Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([CH2:11]Cl)[N:10]=2)[CH:7]=1.[N:13]1([C:19]2[CH:27]=[CH:26][C:22]([C:23]([NH2:25])=[O:24])=[CH:21][CH:20]=2)[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.C(N(CC)CC)C>C(O)CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([CH2:11][N:16]3[CH2:15][CH2:14][N:13]([C:19]4[CH:20]=[CH:21][C:22]([C:23]([NH2:25])=[O:24])=[CH:26][CH:27]=4)[CH2:18][CH2:17]3)[N:10]=2)[CH:7]=1
Reactant: NC(=O)c1ccc(N2CCNCC2)cc1
Reactant: ClCc1cn2cc(Br)ccc2n1
Solvent: CCN(CC)CC
Solvent: OCCO
Product: NC(=O)c1ccc(N2CCN(Cc3cn4cc(Br)ccc4n3)CC2)cc1
Yield: 48.4 %

Procedure:
Following the general procedure of Example 2, Step 3, and making noncritical variations, 6-bromo-2-(chloromethyl)imidazo[1,2-a]pyridine (Example 15, Step 1; 0.252 g), 4-(piperazin-1-yl)benzamide (Example 3, Step 1; 0.211 g), triethylamine (0.104 g), and ethylene glycol (2 mL) give 0.206 g of the title compound after crystallization from methanol/dichloromethane/hexane; mp 238-239° C.; MS m/z 413,415; IR (mineral oil) 1612, 1656, 3379, 1331, 1240 cm-1. 1H NMR (DMSO-d6) δ2.60, 3.25, 3.66, 6.92, 7.04, 7.32, 7.49, 7.71, 7.73, 7.83, 8.87.
Reaction SMILES: [H-].[Na+].[C:3]1([CH2:9][CH2:10][C:11]2[N:21]3[C:22]4[C:17]([CH:18]([OH:23])[CH2:19][CH2:20]3)=[CH:16][CH:15]=[CH:14][C:13]=4[N:12]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[CH2:25][C:26]1[CH:35]=[CH:34][CH:33]=[CH:32][C:27]=1[C:28]([O:30][CH3:31])=[O:29]>CN(C)C=O>[CH3:31][O:30][C:28]([C:27]1[CH:32]=[CH:33][CH:34]=[CH:35][C:26]=1[CH2:25][O:23][CH:18]1[C:17]2[C:22]3=[C:13]([N:12]=[C:11]([CH2:10][CH2:9][C:3]4[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=4)[N:21]3[CH2:20][CH2:19]1)[CH:14]=[CH:15][CH:16]=2)=[O:29]
Reactant: COC(=O)c1ccccc1CBr
Reactant: OC1CCn2c(CCc3ccccc3)nc3cccc1c32
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccccc1COC1CCn2c(CCc3ccccc3)nc3cccc1c32
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.7 %

Procedure:
A portion (1.15 g) of 60% sodium hydride was added to 50 mL of anhydrous N,N-dimethylformamide (DMF) in an argon atmosphere; 2.0 g of 5,6-dihydro-2-(2-phenylethyl)-4H-imidazo[4,5,1-ij]quinolin-6-ol obtained in Example 4 was dissolved in anhydrous DMF (40 mL) and the solution was added dropwise to the first mentioned solution at room temperature. After stirring for 1 hr at room temperature, a solution of methyl o-bromomethylbenzoate (6.6 g) in anhydrous DMF (40 mL) was added dropwise and the mixture was stirred for 1 hr. The reaction solution was poured into ice water (500 mL), and extracted with ethyl acetate, the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to yield the titled compound as a yellow oil (2.38 g).
Reaction SMILES: C([C@H:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][C@H:5]1[OH:13])(O)=O.[N:14]([O-])=O.[Na+]>OS(O)(=O)=O>[NH2:14][C@H:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][C@H:5]1[OH:13]
Reactant: O=C(O)[C@H]1c2ccccc2C[C@H]1O
Reactant: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: N[C@H]1c2ccccc2C[C@H]1O
Temperature: 2.5 °C

Procedure:
The hydrazide of (1S,2R)-1-carboxy-2-hydroxyindane (0.5 gram) is reacted with a solution of 0.5 grams of sodium nitrite in 10 ml of 5% H2SO4. The reaction mixture is maintained for 1 hour at 0-5° C., followed extraction of the reaction mixture with ethyl acetate, followed by basification of the resulting aqueous solution with NaOH, extraction with methyl t-butyl ether, drying of the extracts over MgSO4, filtration, and the removal of solvent by rotary evaporation. The product (1S,2R)-1-amino-2-indanol is isolated as a light yellow oil.
Reaction SMILES: F[C:2]1[C:3]([N+:18]([O-:20])=[O:19])=[C:4]([CH:14]=[C:15]([F:17])[CH:16]=1)[NH:5][C:6]1[CH:11]=[CH:10][C:9]([I:12])=[CH:8][C:7]=1[F:13].[NH2:21][C:22]1[CH:23]=[C:24]([OH:29])[CH:25]=[CH:26][C:27]=1[F:28].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[NH2:21][C:22]1[CH:23]=[C:24]([CH:25]=[CH:26][C:27]=1[F:28])[O:29][C:2]1[C:3]([N+:18]([O-:20])=[O:19])=[C:4]([CH:14]=[C:15]([F:17])[CH:16]=1)[NH:5][C:6]1[CH:11]=[CH:10][C:9]([I:12])=[CH:8][C:7]=1[F:13]
Reactant: Nc1cc(O)ccc1F
Reactant: O=[N+]([O-])c1c(F)cc(F)cc1Nc1ccc(I)cc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Nc1cc(Oc2cc(F)cc(Nc3ccc(I)cc3F)c2[N+](=O)[O-])ccc1F
Temperature: 25 °C
Reaction time: 72 h
Yield: 59 %

Procedure:
1 g of 3,5-difluoro-N-(2-fluoro-4-iodophenyl)-2-nitroaniline (Intermediate 1A; 2.537 mmol, 1 eq.), 194 mg 3-amino-4-fluorophenol (1.522 mmol, 0.6 eq.) and 1.240 g caesium carbonate (3.806 mmol, 1.5 eq.) were suspended in 12 mL DMF and stirred at rt for 72 h. The reaction mixture was partitioned between butan-2-one and half saturated brine. The layers were separated and the aqueous layer was reextracted twice with ethyl butan-2-one. The combined organic layers were washed with brine, dried, filtered and concentrated in vacuo. The crude product was purified by flash column chromatography (n-hexane/ethyl acetate gradient) providing 450 mg of a mixture of the desired product with its para regioisomer that eluted with the same retention time (63% UV purity). This material was used without further purification.
Reaction SMILES: [CH:1]1([C:6]([N:8]2[CH2:13][CH:12]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][CH3:21])=[CH:16][CH:15]=3)[CH2:11][CH:10]([C:22](O)=[O:23])[CH2:9]2)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[F:25][C:26]1[CH:27]=[C:28]([CH:30]=[CH:31][CH:32]=1)[NH2:29]>>[CH:1]1([C:6]([N:8]2[CH2:13][CH:12]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][CH3:21])=[CH:16][CH:15]=3)[CH2:11][CH:10]([C:22]([NH:29][C:28]3[CH:30]=[CH:31][CH:32]=[C:26]([F:25])[CH:27]=3)=[O:23])[CH2:9]2)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Nc1cccc(F)c1
Reactant: CCc1ccc(C2CC(C(=O)O)CN(C(=O)C3CCCC3)C2)cc1
Product: CCc1ccc(C2CC(C(=O)Nc3cccc(F)c3)CN(C(=O)C3CCCC3)C2)cc1

Procedure:
66 mg (0.20 mmol) of 1-(cyclopentylcarbonyl)-5-(4-ethylphenyl)piperidine-3-carboxylic acid (Example 7A) and 24 mg (0.22 mmol, 1.1 eq.) of 3-fluoroaniline were reacted according to General Method 1. Yield: 38 mg (45% of theory)
Reaction SMILES: C[O:2][CH2:3][CH:4]([O:13][C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[C:16]([C:22]([F:25])([F:24])[F:23])[CH:15]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.B(Br)(Br)Br>C(Cl)Cl>[OH:2][CH2:3][CH:4]([O:13][C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[C:16]([C:22]([F:23])([F:24])[F:25])[CH:15]=1)[CH2:5][O:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: COCC(COc1ccccc1)Oc1ccc(C#N)c(C(F)(F)F)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: N#Cc1ccc(OC(CO)COc2ccccc2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The starting material, 4-(1-methoxymethyl-2-phenoxy-ethoxy)-2-trifluoromethyl-benzonitrile, which is the product of Example 27, (0.5 g, 1.4 mmol) was dissolved in 10 ml of dry CH2Cl2, it was cooled to −78° C. before addition of BBr3 (4.3 ml of 1.0M solution in CH2Cl2). After 2 hours, the reaction mixture was gradually warmed up to room temperature; the reaction was quenched with 45 ml of saturated NaHCO3, extracted with CHCl3 (3×20 ml). Purification: Silica Gel
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([NH2:16])[N:10]=2)[C:5]([F:8])=[N:6][CH:7]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.[F-].[Cs+].C([Sn](CCCC)(CCCC)[C:58]([O:60][CH2:61][CH3:62])=[CH2:59])CCC>O1CCOCC1.CN(C=O)C.C(O[Pd]OC(=O)C)(=O)C>[CH2:61]([O:60][C:58]([C:2]1[CH:3]=[C:4]([C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([NH2:16])[N:10]=2)[C:5]([F:8])=[N:6][CH:7]=1)=[CH2:59])[CH3:62]
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: Cc1nc(N)nc(-c2cc(Cl)cnc2F)n1
Agent: CC(=O)O[Pd]OC(C)=O
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: C=C(OCC)c1cnc(F)c(-c2nc(C)nc(N)n2)c1
Temperature: 120 °C
Yield: 64.7 %

Procedure:
A mixture of 4-(5-chloro-2-fluoropyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (273 mg, 1.14 mmol), X-Phos (50 mg, 0.11 mmol), diacetoxypalladium (24 mg, 0.11 mmol), cesium fluoride (519 mg, 3.42 mmol) and tributyl(1-ethoxyvinyl)stannane (0.54 mL, 1.60 mmol) in 1,4-dioxane (4 mL) and DMF (1 mL) was heated in a microwave at 120° C. for 1 h. The reaction mixture was passed through a short path of a neutral alumina column, eluted with 50 mL of DCM followed by 150 mL of EtOAc. The fractions containing the desired mass [m/z (ESI, positive ion) 276.0 (M+H)+] were collected and concentrated to give the title compound (203 mg, 64.7% yield) as an off white crystalline solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.60 (2 H, m), 7.67 (2 H, m), 4.93 (1 H, d, J=3.1 Hz), 4.67 (1 H, d, J=3.1 Hz), 3.95 (2H, m), 2.38 (3 H, s), 1.11 (3 H, m). m/z (ESI, positive ion) 276.0 (M+H)+.
Reaction SMILES: [CH:1]([C:3]1[N:7]([CH:8]([CH3:10])[CH3:9])[N:6]=[C:5]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:4]=1)=O.[NH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH3:9][CH:8]([N:7]1[C:3]([CH2:1][N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[CH:4][C:5]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[N:6]1)[CH3:10]
Reactant: CC(C)n1nc(C(=O)OC(C)(C)C)cc1C=O
Reactant: C1COCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)n1nc(C(=O)OC(C)(C)C)cc1CN1CCOCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1,1-Dimethylethyl 5-formyl-1-(1-methylethyl)-1H-pyrazole-3-carboxylate (118 mg) was dissolved in anhydrous DCM (10 ml), morpholine (0.048 ml) was added and the mixture was stirred under nitrogen for 2 h at RT. Sodium triacetoxyborohydride (210 mg) was added and the mixture was stirred at RT for 18 h. Sodium bicarbonate solution (20 ml) and DCM (20 ml) were added and separated then the aqueous layer was re-extracted with DCM (2×20 ml) and separated by hydrophobic frit. The combined organic layers were concentrated in vacuo and the residue was purified by flash chromatography on silica gel (20 g silica) eluting with a gradient of 0-100% ethyl acetate in cyclohexane over 20 mins to give the title compound (101 mg) as a white solid.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:27])=[C:9]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][C:20]([O:22]CC)=[O:21])=[CH:15][C:14]=2[O:25][CH3:26])[N:10]=1.Cl>[OH-].[K+]>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:27])=[C:9]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][C:20]([OH:22])=[O:21])=[CH:15][C:14]=2[O:25][CH3:26])[N:10]=1
Reactant: CCOC(=O)Cc1ccc(OCc2nc(-c3ccco3)oc2C)c(OC)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Product: COc1cc(CC(=O)O)ccc1OCc1nc(-c2ccco2)oc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.9 %

Procedure:
Ethyl (4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxyphenyl)acetate (6.19 g) was dissolved in 0.25N potassium hydroxide mixed solution (potassium hydroxide 7.01 g/methanol 125 mL/tetrahydrofuran 354 mL/distilled water 21 mL), and the mixture was stirred overnight at room temperature. The reaction mixture was acidified by adding hydrochloric acid, and the mixture was extracted with ethyl acetate. The extract was washed successively with distilled water and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was recrystallized from ethanol-diisopropyl ether to give (4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxyphenyl)acetic acid as a white solid (5.43 g, yield 95%). melting point: 162-164° C.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[Si:18]([CH3:21])([CH3:20])[CH3:19].CCCCCC>ClCCl>[CH3:19][Si:18]([CH3:21])([CH3:20])[O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: C[Si](C)(C)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCCCCC
Product: C[Si](C)(C)Oc1ccc(C=O)cc1

Procedure:
To a stirred solution of 122 g 4-hydroxybenzaldehyde (1.0 mol, available from Aldrich) and 111 g triethylamine (1.1 mol, available from Aldrich) in 1.0 L dichloromethane was added dropwise 108 g chlorotrimethylsilane (1.1 mol). This mixture was allowed to stand at room temperature for three days before 500 mL hexane was added. The mixture was filtered to remove triethylamine hydrochloride, and most of the solvent was removed at reduced pressure. A 200 mL portion of hexane was then added, the mixture filtered again, and solvent removed at reduced pressure to leave the desired product.
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)C.[CH:8]([C:10]1[C:17]([CH3:18])=[CH:16][C:13]([C:14]#[N:15])=[C:12]([O:19][CH3:20])[CH:11]=1)=[O:9]>C1COCC1.CS(C)=O>[CH3:20][O:19][C:12]1[CH:11]=[C:10]([CH:8]2[CH2:4][O:9]2)[C:17]([CH3:18])=[CH:16][C:13]=1[C:14]#[N:15]
Reactant: COc1cc(C=O)c(C)cc1C#N
Reactant: C[S+](C)C
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: COc1cc(C2CO2)c(C)cc1C#N
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a cool solution of NaH (1.20 g, 30.0 mmol) in THF (300 ml) was added dropwise a solution of trimethylsulfonium iodide (8.74 g, 42.8 mmol) in DMSO (80 mL). The resulting mixture was stirred at 0° C. under N2 for 20 min. The solution of 4-formyl-2-methoxy-5-methylbenzonitrile (5.00 g, 28.5 mmol) in THF (60 mL) was added. The resulting reaction mixture was stirred at 0° C. under N2 for 1 hr, and then it was warmed gradually to room temperature and stirred at that temperature for 12 hr. The starting material was consumed as indicated by TLC (25% ethyl acetate/hexanes). The reaction mixture was cooled to 0° C. and quenched with dropwise addition of water. The mixture was extracted with ethyl acetate (2×200 ml). The combined organic layers were washed with water, brine, then dried (MgSO4) and filtered. The filtrate was concentrated in vacuo. The residue was purified via column chromatography (silica gel, 10-30% EtOAc-hexanes) to afford 2-methoxy-5-methyl-4-(oxiran-2-yl)benzonitrile. 1H NMR (CDCl3, 500 MHz) δ 7.35 (s, 1H), 6.88 (s, 1H), 4.01 (s, 1H), 3.92 (s, 3H), 3.25 (s, 1H), 2.65 (d, J=2.6 Hz, 1H), 2.37 (s, 3H); LC/MS: (IE, m/z) [M+1]+=190.0; tR=2.85 min.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C:10]([CH2:15]O)([CH3:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.[CH3:24][S:25](Cl)(=[O:27])=[O:26].CCOCC>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C:10]([CH2:15][S:25]([CH3:24])(=[O:27])=[O:26])([CH3:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CC1(CO)CCCN(C(=O)OC(C)(C)C)C1
Solvent: CCOCC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(CS(C)(=O)=O)CCCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 97.9 %

Procedure:
To a 0° C. stirred solution of Intermediate 55 (0.844 g, 3.68 mmol) in dry CH2Cl2 (25 ml) was added Et3N (0.513 ml, 3.682 mmol) and the reaction was stirred for 15 minutes. Methansulfonyl chloride (0.285 ml, 3.682 mmol) was added dropwise and the reaction was allowed to warm to room temperature overnight with good stirring. The reaction was complete by TLC, and Et2O (100 ml) was added. The mixture was filtered and the filter caked was washed with additional Et2O. The filtrate was then concentrated under reduced pressure. The residue was chromatographed with hexanes/EtOAc (0>25%) to yield 1.05 g (93.1%) of 3-methanesulfonylmethyl-3-methyl-piperidine-1-carboxylic acid tert-butyl ester (Intermediate 56). 1H NMR (400 MHz, CDCl3) δ ppm 1.0 (s, 3 H), 1.4 (m, 1 H), 1.4 (s, 9 H), 1.6 (m, 3 H), 3.0 (s, 3 H), 3.2 (s, 1 H), 3.5 (s, 2 H), 4.0 (d, J=2.4 Hz, 2 H).
Reaction SMILES: C1(C)C=CC(S([C:10]([OH:31])([OH:30])[CH2:11][CH:12]([CH2:14][CH2:15][CH2:16][CH:17]([CH2:19][CH2:20][CH2:21][CH:22]([CH2:24][CH2:25][CH2:26][CH:27]([CH3:29])[CH3:28])[CH3:23])[CH3:18])[CH3:13])(=O)=O)=CC=1.[N-:33]=[N+:34]=[N-:35].[Na+].[N-]=[N+]=[N-]>CN(C)C=O>[N:33]([C:10]([OH:31])([OH:30])[CH2:11][CH:12]([CH2:14][CH2:15][CH2:16][CH:17]([CH2:19][CH2:20][CH2:21][CH:22]([CH2:24][CH2:25][CH2:26][CH:27]([CH3:29])[CH3:28])[CH3:23])[CH3:18])[CH3:13])=[N+:34]=[N-:35]
Reactant: Cc1ccc(S(=O)(=O)C(O)(O)CC(C)CCCC(C)CCCC(C)CCCC(C)C)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)CCCC(C)CCCC(C)CCCC(C)CC(O)(O)N=[N+]=[N-]
Yield: 81.6 %

Procedure:
The yielded phytandiol derivative (0.48 g) was dissolved in 25 ml of dimethyl formamide and 0.06 g (1.00 mmol) of sodium azide (Sigma-Aldrich) was added, followed by reflux for 5 hr in order to substitute azide for para-toluene sulfonyl group. The reaction mixture was extracted with 50 ml of methylene chloride solution and washed with saline. Following drying over anhydrous magnesium sulfate, filtration and concentration, 0.29 g of azido phytandiol derivative was yielded.
Reaction SMILES: [Na].[CH2:2]([O:4][C:5](=[O:12])[CH2:6][C:7]([O:9][CH2:10]C)=[O:8])C.C[O-].[Na+].Cl[CH2:17][CH2:18][CH2:19][CH2:20][O:21][CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][O:23]1>>[CH3:2][O:4][C:5](=[O:12])[CH:6]([CH2:17][CH2:18][CH2:19][CH2:20][O:21][CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][O:23]1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: ClCCCCOC1CCCCO1
Reactant: CCOC(=O)CC(=O)OCC
Agent: C[O-]
Agent: [Na+]
Agent: [Na]
Product: COC(=O)C(CCCCOC1CCCCO1)C(=O)OC

Procedure:
7.9 g (0.3 mol) of sodium in a stream of nitrogen was placed in a 500-ml 3-necked flash with reflux condenser, drying tube and dropping funnel with pressure equalisation. Next, 250 ml of anhydrous methanol was carefully added dropwise and agitated until the sodium had completely dissolved. A methanolic solution of 95.4 g (0.58 mol) malonic acid diethyl ester was added very slowly dropwise to the still-warm sodium methanolate solution. At the end of the addition process, the mixture was reflux-boiled for a further hour, after which 0.5 mol of 1-chloro-4-tetrahydro-pyranyloxybutane was slowly added dropwise. The mixture was then reflux-boiled overnight.
Reaction SMILES: CN(C=O)C.[NH2:6][CH:7]([CH3:20])[CH2:8][C:9]1[C:17]2[C:12](=[C:13]([O:18][CH3:19])[CH:14]=[CH:15][CH:16]=2)[NH:11][CH:10]=1.[Cl:21][C:22]1[CH:23]=[C:24]([CH:30]=[CH:31][CH:32]=1)[CH:25]([OH:29])[C:26](O)=[O:27].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>C(OCC)(=O)C.C(N(CC)CC)C>[CH3:19][O:18][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:12]=1[NH:11][CH:10]=[C:9]2[CH2:8][CH:7]([NH:6][C:26](=[O:27])[CH:25]([C:24]1[CH:30]=[CH:31][CH:32]=[C:22]([Cl:21])[CH:23]=1)[OH:29])[CH3:20]
Reactant: O=C(O)C(O)c1cccc(Cl)c1
Reactant: COc1cccc2c(CC(C)N)c[nH]c12
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cccc2c(CC(C)NC(=O)C(O)c3cccc(Cl)c3)c[nH]c12
Temperature: 25 °C
Reaction time: 5 h
Yield: 94.1 %

Procedure:
To a DMF solution (80 ml) containing 3-(2-aminopropyl)-7-methoxyindole (12.24 g) and 3-chloromandelic acid (7.46 g) is added benzotriazole-N-oxytris(dimethylamino)phosphonium hexafluorophosphate (17.68 g), and then thereto is added dropwise triethylamine (9.8 ml). The mixture is stirred at room temperature for five hours, and to the reaction mixture is added ethyl acetate. The mixture is washed successively with water, 10% aqueous citric acid solution, water, a saturated aqueous sodium hydrogen carbonate solution, water and a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The mixture is evaporated to remove the solvent under reduced pressure, and the residue is purified by silica gel column chromatography (eluent; ethyl acetate/n-hexane=1:1→2:1) to give N-[3-(7-methoxyindol-3-yl)-2-propyl]-3-chloromandelamide (14.02 g) as an oily product.
Reaction SMILES: [NH:1]1[CH2:5][CH:4]=[CH:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Cl[C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14]>C(Cl)Cl>[CH2:16]([O:15][C:13]([N:1]1[CH2:5][CH:4]=[CH:3][CH2:2]1)=[O:14])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: C1=CCNC1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1CC=CC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 78.5 %

Procedure:
To a solution of 3-pyrroline (1.3 g, 18.8 mmol) and anhyd. potassium carbonate (15.3 g, 144.6 mmol) in methylene chloride (30 mL) was added dropwise benzyl chloroformate (7.4 g, 43.4 mmol) at 0° C. and stirred for 20 min. The reaction mixture was warmed to room temperature and stirred further for 2 hrs. The mixture was washed with cold water (30 mL) and brine (20 mL) and dried (MgSO4). After evaporation of solvents, the residue was purified by flash column chromatography (EtOAc/hexane (1:10)) to give 1-benzyloxycarbonyl-3-pyrroline (3 g, 78%). To a solution of catalytic amount of osmium tetroxide in water (15 mL) and acetone (7 ml) was added N-methylmorpholine 1H2O (479 mg, 3.5 mmol) and 1-benzyloxycarbonyl-3-pyrroline (600 mg, 3.0 mmol), and stirred overnight. To the reaction mixture were added sodium hydrosulfite (0.1 g) and florisil (2 g) and stirred for 30 min. The reaction mixture was filtered and washed with acetone (10 mL×2). The combined organic solution was dried (MgSO4), evaporated, and purified by flash column chromatography (EtOAc/hexane (1:1) -EtOAc only) to give meso-1-benzyloxycarbonyl-3,4-dihydroxypyrrolidine (586 mg, 84%) as an oil.
Reaction SMILES: [CH2:1]([N:8]([CH2:23][CH2:24][CH:25]=C)[C:9](=[O:22])[C@@H:10]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:11][CH:12]=C)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(Cl)CCl.Cl[Ru](=C1N(C2C(C)=CC(C)=CC=2C)CCN1C1C(C)=CC(C)=CC=1C)(Cl)(=CC1C=CC=CC=1)[P](C1CCCCC1)(C1CCCCC1)C1CCCCC1>[CH2:1]([N:8]1[CH2:23][CH2:24][CH:25]=[CH:12][CH2:11][C@H:10]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:19])([CH3:18])[CH3:20])[C:9]1=[O:22])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=CCCN(Cc1ccccc1)C(=O)[C@H](CC=C)NC(=O)OC(C)(C)C
Agent: Cc1cc(C)c(N2CCN(c3c(C)cc(C)cc3C)C2=[Ru](Cl)(Cl)(=Cc2ccccc2)[P](C2CCCCC2)(C2CCCCC2)C2CCCCC2)c(C)c1
Agent: CC(C)(C)OC(=O)N[C@H]1C/C=C\CCN(Cc2ccccc2)C1=O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N[C@H]1CC=CCCN(Cc2ccccc2)C1=O
Temperature: 57.5 °C
Reaction time: 13 h

Procedure:
A solution of (S)-tert-butyl 1-(benzyl(but-3-enyl)amino)-1-oxopent-4-en-2-ylcarbamate (255 mg, 0.711 mmol) in ClCH2CH2Cl (120 mL) was degassed with argon for 5 min. Then, the Grubbs II catalyst (30 mg, 0.036 mmol) was added. The reaction mixture was stirred at 55-60° C. under argon for 13 hr. The reaction mixture was then cooled to rt and concentrated. The brownish residue was purified using silica gel chromatography (ISCO system) eluting with a gradient of 0-30% EtOAc/Hex to give (S,Z)-tert-butyl 1-benzyl-2-oxo-1,2,3,4,7,8-hexahydroazocin-3-ylcarbamate (110 mg, 0.333 mmol, 46.8% yield) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ ppm 7.36-7.19 (m, 5H), 5.95 (d, J=6.5 Hz, 1H), 5.75-5.65 (m, 1H), 5.49-5.39 (m, 1H), 4.96 (d, J=14.8 Hz, 1H), 4.88 (q, J=6.8 Hz, 1H), 4.17 (d, J=14.9 Hz, 1H), 3.89-3.75 (m, 1H), 3.17 (dt, J=15.3, 5.8 Hz, 1H), 2.94-2.83 (m, 1H), 2.51-2.39 (m, 1H), 2.38-2.25 (m, 2H), 1.46 (s, 9H).