Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][SH:2].[CH:3]([C:5]1[CH:14]=[CH:13][CH:12]=[CH:11][C:6]=1[C:7]([O:9]C)=O)=O.[C:15]1([C:21]2[CH2:22][CH2:23][N:24]([CH2:27][CH2:28][CH2:29][NH2:30])[CH2:25][CH:26]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[OH-].[Na+].[C:33]([OH:38])(=[O:37])[C:34]([OH:36])=[O:35]>O1CCCC1.C(OCC)(=O)C.C(C(C)=O)C>[C:33]([OH:38])(=[O:37])[C:34]([OH:36])=[O:35].[CH3:1][S:2][CH:3]1[C:5]2[C:6](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:7](=[O:9])[N:30]1[CH2:29][CH2:28][CH2:27][N:24]1[CH2:23][CH:22]=[C:21]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:26][CH2:25]1
Reactant: COC(=O)c1ccccc1C=O
Reactant: CS
Reactant: NCCCN1CC=C(c2ccccc2)CC1
Agent: O=C(O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCC(C)=O
Solvent: C1CCOC1
Product: CSC1c2ccccc2C(=O)N1CCCN1CC=C(c2ccccc2)CC1
Reaction time: 1 h

Procedure:
5 cc of methylmercaptan is added to a solution of methyl 2-formylbenzoate (3.6 g) and 3-(4-phenyl-1,2,3,6-tetrahydro-1-pyridyl)-1-aminopropane (9.6 g)in tetrahydrofuran (255 cc) in an autoclave, at a temperature close to -20° C. in the course of 5 minutes. The solution is heated to a temperature close to 60° C. for 4 hours. After cooling to a temperature close to 20° C., the solution is poured into 1N sodium hydroxide (300 cc) and washed with distilled water (3×500 cc). The organic extract is dried over anhydrous magnesium sulphate, filtered and concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 40° C. The residue obtained is dissolved in ethyl acetate (20 cc) and poured onto silica (750 g) contained in a column of 8 cm diameter. Elution is carried out with ethyl acetate. The first 3400 cc are eliminated and the next 3100 cc are evaporated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 40° C. The residue obtained is dissolved in methyl ethyl ketone (70 cc). A solution of oxalic acid (1.7 g) in methyl ethyl ketone (20 cc) is added and agitation continued for 1 hour at a temperature close to 20° C. The precipitate formed is separated by filtration. 5.9 g of 3-methylthio-2-[3-(4-phenyl-1,2,3,6-tetrahydro-1-pyridyl)propyl]-1-isoindolinone oxalate are thus obtained, melting at 169° C.
Reaction SMILES: [N+:1]([C:4]1[S:8][C:7]([CH:9]=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].C1N2CCN(CC2)C1.[CH2:19]([O:21][C:22]([C:24]1[C:28]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[C:27]([N:34]=CC2SC=CC=2)[S:26][C:25]=1[N:41]=[CH:42][C:43]1[S:44][CH:45]=[CH:46][CH:47]=1)=[O:23])[CH3:20]>C1(C)C=CC=CC=1.Cl[Ti](Cl)(Cl)Cl>[CH2:32]([O:31][C:29]([C:28]1[C:24]([C:22]([O:21][CH2:19][CH3:20])=[O:23])=[C:25]([N:41]=[CH:42][C:43]2[S:44][CH:45]=[CH:46][CH:47]=2)[S:26][C:27]=1[N:34]=[CH:9][C:7]1[S:8][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)=[O:30])[CH3:33]
Reactant: CCOC(=O)c1c(N=Cc2cccs2)sc(N=Cc2cccs2)c1C(=O)OCC
Reactant: O=Cc1ccc([N+](=O)[O-])s1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: C1CN2CCN1CC2
Solvent: Cc1ccccc1
Product: CCOC(=O)c1c(N=Cc2cccs2)sc(N=Cc2ccc([N+](=O)[O-])s2)c1C(=O)OCC

Procedure:
5-Nitrothiophene-2-carbaldehyde (9 mg) was mixed in toluene under nitrogen at 0° C. with DABCO (7 mg), TiCl4 in solution in toluene (59 μL) and 2,5-bis-[(thiophen-2-ylmethylene)-amino]-thiophene-3,4-dicarboxylic acid diethyl ester (12 mg). The mixture was refluxed for six hours, concentrated and the product isolated as a red powder after purification by flash chromatography. M.p.: 220°-222° C. 1H-NMR (300 MHz, [D] acetone): δ=8.81 (s, 1H), 8.79 (s, 1H), 8.10 (d, 1H, 3.2 Hz), 7.91 (d, 1H, 3J=4.1 Hz), 7.81 (d, 1H, 2.9 Hz), 7.78 (d, 1H, 3J=4.6 Hz), 7.29 (dd, 1H, 2.7 Hz and 3.8 Hz), 4.38 (q, 2H, 3J=5.3 Hz), 4.32 (q, 2H, 3J=5.3 Hz), 1.41 (t, 3H, 3J=5.3 Hz), 1.36 (t, 3H, 3J=5.3 Hz). 13C-NMR (300 MHz, [D] acetone): δ=176.9, 174.2, 169.1, 166.5, 155.1, 151.7, 146.6, 142.2, 140.9, 136.1, 135.9, 134.0, 132.7, 130.0, 129.0, 127.5, 61.5, 61.3, 14.2, 14.0.
Reaction SMILES: [C:1]1([NH:7][CH:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:9]([N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:22][C:23]1[CH:24]=[C:25]([NH:29][C:30](=[O:36])[NH:31][CH2:32][C:33](O)=[O:34])[CH:26]=[CH:27][CH:28]=1.S(Cl)(Cl)=O.C(=O)(O)[O-].[Na+]>ClCCCl.C(Cl)Cl>[CH3:22][C:23]1[CH:24]=[C:25]([NH:29][C:30](=[O:36])[NH:31][CH2:32][C:33]([N:7]([CH:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:9](=[O:10])[N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[O:34])[CH:26]=[CH:27][CH:28]=1
Reactant: O=C(C(Nc1ccccc1)c1ccccc1)N1CCCC1
Reactant: Cc1cccc(NC(=O)NCC(=O)O)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Solvent: ClCCCl
Product: Cc1cccc(NC(=O)NCC(=O)N(c2ccccc2)C(C(=O)N2CCCC2)c2ccccc2)c1
Yield: 20.5 %

Procedure:
A suspension of 1.6 g of (RS)-1-(α-phenylaminophenylacetyl)pyrrolidine and 1.2 g of 2-[3-(3-methylphenyl)ureido]acetic acid in 50 cm3 of anhydrous 1,2-dichlorethane is heated to reflux. 0.68 g of thionyl chloride is added, maintaining reflux until the evolution of gas has ceased. The reaction mixture is then poured into 30 cm3 of a saturated aqueous sodium bicarbonate solution and 50 cm3 of methylene chloride are then added. The organic phase is washed with 50 cm3 of distilled water, dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. The product obtained is purified by chromatography on 50 g of silica (0.065-0.200 mm) contained in a column 2.2 cm in diameter [eluent: ethyl acetate/methylene chloride (50-50 by volume)], collecting 25 cm3 fractions. Fractions 9 to 22 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. After recrystallization from a mixture of ethyl acetate and acetonitrile (90-10 by volume), 0.55 g of (RS)-2-[3-(3-methylphenyl)ureido]-N-[2-oxo-1-phenyl-2-(1-pyrrolidinyl)ethyl]-N-phenylacetamide melting at 138° C. is obtained.
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8][N:9]([S:27]([C:30]1[CH:35]=[C:34]([Cl:36])[CH:33]=[C:32]([Cl:37])[CH:31]=1)(=[O:29])=[O:28])[C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[N:15]([C:19](=[O:22])[NH:20][CH3:21])[CH2:14][CH:13]2[C:23](OC)=[O:24])=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Li+].C(OCC)(=O)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1>[Cl:37][C:32]1[CH:31]=[C:30]([S:27]([N:9]([CH2:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[N:15]([C:19](=[O:22])[NH:20][CH3:21])[CH2:14][CH:13]3[CH2:23][OH:24])(=[O:29])=[O:28])[CH:35]=[C:34]([Cl:36])[CH:33]=1
Reactant: CNC(=O)N1CC(C(=O)OC)c2cc(N(CC(=O)OC(C)(C)C)S(=O)(=O)c3cc(Cl)cc(Cl)c3)ccc21
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CNC(=O)N1CC(CO)c2cc(N(CC(=O)OC(C)(C)C)S(=O)(=O)c3cc(Cl)cc(Cl)c3)ccc21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
110 mg methyl 5-[tert-butoxycarbonylmethyl-(3,5-dichloro-phenylsulphonyl)-amino]-1-methylcarbamoyl-2,3-dihydro-1H-indole-3-carboxylate are dissolved in 3 ml of tetrahydrofuran, cooled to 0° C., combined with 4.2 mg lithium borohydride and stirred for 1 hour. Then the mixture is allowed to come up to ambient temperature and stirred overnight. Then it is divided between ethyl acetate and ice water, the pH is adjusted to 4 by the addition of citric acid and the phases are separated. The organic phase is washed with water and saturated sodium chloride solution, dried on magnesium sulphate and freed from the solvents in vacuo. The residue is chromatographed on silica gel (ethyl acetate).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([F:9])[CH:3]=1.[Li]CCCC.Cl[Si](C)(C)CC[Si](Cl)(C)C.Cl[C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27]>C1COCC1>[NH2:6][C:5]1[C:4]([F:9])=[C:3]([C:2]([Cl:1])=[CH:8][CH:7]=1)[C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: Nc1ccc(Cl)cc1F
Agent: C[Si](C)(Cl)CC[Si](C)(C)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Nc1ccc(Cl)c(C(=O)OCc2ccccc2)c1F
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 44.8 %

Procedure:
A flame dried flask equipped with a stir bar and rubber septum was charged with 4-chloro-2-fluoroaniline (5.00 g, 34.35 mmol) and dry THF (170 mL). This solution was chilled to −78° C., and n-BuLi (14.7 mL, 1.07 eq. of 2.5M solution in hexanes) was then added over a 15 minute period. This mixture was stirred at −78° C. for 20 minutes, and then a THF solution (25 mL) of 1,2-bis(chlorodimethylsilyl)ethane (7.76 g, 1.05 eq.) was added slowly (over a 10 minute period) to the reaction mixture. This was stirred for 1 hour, and then 2.5M n-BuLi in hexanes (15.11 mL, 1.1 eq.) was added slowly. After allowing the mixture to warm to room temperature for one hour, the mixture was chilled back to −78° C. A third allotment of n-BuLi (15.66 mL, 1.14 eq.) was added slowly, and the mixture was stirred at −78° C. for 75 minutes. Benzyl chloroformate (7.40 g, 1.2 eq.) was then added slowly, and the mixture was stirred at −78° C. for one hour. The cooling bath was then removed. The mixture was allowed to warm for 30 minutes and then quenched with water (70 mL) and concentrated HCl (25 mL). The mixture was allowed to continue to warm to room temperature. The mixture was then extracted with EtOAc. The extracts were washed twice with a saturated Na2HCO3 solution, once with water, dried over sodium sulfate and concentrated. The resulting residue was flashed on a 65 Biotage (30% ethyl acetate/hexane) to produce benzyl 3-amino-6-chloro-2-fluorobenzoate (4.3 g, 45%) as an oil. 1H NMR (DMSO-d6, 400 MHz) δ 7.37-7.48 (m, 5H), 7.07 (dd, 1H, J=8, 2), 6.87 (t, 1H, J=8), 5.61 (br s, 2H), 5.40 (s, 2H).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:30])[CH2:10][NH:11][C:12](=[O:29])[C@@H:13]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[NH:14]C(OC(C)(C)C)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN1CCOCC1.ClC1C(O[C:46](=[O:64])[C@H:47]([CH2:56][C:57]2[CH:62]=[CH:61][C:60]([OH:63])=[CH:59][CH:58]=2)[NH:48][C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])=C(Cl)C(Cl)=C(Cl)C=1Cl>C(OCC)(=O)C.Cl>[CH2:1]([O:8][C:9](=[O:30])[CH2:10][NH:11][C:12](=[O:29])[C@@H:13]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[NH:14][C:46](=[O:64])[C@H:47]([CH2:56][C:57]1[CH:58]=[CH:59][C:60]([OH:63])=[CH:61][CH:62]=1)[NH:48][C:49]([O:51][C:52]([CH3:53])([CH3:54])[CH3:55])=[O:50])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)Oc1c(Cl)c(Cl)c(Cl)c(Cl)c1Cl
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)C(=O)NCC(=O)OCc1ccccc1
Agent: Cl
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)N[C@H](Cc1ccccc1)C(=O)NCC(=O)OCc1ccccc1
Reaction time: 0.5 h
Yield: 90.7 %

Procedure:
18.55 g (45 mmoles) of the protected dipeptide ester obtained in Step 1 above are dissolved in 60 ml of ethyl acetate containing 11-15% of hydrochloric acid. After 0.5 hours of standing the solution is evaporated, and the residue is dried in a vacuum desiccator above potassium hydroxide. The resulting substance, Rf3 =0.4-0.5, is dissolved in 40 ml of dimethyl formamide, and 5.0 ml (45 mmoles) of N-methylmorpholine and 26.2 g (49.5 mmoles) of tert.-butoxycarbonyl-L-tyrosine pentachlorophenyl ester are added. The reaction mixture is stirred for 16-20 hours. During the first two hours 5.5 ml (49.5 mmoles) of N-methylmorpholine are added to the mixture in five portions. The reaction mixture is evaporated under reduced pressure, the residue is dissolved in a mixture of 300 ml of ethyl acetate and 50 ml of water, the ethyl acetate phase is separated, washed twice with 50 ml of 1 n aqueous hydrochloric acid cooled with ice water and then twice with 50 ml of water, each, dried over sodium sulfate, decolourized with carbon, filtered, and the filtrate is evaporated under reduced pressure. The crystalline residue is suspended in diisopropyl ether, the solid is filtered off, washed with diisopropyl ether, and dried in a vacuum desiccator. 23.5 g (90.8%) of tert.-butoxycarbonyl-L-tyrosyl-D-phenylalanyl-glycine benzyl ester are obtained; m.p.: 169° C., Rf10 =0.45-0.55, [α]D20 +16.3° (c=1%, in dimethyl formamide).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[F:7][C:8]1[CH:9]=[CH:10][C:11]2[O:15][CH:14]=[C:13]([C:16](OC)=O)[C:12]=2[CH:20]=1.C(Cl)[Cl:22]>O1CCCC1>[Cl:22][CH2:16][C:13]1[C:12]2[CH:20]=[C:8]([F:7])[CH:9]=[CH:10][C:11]=2[O:15][CH:14]=1
Reactant: COC(=O)c1coc2ccc(F)cc12
Reactant: ClCCl
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Fc1ccc2occ(CCl)c2c1
Temperature: 55 °C
Reaction time: 2 h

Procedure:
Lithium aluminium hydride (15 g) was suspended in tetrahydrofuran (400 mL) under a nitrogen atmosphere followed by dropwise addition of a solution of methyl 5-fluorobenzofuran-3-carboxylate (58 g) in tetrahydrofuran (300 mL). The temperature increased to 55° C. during the addition. After stirring for 2 h the reaction was quenched succesively with water (30 mL), 15% aq. sodium hydroxide (15 mL), and water (75 mL). Further tetrahydrofuran (500 mL) was added and the mixture stirred for 1 h. The mixture was filtered and the precipitate extracted with a mixture of methylene chloride (1 L) and ethanol (0.5 L). The combined organic phases were concentrated in vacuo giving an oil which was applied to silica gel flash chromatography (eluent: methylene chloride/25% aq. NH3 99:1). The resulting yellow oil, 5-fluorobenzofuran-3-ylmethanol (14.4 g) crystallised on standing. A solution of 5-fluorobenzofuran-3-ylmethanol (14 g) in methylene chloride (250 mL) was treated succesively with 5 drops of dimethylformamide and thionyl chloride (28 mL). After stirring for 16 h at room temperature the reaction was concentrated in vacuo giving 3-chloromethyl-5-fluorobenzofuran as an oil (19.4 g). A suspension of sodium cyanide (10 g) in dimethylsulfoxide (150 mL) was heated to 80° C. followed by quick addition of a solution of 3-chloromethyl-5-fluorobenzofuran (10 g) in dimethylsulfoxide (50 mL). The mixture was kept at 80° C. for ½ h and then poured onto ice. Standard work-up with diethyl ether gave a dark crystalline material, 5-fluorobenzofuran-3-ylacetonitrile (8.8 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[CH2:14][CH:13](CC3CCN(CC4C=CC=CC=4)CC3)[C:11](=[O:12])[C:6]2=[CH:7][C:8]=1[O:9][CH3:10].COC1C=C2C(=CC=1OC)C(=O)CC2.[N:43]1[CH:48]=[CH:47][C:46]([CH:49]=O)=[CH:45][CH:44]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:6](=[CH:7][C:8]=1[O:9][CH3:10])[C:11](=[O:12])[CH:49]([C:46]1[CH:45]=[CH:44][N:43]=[CH:48][CH:47]=1)[C:14]2=[CH2:13]
Reactant: O=Cc1ccncc1
Reactant: COc1cc2c(cc1OC)C(=O)C(CC1CCN(Cc3ccccc3)CC1)C2
Agent: COc1cc2c(cc1OC)C(=O)CC2
Product: C=C1c2cc(OC)c(OC)cc2C(=O)C1c1ccncc1

Procedure:
U.S. Pat. No. 4,895,481, incorporated herein by reference in its entirety, describes donepezil, its related compounds along with their pharmaceutical acceptable salts including composition and method of treatment using them. The process for the preparation of donepezil is disclosed by the aforesaid product patent involves the conversion of 1-benzyl-4-piperidinone to 1-benzyl-4-piperidine carboxaldehyde in the presence of n-butyl lithium, which on further reaction with 5,6-dimethoxy-1-indanone in the presence of strong base such as lithium diisopropylamide under inert atmosphere followed by reduction of the obtained compound to give the title compound of Formula (I) with an overall yield of 27.4%. U.S. Pat. No. 5,606,064, incorporated herein by reference in its entirety, also discloses the process for the preparation of donepezil, which involves reacting 5,6-dimethoxy indanone and pyridine-4-carboxaldehyde to yield 5,6 dimethoxy-2-pyridin-4-yl methylene-indan-1-one, which upon condensation with benzyl bromide followed by reduction of the obtained compound with platinum oxide to afford the title compound with an overall yield of 58.5%. U.S. Pat. No. 6,252,081 B1, incorporated herein by reference in its entirety, also discloses a process for preparation of donepezil (e.g., examples 1, 2, and 3) that provides a satisfactory yield, but utilizes platinum oxide as a reagent. International Application No. WO 97/22584 discloses a process for preparation of donepezil in the (preparations 1–3 and examples 1–6), with an asserted overall yield of 19.3%.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][C:8]1[C:12]([C:13]([OH:15])=O)=[CH:11][O:10][N:9]=1.[Cl:16][C:17]1[C:18]([NH2:24])=[N:19][C:20]([NH2:23])=[CH:21][N:22]=1>CN(C)C=O.N1C=CC=CC=1>[NH2:24][C:18]1[N:19]=[C:20]([NH:23][C:13]([C:12]2[C:8]([CH3:7])=[N:9][O:10][CH:11]=2)=[O:15])[CH:21]=[N:22][C:17]=1[Cl:16]
Reactant: Cc1nocc1C(=O)O
Reactant: Nc1cnc(Cl)c(N)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: Cc1nocc1C(=O)Nc1cnc(Cl)c(N)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 49.3 %

Procedure:
Oxalyl chloride (0.06 ml, 0.69 mmol) was added to a solution of 3-Methyl-isoxazole-4-carboxylic acid (0.06 g, 0.48 mmol) followed by 1 drop of dimethylformamide. The mixture was stirred at room temperature for 4 hours before concentrating in vacuo and azeotroping with dichloromethane. The residue was taken up in pyridine (1 ml) and added to a solution of 3-chloro-pyrazine-2,6-diamine (Preparation 1) (0.035 g, 0.24 mmol) in anhydrous pyridine (3 ml) and the mixture heated at 50° C. for 3 hours before cooling to room temperature and concentrating to dryness in vacuo. The residue was purified by silica gel column chromatography, eluting with ethyl acetate:heptane 1:1, to afford the product as a white solid (30 mg).
Reaction SMILES: [CH3:1][CH:2]([CH2:6][CH3:7])[C:3]([OH:5])=[O:4].[CH3:8]C(C)CCO>>[CH3:8][CH:6]([CH3:7])[CH2:2][C:3]([OH:5])=[O:4].[C:3]([OH:5])(=[O:4])[CH:2]([CH3:6])[CH3:1]
Reactant: CCC(C)C(=O)O
Reactant: CC(C)CCO
Product: CC(C)C(=O)O
Product: CC(C)CC(=O)O

Procedure:
A process for the preparation of 3-methyl-butyric acid comprising (a) oxidizing 3-methyl-butanol with the strain Gluconobacter roseus DSM 9364 to produce 3-methyl-butyric acid and (b) recovering the 3-methyl-butyric add produced in (a).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([CH3:11])[CH:3]=1.[F:12][C:13]([F:17])([F:16])[CH2:14][NH2:15].Cl.C(N(CC)CCCN=C=NCC)C.O>CN(C)C=O>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:15][CH2:14][C:13]([F:17])([F:16])[F:12])=[O:8])=[C:4]([CH3:11])[CH:3]=1
Reactant: Cc1cc(Br)ccc1C(=O)O
Reactant: NCC(F)(F)F
Agent: CCN=C=NCCCN(CC)CC
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(Br)ccc1C(=O)NCC(F)(F)F
Temperature: 25 °C
Yield: 58.1 %

Procedure:
In a solution of 5.00 g of 4-bromo-2-methyl benzoic acid and 3.45 g of 2,2,2-trifluoroethylamine in 30 ml of N,N-dimethylformamide, 5.79 g of 1-[3-(diethylamino)propyl]-3-ethylcarbodiimide hydrochloride was added with stirring at room temperature, and stirred at the same temperature for 1.5 hour. After the completion of the reaction, 80 ml of water was added, and precipitated crystal was filtered off, washed with water and dried to obtain 4.00 g of the aimed product as white crystal.
Reaction SMILES: [Br:1][C:2]([Br:5])(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:25]([C:30]1[CH:35]=[CH:34][C:33]([C@H:36]2[CH2:41][CH2:40][C@H:39]([CH:42]=O)[CH2:38][CH2:37]2)=[CH:32][CH:31]=1)[CH2:26][CH2:27][CH2:28][CH3:29].CCCCCC>C(Cl)Cl>[Br:1][C:2]([Br:5])=[CH:42][C@H:39]1[CH2:38][CH2:37][C@H:36]([C:33]2[CH:32]=[CH:31][C:30]([CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[CH:35][CH:34]=2)[CH2:41][CH2:40]1
Reactant: BrC(Br)(Br)Br
Reactant: CCCCCc1ccc([C@H]2CC[C@H](C=O)CC2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCCCCC
Product: CCCCCc1ccc([C@H]2CC[C@H](C=C(Br)Br)CC2)cc1
Temperature: -10 °C
Reaction time: 0.02 h

Procedure:
A solution of 5.0 g of tetrabromomethane in 60 ml of methylene chloride was placed a -10° C. in a sulphonation flask under argon gasification and treated within 5 minutes with a solution of 7.9 g of triphenylphosphine in 20 ml of methylene chloride. The resulting clear orange solution was stirred at -10° C. for a further 1 minute and then a solution of 1.95 g of trans-4-(p-pentylphenyl)cyclohexanecarboxaldehyde in 20 ml of methylene chloride was added dropwise within 3 minutes. The mixture was subsequently left to stand at -18° C. overnight, then poured into 600 ml of hexane and the separated precipitate was filtered off (rinsing with hexane). The concentrated filtrate was digested with 300 ml of hexane, left to stand at -18° C. for 30 minutes, filtered (rinsing with hexane) and the filtrate was concetrated. Low-pressure chromatography (0.5 bar) of the residue (1.87 g) on silica gel with hexane gave 503 mg of 1-[trans-4-(2,2-dibromovinyl)cyclohexyl)-4-pentylbenzene as colourless crystals (purity 95.8%); m.p. 35°-37.7° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[NH:5][C:6]2[C:11]([CH:12]=1)=[CH:10][C:9]([CH:13]=O)=[CH:8][CH:7]=2.[NH2:15][C:16]1[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[C:21]([O:27][CH3:28])[C:17]=1[C:18]([NH2:20])=[O:19].S([O-])(O)=O.[Na+].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CN(C)C(=O)C>[OH:1][CH2:2][CH2:3][C:4]1[NH:5][C:6]2[C:11]([CH:12]=1)=[CH:10][C:9]([C:13]1[NH:20][C:18](=[O:19])[C:17]3[C:16](=[CH:24][C:23]([O:25][CH3:26])=[CH:22][C:21]=3[O:27][CH3:28])[N:15]=1)=[CH:8][CH:7]=2
Reactant: O=Cc1ccc2[nH]c(CCO)cc2c1
Reactant: COc1cc(N)c(C(N)=O)c(OC)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: COc1cc(OC)c2c(=O)[nH]c(-c3ccc4[nH]c(CCO)cc4c3)nc2c1
Temperature: 120 °C
Reaction time: 16 h

Procedure:
To a solution of 2-(2-hydroxy-ethyl)-1H-indole-5-carbaldehyde (0.300 g, 1.58 mmol) and 2-amino-4,6-dimethoxy-benzamide (0.370 g, 1.90 mmol) in N,N-dimethylacetamide (5 mL) were added sodium hydrogen sulfite (58.5 wt %) (0.350 g, 1.90 mmol) and p-toluenesulfonic acid monohydrate (60 mg, 0.32 mmol). The reaction mixture was stirred at 120° C. for 16 hours under nitrogen and cooled to room temperature. The solvent was evaporated under reduced pressure. Water (20 mL) was added and the solid was separated by filtration, washed with water (30 mL) and dried under vacuum. Crude compound was purified by the Simpliflash system (5:20:75 methanol/ethyl acetate/CH2Cl2 as eluent) to give the title compound as an off-white solid. Yield: 0.22 g (38%). MP 237-238° C. 1H NMR (400 MHz, DMSO-d6): δ 11.83 (br s, 1H), 11.20 (s, 1H), 8.34 (s, 1H), 7.90 (d, J=8.2 Hz, 1H), 7.37 (d, J=8.6 Hz, 1H), 6.73 (d, J=1.9 Hz, 1H), 6.48 (d, J=1.9 Hz, 1H), 6.30 (s, 1H), 4.81 (t, J=5.1 Hz, 1H), 3.89 (s, 3H), 3.84 (s, 3H), 3.75 (q, J=6.63 Hz, 2H), 2.89 (t, J=7.0 Hz, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH2:6][CH2:7][C:8]([NH2:17])([C:14]([OH:16])=[O:15])[CH2:9]2)[CH3:2].C(N(CC)CC)C.[C:25](=O)([O:41]N1C(=O)CCC1=O)[O:26][CH2:27][CH:28]1[C:40]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[C:34]2[C:29]1=[CH:30][CH:31]=[CH:32][CH:33]=2>C(#N)C.O>[C:25]([CH:9]1[C:10]2[C:5](=[C:4]([O:3][CH2:1][CH3:2])[CH:13]=[CH:12][CH:11]=2)[CH2:6][CH2:7][C:8]1([NH2:17])[C:14]([OH:16])=[O:15])([O:26][CH2:27][CH:28]1[C:29]2[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:35]2[C:40]1=[CH:39][CH:38]=[CH:37][CH:36]=2)=[O:41]
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)ON1C(=O)CCC1=O
Reactant: CCOc1cccc2c1CCC(N)(C(=O)O)C2
Solvent: CC#N
Solvent: O
Solvent: CCN(CC)CC
Product: CCOc1cccc2c1CCC(N)(C(=O)O)C2C(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 48 h
Yield: 107.9 %

Procedure:
A mixture of racemic 5-ethoxy-2-aminotetraline-2-carboxylic acid (2.22 g, 9.44 mmole), triethylamine (2.00 ml, 14.3 mmole), 9-fluorenylmethyl succinimidyl carbonate (Fmoc-OSu, 4.81 g, 14.3 mmole) in acetonitrile (75 ml) and water (75 ml) was stirred at room temperature for two days. TLC analysis of the reaction indicated the presence of starting material amino acid. 9-fluorenylmethyl succinimidyl carbonate (645 mg) and triethylamine (1.0 ml) was added and the mixture was stirred at room temperature for another day. The reaction mixture was concentrated in vacuo to remove most of the acetonitrile, acidified to pH˜3 with 10% aqueous citric acid solution, and the white emulsion extracted three times with ethyl acetate. The combined organic layers were washed with water, brine, dried over magnesium sulfate. Filtration and concentration gave a crude oil which was purified by column chromatography (eluted with 3→5→10% methanol/methylene chloride) to give racemic Fmoc-5-ethoxy-2-aminotetraline-2-carboxylic acid (4.66 g, >quantitative yield) as a white solid. HRMS (FAB): C28H28NO5 (M+H) calc. 458.1967; observed: 458.1985.