Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:18]([F:19])=[C:17]2[C:9]([C:10]3[CH:11]=[CH:12][C:13](B(O)O)=[C:14]([F:20])[C:15]=3[CH2:16]2)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].C(O)C.C(=O)([O-])[O-].[Na+].[Na+].[CH2:33]([C:38]1[CH:43]=[CH:42][C:41](Br)=[CH:40][CH:39]=1)[CH2:34][CH2:35][CH2:36][CH3:37]>O.C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([O:5][C:6]1[CH:7]=[CH:8][C:9]2[C:10]3[C:15](=[C:14]([F:20])[C:13]([C:41]4[CH:40]=[CH:39][C:38]([CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[CH:43][CH:42]=4)=[CH:12][CH:11]=3)[CH2:16][C:17]=2[C:18]=1[F:19])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1ccc2c(c1F)Cc1c-2ccc(B(O)O)c1F
Reactant: CCCCCc1ccc(Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCCCCc1ccc(-c2ccc3c(c2F)Cc2c-3ccc(OCCCC)c2F)cc1

Procedure:
12 mmol of 7-butoxy-1,8-difluorofluorene-2-boronic acid (Example 6, 1st stage), 20 ml of ethanol, a solution of 24 mmol of sodium carbonate in 20 ml of water and 1 mol % of tetrakis(triphenylphosphine)palladium(0) are added to a solution of 12 mmol of 4-n-pentylbromobenzene in 40 ml of toluene. The mixture is heated to boiling until the reaction is complete. After cooling, the mixture is admixed with 100 ml of water, the phases are separated and the aqueous phase is extracted with toluene. The combined organic phases are washed with saturated NaCI solution and dried over sodium sulfate, and the solvents are removed under reduced pressure. The crude product is chromatographed on silica gel (2:5 dichloromethane/heptane) and recrystallized from heptane. 2-Butoxy-1,8-difluoro-7-(4-n-pentylphenyl)fluorene is obtained.
Reaction SMILES: [CH:1]1([CH:6]2[CH2:15][CH2:14][C:13]3[C:8]4=[C:9]([C:16]([C:18](O)=[O:19])=[CH:17][N:7]24)[CH:10]=[CH:11][CH:12]=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C([Cl:24])=O.[CH2:27]([N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)[CH3:28]>ClCCl>[ClH:24].[CH:1]1([CH:6]2[CH2:15][CH2:14][C:13]3[C:8]4=[C:9]([C:16]([C:18]([N:32]5[CH2:33][CH2:34][N:29]([CH2:27][CH3:28])[CH2:30][CH2:31]5)=[O:19])=[CH:17][N:7]24)[CH:10]=[CH:11][CH:12]=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1cn2c3c(cccc13)CCC2C1CCCC1
Reactant: CCN1CCNCC1
Solvent: ClCCl
Product: CCN1CCN(C(=O)c2cn3c4c(cccc24)CCC3C2CCCC2)CC1
Product: Cl
Reaction time: 1 h
Yield: 85.8 %

Procedure:
To a solution of 4-cyclopentyl-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline-1-carboxylic acid (342 mg, 1.27 mmol) in dichloromethane (20 ml) was added oxalyl chloride (218 μL, 3.18 mmol) and the reaction mixture stirred for 1 h. A further portion of oxalyl chloride (436 μL, 6.36 mmol) was then added and the reaction stirred overnight. Solvent and excess reagents were then removed in vacuo to leave a green solid. The green solid was dissolved in dichloromethane (20 ml) and N-ethylpiperazine (323 μL, 2.54 mmol) was added dropwise. The resulting reaction mixture was stirred for 1 h and then poured into a separating funnel. The organic layer was washed with saturated potassium bicarbonate solution (20 ml) and brine (20 ml), dried (MgSO4) and the solvent removed in vacuo to leave a brown oil. The oil was purified by flash chromatography eluting with 0-5% (v/v) methanol in dichloromethane to give the title compound (400 mg, 1.09 mmol). 1H NMR (400 MHz, CD3OD) δH 1.31-1.43 (4H, m), 1.45-1.79 (6H, m), 1.87-1.96 (1H, m), 2.05-2.24 (2H, m), 2.30-2.37 (1H, m), 2.90 (1H, dt, J 16.6, 3.9), 3.03-3.20 (3H, m), 3.26 (2H, q, J 7.5), 3.45-3.65 (4H, m), 4.16-4.23 (1H, m), 4.57 (2H, d, J 14.7), 6.99 (1H, d, J 7.1), 7.12 (1H, t, J 8.0), 7.48 (1H, d, J 8.0), 7.76 (1H, s); EsIMS: m/z=366.3 [M+H]+, 252.1.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[C:11]([C:19]([F:22])([F:21])[F:20])=[CH:10][C:9]=1[NH2:23])([CH3:4])([CH3:3])[CH3:2].C([O:29][C:30](=O)[CH2:31][C:32](=[O:45])[C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([C:39]2[CH:40]=[N:41][CH:42]=[CH:43][CH:44]=2)[CH:34]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[C:11]([C:19]([F:21])([F:22])[F:20])=[CH:10][C:9]=1[NH:23][C:30](=[O:29])[CH2:31][C:32](=[O:45])[C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([C:39]2[CH:40]=[N:41][CH:42]=[CH:43][CH:44]=2)[CH:34]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cc(N2CCCC2)c(C(F)(F)F)cc1N
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2cccnc2)c1
Product: CC(C)(C)OC(=O)Nc1cc(N2CCCC2)c(C(F)(F)F)cc1NC(=O)CC(=O)c1cccc(-c2cccnc2)c1

Procedure:
The title compound was prepared from (2-amino-5-pyrrolidin-1-yl-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J27) (259 mg, 0.75 mmol) and 3-oxo-3-(3-pyridin-3-yl-phenyl)-propionic acid tert-butyl ester (Example K1) (223 mg, 0.75 mmol) according to the general procedure M. Obtained as a yellow foam (259 mg, 61%).
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1.[CH3:10][O-:11].[Na+].O>C(#N)C>[Br:1][C:2]1[C:3]([O:11][CH3:10])=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1
Reactant: Clc1ccc(Br)c(Cl)n1
Reactant: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: COc1nc(Cl)ccc1Br
Temperature: 25 °C
Yield: 93.2 %

Procedure:
To a solution of 3-bromo-2,6-dichloropyridine (3.00 g, 13.2 mmol) in acetonitrile (20 mL) was added sodium methoxide (methanol solution, 4.83 mol/L, 3.0 mL) dropwise at 0° C. The mixture was stirred at room temperature over night. To the mixture was added 30 mL of water, and the organic was evaporated. The resulting suspension was filtered, and the pad was washed with water for several times. The pad was dried under reduce pressure to give title compound (2.74 g, 93.2%) as white solid.
Reaction SMILES: C([NH:5][C:6]([C:8]1[N:9]=[C:10]([N:18]2[CH2:23][CH2:22][CH:21]([NH:24][C:25]([C:27]3[NH:28][C:29]([CH3:34])=[C:30]([Cl:33])[C:31]=3[Cl:32])=[O:26])[CH2:20][CH2:19]2)[S:11][C:12]=1[C:13]([O:15]CC)=[O:14])=O)(C)(C)C.[Li+].[OH-].C1COCC1.Cl>O.CO>[C:6]([C:8]1[N:9]=[C:10]([N:18]2[CH2:23][CH2:22][CH:21]([NH:24][C:25]([C:27]3[NH:28][C:29]([CH3:34])=[C:30]([Cl:33])[C:31]=3[Cl:32])=[O:26])[CH2:20][CH2:19]2)[S:11][C:12]=1[C:13]([OH:15])=[O:14])#[N:5]
Reactant: CCOC(=O)c1sc(N2CCC(NC(=O)c3[nH]c(C)c(Cl)c3Cl)CC2)nc1C(=O)NC(C)(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: Cc1[nH]c(C(=O)NC2CCN(c3nc(C#N)c(C(=O)O)s3)CC2)c(Cl)c1Cl
Yield: 79.1 %

Procedure:
A solution of ethyl 4-[(tert-butylamino)carbonyl]-2-(4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}piperidin-1-yl)-1,3-thiazole-5-carboxylate (Example 340; 140 mg, 0.31 mmol) and 2 N LiOH in water (0.93 ml, 1.86 mmol) in 6 ml 1:1 THF:MeOH was heated at 80° C. for 30 min in a microwave reactor. 1 N HCl (1.86 ml) was added and the mixture was diluted with water. Precipitated material was filtered and rinsed well with water. Drying of the precipitate in vacuo gave 105 mg of product.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([Br:10])=[C:6]([CH3:11])[CH:5]=1.[N+:13]([O-])([O-:15])=[O:14].[K+].CCOC(C)=O>OS(O)(=O)=O.C(O)(C(F)(F)F)=O>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:5]=[C:6]([CH3:11])[C:7]([Br:10])=[C:8]([N+:13]([O-:15])=[O:14])[CH:9]=1
Reactant: COC(=O)c1ccc(Br)c(C)c1
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1cc(C)c(Br)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
4-Bromo-3-methylbenzoic acid methyl ester (10.13 g, 44 mmol) was dissolved in a mixture of H2SO4 120 mL and TFA (15 mL) at room temperature. The solution was cooled on an ice bath and KNO3 (4.65 g, 46 mmol) was added portionwise over 30 min. The mixture was stirred at ambient temperature for 4 hours during which it warmed to rt. TLC analysis (after mini aqueous workup) showed total disappearance of starting material (30% EtOAc/Hex). The solution was poured onto ice and the aqueous slurry was extracted with EtOAc (3×150 mL). The organic layer was washed with 5% Na2CO3 (3×75 mL), NaHCO3 (3×50 mL), water (2×100 mL), brine (100 mL), then was dried over sodium sulfate. Concentration of the solution yielded a yellowish solid/gel substance (11.6 g) which was one spot by TLC. 1H NMR analysis shows two (major) products in ˜2:1 ratio, corresponding to the o- and m-nitrobenzoate derivatives. The material was carried onto the next step without further purification.
Reaction SMILES: [ClH:1].[NH2:2][CH:3]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[CH:11]=1)[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].Cl[C:20]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:21]=1[CH2:27][C:28](Cl)=[O:29]>>[Cl:1][CH:27]([C:21]1[CH:22]=[CH:23][C:24]([Cl:26])=[CH:25][CH:20]=1)[C:28]([NH:2][CH:3]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[CH:11]=1)[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])=[O:29]
Reactant: O=C(Cl)Cc1ccc(Cl)cc1Cl
Reactant: CCOC(=O)CC(N)c1cccc([N+](=O)[O-])c1
Reactant: Cl
Product: CCOC(=O)CC(NC(=O)C(Cl)c1ccc(Cl)cc1)c1cccc([N+](=O)[O-])c1

Procedure:
Corresponding to Example 3a, 5.0 g of (1b) were acetylated by addition of 2,4-dichlorophenylacetyl chloride. A white solid was obtained (yield: 3.1 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[S:10][C:9]([S:11][CH3:12])=[N:8][C:7]=2[CH:13]=1.[C:14]1([CH3:25])[CH:19]=[CH:18][C:17]([S:20]([O:23]C)(=[O:22])=[O:21])=[CH:16][CH:15]=1>>[S:20]([C:17]1[CH:18]=[CH:19][C:14]([CH3:25])=[CH:15][CH:16]=1)([O-:23])(=[O:22])=[O:21].[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[S:10][C:9]([S:11][CH3:12])=[N+:8]([CH3:14])[C:7]=2[CH:13]=1
Reactant: COc1ccc2sc(SC)nc2c1
Reactant: COS(=O)(=O)c1ccc(C)cc1
Product: COc1ccc2sc(SC)[n+](C)c2c1
Product: Cc1ccc(S(=O)(=O)[O-])cc1

Procedure:
5-Methoxy-2-(methylthio)benzothiazole (7 g, 0.033 mol) and methyl p-toluenesulfonate (6.77 g, 0.036 mol) were heated to 128°-163° C. for 22 minutes. The resulting solid, after cooling, was triturated with acetone, filtered, and acetone washed until washings were colorless, yielding 12.13 g (96%).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]1[C:21](O)=[O:22])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN=C=NCCCN(C)C.Cl.C1C=NC2N(O)N=NC=2C=1.C(N(CC)CC)C.[NH2:53][C:54]1[C:62]([NH2:63])=[CH:61][CH:60]=[CH:59][C:55]=1[C:56]([NH2:58])=[O:57]>CN(C=O)C>[NH2:53][C:54]1[C:55]([C:56](=[O:57])[NH2:58])=[CH:59][CH:60]=[CH:61][C:62]=1[NH:63][C:21]([CH:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:19][CH2:20][N:11]1[C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:10])=[O:22]
Reactant: NC(=O)c1cccc(N)c1N
Reactant: O=C(O)C1c2ccccc2CCN1C(=O)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: NC(=O)c1cccc(NC(=O)C2c3ccccc3CCN2C(=O)OCc2ccccc2)c1N
Temperature: 55 °C
Reaction time: 0.17 h

Procedure:
Step-1: To a solution of 2-((benzyloxy)carbonyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid (560 mg, 1.8 mmol) in anhydrous DMF (7 ml) was added EDC.HCl (1.035 g, 5.4 mmol), HOAt (367 mg, 2.7 mmol) and triethylamine (0.375 ml, 2.7 mmol) at RT and the mixture was stirred for 10 min. To this reaction mixture, 2,3-diaminobenzamide (302 mg, 2 mmol) was added and heated to 55° C. over night. The reaction mixture was poured into ice cold water and stirred for 30 min. The precipitate formed was filtered and dried under vacuum to yield benzyl 1-((2-amino-3-carbamoylphenyl)carbamoyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate. MS (ES+): m/z 445.22 [M+H]+
Reaction SMILES: [OH-].[K+].N([CH:10]([C:27]1[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=1)P(OC1C=CC=CC=1)(OC1C=CC=CC=1)=O)C1C=CC=CC=1.[N+:36]([C:39]1[CH:46]=[CH:45][C:42]([CH:43]=[O:44])=[CH:41][CH:40]=1)([O-:38])=[O:37]>CO.C1COCC1>[N+:36]([C:39]1[CH:40]=[CH:41][C:42]([C:43](=[O:44])[CH2:10][C:27]2[CH:28]=[CH:29][C:30]([N+:33]([O-:35])=[O:34])=[CH:31][CH:32]=2)=[CH:45][CH:46]=1)([O-:38])=[O:37]
Reactant: O=[N+]([O-])c1ccc(C(Nc2ccccc2)P(=O)(Oc2ccccc2)Oc2ccccc2)cc1
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(Cc1ccc([N+](=O)[O-])cc1)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.7 %

Procedure:
A solution of KOH (7.56 g, 0.13 mol) in MeOH (75 ml) was added to the phosphonate ester 33 (62.1 g, 0.13 mol) in THF (400 ml) at -78° C. for 0.5 hour and p-nitrobenzaldehyde (20.3 g, 0.13 mol) in 200 ml of THF was added over 0.5 hour. The reaction was warmed to room temperature and stirred an additional 2 hours. THF was removed under reduced pressure. The residue was taken up in EtOAc and washed twice with 5% aqueous NaHCO3 and once with brine. The ethyl acetate was removed under reduced pressure. The dark red enemine was dissolved in CH3OH (600 ml) and concentrated HCl (0.2 ml) was added. The solution was stirred for 1 hour at room temperature and diluted with H2O (500 ml). The solid was filtered, washed with ether and dried to afford 34 (35.6 g, 82.0%), m.p. 131°-133° C.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[CH2:11][CH2:12][CH2:13][O:14][CH2:15][C:16](=O)[CH2:17][C:18]([O:20][CH:21]([CH3:23])[CH3:22])=[O:19].[Cl:25][C:26]1[CH:33]=[CH:32][CH:31]=[CH:30][C:27]=1[CH:28]=O.[C:34]([NH:38][C:39](=[O:44])/[CH:40]=[C:41](\[NH2:43])/[CH3:42])([CH3:37])([CH3:36])[CH3:35]>>[C:34]([NH:38][C:39]([C:40]1[CH:28]([C:27]2[CH:30]=[CH:31][CH:32]=[CH:33][C:26]=2[Cl:25])[C:17]([C:18]([O:20][CH:21]([CH3:23])[CH3:22])=[O:19])=[C:16]([CH2:15][O:14][CH2:13][CH2:12][CH2:11][C:3]2[N:2]([CH3:1])[C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=3[N:4]=2)[NH:43][C:41]=1[CH3:42])=[O:44])([CH3:37])([CH3:36])[CH3:35]
Reactant: C/C(N)=C/C(=O)NC(C)(C)C
Reactant: O=Cc1ccccc1Cl
Reactant: CC(C)OC(=O)CC(=O)COCCCc1nc2ccccc2n1C
Product: CC1=C(C(=O)NC(C)(C)C)C(c2ccccc2Cl)C(C(=O)OC(C)C)=C(COCCCc2nc3ccccc3n2C)N1

Procedure:
The procedure of Example 21(c) was followed using isopropyl 4-[3-(1-methylbenzimidazol-2-yl)propoxy]-3-ketobutanoate, 2-chlorobenzaldehyde and N-t-butyl-3-aminocrotonamide as starting materials to yield the title compound as a white solid m.p. 216° C. Found: C, 66.62; H, 6.78; N, 9.35. C33H41ClN4O4 requires C, 66.82; H, 6.97; N, 9.45%.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].C[O:8][C:9]([C@@H:11]1[CH2:15][C@@H:14]([S:16][C:17]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:13][N:12]1[S:36]([C:39]1[CH:48]=[CH:47][C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[CH:40]=1)(=[O:38])=[O:37])=O.C(Cl)Cl.CCOC(C)=O>C1COCC1>[CH:40]1[C:41]2[C:46](=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH:47]=[CH:48][C:39]=1[S:36]([N:12]1[CH2:13][C@H:14]([S:16][C:17]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:15][C@H:11]1[CH2:9][OH:8])(=[O:38])=[O:37]
Reactant: COC(=O)[C@@H]1C[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)CN1S(=O)(=O)c1ccc2ccccc2c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=S(=O)(c1ccc2ccccc2c1)N1C[C@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)C[C@H]1CO
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 81 %

Procedure:
Ester reduction, Method A: 57 ml (57 mmol, 1M THF solution) of LAH was added during 15 min to a cold solution (−20° C.) of 28.2 g (47.5 mmol, ca. (2S,4R)/(2R,4R)-isomer ca 4:1) (2S,4R)-1-(naphthalene-2-sulfonyl)-4-tritylsulfanyl-pyrrolidine-2-carboxylic acid methyl ester in 460 ml THF. The reaction was stirred for 20 min, cooled to −78° C. and quenched with a suspension of 15 g silica gel/15 g MgSO4 7H2O in 60 ml aqueous 10% KHSO4. The suspension was stirred for 15 min at room temperature, filtered and washed with THF. After evaporation of the THF, the residue was taken up in CH2Cl2, dried over Na2SO4 and evaporated to give 29.2 g crude product. Flash column chromatography on silica gel with CH2Cl2/EtOAc(2.5%) to CH2Cl2/EtOAc(10%) gave 21.7 g (81%) of (2S,4R)-[1-(naphthalene-2-sulfonyl)-4-tritylsulfanyl-pyrrolidin-2-yl]-methanol and 1.0 g (4%) of [(2R,4R)-4-mercapto-1-(naphthalene-2-sulfonyl)-pyrrolidin-2-yl]MS: 566 (MH+).
Reaction SMILES: CN(C)CCN(C)C.[Li][CH:10]([CH2:12][CH3:13])[CH3:11].[CH3:14][O:15][C:16]1C=C[C:19]([C:20]([N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])=[O:21])=[CH:18][CH:17]=1.C(I)C>C1COCC1>[CH2:12]([C:10]1[CH:11]=[C:16]([O:15][CH3:14])[CH:17]=[CH:18][C:19]=1[C:20]([N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])=[O:21])[CH3:13]
Reactant: CCN(CC)C(=O)c1ccc(OC)cc1
Reactant: [Li]C(C)CC
Agent: CN(C)CCN(C)C
Solvent: CCI
Solvent: C1CCOC1
Product: CCc1cc(OC)ccc1C(=O)N(CC)CC
Temperature: -78 °C
Reaction time: 1.17 h

Procedure:
To a solution of tetramethylethylenediamine (50.3 mL) in THF (800 mL) at -78° C. was added sec-BuLi (308 mL, 1.08M), followed by 4-methoxy-N,N-diethylbenzamide, (62.2 g). The mixture was stirred at -78° C. for 70 minutes, then ethyliodide (26.63 g, 333 mmol) was added over 35 minutes. The reaction mixture was warmed to room temperature and stirred for 1.5 hours. The reaction mixture was quenched with saturated NH4Cl (100 mL). The organic layer was separated, dried over Na2SO4 and concentrated in vacuo. The residue was purified by a kugelrohr distillation at 190°-210° C. under high vacuum to afford 58.1 g of 2-ethyl-4-methoxy-N,N-diethylbenzamide.
Reaction SMILES: C[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([N:11]([S:13]([C:16]2[CH:21]=[CH:20][C:19](F)=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH3:12])[C:3]=1[CH3:23].[OH:24][CH2:25][CH2:26][CH2:27][CH2:28][NH:29][C:30]([C:32]1[CH:40]=[CH:39][C:35]2[O:36][CH2:37][O:38][C:34]=2[CH:33]=1)=[O:31]>>[O:36]1[C:35]2[CH:39]=[CH:40][C:32]([C:30]([NH:29][CH2:28][CH2:27][CH2:26][CH2:25][O:24][C:19]3[CH:20]=[CH:21][C:16]([S:13]([N:11]([CH3:12])[C:4]4[C:3]([CH3:23])=[CH:2][CH:10]=[CH:9][C:5]=4[C:6]([OH:8])=[O:7])(=[O:15])=[O:14])=[CH:17][CH:18]=3)=[O:31])=[CH:33][C:34]=2[O:38][CH2:37]1
Reactant: O=C(NCCCCO)c1ccc2c(c1)OCO2
Reactant: Cc1ccc(C(=O)O)c(N(C)S(=O)(=O)c2ccc(F)cc2)c1C
Product: Cc1cccc(C(=O)O)c1N(C)S(=O)(=O)c1ccc(OCCCCNC(=O)c2ccc3c(c2)OCO3)cc1
Yield: 60 %

Procedure:
The product of Example 2 (0.30 g, 0.92 mmol) was coupled to N-(4-hydroxybutyl)-1,3-benzodioxole-5-carboxamide, prepared according to Example 21, (0.23 g, 0.96 mmol) using the procedure of Example 3 to provide 0.30 g (60% yield) of yellow solid. MP 110° C.; 1H NMR (DMSO-d6): δ1.66-1.80 (m, CH2, CH2) 1.89 (s, CH3), 3.1 (s, CH3), 3.39-3.45 (m, CH2), 4.08 (t, CH2), 6.08 (s, CH2), 6.9 (d, 1 Ar H), 7.04-7.08 (d,d 2 Ar H), 7.33-7.45 (m, 5 Ar H), 7.53-7.58 (m, 2 Ar H), 8.39 (t, NH), 12.8 (s, OH). Electrospray Mass Spec: m/z 541.2 (M+H)+.
Reaction SMILES: C([O:3][C:4](=[O:35])[CH2:5][N:6]1[CH2:11][CH2:10][CH2:9][CH:8]([NH:12][C:13]([C:15]2[CH:16]=[N:17][C:18]([O:21][CH2:22][C:23]3[C:24]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[N:25][O:26][C:27]=3[CH3:28])=[CH:19][CH:20]=2)=[O:14])[CH2:7]1)C.O.[OH-].[Li+]>C1COCC1.O.CO.Cl>[CH3:28][C:27]1[O:26][N:25]=[C:24]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:23]=1[CH2:22][O:21][C:18]1[N:17]=[CH:16][C:15]([C:13]([NH:12][CH:8]2[CH2:9][CH2:10][CH2:11][N:6]([CH2:5][C:4]([OH:35])=[O:3])[CH2:7]2)=[O:14])=[CH:20][CH:19]=1
Reactant: CCOC(=O)CN1CCCC(NC(=O)c2ccc(OCc3c(-c4ccccc4)noc3C)nc2)C1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)NC2CCCN(CC(=O)O)C2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.8 %

Procedure:
To a solution of (3-{[6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridine-3-carbonyl]-amino}-piperidin-1-yl)-acetic acid ethyl ester (538 mg, 1.1 mmol) in THF (5 mL) was added a solution of lithium hydroxide monohydrate (94 mg, 2.2 mmol) in water (5 mL) and methanol (1 mL) added and the resulting mixture stirred at room temperature overnight. The mixture was acidified to pH 4 with HCl (25%, 3 drops) and methanol (2 drops) added. A gum began to form and the mixture was cooled at 0° C. for 1.5 h and then the aqueous layer decanted off. Trituration with diethylether and hexane afforded the title compound (420 mg, 83%) which was obtained as an off white solid. MS: m/e=449.0 [M−H]−.
Reaction SMILES: [CH3:1][Si:2]([C:5]#[C:6][C:7]1[C:8](=[O:14])[NH:9][C:10](=[O:13])[NH:11][CH:12]=1)([CH3:4])[CH3:3].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.Br[CH:30]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>CC#N.Cl[Si](C)(C)C>[CH:30]([N:11]1[CH:12]=[C:7]([C:6]#[C:5][Si:2]([CH3:3])([CH3:4])[CH3:1])[C:8](=[O:14])[NH:9][C:10]1=[O:13])([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: C[Si](C)(C)C#Cc1c[nH]c(=O)[nH]c1=O
Reactant: BrC(c1ccccc1)c1ccccc1
Agent: C[Si](C)(C)Cl
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: CC#N
Product: C[Si](C)(C)C#Cc1cn(C(c2ccccc2)c2ccccc2)c(=O)[nH]c1=O
Temperature: 25 °C

Procedure:
2.09 g (10 mmol) 5-TMSU (5-trimethylsilanylethynyluracil) dried over P4O10 are suspended in about 50 mL absolute MeCN, then 6 mL (25 mmol) BSA and a few drops of chlorotrimethylsilane are added via a septum, and the suspension is stirred at room temperature under argon until it is completely clear. Then 2.72 g (11 mmol) 1-bromodiphenylmethane are added to the resulting solution. The batch is now stirred for 24 h on an oil bath under exclusion from moisture at 84° C. The dark brown solution is concentrated and left to stand in the ice bath. The brown raw product that precipitates is separated, washed with a little cold MeCN, and recrystallized from about 50 mL MeCN.
Reaction SMILES: [CH2:1]([OH:13])[C@H:2]([OH:12])[C@@H:3](O)[C@H:4]([OH:10])[C:5]([C:7]([OH:9])=[O:8])=[O:6].Cl.O>[Cl-].C[N+](C)(C)CCCCCCCCCCCCCCCC.C1(C)C=CC=CC=1.C(OC(C)C)(C)C>[O:8]=[C:7]1[O:9][C@H:3]([C@H:2]([CH2:1][OH:13])[OH:12])[C:4]([OH:10])=[C:5]1[OH:6]
Reactant: O=C(O)C(=O)[C@@H](O)[C@H](O)[C@@H](O)CO
Agent: CCCCCCCCCCCCCCCC[N+](C)(C)C
Agent: Cl
Agent: [Cl-]
Solvent: O
Solvent: CC(C)OC(C)C
Solvent: Cc1ccccc1
Product: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Temperature: 60 °C
Reaction time: 1 h

Procedure:
A mixture of 2-keto-L-gulonic acid (125 g, 0.579 mol, content: 89.9%, water: 8.7%) and trimethylcetylammonium chloride (0.137 g) was stirred in toluene (240 ml) and diisopropyl ether (170 ml), and 36% conc. hydrochloric acid (15.6 g) was added. At this time, the amount of water in the reaction system was calculated as 2.0 mol per mol of 2-keto-L-gulonic acid. This mixture was stirred at 60° C. for 1 hour, a solution of hydrogen chloride gas (15.5 g) in diisopropyl ether (70 ml) was added, and the mixture was stirred at the same temperature for 5 hours. Then, about 500 g of the solvent was distilled away under reduced pressure while continuously introducing toluene (720 ml). The residue was filtered to give crude crystals of L-ascorbic acid. The crude crystals were dissolved in water. Quantitative analysis of the solution by HPLC showed that the solution contained L-ascorbic acid (93.8 g, yield: 92.0%) and 2-keto-L-gulonic acid (0.3 g, residual ratio: 0.3%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([OH:18])[CH2:16]Cl)=[CH:11][C:10]=1[N+:19]([O-:21])=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].CC(O)=O.O>C1COCC1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]2[CH2:16][O:18]2)=[CH:11][C:10]=1[N+:19]([O-:21])=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1cc(C(O)CCl)ccc1OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: O=[N+]([O-])c1cc([C@@H]2CO2)ccc1OCc1ccccc1
Reaction time: 1 h

Procedure:
151.8 g (0.49 mol) of 1-(4-benzyloxy-3-nitrophenyl)-2-chloroethanol was dissolved in THF (0.75 L) and treated dropwise with NaOH (4 mol/L, 182 mL, 0.73 mol). After 1 hour, AcOH (30 mL) was added followed by water (2.5 L). The mixture was cooled and the precipitated product was recovered by filtration and dried under vacuum at 65° C. Yield: 133.0 g (99.3%); mass spectroscopy: [M+H]+=272; m.p.=66° C.; e.e. 99.5%.