Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(O)(=O)=O.[CH:6]1([NH:12][C:13]([CH:15]2[CH:23]3[C:18]4([CH:27]=[CH:26][CH:25]=[CH:24][C:19]4=[N:20][CH2:21][CH2:22]3)[S:17][CH2:16]2)=[O:14])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.C(Cl)(Cl)Cl.[CH2:32]([O:39][C:40](Cl)=[O:41])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C(N(CC)CC)C>[CH:6]1([NH:12][C:13]([CH:15]2[CH:23]3[C:18]4([CH:27]=[CH:26][CH:25]=[CH:24][C:19]4=[N:20][CH2:21][CH2:22]3)[S:17][CH:16]2[C:40]([O:39][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[O:41])=[O:14])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=C(NC1CCCCC1)C1CSC23C=CC=CC2=NCCC13
Agent: CS(=O)(=O)O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=C(OCc1ccccc1)C1SC23C=CC=CC2=NCCC3C1C(=O)NC1CCCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
30 g of N-cyclohexyl-1,2,3,4-tetrahydrobenzo[b]thieno[2,3-c]pyridine-3-carboxamide methanesulfonate was added to a solution of 300 ml of chloroform and 16.23 g of triethylamine and the resulting mixture was stirred at room temperature for 1 hour. Then 41.5 ml of benzyloxycarbonyl chloride was added thereto under ice-cooling and the resulting mixture was stirred at room temperature for 3 hours. The reaction mixture was washed with 20 ml of water thrice and dried over magnesium sulfate. The reaction mixture was distilled under reduced pressure and the residue was separated by silica gel column chromatography (solvent: chloroform). Thus 23.6 g of N-cyclohexyl-2-(benzyloxycarbonyl)-1,2,3,4-tetrahydrobenzo[b]thieno[2,3-c]pyridine-3-carboxamide (yield: 87%) was obtained. The NMR data of this product were as follows. It was confirmed that this product is N-cyclohexyl-2-(benzyloxycarbonyl)-1,2,3,4-tetrahydrobenzo[b]thieno[2,3-c]pyridine-3-carboxamide.
Reaction SMILES: C(OC([NH:8][CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:15]=2)[CH2:10]1)=O)(C)(C)C.[ClH:25].O1CCOCC1>C(O)(=O)C>[ClH:25].[NH2:8][CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:15]=2)[CH2:10]1
Reactant: CC(C)(C)OC(=O)NC1Cc2ccc(Oc3ccccc3)cc2C1
Agent: Cl
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: NC1Cc2ccc(Oc3ccccc3)cc2C1

Procedure:
Using 2-(tert-butoxycarbonylamino)-5-phenoxyindan (120 mg, 0.36 mmol), 4N hydrochloric acid-dioxane (1.7 ml) and acetic acid (5.1 ml), a similar procedure to Production Example 213 was carried out to obtain 2-amino-5-phenoxyindan hydrochloride (99 mg, 0.36 mmol) having the following physical properties:
Reaction SMILES: [C:1]1([CH3:21])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8](=[O:20])[NH:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:17]([OH:19])=O)=[CH:12][CH:11]=1.[CH2:22]([O:29][C:30](=[O:37])[C@H:31]([CH2:33][CH:34]([CH3:36])C)[NH2:32])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[CH:38]1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C.O.C(N(CC)CC)C>[CH2:22]([O:29][C:30](=[O:37])[C:31]([CH3:38])([NH:32][C:17](=[O:19])[CH2:16][C:13]1[CH:12]=[CH:11][C:10]([NH:9][C:8]([NH:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[CH3:21])=[O:20])=[CH:15][CH:14]=1)[CH2:33][CH2:34][CH3:36])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: Cc1ccccc1NC(=O)Nc1ccc(CC(=O)O)cc1
Reactant: On1nnc2ccccc21
Reactant: CC(C)C[C@H](N)C(=O)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCC(C)(NC(=O)Cc1ccc(NC(=O)Nc2ccccc2C)cc1)C(=O)OCc1ccccc1
Yield: 77.7 %

Procedure:
To a stirred solution of [4-(3-o-tolyl-ureido)-phenyl]-acetic acid (3.0 g), L-leucine benzyl ester (4.2 g), triethylamine (1.6 ml), and HOBT (1.6 g) in dry DMF (50 ml) at room temperature was added EDCI (2.4 g). After 16 h the mixture was poured into water (400 ml) and extracted with EtOAc (400 ml×2). The combined organics were washed with 5% citric acid (100 ml); saturated NaHCO3 (100 ml); water (100 ml), brine (100 ml); dried over MgSO4; filtered, and concentrated under reduced pressure to about 100 ml. The resulting suspension was filtered to give 4.0 g of the title compound as a white solid. MS [M+1]+488.2; 1H nmr (400 MHz, DMSO-d6) δ0.79 (d, J=6.4 Hz, 3H), 0.86 (d, J=6.4 Hz, 3H), 1.45-1.63 (m, 3H), 2.21 (s, 3H), 3.37 (s, 2H), 4.26-4.31 (m, 1H), 5.07 (s, 2H), 6.91 (t, 1H), 7.09-7.15 (m, 4H), 7.29-7.37 (m, 7H), 7.81 (d, 1H), 7.86 (s, 1H), 8.44 (d, 1H), 8.93 (s, 1H).
Reaction SMILES: [C:1]1([NH:7][C:8]2([C:22](=[O:24])[CH3:23])[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:25]([O:29][C:30](=[O:33])[CH2:31]C)(=[O:28])[CH2:26][CH3:27].[OH-:34].[NH4+]>>[C:30]([OH:29])(=[O:33])[C:31]([OH:24])=[O:34].[C:22]([C:8]1([N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:25](=[O:28])[CH2:26][CH3:27])[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:10][CH2:9]1)(=[O:24])[CH3:23]
Reactant: CCC(=O)OC(=O)CC
Reactant: CC(=O)C1(Nc2ccccc2)CCN(CCc2ccccc2)CC1
Reactant: [OH-]
Agent: [NH4+]
Product: CCC(=O)N(c1ccccc1)C1(C(C)=O)CCN(CCc2ccccc2)CC1
Product: O=C(O)C(=O)O
Temperature: 180 °C
Reaction time: 5 h

Procedure:
A mixture of 4.8 parts of 1-[4-(phenylamino)-1-(2-phenylethyl)-4-piperidinyl]ethanone and 15 parts of propanoic acid, anhydride is stirred for 5 hours at 180° C. (oil-bath). Stirring is continued overnight, while meantime the mixture is allowed to reach room temperature. The reaction mixture is poured onto ice-water and the whole is alkalized with a concentrated ammonium hydroxide solution. The product is extracted with benzene. The extract is washed twice with water, dried, filtered and evaporated in vacuo. The residue is dissolved in 1,1'-oxybisethane and the solution is stirred with activated charcoal. The latter is filtered off and the filtrate is evaporated. The residue is converted into the ethanedioate salt in 2-propanol. The salt is filtered off and crystallized from 2-propanol, yielding N-[4-acetyl-1-(2-phenylethyl)-4-piperidinyl]-N-phenylpropanamide ethanedioate; mp. 196.8° C.
Reaction SMILES: CC(C)([O-])C.[K+].[CH2:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8]1.[C:16]([O:20][CH2:21][CH2:22][CH2:23][CH3:24])(=[O:19])[CH:17]=[CH2:18]>>[CH2:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([CH2:18][CH2:17][C:16]([O:20][CH2:21][CH2:22][CH2:23][CH3:24])=[O:19])=[CH:8]1
Reactant: C1=Cc2ccccc2C1
Reactant: C=CC(=O)OCCCC
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: CCCCOC(=O)CCC1=CCc2ccccc21
Reaction time: 1 h

Procedure:
To a mixture of 4-5 g. of solid potassium t-butoxide in 464 g. (4.0 mole) of indene heated to 120° is added dropwise over 11/2 hours 256 g. (2.0 mole) of n-butyl acrylate at 100°-120°. After 1 hour longer at 120°-150°, the mixture is cooled, treated with 25 ml. acetic acid and filtered. Distillation affords 256 g. (57%) of product collected at 143°-160° (2 mm. torr.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[O:14][CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][C@H:9]2[CH2:22]OS(C)(=O)=O)=[CH:4][C:3]=1[F:28].[O:29]=[C:30]1[C:35]([C:36]([O:38][CH3:39])=[O:37])=[CH:34][CH:33]=[CH:32][NH:31]1>>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[O:14][CH2:13][CH2:12][NH:11][CH2:10][C@H:9]2[CH2:22][N:31]2[CH:32]=[CH:33][CH:34]=[C:35]([C:36]([O:38][CH3:39])=[O:37])[C:30]2=[O:29])=[CH:4][C:3]=1[F:28]
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(F)c2)[C@H](COS(C)(=O)=O)C1
Reactant: COC(=O)c1ccc[nH]c1=O
Product: COC(=O)c1cccn(C[C@@H]2CNCCO[C@H]2c2ccc(Cl)c(F)c2)c1=O
Product: Cl

Procedure:
Using tert-butyl (6S,7R)-7-(4-chloro-3-fluorophenyl)-6-{[(methylsulfonyl)oxy]methyl}-1,4-oxazepane-4-carboxylate and methyl 2-oxo-1,2-dihydropyridine-3-carboxylate, and by a method similar to that in Example 31, steps C and E, the title compound was obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]([O:10][CH3:11])=[O:9])[S:5][C:6]=1[CH3:7].[CH3:12][N:13]1[C:17](B2OC(C)(C)C(C)(C)O2)=[CH:16][CH:15]=[N:14]1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH3:7][C:6]1[S:5][C:4]([C:8]([O:10][CH3:11])=[O:9])=[CH:3][C:2]=1[C:17]1[N:13]([CH3:12])[N:14]=[CH:15][CH:16]=1
Reactant: COC(=O)c1cc(Br)c(C)s1
Reactant: Cn1nccc1B1OC(C)(C)C(C)(C)O1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1cc(-c2ccnn2C)c(C)s1
Temperature: 85 °C

Procedure:
To a 125 mL sealed flask was added methyl 4-bromo-5-methyl-2-thiophenecarboxylate (1.56 g, 6.64 mmol) [Prepared according to the procedure of Preparation 10], 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.67 g, 8.03 mmol) [prepared according to the procedure of Preparation 7], K2CO3 (2.76 g, 19.97 mmol) and Pd(PtBu3)2 (170 mg, 0.33 mmol) in 1,4-Dioxane (27 ml) and water (7 ml). The reaction mixture was heated to 85° C. in a sealed tube for 3 hours, cooled to room temperature and partitioned between H2O and CHCl3. The organic fraction was dried (Na2SO4), adsorbed onto silica and purified via column chromatography (0-15% EtOAc/Hexane). (385 mg, 1.4 mmol, 30%): LC-MS (ES) m/z=237 (M+H)+.
Reaction SMILES: [OH:1][N:2]1[C:6](=O)[CH2:5][CH2:4][C:3]1=O.C(N(CC)CC)C.[Br:16][C:17]([CH3:22])([CH3:21])[C:18](Br)=[O:19]>C(Cl)Cl>[N:2]1([O:1][C:18](=[O:19])[C:17]([Br:16])([CH3:22])[CH3:21])[CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: O=C1CCC(=O)N1O
Reactant: CC(C)(Br)C(=O)Br
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(Br)C(=O)ON1CCCC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 42.7 %

Procedure:
A solution of N-hydroxysuccinimide (NHS) (3.0 g, 26 mmol) in dry methylene chloride (300 mL) was stirred under an inert (argon or nitrogen) atmosphere. Triethylamine (7.3 mL, 52 mmol) was added, the mixture was cooled to 0° C., and 2-bromo-2-methylpropionyl bromide (3.9 mL, 31 mmol) was added dropwise over a period of 15 minutes. The mixture was stirred for 1 hour at 0° C., then warmed to room temperature and stirred overnight. Most of the solvent was removed by evaporation, and the remaining mixture was diluted with cold water (400 mL), and extracted with diethyl ether (3×30 mL), then washed with aqueous potassium carbonate (3×30 mL) and 1M HCl(aq) (3×30 mL). The organic layer was dried over anhydrous magnesium sulfate, then filtered and concentrated to give a brown solid. Crystallization from ethyl acetate gave the desired product as a white powder (2.62 g, 39%). 1H NMR (CDCl3) δ (ppm) 2.09 (s, 6H, CH3)2Br), 2.88 (s, 4H, HNHS); 13C NMR (CDCl3) δ (ppm) 25.7 (CNHS), 30.8 (C(CH3)2Br), 51.3 (C(CH3)2Br), 167.6 (C═O), 168.7 (CNHS═O).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C:8]1[CH:17]=[CH:16][C:11]([C:12]([O:14]C)=[O:13])=[CH:10][C:9]=1[C:18]([F:21])([F:20])[F:19].[OH-].[Li+]>C1COCC1.O>[CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C:8]1[CH:17]=[CH:16][C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]=1[C:18]([F:20])([F:19])[F:21]
Reactant: COC(=O)c1ccc(N2CCCCC2C)c(C(F)(F)F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC1CCCCN1c1ccc(C(=O)O)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a stirred solution of methyl 4-(2-methylpiperidin-1-yl)-3-(trifluoromethyl)benzoate (6.6 g, 21.9 mmol) in THF (50 mL) and water (5 mL) was added lithium hydroxide (1.84 g, 43.8 mmol). The resulting mixture was stirred at RT for 12 hours. Solvents were removed under vacuum and the resulting mass was diluted with water. The aqueous layer was washed with DCM (2×50 mL), and then acidified with a concentrated aqueous solution of HCl (pH=4). It was extracted with EtOAc (2×100 mL). The EtOAc layer was washed with brine and dried over sodium sulfate, affording the title compound as a white solid. 1H NMR (DMSO-d6, 400 MHz) δ 13.30 (bs, 1H), 8.17 (m, 2H), 7.69 (d, 1H), 3.08 (m, 1H), 2.88 (m, 1H), 2.50 (m, 1H), 1.90 (m, 2H), 1.75 (m, 2H), 1.45 (m, 1H), 1.41 (m, 1H), 0.77 (d, 3H). LC/MS (Method A): 288.1 (M+H)+. HPLC (Method B) Rt 3.71 min (Purity: 98.3%).
Reaction SMILES: [CH:1]1([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][CH2:16][C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)=[CH:11][CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[CH3:29][S:30](Cl)(=[O:32])=[O:31]>ClCCl>[CH:1]1([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([N:15]([CH2:16][C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[S:30]([CH3:29])(=[O:32])=[O:31])=[CH:11][CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CS(=O)(=O)Cl
Reactant: c1cncc(CNc2ccc(OCC3CCCCC3)cc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CS(=O)(=O)N(Cc1cccnc1)c1ccc(OCC2CCCCC2)cc1

Procedure:
A 3.5 g. portion of 3-(4-cyclohexylmethoxyphenylaminomethyl)pyridine was dissolved in 15 ml. of dichloromethane, and 2.76 g. of potassium carbonate and 1.55 ml. of methanesulfonyl chloride were added. The mixture was stirred with gentle heating for 20 hours, and was then extracted with aqueous sodium bicarbonate, dried over magnesium sulfate and evaporated under vacuum. The residue was dissolved in chloroform and chromatographed over silica gel, eluting with chloroform. The product-containing fractions were combined and evaporated, and the residue was triturated with diethyl ether, filtered and dried to obtain 2.33 g. of impure product, which was further washed with diethyl ether to obtain 1.88 g. of the desired product, m.p. 36°-140°.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]Br)=[CH:4][CH:3]=1.[CH3:16][O-:17].[Na+]>CO>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][O:17][CH3:16])=[CH:4][CH:3]=1
Reactant: C[O-]
Reactant: BrCCCCCCOc1ccc(Br)cc1
Agent: [Na+]
Solvent: CO
Product: COCCCCCCOc1ccc(Br)cc1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
A mixture of 1-bromo-4-(6-bromohexyloxy)benzene (6.0 g) and sodium methylate (28% in methanol) (10.3 ml) in methanol (30 ml) was stirred for 2 hours at 70° C. (bath temp.), and then the solvent was evaporated. The residue was neutralized by 1N-hydrochloric acid and extracted with ethyl acetate (100 ml), and washed with water and brine. The organic layer was dried over magnesium sulfate. Magnesium sulfate was filtered off, and the filtrate was evaporated under reduced pressure to give a crude product. The crude product was purified by silica gel chromatography (20:1-10:1 hexane-ethyl acetate) to give 1-bromo-4-(6-methoxyhexyloxy)benzene (15.61 g) as a colorless oil.
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[N:7][C:8]([O:20][CH:21]2[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]2)=[CH:9][C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([O:18][CH3:19])[CH:12]=1)[CH2:2][CH2:3][CH3:4].[CH:28]1(O)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[ClH:68]>C1COCC1.C(Cl)Cl.CCOCC>[ClH:68].[ClH:68].[CH2:1]([C:5]1[N:6]=[N:7][C:8]([O:20][CH:21]2[CH2:22][CH2:23][N:24]([CH3:27])[CH2:25][CH2:26]2)=[CH:9][C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)=[C:13]([O:18][CH3:19])[CH:12]=1)[CH2:2][CH2:3][CH3:4]
Reactant: OC1CCCCC1
Reactant: CCCCc1nnc(OC2CCN(C)CC2)cc1-c1ccc(O)c(OC)c1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: ClCCl
Product: CCCCc1nnc(OC2CCN(C)CC2)cc1-c1ccc(OC2CCCCC2)c(OC)c1

Procedure:
To a solution of 4-[3-butyl-6-(1-methyl-piperidin-4-yloxy)-pyridazin-4-yl]-2-methoxy-phenol (1.0 mmol, 371 mg) in dry THF (3.0 mL) was added cyclohexanol (3.0 mmol, 317 μL) and triphenylphosphine (3.0 mmol, 787 mg). While sonicating, diisopropyl azodicarboxylate (3.0 mmol, 591 μL) was added. And the mixture was sonicated for another 1 hour then condensed. The residue was purified by silica gel chromatography (DCM to DCM+10% MeOH) to afford a colorless sticky solid, which was dissolved in DCM (5.0 mL), 2N HCl in ether (5.0 mL) was added, condensed, triturated with hexanes to provide the title compound (332 mg). LCMS: m/z 455 [M+1]. 1H NMR (400 MHz, CD3OD): δ 7.09 (1H, d), 6.98-7.03 (2H, m), 6.90-6.93 (1H, m), 5.45 (1H, bs), 4.30-4.38 (1H, m), 3.85 (3H, s), 3.10-3.37 (4H, m), 2.90-2.96 (2H, m), 2.79 (3H, s), 2.10-2.35 (4H, m), 1.96-2.03 (2H, m), 1.80-1.87 (2H, m), 1.31-1.63 (8H, m), 1.20-1.29 (2H, m), 0.80 (3H, t).
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[C@@H:8]([OH:9])[C@H:7]([CH2:10][C:11]2[CH:16]=[C:15]([O:17][C@@:18]([CH3:25])(OC)[C:19]([F:22])([F:21])[F:20])[C:14]([N+:26]([O-:28])=[O:27])=[C:13]([F:29])[CH:12]=2)[CH2:6][S:5][CH2:4]1.C[C:31]([O-:33])=O.[Na+].[C:35]([C:39]1[CH:40]=[C:41]([CH:44]=[CH:45][CH:46]=1)[CH:42]=O)([CH3:38])([CH3:37])[CH3:36].[BH3-]C#N.[Na+]>CO.C(Cl)Cl.C(O)(=O)C>[C:35]([C:39]1[CH:40]=[C:41]([CH:44]=[CH:45][CH:46]=1)[CH2:42][NH:2][C@@H:3]1[C@@H:8]([OH:9])[C@H:7]([CH2:10][C:11]2[CH:16]=[C:15]([O:17][C@H:18]([CH2:25][O:33][CH3:31])[C:19]([F:22])([F:20])[F:21])[C:14]([N+:26]([O-:28])=[O:27])=[C:13]([F:29])[CH:12]=2)[CH2:6][S:5][CH2:4]1)([CH3:38])([CH3:36])[CH3:37]
Reactant: CO[C@](C)(Oc1cc(C[C@@H]2CSC[C@H](N)[C@H]2O)cc(F)c1[N+](=O)[O-])C(F)(F)F
Reactant: CC(C)(C)c1cccc(C=O)c1
Reactant: CC(=O)[O-]
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CO
Product: COC[C@@H](Oc1cc(C[C@@H]2CSC[C@H](NCc3cccc(C(C)(C)C)c3)[C@H]2O)cc(F)c1[N+](=O)[O-])C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of (3R,4S,5S)-3-amino-5-[3-fluoro-4-nitro-5-((R)-2,2,2-trifluoro-1-methoxy-methyl-ethoxy)-benzyl]-tetrahydro-thiopyran-4-ol hydrochloride (1.217 g, 2.52 mmol) in MeOH-CH2Cl2 1:2 (28 mL) was added NaOAc (0.517 g, 6.3 mmol), powdered molecular sieves (4A) and 3-tert-butyl-benzaldehyde (CAS registry 23039-28-3) (0.413 g, 2.55 mmol). The reaction mixture was stirred at 25° C. for 16 h, acetic acid (0.5 mL) was added followed by NaBH3CN (0.396 g, 6.3 mmol). The reaction mixture was stirred at room temperature for 3 h and was quenched by adding 2N aq. HCl solution. EtOAc was added and the solution was washed with 2N K2CO3 solution and with brine. The organic phase was dried over Na2SO4, filtered and evaporated. The title compound was obtained after purification by flash-chromatography on NH4OH deactivated silica gel (90 g, toluene-EtOAc 1:1) as a light yellow oil: TLC (toluene-ETA 85:15) Rf=0.52; HPLC RtA=2.178 min; ESIMS [M+H]+=575; 1H NMR (600 MHz, CDCl3): δ 7.33 (s, 1H), 7.28 (s, 1H), 7.26 (m, 2H), 7.18-7.08 (m, 2H), 5.7 (broad, 1H), 5.06 (d, 1H), 3.9-3.78 (m, 2H), 3.71-3.62 (m, 2H), 3.31 (s, 3H), 3.22 (d, 1H), 2.90 (m, 1H), 2.82 (d, 1H), 2.55 (m, 1H), 2.48 (s broad, 1H), 2.41 (m, 1H), 2.35-2.20 (m, 3H), 1.93 (m, 1H), 1.25 (s, 9H).
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][N:3]1[CH:12]([CH:25]([OH:37])[CH2:26][NH:27][S:28]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)(=[O:30])=[O:29])[CH:13]([NH:21][C:22]([CH3:24])=[O:23])[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O>ClCCl.CCOCC>[O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][N:3]1[CH:12]([C:25](=[O:37])[CH2:26][NH:27][S:28]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)(=[O:30])=[O:29])[CH:13]([NH:21][C:22]([CH3:24])=[O:23])[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15]
Reactant: CC(=O)NC(C(=O)OC(C)(C)C)C(C(O)CNS(=O)(=O)c1ccccc1)N1CCc2ccccc2C1=O
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: CCOCC
Solvent: ClCCl
Product: CC(=O)NC(C(=O)OC(C)(C)C)C(C(=O)CNS(=O)(=O)c1ccccc1)N1CCc2ccccc2C1=O
Yield: 50 %

Procedure:
To 3-(1,2,3,4-tetrahydro-1-oxo-isoquinoline-2-yl)-acetamino-5-benzenesulfonylamino-4-hydroxy-pentanoic acid, tert-butyl ester (0.9 g, 1.7 mMol) in 20 mL of dichloromethane was added 1.1.1-triacetoxy-1.1-dihydro-1.2-benziodoxol-3-(1H)-one (Dess Martin periodinane, 1.08 g, 2.5 mMol). After 2 hours at room temperature the reaction mixture was diluted with ether, filtered, washed with sodium hydrogen carbonate and water, dried over sodium sulfate, and concentrated under reduced pressure. Chromatography over silica (elution with dichloromethane/methanol 15:1) gave 3-(1,2,3,4-tetrahydro-1-oxo-isoquinoline-2-yl)-acetamino-5-benzenesulfonylamino-4-oxo-pentanoic acid, tert-butyl ester (0.45 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][NH:13][S:14]([CH3:17])(=[O:16])=[O:15])=[CH:7][CH:6]=1.Br[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][CH2:29][CH3:30])=[CH:23][CH:22]=1.C([O-])([O-])=O.[K+].[K+].Cl>CCOC(C)=O.C(#N)C>[CH3:1][O:2][C:3](=[O:18])[CH2:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:11][CH2:12][N:13]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][CH2:29][CH3:30])=[CH:23][CH:22]=2)[S:14]([CH3:17])(=[O:15])=[O:16])=[CH:9][CH:10]=1
Reactant: CCCCc1ccc(CBr)cc1
Reactant: COC(=O)Cc1ccc(CCNS(C)(=O)=O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCCCc1ccc(CN(CCc2ccc(CC(=O)OC)cc2)S(C)(=O)=O)cc1

Procedure:
A mixture of [4-[2-methanesulfonylamino-ethyl]-phenyl]-acetic acid methyl ester (38 mg, 0.14 mmol), 1-bromomethyl-4-butylbenzene (35 mg, 0.15 mmol), K2CO3 (25 mg, 0.182 mmol) and acetonitrile was heated at reflux for 1 h. Aqueous HCl (2 mL, 1N) and EtOAc (30 mL) were added to the reaction. The organic solution was dried with MgSO4, filtered, and concentrated in vacuo. The product was purified by flash chromatography (30% EtOAc/hexanes) to afford the title compound of Step A. 1H NMR (400 MHz, CDCl3) δ 7.28–7.05 (m, 8H), 4.37 (s, 2H), 3.65 (s, 3H), 3.58 (s, 2H), 3.26 (t, 2H), 2.77 (t, 2H), 2.69 (s, 3H), 2.60 (t, 2H), 1.59 (m, 2H), 1.37 (m, 2H), 0.94 (t, 3H).
Reaction SMILES: Cl[C:2](=[N:8][OH:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4].CO[C:12]([C:14]1[CH:19]=[CH:18][C:17]([C:20]([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=3)=[CH:27][N:26]=2)([CH3:24])[CH:21]([CH3:23])[CH3:22])=[CH:16][CH:15]=1)=[CH2:13].C(N(CC)CC)C.C(O)(C(F)(F)F)=O>C1COCC1>[CH3:24][C:20]([C:17]1[CH:16]=[CH:15][C:14]([C:12]2[O:9][N:8]=[C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH:13]=2)=[CH:19][CH:18]=1)([C:25]1[CH:30]=[CH:29][C:28]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=2)=[CH:27][N:26]=1)[CH:21]([CH3:23])[CH3:22]
Reactant: C=C(OC)c1ccc(C(C)(c2ccc(OCc3ccccn3)cn2)C(C)C)cc1
Reactant: CCOC(=O)C(Cl)=NO
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cc(-c2ccc(C(C)(c3ccc(OCc4ccccn4)cn3)C(C)C)cc2)on1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
Ethyl 2-chloro-2-(hydroxyimino)acetate (3.15 g, 20.7 mmol) was added to a stirred solution of 1b (crude product from Step B; 6.91 mmol) and triethylamine (9.60 mL, 69.1 mmol) in THF (100 mL) at rt. After approximately 1 h, the reaction mixture was acidified to pH ˜1 by the addition of TFA, and the resulting mixture was heated to 50° C. After 1 h, the reaction mixture was concentrated in vacuo, the residue redissolved in TFA (30 mL) and the resulting solution was heated to 50° C. for an additional 1 h. After evaporation of the volatiles in vacuo, the crude residue was dissolved in EtOAc and carefully neutralized by the addition of saturated aqueous sodium bicarbonate. The organic layer was separated, dried (sodium sulfate), concentrated in vacuo, and the resulting crude residue was purified by flash chromatography on silica gel (gradient elution; 0%-100% EtOAc/hexanes as eluent) to afford the title compound 1c. m/z (ES) 472 (MH)+. 1HNMR (500 MHz, CDCl3): δ 8.61 (d, 1H, J=3.5 Hz), 8.40 (d, 1H, J=2.2 Hz), 7.77 (m, 1H), 7.70 (d, 2H, J=8.5 Hz), 7.55 (d, 1H, J=7.7 Hz), 7.49 (d, 2H, J=8.4 Hz), 7.20 (m, 3H), 6.87 (s, 1H), 5.24 (s, 2H), 4.48 (q, 211, J=7.1 Hz), 3.11 (m, 1H, J=6.6 Hz), 1.70 (s, 3H), 1.46 (t, 311, J=7.1 Hz), 0.87 (d, 3H, J=6.7 Hz), 0.80 (d, 3H, J=6.9 Hz).