Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:21]2[C@:16]([CH3:24])([C@H:17]3[CH2:23][C@H:18]3[C:19](=[O:22])[CH:20]=2)[C@@H:15]2[C@H:4]([C@H:5]3[C@:12]([CH3:26])([CH2:13][C@H:14]2[OH:25])[C@@:8]([O:27][C:28](=[O:30])[CH3:29])([C:9](=[O:11])[CH3:10])[CH2:7][CH2:6]3)[CH:3]=1.ClC1C2[C@](C)([C@H]3C[C@H]3C(=O)C=2)[C@@H]2[C@H]([C@H]3[C@](C)(CC2)[C@@](OC(=O)C)(C(=O)C)CC3)C=1.[C:60]1(=[O:66])[O:65][C:63](=[O:64])[CH2:62][CH2:61]1>>[C:60]([O:25][C@@H:14]1[CH2:13][C@@:12]2([CH3:26])[C@@H:5]([CH2:6][CH2:7][C@:8]2([O:27][C:28](=[O:30])[CH3:29])[C:9](=[O:11])[CH3:10])[C@H:4]2[C@H:15]1[C@:16]1([CH3:24])[C:21]([C:2]([Cl:1])=[CH:3]2)=[CH:20][C:19](=[O:22])[C@@H:18]2[CH2:23][C@H:17]12)(=[O:66])[CH2:61][CH2:62][C:63]([OH:65])=[O:64]
Reactant: CC(=O)O[C@]1(C(C)=O)CC[C@H]2[C@@H]3C=C(Cl)C4=CC(=O)[C@@H]5C[C@@H]5[C@]4(C)[C@H]3[C@H](O)C[C@@]21C
Reactant: O=C1CCC(=O)O1
Agent: CC(=O)O[C@]1(C(C)=O)CC[C@H]2[C@@H]3C=C(Cl)C4=CC(=O)[C@@H]5C[C@@H]5[C@]4(C)[C@H]3CC[C@@]21C
Product: CC(=O)O[C@]1(C(C)=O)CC[C@H]2[C@@H]3C=C(Cl)C4=CC(=O)[C@@H]5C[C@@H]5[C@]4(C)[C@H]3[C@H](OC(=O)CCC(=O)O)C[C@@]21C

Procedure:
0.433 g. of 6-chloro-11α-hydroxy-17-acetoxy-1α,2α-methylene-4,6-pregnadiene-3,20-dione -- prepared from 6-chloro-17-acetoxy-1α,2α-methylene-4,6-pregnadiene-3,20-dione by microbiological hydroxylation as described in the following paragraph -- is reacted analogously to A9 with succinic acid anhydride and worked up. After purification by way of the sodium salt, 230 mg. of (6-chloro-17-acetoxy-3,20-dioxo-1α,2α-methylene-4,6-pregnadien-11α-yl) hydrogen succinate is obtained as a foam. UV: ε280 = 15,500.
Reaction SMILES: [F:1][C:2]([F:20])([CH:17]([F:19])[F:18])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:15]=[CH:14][NH:13][C:12]2=[O:16])=[CH:7][CH:6]=1.[H][H]>[C].[Pd].C(O)(=O)C>[F:20][C:2]([F:1])([CH:17]([F:19])[F:18])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:15][CH2:14][NH:13][C:12]2=[O:16])=[CH:7][CH:6]=1
Reactant: O=c1[nH]ccn1-c1ccc(OCC(F)(F)C(F)F)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Product: O=C1NCCN1c1ccc(OCC(F)(F)C(F)F)cc1
Yield: 92.4 %

Procedure:
To a solution of 10 ml of acetic acid and 2.0 g of 1-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-2-(1H,3H)-imidazolone was added 0.5 g of 10% palladium-carbon. The mixture was stirred in a hydrogen atmosphere for 7.5 hours. The catalyst was separated by filtration, washed with acetic acid and the filtrate and the washing were collected, followed by distilling off the solvent under reduced pressure. To the residue were added 40 ml of water and 40 ml of ethyl acetate to fractionate, and the ethyl acetate phase was dried over magnesium sulfate and the solvent was distilled off under reduced pressure. to give colorless crystals. The obtained colorless crystals were washed with diisopropyl ether to give 1.86 g of 1-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-2-imidazolidinone as colorless crystals.
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:24])[C@H:10]([NH:16][C:17](=O)[O:18]C(C)(C)C)[CH2:11][O:12][CH:13]([F:15])[F:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.F[C:26](F)(F)C(O)=O>ClCCl>[C:17]([NH:16][C@H:10]([CH2:11][O:12][CH:13]([F:15])[F:14])[C:9]([NH:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:24])(=[O:18])[CH3:26]
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N[C@H](COC(F)F)C(=O)NCc1ccccc1
Solvent: ClCCl
Product: CC(=O)N[C@H](COC(F)F)C(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77.2 %

Procedure:
tert-Butyl {(1R)-2-(benzylamino)-1-[(difluoromethoxy)methyl]-2-oxoethyl}carbamate (340 mg, 0.987 mmol) was stirred with trifluoroacetic acid (2.25 mL) and dichloromethane (2.5 mL) in an ice bath for an hour. The reaction mixture was concentrated, stirred with acetic anhydride-pyridine (1:1, 5.8 mL) at room temperature for 30 minutes and then diluted with ethyl acetate, washed with saturated sodium bicarbonate, brine, 0.5N HCl and brine again. The organic layer was dried, concentrated, and triturated with diethyl ether to give (2R)-2-(acetylamino)-N-benzyl-3-(difluoromethoxy)propanamide (230.5 mg, 77.2%) as a white solid. Mp: 186.9° C. 1H NMR (300 MHz, DMSO-d6): δ(ppm) 8.60 (t, 1H), 8.30 (d, 1H), 7.28-7.45 (m, 5H), 6.67 (wt, 1H), 4.58 (m, 1H), 4.40 (d, 2H), 3.98 (d, 2H) and 1.88 (s, 3H).
Reaction SMILES: C[C@@H](PC)[C]1[C](P(C2C3C(=CC=CC=3)C=CC=2)C2C3C(=CC=CC=3)C=CC=2)[CH][CH][CH]1.[CH2:31]([C:38]1[C:47]2[C:42](=[CH:43][C:44]([F:50])=[C:45]([O:48][CH3:49])[CH:46]=2)[CH2:41][CH2:40][C:39]=1[NH:51][C:52](=[O:55])[CH2:53][CH3:54])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.[H][H]>[Rh+].ClC1CCCCC=CC=1.CO>[CH2:31]([C@@H:38]1[C:47]2[C:42](=[CH:43][C:44]([F:50])=[C:45]([O:48][CH3:49])[CH:46]=2)[CH2:41][CH2:40][C@@H:39]1[NH:51][C:52](=[O:55])[CH2:53][CH3:54])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: [H][H]
Reactant: CCC(=O)NC1=C(Cc2ccccc2)c2cc(OC)c(F)cc2CC1
Agent: [Rh+]
Agent: CP[C@H](C)[C]1[CH][CH][CH][C]1P(c1cccc2ccccc12)c1cccc2ccccc12
Agent: ClC1=CC=CCCCC1
Solvent: CO
Product: CCC(=O)N[C@H]1CCc2cc(F)c(OC)cc2[C@H]1Cc1ccccc1
Temperature: 50 °C
Reaction time: 0.33 h
Yield: 91.9 %

Procedure:
Chlorocyclooctadiene rhodium(I) dimer (0.648 g, 2.63 mmol of Rh), Josiphos SL-J216-2 (1.779 g, 2.77 mmol), and N-(1-benzyl-6-fluoro-7-methoxy-3,4-dihydronaphthalen-2-yl)propionamide (93.96 g, 277 mmol) were combined in a metal reactor, and the vessel was inerted with argon. Degassed methanol (940 ml) was added, and the mixture was agitated under 20 psi of argon at 50° C. for 20 min. The vessel was pressurized with 60 psig of hydrogen and agitated at 55° C. for 14 hrs. HPLC analysis indicated complete conversion and 94.7% ee. The mixture was concentrated, and the resulting solid was precipitated from MeOH to yield 86.9 g (yield: 92%) of the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([S:15][CH2:16][C:17]#[CH:18])=[CH:11][C:10]=1[CH3:19])([CH3:4])([CH3:3])[CH3:2].I[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[C:1]([O:5][C:6](=[O:20])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([S:15][CH2:16][C:17]#[C:18][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:11][C:10]=1[CH3:19])([CH3:4])([CH3:3])[CH3:2]
Reactant: Ic1ccccc1
Reactant: C#CCSc1ccc(OCC(=O)OC(C)(C)C)c(C)c1
Product: Cc1cc(SCC#Cc2ccccc2)ccc1OCC(=O)OC(C)(C)C

Procedure:
In analogy to the procedure described in example 5B], (2-methyl-4-prop-2-ynylsulfanyl-phenoxy)-acetic acid tert-butyl ester (example 5A]) and iodo-benzene gave the title compound as a colorless oil.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][NH:6][S:7]([C:10]1[C:15]([Cl:16])=[CH:14][CH:13]=[C:12]([N+:17]([O-:19])=[O:18])[C:11]=1Cl)(=[O:9])=[O:8])[CH3:2].[H-].[Na+].[OH2:23]>>[CH2:1]([O:3][CH2:4][CH2:5][NH:6][S:7]([C:10]1[C:15]([Cl:16])=[CH:14][CH:13]=[C:12]([N+:17]([O-:19])=[O:18])[C:11]=1[OH:23])(=[O:9])=[O:8])[CH3:2]
Reactant: CCOCCNS(=O)(=O)c1c(Cl)ccc([N+](=O)[O-])c1Cl
Reactant: O
Agent: [H-]
Agent: [Na+]
Product: CCOCCNS(=O)(=O)c1c(Cl)ccc([N+](=O)[O-])c1O

Procedure:
Following the general hydrolysis procedure outlined in example 15, N-(2-ethoxyethyl)-2,6-dichloro-3-nitrobenzenesulfonamide (1.78 g, 5.16 mmol), 80% NaH (0.46 g, 15.48mmol) and water (111 μL, 6.20mmol) were reacted. The crude product (1.63 g) was carried onto the next step without purification. LC-MS (m/z) 325.0(M+).
Reaction SMILES: [CH3:1][NH:2][CH3:3].Cl.[N+:5]([C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:19][CH2:18][CH:17]([C:20](Cl)=[O:21])[CH2:16][CH2:15]2)=[CH:10][CH:9]=1)([O-:7])=[O:6]>>[CH3:1][N:2]([CH3:3])[C:20]([CH:17]1[CH2:18][CH2:19][N:14]([C:11]2[CH:12]=[CH:13][C:8]([N+:5]([O-:7])=[O:6])=[CH:9][CH:10]=2)[CH2:15][CH2:16]1)=[O:21]
Reactant: O=C(Cl)C1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Reactant: CNC
Agent: Cl
Product: CN(C)C(=O)C1CCN(c2ccc([N+](=O)[O-])cc2)CC1

Procedure:
Dimethylamine (2.0 M solution in tetrahydrofuran, 2 mL) is added to 1-(4-nitrophenyl)piperidine-4-carboxylic acid chloride hydrochloride (0.15 g, 0.5 mmol). When the combined compounds fully reacted, the reaction mixture is concentrated under reduced pressure, then taken up in methanol. Water is added and the resulting solid is collected to give 1-(4-nitro-phenyl)-piperidine-4-carboxylic acid dimethylamide, which is used without further purification in the subsequent step.
Reaction SMILES: C([O:3][C:4](=[O:18])[CH:5]([C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]([NH2:17])=[NH:16])=[CH:10][CH:9]=1)[CH2:6][SH:7])C.[Li+].[OH-].FC(F)(F)C(O)=O>O.C(O)C.O1CCCC1>[NH:14]([C:11]1[CH:10]=[CH:9][C:8]([CH:5]([CH2:6][SH:7])[C:4]([OH:18])=[O:3])=[CH:13][CH:12]=1)[C:15]([NH2:17])=[NH:16]
Reactant: CCOC(=O)C(CS)c1ccc(NC(=N)N)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: N=C(N)Nc1ccc(C(CS)C(=O)O)cc1
Reaction time: 18 h

Procedure:
To a solution of 2-(4-guanidinophenyl)-3-mercaptopropanoic acid ethyl ester (60 mg) in 1:1:1 water/ethanol/tetrahydrofuran at 0° C. was added LiOH (130 mg). The reaction was stirred for 18 hours, acidified to pH 2 with trifluoroacetic acid and purified by preparative HPLC to afford 2-(4-guanidinophenyl)-3-mercaptopropanoic acid, as a trifluoroacetic acid salt, (15 mg); NMR (D2O) 2.75-2.83 (dd, 1), 2.98-3.05 (dd, 1), 3.75-3.80 (dd, 1), 7.19 (d, 2), 7.32 (d, 2) ppm.
Reaction SMILES: [OH:1][C:2]1[C:7]([O:8][CH3:9])=[C:6]([O:10][CH3:11])[CH:5]=[C:4]([CH3:12])[C:3]=1[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]([O:36]C)=[O:35].[OH-].[Na+]>CO>[OH:1][C:2]1[C:7]([O:8][CH3:9])=[C:6]([O:10][CH3:11])[CH:5]=[C:4]([CH3:12])[C:3]=1[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]([OH:36])=[O:35]
Reactant: COC(=O)CCCCCCCCCCCCCCCCCCCCCc1c(C)cc(OC)c(OC)c1O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1cc(C)c(CCCCCCCCCCCCCCCCCCCCCC(=O)O)c(O)c1OC
Reaction time: 1.5 h

Procedure:
In 15 ml of methanol is dissolved 300 mg of methyl 22-(2-hydroxy-3,4-dimethoxy-6-methylphenyl)docosanoate followed by addition of 20 ml of a 14% aqueous solution of sodium hydroxide. The mixture is stirred at 50°-60° C. for 1.5 hours. The reaction mixture is made acidic with 3N--HCl and extracted with ethyl acetate. The extract is washed with water and, after drying, the solvent is distilled off under reduced pressure. The residue is recrystallized from methanol to obtain 22-(2-hydroxy-3,4-dimethoxy-6-methylphenyl)docosanoic acid (IV:n=21), m.p. 67° C.-68° C. NMR(δ, in deuteriochloroform): 1.27(38H,b,CH2), 2.24(3H,s,nuclear CH3), 2.28-2.56(4H,m,CH2COO, nuclear CH2), 3.80(3H,s,OCH3), 3.84(3H,s,OCH3), 6.24(1H,s, nuclear H)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]([CH2:7][O:8][C:9]([C:11]2[CH:16]=[CH:15][C:14](=[O:17])[NH:13][CH:12]=2)=[O:10])=[CH:5][CH:4]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:27][CH2:28][OH:29]>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][O:8][C:9]([C:11]2[CH:16]=[CH:15][C:14](=[O:17])[N:13]([CH2:27][CH2:28][OH:29])[CH:12]=2)=[O:10])=[CH:18][CH:19]=1
Reactant: COc1ccc(COC(=O)c2ccc(=O)[nH]c2)cc1
Reactant: OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(COC(=O)c2ccc(=O)n(CCO)c2)cc1
Yield: 79.6 %

Procedure:
To a solution of 6-oxo-1,6-dihydro-pyridine-3-carboxylic acid 4-methoxybenzyl ester (4.41 g, 17 mmol) and K2CO3 (2.58 g, 18.7 mmol) in DMF (100 mL) at room temperature, was added 2-bromoethanol (2.02 g, 16.2 mmol). The reaction mixture was stirred at 80° C. for 30 h, whereupon the DMF was evaporated under vacuum. The crude product was column chromatographed (silica gel, 2→5% MeOH in CH2Cl2), to give 3.91 g of 1-(2-hydroxyethyl)-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid 4-methoxybenzyl ester.
Reaction SMILES: [CH3:1][C:2]([CH3:32])([CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[NH:21][C:22]([C:25]([CH3:31])([CH3:30])[C:26]([F:29])([F:28])[F:27])=[CH:23][N:24]=3)=[CH:16][N:15]=2)=[CH:10][CH:9]=1)[C:3]([OH:5])=[O:4].[OH-].[Na+:34].CO>C(#N)C>[CH3:1][C:2]([CH3:32])([CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[NH:21][C:22]([C:25]([CH3:31])([CH3:30])[C:26]([F:29])([F:27])[F:28])=[CH:23][N:24]=3)=[CH:16][N:15]=2)=[CH:10][CH:9]=1)[C:3]([O-:5])=[O:4].[Na+:34]
Reactant: CC(C)(COc1ccc(-c2ccc(-c3ncc(C(C)(C)C(F)(F)F)[nH]3)cn2)cc1)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC#N
Product: CC(C)(COc1ccc(-c2ccc(-c3ncc(C(C)(C)C(F)(F)F)[nH]3)cn2)cc1)C(=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In acetonitrile (4 mL) was suspended 2,2-dimethyl-3-(4-{5-[5-(2,2,2-trifluoro-1,1-dimethylethyl)-1H-imidazol-2-yl]pyridin-2-yl}phenoxy)propanoic acid (175 mg), and 2N aqueous sodium hydroxide solution (391 μL) was added dropwise to the suspension. After adding acetonitrile (1 mL), the reaction mixture was stirred at room temperature overnight. Methanol was added until the reaction mixture became uniform solution, and tar-state insoluble material was separated by filtration. The filtrate was concentrated under reduced pressure, and the obtained solid residue was pulverized by ether, collected by filtration, washed with ether, and dried at room temperature in vacuum to obtain sodium 2,2-dimethyl-3-(4-{5-[5-(2,2,2-trifluoro-1,1-dimethylethyl)-1H-imidazol-2-yl]pyridin-2-yl}phenoxy)propanoate (174 mg).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[OH:7][C:8]1[CH:9]=[C:10]([CH:21]=[C:22]([O:24][C@@H:25]([CH3:29])[CH2:26][O:27][CH3:28])[CH:23]=1)[C:11]([NH:13][C:14]1[CH:19]=[N:18][C:17]([CH3:20])=[CH:16][N:15]=1)=[O:12].[N:30]1([C:34]([C:36]2[CH:41]=[CH:40][C:39](Br)=[CH:38][N:37]=2)=[O:35])[CH2:33][CH2:32][CH2:31]1>CC(N(C)C)=O>[N:30]1([C:34]([C:36]2[N:37]=[CH:38][C:39]([O:7][C:8]3[CH:9]=[C:10]([CH:21]=[C:22]([O:24][C@@H:25]([CH3:29])[CH2:26][O:27][CH3:28])[CH:23]=3)[C:11]([NH:13][C:14]3[CH:19]=[N:18][C:17]([CH3:20])=[CH:16][N:15]=3)=[O:12])=[CH:40][CH:41]=2)=[O:35])[CH2:33][CH2:32][CH2:31]1
Reactant: O=C(c1ccc(Br)cn1)N1CCC1
Reactant: COC[C@H](C)Oc1cc(O)cc(C(=O)Nc2cnc(C)cn2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: COC[C@H](C)Oc1cc(Oc2ccc(C(=O)N3CCC3)nc2)cc(C(=O)Nc2cnc(C)cn2)c1
Temperature: 160 °C

Procedure:
Cesium carbonate (489 mg, 1.5 mmol) was added to a solution of 3-hydroxy-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}-N-(5-methylpyrazin-2-yl)benzamide (159 mg, 0.5 mmol) and 2-(azetidin-1-ylcarbonyl)-5-bromopyridine (181 mg, 0.75 mmol) and bromotris(triphenylphosphine)copper (93 mg, 0.1 mmol) in DMA (5 mL) and the stirred mixture heated at 160° C. in a microwave reactor for 4 hours. The mixture was cooled to RT and ambient pressure, partitioned between water (75 mL) and ethyl acetate (50 mL), the organic layer washed with brine, dried (MgSO4) and evaporated in vacuo. The residue was chromatographed on silica, eluting with ethyl acetate, to give the desired compound that was crystallised from ether (45 mg, melting onset 113.8° C.). The compound may also be crystallised from ethyl acetate, giving rise to an alternative crystalline form (melting onset 132.7° C.). 1H NMR δ (CDCl3): 1.3 (d, 3H), 2.3 (m, 2H), 2.5 (s, 3H), 3.3 (s, 3H), 3.45-3.55 (m, 2H), 4.2 (t, 2H), 4.55 (m, 1H), 4.65 (t, 2H), 6.75 (d, 1H), 7.05 (d, 1H), 7.25 (s, 1H), 7.3 (d, 1H), 8.0 (s, 1H), 8.05 (d, 1H), 8.25 (d, 1H), 8.3 (s, 1H) and 9.45 (s, 1H). m/z 478 (M+H)+.
Reaction SMILES: [C:1]([NH:4][C@@H:5]1[CH2:10][C@H:9]([NH:11][CH:12]([CH3:14])[CH3:13])[CH2:8][CH2:7][C@@H:6]1[N:15]1[CH2:19][CH2:18][C@H:17]([NH:20][C:21](=[O:30])[O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:16]1=[O:31])(=[O:3])[CH3:2].C=O.[CH2:34](N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[C:1]([NH:4][C@@H:5]1[CH2:10][C@H:9]([N:11]([CH:12]([CH3:14])[CH3:13])[CH3:34])[CH2:8][CH2:7][C@@H:6]1[N:15]1[CH2:19][CH2:18][C@H:17]([NH:20][C:21](=[O:30])[O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:16]1=[O:31])(=[O:3])[CH3:2]
Reactant: CCN(CC)CC
Reactant: CC(=O)N[C@@H]1C[C@H](NC(C)C)CC[C@@H]1N1CC[C@H](NC(=O)OCc2ccccc2)C1=O
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)N[C@@H]1C[C@H](N(C)C(C)C)CC[C@@H]1N1CC[C@H](NC(=O)OCc2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Example 1, Step 9 (See Alternative Step 9, below): A stirring solution of benzyl (S)-1-((1S,2R,4R)-2-acetamido-4-(isopropylamino)cyclohexyl)-2-oxopyrrolidin-3-ylcarbamate (˜115 mmol) in dichloromethane (600 mL) was cooled to 0° C. and charged sequentially with formaldehyde (18.6 g, 37 wt % solution), triethylamine (23 mL), and sodium triacetoxyborohydride (28.7 g). The mixture was stirred at room temperature for 30 minutes and diluted with dichloromethane (up to 1.2 L). This solution was washed thrice with 500 mL sat. NaHCO3+NaOH (sat. NaHCO3, pH to 11 w/1N NaOH). The organic layer was extracted with aq. HCl (200 mL 1N HCl+600 mL water). The aqueous phase was basified with sat. NaHCO3 (500 mL) and then 1N NaOH (100 mL) until pH 11. The aqueous phase was extracted with dichloromethane (1.2 L). The organic extracts were combined, dried (Na2SO4), filtered, and concentrated in vacuo to give benzyl (S)-1-((1S,2R,4R)-2-acetamido-4-(isopropyl(methyl)amino)cyclohexyl)-2-oxopyrrolidin-3-ylcarbamate as an oil, which was used directly in Step 10 below. LC/MS found [M+H]+=445.4. 1H-NMR (400 MHz, d4-MeOH): δ 7.3-7.4 (m, 5H), 5.12 (s, 2H), 4.33 (br s, 1H), 4.25 (t, J=9.2 Hz, 1H), 4.11 (br s, 1H), 3.5-3.6 (m, 2H), 2.77 (v br s, 2H), 2.41 (m, 1H), 2.26 (s, 3H), 2.0-2.1 (m, 2H), 1.92 (s, 3H), 1.7-1.9 (m, 5H), 1.10 (app. dd, J=17, 6.4 Hz, 6H).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]([O:36][C:37](=[O:39])[CH3:38])[C:8]2[CH2:19][S:18][CH2:17][C@@H:16]([C:20]([O:22][CH3:23])=[O:21])[NH:15][C:14](=[O:24])[C@@H:13]([NH:25]C(OC(C)(C)C)=O)[CH2:12][O:11][C:10](=[O:33])[C:9]=2[C:34]=1[CH3:35])(=[O:3])[CH3:2].P([O-])(O)(O)=O.[Na+].[OH-].[Na+]>FC(F)(F)C(O)=O>[C:1]([O:4][C:5]1[CH:6]=[C:7]([O:36][C:37](=[O:39])[CH3:38])[C:8]2[CH2:19][S:18][CH2:17][C@@H:16]([C:20]([O:22][CH3:23])=[O:21])[NH:15][C:14](=[O:24])[C@@H:13]([NH2:25])[CH2:12][O:11][C:10](=[O:33])[C:9]=2[C:34]=1[CH3:35])(=[O:3])[CH3:2]
Reactant: COC(=O)[C@@H]1CSCc2c(OC(C)=O)cc(OC(C)=O)c(C)c2C(=O)OC[C@H](NC(=O)OC(C)(C)C)C(=O)N1
Agent: O=P([O-])(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@@H]1CSCc2c(OC(C)=O)cc(OC(C)=O)c(C)c2C(=O)OC[C@H](N)C(=O)N1

Procedure:
A solution of 114 mg of t-butyl (4R,75)-12,14-diacetoxy-1,3,4,5,6,7,8,10-octahydro-4-methoxycarbonyl-11-methyl-6,10-dioxo -9,2,5-benzoxathiaazacyclododecine-7-carbamate in 2.4 ml of trifiuoroacetic acid was stirred at 0° C. for 30 minutes. The solution was poured onto a mixture of 20 ml of 0.5M aqueous sodium dihydrogenphosphate solution, 4.7 ml of 28% aqueous sodium hydroxide solution and crushed ice. The pH was adjusted to 9 by the addition of sodium hydroxide and the mixture was then extracted with methylene chloride. The organic layer was washed with brine, dried over sodium sulfate and evaporated in vacuo. The residue was dissolved in methylene chloride and crystallized by the addition of n-hexane to give methyl (4R,7S)-12,14-diacetoxy-7-amino-1,3,4,5,6,7,8,10-octahydro-11-methyl-6,10-dioxo-9,2,5-benzoxathiaazacyclododecine-4-carboxylate as a white powder.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH:5]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[NH:16]1[CH2:19][CH:18]([NH:20][C:21]([CH2:23][NH:24][C:25](=[O:36])[C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=2)=[O:22])[CH2:17]1>>[C:12]([C:11]1[CH:14]=[CH:15][C:8]([CH:5]2[CH2:6][CH2:7][CH:2]([N:16]3[CH2:19][CH:18]([NH:20][C:21]([CH2:23][NH:24][C:25](=[O:36])[C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:33])[F:34])[CH:27]=4)=[O:22])[CH2:17]3)[CH2:3][CH2:4]2)=[CH:9][CH:10]=1)#[N:13]
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Reactant: N#Cc1ccc(C2CCC(=O)CC2)cc1
Product: N#Cc1ccc(C2CCC(N3CC(NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)cc1

Procedure:
The title compound was prepared as a white solid by the reductive amination of 4-(4-oxo-cyclohexyl)-benzonitrile and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide (as prepared in step B of Example 4) using the procedure described in Step C of Example 4.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]2[C:10]([C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:24][C@H:23]([CH2:25][N:26]=[N+]=[N-])[O:22][C:21]4=[O:29])=[CH:16][CH:15]=3)([CH2:11]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]2[C:10]([C:14]3[CH:15]=[CH:16][C:17]([N:20]4[CH2:24][C@H:23]([CH2:25][NH2:26])[O:22][C:21]4=[O:29])=[CH:18][CH:19]=3)([CH2:11]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC2CC2(c2ccc(N3C[C@H](CN=[N+]=[N-])OC3=O)cc2)C1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CC2CC2(c2ccc(N3C[C@H](CN)OC3=O)cc2)C1
Temperature: 25 °C
Reaction time: 6 h
Yield: 61.8 %

Procedure:
A mixture of 1-[4-{5(R)-azidomethyl-2-oxo-oxazolidin-3-yl}-phenyl]-3-aza-bicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (Intermediate IV, Step 6) (750 mg, 1.95 mmol) and triphenylphosphine (700 mg, 2.1 mmol) in THF (30 mL) was stirred at r.t. for 6 h. Water (1.5 mL) was added and the reaction mixture was stirred at 80° C. for 12 h. The reaction mixture was then diluted with water (100 mL) and extracted with ethyl acetate (3×100 mL). The organic layer was washed with brine (100 mL), dried over anhydrous sodium sulphate and concentrated in vacuo. The residue was purified by column chromatography (silica gel, 0.5:9.5 MeOH:CHCl3) to provide the title compound (450 mg, 62%) as off white solid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[CH:10][C:11]([C:13]2[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=2)[C:16]#[N:17])=O)=[CH:5][CH:4]=1)#[N:2].C1(P(=[CH:40][C:41]([O:43][CH3:44])=[O:42])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1>[C:16]([C:15]1[CH:14]=[C:13]([C:11]([CH:10]=[CH:9][C:6]2[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)=[CH:40][C:41]([O:43][CH3:44])=[O:42])[CH:20]=[CH:19][CH:18]=1)#[N:17]
Reactant: N#Cc1ccc(C=CC(=O)c2cccc(C#N)c2)cc1
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: COC(=O)C=C(C=Cc1ccc(C#N)cc1)c1cccc(C#N)c1
Temperature: 100 °C
Yield: 86.2 %

Procedure:
Part B. 3-[3-(4-cyanophenyl)-1-oxo-2-propenyl]benzonitrile (2 gm, 7.75 mmol) was suspended in dry toluene and methyl (triphenylphosphoranylidene)acetate (2.59 gm, 7.75 mmol) added. The mixture was then heated at 100° C. for 24 hours, cooled and the solvent removed under vacuum. The residue was chromatographed on silica gel eluting ethyl acetate:hexanes (25:75, v:v) to give methyl 3-(3-cyanophenyl)-5-(4-cyanophenyl)-2,4-pentadienoate as an oil 2.1 gm (87%). MS: (M+H)+ 315; 1H NMR (CDCl3): 3.60 (s, 3H), 3.80 (s, 3H), 5.90 (s, 1H), 6.23 (m, 2H), 6.45 (d, 1H), 7.15 (d, 1H), 7.55 (m, 16H), 8.60 (d, 1H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[S:19][C:20]([C:24]([O:26]CC)=[O:25])=[C:21]([CH3:23])[N:22]=3)=[CH:14][CH:13]=2)=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8].[OH-].[Li+].CO>ClCCl>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[S:19][C:20]([C:24]([OH:26])=[O:25])=[C:21]([CH3:23])[N:22]=3)=[CH:14][CH:13]=2)=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCOC(=O)c1sc(-c2ccc(NC(=O)c3nc(Cl)c(CC)[nH]3)cc2)nc1C
Agent: [Li+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: CCc1[nH]c(C(=O)Nc2ccc(-c3nc(C)c(C(=O)O)s3)cc2)nc1Cl
Yield: 76.8 %

Procedure:
The same operation as in Example (90g) was performed using ethyl 2-(4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}phenyl)-4-methyl-1,3-thiazole-5-carboxylate obtained in Example (94c) (96 mg, 0.23 mmol), 2 N lithium hydroxide (2 mL, 4 mmol), methanol (5 mL) and dichloromethane (3 mL). Purification by reverse phase chromatography (elution solvent: THF/water=0/1, 1/1, 4/1) gave 69 mg of the title compound as a light brown solid (77%).