Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:6]=[CH:7][C:8]([CH3:19])=[C:9](OS(C(F)(F)F)(=O)=O)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:27][Si:28]([C:31]#[CH:32])([CH3:30])[CH3:29].CN(C)C=O>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CCCCCC>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([CH3:19])=[C:9]([C:32]#[C:31][Si:28]([CH3:30])([CH3:29])[CH3:27])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C#C[Si](C)(C)C
Reactant: Cc1ccc(C(C)(C)C)cc1OS(=O)(=O)C(F)(F)F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: Cc1ccc(C(C)(C)C)cc1C#C[Si](C)(C)C
Yield: 69.6 %

Procedure:
Following General Procedure D and using trifluoro-methanesulfonic acid 5-tert-butyl-2-methyl-phenyl ester (Intermediate 108, 0.28 g, 0.94 mmol), triethyl amine (3 mL), trimethylsilyl acetylene (1 mL, 7 mmol), N,N-dimethylformamide (6 mL) and dichlorobis(triphenylphosphine)palladium(II) (0.053 g, 0.076 mmol) followed by flash column chromatography over silica gel (230-400 mesh) using hexane as the eluent, the title compound (0.16 g, 69%) was obtained. 1H NMR (300 MHz, CDCl3): δ 7.44(d, J=1.7 Hz, 1H), 7.22(dd, J=8.2, 1.7 Hz, 1H), 7.10(d, J=8.2 Hz, 1H), 2.39(s, 3H), 1.28(s, 9H), 0.26(s, 9H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[C:11](Cl)(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[C:11]([N:7]1[C:8]2[C:4](=[CH:3][C:2]([CH3:1])=[CH:10][CH:9]=2)[CH:5]=[CH:6]1)(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Cc1ccc2[nH]ccc2c1
Reactant: O=C(Cl)c1ccccc1
Product: Cc1ccc2c(ccn2C(=O)c2ccccc2)c1

Procedure:
The 5-methylindole 1a is benzoylated with benzoyl chloride of a substituted benzoic acid to give N-benzoyl-5-methylindole, 1b. The bromination of 1b with N-bromosuccinimide and a catalytic amount of azobisisobutyronitrile in refluxing carbon tetrachloride affords N-benzoyl-5-bromomethylindole, 1c. ##STR43##
Reaction SMILES: [F:1][C:2]1[C:13]([O:14][CH3:15])=[CH:12][CH:11]=[CH:10][C:3]=1[C:4](N(OC)C)=[O:5]>C1COCC1.C1(C)C=CC=CC=1>[F:1][C:2]1[C:13]([O:14][CH3:15])=[CH:12][CH:11]=[CH:10][C:3]=1[CH:4]=[O:5]
Reactant: COc1cccc(C(=O)N(C)OC)c1F
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COc1cccc(C=O)c1F
Temperature: -78 °C
Reaction time: 3 h
Yield: 84.7 %

Procedure:
To a solution of 2-fluoro-3,N-dimethoxy-N-methyl-benzamide (2.30 g, 10.8 mmol) in THF (20 mL) at −78° C. was added 1M DEBAL-H in toluene.(12 mL, 12 mmol). The reaction stirred at −78° C. for 3 h and then the remaining 1M DIDAL-H in toluene (4.2 mL, 4.2 mmol) was added to the reaction. The reaction was allowed to stir at −78° C. for 30 min and was then warmed to rt. The reaction was quenched slowly with saturated aqueous NH4Cl. The organic phase was separated and the aqueous phase was extracted with 2×50 mL ethyl acetate. The combined organic phases were washed successively with 1N HCl and brine. The organic phase was dried (MgSO4) and concentrated in vacuo. The residue was purified by flash chromatography eluting silica gel with EtOAc:hexane [0:100 to 1:1] to yield the title compound (1.41 g, 85%): δH (300 MHz, CDCl3): 10.38 (1H, s), 7.43-7.40 (1H, m), 7.24-7.15 (2H, m), 3.95 (3H, s).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([CH2:31][C:32]2[S:33][C:34](Br)=[CH:35][CH:36]=2)[CH:25]=1)(=[O:3])[CH3:2].[F:38][C:39]1[CH:44]=[CH:43][C:42](B(O)O)=[CH:41][N:40]=1.[F-].[Cs+].C(=O)([O-])O.[Na+]>COCCOC>[C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([CH2:31][C:32]2[S:33][C:34]([C:42]3[CH:41]=[N:40][C:39]([F:38])=[CH:44][CH:43]=3)=[CH:35][CH:36]=2)[CH:25]=1)(=[O:3])[CH3:2]
Reactant: OB(O)c1ccc(F)nc1
Reactant: CC(=O)OC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc(Br)s3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: O=C([O-])O
Agent: [Cs+]
Agent: [F-]
Solvent: COCCOC
Product: CC(=O)OC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc(-c4ccc(F)nc4)s3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Yield: 60.1 %

Procedure:
A suspension of 1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-4-chloro-3-(5-bromo-2-thienylmethyl)benzene (13.5 g; prepared as described in PCT Publication WO 2005/012326), 2-fluoropyridine-5-boronic acid (Frontier Scientific, 4.63 g), cesium fluoride (19.96 g) and tetrakis(triphenylphosphin)palladium(0) (2.53 g) in 1,2-dimethoxyethane (200 ml) was refluxed for 1.5 hours. The reaction mixture was poured into a saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was dissolved in ethyl acetate, and the mixture was treated with activated carbon and filtered through aminosilane-treated silica gel (27 ml) pad. The filtrate was evaporated under reduced pressure, and the residue was purified by silica gel flash column chromatography (hexane:ethyl acetate:dichloromethane 2:1:1) and recrystallized from methanol to yield 1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-4-chloro-3-(5-(6-fluoro-3-pyridyl)-2-thienylmethyl)benzene (8.33 g) as a colorless crystal.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1([OH:21])[C:18]2[C:13](=[CH:14][CH:15]=[C:16](I)[CH:17]=2)[NH:12][C:11]1=[O:20])[CH3:2].[CH3:22][N:23](C=O)C>[C-]#N.[Zn+2].[C-]#N>[C:22]([C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11](=[O:20])[C:10]2([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[O:3][CH2:1][CH3:2])[OH:21])#[N:23]
Reactant: CCOc1ccccc1C1(O)C(=O)Nc2ccc(I)cc21
Reactant: CN(C)C=O
Agent: [C-]#N
Agent: [Zn+2]
Product: CCOc1ccccc1C1(O)C(=O)Nc2ccc(C#N)cc21
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
37.2 g (94 mMol) of the product 1a and 11.1 g (94 mMol) of zinc cyanide in 300 ml of DMF were heated to 95° C. Then 1.6 g (1.38 mMol) of tetrakis-(triphenylphosphine)palladium(0) were added in portions every 10 minutes. After 45 minutes, the reaction mixture was poured into ice-water and extracted with ethyl acetate. The organic phase was washed with saturated NaCl solution, dried and concentrated in vacuo. The residue obtained in this way crystallizes from a little ethyl acetate. 24 g of the product were obtained.
Reaction SMILES: C[O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[C:6]([C:14]#[N:15])[CH:5]=1.O.O.[OH-].[Li+]>O1CCOCC1>[C:14]([C:6]1[CH:5]=[C:4]([CH:9]=[C:8]([C:10]([F:11])([F:12])[F:13])[CH:7]=1)[C:3]([OH:16])=[O:2])#[N:15]
Reactant: COC(=O)c1cc(C#N)cc(C(F)(F)F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: N#Cc1cc(C(=O)O)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3-cyano-5-trifluoromethyl-benzoic acid methyl ester (0.084 g, 0.367 mmol) in dioxane (0.5 mL) was added water (0.5 mL) and lithium hydroxide monohydrate (19.2 mg, 0.458 mmol) and the resulting mixture was stirred at room temperature for 1 h. The reaction mixture was evaporated, the residue was taken up in dioxane and 10% aqueous citric acid solution and the layers were separated. The aqueous layer was extracted twice with EtOAc and the organic layers were washed with brine, dried over MgSO4, filtered and evaporated. Light brown solid (0.09 g; 98%). MS (ESI): m/z=214.01 [M−H]−.
Reaction SMILES: [C:1]1([CH3:8])[C:6]([OH:7])=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH:10]([CH3:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH3:8][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][C:6]=1[O:7][CH:10]([CH3:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: Cc1ccccc1O
Reactant: CCOC(=O)C(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)Oc1ccccc1C
Temperature: 70 °C

Procedure:
A mixture of 10.8 g (0.1 mol) of o-cresol, 18.1 g (0.1 mol) of ethyl 2-bromopropionate, and 14.5 g of K2CO3 in 50 ml of DMF is heated at 70° C. for 3 days. The reaction mixture is poured into H2O, and extracted with ethyl acetate. The organic solution is dried and evaporated to give ethyl 2-(2-methylphenoxy)propionate which is used directly in the next step.
Reaction SMILES: [F:1][C:2]1[C:7]2[N:8]=[CH:9][O:10][C:6]=2[CH:5]=[C:4]([C:11]([NH:13][O:14][CH2:15][CH2:16][O:17]C=C)=[O:12])[C:3]=1[NH:20][C:21]1[CH:26]=[CH:25][C:24]([I:27])=[CH:23][C:22]=1[F:28].Cl>C(Cl)Cl>[F:1][C:2]1[C:7]2[N:8]=[CH:9][O:10][C:6]=2[CH:5]=[C:4]([C:11]([NH:13][O:14][CH2:15][CH2:16][OH:17])=[O:12])[C:3]=1[NH:20][C:21]1[CH:26]=[CH:25][C:24]([I:27])=[CH:23][C:22]=1[F:28]
Reactant: C=COCCONC(=O)c1cc2ocnc2c(F)c1Nc1ccc(I)cc1F
Agent: Cl
Solvent: ClCCl
Product: O=C(NOCCO)c1cc2ocnc2c(F)c1Nc1ccc(I)cc1F
Reaction time: 1 h
Yield: 88.9 %

Procedure:
To a solution of compound 4-fluoro-5-((2-fluoro-4-iodophenyl)amino)-N-(2-(vinyloxy)ethoxy)benzo[d]oxazole-6-carboxamide (450 mg, 0.9 mmol) in CH2Cl2 (10 mL) was added 1.0 N HCl (aq., 6.7 mL, 6.72 mmol). After stirring for 1 h, the reaction mixture was washed with saturated NaHCO3 (aq.). The aqueous layer was washed with CH2Cl2 (10 mL×2). The combined organic layer was washed with water (10 mL) and brine (10 mL), dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (CH2Cl2/MeOH, 50:1, v/v) and gave the desired product (white solid, 380 mg, 88.9% yield). 1H NMR (400 MHz, DMSO-d6): δ 11.75 (s, 1H), 8.96 (s, 1H), 8.01 (s, 1H), 7.88 (s, 1H), 7.53 (d, J=9.4 Hz, 1H), 7.28 (d, J=8.7 Hz, 1H), 6.39 (m, 1H), 4.70 (s, 1H), 3.83 (s, 2H), 3.56 (s, 2H). MS APCI (+) m/z: 476.1, [M+H].
Reaction SMILES: [C:1]([CH2:6][N:7]=[CH:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH3:18])[CH:10]=1)([O:3][CH2:4][CH3:5])=[O:2].[CH3:19][O:20][C:21]1[CH:22]=[C:23]([C:29]([CH:36]([CH3:38])[CH3:37])([CH2:32][CH2:33][CH2:34]I)[C:30]#[N:31])[CH:24]=[CH:25][C:26]=1[O:27][CH3:28]>>[C:1]([CH:6]([N:7]=[CH:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH3:18])[CH:10]=1)[CH2:34][CH2:33][CH2:32][C:29]([C:23]1[CH:24]=[CH:25][C:26]([O:27][CH3:28])=[C:21]([O:20][CH3:19])[CH:22]=1)([C:30]#[N:31])[CH:36]([CH3:38])[CH3:37])([O:3][CH2:4][CH3:5])=[O:2]
Reactant: CCOC(=O)CN=Cc1ccc(OC)c(OC)c1
Reactant: COc1ccc(C(C#N)(CCCI)C(C)C)cc1OC
Product: CCOC(=O)C(CCCC(C#N)(c1ccc(OC)c(OC)c1)C(C)C)N=Cc1ccc(OC)c(OC)c1

Procedure:
The resulting imine of formula 24 is then deprotonated using a suitable strong base, and allowed to react with a compound of formula 22 to produce a compound of formula 25 (step 2). For example, 1-(carboethoxy)methyliminomethyl-3,4-dimethoxybenzene (24) is suspended in a solution of LiNiPr2 in THF/HMPA at -78° C., then reacted with 2-(3,4-dimethoxyphenyl)-2-isopropyl-2-(3-iodopropyl)acetonitrile (22) to produce N-[1-carboethoxy-5-(3,4-dimethoxyphenyl)-5-cyano-5-(isopropyl)pentyl]iminomethyl-3,4-dimethoxybenzene (25).
Reaction SMILES: O[CH:2]([CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:3][C:4](O)=O.O[CH:17]([CH2:22][CH2:23][CH2:24]COC1C=CC=CC=1)[CH2:18][C:19]([OH:21])=[O:20]>>[O:9]([CH2:8][CH2:7][CH2:2][CH2:3][CH2:4][CH2:24][CH2:23][CH2:22][CH2:17][CH2:18][C:19]([OH:21])=[O:20])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C(O)CC(O)CCOc1ccccc1
Reactant: O=C(O)CC(O)CCCCOc1ccccc1
Product: O=C(O)CCCCCCCCCCOc1ccccc1

Procedure:
Also, in Macromolecules, 29, 3432-3435 (1996), it is reported that using Pseudomonas oleovorans, PHA containing 3-hydroxy-4-phenoxybutyric acid and 3-hydroxy-6-phenoxyhexanoic acid as units is produced from 6-phenoxyhexanoic acid, PHA containing 3-hydroxy-4-phenoxybutyric acid, 3-hydroxy-6-phenoxyhexanoic acid and 3-hydroxy-8-phenoxyoctanoic acid as units is produced from 8-phenoxyoctanoic acid, and PHA containing 3-hydroxy-5-phenoxyvaleric acid and 3-hydroxy-7-phenoxyheptanoic acid as units is produced from 11-phenoxyundecanoic acid. Yields of polymers in this report are extracted and are shown in the following.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([CH3:8])[CH:7]=1.[CH2:10](Br)[CH:11]=[CH2:12].C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[CH3:1][C:2]1[CH:3]=[C:4]([O:9][CH2:12][CH:11]=[CH2:10])[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: C=CCBr
Reactant: Cc1cc(C)cc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: C=CCOc1cc(C)cc(C)c1
Yield: 104.6 %

Procedure:
46.73 g (383 mmol) of 3,5-dimethylphenol (Compound No. 1) was dissolved in 100 ml of methyl ethyl ketone. To this solution, 55.6 g (460 mmol) of allyl bromide and 79.3 g (575 mmol) of anhydrous potassium carbonate were added. The thus obtained mixture was refluxed overnight under an argon atmosphere. The reaction mixture was then extracted with hexane. The extract was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and concentrated, whereby 65.0 g of a crude 3,5-dimethyl-1-(2-propenyloxy)benzene (Compound No. 2) was obtained as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([CH3:8])[CH:7]=1.[CH2:10](Br)[CH:11]=[CH2:12]>>[CH2:12]([O:9][C:4]1[CH:5]=[C:6]([CH3:8])[CH:7]=[C:2]([CH3:1])[CH:3]=1)[CH:11]=[CH2:10]
Reactant: Cc1cc(C)cc(O)c1
Reactant: C=CCBr
Product: C=CCOc1cc(C)cc(C)c1
Yield: 78 %

Procedure:
Using 3,5-dimethylphenol and allyl bromide, the title compound was synthesized in the same manner as in Reference Example 213. Yield 78%. Oily matter.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:16]3[CH:17]=[C:18]4[O:23][CH2:22][O:21][C:19]4=[CH:20][C:15]=3[CH2:14][CH:13]([CH3:24])[N:12]([C:25](=[O:27])[CH3:26])[N:11]=2)=[CH:6][CH:5]=1)([O-])=O>CO>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:16]3[CH:17]=[C:18]4[O:23][CH2:22][O:21][C:19]4=[CH:20][C:15]=3[CH2:14][CH:13]([CH3:24])[N:12]([C:25](=[O:27])[CH3:26])[N:11]=2)=[CH:6][CH:5]=1
Reactant: CC(=O)N1N=C(c2ccc([N+](=O)[O-])cc2)c2cc3c(cc2CC1C)OCO3
Solvent: CO
Product: CC(=O)N1N=C(c2ccc(N)cc2)c2cc3c(cc2CC1C)OCO3

Procedure:
The title compound was prepared from the compound of Example 126 using the process described in Example 128. Melting point 169°-172° C. [α]D =-321.34° (c=1, MeOH) Enantiomeric purity: >99%
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.Br[C:37]1[CH:48]=[CH:47][C:40]([C:41]([NH:43][CH:44]2[CH2:46][CH2:45]2)=[O:42])=[CH:39][N:38]=1.C(OC(C)C)(=O)C>>[CH:44]1([NH:43][C:41](=[O:42])[C:40]2[CH:47]=[CH:48][C:37]([C:16]3[CH:17]=[CH:18][C:13]([C@@H:11]([N:7]4[CH2:6][CH2:5][C@:4]([CH2:3][C:2]([OH:1])([CH3:35])[CH3:34])([C:28]5[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=5)[O:9][C:8]4=[O:10])[CH3:12])=[CH:14][CH:15]=3)=[N:38][CH:39]=2)[CH2:46][CH2:45]1
Reactant: O=C(NC1CC1)c1ccc(Br)nc1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Solvent: CC(=O)OC(C)C
Product: C[C@@H](c1ccc(-c2ccc(C(=O)NC3CC3)cn2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared from (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one and 6-bromo-N-cyclopropylnicotinamide following a procedure analogous to that described in Example 14. LC-MS Method 1 tR=1.74 min, m/z=456.1; 1H NMR (CDCl3) 0.61 (m, 2H), 0.82 (m, 2H), 1.13 (s, 3H), 1.22 (s, 3H), 1.49 (d, 3H), 2.17 (m, 3H), 2.21 (m, 1H), 2.31 (m, 1H), 2.79 (m, 1H), 2.88 (m, 1H), 5.66 (m, 1H), 6.40 (s, 1H), 6.99 (d, 1H), 7.20-7.31 (m, 5H), 7.60 (d, 1H), 7.68 (d, 2H), 8.07 (d, 1H), 8.89 (s, 1H). The compound was dissolved in refluxing isopropyl acetate and allowed to cool slowly to it to afford a solid with mp 191-194° C.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[NH2:15][C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>O1CCCC1.C(O)(=O)C>[C:19]1([CH3:22])[CH:20]=[CH:21][C:16]([NH:15][CH:2]2[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]2)=[CH:17][CH:18]=1
Reactant: Cc1ccc(N)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: Cc1ccc(NC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Reaction time: 48 h
Yield: 89 %

Procedure:
To a solution of tert-butyl 4-oxopiperidin-1-carboxylate (5.01 g) and p-toluidine (2.69 g) dissolved in tetrahydrofuran (50 mL) were added sodium triacetoxyborohydride (7.99 g) and then acetic acid (3.0 mL). The reaction solution was stirred for 2 days. The reaction solution was poured into saturated aqueous sodium bicarbonate solution, and it was extracted with ethyl acetate. The extract was washed in turn with water and saturated aqueous sodium chloride solution, and dried (MgSO4). The solvent was distilled off under reduced pressure, and the resulting residue was purified by chromatography (silica gel, 20% ethyl acetate/hexane) to give the title compound (6.49 g).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7]Br)([O-:3])=[O:2].[NH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1>C1COCC1>[N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7][N:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1)([O-:3])=[O:2]
Reactant: C1CCNC1
Reactant: O=[N+]([O-])c1cccc(CBr)c1
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cccc(CN2CCCC2)c1

Procedure:
To a solution of 3-nitrobenzylbromide (3 g, 13.9 mmol) in anhydrous THF (30 ml) was added a solution of pyrrolidine (2.3 ml, 27.8 mmol) in anhydrous THF (10 ml) dropwise with stirring. Following the addition the mixture was stirred at ambient temperature overnight. The reaction mixture was filtered. The filter cake was washed with a small volume of anhydrous THF and the filtrate was concentrated to leave the intermediate 1-(3-nitrobenzyl)pyrrolidine as an oil. This oil was dissolved in methanol (50 ml) and three equivalents of both ammonium chloride and sodium sulfide nonahydrate were added. The mixture was heated to reflux for 2 hours. After cooling the mixture was filtered. The filtercake was washed with methanol and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate and dried over sodium sulfate. Filtration and evaporation of solvent left 2i quantitatively as yellow crystals.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=[O:6].[CH2:12](Br)[CH:13]=[CH2:14].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:14]([O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=[O:6])[CH:13]=[CH2:12]
Reactant: COc1ccc(C=O)cc1O
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCOc1cc(C=O)ccc1OC

Procedure:
The title compound was prepared analogously to intermediate 2 (4-methoxy-3-propoxy-benzaldehyde) by reaction of 3-hydroxy-4-methoxy-benzaldehyde with allylbromide in DMF using K2CO3 as base (see also A. W. White, R. Almassy, A. H. Calvert, N. J. Curtin, R. J. Griffin, Z. Hostomsky, K. Maegley, D. R. Newell, S. Srinivasan, B. T. Golding J. Med. Chem. 2000, 43, 4084-4097).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:13])=[C:6]2[C:10]=1[NH:9][CH:8]=[C:7]2[C:11]#[N:12].N1C=CC=CC=1.[C:20]([C:22]1[CH:23]=[C:24]([S:28](Cl)(=[O:30])=[O:29])[CH:25]=[CH:26][CH:27]=1)#[N:21]>O1CCCC1>[C:11]([C:7]1[C:6]2[C:10](=[C:2]([NH:1][S:28]([C:24]3[CH:25]=[CH:26][CH:27]=[C:22]([C:20]#[N:21])[CH:23]=3)(=[O:30])=[O:29])[CH:3]=[CH:4][C:5]=2[CH3:13])[NH:9][CH:8]=1)#[N:12]
Reactant: Cc1ccc(N)c2[nH]cc(C#N)c12
Reactant: N#Cc1cccc(S(=O)(=O)Cl)c1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: Cc1ccc(NS(=O)(=O)c2cccc(C#N)c2)c2[nH]cc(C#N)c12
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 47.4 %

Procedure:
To a solution of 7-amino-3-cyano-4-methyl-1H-indole (10 g, 58.4 mmol) in tetrahydrofuran (200 ml) were added pyridine (20 ml) and 3-cyanobenzenesulfonyl chloride (12.5 g), followed by stirring at room temperature for 3.5 hours. After further adding 2N hydrochloric acid (100 ml), extraction was performed with ethyl acetate. The organic layer was washed with water (twice) and brine in that order, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1-3:2). A mixed solvent of ethanol-hexane (1:2) was added thereto, and after sonication, the precipitate was collected by filtration and washed with a mixed solvent of ethanol-hexane (1:3). The mixture was dried overnight under reduced pressure to give the title compound (9.33 g, 27.7 mmol, 47% yield).
Reaction SMILES: [BH4-].[Na+].[O:3]=[C:4]1[CH2:18][C@@H:7]2[CH2:8][N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:10][C@@H:6]2[CH2:5]1>CO>[OH:3][CH:4]1[CH2:18][C@@H:7]2[CH2:8][N:9]([C:11]([O:13][C:14]([CH3:16])([CH3:15])[CH3:17])=[O:12])[CH2:10][C@@H:6]2[CH2:5]1
Reactant: CC(C)(C)OC(=O)N1C[C@H]2CC(=O)C[C@H]2C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)N1C[C@H]2CC(O)C[C@H]2C1
Reaction time: 1 h
Yield: 96.8 %

Procedure:
Sodium borohydride (0.15 g, 4.00 mmol), was added to a solution of 1,1-dimethylethyl(3aR,6aS)-5-oxo-hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (0.45 g, 2.00 mmol) in 10 mL methanol at 0° C. and the reaction mixture was stirred for 1 h at this temperature. The solvent was evaporated, the crude mixture was diluted with 100 mL ethyl acetate and washed with water (30 mL), 1M aqueous hydrochloric acid and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to give 1,1-dimethylethyl(3aR,6aS)-5-(hydroxy)-hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (0.44 g, 98%). 1H NMR (400 MHz, d6-DMSO): 4.08 (m, 1H), 3.40 (m, 2H), 3.30 (m, 2H), 2.50 (m, 2H), 1.98 (m, 2H), 1.40 (s, 9H), 1.30 (m, 2H). MS (EI) for C12H21NO3: 228 (MH+).
Reaction SMILES: [H-].[Na+].[CH:3]1[C:8]([OH:9])=[CH:7][CH:6]=[CH:5][C:4]=1[CH3:10].Br[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1>N1C=CC=CC=1.[Cu]Cl>[C:4]1([CH3:10])[CH:5]=[CH:6][CH:7]=[C:8]([O:9][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[CH:3]=1
Reactant: COc1ccc(Br)cc1
Reactant: Cc1cccc(O)c1
Agent: Cl[Cu]
Agent: [H-]
Agent: [Na+]
Solvent: c1ccncc1
Product: COc1ccc(Oc2cccc(C)c2)cc1
Temperature: 170 °C

Procedure:
21.8 g of sodium hydride (55% in oil) are introduced into 100 ml of absolute pyridine and treated dropwise during 1 hour with 54.1 g of m-cresol in 200 ml of pyridine. After completion of the reaction 1.2 g of copper (I) chloride are added and subsequently 93.5 g of 4-bromoanisole are added dropwise at reflux temperature during 1 hour. After heating at reflux for 4 hours the pyridine is distilled off, whereby at the end the mixture is warmed to 170° C. (internal temperature). After 2 hours 350 ml of water are added dropwise while cooling with ice, followed by 500 ml of diethyl ether and an additional 150 ml of water. The mixture is suction filtered over Celite and the phases are separated. The organic phase is washed in sequence with 200 ml of 2N hydrochloric acid, three times with 100 ml of 2N sodium hydroxide each time, with 200 ml of water and with 200 ml of saturated sodium chloride solution. After drying over anhydrous sodium sulfate and evaporation there is obtained a brown-red oil which is firstly filtered over a five-fold amount of silica gel with n-hexane/diethyl ether and then distilled to yield pure p-(m-tolyloxy)anisole; b.p. 106°-108° C./0.04 Torr; nD20 =1.5738.