Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[CH2:3]([C@@H:5]1[CH2:9][C@@H:8]([OH:10])[CH2:7][C@@H:6]1[C:11]([O:13]CC)=[O:12])[CH3:4].CCOCC>C([C@@H]1C[C@@H](O)C[C@@H]1C(O)=O)C>[CH2:3]([CH:5]1[CH2:9][CH:8]([OH:10])[CH2:7][CH:6]1[C:11]([OH:13])=[O:12])[CH3:4]
Reactant: CCOC(=O)[C@H]1C[C@H](O)C[C@H]1CC
Agent: CC[C@@H]1C[C@@H](O)C[C@@H]1C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: CCC1CC(O)CC1C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Aqueous sodium hydroxide (1N, 32.4 mL, 32.4 mmol) was added to a scalemic mixture enriched in (1S,2R,4R)-ethyl 2-ethyl-4-hydroxycyclopentanecarboxylate (3.02 g, 16.21 mmol) and the reaction mixture was stirred at ambient temperature overnight. Ether (15 mL) was added and the layers were separated. The aqueous layer was cooled to about 0° C. Aqueous HCl (5N) was slowly added to bring pH to about 1. The aqueous suspension was extracted with EtOAc (4×40 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous MgSO4, filtered and concd under reduced pressure to give a scalemic mixture enriched in (1S,2R,4R)-2-ethyl-4-hydroxycyclopentanecarboxylic acid (2.56 g, 100%): LC/MS (Table 1, Method b) Rt=1.36 min; MS m/z: 157 (M−H)−.
Reaction SMILES: [CH:1](NC(C)C)(C)C.C([Li])CCC.[Br:13][C:14]1[CH:15]=[C:16]([CH2:20][C:21]([OH:23])=[O:22])[CH:17]=[CH:18][CH:19]=1.CI.[Cl-].[Na+].Cl>C1COCC1>[Br:13][C:14]1[CH:15]=[C:16]([CH:20]([CH3:1])[C:21]([OH:23])=[O:22])[CH:17]=[CH:18][CH:19]=1
Reactant: O=C(O)Cc1cccc(Br)c1
Reactant: CC(C)NC(C)C
Agent: Cl
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CI
Solvent: C1CCOC1
Product: CC(C(=O)O)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 84.5 %

Procedure:
To a solution of diisopropylamine (0.97 g, 9.6 mmol) in THF (20 mL) at room temperature was added n-butyl lithium (2.5 N in hexane, 4 mL, 10 mmol) and the resulting solution was stirred at room temperature for 15 minutes. To above solution was added a solution of 3-bromophenylacetic acid (1.0 g, 4.6 mmol) in THF (10 mL) dropwise at room temperature and the stirring was continued for another 15 minutes. Methyl iodide (1.49 g, 10.5 mmol) was added and the resulting mixture was stirred at room temperature for 15 minutes. Satuated sodium chloride (30 mL) was added and the aqueous phase was adjusted to pH 5 by addition of hydrochloric acid (1 N). The resulting mixture was extracted with ethyl acetate (20 mL×3) and the combined organic extracts were dried over sodium sulfate, filtered, and concentrated. The residue was purified by flash chromatography on silica gel using a gradient of formic acid and methanol in dichloromethane to afford 2-(3-bromo-phenyl)-propionic acid (890 mg, 84%) as a white solid. MS: m/z 229 (M+H+).
Reaction SMILES: COC1C=CC(C[N:8]2[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][N:12]=[CH:13][CH:14]=3)[C:9]2=[O:18])=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.CO.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(Cl)(Cl)Cl>[C:9]1(=[O:18])[C:10]2[C:15](=[CH:14][CH:13]=[N:12][CH:11]=2)[CH2:16][CH2:17][NH:8]1
Reactant: COc1ccc(CN2CCc3ccncc3C2=O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: Cc1ccccc1
Product: O=C1NCCc2ccncc21
Yield: 72.4 %

Procedure:
2-(4-Methoxybenzyl)-3,4-dihydro-2,7-naphthyridin-1(2H)-one (I-65e: 700 mg, 2.6089 mmol) and p-toluene sulphonic acid (1.985 g, 10.436 mmol) in toluene (15 mL) were refluxed for 6 hours. The reaction was monitored by TLC (10% methanol in CHCl3). The reaction mass was neutralized with sodium carbonate solution, distilled off the solvent and added 10% methanol in CHCl3. The solid precipitated was filtered and distilled off the solvent to afford the crude product. Purification by column chromatography on silica gel (7% methanol in DCM) afforded 280 mg of the product (72.53% yield).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11][C:10]3[CH:12]=[C:13]([C:16]([OH:18])=[O:17])[CH:14]=[CH:15][C:9]=3[CH:8]=[CH:7][C:6]=2[CH:19]=1.[CH3:20]N(C)C=O.C(=O)([O-])[O-].[K+].[K+].CI>O>[CH3:20][O:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11][C:10]3[CH:12]=[C:13]([C:16]([OH:18])=[O:17])[CH:14]=[CH:15][C:9]=3[CH:8]=[CH:7][C:6]=2[CH:19]=1
Reactant: O=C(O)c1ccc2c(c1)Sc1ccc(O)cc1C=C2
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CI
Product: COc1ccc2c(c1)C=Cc1ccc(C(=O)O)cc1S2

Procedure:
1 G. 8-hydroxydibenzo[b,f]thiepin-3-carboxylic acid is stirred in 50 cc. dimethylformamide with 1.5 g. potassium carbonate and 3 cc. methyl iodide. 100 cc. water is added to the reaction mixture, heated for three hours and then extracted with ethyl acetate, and the aqueous layer acidified. The precipitated solid is filtered, washed with water and a small volume of cold methanol, and dried. Yield of the desired material 700 mg.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N:11]1[C:15]2[CH2:16][CH2:17][CH2:18][CH2:19][C:14]=2[N:13]=[C:12]1[CH3:20])[C:5]([OH:7])=O.C(N(C(C)C)CC)(C)C.[Cl:30][C:31]1[CH:42]=[CH:41][C:34]2[NH:35][C:36]([C@@H:38]([NH2:40])[CH3:39])=[N:37][C:33]=2[CH:32]=1.ClCl>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N:11]1[C:15]2[CH2:16][CH2:17][CH2:18][CH2:19][C:14]=2[N:13]=[C:12]1[CH3:20])[C:5]([NH:40][C@H:38]([C:36]1[NH:35][C:34]2[CH:41]=[CH:42][C:31]([Cl:30])=[CH:32][C:33]=2[N:37]=1)[CH3:39])=[O:7]
Reactant: C[C@H](N)c1nc2cc(Cl)ccc2[nH]1
Reactant: Cc1nc2c(n1-c1ccc(C(=O)O)cc1Cl)CCCC2
Agent: ClCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc2c(n1-c1ccc(C(=O)N[C@@H](C)c3nc4cc(Cl)ccc4[nH]3)cc1Cl)CCCC2
Yield: 35 %

Procedure:
Prepared analogously to Example 1d from 3-chloro-4-(2-methyl-4,5,6,7-tetrahydrobenzimidazol-1-yl)benzoic acid, PFTU, diisopropylethylamine, and (1S)-1-(5-chloro-1H-benzimidazol-2-yl)ethylamine in dimethylformamide. Yield: 35%; C24H23Cl2N5O (468.386); mass spectrum: (M+H)+=466/468/470 (chlorine isotope).
Reaction SMILES: [C:1]([Mg]Br)#[CH:2].[CH3:5][N:6]1[CH2:11][CH2:10][CH2:9][C:8](=[O:12])[C:7]1=[O:13]>O1CCCC1>[C:1]([C:8]1([OH:12])[CH2:9][CH2:10][CH2:11][N:6]([CH3:5])[C:7]1=[O:13])#[CH:2]
Reactant: C#C[Mg]Br
Reactant: CN1CCCC(=O)C1=O
Solvent: C1CCOC1
Product: C#CC1(O)CCCN(C)C1=O
Reaction time: 0.02 h
Yield: 30 %

Procedure:
To a solution of ethynylmagnesium bromide (0.5M in tetrahydrofuran, 4 mL, 2 mmol) maintained under nitrogen at −20° C. was added a solution of 1-methylpiperidine-2,3-dione (220 mg, 0.87 mmol) in tetrahydrofuran (3 mL) dropwise with stirring within 1 min. The reaction mixture was stirred for 2 hr at room temperature and then quenched by the addition of saturated ammonium chloride solution (1 mL). The mixture was diluted with DCM (50 mL), dried over anhydrous sodium sulfate and concentrated under vacuum. The crude residue was purified on a silica gel column, elution with ethyl acetate/petroleum ether (0:1-1:0) afforded the title compound (40 mg, 30%) as a brown oil: 1H NMR (400 MHz, CDCl3) delta 4.23 (s, 1H), 3.35-3.30 (m, 2H), 2.95 (s, 3H), 2.47 (s, 1H), 2.35-2.16 (m, 2H), 1.97-1.90 (m, 2H). LC-MS m/z=+154 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5](Cl)[CH2:4][CH2:3]1.[Mg].Cl[CH:11]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[CH:15]=[CH:14][C:13]2[CH:22]=[CH:23][CH:24]=[CH:25][C:12]1=2>O1CCCC1.C1C=CC=CC=1.O>[CH:22]1[C:13]2[CH:14]=[CH:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[CH:11]([CH:5]3[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]3)[C:12]=2[CH:25]=[CH:24][CH:23]=1
Reactant: ClC1c2ccccc2C=Cc2ccccc21
Reactant: CN1CCC(Cl)CC1
Agent: [Mg]
Solvent: c1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: CN1CCC(C2c3ccccc3C=Cc3ccccc32)CC1

Procedure:
A Grignard solution prepared from 13.4 grams (0.1 mole) of 1-methyl-4-chloropiperidine, 2.43 grams (0.1 gram atom) of magnesium and 100 milliliters of tetrahydrofuran is added dropwise with stirring to a cooled solution of 17.0 grams (0.075 mole) of 5-chloro-5H-dibenzo[a,d]cycloheptene in 100 milliliters of tetrahydrofuran. After completion of the addition, stirring is continued for several hours at ambient temperature. The solvent is then vaporized under reduced pressure to obtain a residue which is dissolved in a biphasic mixture of benzene and water. The benzene solution is washed, dried filtered and the solvent vaporized as previously described to obtain the desired 4-(5H-dibenzo[a,d]cyclohepten-5-yl)-1-methylpiperidine, equational isomer as residue.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:8])[CH2:5][C:6]#[N:7])[CH3:2].[O-]CC.[Na+].[Br-].Br[CH2:15][CH2:16][CH2:17][S:18][C:19]1[CH:29]=[CH:28][C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:21][CH:20]=1>C(O)C>[C:6]([CH:5]([C:4]([O:3][CH2:1][CH3:2])=[O:8])[CH2:15][CH2:16][CH2:17][S:18][C:19]1[CH:29]=[CH:28][C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:21][CH:20]=1)#[N:7]
Reactant: CCOC(=O)CC#N
Reactant: CCOC(=O)c1ccc(SCCCBr)cc1
Agent: CC[O-]
Agent: [Br-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1ccc(SCCCC(C#N)C(=O)OCC)cc1
Yield: 71.4 %

Procedure:
Ethylcyanoacetate (6.30 g, 55.7 mmoles) was added to a solution of sodium ethoxide (50 mmoles) in ethanol (25 mL) and refluxed 15 minutes. After cooling, the mixture was treated with bromide, 1A, (7.68 g, 25.3 mmoles) as a solution in ethanol (25 mL) and refluxed for 6 hours. The mixture was filtered, and the filtrate was treated with acetic acid to pH 7.0 and was evaporated to a viscous residue. The residue was partitioned between water (50 mL) and ether (50 mL), and the ether phase collected. The aqueous phase was washed with 4 volumes (50 mL) of ether, and the combined ether fractions were dried (CaSO4) and filtered. The filtrate was evaporated in vacuo, and the residue chromatographed (400 g silica, 3:1 hexane/ethyl acetate) to yield 6.06 g (70%) of the title compound, 1B, as a pale yellow oil. NMR (DMSO-d6) δ1.17 (t, 3H, CH3 of benzoate ether), 1.7 (m, 2H, CH2CH2 --CH2), 1.95 (m, 2H, CH2 --CH2CH2 --S), 1.28 (t, 3H, CH3 of acetate ester), 3.1 (m, 2H, CH2 --S), 4.15 (m, 1H, CH), 4.15 (q, 2H, CH2 of benzoate ester), 4.28 (q, 2H, CH2 of acetate ester), 7.4 (d, 2H, benzoate H's ortho to S), 7.85 (d, 2H, benzoate H's ortho to carbonyl). Compound 1B was used in the next reaction without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:13])=[CH:7][C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1.[CH2:14]([OH:18])[C:15](O)=[O:16]>O>[OH:18][CH2:14][C:15]([NH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:13])=[CH:7][C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1)=[O:16]
Reactant: Cc1cc(=O)oc2cc(N)ccc12
Reactant: O=C(O)CO
Solvent: O
Product: Cc1cc(=O)oc2cc(NC(=O)CO)ccc12
Reaction time: 0.5 h

Procedure:
8.7 g of 7-amino-4-methyl-coumarin are stirred, under nitrogen, in a round-bottomed flask, together with 7.6 g of glycollic acid at an oil bath temperature of 150°-160°. The reaction mass becomes crystalline after about 30 minutes. It is diluted with water and the product is filtered off with suction and recrystallised from 200 ml of dimethylformamide and 100 ml of ethanol. 7-Hydroxyacetamido-4-methyl-coumarin with a melting point of 253°-254° is obtained.
Reaction SMILES: [F:1][CH2:2][CH2:3][O:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]2)=[CH:8][CH:7]=1.[ClH:25]>O1CCOCC1>[ClH:25].[F:1][CH2:2][CH2:3][O:4][CH2:5][C:6]1[CH:7]=[CH:8][C:9]([N:12]2[CH2:13][CH2:14][NH:15][CH2:16][CH2:17]2)=[CH:10][CH:11]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(COCCF)cc2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: FCCOCc1ccc(N2CCNCC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
Tert-butyl 4-(4-((2-fluoroethoxy)methyl)phenyl)piperazine-1-carboxylate (100 mg, 0.29 mmol) was dissolved in a 4.0M solution of HCl in dioxane (1 mL) and stirred at room temperature. After 1 h, 1-(4-((2-fluoroethoxy)methyl)-phenyl)piperazine hydrochloride was collected as a white solid via filtration (74 mg, 91% yield). 1H NMR (300 MHz, DMSO-d6): δ 10.45 (br s, 1H), 9.71 (br s, 1H), 7.26 (d, 2H, J=8.7 Hz), 7.05 (d, 2H, J=8.7 Hz), 4.61 (m, 1H), 4.45 (m, 1H), 4.43 (s, 2H), 3.67 (tn, 1H), 3.57 (m, 1H), 3.45 (dd, 4H, J=5.5, 4.9 Hz), 3.22 (m, 4H); 19F NMR (282.4 MHz, CDCl3): δ−221.40 (m, 1F); 13C NMR (75.5 MHz, DMSO): δ 148.5, 130.7, 128.9, 116.4, 84.0 (82.0), 71.7, 68.7 (68.6), 46.0, 42.2; HRMS calcd for C13H19FN2O: 239.15542 found 239.15540.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(Cl)(Cl)=O.[CH3:16]O>>[Br:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:16])=[O:5]
Reactant: Cc1ccc(C(=O)O)c(Br)c1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(C)cc1Br
Yield: 97 %

Procedure:
To a solution of 2-bromo-4-methylbenzoic acid (21.5 g, 100 mmol) in MeOH (250 mL) was added thionyl chloride (10.9 mL, 150 mmol) dropwise and then the reaction mixture was refluxed for 4 h. MeOH was distilled out and water was added. It was extracted with EA and the organic layer was washed with saturated sodium bicarbonate solution, brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography over silica gel eluted with PE-EA (20:1) to give methyl 2-bromo-4-methylbenzoate (22.3 g, yield 97%) as colorless oil.
Reaction SMILES: [C:1]1([CH:7]2[O:11][CH:10]([CH2:12][O:13][CH3:14])[CH2:9][O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:15]N1C(=O)CCC1=O.CCCCCCC.C(OCC)(=O)C>ClC(Cl)C>[C:7]([O:11][CH:10]([CH2:12][O:13][CH3:14])[CH2:9][Br:15])(=[O:8])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COCC1COC(c2ccccc2)O1
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Solvent: CC(Cl)Cl
Product: COCC(CBr)OC(=O)c1ccccc1
Reaction time: 1 h
Yield: 93 %

Procedure:
To a solution of 13.6 g (0.07 mol) of 2-phenyl 4-methoxymethyl 1,3-dioxolane (S) (Austr. J. Chem. 761, 29, 1976) in 40 ml of dichloroethane, are gradually added 12.5 g (0.07 mol) of N-bromosuccinimide while keeping temperature at 25° C. After 1 h of stirring, the reaction medium is poured on water. The organic phase is washed with a solution of sodium thiosulphate, and then with water, dried over magnesium sulphate and concentrated. The product is obtained with a 93% yield, after chromatography (Silica, Heptane:60. Ethyl acetate:40).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:21]=[CH:20][C:10]([N:11]([Si](C)(C)C)[Si](C)(C)C)=[CH:9][CH:8]=1.[C:22](=[N:25][S:26]([C:28]([CH3:31])([CH3:30])[CH3:29])=[O:27])([CH3:24])[CH3:23]>C1COCC1>[NH2:11][C:10]1[CH:20]=[CH:21][C:7]([C:22]([NH:25][S:26]([C:28]([CH3:31])([CH3:30])[CH3:29])=[O:27])([CH3:24])[CH3:23])=[CH:8][CH:9]=1
Reactant: CC(C)=NS(=O)C(C)(C)C
Reactant: C[Si](C)(C)N(c1ccc(Br)cc1)[Si](C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(NS(=O)C(C)(C)C)c1ccc(N)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 12 %

Procedure:
A solution of n-butyllithium in hexanes (1.65 M, 5.2 mL) was added dropwise to a solution of 4-bromo-N,N-bis(trimethylsilyl)aniline (2.55 mL) in THF (14 mL) at −78° C. The resulting mixture was stirred for 1.5 h at −78° C. before a solution of N-isopropylidene-2-methylpropane-2-sulfinamide in THF (2.8 mL) was added dropwise at −78° C. The reaction mixture was stirred for an additional 1 h at −78° C. then allowed to warm to room temperature. After being stirred for 18 h at room temperature, the reaction mixture was poured into ice cooled saturated sodium bicarbonate solution. The aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with saturated sodium bicarbonate solution and brine and then dried over anhydrous sodium sulfate. The dried solution was filtered and the filtrate was concentrated to dryness. The residue was diluted with diisopropylether and extracted with 1 M citric acid solution. The aqueous extracts were combined and basified with sodium bicarbonate solid to pH>7. The basic aqueous layer was extracted with ethyl acetate and the organic layer was washed with brine. The organics were dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification by column chromatography (50-100% ethyl acetate in hexanes) gave the product (173 mg, 12%). 400 M Hz 1H-NMR (CDCl3) δ: 7.26 (d, J=8.7 Hz, 2H), 6.65 (d, J=8.7 Hz, 2H), 3.66 (brs, 1H), 3.31 (s, 1H), 1.67 (s, 3H), 1.64 (s, 3H), 1.20 (s, 9H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[CH2:7]/[N:8]=[CH:9]/[CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:4])([CH3:3])[CH3:2].[Br:16][C:17]1[CH:22]=[CH:21][C:20](/[C:23](=[CH:26]/[C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[C:28]=2[F:34])/[C:24]#[N:25])=[CH:19][CH:18]=1.C(N(CC)CC)C>ClCCl>[C:1]([O:5][C:6]([CH:7]1[CH:26]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[C:28]=2[F:34])[C:23]([C:20]2[CH:19]=[CH:18][C:17]([Br:16])=[CH:22][CH:21]=2)([C:24]#[N:25])[CH:9]([CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])[NH:8]1)=[O:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: N#C/C(=C\c1cccc(Cl)c1F)c1ccc(Br)cc1
Reactant: CC(C)(C)C/C=N/CC(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)CC1NC(C(=O)OC(C)(C)C)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Br)cc1
Yield: 55.6 %

Procedure:
In a manner similar to the method described in Example 1c, [3,3-dimethyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester prepared in Example 1a (1.1 g, 5 mmol) was reacted with (Z)-2-(4-bromo-phenyl)-3-(3-chloro-2-fluoro-phenyl)-acrylonitrile (1.2 g, 3.6 mmol) prepared in Example 54a, AgF (1.3 g, 10 mmol), and triethylamine (2 g, 20 mmol) in dichloromethane (100 mL) at room temperature for 3 h to give rac-(2R,3S,4R,5S)-4-(4-bromo-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester as a white foam (1.1 g, 56%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][CH2:14][CH2:15][CH2:16][C@@H:17]([C:36]([OH:38])=[O:37])[NH:18][C:19]([O:21][CH2:22][CH:23]2[C:35]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[C:29]3[C:24]2=[CH:25][CH:26]=[CH:27][CH:28]=3)=[O:20])(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-])=O>CO.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([S:10]([NH:13][CH2:14][CH2:15][CH2:16][C@@H:17]([C:36]([OH:38])=[O:37])[NH:18][C:19]([O:21][CH2:22][CH:23]2[C:35]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[C:29]3[C:24]2=[CH:25][CH:26]=[CH:27][CH:28]=3)=[O:20])(=[O:11])=[O:12])=[CH:8][CH:9]=1
Reactant: O=C(N[C@@H](CCCNS(=O)(=O)c1ccc([N+](=O)[O-])cc1)C(=O)O)OCC1c2ccccc2-c2ccccc21
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(S(=O)(=O)NCCC[C@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)O)cc1
Yield: 96 %

Procedure:
The product obtained from example 28 (54.0 mg, 0.10 mmol) was dissolved in MeOH (5 mL) and then hydrogenated using 10% Pd/C as catalyst at atmospheric pressure for 1 h. The catalyst was filtered off and the filtrate was evaporated in vacuo to yield 96% of the title compound.
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([NH:14][C:15](=[NH:20])[CH2:16][CH2:17][CH2:18][CH3:19])=[O:13])=[CH:7][CH:6]=1)([O-])=O.[OH-].[Na+]>O>[NH2:2][C:5]1[CH:6]=[CH:7][C:8]([NH:11][C:12]([NH:14][C:15](=[NH:20])[CH2:16][CH2:17][CH2:18][CH3:19])=[O:13])=[CH:9][CH:10]=1
Reactant: CCCCC(=N)NC(=O)Nc1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCCC(=N)NC(=O)Nc1ccc(N)cc1

Procedure:
A solution of 30 g. of 1-(4-nitrophenyl)-3-(pentanimidoyl)urea hydrochloride (see Example 9) in 300 ml. ice-cold water was treated with 8 g. sodium hydroxide in 40 ml. water. The mixture was extracted with ether and the ethereal solution was dried over calcium sulfate and evaporated to dryness. The residue was taken up in 400 ml. absolute alcohol and hydrogenated over Raney nickel at 392 pounds pressure and at room temperature until the hydrogen uptake was complete. The catalyst was removed by filtration and the solvent was removed under reduced pressure at 50°C. to give after recrystallization successively from ether and benzene 13.5 g. of 1-(4-aminophenyl)-3-(pentanimidoyl)urea; m.p. 102°-103°C.
Reaction SMILES: [OH:1][CH:2]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH:4]=[CH:3]1>CCCCCCC.[O-2].[O-2].[Mn+4]>[CH:4]1[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:2](=[O:1])[CH:3]=1
Reactant: OC1C=CCCCCCCCCCCCC1
Agent: [Mn+4]
Agent: [O-2]
Solvent: CCCCCCC
Product: O=C1C=CCCCCCCCCCCCC1
Reaction time: 22 h

Procedure:
3-Hydroxycyclopentadecene (20.1 g) in dried n-heptane was stirred at room temperature and a total of 100 g manganese dioxide was added in four batches of 50, 25, 15 and 10 g respectively over a period of 6 hours. After 22 hours the conversion as indicated by GLC was 100%. The mixture was filtered and the filtrate was then stirred with active charcoal and refiltered. The solvent was then removed from the filtrate under reduced pressure to yield the required product.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[CH2:4][CH2:5][CH2:6]/[CH:7]=[CH:8]\[CH2:9][C@@H:10]1[C@@H:14]([C@@H:15]([OH:25])/[CH:16]=[CH:17]/[C:18]([CH3:24])([CH3:23])[CH2:19][CH2:20][CH2:21][CH3:22])[C@H:13]([CH3:26])[CH2:12][C:11]1=[O:27].N1C=CC=CC=1.[C:35](OC(=O)C)(=[O:37])[CH3:36]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:1][O:2][C:3](=[O:28])[CH2:4][CH2:5][CH2:6]/[CH:7]=[CH:8]\[CH2:9][C@@H:10]1[C@@H:14]([C@@H:15]([O:25][C:35](=[O:37])[CH3:36])/[CH:16]=[CH:17]/[C:18]([CH3:23])([CH3:24])[CH2:19][CH2:20][CH2:21][CH3:22])[C@H:13]([CH3:26])[CH2:12][C:11]1=[O:27]
Reactant: CCCCC(C)(C)/C=C/[C@H](O)[C@H]1[C@H](C)CC(=O)[C@@H]1C/C=C\CCCC(=O)OC
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCC(C)(C)/C=C/[C@H](OC(C)=O)[C@H]1[C@H](C)CC(=O)[C@@H]1C/C=C\CCCC(=O)OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of the crude optically active (5Z,11alpha, 13S,14E)-13-(hydroxy)-11,16,16-trimethyl-9-oxoprosta-5,14-dien-1-oic acid methyl ester (9.2 g) in methylene chloride (100 mL) was treated with pyridine (5.5 mL) and 4-dimethylaminopyridine (0.5 g), cooled to 0°, and treated with acetic anhydride (3.4 mL). The resulting mixture was stirred overnight at room temperature and then washed with 2N HCL, water, NaHCO3 solution, and brine (75 mL of each). After drying over sodium sulfate, the solvent was stripped off leaving 9.7 g (~100%) of crude optically active (5Z,11alpha,13S,14E)-13-(acetyloxy)-11,16,16-trimethyl-9-oxoprosta-5,14-dien-1-oic acid methyl ester as a yellow oil. This material was used as is in Example XXII.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:18]=1[CH:17]=[C:16]([OH:19])[CH:15]=[CH:14]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Si:20](Cl)([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21].N1C=CN=C1>>[C:1]([O:5][C:6]([NH:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])[CH:17]=2)[CH:12]=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cccc2ccc(O)cc12
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Product: CC(C)(C)OC(=O)Nc1cccc2ccc(O[Si](C)(C)C(C)(C)C)cc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 8-(tert-butoxycarbonylamino)-2-naphthol, as described above in Step A, (43.2 g, 0.167 mol), tert-butyldimethylsilyl chloride (32.7 g, 0.217 mol), and imidazole (25.0 g, 0.367 mol) in dry, degassed DMF (400 mL) was stirred, under argon, at ambient temperature for 30 min. The solvent was removed under reduced pressure and the residue was partitioned between H2O (1 L) and Et2O (2 L). The aqueous layer was extracted further with Et2O (1 L) and the combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography on silica, eluting with hexane—50% CH2Cl2 to yield the desired product as a pale solid.