Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([CH:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[N:10]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:9]=2)=[CH:4][CH:3]=1.[CH3:25][C:26]([CH3:28])=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.C(O)(=O)C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:12]=[C:11]([CH:13]3[CH2:18][CH2:17][N:16]([CH:26]([CH3:28])[CH3:25])[CH2:15][CH2:14]3)[N:10]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:9]=2)=[CH:6][CH:7]=1
Reactant: Clc1ccc(-c2cc(C3CCNCC3)n(-c3ccccc3)n2)cc1
Reactant: CC(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)N1CCC(c2cc(-c3ccc(Cl)cc3)nn2-c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of INTERMEDIATE 5 (30 mg, 0.089 mmol) in DCM (0.5 mL) were added acetone (0.026 mL, 0.355 mmol), triacetoxyborohydride (75 mg, 0.355 mmol) and acetic acid (10.7 mg, 0.178 mmol). The mixture was stirred at room temperature overnight, quenched with 1 N NaOH, and extracted with EtOAc. The organic layer was washed with water, dried (MgSO4) and concentrated. The residue was purified by preparative TLC (4% MeOH/DCM) to give the title compound. LC-MS m/z 380.16 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([NH:17]C(OC(C)(C)C)=O)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>ClCCl>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([NH2:17])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)NC1CCN(C(=O)OCc2ccccc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC1CCN(C(=O)OCc2ccccc2)CC1

Procedure:
A solution of 4.4 g 4-tert-butoxycarbonylamino-piperidine-1-carboxylic acid benzyl ester in 90 ml dichloromethane was stirred in the presence of 10 ml TFA for 3 h. The product was obtained after evaporation of the solvent and used without further purification.
Reaction SMILES: C([NH:4][C:5]1[C:6]([N+:14]([O-:16])=[O:15])=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=[O:9])(=O)C.S(=O)(=O)(O)O.[CH2:22](O)[CH3:23]>>[NH2:4][C:5]1[C:6]([N+:14]([O-:16])=[O:15])=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([O:10][CH2:22][CH3:23])=[O:9]
Reactant: CCO
Reactant: CC(=O)Nc1cccc(C(=O)O)c1[N+](=O)[O-]
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1cccc(N)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 23 h

Procedure:
A mixture of 20.2 of 3-acetylamino-2-nitrobenzoic acid, 11.4 g of 97% sulfuric acid and 300 ml of ethanol was stirred for 23 hours while being heat-refluxed. One-hundred milliliters of ethanol were distilled off under reduced pressure, and the residue was cooled to room temperature. Subsequently, the reaction solution was poured into 200 ml of ice water containing 19.5 g of sodium hydrogencarbonate. The crystals precipitated were separated through filtration, and were washed with water. Further, these crystals were dispersed in 30 ml of a mixed solution of ethyl acetate and hexane at a ratio of 1:2. The crystals were separated through filtration, washed with hexane, and then dried to give 18.0 g of ethyl 3-amino-2-nitrobenzoate.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][CH3:8])(=[O:6])[CH2:4][OH:5].F[C:10]1[CH:15]=[CH:14][C:13]([S:16]([NH2:19])(=[O:18])=[O:17])=[CH:12][CH:11]=1.Cl>CN(C=O)C>[CH3:8][O:7][C:3](=[O:6])[CH2:4][O:5][C:10]1[CH:15]=[CH:14][C:13]([S:16]([NH2:19])(=[O:18])=[O:17])=[CH:12][CH:11]=1
Reactant: NS(=O)(=O)c1ccc(F)cc1
Reactant: COC(=O)CO
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)COc1ccc(S(N)(=O)=O)cc1
Temperature: 50 °C
Reaction time: 10 h
Yield: 32 %

Procedure:
To a stirred suspension of NaH (2.8 g, 0.07 mol, 50% in mineral oil) in DMF (50 mL) is added dropwise methyl glycolate (5.5 g, 0.06 mol) over a period of 10 min. The mixture is heated up to 50° C. for 3 h and cooled down to room temperature. 4-Fluorobenzenesulfonamide g, 0.0114 mol) is added portionwise. After stirring at 50° C. for 10 h, the reaction mixture is cooled down and poured into ice-water containing HCl. The product is extracted with DCM (2×100 mL). The combined organic phase is washed with water and dried over Na2SO4. The solvent is evaporated under reduced pressure and the residue is purified by chromatography (silica gel, 60-120 mesh) with chloroform/methanol (9/1) as eluent to afford 900 mg (32%) of the title compound as a solid. 1H NMR (CDCl3, 400 MHz) δ 7.68-721 (m, 2H), 7.10-7.12 (m, 2H), 6.45 (br s, 2H), 4.51 (s, 2H), 3.86 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:43]=[CH:42][C:6]([CH2:7][NH:8][C:9]2[O:10][C:11]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[N:19]([S:23]([C:26]3[CH:32]=[CH:31][C:29]([CH3:30])=[CH:28][CH:27]=3)(=[O:25])=[O:24])[CH:18]=[C:17]4B3OC(C)(C)C(C)(C)O3)=[N:12][N:13]=2)=[CH:5][CH:4]=1.Br[C:45]1[CH:50]=[N:49][CH:48]=[C:47]([CH:51]2[CH2:53][CH2:52]2)[N:46]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1>[CH:51]1([C:47]2[N:46]=[C:45]([C:17]3[C:16]4[C:20](=[CH:21][CH:22]=[C:14]([C:11]5[O:10][C:9]([NH:8][CH2:7][C:6]6[CH:42]=[CH:43][C:3]([O:2][CH3:1])=[CH:4][CH:5]=6)=[N:13][N:12]=5)[CH:15]=4)[N:19]([S:23]([C:26]4[CH:32]=[CH:31][C:29]([CH3:30])=[CH:28][CH:27]=4)(=[O:25])=[O:24])[CH:18]=3)[CH:50]=[N:49][CH:48]=2)[CH2:53][CH2:52]1
Reactant: COc1ccc(CNc2nnc(-c3ccc4c(c3)c(B3OC(C)(C)C(C)(C)O3)cn4S(=O)(=O)c3ccc(C)cc3)o2)cc1
Reactant: Brc1cncc(C2CC2)n1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(CNc2nnc(-c3ccc4c(c3)c(-c3cncc(C5CC5)n3)cn4S(=O)(=O)c3ccc(C)cc3)o2)cc1
Temperature: 120 °C
Yield: 67.5 %

Procedure:
A mixture of N-(4-methoxybenzyl)-5-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-indol-5-yl)-1,3,4-oxadiazol-2-amine (240 mg, 0.400 mmol), 2-bromo-6-cyclopropylpyrazine (CombiPhos Catalysts, Inc., Princeton, N.J.; 88 mg, 0.440 mmol), potassium phosphate (255 mg, 1.199 mmol), Pd2(dba)3 (10.98 mg, 0.012 mmol), and dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (XPhos; 11.43 mg, 0.024 mmol) in dioxane (4.0 mL) and water (0.400 mL) was sparged with argon then heated at 120° C. (microwave) for 20 min. The reaction was cooled to RT, diluted with DCM (20 mL), and concentrated onto silica gel. Chromatographic purification (silica gel, 0-100% EtOAc/Hex) furnished 5-(3-(6-cyclopropylpyrazin-2-yl)-1-tosyl-1H-indol-5-yl)-N-(4-methoxybenzyl)-1,3,4-oxadiazol-2-amine (160 mg, 0.270 mmol, 68%) as a light-yellow solid: MS (ESI, pos. ion) m/z: 593.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:9]([S:11][CH:12]([CH3:14])[CH3:13])=[C:8]([C:15]([OH:17])=O)[S:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.C(N1C=CN=C1)([N:20]1C=CN=C1)=O.[OH-].[NH4+]>C(#N)C>[Cl:1][C:2]1[C:10]2[C:9]([S:11][CH:12]([CH3:14])[CH3:13])=[C:8]([C:15]([NH2:20])=[O:17])[S:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)Sc1c(C(=O)O)sc2cccc(Cl)c12
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: [NH4+]
Agent: [OH-]
Solvent: CC#N
Product: CC(C)Sc1c(C(N)=O)sc2cccc(Cl)c12
Yield: 35 %

Procedure:
A mixture of 4-chloro-3-[(1-methylethyl)thio]benzo[b]thiophene-2-carboxylic acid (0.43 g, 1.5 mmol) and 1,1'-carbonyldiimidazole (0.25 g, 1.5 mmol) in 5.0 mL of acetonitrile is stirred at reflux for 2 hours. The cooled reaction solution is added slowly to 20 mL of cold ammonium hydroxide solution. The precipitated solid is filtered, washed with water, and recrystallized from aqueous acetonitrile to give 0.15 g (35%) of product; mp=182°-184° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:20])=[C:6]([C@:8]2([CH3:19])[C:13]([F:15])([F:14])[C:12]([CH3:17])([CH3:16])[O:11][C:10]([NH2:18])=[N:9]2)[CH:7]=1.[C:21]([C:23]1[CH:24]=[CH:25][C:26]([C:29](O)=[O:30])=[N:27][CH:28]=1)#[N:22]>>[NH2:18][C:10]1[O:11][C:12]([CH3:16])([CH3:17])[C:13]([F:14])([F:15])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:29]([C:26]3[CH:25]=[CH:24][C:23]([C:21]#[N:22])=[CH:28][N:27]=3)=[O:30])[CH:3]=[CH:4][C:5]=2[F:20])([CH3:19])[N:9]=1
Reactant: CC1(C)OC(N)=N[C@](C)(c2cc(N)ccc2F)C1(F)F
Reactant: N#Cc1ccc(C(=O)O)nc1
Product: CC1(C)OC(N)=N[C@](C)(c2cc(NC(=O)c3ccc(C#N)cn3)ccc2F)C1(F)F

Procedure:
The condensation of (R)-4-(5-amino-2-fluoro-phenyl)-5,5-difluoro-4,6,6-trimethyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate XI-2) and 5-cyano-pyridine-2-carboxylic acid following procedure I yielded the title compound as an off-white foam. MS (ISP): m/z=418.2 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[C:9]([OH:11])=O)=[CH:4][CH:3]=1.[NH2:19][CH2:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][CH:26]([C:29]2[CH:30]=[C:31]([NH:35][C:36]([CH:38]3[CH2:40][CH2:39]3)=[O:37])[CH:32]=[CH:33][CH:34]=2)[CH2:25][CH2:24]1>>[CH3:18][C:15]1[CH:16]=[CH:17][C:12]([CH:8]([C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=2)[C:9]([NH:19][CH2:20][CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][CH:26]([C:29]3[CH:30]=[C:31]([NH:35][C:36]([CH:38]4[CH2:40][CH2:39]4)=[O:37])[CH:32]=[CH:33][CH:34]=3)[CH2:25][CH2:24]2)=[O:11])=[CH:13][CH:14]=1
Reactant: NCCCN1CCC(c2cccc(NC(=O)C3CC3)c2)CC1
Reactant: Cc1ccc(C(C(=O)O)c2ccc(C)cc2)cc1
Product: Cc1ccc(C(C(=O)NCCCN2CCC(c3cccc(NC(=O)C4CC4)c3)CC2)c2ccc(C)cc2)cc1

Procedure:
Example 111 was prepared from bis(4-methylphenyl)acetic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}cyclo propanecarboxamide according to the procedures described in Scheme 10: 1H NMR (400 MHz, CDCl3) δ 8.24–8.04 (br, 1H), 8.04–7.95 (br, 1H), 7.59–6.92 (m, 10H), 6.90–6.76 (m, 1H), 4.98–4.82 (br, 1H), 4.72 (s, 1H), 3.42–3.25 (m, 2H), 3.25–3.08 (m, 2H), 2.75–2.56 (m, 2H), 2.56–2.40 (m, 1H), 2.35–2.17 (m, 2H), 2.26 (s, 6H), 1.99–1.68 (m, 6H), 1.57–1.44 (m, 1H), 1.12–0.99 (m, 2H), 0.87–0.70 (m, 2H); ESMS m/e: 524.3 (M+H)+; Anal. Calc. for (HCl salt) C34H42ClF2N3O2.0.29CHCl3: C, 69.23; H, 7.16; N, 7.06. Found: C, 68.96; H, 7.35; N, 7.31.
Reaction SMILES: Cl.Br[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.[C:9]([Si:11]([CH3:14])([CH3:13])[CH3:12])#[CH:10].C(N(C(C)C)CC)(C)C>CN(C=O)C.C(Cl)Cl.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:12][Si:11]([C:9]#[C:10][C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1)([CH3:14])[CH3:13]
Reactant: Brc1ccncc1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: C[Si](C)(C)C#Cc1ccncc1

Procedure:
Heat a mixture of 4-bromopyridine hydrochloride (1.0 eq), ethynyl-trimethyl-silane (2.0 eq), PdCl2(PPh3)2 (0.1 eq), CuI (0.2 eq) and diisopropyl ethyl amine (10 eq) in DMF at 70° C. for 18 hours. Dilute with methylene chloride, and wash with water. Dry over MgSO4, filter and concentrate in vacuo. Purify the residue by flash chromatography on silica gel to give the title compound. MS (IS) 176.0 (M+1); TLC (20% ether in hexanes): Rf=0.1.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.C1(C)C=CC=CC=1.[C:18]([C:20]1[S:24][CH:23]=[N:22][C:21]=1[C:25](OC)=[O:26])#[CH:19].Cl>C1(C)C=CC=CC=1.[Cl-].[Na+].O>[C:18]([C:20]1[S:24][CH:23]=[N:22][C:21]=1[CH2:25][OH:26])#[CH:19]
Reactant: C#Cc1scnc1C(=O)OC
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [Cl-]
Solvent: O
Solvent: Cc1ccccc1
Product: C#Cc1scnc1CO
Reaction time: 1 h
Yield: 92.3 %

Procedure:
A 1.0 M diisobutylaluminum hydride/toluene solution (165 ml) was added dropwise to a solution of 25.05 g of 5-ethynyl-4-methoxycarbonylthiazole in 450 ml of toluene under an argon atmosphere at −40° C. The mixture was stirred at the same temperature for one hr. Thereafter, the reaction solution was poured into brine, and 200 ml of 1 N aqueous hydrochloric acid was added thereto. The insolubles were removed by filtration through Celite, and the filtrate was extracted four times with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, was filtered, and was concentrated under the reduced pressure. The residue was dissolved in 300 ml of ethanol and 150 ml of THF. Sodium borohydride (2.2 g) was added to the solution in an argon atmosphere, under ice cooling, and the mixture was stirred at room temperature for one hr. Brine was added to the reaction solution, the mixture was adjusted to pH 3 by the addition of 1 N aqueous hydrochloric acid, and the organic solvent was removed by distillation under the reduced pressure. The residue was extracted three times with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, was filtered, and was concentrated under the reduced pressure. The residue was purified by column chromatography on silica gel (chloroform:ethyl acetate=3:1 to 1:1) to give 19.25 g of 5-ethynyl-4-hydroxymethylthiazole.
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:14][CH2:15][CH:16]2[CH2:20][CH2:19][CH2:18][N:17]2[CH3:21])[C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([N+:11]([O-])=O)=[CH:6][CH:5]=2>C(O)C.[Pd]>[CH3:1][C:2]1[N:3]([CH2:14][CH2:15][CH:16]2[CH2:20][CH2:19][CH2:18][N:17]2[CH3:21])[C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([NH2:11])=[CH:6][CH:5]=2
Reactant: Cc1cc2cc([N+](=O)[O-])ccc2n1CCC1CCCN1C
Agent: [Pd]
Solvent: CCO
Product: Cc1cc2cc(N)ccc2n1CCC1CCCN1C
Reaction time: 8 h
Yield: 76 %

Procedure:
A solution of compound 29 (0.5 g, 1.739 mmol) in dry ethanol (3 mL) was treated with Pd—C (˜0.05 g) and flushed with hydrogen gas. The reaction was stirred under hydrogen atm. for overnight. The reaction was filtered through celite bed, washed with methanol (3×15 mL) and dried to obtain crude compound 31 (0.34 g, 77%) as a syrup. 1H NMR (DMSO-d6) δ 1.40-1.67 (m, 4H), 1.82-1.93 (m, 2H), 1.98-2.10 (m, 2H), 2.18 (s, 3H), 2.31 (s, 3H), 2.90-2.96 (m, 1H), 3.97 (t, 2H, J=7.5 Hz), 4.39 (s, 2H), 5.88 (s, 1H), 6.43 (dd, 1H, J=2.1, 8.4 Hz), 6.57 (d, 1H, J=1.8 Hz), 7.00 (d, 1H, J=8.7 Hz); ESI-MS (m/z, %) 258 (MH+, 28), 161 (100).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]([CH3:26])([CH2:21][CH2:22][CH:23]([CH3:25])[CH3:24])[C:9](N[C@H](C2C=CC=CC=2)CO)=[O:10])=[CH:4][CH:3]=1.S(=O)(=O)(O)[OH:28]>O1CCOCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C@@:8]([CH3:26])([CH2:21][CH2:22][CH:23]([CH3:25])[CH3:24])[C:9]([OH:10])=[O:28])=[CH:6][CH:7]=1
Reactant: CC(C)CC[C@@](C)(C(=O)N[C@@H](CO)c1ccccc1)c1ccc(F)cc1
Reactant: O=S(=O)(O)O
Solvent: C1COCCO1
Product: CC(C)CC[C@@](C)(C(=O)O)c1ccc(F)cc1
Yield: 100 %

Procedure:
A solution of the product of Example 22D (6.15 g, 17.2 mmol) in dioxane (100 mL) was treated with 4 M sulfuric acid solution (100 mL), and the mixture was warmed at reflux for 48 h. The solution was cooled and extracted with dichloromethane (3×). The combined organic layers were dried (Na2SO4) and concentrated in vacuo to afford the title compound (4.16 g, 100%) as an amber oil. 1H NMR (300 MHz, CDCl3): δ 0.86 (t, J=6.43 Hz, 6 H) 1.05 (m, 2 H) 1.51 (m, 4 H) 1.96 (m, 2 H) 7.02 (m, 2 H) 7.34 (m, 2 H). Specific Rotation: [□]D−10.6°(c 2.15, EtOH).
Reaction SMILES: O.S.[Na].[CH2:4]([O:11][C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][CH:13]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>C(O)C>[CH2:4]([O:11][C:12]1[CH:13]=[CH:14][C:15]([NH2:18])=[CH:16][CH:17]=1)[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: O=[N+]([O-])c1ccc(OCc2ccccc2)cc1
Agent: S
Agent: [Na]
Solvent: CCO
Solvent: O
Product: Nc1ccc(OCc2ccccc2)cc1

Procedure:
Sodium hydrogen sulphide monohydrate (40 g) was added to a solution of 4-benzyloxynitrobenzene (25 g) in ethanol (800 ml) and the reaction mixture heated under reflux for four hours. The solvent was removed and the residue was treated with water and extracted into ether. The ether extract was dried and evaporated to give 4-benzyloxyaniline which was purified by extraction with hexane.
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:10](=[O:11])[N:9]2[C@@H:5]1[C@@H:6]([CH3:52])[C:7]([S:25][C@@H:26]1[CH2:30][N:29](C(OCC3C=CC([N+]([O-])=O)=CC=3)=O)[C@H:28]([CH2:44][O:45][CH2:46][CH2:47][NH:48][C:49]([NH2:51])=[O:50])[CH2:27]1)=[C:8]2[C:12]([O:14]CC1C=CC([N+]([O-])=O)=CC=1)=[O:13])[CH3:3].P([O-])([O-])([O-])=O.[H][H]>[OH-].[OH-].[Pd+2].O1CCCC1>[OH:1][C@@H:2]([C@H:4]1[C:10](=[O:11])[N:9]2[C@@H:5]1[C@@H:6]([CH3:52])[C:7]([S:25][C@@H:26]1[CH2:30][NH:29][C@H:28]([CH2:44][O:45][CH2:46][CH2:47][NH:48][C:49]([NH2:51])=[O:50])[CH2:27]1)=[C:8]2[C:12]([OH:14])=[O:13])[CH3:3]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](COCCNC(N)=O)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)[C@H](C)[C@H]12
Reactant: [H][H]
Agent: [Pd+2]
Agent: O=P([O-])([O-])[O-]
Agent: [OH-]
Solvent: C1CCOC1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)O)=C(S[C@@H]3CN[C@H](COCCNC(N)=O)C3)[C@H](C)[C@H]12
Yield: 46.2 %

Procedure:
A mixture of 4-nitrobenzyl (4R,5S,6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-3-[(2S,4S)-1-(4-nitrobenzyloxycarbonyl)-2-{(2-ureidoethyl)oxylmethyl}pyrrolidin-4-yl]thio-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (0.75 g), tetrahydrofuran (40 ml), 0.1M phosphate buffer (pH 6.5) (20 ml) and 20% palladium hydroxide on carbon (0.20 g) was stirred at ambient temperature for 5 hours under atmospheric pressure of hydrogen. The catalyst was removed by filtration and the filtrate was concentrated under reduced pressure to remove tetrahydrofuran. The residual solution was washed with ethyl acetate (40 ml×2) and the organic solvent was removed by evaporation. The residual solution was subjected to a column chromatography on nonionic adsorption resin "Diaion HP-20" (40 ml) eluting with a mixture of acetone and water (5:95 V/V), and lyophilized to give (4R,5S,6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-3-[(2S,4S)-2-{(2-ureidoethyl)oxymethyl}pyrrolidin-4-yl]thio-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid (0.20 g).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C(=O)([O-])[O-].[K+].[K+].Br[CH2:21][C:22]([O:24][CH3:25])=[O:23]>CN(C)C=O>[CH3:13][O:12][C:9]1[CH:10]=[CH:11][C:2]([O:1][CH2:21][C:22]([O:24][CH3:25])=[O:23])=[C:3]([CH:8]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)CBr
Reactant: COC(=O)c1cc(OC)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)COc1ccc(OC)cc1C(=O)OC
Temperature: 25 °C
Reaction time: 24 h
Yield: 78 %

Procedure:
A mixture of 50.0 g (0.27 mole) of 2-hydroxy-5-methoxybenzoic acid, methyl ester, 88.0 g (0.64 mole) of anhydrous potassium carbonate, and 25.4 ml (46.4 g, 0.30 mole) of methyl bromoacetate in 300 ml of N,N-dimethylformamide is stirred at room temperature for 24 hours. The reaction mixture is added to 1100 g of ice/water, stirred for 1 hour, and the precipitated crude product is filtered and washed with water. Recrystallization from aqueous methanol yields 54.7 g (78% yield) of analytically pure 5-methoxy-2-(2-methoxy-2-oxoethoxy) benzoic acid, methyl ester, mp 82°-85° C.
Reaction SMILES: [CH3:1][N:2]([C:15]1[CH:20]=[CH:19][C:18]([N:21]=[N:22][C:23]2[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=2)=[CH:17][CH:16]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][OH:14].[C:32](Cl)(=[O:36])[C:33]([CH3:35])=[CH2:34]>>[N+:29]([C:26]1[CH:27]=[CH:28][C:23]([N:22]=[N:21][C:18]2[CH:19]=[CH:20][C:15]([N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:32](=[O:36])[C:33]([CH3:35])=[CH2:34])=[CH:16][CH:17]=2)=[CH:24][CH:25]=1)([O-:31])=[O:30]
Reactant: CN(CCCCCCCCCCCO)c1ccc(N=Nc2ccc([N+](=O)[O-])cc2)cc1
Reactant: C=C(C)C(=O)Cl
Product: C=C(C)C(=O)OCCCCCCCCCCCN(C)c1ccc(N=Nc2ccc([N+](=O)[O-])cc2)cc1

Procedure:
The 4'-[N-methyl-N-(11-hydroxyundecyl)-amino]-4-nitroazobenzene obtained in process step 1 was reacted with methacryloyl chloride according to the method stated in Example 2, Section 2, to give 4-nitro-4'-[N-methyl-N-(11-methacryloyloxyundec-1-yl)-amino]-azobenzene [methacrylate (A)]. The resulting product had the following physicochemical properties: IR spectrum (KBr pellet): bands at 2,900, 2,850, 1,705, 1,585, 1,490, 1,325, 1,120, 1,150, 1,095, 850 and 810 cm-1 ; 1H nuclear magnetic resonance spectrum (400 MHz, CDCl3, tetramethylsilane as internal standard, chemical shift δ (in ppm): 1.3 to 1.65 (multiplet, 18H), 1.9 (singlet, 3H), 3.1 (singlet, 3H), 3.4 (triplet, 2H), 4.3 (triplet, 2H), 5.6 (singlet, 1H), 6.1 (singlet, 1H), 6.7 (doublet, 2H), 7.9 (doublet, 4H), 8.3 (doublet, 2H); elemental analysis: calculated: 67.3% C, 8.03% H, 13.13% N, 11.25% 0; found: 66.1% C, 7.7% H, 13.8% N, 12.1% 0.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.Cl.[CH3:19][O:20][C:21](=[O:24])[CH2:22][NH2:23]>CO.C(Cl)Cl>[CH3:19][O:20][C:21](=[O:24])[CH2:22][NH:23][C:15](=[O:17])[C@H:13]([CH3:14])[NH:12][C:10](=[O:11])[CH2:9][C:4]1[CH:5]=[C:6]([F:8])[CH:7]=[C:2]([F:1])[CH:3]=1
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Reactant: COC(=O)CN
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: COC(=O)CNC(=O)[C@H](C)NC(=O)Cc1cc(F)cc(F)c1

Procedure:
Following General Procedure A and using N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and glycine methyl ester hydrochloride (Bachem), the title compound was prepared as a solid (mp=158-160° C.). The reaction was monitored by tlc (Rf=0.61 in 10%MeOH/DCM) and the product was purified by silica gel chromatography.
Reaction SMILES: [O:1]=[S:2]1(=[O:57])[CH2:7][C@@H:6]2[CH2:8][C@H:3]1[CH2:4][N:5]2[CH2:9][CH2:10][NH:11][C@:12]12[CH2:53][CH2:52][C@@H:51]([C:54]([CH3:56])=[CH2:55])[C@@H:13]1[C@@H:14]1[C@@:27]([CH3:30])([CH2:28][CH2:29]2)[C@@:26]2([CH3:31])[C@@H:17]([C@:18]3([CH3:50])[C@@H:23]([CH2:24][CH2:25]2)[C:22]([CH3:33])([CH3:32])[C:21]([C:34]2[CH2:39][CH2:38][C@H:37]([C:40]([O:42]CC4C=CC=CC=4)=[O:41])[CH2:36][CH:35]=2)=[CH:20][CH2:19]3)[CH2:16][CH2:15]1.[OH-].[Na+]>C(#N)C>[O:57]=[S:2]1(=[O:1])[CH2:7][C@@H:6]2[CH2:8][C@H:3]1[CH2:4][N:5]2[CH2:9][CH2:10][NH:11][C@:12]12[CH2:53][CH2:52][C@@H:51]([C:54]([CH3:56])=[CH2:55])[C@@H:13]1[C@@H:14]1[C@@:27]([CH3:30])([CH2:28][CH2:29]2)[C@@:26]2([CH3:31])[C@@H:17]([C@:18]3([CH3:50])[C@@H:23]([CH2:24][CH2:25]2)[C:22]([CH3:32])([CH3:33])[C:21]([C:34]2[CH2:39][CH2:38][C@H:37]([C:40]([OH:42])=[O:41])[CH2:36][CH:35]=2)=[CH:20][CH2:19]3)[CH2:16][CH2:15]1
Reactant: C=C(C)[C@@H]1CC[C@]2(NCCN3C[C@@H]4C[C@H]3CS4(=O)=O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(C6=CC[C@@H](C(=O)OCc7ccccc7)CC6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Product: C=C(C)[C@@H]1CC[C@]2(NCCN3C[C@@H]4C[C@H]3CS4(=O)=O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(C6=CC[C@@H](C(=O)O)CC6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 80 °C
Yield: 49.6 %

Procedure:
A mixture of (S)-benzyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-((1S,4S)-2,2-dioxido-2-thia-5-azabicyclo[2.2.1]heptan-5-yl)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)cyclohex-3-enecarboxylate (5 mg, 6.27 μmol) and sodium hydroxide (0.063 mL, 0.063 mmol) in acetonitrile (1 mL) was heated up at 80° C. for 3 hours. The reaction mixture was filtered and purified by HPLC to provide (S)-4-((1R,3 aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-((1S,4S)-2,2-dioxido-2-thia-5-azabicyclo[2.2.1]heptan-5-yl)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)cyclohex-3-enecarboxylic acid (2.2 mg, 47% yield) as a white solid. LCMS: m/e 707.8 (M+H)+, 1.82 min (method 5). 1H NMR (400 MHz, Acetic) δ 5.37 (br. s., 1H), 5.22 (d, J=4.3 Hz, 1H), 4.80 (s, 1H), 4.70 (s, 1H), 4.10 (br. s., 1H), 3.79-3.65 (m, 1H), 3.50-3.32 (m, 3H), 3.28-3.00 (m, 5H), 2.93-2.75 (m, 1H), 2.56 (d, J=12.3 Hz, 2H), 2.49-2.39 (m, 1H), 2.32 (br. s., 2H), 2.23-1.10 (m, 26H), 1.72 (s, 3H), 1.16 (s, 3H), 1.07 (s, 3H), 1.00 (s, 3H), 0.94 (s, 3H), 0.92 (s, 3H).