Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.Br[CH2:11][CH:12]1[CH2:16][CH2:15][CH2:14][O:13]1.[I-].[Na+]>>[O:13]1[CH2:14][CH2:15][CH2:16][CH:12]1[CH2:11][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: BrCC1CCCO1
Agent: [I-]
Agent: [Na+]
Product: O=Cc1ccc(OCC2CCCO2)cc1
Yield: 99.9 %

Procedure:
The compound was synthesized as in Example 24.1, using 4-hydroxybenzaldehyde (200 mg, 1.64 mmol) and 2-(bromomethyl)tetrahydrofuran (541 mg, 1.97 mmol) in place of 1-chloro-3,3-dimethylbutane (no sodium iodide was used) to give 4-((tetrahydrofuran-2-yl)methoxy)benzaldehyde (338 mg, quant. crude) as a yellow oil that was used without further purification or characterization.
Reaction SMILES: [C:1]([NH:4][OH:5])(=[O:3])[CH3:2].[CH3:6][N:7]=[C:8]=[O:9]>C(N(CC)CC)C.C(Cl)Cl>[CH3:6][NH:7][C:8]([N:4]([O:5][C:8]([NH:7][CH3:6])=[O:9])[C:1](=[O:3])[CH3:2])=[O:9]
Reactant: CC(=O)NO
Reactant: CN=C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CNC(=O)ON(C(C)=O)C(=O)NC
Reaction time: 1 h

Procedure:
A mixture of acetohydroxamic acid (7.5 grams), methyl isocyanate (12.0 grams), 80 milliliters (ml) of methylene chloride, and about three drops of triethylamine were stirred together for about one hour in order to obtain solution. The solution was allowed to stand at room temperature overnight after which the solvent was removed under vacuum, leaving a residue. The residue was recrystallized from methylene chloride leaving the desired N-((methylamino)carbonyl)-N-(((methylamino)carbonyl)oxy)acetamide as white crystals having a melting point (m.p.) of 121°-123.5° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=[CH:4][C:5]2[N:6]([C:8](=[O:11])[NH:9][N:10]=2)[N:7]=1.Cl[CH2:20][C:21]1[CH:22]=[CH:23][C:24]([C:27]([F:30])([F:29])[F:28])=[N:25][CH:26]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[Cl:1][C:2]1[C:3]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=[CH:4][C:5]2[N:6]([C:8](=[O:11])[N:9]([CH2:20][C:21]3[CH:26]=[N:25][C:24]([C:27]([F:30])([F:28])[F:29])=[CH:23][CH:22]=3)[N:10]=2)[N:7]=1
Reactant: FC(F)(F)c1ccc(CCl)cn1
Reactant: O=c1[nH]nc2cc(-c3ccc(Cl)cc3)c(Cl)nn12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1n(Cc2ccc(C(F)(F)F)nc2)nc2cc(-c3ccc(Cl)cc3)c(Cl)nn12
Temperature: 70 °C
Reaction time: 0.33 h
Yield: 83.3 %

Procedure:
A suspension of 6-chloro-7-(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one (843 mg, 3 mmol), 5-chloromethyl-2-(trifluoromethyl)pyridine (704 mg, 3.6 mmol) and solid K2CO3 (830 mg, 6 mmol) in anhydrous DMF (10 mL) was stirred at 70° C. for 20 min. Analysis by HPLC/MS indicated the reaction was complete. After cooling to room temperature, the reaction was diluted with water and extracted with EtOAc (40 mL×3). The combined EtOAc extracts were washed with saturated aqueous NaCl, dried (Na2SO4) and concentrated under reduced pressure. The crude product was purified by trituration with CH2Cl2-hexanes to afford 1.10 g (84%) of the title compound as a yellow solid. LC/MS (method A): retention time=3.50 min, (M+H)+=440.
Reaction SMILES: C(O[C:9](=[O:32])[CH:10]([N:21]1[CH:25]=[CH:24][CH:23]=[C:22]1[C:26](=[O:31])C(Cl)(Cl)Cl)[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])C1C=CC=CC=1.[Cl:33][C:34]1[CH:35]=[C:36]([CH:39]=[CH:40][C:41]=1[Cl:42])[CH2:37][NH2:38].C(N(CC)CC)C.Cl>CN(C)C=O>[CH2:14]([O:13][C:11]([CH:10]1[N:21]2[CH:25]=[CH:24][CH:23]=[C:22]2[C:26](=[O:31])[N:38]([CH2:37][C:36]2[CH:39]=[CH:40][C:41]([Cl:42])=[C:34]([Cl:33])[CH:35]=2)[C:9]1=[O:32])=[O:12])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=C(OCc1ccccc1)C(C(=O)OCc1ccccc1)n1cccc1C(=O)C(Cl)(Cl)Cl
Reactant: NCc1ccc(Cl)c(Cl)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)C1C(=O)N(Cc2ccc(Cl)c(Cl)c2)C(=O)c2cccn21
Temperature: 70 °C
Reaction time: 2 h
Yield: 59.5 %

Procedure:
A mixture of 2-(2-trichloroacetylpyrrol-1-yl)malonic acid dibenzyl ester (30.0 g), 3,4 dichlorobenzylamine (11.7 g) and triethylamine (18.4 g, 25.0 ml) in anhydrous dimethylformamide (70 ml) was stirred under the stream of nitrogen at 70° C. for 2 hours. After cooling, the reaction mixture was poured into 5% hydrochloric acid and extracted with ethyl acetate. The extracts were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was chromatographed on silica gel using n-hexane/ethyl acetate (3:1) as the eluent. Fractions containing the title compound were pooled and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate/n-hexane to give the title compound (16.0 g, 59.5%) as colorless crystals, mp 104°-106° C.
Reaction SMILES: CC1(C)[NH:7][C:6](=[O:8])[C:5]2[CH:9]=[C:10]([OH:13])[CH:11]=[CH:12][C:4]=2[O:3]1.[CH3:15][C:16]([N+:24]([O-:26])=[O:25])([CH3:23])[CH2:17]OS(C)(=O)=O.C(=O)([O-])[O-].[K+].[K+].O>COCCOCCOC>[CH3:15][C:16]([N+:24]([O-:26])=[O:25])([CH3:23])[CH2:17][O:13][C:10]1[CH:9]=[C:5]([C:6]([NH2:7])=[O:8])[C:4]([OH:3])=[CH:12][CH:11]=1
Reactant: CC1(C)NC(=O)c2cc(O)ccc2O1
Reactant: CC(C)(COS(C)(=O)=O)[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOCCOC
Product: CC(C)(COc1ccc(O)c(C(N)=O)c1)[N+](=O)[O-]
Reaction time: 9 h

Procedure:
A mixture of 84.3 g of 2,3-dihydro-2,2-dimethyl-6-hydroxy-4H-1,3-benzoxazin-4-one, 144.2 g of methanesulfonic acid-(2-methyl-2-nitropropyl)-ester and 121 g of anhydrous potassium carbonate in 440 ml of diethylene glycol dimethyl ether is stirred for 9 hours in a bath at about 150°. The reaction mixture is cooled, poured into 4000 ml of water, and extracted with 3000 ml of ethyl acetate. The oil, obtained by concentrating the organic phase by evaporation, is dissolved in 250 ml of dioxane, and about 750 ml of 2N hydrochloric acid is added until an acid reaction occurs. The solution is held for 11/2 hours at 80°-100°; it is then concentrated under reduced pressure to half its volume, and extracted three times with 500 ml of ethyl acetate each time. The combined organic phases are washed with 200 ml of water, then with saturated sodium bicarbonate solution, and finally with saturated sodium chloride solution; they are subsequently dried over magnesium sulfate and concentrated by evaporation. The dark brown oil thus obtained is chromatographed on 500 g of silica gel. Elution with ether yields crystalline 5-(2-methyl-2-nitropropoxy)-salicylamide, m.p. 145°-148°.
Reaction SMILES: C([O:3][C:4](=[O:22])[CH2:5][NH:6][C:7]1[C:12]([NH:13][C:14]([C:16]2[S:17][C:18]([CH3:21])=[CH:19][CH:20]=2)=O)=[CH:11][CH:10]=[CH:9][N:8]=1)C.O.[OH-].[K+]>C(O)CO>[CH3:21][C:18]1[S:17][C:16]([C:14]2[N:6]([CH2:5][C:4]([OH:3])=[O:22])[C:7]3=[N:8][CH:9]=[CH:10][CH:11]=[C:12]3[N:13]=2)=[CH:20][CH:19]=1
Reactant: CCOC(=O)CNc1ncccc1NC(=O)c1ccc(C)s1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: OCCO
Product: Cc1ccc(-c2nc3cccnc3n2CC(=O)O)s1
Yield: 65.3 %

Procedure:
A suspension of N-[3-[(5-methyl-2-thienylcarbonyl)amino]-2-pyridinyl]glycine ethyl ester (93.8 g, 0.293 mole) was refluxed in ethylene glycol (500 ml) for 45 minutes. The solution was cooled and water 9200 ml) and solid potassium hydroxide pellets (23.25 g, 0.41 mole) were added. The resulting solution was refluxed for one hour and then filtered hot into ice water (2 liters) and acidified with 3N hydrochloric acid to give a solid which was collected by filtration and dried to give 52.3 g of crude title compound (65% yield). A 2.0 g portion was dissolved in hot methanol, treated with charcoal, filtered while hot, and cooled to room temperature. Addition of water caused a precipitate to form which was collected by filtration and dried under high vacuum at room temperature overnight to gibe 0.68 g of title compound, mp>250° C.
Reaction SMILES: CO.[N:3]1[CH:8]=[CH:7][C:6]([O:9][CH:10]([C:12]2[CH:21]=[CH:20][C:15]([C:16]([O:18]C)=[O:17])=[CH:14][CH:13]=2)[CH3:11])=[CH:5][CH:4]=1.[OH-].[Li+].Cl>O>[N:3]1[CH:4]=[CH:5][C:6]([O:9][CH:10]([C:12]2[CH:13]=[CH:14][C:15]([C:16]([OH:18])=[O:17])=[CH:20][CH:21]=2)[CH3:11])=[CH:7][CH:8]=1
Reactant: COC(=O)c1ccc(C(C)Oc2ccncc2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(Oc1ccncc1)c1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 88.5 %

Procedure:
To a mixed solution of methanol (10 mL) and water (2 mL), methyl 4-(1-(pyridin-4-yloxy)ethyl)benzoate (151 mg, 0.59 mmol) and lithium hydroxide were added. The mixture was stirred at room temperature for 12 hours. Then the reaction mixture was acidified by hydrogen chloride aqueous solution (1N) to adjust pH=6, and then extracted with dichloromethane (20 mL×3). And the mixture was concentrated to give 4-(1-(pyridin-4-yloxy)ethyl)benzoic acid (127 mg, 88%).
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][C:19]3[CH:20]=[C:21]([CH3:25])[CH:22]=[CH:23][CH:24]=3)=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:3]1.Cl[CH2:34][C:35]1[CH:36]=[CH:37][C:38]2[O:43][CH2:42][C:41](=[O:44])[N:40]([CH2:45][CH2:46][CH2:47][O:48][CH3:49])[C:39]=2[CH:50]=1>>[CH3:49][O:48][CH2:47][CH2:46][CH2:45][N:40]1[C:39]2[CH:50]=[C:35]([CH2:34][O:1][CH:2]3[CH:7]([C:8]4[CH:9]=[CH:10][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][C:19]5[CH:20]=[C:21]([CH3:25])[CH:22]=[CH:23][CH:24]=5)=[CH:12][CH:13]=4)[CH2:6][CH2:5][N:4]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:3]3)[CH:36]=[CH:37][C:38]=2[O:43][CH2:42][C:41]1=[O:44]
Reactant: Cc1cccc(OCCCOc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3O)cc2)c1
Reactant: COCCCN1C(=O)COc2ccc(CCl)cc21
Product: COCCCN1C(=O)COc2ccc(COC3CN(C(=O)OC(C)(C)C)CCC3c3ccc(OCCCOc4cccc(C)c4)cc3)cc21

Procedure:
Analogously to Method D, 1.10 g of tert-butyl 3-hydroxy-4-[4-(3-m-tolyloxypropoxy)phenyl]piperidine-1-carboxylate and 0.693 g 6-chloromethyl-4-(3-methoxypropyl)-4H-benzo[1,4]oxazin-3-one (Example 2a) are reacted. The title compound is obtained as a colourless oil. Rf=0.60 (1:1 EtOAc-heptane); Rt=6.14.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[C:11]([N+:12]([O-])=O)=[C:10]([O:15][CH2:16][C:17]([F:20])([F:19])[F:18])[CH:9]=[C:8]([CH3:21])[N:7]=1.[H][H]>O1CCOCC1.CO.[Ni]>[NH2:12][C:11]1[C:6]([O:5][CH2:4][CH2:3][O:2][CH3:1])=[N:7][C:8]([CH3:21])=[CH:9][C:10]=1[O:15][CH2:16][C:17]([F:18])([F:19])[F:20]
Reactant: [H][H]
Reactant: COCCOc1nc(C)cc(OCC(F)(F)F)c1[N+](=O)[O-]
Agent: [Ni]
Solvent: CO
Solvent: C1COCCO1
Product: COCCOc1nc(C)cc(OCC(F)(F)F)c1N

Procedure:
2-[(2-Methoxyethyl)oxy]-6-methyl-3-nitro-4-[(2,2,2-trifluoroethyl)oxy]pyridine (1.65 g, 5.32 mmol) was dissolved in a mixed solvent of dioxane (30 mL)-methanol (30 mL). Raney nickel (ethanol suspension, 3 mL) was added to the solution. In a hydrogen atmosphere, the mixture was stirred at room temperature for 26 hours. The reaction mixture was subjected to filtration, and the filtrate was concentrated under reduced pressure, to thereby yield 3-amino-2-[(2-methoxyethyl)oxy]-6-methyl-4-[(2,2,2-trifluoroethyl)oxy]pyridine as a pale yellow oil (1.49 g, 99%).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([C:8]([OH:10])=O)=[C:5]([CH3:7])[N:6]=1.[NH2:11][C:12]1[CH:13]=[C:14]([CH:31]=[CH:32][C:33]=1[CH3:34])[O:15][C:16]1[CH:17]=[CH:18][C:19]2[N:20]([CH:22]=[C:23]([NH:25][C:26]([CH:28]3[CH2:30][CH2:29]3)=[O:27])[N:24]=2)[N:21]=1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C>CN(C)C=O>[CH:28]1([C:26]([NH:25][C:23]2[N:24]=[C:19]3[CH:18]=[CH:17][C:16]([O:15][C:14]4[CH:31]=[CH:32][C:33]([CH3:34])=[C:12]([NH:11][C:8]([C:4]5[S:3][C:2]([CH3:1])=[N:6][C:5]=5[CH3:7])=[O:10])[CH:13]=4)=[N:21][N:20]3[CH:22]=2)=[O:27])[CH2:29][CH2:30]1
Reactant: Cc1nc(C)c(C(=O)O)s1
Reactant: Cc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)cc1N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1nc(C)c(C(=O)Nc2cc(Oc3ccc4nc(NC(=O)C5CC5)cn4n3)ccc2C)s1
Yield: 41.8 %

Procedure:
In the same manner as in Example 261 and using 2,4-dimethyl-1,3-thiazole-5-carboxylic acid (130 mg, 0.80 mmol), N-[6-(3-amino-4-methylphenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (200 mg, 0.62 mmol), 1-hydroxybenzotriazole (110 mg, 0.80 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (150 mg, 0.80 mmol), triethylamine (94 mg, 0.93 mmol) and N,N-dimethylformamide (5 mL) as starting materials, the title compound (120 mg, 41%) was obtained as a pale-yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12](I)=[C:13]([Cl:17])[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[O:19]1[CH2:24][CH2:23][CH:22]([OH:25])[CH2:21][CH2:20]1>>[C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([O:25][CH:22]3[CH2:23][CH2:24][O:19][CH2:20][CH2:21]3)=[C:13]([Cl:17])[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1Cc2cc(Cl)c(I)cc2C1
Reactant: OC1CCOCC1
Product: CC(C)(C)OC(=O)N1Cc2cc(Cl)c(OC3CCOCC3)cc2C1

Procedure:
Prepared in analogy to Example A6(a) from 5-chloro-6-iodo-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester (Example A3(c)) and tetrahydro-4H-pyran-4-ol. Off-white solid. MS (m/e): 300.1 ([{37Cl}M+H-Me2C═CH2]+, 36%), 298.3 ([{35Cl}M+H-Me2C═CH2]+, 100%).
Reaction SMILES: C(N(CC)CC)C.Cl.[Br:9][C:10]1[CH:11]=[C:12]([NH:16][NH2:17])[CH:13]=[CH:14][CH:15]=1.[CH:18]1([C:22](Cl)=[O:23])[CH2:21][CH2:20][CH2:19]1>ClCCl>[Br:9][C:10]1[CH:11]=[C:12]([NH:16][NH:17][C:22]([CH:18]2[CH2:21][CH2:20][CH2:19]2)=[O:23])[CH:13]=[CH:14][CH:15]=1
Reactant: O=C(Cl)C1CCC1
Reactant: NNc1cccc(Br)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NNc1cccc(Br)c1)C1CCC1
Reaction time: 1.5 h
Yield: 59.8 %

Procedure:
Triethylamine (6.90 mL, 49.22 mmol) was added dropwise to a suspension of 3-bromophenylhydrazine hydrochloride (5.00 g, 22.37 mmol) in dichloromethane (60 mL) to give a solution. The mixture was cooled in an ice-salt bath and then cyclobutanecarbonyl chloride (2.68 mL, 23.49 mmol) in dichloromethane (10 mL) was added dropwise at such a rate that the internal temperature did not exceed −10° C. After the addition, the mixture was stirred at −5° C. to −10° C. for 1.5 hours. The cooling bath was removed and the mixture was stirred for a further 2 hours at room temperature. The mixture was evaporated in vacuo and 4% aqueous sodium hydrogen carbonate solution was added. The mixture was filtered and the semi-solid was washed with 4% aqueous sodium hydrogen carbonate solution, water and diethyl ether and dried in vacuo to give the title compound (3.60 g, 60%) as a white solid.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1([OH:27])[CH2:22][C:21]2[C:20]([OH:23])=[C:19]3[C:10]([C:11](=[O:25])[C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=4[C:18]3=[O:24])=[C:9]([OH:26])[C:8]=2[CH2:7][CH2:6]1)=[O:4].[C:28]([O-:34])(=[O:33])[CH2:29][CH2:30][CH2:31][CH3:32].[Na+]>CC(C)=O>[C:28]([O:34][CH2:2][C:3]([C:5]1([OH:27])[CH2:22][C:21]2[C:20]([OH:23])=[C:19]3[C:10]([C:11](=[O:25])[C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=4[C:18]3=[O:24])=[C:9]([OH:26])[C:8]=2[CH2:7][CH2:6]1)=[O:4])(=[O:33])[CH2:29][CH2:30][CH2:31][CH3:32]
Reactant: CCCCC(=O)[O-]
Reactant: O=C1c2ccccc2C(=O)c2c(O)c3c(c(O)c21)CCC(O)(C(=O)CBr)C3
Agent: [Na+]
Solvent: CC(C)=O
Product: CCCCC(=O)OCC(=O)C1(O)CCc2c(O)c3c(c(O)c2C1)C(=O)c1ccccc1C3=O
Temperature: 25 °C

Procedure:
A mixture of 9-bromoacetyl-6,9,11-trihydroxy-5,7,8,9,10,12-hexahydronaphthacene-5,12-dione (1.00 g) obtained in Reference Example 1-(1), sodium valerate (1.44 g) and acetone (50 ml) was stirred under reflux for 5 hours, cooled to room temperature and concentrated under reduced pressure. The residue was triturated with an adequate quantity of ether, and solid substances were filtered to give reddish crystals of 9-valeryloxyacetyl-6,9,11-trihydroxy-5,7,8,9,10,12-hexahydronaphthacene-5,12-dione. M.P., 170°-172° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[C:10]2[C:5](=[C:6]([NH2:11])[CH:7]=[CH:8][CH:9]=2)[C@H:4]([CH3:12])[CH2:3]1.[H][H]>C1(C)C=CC=CC=1>[CH3:1][C:2]1([CH3:13])[C:10]2[C:5](=[C:6]([NH2:11])[CH:7]=[CH:8][CH:9]=2)[CH:4]([CH3:12])[CH2:3]1
Reactant: [H][H]
Reactant: C[C@@H]1CC(C)(C)c2cccc(N)c21
Solvent: Cc1ccccc1
Product: CC1CC(C)(C)c2cccc(N)c21
Reaction time: 1 h

Procedure:
Into a reaction vessel were charged 31.7 parts by weight of (3R)-1,1,3-trimethyl-4-aminoindane (optical purity of 67.0% ee) and 0.36 parts by weight of 5% palladium-alumina, thereby obtaining a mixture. The reaction vessel was sealed and the gas in the reaction vessel was replaced with nitrogen. While the mixture was stirred, into the reaction vessel was charged hydrogen until the internal pressure of hydrogen in the reaction vessel reached 0.5 MPa, and the mixture was stirred at an internal temperature of 60° C. After 1 hour, the gas in the reaction vessel was replaced with nitrogen, and the mixture was stirred at an internal temperature of 155° C. and an internal pressure of 0.1 MPa for 7 hours, thereby obtaining a reaction mixture. The obtained reaction mixture was cooled and filtered. The obtained solid was washed with 45 parts by weight of toluene. The washing liquid recovered after washing and the filtrate obtained by filtration were combined to obtain a solution of 73.4 parts by weight of 1,1,3-trimethyl-4-aminoindane in toluene. The obtained 1,1,3-trimethyl-4-aminoindane had an optical purity of 4.5% ee and a recovery rate of 98.7%.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[C:7]([O:9][CH2:10][CH3:11])=[O:8].C(O)[C:13]1[CH:18]=[CH:17]C=[CH:15][CH:14]=1>>[O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[C:7]([O:9][CH2:10][C:11]1[CH:17]=[CH:18][CH:13]=[CH:14][CH:15]=1)=[O:8]
Reactant: CCOC(=O)C1CCCC1=O
Reactant: OCc1ccccc1
Product: O=C1CCCC1C(=O)OCc1ccccc1
Temperature: 175 °C
Yield: 93.1 %

Procedure:
To ethyl 2-oxocyclopentanecarboxylate (4 g, 25.6 mmol) was added benzyl alcohol (3.6 g, 33.3 mmol) and the resulting mixture was heated to 175° C. for 1 hour. The reaction mixture was concentrated under reduced pressure using a high vacuum pump to yield benzyl 2-oxocyclopentanecarboxylate (5.2 g, 23.84 mmol, 93% yield) as an oil. This compound was used for the next step without further purification.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[O:17][C:6]2=[C:7]3[C:12](=[C:13]([CH3:15])[CH:14]=[C:5]2[CH2:4]1)[NH:11][C:10](=[O:16])[CH:9]=[CH:8]3.[C:18]([NH:28][C:29]([CH3:34])([C:31](O)=[O:32])[CH3:30])([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19].CCN=C=NCCCN(C)C.Cl>CN(C)C=O.N1C=CC=CC=1>[C:18]([NH:28][C:29]([CH3:34])([C:31]([NH:1][CH2:2][CH:3]1[O:17][C:6]2=[C:7]3[C:12](=[C:13]([CH3:15])[CH:14]=[C:5]2[CH2:4]1)[NH:11][C:10](=[O:16])[CH:9]=[CH:8]3)=[O:32])[CH3:30])([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19]
Reactant: CC(C)(NC(=O)OCc1ccccc1)C(=O)O
Reactant: Cc1cc2c(c3ccc(=O)[nH]c13)OC(CN)C2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: Cc1cc2c(c3ccc(=O)[nH]c13)OC(CNC(=O)C(C)(C)NC(=O)OCc1ccccc1)C2
Temperature: 50 °C
Reaction time: 48 h
Yield: 43.6 %

Procedure:
2-Aminomethyl-5-methyl-2,3,6,7-tetrahydrofuro-[2,3-f]quinoline-7-one (3.00 g, 13.0 mmol) was dissolved in a solvent mixture of dimethylformamide (200 ml) and pyridine (100 ml). To this solution, N-carbobenzyloxy-α-methylalanine (4.64 g, 19.5 mmol) and WSC-HCl (3.48 g, 19.5 mmol) were added and the mixture was stirred at 50° C. for 48 hours. The reaction mixture was condensed under reduced pressure, and the residue was subjected to extraction using a solvent mixture (chloroform--methanol =4:1) combined with 1N-HCl. The organic phase was washed with saturated aqueous NaCl solution, followed by drying and condensing under reduced pressure. The resultant residue was purified by silica gel column chromatography (chloroform: methanol=25:1). The crude crystals were subjected to a recrystallizing procedure from chloroform--methanol. As a result, 2.55 g of the title compound was obtained as colorless powdery crystals (43.7%).
Reaction SMILES: CC([O-])(C)C.[K+].[CH3:7][CH2:8][SH:9].[C:10]([O:14][C:15]([N:17]1[CH2:21][CH2:20][CH2:19][C@H:18]1[CH:22]=[C:23]([C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26])[CH3:24])=[O:16])([CH3:13])([CH3:12])[CH3:11]>C1COCC1>[C:10]([O:14][C:15]([N:17]1[CH2:21][CH2:20][CH2:19][C@H:18]1[C@H:22]([S:9][CH2:8][CH3:7])[C@H:23]([C:25]([O:27][CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)=[O:26])[CH3:24])=[O:16])([CH3:11])([CH3:12])[CH3:13]
Reactant: CC(=C[C@@H]1CCCN1C(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Reactant: CCS
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCS[C@H]([C@@H](C)C(=O)OCc1ccccc1)[C@@H]1CCCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.1 %

Procedure:
To a stirred suspension of t-BuOK (609 mg, 5.43 mmol) in THF (90 ml) was added EtSH (8.04 ml, 0.11 mol). After stirring for 30 min at room temperature, a solution of (2S)-2-(2-benzyloxycarbonyl-propenyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (3.75 g, 10.8 mmol) in THF (75 ml) was added to the mixture. After 2.5 h, the mixture was quenched with saturated NH4Cl aqueous solution, and then concentrated in vacuo. The residue was diluted with EtOAc (400 ml), and washed with saturated NH4Cl aqueous solution (150 ml), saturated NaHCO3 aqueous solution (150 ml) and H2O (150 ml). The organic layer was dried over anhydrous Na2SO4, and then concentrated in vacuo. The residue was purified by column chromatography on silica gel (hexane/EtOAc=12/1 to 8/1) to give (2S)-2-[(1R,2S)-2-benzyloxycarbonyl-1-ethylsulfanyl-propyl]-pyrrolidine-1-carboxylic acid tert-butyl ester (3.66 g, 83%).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:7][CH:8]=1.[N:15]1[CH:20]=[CH:19][CH:18]=[C:17](B(O)O)[CH:16]=1>>[C:9]1([C:6]2[CH:5]=[CH:4][C:3]([CH2:2][C:17]3[CH:16]=[N:15][CH:20]=[CH:19][CH:18]=3)=[CH:8][N:7]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: OB(O)c1cccnc1
Reactant: BrCc1ccc(-c2ccccc2)nc1
Product: c1ccc(-c2ccc(Cc3cccnc3)cn2)cc1
Reaction time: 0.5 h

Procedure:
Synthesized using compound 61a (100 mg, 0.40 mmol) and 3-pyridineboronic acid (74 mg, 0.61 mmol) according to Method C. Crude product was purified by flash chromatography on silica-gel using a mixture of hexane/ethyl acetate (2:1) as eluent. After flash chromatography the product was solved in ethyl acetate and a few drops of conc. HCl and water were added. After stirring for 30 minutes the phases were separated and water phase was neutralized with aqueous Na2CO3-solution (2M). After extraction with ethyl acetate and drying over MgSO4 the solvent was removed under vacuum. Beige solid. Yield: 32 mg, 32%. 1H NMR (CDCl3, 500 MHz): δH (ppm)=3.80 (s, 2H), 6.99-7.06 (m, 1H), 7.15-7.20 (m, 1H), 7.21-7.35 (m, 4H), 7.45 (d, J=8.2 Hz, 1H), 7.72-7.77 (m, 2H), 8.28 (dd, J=4.7, 1.3 Hz, 1H), 8.36 (d, J=1.9 Hz, 1H), 8.33 (d, J=1.9 Hz, 1H); 13C NMR (CDCl3, 125 MHz): δC (ppm)=35.9, 120.4, 123.6, 126.8, 128.7, 128.9, 133.6, 135.4, 136.2, 137.0, 139.0, 148.1, 149.9, 150.1, 155.9; (ESI): m/z=246.98 [M+H]+.