Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:11]([Cl:12])=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][C:9]2=[O:13])=[CH:4][C:3]=1[O:14][CH3:15].[Br:16]Br>C(O)(=O)C>[Br:16][CH:8]1[CH2:7][CH2:6][C:5]2[C:10](=[C:11]([Cl:12])[C:2]([Cl:1])=[C:3]([O:14][CH3:15])[CH:4]=2)[C:9]1=[O:13]
Reactant: COc1cc2c(c(Cl)c1Cl)C(=O)CCC2
Reactant: BrBr
Solvent: CC(=O)O
Product: COc1cc2c(c(Cl)c1Cl)C(=O)C(Br)CC2
Temperature: 0 °C

Procedure:
7,8-Dichloro-6-methoxy-1-tetralone (2.7 g, 0.011 mole) was suspended in acetic acid (45 ml) warmed slightly with stirring, and 0.57 ml of bromine in 5 ml of acetic acid was added over a 20 minute time period. The reaction mixture was stirred for 10 minutes, and then poured into 200 ml of stirred ice water. A white solid was filtered from the reaction mixture, dissolved in ether (75 ml), washed with brine, dried over MgSO4, evaporated in vacuo and directly used in the next step.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5](I)=[C:6]([CH:9]=1)[C:7]#[N:8].C(Cl)(Cl)Cl.P(C(C)(C)C)(C(C)(C)C)C(C)(C)C.[O:28]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29]1.[F-].[Cs+]>CN(C)C=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[O:28]1[CH:32]=[CH:31][C:30]([C:5]2[CH:4]=[CH:3][C:2]([OH:1])=[CH:9][C:6]=2[C:7]#[N:8])=[CH:29]1
Reactant: OB(O)c1ccoc1
Reactant: N#Cc1cc(O)ccc1I
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: N#Cc1cc(O)ccc1-c1ccoc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
5-Hydroxy-2-iodo-benzonitrile (70 mg, 0.29 mmol), Pd2(dba)3.CHCl3(25 mg, 0.01 mmol) and P(tBu)3 (0.05 mL, 10% in hexane, 0.016 mmol), 3-furanboronic acid (40 mg, 0.36 mmol) and CsF (200 mg, 1.32 mmol) were suspended in N,N-dimethylformamide (5 mL). The mixture is then degassed and stirred at room temperature for 4 hours. After aqueous workup, the residue is purified with chromatography and directly employed in the next step.
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:30]([NH2:32])=[O:31])[CH:17]=[C:18](B4OC(C)(C)C(C)(C)O4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2].Br[C:34]1[CH:35]=[N:36][N:37]([CH2:39][CH2:40][N:41]([CH3:43])[CH3:42])[CH:38]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:42][N:41]([CH3:43])[CH2:40][CH2:39][N:37]1[CH:38]=[C:34]([C:18]2[CH:19]=[C:20]3[C:15](=[C:16]([C:30]([NH2:32])=[O:31])[CH:17]=2)[NH:14][CH:13]=[C:12]3[CH:9]2[CH2:8][CH2:7][N:6]([S:3]([CH2:1][CH3:2])(=[O:4])=[O:5])[CH2:11][CH2:10]2)[CH:35]=[N:36]1
Reactant: CN(C)CCn1cc(Br)cn1
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(B4OC(C)(C)C(C)(C)O4)cc23)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cnn(CCN(C)C)c4)cc23)CC1
Yield: 15.1 %

Procedure:
A solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-7-carboxamide (40 mg, 0.084 mmol), [2-(4-bromo-1H-pyrazol-1-yl)ethyl]dimethylamine (27 mg, 0.126 mmol) and sodium carbonate (53 mg, 0.5 mmol) was suspended in dioxane (750 μL) and water (250 μL). This was flushed with argon for 10 min before the addition of tetrakis(triphenylphosphine)palladium(0) (5 mg, 0.004 mmol). The resulting mixture was reacted in a microwave for 20 min at 120° C. then diluted with EtOAc (10 mL). The mixture was filtered through Celite and an aqueous wash was performed. It was then purified by Gilson Preparatory HPLC to give 6 mg of the title compound (15%).
Reaction SMILES: CN(OC)[C:3]([C:5]1[C:13]2[N:12]=[C:11]([CH3:14])[N:10]([CH2:15][C:16]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH:19]=[CH:18][CH:17]=3)[C:9]=2[CH:8]=[C:7]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[CH:6]=1)=[O:4].[CH3:34][Mg]Cl>O1CCCC1>[CH3:14][C:11]1[N:10]([CH2:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=[CH:18][CH:17]=2)[C:9]2[CH:8]=[C:7]([N:26]3[CH2:27][CH2:28][O:29][CH2:30][CH2:31]3)[CH:6]=[C:5]([C:3](=[O:4])[CH3:34])[C:13]=2[N:12]=1
Reactant: CON(C)C(=O)c1cc(N2CCOCC2)cc2c1nc(C)n2Cc1cccc2ccccc12
Reactant: C[Mg]Cl
Solvent: C1CCOC1
Product: CC(=O)c1cc(N2CCOCC2)cc2c1nc(C)n2Cc1cccc2ccccc12
Temperature: 0 °C
Reaction time: 2 h
Yield: 62.6 %

Procedure:
To a solution of N,2-dimethyl-N-(methyloxy)-6-(4-morpholinyl)-1-(1-naphthalenylmethyl)-1H-benzimidazole-4-carboxamide (82 mg, 0.184 mmol) in Tetrahydrofuran (THF) (10 mL) was added a 3.0 M solution of methylmagnesium chloride (0.123 mL, 0.369 mmol) in THF at 0° C. The resulting reaction mixture was stirred at 0° C. for 2 h and then quenched very carefully with saturated aqueous ammonium chloride. The mixture was diluted with ethyl acetate (50 mL) and the aqueous phase was extracted with ethyl acetate (50 mL×2). The combined organic phases were washed with brine (50 mL), dried over (MgSO4), and filtered. The solution was concentrated under reduced pressure. The crude product was purified on a silica column (40˜60% EtOAc/Hexane) to give the product (46 mg, 59%). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.47 (s, 3H), 3.00 (s, 3H), 3.02-3.10 (m, 4H), 3.59-3.73 (m, 4H), 6.06 (s, 2H), 6.33 (d, J=6.82 Hz, 1H), 7.21-7.42 (m, 3H), 7.52-7.76 (m, 2H), 7.86 (d, J=8.34 Hz, 1H), 8.02 (d, J=7.33 Hz, 1H), 8.25 (d, 1H). MS (ES+) m/e 399.9[M+H]+.
Reaction SMILES: CC(C)([O-])C.[K+].C([NH:10][OH:11])(=O)C.[F:12][CH:13]([F:24])[O:14][C:15]1[CH:22]=[CH:21][CH:20]=[C:19](F)[C:16]=1[C:17]#[N:18]>CN(C)C=O>[NH2:18][C:17]1[C:16]2[C:15]([O:14][CH:13]([F:24])[F:12])=[CH:22][CH:21]=[CH:20][C:19]=2[O:11][N:10]=1
Reactant: N#Cc1c(F)cccc1OC(F)F
Reactant: CC(=O)NO
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1noc2cccc(OC(F)F)c12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
8.00 g (71.29 mmol) of potassium tert-butoxide and 5.20 g (69.27 mmol) of acetohydroxamic acid are dissolved in 50 ml of dry dimethylformamide and stirred at room temperature for 1 hour. After the addition of 4.40 g (23.51 mmol) of 2-(difluoromethoxy)-6-fluorobenzonitrile, the mixture is stirred first at room temperature for 3 hours and then at 60° C. for 16 hours. The mixture is concentrated under reduced pressure, the residue is stirred with water and the pale olive-coloured precipitate is filtered off with suction. This gives 4.4 g of product, which, according to LC-MS, is about 89% pure.
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([CH2:12][C:13]([OH:15])=O)=[CH:8][CH:7]=2)[CH:5]=[N:4][N:3]=[N:2]1.[CH:16]12[CH2:22][CH:19]([NH:20][CH2:21]1)[CH2:18][N:17]2[C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24].C(Cl)CCl.C(N(CC)CC)C>C(Cl)Cl>[N:1]1([C:6]2[CH:7]=[CH:8][C:9]([CH2:12][C:13]([N:20]3[CH2:21][CH:16]4[CH2:22][CH:19]3[CH2:18][N:17]4[C:23]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:24])=[O:15])=[CH:10][CH:11]=2)[CH:5]=[N:4][N:3]=[N:2]1
Reactant: O=C(O)Cc1ccc(-n2cnnn2)cc1
Reactant: O=C(OCc1ccccc1)N1CC2CC1CN2
Solvent: CCN(CC)CC
Solvent: ClCCCl
Solvent: ClCCl
Product: O=C(Cc1ccc(-n2cnnn2)cc1)N1CC2CC1CN2C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
[4-(1H-Tetrazol-1-yl)phenyl]acetic acid (303 mg, 1.48 mmol) was combined with benzyl 2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (399 mg, 1.48 mmol), EDC (341 mg, 1.78 mmol), and triethylamine (0.248 mL, 1.78 mmol) in DCM (30 mL) and stirred overnight at room temperature. The mixture was washed with 1 M HCl solution, saturated sodium bicarbonate solution, and brine. The organic layer was dried over MgSO4, filtered and concentrated. The crude product was purified by MPLC eluting with a 0-5% gradient of methanol in ethyl acetate to afford benzyl 5-{[4-(1H-tetrazol-1-yl)phenyl]acetyl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate. LC/MS: [(M+1)]+=419;
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.Br[CH2:8][C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]#[N:18])[CH:12]=1)=O.[OH-].[NH4+]>C(O)C>[C:17]([C:13]1[CH:12]=[C:11]([C:9]2[N:1]=[C:2]3[N:6]([CH:8]=2)[CH:5]=[CH:4][S:3]3)[CH:16]=[CH:15][CH:14]=1)#[N:18]
Reactant: N#Cc1cccc(C(=O)CBr)c1
Reactant: Nc1nccs1
Agent: [NH4+]
Agent: [OH-]
Solvent: CCO
Product: N#Cc1cccc(-c2cn3ccsc3n2)c1
Reaction time: 20 h
Yield: 81 %

Procedure:
To a mixture of 2-aminothiazole (3.29 g, 32.9 mmol) and 2-bromo-3′-cyano-acetophenone (7.37 g, 32.9 mmol) was added absolute ethanol (250 mL). The reaction was allowed to reflux with vigorous stirring for 20 hours. The reaction mixture was reduced to half its original volume in vacuo. The remaining suspension was poured onto ice-water (200 mL) and the resulting mixture was basified by addition of ammonium hydroxide solution (30%, 100 mL). Product was collected by filtration and washed with water (50 mL), dried in a vacuum oven at 50° C. to provide 6-(3-cyanophenyl)-imidazo[2,1-b]thiazole (6.0 g, 81%). It was used with out further purification. LCMS: 226 [M+H].
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:11]=2[F:17])=[CH:6][C:7]=1[C:8]#[N:9].O.[NH2:19][NH2:20]>C(O)C>[F:17][C:11]1[C:12]([F:16])=[CH:13][CH:14]=[CH:15][C:10]=1[C:5]1[CH:6]=[C:7]2[C:8]([NH2:9])=[N:4][NH:3][C:2]2=[N:19][N:20]=1
Reactant: N#Cc1cc(-c2cccc(F)c2F)nnc1Cl
Reactant: NN
Solvent: O
Solvent: CCO
Product: Nc1n[nH]c2nnc(-c3cccc(F)c3F)cc12

Procedure:
3-Chloro-6-(2,3-difluorophenyl)pyridazine-4-carbonitrile (2.82 g, 11.2 mmol) and hydrazine hydrate (1.25 mL, 25.8 mmol) were stirred at reflux in ethanol (50 mL) for 1 hour. The mixture was cooled and evaporated to dryness. The residue was triturated with water, and the solid was filtered off and dried, giving the title compound as a solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH2:19])([CH3:4])([CH3:3])[CH3:2].C([O:25][C:26](=O)[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[CH:37]=[N:38][C:39]([CH3:43])=[CH:40][C:41]=2[CH3:42])[CH:31]=1)=[O:29])(C)(C)C>>[C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH:19][C:26](=[O:25])[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[CH:37]=[N:38][C:39]([CH3:43])=[CH:40][C:41]=2[CH3:42])[CH:31]=1)=[O:29])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc(C)c(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)cn1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Product: Cc1cc(C)c(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)c(C)cc3NC(=O)OC(C)(C)C)c2)cn1

Procedure:
The title compound was prepared from (2-amino-5-methyl-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J20) (218 mg, 0.75 mmol) and 3-[3-(4,6-dimethyl-pyridin-3-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K32) (244 mg, 0.75 mmol) according to the general procedure M. Obtained as a light yellow foam (322 mg, 79%).
Reaction SMILES: C([O:4][CH:5]1[CH2:10][CH2:9][CH2:8][N:7]([C:11]2[N:12]=[C:13]3[CH:32]=[C:31](/[CH:33]=[CH:34]/[C:35]4[S:36][CH:37]=[C:38]([CH:40]([CH3:42])[CH3:41])[N:39]=4)[CH:30]=[CH:29][N:14]3[C:15](=[O:28])[C:16]=2/[CH:17]=[CH:18]/[C:19]2[N:23](CCC#N)[N:22]=[N:21][N:20]=2)[CH2:6]1)(=O)C.O1CCCC1.C[O-].[Na+].[Cl-].[NH4+]>CO>[OH:4][CH:5]1[CH2:10][CH2:9][CH2:8][N:7]([C:11]2[N:12]=[C:13]3[CH:32]=[C:31](/[CH:33]=[CH:34]/[C:35]4[S:36][CH:37]=[C:38]([CH:40]([CH3:42])[CH3:41])[N:39]=4)[CH:30]=[CH:29][N:14]3[C:15](=[O:28])[C:16]=2/[CH:17]=[CH:18]/[C:19]2[NH:20][N:21]=[N:22][N:23]=2)[CH2:6]1
Reactant: CC(=O)OC1CCCN(c2nc3cc(/C=C/c4nc(C(C)C)cs4)ccn3c(=O)c2/C=C/c2nnnn2CCC#N)C1
Agent: C[O-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)c1csc(/C=C/c2ccn3c(=O)c(/C=C/c4nnn[nH]4)c(N4CCCC(O)C4)nc3c2)n1
Reaction time: 4 h
Yield: 58.6 %

Procedure:
The 1-(3-{(E)-2-[1-(2-cyanoethyl)-1H-1,2,3,4-tetraazol-5-yl]-1-ethenyl}-8[(E)-2-(4-isopropyl-1,3-thiazol-2-yl)-1-ethenyl]-4-oxo-4H-pyrido[1,2-a]pyrimidin-2-yl)3-piperidyl acetate (25.9 mg, 0.0442 mmol) obtained in (C) was suspended in methanol (0.5 ml) and anhydrous tetrahydrofuran (1.0 ml), added with sodium methoxide (4.8 mg, 0.0884 mmol) under ice cooling, and then stirred for 4 hours. The reaction solution was further added with sodium methoxide (4.8 mg, 0.0884 mmol) and stirred for 1 hour. The reaction mixture was added with saturated aqueous ammonium chloride and extracted with chloroform, and the organic layer was dried over magnesium sulfate. Then, the solvent was evaporated under reduced pressure, and the residue was purified by thin layer chromatography (chloroform:methanol=10:1, v/v) to obtain the title compound (12.7 mg, 59%).
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.[Br:6][C:7]1[CH:8]=[C:9]([CH2:12][O:13][Si](C(C)(C)C)(C2C=CC=CC=2)C2C=CC=CC=2)[S:10][CH:11]=1>CC#N>[Br:6][C:7]1[CH:8]=[C:9]([CH2:12][OH:13])[S:10][C:11]=1[Cl:4]
Reactant: O=S(=O)(Cl)Cl
Reactant: CC(C)(C)[Si](OCc1cc(Br)cs1)(c1ccccc1)c1ccccc1
Solvent: CC#N
Product: OCc1cc(Br)c(Cl)s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Sulfuryl chloride (0.6 ml) was added to a solution of ((4-bromothiophen-2-yl)methoxy)(tert-butyl)diphenylsilane (2.0 g) in CH3CN (20 ml) at room temperature. The mixture was stirred at room temperature overnight. The mixture was quenched with saturated sodium thiosulfate solution (40 ml) at room temperature and extracted with EtOAc. The organic layer was separated, washed with water and brine successively, dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane/EtOAc) to give the title compound (182 mg) as a brown oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[CH:4]([C:6]1[CH:21]=[CH:20][C:9]2[C:10](=[O:19])[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH:13]=[CH:14][C:8]=2[CH:7]=1)[CH3:5].C1C=CC=CC=1.P(Cl)(Cl)(Cl)(Cl)Cl.[CH2:35](O)[CH2:36][OH:37]>CCOCC.O.C(#N)C.C(N(CC)CC)C>[CH3:1][O:2][C:3](=[O:22])[CH:4]([C:6]1[CH:21]=[CH:20][C:9]2[C:10]3([O:37][CH2:36][CH2:35][O:19]3)[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH:13]=[CH:14][C:8]=2[CH:7]=1)[CH3:5]
Reactant: COC(=O)C(C)c1ccc2c(=O)c3ccccc3ccc2c1
Reactant: OCCO
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: c1ccccc1
Product: COC(=O)C(C)c1ccc2c(c1)C=Cc1ccccc1C21OCCO1

Procedure:
1.1 Gm. of 2-(5H-dibenzo[a,d]cyclohepten-5-on-2-yl)propionic acid methyl ester is stirred in 10 ml. of benzene containing 0.9 gm. of phosphorus pentachloride for one hour. The solution is then added to a stirred, ice cooled mixture of 2.4 ml. of ethylene glycol, 2.5 ml. of triethylamine, and 13 ml. of acetonitrile. The mixture is allowed to attain room temperature, and then water and ether are added. The ethereal layer is washed several times with water, then dried and evaporated to give a quantitative yield of 2-(5,5-ethylenedioxy-5H-dibenzo[a,d]cyclohepten-2-yl)propionic acid methyl ester. Use of 2-(5H-dibenzo[a,d]cyclohepten-5-on-2-yl)acetic acid methyl ester gives a similar yield of 2-(5,5-ethylenedioxy-5H-dibenzo[a,d]cyclohepten-2-yl)acetic acid methyl ester.
Reaction SMILES: [CH3:1][N:2]([CH3:6])[C:3](Cl)=[O:4].[Cl:7][C:8]1[CH:9]=[C:10]([CH:26]=[CH:27][C:28]=1[Cl:29])[CH2:11][N:12]1[C:20]2[C:15](=[C:16]([OH:21])[CH:17]=[CH:18][CH:19]=2)[CH:14]=[C:13]1[C:22]([O:24][CH3:25])=[O:23].C(N(CC)CC)C>CN(C1C=CN=CC=1)C.ClCCl>[Cl:7][C:8]1[CH:9]=[C:10]([CH:26]=[CH:27][C:28]=1[Cl:29])[CH2:11][N:12]1[C:20]2[C:15](=[C:16]([O:21][C:3](=[O:4])[N:2]([CH3:6])[CH3:1])[CH:17]=[CH:18][CH:19]=2)[CH:14]=[C:13]1[C:22]([O:24][CH3:25])=[O:23]
Reactant: CN(C)C(=O)Cl
Reactant: COC(=O)c1cc2c(O)cccc2n1Cc1ccc(Cl)c(Cl)c1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1cc2c(OC(=O)N(C)C)cccc2n1Cc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 73.2 %

Procedure:
Dimethylcarbamyl chloride (83 mg) was added to a stirred solution of methyl N-(3,4-dichlorobenzyl)-4-hydroxyindole-2-carboxylate (150 mg), triethylamine (65 mg) and DMAP (5 mg) in dichloromethane. The reaction was stirred for 16 hours at room temperature under an atmosphere of nitrogen. The reaction was washed with hydrochloric acie (2M, 70 ml), saturated aqueous sodium hydrogencarbonate solution, water and saturated sodium chloride solution. Combined organic extracts were dried (MgSO4), concentrated in vacuo and the residue purified by column chromatography using 60% ethyl acetate:iso-hexane as eluent to give the product as a colourless gum (132 mg,74%); NMR d (CD3SOCD3) 2.94 (s, 3H), 3.12 (s, 3H), 3.81 (s, 3H), 5.82 (s, 2H), 6.91 (m, 2H), 7.21 (s, 1H), 7.27-7.36 (m, 2H), 7.46 (d, 1H), 7.52 (d, 1H); M/z (+) 421 (MH+).
Reaction SMILES: [OH-].[In+3:2].[OH-].[OH-].[S:5](=[O:9])(=[O:8])([OH:7])[OH:6]>>[S:5]([O-:9])([O-:8])(=[O:7])=[O:6].[In+3:2].[S:5]([O-:9])([O-:8])(=[O:7])=[O:6].[S:5]([O-:9])([O-:8])(=[O:7])=[O:6].[In+3:2]
Reactant: O=S(=O)(O)O
Agent: [In+3]
Agent: [OH-]
Product: O=S(=O)([O-])[O-]

Procedure:
Furthermore, Japanese Patent Application Laid-open No. 2002-69684 (hereinafter, referred to as Patent Document 3) discloses an indium recovering method including a step of dissolving an ITO indium-containing scrap with a hydrochloric acid to obtain an indium chloride solution; a step of adding a sodium hydroxide solution into the indium chloride solution to remove tin contained in the scrap as tin hydroxide and further adding a sodium hydroxide solution to obtain indium hydroxide; a step of filtering indium hydroxide and thereafter adding a sulfuric acid to obtain indium sulfate; and performing electrowinning of indium.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1.C([Mg]Br)C=C.C(OCC)C.[C:19]([C:23]1[CH:28]=[CH:27][C:26]([C:29]2[O:34][C:33](=[O:35])[C:32]3[CH:36]=[N:37][CH:38]=[CH:39][C:31]=3[N:30]=2)=[CH:25][CH:24]=1)([CH3:22])([CH3:21])[CH3:20]>C1COCC1>[C:19]([C:23]1[CH:28]=[CH:27][C:26]([C:29]([NH:30][C:31]2[CH:39]=[CH:38][N:37]=[CH:36][C:32]=2[C:33]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=2)=[O:35])=[O:34])=[CH:25][CH:24]=1)([CH3:22])([CH3:20])[CH3:21]
Reactant: Nc1ccc(Cl)cn1
Reactant: CC(C)(C)c1ccc(-c2nc3ccncc3c(=O)o2)cc1
Agent: C=CC[Mg]Br
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(C(=O)Nc2ccncc2C(=O)Nc2ccc(Cl)cn2)cc1
Reaction time: 0.33 h
Yield: 82.3 %

Procedure:
To a stirring solution of 2-amino-5-chloropyridine (0.11 g, 0.85 mmol) in THF (12 mL) at 0° C. was added a 1 M solution of allylmagnesium bromide in diethyl ether (0.83 mL, 0.83 mmol). After 20 min, 2-[4-t-butylphenyl]-4H-6-aza-3,1-benzoxazin-4-one (0.115 g, 0.41 mmol) was added and the cold bath was removed. After 2 h, the mixture was diluted with ethyl acetate and washed three times with brine. The organic phase was dried (MgSO4), filtered and concentrated in vacuo. The solid was recrystallized from diethyl ether then washed several times with mixtures of ether/hexanes and dried to give 0.138 g (82%) of pale yellow needles.
Reaction SMILES: C[C@@:2]([NH:15]N)([C:12]([OH:14])=[O:13])[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([OH:11])=[C:8]([OH:10])[CH:9]=1>C1C(CCN)=CC(O)=C(O)C=1>[CH:5]1[C:4]([CH2:3][C@H:2]([NH2:15])[C:12]([OH:14])=[O:13])=[CH:9][C:8]([OH:10])=[C:7]([OH:11])[CH:6]=1
Reactant: C[C@@](Cc1ccc(O)c(O)c1)(NN)C(=O)O
Agent: NCCc1ccc(O)c(O)c1
Product: N[C@@H](Cc1ccc(O)c(O)c1)C(=O)O
Yield: 458.9 %

Procedure:
The in vitro dissolution profile of Sinemet® CR 50-200 tablets, containing 50 mg carbidopa and 200 mg levodopa were obtained under simulated gastric conditions. The dissolution tests were performed in 900 mL of a 0.1 N HCl-pH 1.2 solution, in a USP II apparatus at a temperature of 37° C. The paddle speed was set at 50 rpm. Samples of dissolution media were collected at predetermined intervals and analyzed by HPLC. The dissolution profiles of levodopa and carbidopa obtained from HPLC analysis are shown in FIG. 13.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C:2]1=[O:6].[H-].[Na+].Cl[CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1/[CH:21]=[CH:22]/[CH:23]([CH2:36][C:37]1[CH:42]=[CH:41][C:40]([C:43]([O:45][CH3:46])=[O:44])=[CH:39][CH:38]=1)[CH2:24][CH2:25][C:26]1[CH:35]=[CH:34][C:29]([C:30]([O:32][CH3:33])=[O:31])=[CH:28][CH:27]=1.[Cl-].[NH4+]>CN(C=O)C>[CH3:46][O:45][C:43]([C:40]1[CH:39]=[CH:38][C:37]([CH2:36][CH:23](/[CH:22]=[CH:21]/[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[O:14][CH2:13][CH2:12][CH2:11][CH2:10][N:1]2[CH2:5][CH2:4][CH2:3][C:2]2=[O:6])[CH2:24][CH2:25][C:26]2[CH:35]=[CH:34][C:29]([C:30]([O:32][CH3:33])=[O:31])=[CH:28][CH:27]=2)=[CH:42][CH:41]=1)=[O:44]
Reactant: O=C1CCCN1
Reactant: COC(=O)c1ccc(CCC(/C=C/c2ccccc2OCCCCCl)Cc2ccc(C(=O)OC)cc2)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(CCC(/C=C/c2ccccc2OCCCCN2CCCC2=O)Cc2ccc(C(=O)OC)cc2)cc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A solution of 16.7 mg (0.196 mmol) of pyrrolidin-2-one [CAS Reg. No. 616-45-5] are initially charged in 1.0 ml of dry DMF, and 8 mg (0.201 mmol) of sodium hydride (60% in paraffin oil) are added. The mixture is stirred at room temperature for 45 min. The reaction solution is then cooled to 0° C. and a solution of 30 mg (0.056 mmol) of methyl 4-{(4E)-5-[2-(4-chlorobutoxy)phenyl]-3-[4-(methoxycarbonyl)benzyl]pent-4-en-1-yl}benzoate (racemate; Example 31A) in 0.5 ml of dry DMF is added. The mixture is stirred at room temperature for 1.5 h. The reaction solution is then carefully poured into 15 ml of ice-cold 10% strength ammonium chloride solution. The mixture is extracted twice with dichloromethane. The combined organic phases are dried over sodium sulfate, filtered and concentrated. This gives 19 mg (32.5 μmol, 58% of theory) of a colorless oil which is reacted without further purification.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Br[C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=1>CC1C=CC=CC=1C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:14][C:11]1[CH:12]=[CH:13][C:8]([N:1]2[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)=[CH:9][CH:10]=1
Reactant: Fc1ccc(Br)cc1
Reactant: C1CNCCN1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1C
Product: Fc1ccc(N2CCNCC2)cc1
Temperature: 120 °C
Yield: 95 %

Procedure:
A 200 ml Kjeldahl flask equipped with a cooling condenser and a thermometer was charged with a solution of 22.0 g of piperazine in 20 ml of o-xylene, a solution of 7.47 g of 1-bromo-4-fluorobenzene in 20 ml of o-xylene, and a solution of 5.66 g of NaOBut in 20 ml of o-xylene, and further with a solution of 48 mg of palladium acetate in 5 ml of o-xylene (the ratio of palladium atom/1-bromo-4-fluorobenzene=0.5% by mole). The flask was flushed with nitrogen for about 20 minutes while the content was stirred, and 0.25 ml of tri-tert.-butylphosphine was added. Then the mixture was heated to 120° C., and maintained at that temperature for 3 hours with stirring. After completion of the reaction, 80 ml of water was added to cool the reaction product. The mixture was introduced in a separatory funnel and the organic phase was separated. The lower aqueous phase was extracted with 40 ml of o-xylene. The organic phase was dried over sodium sulfate. Gas chromatographic analysis of the obtained product by the internal standard method revealed that the intended arylamine, i.e., N-(4-fluorophenyl)piperazine was obtained in a yield of 95% by mole.