c1

Procedure:
The title compound was prepared from 2-(benzo[1,2,5]thiadiazole-4-sulfonylamino)-5-chloro-benzoic acid and (±)-2-(3,4-dichloro-phenyl)-propylamine hydrochloride as in EXAMPLE 1, Part C. HPLC: RT=11.76 min. MS (ESI−): mass calcd. for C22H17Cl3N4O3S2, 553.98; m/z found, 553/555 [M−H]−. 1H NMR (400 MHz, CDCl3): 11.05 (s, 1H), 8.30 (dd, J=7.0, 1.0, 1H), 8.21 (d, 8.0, 1H), 7.70-7.66 (m, 1H), 7.65-7.63 (m, 1H), 7.41 (d, J=8.2, 1H), 7.29 (dd, J=4.6, 2.1, 2H), 7.05 (dd, J=9.6, 2.1, 2H), 5.80 (s, 1H), 3.67-3.60 (m, 1H), 3.32-3.26 (m, 1H), 3.02-2.97 (m, 1H), 1.30 (d, J=7.0, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:30]=[CH:29][C:6]([CH2:7][NH:8][C:9]2[N:14]=[C:13]([CH2:15][CH2:16][CH2:17][CH2:18][CH:19](O)[CH:20]=[CH:21][C:22]3[CH:27]=CN=CN=3)[CH:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.C(O)(=O)CC.Cl.[Cl-].[Na+].O.[C:40]([CH3:50])(OCC)([O:44]CC)[O:41][CH2:42][CH3:43]>>[CH2:42]([O:41][C:40](=[O:44])[CH2:50][CH:21]([C:22]1[CH:27]=[N:14][CH:9]=[N:8][CH:7]=1)[CH:20]=[CH:19][CH2:18][CH2:17][CH2:16][CH2:15][C:13]1[CH:12]=[CH:11][CH:10]=[C:9]([NH:8][CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:30][CH:29]=2)[N:14]=1)[CH3:43]
Reactant: CCOC(C)(OCC)OCC
Reactant: COc1ccc(CNc2cccc(CCCCC(O)C=Cc3ccncn3)n2)cc1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCC(=O)O
Product: CCOC(=O)CC(C=CCCCCc1cccc(NCc2ccc(OC)cc2)n1)c1cncnc1
Temperature: 25 °C

Procedure:
A solution of the allylic alcohol 6-9 (1.6 g, 3.37 mmol) in (EtO)3CMe (10 mL) was treated with 100 uL of a 1 mL solution of (EtO)3CMe containing 10 uL of propionic acid. The yellow solution was heated at 150° for 90 minutes. The solution was cooled to room temperature and poured into 1N HCl/brine. The mixture was extracted with CHCl3, dried, concentrated, and purified on silica gel (5%MeOH/CHCl3) to give 2.01 g of 6-10.
Reaction SMILES: C(O)C(C)C.[OH-].[NH3+:7][NH2:8].[CH2:9]([O:16][C:17]1[CH:26]=[CH:25][C:20]([C:21](OC)=[O:22])=[C:19]([CH2:27][CH3:28])[C:18]=1[CH3:29])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>CC(O)C>[CH2:9]([O:16][C:17]1[CH:26]=[CH:25][C:20]([C:21]([NH:7][NH2:8])=[O:22])=[C:19]([CH2:27][CH3:28])[C:18]=1[CH3:29])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CCc1c(C(=O)OC)ccc(OCc2ccccc2)c1C
Reactant: N[NH3+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: CC(C)CO
Product: CCc1c(C(=O)NN)ccc(OCc2ccccc2)c1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
20 ml of 2-propanol and 10 ml of isobutanol (2-methylpropan-1-ol) and also 20.0 ml of hydrazinium hydroxide are added to 17.5 g of methyl 4-benzyloxy-2-ethyl-3-methylbenzoate (C1). The reaction mixture is subsequently heated under reflux for 18 h overnight. After cooling, a further 30 ml of 2-propanol are added to the solution, which is subsequently stirred at room temperature for 30 min. The precipitate is filtered off with suction, and the filter cake is rinsed a number of times with a little 2-propanol. The product is subsequently recrystallised from 2-propanol, and the precipitate obtained is dried overnight in vacuo, giving 12.3 g of the title compound as a colourless, amorphous solid having a melting point of 179° C.; MS: 284.2 (M+); TLC: Rf=0.27 (ethyl acetate/ethanol 97:3 parts by volume).
Reaction SMILES: [C:1]([N:8]1[CH2:11][CH:10]([NH2:12])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CCN(CC)CC.[C:20](Cl)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(Cl)Cl>[C:20]([NH:12][CH:10]1[CH2:11][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:9]1)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CC(N)C1
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC(NC(=O)c2ccccc2)C1
Reaction time: 3 h
Yield: 98.5 %

Procedure:
To a solution of 1-Boc-3-aminoazetidine 1a (1.2 g, 6.98 mmol) and Et3N (2.4 mL, 17.3 mmol) in CH2Cl2 (70 mL) at 0° C. was added benzoyl chloride 1b (0.89 mL, 7.68 mmol). The reaction was kept at 0° C. for 3 h, quenched with aq. NaHCO3, and the resulting mixture was extracted with CH2Cl2. The organic solution was dried over Na2SO4 and concentrated. Purification by flash column chromatography (silica gel, 40% EtOAc/heptane) gave compound 1c (1.9 g).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:14][N:15]([CH2:28][CH2:29][CH2:30][CH:31]=[CH2:32])[S:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[N+:25]([O-:27])=[O:26])(=[O:18])=[O:17])[C:10]([O:12]C)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1COCC1.CO.[OH-].[Li+]>O>[C:1]([O:5][C:6]([NH:8][CH:9]([CH2:14][N:15]([CH2:28][CH2:29][CH2:30][CH:31]=[CH2:32])[S:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[N+:25]([O-:27])=[O:26])(=[O:18])=[O:17])[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=CCCCN(C[C@H](NC(=O)OC(C)(C)C)C(=O)OC)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: C=CCCCN(CC(NC(=O)OC(C)(C)C)C(=O)O)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 15 h
Yield: 88.7 %

Procedure:
(S)-methyl 2-(tert-butoxycarbonyl)-3-(2-nitro-N-(pent-4-enyl)phenylsulfonamido)-propanoate iv (500 mg, 1.06 mmol) was dissolved in the mixed solvent system: THF (4 mL), methanol (1 mL), and water (2 mL). Powdered lithium hydroxide (250 mg, 10.4 mmol) was added. The light yellow slurry was stirred at rt for 15 h, and then concentrated in vacuo. The residue was partitioned between ether and water. The ether phase was discarded, and the aqueous phase was treated with 1 N HCl until the pH was 4. This acidic solution was extracted with ethyl acetate four times. The combined ethyl acetate extracts were dried (MgSO4) and concentrated in vacuo to give 430 mg (89%) of 2-(tert-butoxycarbonylamino)-3-(2-nitro-N-(pent-4-enyl)phenylsulfonamido)propanoic acid (Example 26) as a yellow oil. 1H NMR (CD3OD, 300 MHz) δ 1.38 (s, 9H), 1.51-1.60 (m, 2H), 1.89-1.98 (m, 2H), 3.28-3.32 (m, 2H), 3.59-3.64 (dd, J=14.95, 9.46 Hz, 1H), 3.71-3.74 (m, 1H), 4.33 (dd, J=9.61, 4.43 Hz, 1H), 4.87-4.94 (m, 2H), 5.63-5.72 (m, 1H), 7.71-7.77 (m, 3H), 8.01 (dd, J=7.48, 1.37 Hz, 1H); MS m/z 358 (M++1-Boc).
Reaction SMILES: [OH:1][C:2]1[C:11]2[O:10][CH2:9][CH:8]([O:12][N+:13]([O-:15])=[O:14])[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[S:16]([NH:20][C@H:21]([C:29](O)=[O:30])[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([CH3:19])(=[O:18])=[O:17].C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl.CN(C)C1C=CN=CC=1>[S:16]([NH:20][C@H:21]([C:29]([O:1][C:2]1[C:11]2[O:10][CH2:9][C@H:8]([O:12][N+:13]([O-:15])=[O:14])[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1)=[O:30])[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([CH3:19])(=[O:17])=[O:18]
Reactant: CS(=O)(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reactant: O=[N+]([O-])OC1COc2c(O)cccc2C1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=O)N[C@@H](Cc1ccccc1)C(=O)Oc1cccc2c1OC[C@H](O[N+](=O)[O-])C2
Temperature: 25 °C
Yield: 19.5 %

Procedure:
31.8 g of 3,4-dihydro-8-hydroxy-3-nitroxy-2H-1-benzopyran was dissolved in 500 ml of methylene chloride, and 36.6 g of N-mesyl-L-phenylalanine and 3.7 g of 4-dimethylaminopyridine were added. With stirring at room temperature, a solution of 40 g of dicyclohexylcarbodiimide in 130 ml of methylene chloride was added, and the mixture was stirred overnight at room temperature. The precipitate was removed from the reaction mixture by filtration. The filtrate was concentrated, and the residue was dissolved in ethyl acetate and washed successively with 5% hydrochloric acid, a 5% aqueous solution of sodium hydroxide and water. The solvent was then evaporated. The residue was dissolved in tetrahydrofuran. The insoluble materials were removed by filtration. Hexane was added, and the solution was left to stand. The precipitated crystals were collected by filtration, and recrystallized from acetone to give 12.8 g (yield 19.4%) of the desired product as colorless prisms having a melting point of 191° to 195° C. (decomp.).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][Br:13].[C:15]1([P:21]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[I-].[Na+]>C(#N)C>[Br-:13].[CH3:1][O:2][C:3]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][P+:21]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:14]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: COC(=O)CCCCCCCCCBr
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: COC(=O)CCCCCCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Product: [Br-]

Procedure:
A mixture of methyl-10bromodecanoate (5.22 g), triphenylphosphine (7.74 g) and sodium iodide (0.3 g) in acetonitrile (50 ml) was refluxed for 24 hours.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([CH3:9])[CH:3]=1.ClC1C=CC=C(C(OO)=[O:18])C=1>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[N+:5]([O-:18])=[C:4]([CH3:9])[CH:3]=1
Reactant: Cc1cc(Br)cc(C)n1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cc1cc(Br)cc(C)[n+]1[O-]
Temperature: 0 °C
Reaction time: 5 h

Procedure:
4-Bromo-2,6-dimethylpyridine (0.5 g, 2.69 mmol) was dissolved in DCM (10 ml), cooled to 0° C. and combined with a solution of m-chloroperbenzoic acid in DCM (75%, 0.928 g, 4.03 mmol in 5 ml). The resulting mixture was stirred at 0° C. for 15 minutes and for 5 hours at room temperature. The mixture was washed with saturated sodium bicarbonate solution, the phases were separated with a phase separator, the organic phase was evaporated under reduced pressure. The residue was purified by column chromatography (silica, gradient of 0.5 to 10% methanol in DCM). 475 of a yellow solid was obtained (2.35 mmol, 88%). MS (ESI) m/z=204.0 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@:8]([C@@H:16]2[CH2:21][CH2:20][CH2:19][N:18]([C:22]([NH:24][C@@H:25]([CH2:28][CH:29]3[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]3)[CH2:26][OH:27])=[O:23])[CH2:17]2)([OH:15])[CH2:9][CH2:10][CH2:11][CH2:12][O:13][CH3:14])[CH:5]=[CH:6][CH:7]=1.[Si:35](OC[C@@H](NC(=O)OC1C=CC([N+]([O-])=O)=CC=1)CC1CCCCC1)([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36].ClC1C=C([C@]([C@@H]2CCCNC2)(O)CCCCOC)C=CC=1>>[Si:35]([O:27][CH2:26][C@@H:25]([NH:24][C:22]([N:18]1[CH2:19][CH2:20][CH2:21][C@@H:16]([C@@:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)([OH:15])[CH2:9][CH2:10][CH2:11][CH2:12][O:13][CH3:14])[CH2:17]1)=[O:23])[CH2:28][CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1)([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36]
Reactant: CC(C)(C)[Si](C)(C)OC[C@H](CC1CCCCC1)NC(=O)Oc1ccc([N+](=O)[O-])cc1
Reactant: COCCCC[C@@](O)(c1cccc(Cl)c1)[C@@H]1CCCN(C(=O)N[C@H](CO)CC2CCCCC2)C1
Agent: COCCCC[C@@](O)(c1cccc(Cl)c1)[C@@H]1CCCNC1
Product: COCCCC[C@@](O)(c1cccc(Cl)c1)[C@@H]1CCCN(C(=O)N[C@H](CO[Si](C)(C)C(C)(C)C)CC2CCCCC2)C1

Procedure:
(3R)-3-((S)-1-(3-chlorophenyl)-1-hydroxy-5-methoxypentyl)-N—((S)-3-cyclohexyl-1-hydroxypropan-2-yl)piperidine-1-carboxamide (I-158A) was prepared by applying analogous procedures to those described in Example 32 Step 1 to (S)-4-nitrophenyl 1-(tert-butyldimethylsilyloxy)-3-cyclohexylpropan-2-ylcarbamate and (S)-1-(3-chlorophenyl)-5-methoxy-1-((R)-piperidin-3-yl)pentan-1-ol to afford (R)—N—((S)-1-(tert-butyldimethylsilyloxy)-3-cyclohexylpropan-2-yl)-3-((S)-1-(3-chlorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide followed by removal of the t-butyldimethylsilyl group with aqueous acid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Br:14])=[N:4][C:5]([CH3:13])=[C:6]([CH:12]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8].[CH3:15][CH2:16][C:17](=O)[CH2:18][CH3:19].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].FC(F)(F)C(O)=O>C(OCC)(=O)C>[Br:14][C:3]1[C:2]([NH:1][CH:17]([CH2:18][CH3:19])[CH2:16][CH3:15])=[CH:12][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:5]([CH3:13])[N:4]=1
Reactant: CCC(=O)CC
Reactant: CCOC(=O)c1cc(N)c(Br)nc1C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc(NC(CC)CC)c(Br)nc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.5 %

Procedure:
To a solution of ethyl 5-amino-6-bromo-2-methylnicotinate (1.267 g, 4.89 mmol) in ethyl acetate (30 ml) were added 3-pentanone (0.463 g, 5.38 mmol), sodium triacetoxyborohydride (1.244 g, 5.868 mmol) and trifluoroacetic acid (1.15 g, 9.78 mmol) at room temperature. After stirring overnight at room temperature, another portion of sodium triacetoxyborohydride (0.6 g, 2.83 mmol) was added. The reaction mixture was stirred for another 6 hours. The reaction mixture was quenched with water (20 ml). The organic layer was washed with saturated sodium bicarbonate and brine. After evaporation of solvent, ethyl 6-bromo-2-methyl-5-(pentan-3-ylamino)nicotinate (1.20 g, 74.6% yield) was purified by column chromatography with 7% ethyl acetate/Hexane as eluent. 1H NMR (400 MHz, CDCl3): 7.35 (s, 1H), 4.40 (q, J=6.8 Hz, 2H), 4.10 (br, s, 1H), 3.30 (m, 1H), 2.68 (s, 3H), 1.8-1.5 (m, 4H), 1.42 (t, J=6.8 Hz, 3H), 1.0 (t, J=7.2 Hz, 6H). MS (EI) for C14H21BrN2O2: 329.1 (MH+).