Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:14]([O-:16])=[O:15])=[C:6]([CH:13]=1)[O:7][CH:8]([CH3:12])[C:9]([OH:11])=[O:10].[OH-].[Na+].CS(C)=[O:21]>O>[OH:21][C:2]1[CH:3]=[CH:4][C:5]([N+:14]([O-:16])=[O:15])=[C:6]([CH:13]=1)[O:7][CH:8]([CH3:12])[C:9]([OH:11])=[O:10]
Reactant: CS(C)=O
Reactant: CC(Oc1cc(F)ccc1[N+](=O)[O-])C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(Oc1cc(O)ccc1[N+](=O)[O-])C(=O)O
Reaction time: 8 h

Procedure:
5 Grams (21.8 moles) of 2-(5-fluoro-2-nitrophenoxy)propionic acid was heated for two hours with 5 ml of 25 percent (by weight) aqueous sodium hydroxide and 100 ml of DMSO and allowed to stand overnight. The mixture was diluted with water and extracted with 1,1,1-trichloroethane (organic discarded), then with ether. The aqueous layer was acidified and extracted with ether. The ether solution was stripped to give 2.5 g of solid product which was recrystallized from ethanol/chloroform to give 1.7 g (35 percent) of the desired product. M.P.=190°-195° C. NMR and IR spectra supported the identification.
Reaction SMILES: C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1.[NH2:15][C:16]1[CH:17]=[N:18][CH:19]=[CH:20][C:21]=1[N:22]1[CH2:27][C@H:26]([CH3:28])[C@H:25]([N:29]=[N+]=[N-])[C@H:24]([NH:32][C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36])[CH2:23]1.[F:40][C:41]1[CH:46]=[CH:45][CH:44]=[C:43]([F:47])[C:42]=1[C:48]1[N:53]=[C:52]([C:54](O)=[O:55])[CH:51]=[CH:50][C:49]=1[F:57].[N-]=[N+]=[N-]>CN(C=O)C.O.CC(O)C.[Pd]>[NH2:29][C@H:25]1[C@@H:26]([CH3:28])[CH2:27][N:22]([C:21]2[CH:20]=[CH:19][N:18]=[CH:17][C:16]=2[NH:15][C:54](=[O:55])[C:52]2[CH:51]=[CH:50][C:49]([F:57])=[C:48]([C:42]3[C:41]([F:40])=[CH:46][CH:45]=[CH:44][C:43]=3[F:47])[N:53]=2)[CH2:23][C@H:24]1[NH:32][C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36]
Reactant: C[C@H]1CN(c2ccncc2N)C[C@@H](NC(=O)OC(C)(C)C)[C@H]1N=[N+]=[N-]
Reactant: O=C(O)c1ccc(F)c(-c2c(F)cccc2F)n1
Agent: [Pd]
Agent: On1nnc2cccnc21
Agent: [N-]=[N+]=[N-]
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: O
Product: C[C@H]1CN(c2ccncc2NC(=O)c2ccc(F)c(-c3c(F)cccc3F)n2)C[C@@H](NC(=O)OC(C)(C)C)[C@H]1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 58 %

Procedure:
EDC (1.5 equiv.) and HOAt (1.5 equiv.) were added to a solution of tert-butyl ((3R,4S,5S)-1-(3-aminopyridin-4-yl)-4-azido-5-methylpiperidin-3-yl)carbamate (1.0 equiv.) and 6-(2,6-difluorophenyl)-5-fluoropicolinic acid (1.3 equiv.) in DMF (0.20 M). The mixture was stirred at ambient temperature overnight. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined extracts were washed sequentially with 1M aqueous sodium hydroxide and brine, dried over sodium sulfate, filtered, concentrated and purified by ISCO SiO2 chromatography. To a degassed a solution of the azide (1.0 equiv.) in 2-propanol (0.10 M) was added Pd/C (0.2 equiv.). The mixture was stirred under H2 for 48 hrs. Filter the mixture over cetlite and wash the cake with MeOH. Concentrate the filtrate to yield tert-butyl ((3R,4S,5S)-4-amino-1-(3-(6-(2,6-difluorophenyl)-5-fluoropicolinamido)pyridin-4-yl)-5-methylpiperidin-3-yl)carbamate in 58% yield). LC/MS (m/z)=557.1 (MH+), Rt=0.69 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:5]=[CH:4][C:3]=1[S:14]([C@H:17]1[CH2:21][N:20]([C:22]([C:24]2([C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=3)[CH2:26][CH2:25]2)=[O:23])[C@H:19]([C:34](O)=[O:35])[CH2:18]1)(=[O:16])=[O:15].[CH:37]1([NH:40][C:41](=[O:48])[C:42](=[O:47])[C@@H:43]([NH2:46])[CH2:44][CH3:45])[CH2:39][CH2:38]1>>[Cl:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:9][CH2:10][O:11][CH2:12][CH2:13]2)[CH:5]=[CH:4][C:3]=1[S:14]([C@H:17]1[CH2:21][N:20]([C:22]([C:24]2([C:27]3[CH:28]=[CH:29][C:30]([Cl:33])=[CH:31][CH:32]=3)[CH2:26][CH2:25]2)=[O:23])[C@H:19]([C:34]([NH:46][C@@H:43]([CH2:44][CH3:45])[C:42](=[O:47])[C:41]([NH:40][CH:37]2[CH2:39][CH2:38]2)=[O:48])=[O:35])[CH2:18]1)(=[O:15])=[O:16]
Reactant: O=C(O)[C@@H]1C[C@@H](S(=O)(=O)c2ccc(N3CCOCC3)cc2Cl)CN1C(=O)C1(c2ccc(Cl)cc2)CC1
Reactant: CC[C@H](N)C(=O)C(=O)NC1CC1
Product: CC[C@H](NC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccc(N3CCOCC3)cc2Cl)CN1C(=O)C1(c2ccc(Cl)cc2)CC1)C(=O)C(=O)NC1CC1

Procedure:
The title compound was prepared in analogy to Example 1, using (2S,4R)-4-(2-Chloro-4-morpholin-4-yl-benzenesulfonyl)-1-[1-(4-chloro-phenyl)-cyclopropane carbonyl]-pyrrolidine-2-carboxylic acid and (S)-3-Amino-2-oxo-pentanoic acid cyclopropylamide in step 1. MS (m/e)=705.19 [M+H+].
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([O:13]CC)=[O:12])=[CH:7][N:6]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][N:26]([CH3:33])[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=3)=[CH:19][CH:18]=2)[N:5]=1)[CH3:2].[OH-].[Na+].O1CCCC1.C(O)C>Cl>[CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:7][N:6]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][N:26]([CH3:33])[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=3)=[CH:19][CH:18]=2)[N:5]=1)[CH3:2]
Reactant: CCOC(=O)CCc1cn(Cc2ccc(OCCN(C)c3ccccn3)cc2)nc1OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOc1nn(Cc2ccc(OCCN(C)c3ccccn3)cc2)cc1CCC(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 55.7 %

Procedure:
A mixture of ethyl 3-[3-ethoxy-1-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl]-1H-pyrazol-4-yl]propionate (769 mg), 1 N aqueous sodium hydroxide solution (4 ml), tetrahydrofuran (8 ml), and ethanol (8 ml) was stirred at room temperature for 3 hours, diluted with 1 N hydrochloric acid (4 ml), and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography, and 3-[3-ethoxy-1-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl]-1H-pyrazol-4-yl]propionic acid (402 mg, yield: 56%) was obtained as a colorless oily substance from the fraction eluted with ethyl acetate.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:4](=[O:18])[CH:3]=1.[Br:19]Br>C(Cl)Cl>[Br:19][C:3]1[C:4](=[O:18])[N:5]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:6]2[C:11]([C:2]=1[OH:1])=[CH:10][CH:9]=[CH:8][N:7]=2
Reactant: O=c1cc(O)c2cccnc2n1-c1ccccc1
Reactant: BrBr
Solvent: ClCCl
Product: O=c1c(Br)c(O)c2cccnc2n1-c1ccccc1
Yield: 65.4 %

Procedure:
To a suspension of 4-hydroxy-1-phenyl-1,8-naphthyridin-2(1H)-one (1 g) in CH2Cl2 (20 mL) was added, dropwise and with stirring, a solution of bromine (0.7 g) in CH2Cl2 (5 mL). The mixture was stirred at room temperature overnight, after which time the product was filtered off, dried in air and recrystallized from acetonitrile to yield 0.87 g of the product, m.p. >280° C.
Reaction SMILES: C1(C)C=CC=CC=1.N(C(C)C)(C(C)C)CC.[C:17]1([C:23]#[CH:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.I[Si:26]([CH3:29])([CH3:28])[CH3:27]>CCCCCC>[C:17]1([C:23]#[C:24][Si:26]([CH3:29])([CH3:28])[CH3:27])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: C[Si](C)(C)I
Reactant: C#Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: C[Si](C)(C)C#Cc1ccccc1
Yield: 89.9 %

Procedure:
A reactor with a capacity of 40 mL, equipped with a magnetic stirrer was filled, under argon atmosphere, with 0.0085 g (0.015 mmol) of [{Ir(μ-Cl)(CO)2}2], and then with 8 mL of anhydrous and deoxidized toluene and 0.7 g (5.4 mmol) of NEt(i-Pr)2. The whole mixture was stirred until the starting iridium(I) complex was dissolved, and then 0.306 g (3mmol) of phenylacetylene and 0.96 g (4.8 mmol) of ISiMe3 were added to the resulting mixture. The reaction was carried out at a temperature of 80° C. until complete conversion of phenylacetylene. After the reaction was completed, the solvent was evaporated at a reduced pressure along with any residual unreacted substrates in order to remove the catalyst from the reaction mixture and then the residue was transferred onto a chromatographic column packed with silica gel and product was isolated using hexane as eluent. The solvent was initially evaporated from the eluate, and the residual product was distilled by means of the “trap-to-trap” technique at a reduced pressure to obtain 0.47 g of phenylethynyltrirnethylsilane, with a yield of 90%.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:18]3[C:17](=[O:19])[CH2:16][CH2:15][CH2:14][C:13]=3[N:12]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=3)[C:11](=[O:30])[N:10]2[C:31]([NH:33][CH:34]2[CH2:39][CH2:38][S:37][CH2:36][CH2:35]2)=[O:32])=[CH:5][CH:4]=1)#[N:2].OO.[O:42]=C1O[C@H]([C@H](CO)O)C([O-])=C1O.[Na+].O>C(O)C.C[Re](=O)(=O)=O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[C:18]3[C:17](=[O:19])[CH2:16][CH2:15][CH2:14][C:13]=3[N:12]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=3)[C:11](=[O:30])[N:10]2[C:31]([NH:33][CH:34]2[CH2:35][CH2:36][S:37](=[O:42])[CH2:38][CH2:39]2)=[O:32])=[CH:7][CH:8]=1)#[N:2]
Reactant: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Reactant: N#Cc1ccc(C2C3=C(CCCC3=O)N(c3cccc(C(F)(F)F)c3)C(=O)N2C(=O)NC2CCSCC2)cc1
Agent: C[Re](=O)(=O)=O
Agent: OO
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: N#Cc1ccc(C2C3=C(CCCC3=O)N(c3cccc(C(F)(F)F)c3)C(=O)N2C(=O)NC2CCS(=O)CC2)cc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A solution of 4-(4-cyanophenyl)-2,5-dioxo-N-(tetrahydro-2H-thiopyran-4-yl)-1-(3-(tri-fluoromethyl)phenyl)-1,2,5,6,7,8-hexahydroquinazoline-3(4H)-carboxamide (intermediate 60, 131 mg, 0.24 mmol) in ethanol (10 mL) is cooled at −78° C. with an acetone/dry ice bath. Aqueous hydrogen peroxide (1 M, 50 μL, 0.05 mmol) is added, and the mixture is stirred at −78° C. for 30 min. Methyltrioxorhenium(VII) (1 mg, 4 μmol) is added, and the mixture is stirred at −78° C. for 2 h. Aqueous sodium ascorbate (10%, 30 mL) and water (30 mL) is added, and the precipitate is filtered and purified by preparative HPLC (Waters Xbridge™-C18, gradient of acetonitrile in water, 0.1% NH3). Yield: 22 mg; ESI mass spectrum [M+H]+=571; Retention time HPLC: 0.51 min (004_CA07).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([CH2:9][O:10][Si](C(C)(C)C)(C)C)[CH:6]=[CH:5][N:4]=1)#[N:2]>CO>[C:1]([C:3]1[CH:8]=[C:7]([CH2:9][OH:10])[CH:6]=[CH:5][N:4]=1)#[N:2]
Reactant: CC(C)(C)[Si](C)(C)OCc1ccnc(C#N)c1
Solvent: CO
Product: N#Cc1cc(CO)ccn1
Yield: 88.6 %

Procedure:
A solution of 2-cyano-4-[{(tert-butyldimethylsilyl)oxy}methyl]pyridine (10.1 g, 40.5 mmol) in 200 mL of anhydrous MeOH is stirred over 12 g of Dowex-50W-H+ ion-exchange resin (pre-washed with MeOH) for a period of 18 hours. After this time, the mixture is filtered and washed with MeOH twice. The combined filtrates are concentrated in vacuo. The crude residue is purified by column chromatography eluting with 50% EtOAc/hexanes to afford the title compound (4.82 g, 35.9 mmol) as an oil.
Reaction SMILES: [C:1]1([CH3:9])[CH:6]=[CH:5][C:4]([Mg]Br)=[CH:3][CH:2]=1.[C:10]1([P:16]([O-])[O:17]CC)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.S(=O)(=O)(O)O>CCOCC>[C:1]1([CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:13]1[CH:14]=[CH:15][C:10]([PH2:16]=[O:17])=[CH:11][CH:12]=1
Reactant: CCOP([O-])c1ccccc1
Reactant: Cc1ccc([Mg]Br)cc1
Agent: O=S(=O)(O)O
Solvent: CCOCC
Product: Cc1ccccc1-c1ccc([PH2]=O)cc1
Yield: 80.9 %

Procedure:
A solution of p-tolylmagnesium bromide [prepared from p-bromotolueme (29.1 g, 0.16 mol) and magnesium (4.38 g, 0.18 g-atom)] in ether (100 mL) was treated with a solution of ethyl phenylphosphonite (13,6 g, 0.08 mol) in ether (50 mL) with vigorous mechanical stirring. The mixture was heated at reflux for 1/2 hr., then 100 mL of 25% sulfuric acid was added cautiously. Three layers formed; the bottom (aqueous) layer was extracted with toluene. Addition of NaHCO3, to the combined upper layers produced a vigorous reaction and a single organic phase. The organic phase was washed with water and with saturated NaCl, dried and evaporated to give an oil (14 g). Kugelrohr distillation at 120°-160° C. (0.1 mmHg) followed by chromatography on silica gel (CHCl3), then 10% MeOH-CHCl3) gave 7.1 g of an oil. This was distilled in the Kugelrohr again (150° C., 0.1 mmHg) to give 6.2 g of product which appears to be pure by NMR and crystallized on standing. 1H NMR (CDCl3) δ 8.0-7.2 (m, 9 H), 8.08 (d, J=480 Hz, 1 H), 2.42 (s, 3 H).
Reaction SMILES: [Cl-].[CH3:2][O:3]C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].[O:34]=[C:35]1[N:43]([CH2:44][CH2:45][CH3:46])[C:42]2[NH:41][C:40]([C:47]34[CH2:54][CH2:53][C:50]([CH:55]=O)([CH2:51][CH2:52]3)[CH2:49][CH2:48]4)=[N:39][C:38]=2[C:37](=[O:57])[N:36]1[CH2:58][CH2:59][CH3:60]>C1COCC1>[O:34]=[C:35]1[N:43]([CH2:44][CH2:45][CH3:46])[C:42]2[NH:41][C:40]([C:47]34[CH2:54][CH2:53][C:50]([CH2:55][CH:2]=[O:3])([CH2:51][CH2:52]3)[CH2:49][CH2:48]4)=[N:39][C:38]=2[C:37](=[O:57])[N:36]1[CH2:58][CH2:59][CH3:60]
Reactant: CCCn1c(=O)c2nc(C34CCC(C=O)(CC3)CC4)[nH]c2n(CCC)c1=O
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCCn1c(=O)c2nc(C34CCC(CC=O)(CC3)CC4)[nH]c2n(CCC)c1=O
Reaction time: 1.5 h
Yield: 75 %

Procedure:
To a stirred suspension of methoxymethyl triphenylphosphonium chloride (1.1 g, 3.2 mmol) in THF (60 ml) at −78° C. was added a solution of KHMDS (0.5 M in toluene, 10 ml, 5 mmol). The resulting yellow mixture was stirred at this temperature for 1.5 h and a solution of 4-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]octane-1-carbaldehyde (372 mg, 1.0 mmol) in THF (12 ml) was added over a period of 20 minutes. The mixture was held at −78° C. for 6 h and allowed to reach ambient temperature overnight (12 h). The reaction mixture was partitioned between saturated aqeuous NH4Cl (100 ml) and EtOAc (100 ml) and the aqueous phase was extracted with EtOAc (50 ml). The combined organic extracts were washed with saturated aqeuous NaCl (100 ml), concentrated in vacuo, redissolved in THF and concentrated to a volume of approx. 20 ml. To the solution was added an equal volume of 1 N HCl and the mixture was stirred overnight. The mixture was diluted with EtOAc (20 ml), the aqueous phase was separated and extracted with EtOAc (10 ml). The combined organic phases were then washed with saturated aqeuous NaCI (2×, 25 ml), dried (MgSO4), filtered and concentrated in vacuo. The resulting orange oil was purified in batches by radial chromatography (2 mm plate) using 3% MeOH and 3% THF in CH2Cl2 as eluent. Product-containing fractions were combined and concentrated to afford 290 mg (75%) of a white solid. MS: 387 (MH+).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[S:29][CH:30]=[CH:31][N:32]=3)=[CH:24][CH:23]=2)=[CH:17][CH:16]=1)=O)(C)(C)C.[ClH:33].O1CCOCC1>>[ClH:33].[NH:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[S:29][CH:30]=[CH:31][N:32]=3)=[CH:24][CH:23]=2)=[CH:17][CH:16]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1ccc(Cc2ccc(-c3nccs3)cc2)cc1
Agent: Cl
Solvent: C1COCCO1
Product: c1csc(-c2ccc(Cc3ccc(OC[C@H]4CCCN4)cc3)cc2)n1
Yield: 83 %

Procedure:
The title compound (60 mg, 83%) was prepared from the product of step 1 (0.09 g, 0.21 mmol) and 4M HCl in dioxane (0.5 ml, 2.1 mmol) using the procedure of Example 146, step 4; 1HNMR (400 MHz, CD3OD) δ 9.42 (br, 1H), 8.96 (br, 1H), 7.89 (d, J=3.6 Hz, 1H), 7.86 (d, J=8.4 Hz, 2H), 7.75 (d, J=3.6 Hz, 1H), 7.32 (d, J=8.4 Hz, 2H), 7.20 (d, J=8.8 Hz, 2H), 6.93 (d, J=8.8 Hz, 2H), 4.22 (dd, J=10.4, 3.6 Hz, 1H), 4.08 (m, 1H), 3.96 (s, 2H), 3.89 (m, 1H), 3.20 (m, 2H), 2.12 (m, 1H), 1.92 (m, 2H), 1.63 (m, 1H); LC/MS (APCI+) 99%, 351 (M+1, 100); HPLC 98.5%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]3([CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]3)[CH2:9][N:8]([C:23]3[C:24]4[C@H:31]([CH3:32])[CH2:30][CH:29]([OH:33])[C:25]=4[N:26]=[CH:27][N:28]=3)[C:5]2=[CH:6][CH:7]=1.[N+:34]([C:37]1[CH:45]=[CH:44][C:40]([C:41](Cl)=[O:42])=[CH:39][CH:38]=1)([O-:36])=[O:35]>C(Cl)Cl.C([O-])(O)=O.[Na+]>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]3([CH2:11][CH2:12][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:14][CH2:15]3)[CH2:9][N:8]([C:23]3[C:24]4[C@H:31]([CH3:32])[CH2:30][C@@H:29]([O:33][C:41](=[O:42])[C:40]5[CH:39]=[CH:38][C:37]([N+:34]([O-:36])=[O:35])=[CH:45][CH:44]=5)[C:25]=4[N:26]=[CH:27][N:28]=3)[C:5]2=[CH:6][CH:7]=1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: C[C@@H]1CC(O)c2ncnc(N3CC4(CCN(C(=O)OC(C)(C)C)CC4)c4cc(Cl)ccc43)c21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: C[C@@H]1C[C@@H](OC(=O)c2ccc([N+](=O)[O-])cc2)c2ncnc(N3CC4(CCN(C(=O)OC(C)(C)C)CC4)c4cc(Cl)ccc43)c21
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 23 %

Procedure:
A solution of tert-butyl 5-chloro-1-((5R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)spiro[indoline-3,4′-piperidine]-1′-carboxylate (0.065 g, 0.14 mmol) and TEA (0.038 ml, 0.28 mmol) in DCM was cooled to about 0° C. To the mixture was added 4-nitrobenzoyl chloride (0.031 g, 0.17 mmol). The reaction was stirred at about 0° C. for about 5 minutes, then warmed to about room temperature and stirred for 1.5 hours. The reaction was diluted with DCM and saturated NaHCO3. The combined extracts were washed with brine, dried over MgSO4, filtered and concentrated. The crude residue was purified by column chromatography (30-50% EtOAc/Hexane) to yield tert-butyl 5-chloro-1-((5R,7R)-5-methyl-7-(4-nitrobenzoyloxy)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)spiro[indoline-3,4′-piperidine]-1′-carboxylate (0.020 g, 23%). LCMS (APCI+) m/z 620, 622 [M+H]+; Rt=4.65 min, and to yield tert-butyl 5-chloro-1-((5R,7S)-5-methyl-7-(4-nitrobenzoyloxy)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)spiro[indoline-3,4′-piperidine]-1′-carboxylate (0.029 g, 29%). LCMS (APCI+) m/z 620, 622 [M+H]+; Rt=4.66 min.
Reaction SMILES: C1(P(O[C:16]2[C@H:17]([CH3:40])[C@@H:18]3[C@@H:35]([C@H:36]([OH:38])[CH3:37])[C:34](=[O:39])[N:19]3[C:20]=2[C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=2)=[O:22])(C2C=CC=CC=2)=O)C=CC=CC=1.[SH:41][C@@H:42]1[CH2:46][N:45]([C:47]([O:49][CH2:50][C:51]2[CH:56]=[CH:55][C:54]([N+:57]([O-:59])=[O:58])=[CH:53][CH:52]=2)=[O:48])[C@@H:44](/[CH:60]=[CH:61]/[C:62]([N:64]2[CH2:68][CH2:67][C@H:66]([NH:69][C:70]([O:72][CH2:73][C:74]3[CH:79]=[CH:78][C:77]([N+:80]([O-:82])=[O:81])=[CH:76][CH:75]=3)=[O:71])[CH2:65]2)=[O:63])[CH2:43]1>C(#N)C.C(N(C(C)C)CC)(C)C>[N+:57]([C:54]1[CH:53]=[CH:52][C:51]([CH2:50][O:49][C:47]([N:45]2[CH2:46][C@@H:42]([S:41][C:16]3[C@H:17]([CH3:40])[C@@H:18]4[C@@H:35]([C@H:36]([OH:38])[CH3:37])[C:34](=[O:39])[N:19]4[C:20]=3[C:21]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=3)=[O:22])[CH2:43][C@@H:44]2/[CH:60]=[CH:61]/[C:62]([N:64]2[CH2:68][CH2:67][C@H:66]([NH:69][C:70]([O:72][CH2:73][C:74]3[CH:75]=[CH:76][C:77]([N+:80]([O-:82])=[O:81])=[CH:78][CH:79]=3)=[O:71])[CH2:65]2)=[O:63])=[O:48])=[CH:56][CH:55]=1)([O-:59])=[O:58]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(OP(=O)(c3ccccc3)c3ccccc3)[C@H](C)[C@H]12
Reactant: O=C(N[C@H]1CCN(C(=O)/C=C/[C@H]2C[C@H](S)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)C1)OCc1ccc([N+](=O)[O-])cc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@H](/C=C/C(=O)N4CC[C@H](NC(=O)OCc5ccc([N+](=O)[O-])cc5)C4)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)[C@H](C)[C@H]12
Reaction time: 24 h
Yield: 70.5 %

Procedure:
To a solution of 4-nitrobenzyl (1R,5R,6S)-2-(diphenylphosphoryloxy)-6-[(1R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate (1.01 g) in anhydrous acetonitrile (10 ml), a solution of (2R,4S)-4-mercapto-1-(4-nitrobenzyloxycarbonyl)-2-[(3S)-3-(4-nitrobenzyloxycarbonylamino)pyrrolidin-1-ylcarbonyl-(E)-ethenyl]-pyrrolidine (972 mg) in anhydrous acetonitrile (10 ml) and diisopropylethylamine (0.296 ml) were added under ice cooling. The resulting mixture was allowed to stand at the same temperature for one day. The reaction mixture was concentrated by evaporation under reduced pressure and the residue was extracted with ethyl acetate. The extract was washed successively with water and saline and then dried over anhydrous sodium sulfate. The solvent was distilled off. The residue was subjected to chromatography on a silica gel column and eluted with methylene chloride-acetone of ratio from (6:1) to (1:1). Desired fractions were combined, followed by distilling off, whereby 4-nitrobenzyl (1R,5S,6S)-2-[(2R,4S)-1-(4-nitrobenzyloxycarbonyl)-2-[(3S)-3-(4-nitrobenzyloxycarbonylamino)pyrrolidin-1-ylcarbonyl-(E)-ethenyl]pyrrolidin-4-ylthio]-6-[(1R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate (1.079 g) was obtained as a powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:6]([CH2:7][NH:8][C:9]2[C:10](=[O:21])[N:11]([CH2:17][C:18]([OH:20])=[O:19])[C:12]([CH3:16])=[C:13](Cl)[N:14]=2)=[CH:5][CH:4]=1.CO>[OH-].[Na+].[Ni]>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][NH:8][C:9]2[C:10](=[O:21])[N:11]([CH2:17][C:18]([OH:20])=[O:19])[C:12]([CH3:16])=[CH:13][N:14]=2)=[CH:22][CH:23]=1
Reactant: COc1ccc(CNc2nc(Cl)c(C)n(CC(=O)O)c2=O)cc1
Agent: [Ni]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(CNc2ncc(C)n(CC(=O)O)c2=O)cc1
Reaction time: 6 h

Procedure:
The acid 18-5 (810 mg) was dissolved in 40 mL 1 N NaOH and 40 mL MeOH at room temperature and was treated with Raney nickel suspension (˜5 g). A second charge of Raney nickel (˜5 g) and 1 N NaOH (20 mL) was added after 3 h. After 6 h, the suspension was filtered through celite washing with water and MeOH. The volatiles were removed in vacuo and the residue then taken up 1 N HCl (˜5 mL). Saturated NaHCO3 solution was added until pH˜7-8 and the solution was extracted exhaustively with EtOAc/THF. After drying (MgSO4), the solvent was removed to give the title compound 18-6 as a solid which was used as such:
Reaction SMILES: [CH:1]([C:9]1[CH:14]=[CH:13][C:12](S([O-])(=O)=O)=[CH:11][CH:10]=1)=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Na+].[NH2-:20].[Na+].N>>[NH2:20][C:12]1[CH:13]=[CH:14][C:9]([CH:1]=[CH:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)=[CH:10][CH:11]=1
Reactant: [NH2-]
Reactant: O=S(=O)([O-])c1ccc(C=Cc2ccccc2)cc1
Agent: N
Agent: [Na+]
Product: Nc1ccc(C=Cc2ccccc2)cc1
Yield: 101.6 %

Procedure:
In a 200-ml autoclave were placed 18.6 grams (0.06 mole) of anhydrous sodium p-styrylbenzene sulfonate, 5.2 grams (0.13 mole) of sodium amide and 50 ml of liquid ammonia in the same manner as in Example 1. The resultant mixture was heated at 120° C for 6 hours. The reaction pressure in the autoclave was 90 atm. during the reaction. After the ammonia was removed, 10 ml of water was added to the reaction mixture for hydrolysis. The product was extracted with ether and the ether was distilled off to produce crude 4-aminostilbene. The recrystallization thereof from ethanol gave 11.9 grams of 4-aminostilbene having a melting point of 151° to 152° C. Yield was 88.5%.