Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]2[O:8][C:9]3[C:10](=[C:12]([C:16]([OH:18])=O)[CH:13]=[CH:14][CH:15]=3)[N:11]=2)=[CH:4][CH:3]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.Cl.Cl.[NH2:43][CH:44]1[CH2:51][CH:50]2[N:52]([CH3:53])[CH:46]([CH2:47][CH2:48][CH2:49]2)[CH2:45]1.C(N(CC)CC)C>CN(C=O)C.ClCCl>[CH3:53][N:52]1[CH:46]2[CH2:47][CH2:48][CH2:49][CH:50]1[CH2:51][CH:44]([NH:43][C:16]([C:12]1[CH:13]=[CH:14][CH:15]=[C:9]3[O:8][C:7]([C:5]4[S:6][C:2]([Cl:1])=[CH:3][CH:4]=4)=[N:11][C:10]=13)=[O:18])[CH2:45]2
Reactant: O=C(O)c1cccc2oc(-c3ccc(Cl)s3)nc12
Reactant: CN1C2CCCC1CC(N)C2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CN1C2CCCC1CC(NC(=O)c1cccc3oc(-c4ccc(Cl)s4)nc13)C2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 11.7 %

Procedure:
A mixture of 2-(5-chlorothiophen-2-yl)benzoxazole-4-carboxylic acid (110 mg, 0.39 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (149 mg, 0.78 mmol), 1-hydroxybenzotriazole (106 mg, 0.78 mmol) and 3-amino-9-methyl-9-azabicyclo[3.3.1]nonane dihydrochloride (111 mg, 0.48 mmol) in DMF (5 mL) was stirred at room temperature for 10 min, then triethylamine (0.22 mL, 1.56 mmol) was added. The resulting reaction mixture was stirred at room temperature overnight. The mixture was diluted with dichloromethane and then washed with a saturated solution of sodium bicarbonate. The aqueous layer was further extracted with dichloromethane (2×50 mL). The combined organic layers were washed with water (2×50 mL), brine (2×50 mL), dried (Na2SO4), filtered and concentrated. The crude material was purified by column chromatography (silica gel, 90:9:1 dichloromethane/methanol/concentrated ammonium hydroxide) and recrystallization from acetonitrile to afford N-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-2-(5-chlorothiophene-2-yl)benzoxazole-4-carboxamide (19 mg, 12%) as a light brown solid: 1H NMR (500 MHz, CDCl3) δ 8.85 (d, J=6.3 Hz, 1H), 8.20 (dd, J=7.8, 1.0 Hz, 1H), 7.73 (d, J=4.0 Hz, 1H), 7.65 (dd, J=8.1, 1.0 Hz, 1H), 7.45 (t, J=7.9 Hz, 1H), 7.06 (d, J=4.1 Hz, 1H), 4.60-4.54 (m, 1H), 3.20-3.10 (m, 2H), 2.67-2.58 (m, 2H), 2.56 (s, 3H), 2.20-2.00 (m, 3H), 1.60-1.45 (m, 3H), 1.25-1.15 (m, 2H); MS (ESI+) m/z 416 (M+H); HPLC>99% (AUC), tR=13.02 min.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11]([CH:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[O:12])=[CH:8][C:9]=1[NH2:10])=[O:4].CO[CH:21]([N:24]([CH3:26])[CH3:25])OC>>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11]([CH:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[O:12])=[CH:8][C:9]=1[N:10]=[CH:21][N:24]([CH3:26])[CH3:25])=[O:4]
Reactant: COC(OC)N(C)C
Reactant: COC(=O)c1sc(C(=O)C2CCOCC2)cc1N
Product: COC(=O)c1sc(C(=O)C2CCOCC2)cc1N=CN(C)C

Procedure:
3-Amino-5-(tetrahydropyran-4-carbonyl)thiophene-2-carboxylic acid methyl ester and dimethoxymethyldimethylamine were reacted by method B. The product with the molecular weight of 324.40 (C15H20N2O4S) was obtained in this way; MS (ESI): 325 (M+H+).
Reaction SMILES: [C:1]1([NH2:8])C=CC=C[C:2]=1[NH2:7].[CH:9]1([C:15](O)=O)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.[OH-].[Na+]>>[CH:9]1([C:15]2[NH:7][CH:2]=[CH:1][N:8]=2)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: Nc1ccccc1N
Reactant: O=C(O)C1CCCCC1
Agent: [Na+]
Agent: [OH-]
Product: c1c[nH]c(C2CCCCC2)n1
Temperature: 140 °C
Reaction time: 8 h
Yield: 91.5 %

Procedure:
A mixture of 7 g of o-phenylenediamine and 12.5 g of cyclohexanecarboxylic acid was melted by heating at 130-150° C. and stirred for 8 hours. The solid after reaction was transferred into 130 g of 1 wt % sodium hydroxide aqueous solution to form a suspension, which was filtered and washed with hot water. The crude crystals thus obtained were recrystallized from methanol/water, filtered, and dried, obtaining 8.9 g of 2-cyclohexylimidazole (yield 69%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]3[N:11]=[C:12]([NH2:23])[N:13]=[C:14]([N:17]4[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]4)[C:15]=3[N:16]=2)=[CH:4][CH:3]=1.N1C=CC=CC=1.[Cl:30][C:31]1[CH:41]=[CH:40][C:34]([O:35][CH2:36][C:37](Cl)=[O:38])=[CH:33][CH:32]=1>CN(C=O)C>[NH2:23][C:12]1[N:13]=[C:14]([N:17]2[CH2:18][CH2:19][N:20]([C:37](=[O:38])[CH2:36][O:35][C:34]3[CH:40]=[CH:41][C:31]([Cl:30])=[CH:32][CH:33]=3)[CH2:21][CH2:22]2)[C:15]2[N:16]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[S:9][C:10]=2[N:11]=1
Reactant: Nc1nc(N2CCNCC2)c2nc(-c3ccc(F)cc3)sc2n1
Reactant: O=C(Cl)COc1ccc(Cl)cc1
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: Nc1nc(N2CCN(C(=O)COc3ccc(Cl)cc3)CC2)c2nc(-c3ccc(F)cc3)sc2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 53.4 %

Procedure:
To a solution of 2-(4-fluorophenyl)-7-(piperazin-1-yl)thiazolo[5,4-d]pyrimidin-5-amine (40 mg, 0.12 mmol) and pyridine (15 μl, 0.18 mmol) in DMF (1 ml) was added 4-chlorophenoxyacetyl chloride (27 mg, 0.13 mmol). The reaction mixture was stirred for 2 hours at room temperature. The reaction mixture was quenched with water, extracted with EtOAc, brine and was dried over Na2SO4. After removing the solvents, the crude residue was purified by flash chromatography on silica (CH2Cl2/MeOH 100:1) to yield the title compound as a white solid (32 mg, 53%).
Reaction SMILES: Cl.C(N=C=NCCCN(C)C)C.[CH2:13]([O:15][P:16]([CH2:21][C:22]([OH:24])=O)([O:18][CH2:19][CH3:20])=[O:17])[CH3:14].[NH2:25][CH:26]([C:30]1[CH:59]=[CH:58][C:33]([O:34][CH2:35][CH2:36][O:37][CH2:38][CH2:39][O:40][CH2:41][CH2:42][N:43]([C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])=[CH:32][CH:31]=1)[CH2:27][CH2:28][CH3:29].C(OCC)(=O)C>CN(C)C1C=CN=CC=1.CN(C)C=O>[CH2:19]([O:18][P:16]([CH2:21][C:22]([NH:25][CH:26]([C:30]1[CH:31]=[CH:32][C:33]([O:34][CH2:35][CH2:36][O:37][CH2:38][CH2:39][O:40][CH2:41][CH2:42][N:43]([C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[C:44]([O:46][C:47]([CH3:48])([CH3:49])[CH3:50])=[O:45])=[CH:58][CH:59]=1)[CH2:27][CH2:28][CH3:29])=[O:24])([O:15][CH2:13][CH3:14])=[O:17])[CH3:20]
Reactant: CCCC(N)c1ccc(OCCOCCOCCN(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc1
Reactant: CCOP(=O)(CC(=O)O)OCC
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCC(NC(=O)CP(=O)(OCC)OCC)c1ccc(OCCOCCOCCN(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.4 %

Procedure:
A mixture of 4-dimethylaminopyridine (DMAP; 197 mg, 1.61 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC.HCl; 309 mg, 1.61 mmol) was added to a stirred solution of diethylphosphonoacetic acid (129 μL, 0.805 mmol) and (2-(2-(2-(4-(1-aminobutyl)phenoxy)ethoxy)ethoxy)ethyl)imidodicarbonic acid, 1,3-bis-tert-butyl ester (45; 400 mg, 0.805 mmol) in N,N-dimethylformamide (10 mL). The resulting mixture was stirred under nitrogen for 3 hours at room temperature, and then poured into 100 mL of ethyl acetate. This solution was washed with 1N aqueous HCl (2×) and sat. brine, dried over sodium sulfate, and concentrated to an oil. Purification by flash silica gel column chromatography, eluting with ethyl acetate, afforded 49 (540 mg, quantitative) as a clear oil: MS (ES+) m/z 675.3 (M+H)+.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[C:12]2[O:11][C:10]([CH3:14])([CH3:13])[CH2:9][C:8]=2[C:7]([C:15]2[C:16]([CH3:28])([CH3:27])[C:17](=[O:26])[N:18]([CH:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[N:19]=2)=[CH:6][CH:5]=1.[CH3:29][O:30][C:31]1[CH:39]=[CH:38][CH:37]=[CH:36][C:32]=1[C:33](Cl)=[O:34]>>[CH3:2][O:3][C:4]1[C:12]2[O:11][C:10]([CH3:14])([CH3:13])[CH2:9][C:8]=2[C:7]([C:15]2[C:16]([CH3:28])([CH3:27])[C:17](=[O:26])[N:18]([CH:20]3[CH2:25][CH2:24][N:23]([C:33]([C:32]4[CH:36]=[CH:37][CH:38]=[CH:39][C:31]=4[O:30][CH3:29])=[O:34])[CH2:22][CH2:21]3)[N:19]=2)=[CH:6][CH:5]=1
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)c2c1OC(C)(C)C2
Reactant: COc1ccccc1C(=O)Cl
Agent: Cl
Product: COc1ccccc1C(=O)N1CCC(N2N=C(c3ccc(OC)c4c3CC(C)(C)O4)C(C)(C)C2=O)CC1

Procedure:
The title compound is prepared analogously as described for GP1 using 5-(7-methoxy-2,2-dimethyl-2,3-dihydro-1-benzofuran-4-yl)-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one hydrochloride (compound B5*HCl) and 2-methoxybenzoyl chloride as starting compounds. The crude product is purified by crystallization from EA and diethyl ether to yield the title compound.
Reaction SMILES: P(N)([O-])[O-].[CH2:5]=[CH:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH3:11][C@:12]12[CH2:29][CH2:28][C@H:27]3[C@@H:17]([CH2:18][CH2:19][C:20]4[C@:25]3([CH3:26])[CH:24]=[CH:23][C:22](=[O:30])[CH:21]=4)[C@@H:16]1[CH2:15][CH2:14][C:13]2=[O:31].C[Si](Cl)(C)C>CCOCC.C(Cl)Cl.[Cu].C1C=CC=CC=1>[CH2:5]([C@@H:24]1[C@@:25]2([CH3:26])[C:20]([CH2:19][CH2:18][C@@H:17]3[C@@H:27]2[CH2:28][CH2:29][C@@:12]2([CH3:11])[C@H:16]3[CH2:15][CH2:14][C:13]2=[O:31])=[CH:21][C:22](=[O:30])[CH2:23]1)[CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: C[C@]12C=CC(=O)C=C1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reactant: C=CCCCC
Agent: [Cu]
Agent: C[Si](C)(C)Cl
Agent: NP([O-])[O-]
Solvent: c1ccccc1
Solvent: CCOCC
Solvent: ClCCl
Product: CCCCCC[C@H]1CC(=O)C=C2CC[C@@H]3[C@H](CC[C@]4(C)C(=O)CC[C@@H]34)[C@]21C
Temperature: 25 °C
Reaction time: 1 h
Yield: 16 %

Procedure:
(C6H6) (10.1 mg, 0.02 mmol, 0.05 eq.) and the phosphoramidite ligand (21.6 mg, 0.040 mmol, 0.10 eq.) were dissolved in Et2O (2.0 mL) under an argon atmosphere and allowed to stir for 1 h at room temperature. In another flask, Cp2ZrHCl (206.0 mg, 0.80 mmol, 2.0 eq.) was added to a stirred, room temperature, solution of 1-hexene (0.13 mL, 1.0 mmol, 2.5 eq.) in CH2Cl2 (0.40 mL) under an argon atmosphere. After stirring for 40 min, the resulting clear yellow solution was transferred via syringe over about 1 min to the stirred solution containing the copper and ligand under an argon atmosphere. The resulting dark mixture was allowed to stir for an additional 10 min before 1,4-androstadiene-3,17-dione (114.0 mg, 0.40 mmol, 1.0 eq.) and TMSCl (0.26 mL, 2.00 mmol, 5.0 eq.) were added sequentially dropwise via syringe. Stirring at room temperature was continued arbitrarily for 15 h before the reaction was quenched by the addition of Et2O (ca 3 mL) and NH4Cl (1 M aq., ca 1.5 mL). The mixture was partitioned between the aqueous and Et2O layers and the former phase was extracted with Et2O (3×10 mL). The combined organic phase was washed with NaHCO3 (sat. aq., ca 10 mL), dried (Na2SO4), filtered and concentrated in vacuo to give an oil. Flash column chromatography of the yellow residue (5:30:65 EtOAc/DCM/petrol; SiO2) gave major diastereomer (1) (+)-1α-hexyl-4-androstene-3,17-dione (75 mg, 0.20 mmol, 50%) and minor diastereomer (1a) (+)-1α-hexyl-4-androstene-3,17-dione (24 mg, 0.064 mmol, 16%). Diastereomeric ratio (3.6:1) was determined by integration of 1H NMR spectra.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.BrBr.[S-:10][C:11]#[N:12].[Na+]>>[OH:7][C:1]1[CH:6]=[CH:5][C:4]([S:10][C:11]#[N:12])=[CH:3][CH:2]=1
Reactant: Oc1ccccc1
Reactant: N#C[S-]
Agent: BrBr
Agent: [Na+]
Product: N#CSc1ccc(O)cc1

Procedure:
The title compound was prepared according to the method of Example 32 from phenol (0.35 mole), bromine (0.35 mole) and sodium thiocyanate (0.35 mole).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([S:9]([CH2:12][NH:13][CH2:14][CH2:15][NH:16][C:17](=[O:28])[CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][CH:21]=2)(=[O:11])=[O:10])=[C:4]([CH3:29])[CH:3]=1.[S].[CH2:31](N)[CH2:32][NH2:33]>>[Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([S:9]([CH2:12][NH:13][CH2:14][CH2:15][NH:16][C:17](=[O:28])[CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]3[NH:33][CH2:32][CH2:31][N:27]=3)=[CH:22][CH:21]=2)(=[O:10])=[O:11])=[C:4]([CH3:29])[CH:3]=1
Reactant: NCCN
Reactant: Cc1cc(S(=O)(=O)CNCCNC(=O)CCc2ccc(C#N)cc2)c(C)cc1Cl
Agent: [S]
Product: Cc1cc(S(=O)(=O)CNCCNC(=O)CCc2ccc(C3=NCCN3)cc2)c(C)cc1Cl

Procedure:
Analogously to 13b), N-{2-[(4-chloro-2,5-dimethylbenzenesulphonyl)methylamino]ethyl}-3-[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]propionamide was prepared from 1.15 g (2.65 mmol) of N-{2-[(4-chloro-2,5-dimethylbenzenesulphonyl)methylamino]ethyl}-3-(4-cyanophenyl)propionamide, 85 mg (2.65 mmol) of sulphur and 4 ml of ethylenediamine.
Reaction SMILES: [F:1][C:2]([S:5][C:6]1[CH:27]=[CH:26][CH:25]=[CH:24][C:7]=1[CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:20]=[C:19]([C:21]([NH2:23])=[O:22])[O:18][N:17]=2)=[CH:12][CH:11]=1)([F:4])[F:3].C1C=C(Cl)C=C(C(OO)=[O:36])C=1>C(Cl)Cl>[F:4][C:2]([F:1])([F:3])[S:5]([C:6]1[CH:27]=[CH:26][CH:25]=[CH:24][C:7]=1[CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:20]=[C:19]([C:21]([NH2:23])=[O:22])[O:18][N:17]=2)=[CH:12][CH:11]=1)=[O:36]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: NC(=O)c1cc(-c2ccc(OCc3ccccc3SC(F)(F)F)cc2)no1
Solvent: ClCCl
Product: NC(=O)c1cc(-c2ccc(OCc3ccccc3S(=O)C(F)(F)F)cc2)no1
Temperature: 0 °C
Reaction time: 1 h
Yield: 25.8 %

Procedure:
A suspension of 3-[4-(2-trifluoromethylsulfanyl-benzyloxy)-phenyl]-isoxazole-5-carboxylic acid amide (which may be prepared as described in Example 1; 60 mg, 0.153 mmol) in CH2Cl2 (8 mL) was cooled to 0° C. in an ice-water bath. MCPBA (130 mg, 5 equivalents) was added and the mixture was stirred at 0° C. for 1 h and then at room temperature overnight. The reaction mixture was washed with 10% aqueous Na2SO3 and saturated aqueous NaHCO3, dried (Na2SO4), filtered, evaporated and purified by chromatography (35-45% EtOAc/hexanes) to give 3-[4-(2-trifluoromethanesulfinyl-benzyloxy)-phenyl]-isoxazole-5-carboxylic acid amide (16.2 mg, 26%) as a white solid. HRMS Calcd. for C18H14F3N2O4S (M+H)+, 411.0621. Found: 411.0617.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:12])[NH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=1)#[CH:14]>>[F:21][C:17]1[CH:16]=[C:15]([C:13]#[C:14][C:2]2[CH:11]=[C:10]3[C:5]([C:6](=[O:12])[NH:7][CH:8]=[N:9]3)=[CH:4][CH:3]=2)[CH:20]=[CH:19][CH:18]=1
Reactant: C#Cc1cccc(F)c1
Reactant: O=c1[nH]cnc2cc(Br)ccc12
Product: O=c1[nH]cnc2cc(C#Cc3cccc(F)c3)ccc12

Procedure:
The title compound was prepared from 7-bromoquinazolin-4(3H)-one and 1-ethynyl-3-fluorobenzene according to the experimental procedure as described in Example 1.1. MS (ESI): 265 (MH+); 1H NMR (300 MHz, DMSO-d6) δ 12.37 (s, 1H), 8.14 (s, 2H), 7.83 (s, 1H), 7.68-7.64 (m, 1H), 7.53-7.49 (m, 3H), 7.36-7.33 (m, 1H). mGluR5 PAM EC50: +.
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[Cl:8].[C:9]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:14]=[CH:13][CH:12]=[C:11]([S:15](Cl)(=[O:17])=[O:16])[CH:10]=1>>[Cl:8][C:3]1[C:4]([CH3:7])=[N:5][O:6][C:2]=1[NH:1][S:15]([C:11]1[CH:10]=[C:9]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:14]=[CH:13][CH:12]=1)(=[O:17])=[O:16]
Reactant: Cc1noc(N)c1Cl
Reactant: O=S(=O)(Cl)c1cccc(-c2ccccc2)c1
Product: Cc1noc(NS(=O)(=O)c2cccc(-c3ccccc3)c2)c1Cl
Yield: 63 %

Procedure:
N-(4-chloro-3-methyl-5-isoxazolyl)-3-biphenylsulfonamide was prepared in the same manner as described in Example 12 from 5-amino-4-chloro-3-methylisoxazole and 3-biphenylsulfonyl chloride in 63% yield. This was purified by HPLC (5% CH3CN to 100% CH3CN over 30 min.) to give a solid, m.p. 84-86° C.
Reaction SMILES: [S:1]([N:11]1[CH2:18][CH2:17][CH2:16][C@@:12]1([OH:19])[C:13](O)=[O:14])([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].CC(C)=NNC(C1C=C(Cl)N=C(Cl)C=1)=O.B#B.Cl>C1COCC1.C(Cl)(Cl)Cl.O>[S:1]([N:11]1[CH2:18][CH2:17][CH2:16][C@@:12]1([OH:19])[CH2:13][OH:14])([C:4]1[CH:5]=[CH:6][C:7]([CH3:8])=[CH:9][CH:10]=1)(=[O:2])=[O:3]
Reactant: Cc1ccc(S(=O)(=O)N2CCC[C@@]2(O)C(=O)O)cc1
Agent: B#B
Agent: CC(C)=NNC(=O)c1cc(Cl)nc(Cl)c1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Solvent: ClC(Cl)Cl
Product: Cc1ccc(S(=O)(=O)N2CCC[C@@]2(O)CO)cc1
Temperature: 0 °C
Reaction time: 18 h
Yield: 91.6 %

Procedure:
A solution of 182.6 g (0.642 mole) N-tosylhydroxy-L-proline, made according to the procedure of P. S. Portoghese and A. A. Mikhail as reported in J. Org. Chem., 31, p 1059, 1966, in 800 ml dry THF was added over a 3 hour period to 1300 ml of 0.5 m diborane in tetrahydrofuran with stirring at 0°C. The reaction mixture solidified into a white opaque gel. This was broken up by hand, 800 ml of tetrahydrofuran was added, and the mixture was refluxed 2.5 hours with mechanical stirring. During this time, most of the solid redissolved. After 18 hours at ambient temperature, the reaction mixture was chilled, and 6N hydrochloric acid was carefully added until gas evolution ceased. One liter of water was added, and the homogeneous solution was diluted with chloroform until two phases formed. The aqueous phase was separated and extracted with additional chloroform. The combined organic phases were washed with water, dried with sodium sulfate, and evaporated in vacuo to leave a semi-solid residue (159.6 g) that gave 80.0 g (50.5%, melting point 130°-132° C), of N-tosylhydroxy-L-prolinol upon crystallization from ethyl acetate. Portoghese and Mikkail reported a melting point of 131°-133° C for the same compound made via the methyl ester of N-tosylhydroxy-L-lproline.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([C:12](=[O:28])[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)=[CH:15][CH:14]=1)=[C:7]([O:29][S:30]([C:33]([F:36])([F:35])[F:34])(=[O:32])=[O:31])[CH:6]=[CH:5]2.C(N(C(C)C)CC)(C)C.[CH3:46][S:47](Cl)(=[O:49])=[O:48].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH3:46][S:47]([O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([C:12](=[O:28])[C:13]1[CH:14]=[CH:15][C:16]([O:19][CH2:20][CH2:21][N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)=[CH:17][CH:18]=1)=[C:7]([O:29][S:30]([C:33]([F:35])([F:36])[F:34])(=[O:32])=[O:31])[CH:6]=[CH:5]2)(=[O:49])=[O:48]
Reactant: O=C(c1ccc(OCCN2CCCCC2)cc1)c1c(OS(=O)(=O)C(F)(F)F)ccc2cc(O)ccc12
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CS(=O)(=O)Oc1ccc2c(C(=O)c3ccc(OCCN4CCCCC4)cc3)c(OS(=O)(=O)C(F)(F)F)ccc2c1
Yield: 98.3 %

Procedure:
Suspend trifluoro-methanesulfonic acid 6-hydroxy-1-[4-(2-piperidin-1-yl-ethoxy)-benzoyl]-naphthalen-2-yl ester (12.5 g, 24 mmol) in dry methylene chloride (100 ml). Add diisopropylethylamine (8.3 mL, 48 mmol). Slowly add methanesulfonyl chloride (2.7 mL, 36 mmol). Pour the reaction into saturated aqueous sodium bicarbonate after 20 minutes and extract with methylene chloride. Wash the organic layer with water, dry with sodium sulfate, filter and concentrate in vacuo to yield 14.2 g (99%) of the title compound as an amber foam. 1H NMR (CDCl3) δ8.05 (d, J-=9.2 Hz, 1H), 7.90 (d, J=1.9 Hz, 1H), 7.76 (d, J=8.2 Hz, 2H), 7.75 (d, J=9.0 Hz, 1H), 7.59 (d, J=9.2 Hz, 1H), 7.43 (dd, J=9.2, 1.7 Hz, 1H), 6.94 (d, J=8.2 Hz, 2H), 4.17 (t, J=5.7 Hz, 2H), 3.23 (s, 3H), 2.79 (t, J=5.2 Hz, 2H), 2.5 (bs, 4H), 1.63-1.57 (m, 4H), 1.48-1.40 (m, 2H); LCMS mass spectrum (ion spray): m/z=602.3 (M+H).
Reaction SMILES: C([O:3][C:4]([CH:6]1[C:11](=[O:12])[CH2:10][CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7]1)=O)C.[BH4-].[Na+]>CO>[C:16]([O:15][C:13]([N:8]1[CH2:9][CH2:10][CH:11]([OH:12])[CH:6]([CH2:4][OH:3])[CH2:7]1)=[O:14])([CH3:19])([CH3:18])[CH3:17]
Reactant: CCOC(=O)C1CN(C(=O)OC(C)(C)C)CCC1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(O)C(CO)C1
Reaction time: 0.5 h

Procedure:
To a stirred solution of 4-oxo-piperidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-ethyl ester (51.59 mmol, 14 g) in methanol (300 mL) was added sodium borohydride (12 g) in 12 portions over 30 min. The reaction mixture was stirred for additional 30 min, and the volatiles were removed under reduced pressure. To the residue was added saturated ammonium chloride (300 mL). The mixture was extracted with ethyl acetate (300 mL), and the organic layer was dried and concentrated under reduced pressure. The residue was purified on a flash silica gel column eluting with ethyl acetate to provide 4-hydroxy-3-hydroxymethyl-piperidine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[O:10])(=[O:3])[CH3:2].[Cl-].[CH3:12][NH2+]C.C=O>>[C:1]([O:4][CH2:5][CH2:6][CH2:7][C:8](=[CH2:12])[CH:9]=[O:10])(=[O:3])[CH3:2]
Reactant: CC(=O)OCCCCC=O
Reactant: C[NH2+]C
Agent: C=O
Agent: [Cl-]
Product: C=C(C=O)CCCOC(C)=O

Procedure:
10 g (69.4 mmol) of 5-acetoxypentanal, 6.37 g (78.2 mmol) of dimethylammonium chloride and 6.1 ml (81.2 mmol) of 37% formaldehyde solution are refluxed for 11/2 hours (bath temperature ~110° C.) with stirring. The mixture is allowed to cool and is extracted three times with ether; the organic phases are combined, dried over MgSO4, filtered and concentrated by evaporation. 5-acetoxy-2-methylenepentanal is obtained in the form of a yellowish oil which can be reacted without further purification.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C@@H:3]([OH:32])[CH2:4][C@@H:5]([NH:19][C:20]([C@@H:22]([NH:27][C:28](=[O:31])[O:29][CH3:30])[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1.[O:40]=[C:41]1[N:45]([CH2:46][C:47]2[N:48]=[C:49]([C:52]3[CH:53]=[N:54][CH:55]=[CH:56][CH:57]=3)[S:50][CH:51]=2)[C:44](=[O:58])[CH2:43][N:42]1[C@@H:59]([C@@H:63]([CH3:66])[CH2:64][CH3:65])[C:60](O)=[O:61].CCOP(ON1N=NC2C=CC=CC=2C1=O)(OCC)=O.C(N(CC)C(C)C)(C)C>C1COCC1>[O:40]=[C:41]1[N:45]([CH2:46][C:47]2[N:48]=[C:49]([C:52]3[CH:53]=[N:54][CH:55]=[CH:56][CH:57]=3)[S:50][CH:51]=2)[C:44](=[O:58])[CH2:43][N:42]1[C@@H:59]([CH:63]([CH3:66])[CH2:64][CH3:65])[C:60]([NH:1][C@@H:2]([CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[C@@H:3]([OH:32])[CH2:4][C@@H:5]([NH:19][C:20]([C@@H:22]([NH:27][C:28](=[O:31])[O:29][CH3:30])[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1)=[O:61]
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@@H](N)Cc1ccccc1)C(C)(C)C
Reactant: CC[C@H](C)[C@@H](C(=O)O)N1CC(=O)N(Cc2csc(-c3cccnc3)n2)C1=O
Agent: CCOP(=O)(OCC)On1nnc2ccccc2c1=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCC(C)[C@@H](C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)C[C@H](Cc1ccc(-c2ccccn2)cc1)NC(=O)[C@@H](NC(=O)OC)C(C)(C)C)N1CC(=O)N(Cc2csc(-c3cccnc3)n2)C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
A solution containing the product from Example 2C (0.030 g, 0.056 mmol) in THF (0.5 mL) was treated with the product from Example 57C (0.036 g, 0.073 mmol), DEPBT (0.025 g, 0.085 mmol), and N,N-diisopropylethylamine (0.049 mL, 0.282 mmol), stirred at 25° C. for 1 hour, and partitioned between ethyl acetate and 10% Na2CO3 solution. The organic phase was washed with additional 10% Na2CO3 solution and brine, dried over MgSO4, filtered and concentrated. The residue was chromatographed on silica gel eluting with 0-100% ethyl acetate/dichloromethane, followed by elution with 0-5% methanol in ethyl acetate to give the title compound (0.044g, 86% yield). 1H NMR (300 MHz, DMSO-d6), δ ppm 0.67 (d, J=6.62 Hz, 3 H), 0.73 (t, J=7.35 Hz, 3 H), 0.90 (m, 12 H), 1.25 (m, 1 H), 1.52 (m, 2 H), 1.75 (m, 1 H), 2.69 (m, 3 H), 3.15 (m, 1 H), 3.50 (s, 3 H), 3.78 (m, 2 H), 4.16 (m, 3 H), 4.67 (d, J=6.62 Hz, 1 H), 4.78 (m, 2 H), 6.67 (d, J=9.93 Hz, 1 H), 6.96 (m, 3 H), 7.07 (m, 2 H), 7.22 (d, J=8.09 Hz, 2 H), 7.31 (m, 1 H), 7.51 (dd, J=7.91, 4.96 Hz, 1 H), 7.64 (s, 1 H), 7.86 (m, 6 H), 8.24 (m, 1 H), 8.64 (m, 2 H), 9.08 (d, J=1.84 Hz, 1 H).