Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC(=O)[C@H:4]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[NH:5][C:6](=[O:23])[CH2:7][N:8]([C:16](OC(C)(C)C)=[O:17])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.S(Cl)(Cl)=O>CO>[CH2:9]([N:8]1[CH2:7][C:6](=[O:23])[NH:5][CH:4]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:16]1=[O:17])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)CN(Cc1ccccc1)C(=O)OC(C)(C)C
Solvent: O=S(Cl)Cl
Solvent: CO
Product: O=C1CN(Cc2ccccc2)C(=O)C(Cc2ccccc2)N1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 91.9 %

Procedure:
To a 0° C. solution of dipeptide 5 (2.18 g, 5.11 mmol) in methanol (30 mL) was slowly added excess thionyl chloride (1.9 mL). The solution stirred at ambient temperature for 2.5 h. The solvent was evaporated and the residue was triturated with ˜30 mL of ether, producing a white solid that was collected by filtration. The solid was dissolved in methanol (40 mL) and treated with ammonium hydroxide (29%, 10 mL) and then stirred for 18 h followed by concentration. The solid residue was partitioned between saturated NaHCO3 (40 mL), water (20 mL) and CHCl3:isopropyl alcohol, 4:1 (40 mL). The organic phase was separated and the aqueous phase extracted with CHCl3:isopropyl alcohol, 4:1 (3×40 mL). The combined organic phases were dried (K2CO3) and concentrated to afford 6 as a white solid (1.382 g, 92% yield). 1H NMR (400 MHz, CDCl3): δ 2.99 (d, part of AB pattern, J=17.6 Hz, 1H), 3.17 (m, AB pattern, 2H), 3.52 (d, part of AB pattern, J=17.6 Hz, 1H), 4.35 (m, 1H), 4.48 (m, AB pattern, J=14.7 Hz, 1H), 6.39 (bs, NH, 1H), 7.13-7.35 (m, 10H, overlapped with CDCl3); 13C NMR (100 MHz, CDCl3): δ 40.5, 48.2, 49.6, 56.4, 127.4, 128.1, 128.59, 128.63, 128.8, 130.0, 134.65, 134.68, 165.2, 166.3.
Reaction SMILES: C([O:8][C:9](=[O:31])[C@@H:10]1[CH2:14][CH2:13][CH2:12][N:11]1[C:15](=[O:30])[CH:16]([CH2:26][CH:27]([CH3:29])[CH3:28])[NH:17][C:18](=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)C1C=CC=CC=1.[H][H]>CO.[C].[Pd]>[C:18]([NH:17][CH:16]([C:15]([N:11]1[CH2:12][CH2:13][CH2:14][C@H:10]1[C:9]([OH:31])=[O:8])=[O:30])[CH2:26][CH:27]([CH3:29])[CH3:28])(=[O:25])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: [H][H]
Reactant: CC(C)CC(NC(=O)c1ccccc1)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC(C)CC(NC(=O)c1ccccc1)C(=O)N1CCC[C@H]1C(=O)O
Yield: 95.3 %

Procedure:
N-benzoyl-D,L-leucyl-L-proline benzyl ester (2 g) was dissolved in methanol (40 ml), and 10% palladium-carbon (200 mg) was added. The resulting mixture aerated with hydrogen was allowed to react at room temperature for 3 h, filtered and concentrated under reduced pressure to remove the solvent to give a white foam-like solid (1.5 g, 98%), which was directly used for the next reaction.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[Cl:12][C:13]1[C:14]([NH:21][CH:22]2[CH2:27][CH2:26][C:25](=[CH:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH2:24][CH2:23]2)=[N:15][CH:16]=[N:17][C:18]=1[CH2:19][CH3:20]>ClCCl>[Cl:12][C:13]1[C:14]([NH:21][CH:22]2[CH2:27][CH2:26][C:25]3([O:9][CH:28]3[CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH2:24][CH2:23]2)=[N:15][CH:16]=[N:17][C:18]=1[CH2:19][CH3:20]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCCC=C1CCC(Nc2ncnc(CC)c2Cl)CC1
Solvent: ClCCl
Product: CCCCCC1OC12CCC(Nc1ncnc(CC)c1Cl)CC2
Reaction time: 4 h

Procedure:
A solution of 4.0 g (0.02 mol) of m-chloroperbenzoic acid (85% strength) in 25 ml of dichloromethane was slowly added dropwise at 0° C. to a solution of 6.4 g (0.02 mol) of 5-chloro-6-ethyl-4-(4-hexylidenecyclohexylamino)pyrimidine (WO 95 07894) in 25 ml of dichloromethane. Stirring of the mixture was continued at room temperature for 4 hours. After the mixture had been allowed to stand overnight, it was extracted by stirring with aqueous sodium hydrogen carbonate solution, and the organic phase was dried and concentrated. The crude product was chromatographed on silica gel (petroleum ether/ethyl acetate 4:1). First, 1.8 g (265.6% of theory) of the isomer having the higher Rf value (0.62) were eluted (colorless crystals, m.p.: 41°-42° C.), followed by 1.2 g (18.2% of theory) of isomer mixture and 0.22 g (3.3% of theory) of the isomer having the lower Rf value (0.53) as a colorless oil.
Reaction SMILES: [C:1]([O:9][CH2:10][CH2:11][CH:12](OCC)[O:13]CC)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C(OCC)C>O1CCCC1>[C:1]([O:9][CH2:10][CH2:11][CH:12]=[O:13])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(CCOC(=O)c1ccccc1)OCC
Agent: Cl
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=CCCOC(=O)c1ccccc1
Yield: 69.5 %

Procedure:
A solution of 57.0 grams (0.226 mole) of 3-ethoxy-4-oxahexyl benzoate in 475 ml of tetrahydrofuran and 475 ml of aqueous 10% hydrochloric acid was stirred at ambient temperature for 18 hours. After this time the reaction mixture was stirred with 700 ml of diethyl ether. The organic layer was separated, washed with water, and then was dried with sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure yielding 28.0 grams of 3-oxopropyl benzoate. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: Cl[C:2]1[N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:10](=[O:18])[C:9]2[C:4](=[CH:5][C:6]([C:19]([O:21][CH3:22])=[O:20])=[CH:7][CH:8]=2)[N:3]=1.C(N(CC)C(C)C)(C)C.[Cl:32][C:33]1[CH:40]=[CH:39][C:36]([CH2:37][NH2:38])=[CH:35][CH:34]=1>C(O)(C)C>[Cl:32][C:33]1[CH:40]=[CH:39][C:36]([CH2:37][NH:38][C:2]2[N:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:10](=[O:18])[C:9]3[C:4](=[CH:5][C:6]([C:19]([O:21][CH3:22])=[O:20])=[CH:7][CH:8]=3)[N:3]=2)=[CH:35][CH:34]=1
Reactant: COC(=O)c1ccc2c(=O)n(-c3ccccc3)c(Cl)nc2c1
Reactant: NCc1ccc(Cl)cc1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc2c(=O)n(-c3ccccc3)c(NCc3ccc(Cl)cc3)nc2c1
Temperature: 100 °C
Reaction time: 1 h
Yield: 28.6 %

Procedure:
To a suspension of methyl 2-chloro-4-oxo-3-phenyl-3,4-dihydroquinazoline-7-carboxylate (0.10 g, 0.25 mmol) in isopropyl alcohol (2.8 mL) was added N,N-diisopropylethylamine (93 μL, 0.53 mmol) and p-chlorobenzylamine (77.3 μL, 0.64 mmol). The reaction mixture was heated to 100° C. and stirred for 1 h. The mixture was then cooled to rt and concentrated. The residue was purified by flash silica gel chromatography (0% to 30% EtOAc/hexanes) to afford methyl 2-[(4-chlorobenzyl)amino]-4-oxo-3-phenyl-3,4-dihydroquinazoline-7-carboxylate (30 mg, 30%). LC-MS: (FA) ES+ 420.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([F:9])=[C:4]([Cl:10])[C:3]=1[CH:11]([OH:13])[CH3:12].[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][CH:24]([N:27]2[CH:31]=[C:30]([C:32]3[C:36]4[CH:37]=[N:38][C:39]([N+:42]([O-:44])=[O:43])=[C:40](O)[C:35]=4[O:34][CH:33]=3)[CH:29]=[N:28]2)[CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([F:9])=[C:4]([Cl:10])[C:3]=1[CH:11]([O:13][C:40]1[C:35]2[O:34][CH:33]=[C:32]([C:30]3[CH:29]=[N:28][N:27]([CH:24]4[CH2:23][CH2:22][N:21]([C:19]([O:18][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:20])[CH2:26][CH2:25]4)[CH:31]=3)[C:36]=2[CH:37]=[N:38][C:39]=1[N+:42]([O-:44])=[O:43])[CH3:12]
Reactant: CC(O)c1c(Cl)c(F)cc(F)c1Cl
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(-c3coc4c(O)c([N+](=O)[O-])ncc34)cn2)CC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(Oc1c([N+](=O)[O-])ncc2c(-c3cnn(C4CCN(C(=O)OC(C)(C)C)CC4)c3)coc12)c1c(Cl)c(F)cc(F)c1Cl
Temperature: 40 °C

Procedure:
1-(2,6-Dichloro-3,5-difluorophenyl)ethanol (133 mg, 0.586 mmol), 4-[4-(7-Hydroxy-6-nitrofuro[3,2-c]pyridin-3-yl)-pyrazol-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (250 mg, 0.52 mmol), PPh3 (410 mg, 1.60 mmol) and THF (20 mL) was added to a dry round bottom flask. Diisopropyl azodicarboxylate (320 mg, 1.60 mmol) was added and the reaction mixture was heated at 40° C. More DIAD (320 mg, 1.60 mmol) was then added and the reaction mixture was heated at 40° C. for 2 h. Purification by flash column chromatography using 10%→40% EtOAc in hexanes afforded the title compound as a yellow solid. MS (ES+): m/z 581.88/583.80 (100/80) [MH+−isobutene]. HPLC: tR=4.29 min (ZQ3, polar—5 min).
Reaction SMILES: C[N:2]1[C:6]([C:7]2[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:9][C:8]=2[C:17]2[CH:26]=[CH:25][CH:24]=[C:23]3[C:18]=2[CH:19]=[CH:20][C:21]([S:27]([OH:30])(=[O:29])=[O:28])=[CH:22]3)=[CH:5][CH:4]=[N:3]1.S(Cl)(Cl)=O.[CH3:35]N(C=O)C>>[CH3:35][N:3]1[CH:4]=[CH:5][C:6]([C:7]2[CH:12]=[C:11]([C:13]([F:16])([F:14])[F:15])[CH:10]=[CH:9][C:8]=2[C:17]2[CH:26]=[CH:25][CH:24]=[C:23]3[C:18]=2[CH:19]=[CH:20][C:21]([S:27]([OH:30])(=[O:28])=[O:29])=[CH:22]3)=[N:2]1
Reactant: Cn1nccc1-c1cc(C(F)(F)F)ccc1-c1cccc2cc(S(=O)(=O)O)ccc12
Reactant: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: Cn1ccc(-c2cc(C(F)(F)F)ccc2-c2cccc3cc(S(=O)(=O)O)ccc23)n1

Procedure:
To a solution of 5-(2-(1-methyl-1H-pyrazol-5-yl)-4-(trifluoromethyl)phenyl)naphthalene-2-sulfonic acid (from Step 2) (0.093 g, 0.214 mmol) in DMF (0.428 mL) was added thionyl chloride (0.031 mL, 0.428 mmol) at 0° C. After 20 minutes LC/MS indicated that the sulfonic acid starting material was converted to the desired product. The reaction mixture was then transferred to a separatory funnel containing water and DCM. The layers were separated and the organic layer was washed twice with water. The resulting organic layer was dried with MgSO4, filtered and concentrated to an oil. m/z (ESI, +ve ion) 450.9 (M+1).
Reaction SMILES: [C:1]([C:3]1([C:14]([O:16]CC)=[O:15])[CH:5]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:4]1([CH3:13])[CH3:12])#[N:2].C(=O)([O-])[O-].[K+].[K+].O.Cl>CO>[C:1]([C:3]1([C:14]([OH:16])=[O:15])[CH:5]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:4]1([CH3:13])[CH3:12])#[N:2]
Reactant: CCOC(=O)C1(C#N)C(c2ccccc2)C1(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CC1(C)C(c2ccccc2)C1(C#N)C(=O)O
Temperature: 25 °C
Yield: 85 %

Procedure:
A mixture of 147 mg (0.60 mmole) of cyclopropanoid cyanoester 10 (produced in accordance with Example VIII), 88 mg (0.64 mmole) of anhydrous potassium carbonate, 0.50 mL of water, and 2.0 mL of methyl alcohol was heated at reflux for 20 minutes. The product was isolated by cooling the mixture to room temperature, cautiously acidifying it by addition of 2 mL of 2M aqueous HCl, subsequent dilution with 20 mL of saturated brine, and extraction with ether. The ether extracts were washed with saturated brine, then dried over anhydrous magnesium sulfate and subsequently filtered. Removal of the ether by evaporation at reduced pressure afforded 110 mg (85% yield) of cyanoacid 18, which was immediately decarboxylated in accordance with Example XVI.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][OH:10].[H-].[Na+].Br[C:14]1[C:15]([NH2:21])=[N:16][CH:17]=[C:18]([Br:20])[N:19]=1>O1CCCC1>[Br:20][C:18]1[N:19]=[C:14]([O:10][CH2:9][C:3]2[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=2[Cl:8])[C:15]([NH2:21])=[N:16][CH:17]=1
Reactant: Nc1ncc(Br)nc1Br
Reactant: OCc1c(Cl)cccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Nc1ncc(Br)nc1OCc1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83 %

Procedure:
To an ice cooled solution of (2,6-dichloro-phenyl)-methanol (5 g, 28.2 mmol) in anhydrous tetrahydrofuran (200 mL) was added sodium hydride (1.13 g, 28.2 mmol, 60% disp.) slowly under nitrogen atmosphere. After stirring for 30 minutes, 3,5-dibromo-pyrazin-2-ylamine (7.08 g, 28.2 mmol) in anhydrous tetrahydrofuran (50 mL) was added via an addition funnel. Once the addition was complete the ice bath was removed and the reaction was refluxed under nitrogen and monitored by reversed phase HPLC. After 18 hr HPLC showed that the majority of the starting 3,5-dibromo-pyrazin-2-ylamine had been consumed and the reaction was allowed to cool to room temperature. The reaction mixture was concentrated in vacuum until 50 mL remained. The mixture was diluted with ethyl acetate (200 mL) and extracted with 50% brine (2×200 mL). The organic layer was dried over anhydrous magnesium sulfate and concentrated in vacuum. The crude product was purified using a silica gel column eluting with 1:1 ethyl acetate/dichloromethane to yield 5-bromo-3-(2,6-dichloro-benzyloxy)-pyrazin-2-ylamine as a white solid (8.17 g, 83% yield).
Reaction SMILES: [C:1]([C:9](=[CH:15][CH2:16][CH3:17])[C:10]([O:12][CH2:13][CH3:14])=[O:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.BrN1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[CH3:17][C:16]1[O:8][C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:15]=1
Reactant: CCC=C(C(=O)OCC)C(=O)c1ccccc1
Agent: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1cc(C)oc1-c1ccccc1
Yield: 92.3 %

Procedure:
A mixture of 4.65 g (0.02 mole) ethyl 2-benzoyl-2-pentenoate and 3.56 g (0.02 mole) N-bromosuccinimide in 50 ml of carbon tetrachloride was heated at reflux for 2 hours. After cooling, the succinimide was removed by filtration and the solution concentrated. Distillation of the crude product gave 4.25 g (92%) of ethyl 5-methyl-2-phenyl-3-furoate, bp 133°-135° C. (0.6 mm).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][CH2:7][C:8]([NH:10][C@H:11]([C:14]([NH:16][CH2:17][C:18]([OH:20])=[O:19])=[O:15])[CH2:12][SH:13])=[O:9])[C:3]([OH:5])=[O:4].[OH-].[Na+].[C:23]([O:28][CH2:29][CH3:30])(=[O:27])[C:24]([CH3:26])=[CH2:25]>O.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:23]([CH:24]([CH3:26])[CH2:25][S:13][CH2:12][C@@H:11]([C:14]([NH:16][CH2:17][C:18]([OH:20])=[O:19])=[O:15])[NH:10][C:8](=[O:9])[CH2:7][CH2:6][C@@H:2]([C:3]([OH:5])=[O:4])[NH2:1])([O:28][CH2:29][CH3:30])=[O:27]
Reactant: N[C@@H](CCC(=O)N[C@@H](CS)C(=O)NCC(=O)O)C(=O)O
Reactant: C=C(C)C(=O)OCC
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Product: CCOC(=O)C(C)CSC[C@H](NC(=O)CC[C@H](N)C(=O)O)C(=O)NCC(=O)O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
In 100 ml of water is dissolved 6.2 g of glutathione and the solution is adjusted to pH 7 with 2N-sodium hydroxide. To this solution is added 4 ml of ethyl methacrylate and the mixture is stirred at room temperature for 48 hours. Thereafter, 4.4 g of copper acetate is added and dissolved and the precipitated copper salt is collected by filtration and rinsed with water. This copper salt is suspended in 150 ml of water and hydrogen sulfide is bubbled through the suspension with stirring to precipitate the copper sulfide. This copper sulfide is filtered off and the filtrate is concentrated. The resulting white crystals are recovered by filtration and recrystallized from water to give 4.5 g of needlets melting at 193°-194° C. (decompn.) TLC, silica gel Rf=0.28 (n-butanol-acetic acid-water=4:1:1)
Reaction SMILES: [CH2:1]1[O:10][C:9]2[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=2[O:2]1.[CH3:11][C:12](OC(C)=O)=[O:13].C([O-])(O)=O.[Na+]>CC(O)=O>[O:10]1[C:9]2[CH:8]=[CH:7][C:5]([NH:6][C:12](=[O:13])[CH3:11])=[CH:4][C:3]=2[O:2][CH2:1]1
Reactant: Nc1ccc2c(c1)OCO2
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(=O)Nc1ccc2c(c1)OCO2
Reaction time: 8 h
Yield: 95 %

Procedure:
To a solution of 3,4-(Methylenedioxy)aniline (8 g, 58.3 mmol) in AcOH (120 ml) was added Ac2O (48 mL). The mixture was stirred for overnight. After reaction, the mixture was poured into saturated NaHCO3 solution, and then filtered. The filtrate was extracted with ethyl acetate to give N-(benzo[d][1,3]dioxol-5-yl)acetamide (10 g, 95%). LCMS: 180[M+1]+; 1H NMR (DMSO-d6) δ 2.0 (s, 3H), 5.96 (s, 2H), 6.82 (d, 1H, J=8.1 Hz), 6.91 (d, 1H, J=2.1 Hz), 7.30 (d, 1H, J=1.8 Hz), 9.84 (s, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH2:7][C@H:8]2[C@@H:10]([C@H:11]([O:13][CH:14]([CH2:17][CH3:18])[CH2:15][CH3:16])[CH:12]=1)[O:9]2)=[O:5])[CH3:2].O1CCCC1.[CH2:24]([NH2:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH2:1]([O:3][C:4]([C:6]1[CH2:7][C@@H:8]([NH:31][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@H:10]([OH:9])[C@H:11]([O:13][CH:14]([CH2:17][CH3:18])[CH2:15][CH3:16])[CH:12]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1=C[C@@H](OC(CC)CC)[C@H]2O[C@H]2C1
Reactant: NCc1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)C1=C[C@@H](OC(CC)CC)[C@@H](O)[C@H](NCc2ccccc2)C1
Reaction time: 12 h
Yield: 95.2 %

Procedure:
To a solution of 5.08 g (20 mmol) (1S,5R,6S)-5-(1-ethyl-propoxy)-7-oxa-bicyclo[4.1.0]hept-3-ene-3-carboxylic acid ethyl ester in 20 ml tetrahydrofuran 1.03 g (4 mmol) magnesium bromide diethyl etherate was added at room temperature. The resulting suspension was treated with 4.40 ml (40 mmol) of benzylamine and heated to reflux under argon with stirring for 12 hours. The reaction mixture was evaporated in a rotary evaporator, the residue treated with 20 ml of ethyl acetate and extracted 6 times with 20 ml of 5N aqueous ammonium chloride solution. The organic phase was dried over 5 g of sodium sulfate, filtered and evaporated to yield 6.88 g of (3R,4S,5R)-5-benzylamino-3-(1-ethyl-propoxy)-4-hydroxy-cyclohex-1-enecarboxylic acid ethyl ester as a brown oil.
Reaction SMILES: C[N:2](C)[CH:3]=[CH:4][C:5]1[C:13]2[O:12][CH:11]=[CH:10][C:9]=2[C:8]([N+:14]([O-:16])=[O:15])=[CH:7][CH:6]=1.NOS(O)(=O)=O.CN(C)C=O>C(OCC)C>[N+:14]([C:8]1[C:9]2[CH:10]=[CH:11][O:12][C:13]=2[C:5]([CH2:4][C:3]#[N:2])=[CH:6][CH:7]=1)([O-:16])=[O:15]
Reactant: CN(C)C=Cc1ccc([N+](=O)[O-])c2ccoc12
Agent: NOS(=O)(=O)O
Solvent: CCOCC
Solvent: CN(C)C=O
Product: N#CCc1ccc([N+](=O)[O-])c2ccoc12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 69.6 %

Procedure:
Add dimethyl[2-(4-nitrobenzofur-7-yl)vinyl]amine (4.8 g, 20.6 mmol) and hydroxylamine-O-sulfonic acid (4.6 g, 40.6 mmol) to dimethylformamide (45 mL) and stir at room temperature for 15 minutes. Heat at 100° C. under nitrogen for 1 hour, cool to room temperature, dilute with diethyl ether, and wash with water and aqueous saturated sodium chloride. Dry over anhydrous magnesium sulfate, filter, and concentrate under reduced pressure. Chromatography on flash silica using 85% hexane, 15% ethyl acetate gives 2.9 g (64%) of the title compound as a light brown solid. Mass spectrum (ES, m/z) (M−1)=200.9.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([CH2:7][O:8][C:9]2[CH:20]=[CH:19][CH:18]=[CH:17][C:10]=2[CH:11]=[CH:12][C:13](OC)=[O:14])=[N:4][C:3]=1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[H-].C([Al+]CC(C)C)C(C)C>>[CH3:1][C:2]1[O:6][C:5]([CH2:7][O:8][C:9]2[CH:20]=[CH:19][CH:18]=[CH:17][C:10]=2/[CH:11]=[CH:12]/[CH2:13][OH:14])=[N:4][C:3]=1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COC(=O)C=Cc1ccccc1OCc1nc(-c2ccccc2)c(C)o1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Product: Cc1oc(COc2ccccc2/C=C/CO)nc1-c1ccccc1

Procedure:
According to the method described for Reference Example 23, methyl 2-(5-methyl-4-phenyl-2-oxazolylmethoxy)cinnamate was subjected to reduction with diisobutylaluminum hydride to give (E)-3-[2-(5-methyl-4-phenyl-2-oxazolylmethoxy)phenyl]-2-propen-1-ol. Recrystallization from ethyl acetate-ether gave colorless prisms, m.p.128°-129° C.
Reaction SMILES: [CH:1]([C:4]1[CH:11]=[C:10]([CH:12]([CH3:14])[CH3:13])[CH:9]=[C:8]([CH:15]([CH3:17])[CH3:16])[C:5]=1[CH2:6]Br)([CH3:3])[CH3:2].[C:18]1(=[O:28])[NH:22][C:21](=[O:23])[C:20]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:19]12.[K]>CN(C)C=O>[CH:1]([C:4]1[CH:11]=[C:10]([CH:12]([CH3:14])[CH3:13])[CH:9]=[C:8]([CH:15]([CH3:17])[CH3:16])[C:5]=1[CH2:6][N:22]1[C:21](=[O:23])[C:20]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:19]2[C:18]1=[O:28])([CH3:3])[CH3:2]
Reactant: CC(C)c1cc(C(C)C)c(CBr)c(C(C)C)c1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Product: CC(C)c1cc(C(C)C)c(CN2C(=O)c3ccccc3C2=O)c(C(C)C)c1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
A mixture of 2,4,6-triisopropylbenzyl bromide (5.00 g, 16.8 mmol), potassium phthalimide (3.71 g, 19.9 mmol), and dimethylformamide were heated for 3 hours at 70° C. The reaction mixture was allowed to stand overnight at room temperature and was then heated at 90° C. for 1 hour. The solvent was removed on the rotary evaporator, ethyl acetate (250 mL) was added, the organic layer was washed with brine, dried over magnesium sulfate, filtered, and concentrated to a white solid. Hexanes (50 mL) and ethyl acetate (5 mL) was added and the solid collected by filtration, 4.18 g (68%). An analytical sample was obtained by silica gel filtration using 9:1, hexanes/ethyl acetate as eluant.
Reaction SMILES: [Li+].[BH4-].[C:3]([C:6]1[CH:7]=[C:8]([N:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]([CH2:21][C:22](OCC)=[O:23])=[C:13]2[C:27]([OH:29])=[O:28])[CH:9]=[CH:10][CH:11]=1)([OH:5])=[O:4]>COCCOC>[C:3]([C:6]1[CH:7]=[C:8]([N:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]([CH2:21][CH2:22][OH:23])=[C:13]2[C:27]([OH:29])=[O:28])[CH:9]=[CH:10][CH:11]=1)([OH:5])=[O:4]
Reactant: CCOC(=O)Cc1c(C(=O)O)n(-c2cccc(C(=O)O)c2)c2ccccc12
Agent: [BH4-]
Agent: [Li+]
Solvent: COCCOC
Product: O=C(O)c1cccc(-n2c(C(=O)O)c(CCO)c3ccccc32)c1
Temperature: 25 °C

Procedure:
To a suspension of LiBH4 (0.157 g, 7.2 mmol) in anhydrous DME (50 mL) was added a solution of 1-(3-carboxy-phenyl)-3-ethoxycarbonylmethyl-1H-indole-2-carboxylic acid in DME containing 3% methanol (10 mL). The reaction mixture was heated at reflux for 1 h and then allowed to cool to room temperature. The reaction was quenched with 1 N HCl at 0° C. and extracted with EtOAc. The extract was dried over Na2SO4 and concentrated to afford 0.78 g of 1-(3-carboxy-phenyl)-3-(2-hydroxyethyl)-1H-indole-2-carboxylic acid as a yellow oil (100% crude yield): 1H NMR (CDCl3, 300 MHz) δ 3.28 (t, J=6.87 Hz, 2H), 3.69 (t, J=6.87 Hz, 2H), 7.03 (d, J=8.20 Hz, 1H); 7.18(t, J=7.25 Hz, 1H), 7.28 (t, J=7.25 Hz, 1H), 7.60–7.68 (m, 2H), 7.76–7.81 (m, 2H), 8.02 (d, J=7.06 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]12[CH2:9][CH2:8][C:5]([C:10]([O:12][CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][O:14]3)=[O:11])([CH2:6][CH2:7]1)[CH2:4][CH2:3]2.C(N(C(C)C)CC)(C)C.Br[CH2:29][C:30]([N:32]1[CH2:36][C@@H:35]([F:37])[CH2:34][C@H:33]1[C:38]#[N:39])=[O:31]>C(#N)C>[O:14]1[CH2:15][CH2:16][CH2:17][CH2:18][CH:13]1[O:12][C:10]([C:5]12[CH2:6][CH2:7][C:2]([NH:1][CH2:29][C:30]([N:32]3[CH2:36][C@@H:35]([F:37])[CH2:34][C@H:33]3[C:38]#[N:39])=[O:31])([CH2:9][CH2:8]1)[CH2:3][CH2:4]2)=[O:11]
Reactant: NC12CCC(C(=O)OC3CCCCO3)(CC1)CC2
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CBr
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)OC3CCCCO3)(CC1)CC2
Reaction time: 4 h
Yield: 79.6 %

Procedure:
2-Tetrahydropyranyl 4-aminobicyclo[2,2,2]octane-1-carboxylate (62.9 mg) was suspended in acetonitrile (1 mL). To this suspension, diisopropylethylamine (47 μL) was added. With the solution chilled in an ice bath, (2S,4S)-1-(2-bromoacetyl)-4-fluoropyrrolidine-2-carbonitrile (53.1 mg) in acetonitrile (0.8 mL) was added and the mixture was stirred for 4 hours. Subsequently, the reaction mixture was concentrated, and ethyl acetate and water were added to dissolve the residue. To this solution, an aqueous sodium bicarbonate solution was added to make the solution basic and the solution was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluant: dichloromethane: methanol=10:1) to obtain (2S,4S)-1-[[N-[4-(2-tetrahydropyranyl)oxycarbonylbicyclo[2,2,2]oct-1-yl]amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (73.3 mg).