Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:15]3[C:10](=[N:11][CH:12]=[CH:13][CH:14]=3)[NH:9][C:8]2=[O:16])[CH2:3][CH2:2]1.Cl[C:18]1[CH:23]=[C:22]([C:24]([N:26]2[C:34]3[C:29](=[C:30]([F:36])[C:31]([F:35])=[CH:32][CH:33]=3)[CH2:28][CH2:27]2)=[O:25])[CH:21]=[CH:20][N:19]=1.C(=O)([O-])[O-].[K+].[K+]>CN1C(=O)CCC1>[F:36][C:30]1[C:31]([F:35])=[CH:32][CH:33]=[C:34]2[C:29]=1[CH2:28][CH2:27][N:26]2[C:24]([C:22]1[CH:23]=[CH:18][N:19]=[C:20]([N:1]2[CH2:2][CH2:3][CH:4]([N:7]3[C:15]4[C:10](=[N:11][CH:12]=[CH:13][CH:14]=4)[NH:9][C:8]3=[O:16])[CH2:5][CH2:6]2)[CH:21]=1)=[O:25]
Reactant: O=C(c1ccnc(Cl)c1)N1CCc2c1ccc(F)c2F
Reactant: O=c1[nH]c2ncccc2n1C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: O=C(c1ccnc(N2CCC(n3c(=O)[nH]c4ncccc43)CC2)c1)N1CCc2c1ccc(F)c2F

Procedure:
0.59 g (2.7 mmol) 1-piperidin-4-yl-1,3-dihydroimidazo[4,5-b]pyridin-2-one, 0.80 g (2.7 mmol) (2-chloro-pyridin-4-yl)-(4,5-difluoro-2,3-dihydro-indol-1-yl)-methanone and 0.39 g (2.8 mmol) potassium carbonate were stirred in 3 mL of NMP for 4 h at 130° C. The reaction mixture was purified by HPLC. The product-containing fractions were combined and freeze-dried.
Reaction SMILES: C(OC(=O)[NH:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH2:23][CH2:24][NH:25][CH2:26][C@@H:27]([C:29]2[CH:34]=[CH:33][C:32]([O:35][CH2:36][C:37]3C=CC=CC=3)=[C:31]([NH:43][S:44]([CH2:47]CC3C=CC=CC=3)(=[O:46])=[O:45])[CH:30]=2)[OH:28])=[CH:17][CH:16]=1)C1C=CC=CC=1.C[OH:57]>C(O)(=O)C.[OH-].[OH-].[Pd+2].ClCCl>[C:36]([OH:57])(=[O:35])[CH3:37].[C:36]([OH:57])(=[O:35])[CH3:37].[NH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH2:23][CH2:24][NH:25][CH2:26][C@@H:27]([C:29]2[CH:34]=[CH:33][C:32]([OH:35])=[C:31]([NH:43][S:44]([CH3:47])(=[O:46])=[O:45])[CH:30]=2)[OH:28])=[CH:17][CH:16]=1
Reactant: CO
Reactant: O=C(NCCCCc1ccc(CCCCNC[C@H](O)c2ccc(OCc3ccccc3)c(NS(=O)(=O)CCc3ccccc3)c2)cc1)OCc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CS(=O)(=O)Nc1cc([C@@H](O)CNCCCCc2ccc(CCCCN)cc2)ccc1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 96 %

Procedure:
A mixture of {4-[4-(4-{2-[3-(benzylmethanesulfonylamino)-4-benzyloxyphenyl]-2-(R)-hydroxyethylamino}butyl)phenyl]butyl}carbamic acid benzyl ester (36) (0.41 g, 0.54 mmol), palladium dihydroxide (0.12 g, 10% Pd(OH)2 on carbon, 50% wet), ten drops of acetic acid, methanol (9 mL), and dichloromethane (6 mL) was stirred at rt for 16 h under atmospheric hydrogen pressure. The catalyst was removed by filtration through a Celite pad and the filtrate was concentrated by rotary evaporation and further dried under high vacuum to give the desired amine diacetic acid salt 39 as a white solid (0.30 g, 96%): m/z (ESI) 450 [C23H35N3O4S+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20]([C:22]4[C:23](=[O:35])[N:24]([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)[N:25]([CH3:28])[C:26]=4[CH3:27])=[O:21])=[CH:15][C:14]=3[F:36])=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CS(O[CH2:48][C@H:49]1[CH2:55][CH2:54][C:51]2([CH2:53][CH2:52]2)[O:50]1)(=O)=O>CN(C)C(=O)C>[CH2:52]1[C:51]2([CH2:54][CH2:55][C@H:49]([CH2:48][O:1][C:2]3[CH:11]=[C:10]4[C:5]([C:6]([O:12][C:13]5[CH:18]=[CH:17][C:16]([NH:19][C:20]([C:22]6[C:23](=[O:35])[N:24]([C:29]7[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=7)[N:25]([CH3:28])[C:26]=6[CH3:27])=[O:21])=[CH:15][C:14]=5[F:36])=[CH:7][CH:8]=[N:9]4)=[CH:4][CH:3]=3)[O:50]2)[CH2:53]1
Reactant: CS(=O)(=O)OC[C@H]1CCC2(CC2)O1
Reactant: Cc1c(C(=O)Nc2ccc(Oc3ccnc4cc(O)ccc34)c(F)c2)c(=O)n(-c2ccccc2)n1C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: Cc1c(C(=O)Nc2ccc(Oc3ccnc4cc(OC[C@H]5CCC6(CC6)O5)ccc34)c(F)c2)c(=O)n(-c2ccccc2)n1C
Temperature: 40 °C
Reaction time: 72 h
Yield: 59.7 %

Procedure:
To a mixture of N-(4-(7-hydroxyquinolin-4-yloxy)-3-fluorophenyl)-2,3-dihydro-1,5-dimethyl-3-oxo-2-phenyl-1H-pyrazole-4-carboxamide (300 mg, 0.62 mmol) and cesium carbonate (1.0 g, 3.1 mmol, Aladdin) in N,N-dimethylacetamide (1 mL) was added ((5R)-4-oxaspiro[2.4]heptane-5-yl)methyl methanesulfonate (187.5 mg, 0.91 mmol) in 3 mL of N,N-dimethylacetamide. After stirring at 40° C. for 3 days, the reaction mixture was concentrated in vacuo and was chromatographed with a silica gel column (1:6 (v/v) n-hexane/EtOAc) to afford the title compound as a colorless solid (220 mg, 60%).
Reaction SMILES: [C:1]([N:6]1[CH2:11][CH2:10][CH2:9][CH2:8][C@@H:7]1[CH2:12][O:13][C:14]1[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-])=O)[C:15]=1[C:16]#[N:17])(=[O:5])[CH2:2][CH2:3][CH3:4].[H][H]>C(O)C.[Pd]>[NH2:22][C:18]1[CH:19]=[CH:20][CH:21]=[C:14]([O:13][CH2:12][C@H:7]2[CH2:8][CH2:9][CH2:10][CH2:11][N:6]2[C:1](=[O:5])[CH2:2][CH2:3][CH3:4])[C:15]=1[C:16]#[N:17]
Reactant: [H][H]
Reactant: CCCC(=O)N1CCCC[C@@H]1COc1cccc([N+](=O)[O-])c1C#N
Agent: [Pd]
Solvent: CCO
Product: CCCC(=O)N1CCCC[C@@H]1COc1cccc(N)c1C#N
Yield: 80.6 %

Procedure:
To a solution of (R)-2-((1-butyrylpiperidin-2-yl)methoxy)-6-nitrobenzonitrile (Example 16b, 1.5 g, 4.53 mmol) in ethanol (40 mL) was added 10% Pd/C (300 mg). The reaction mixture was charged with hydrogen balloon at room temperature overnight then filtered through celite and concentrated under reduced pressure. The residue was purified by Biotage SP-1 (40s column) eluting with EtOAc/Hexane (10%-70%) to give the desired product as an oil (1.1 g, 81%). 1H NMR (400 MHz, DMSO-d6) δ 0.86 (t, J=7.2 Hz, 3H), 1.46-1.65 (m, 7H), 1.77-1.85 (m, 1H), 2.24-2.30 (m, 1H), 2.38-2.42 (m, 1H), 2.56-2.63 (m, 0.5H), 3.1-3.16 (m, 0.5H), 3.71-3.74 (m, 0.3H), 3.92-3.98 (m, 1H), y 2H), 7.15-7.19 (m, 1H). MS 302 (MH+).
Reaction SMILES: [H-].[Na+].[CH3:3][PH:4](=[O:8])[O:5][CH2:6][CH3:7].Br[CH2:10][CH:11]1[CH2:13][CH2:12]1.O>O1CCCC1>[CH:13]1([CH2:12][P:4]([CH3:3])(=[O:8])[O:5][CH2:6][CH3:7])[CH2:11][CH2:10]1
Reactant: CCO[PH](C)=O
Reactant: BrCC1CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOP(C)(=O)CC1CC1
Reaction time: 3 h

Procedure:
A suspension of 2.22 g of sodium hydride (80% in oil) in 50 ml of anhydrous tetrahydrofuran under an inert atmosphere at 20° is treated with 50 ml of an anhydrous tetrahydrofuran solution of 7.24 g of ethyl (methyl)phosphinate at such a rate so that the temperature does not exceed 25°. After the addition is complete the resulting suspension is stirred for 1 hour at room temperature before slow addition of 10.0 g of bromomethylcyclopropane. The reaction mixture is stirred for a further 3 hours at 20° cooled in an ice/water bath and 100 ml of water added carefully. The clear solution is then partitioned between dichloromethane and water. Separation of the organic layer followed by drying and removal of the solvent affords a pale yellow oil. Distillation under high vacuum affords ethyl cyclopropylmethyl(methyl)phosphinate of b.p. 100° C. (10-1 mbar); 1H-NMR (CDCl3): δ (ppm)=4.04 (2H, m, CH2OP) 1.66 (2H, d, CH2P), 1.47 (3H, d, CH3), 1.30 (3H, t, CH3) 0.88 (1H, m, CH), 0.55 (2H, m, CH2), 0.15 (2H, m, CH2).
Reaction SMILES: [NH2:1][CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]([F:25])([F:24])[CH:21]([F:23])[F:22])[CH:14]=1)[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)[OH:4].[CH2:26]([CH:28]([CH2:39][CH3:40])[CH2:29][C:30]1([C:36](O)=[O:37])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1)[CH3:27].O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>C(#N)C.C(OCC)(=O)C>[CH2:39]([CH:28]([CH2:26][CH3:27])[CH2:29][C:30]1([C:36]([NH:1][CH:2]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]([F:25])([F:24])[CH:21]([F:23])[F:22])[CH:14]=2)[CH:3]([C:5]2[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=2)[OH:4])=[O:37])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1)[CH3:40]
Reactant: CCC(CC)CC1(C(=O)O)CCCCC1
Reactant: NC(Cc1cccc(OC(F)(F)C(F)F)c1)C(O)c1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCC(CC)CC1(C(=O)NC(Cc2cccc(OC(F)(F)C(F)F)c2)C(O)c2ccc(F)cc2)CCCCC1
Temperature: 80 °C
Reaction time: 24 h

Procedure:
While stirring (1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-[3-(1,1,2,2-tetrafluoroethoxy)phenyl]propan-1-ol (0.335 g, 0.927 mmol), 1-(2-ethylbutyl)cyclohexanecarboxylic acid (0.22 g, 1.02 mmol), 4-N,N-dimethylaminopyridine (0.11 g, 0.93 mmol) and 1-hydroxybenzotriazole hydrate (0.14 g, 0.93 mmol) in acetonitrile (10 ml), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.18 g, 0.93 mmol) was added, and the mixture was stirred at 80° C. for 1 day. The reaction solution was diluted with ethyl acetate, washed with aqueous sodium hydrogen carbonate solution and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=3/1-2/1) to give the objective substance.
Reaction SMILES: C(#N)C.[OH:4][CH2:5][CH2:6][O:7][C:8]1[CH:27]=[CH:26][C:11]([O:12][CH2:13][CH2:14][O:15][C:16](=[O:25])[C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[C:19]([Cl:24])[CH:18]=2)=[CH:10][CH:9]=1.[C:28](Cl)(=[O:32])[C:29]([CH3:31])=[CH2:30]>CN1CCCC1=O>[C:28]([O:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[CH:10][C:11]([O:12][CH2:13][CH2:14][O:15][C:16](=[O:25])[C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[C:19]([Cl:24])[CH:18]=2)=[CH:26][CH:27]=1)(=[O:32])[C:29]([CH3:31])=[CH2:30]
Reactant: O=C(OCCOc1ccc(OCCO)cc1)c1ccc(O)c(Cl)c1
Reactant: C=C(C)C(=O)Cl
Solvent: CN1CCCC1=O
Solvent: CC#N
Product: C=C(C)C(=O)OCCOc1ccc(OCCOC(=O)c2ccc(O)c(Cl)c2)cc1

Procedure:
A 300-ml eggplant type flask was charged with 16.3 g of 3-chloro-4-hydroxybenzoic acid methyl ester, 87 g of 1,4-(2-hydroxyethoxy)benzene and further with 0.8 g of PTD (p-toluenesulfonic acid monohydrate) as a catalyst to form a mixture. The mixture was stirred with heating on an oil bath, externally regulated at a temperature of 150° C., to react the mixture for 5 hours. The reaction mixture was poured into ice water followed by extracting with ethyl acetate, drying over anhydrous magnesium sulfate, concentrating and separating with a column using ethylacetate/n-hexane to obtain 29 g of 3-chloro-4-hydroxybenzoic acid 2-[4-(β-hydroxyethoxy)-phenoxy]ethyl ester (melting point: 87° to 88° C.). To 50 ml of an acetonitrile solution containing 10 g of the 3-chloro-4-hydroxybenzoic acid 2-[4-(β-hydroxyethoxy)-phenoxy]ethyl ester, 13.9 g of N-methylpyrrolidone and further 8.78 g of methacrylic acid chloride were added with stirring to form a solution. The solution was stirred at 40° C. for 8 hours to react the solution. Thereafter, excess methacrylic acid chloride was removed by means of vacuum distillation. The reaction mixture remaining therein was poured into ice water and the precipitated crystals were obtained by filtration. The crystals were recrystallized with ethylacetate/n-hexane to obtain 3-chloro-4-hydroxybenzoic acid 2-[4-(β-methacryloyloxyethoxy)phenoxy]ethyl ester (melting point: 105° to 106° C.).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[C:12]([C:13]([NH:15][OH:16])=[O:14])=[C:11]([Cl:17])[N:10]([CH3:18])[N:9]=1.[CH2:19](Br)[CH:20]=[CH2:21].Cl>O.C1(C)C=CC=CC=1>[CH2:21]([O:16][NH:15][C:13]([C:12]1[C:8]([Cl:7])=[N:9][N:10]([CH3:18])[C:11]=1[Cl:17])=[O:14])[CH:20]=[CH2:19]
Reactant: C=CCBr
Reactant: Cn1nc(Cl)c(C(=O)NO)c1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: C=CCONC(=O)c1c(Cl)nn(C)c1Cl
Temperature: 50 °C
Reaction time: 3 h
Yield: 72.2 %

Procedure:
In a solution of potassium carbonate (15.8 g, 114 mmol) in water (60 ml), a solution of 3,5-dichloro-1-methylpyrazole-4-carbohydroxamic acid (20.0 g, 95.2 mmol) and allyl bromide (13.8 g, 114 mmol) in toluene (60 ml) was added, and stirred at 50° C. for 3 hours. After cooling to room temperature, the mixture was adjusted to pH 1 by adding 35% hydrochloric acid, precipitated solid was filtered off, washed with water and toluene in that order, and dried to obtain the aimed product (17.2 g). Melting point 96-97° C. Proton nuclear magnetic resonance chemical shift values δ (ppm) (in CDCl3) 3.84 (s, 3H), 4.51 (d, J=6.3 Hz, 2H), 5.3-5.46 (m, 2H), 5.94-6.13 (m, 1H), 8.80 (brs, 1H).
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[N:11]=[C:12]([Cl:20])[S:13][C:14]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16])(C(C)(C)C)(C)C.Cl>O1CCOCC1>[Cl:20][C:12]1[S:13][C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:10]([CH2:9][OH:8])[N:11]=1
Reactant: CCOC(=O)c1sc(Cl)nc1CO[Si](C)(C)C(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CCOC(=O)c1sc(Cl)nc1CO
Yield: 96.2 %

Procedure:
A solution of 17.7 g (53 mmol) of ethyl 4-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-chloro-1,3-thiazole-5-carboxylate (Intermediate 211) and 53 ml (53 mmol) of 1N HCl in dioxane was stirred at room temperature for 1 h. The mixture was extracted 3 times with EtOAc, which was dried (MgSO4) and concentrated to give 11.3 g of an orange oil. Purification by silica gel chromatography affords a solid. NMR (CDCl3): 1.2 (t, 3H), 3.1 (s, broad, 1H), 4.2 (q, 2H), 4.8 (s, 2H).
Reaction SMILES: [CH2:1]([N:8]1[C@@H:12]([CH2:13][OH:14])[C:11](=[O:15])[N:10]([NH:16][C:17](=[O:44])[C@@H:18]([C@@H:23]([C:33](=[O:43])[NH:34][O:35]CC2C=CC=CC=2)[CH2:24]/[CH:25]=[CH:26]/[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:19][CH:20]([CH3:22])[CH3:21])[C:9]1=[O:45])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO.[Pd]>[CH2:1]([N:8]1[C@@H:12]([CH2:13][OH:14])[C:11](=[O:15])[N:10]([NH:16][C:17](=[O:44])[C@@H:18]([C@@H:23]([C:33](=[O:43])[NH:34][OH:35])[CH2:24][CH2:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:19][CH:20]([CH3:22])[CH3:21])[C:9]1=[O:45])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)C[C@@H](C(=O)NN1C(=O)[C@H](CO)N(Cc2ccccc2)C1=O)[C@H](C/C=C/c1ccccc1)C(=O)NOCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC(C)C[C@@H](C(=O)NN1C(=O)[C@H](CO)N(Cc2ccccc2)C1=O)[C@H](CCCc1ccccc1)C(=O)NO
Yield: 30.3 %

Procedure:
A solution of 0.077g of (E)-N-[3-benzyl-4(S)-(hydroxymethyl)-2,5-dioxo-1-imidazolidinyl]-2(R)-[1(S)-(benzyloxycarbamoyl)-4-phenyl-3-butenyl]-4-methylvaleramide in 10 ml of methanol was hydrogenated in the presence of 0.010 g of 10% palladium-on-carbon for 3 hours. The catalyst was removed by filtration and evaporation followed by trituration with diethyl ether gave 0.020 g of N-[3-benzyl-4(S)-(hydroxymethyl)-2,5-dioxo-1-imidazolidinyl]-2(R)-[1(S)-(hydroxycarbamoyl)-4-phenylbutyl]-4-methylvaleramide in the form of a white solid.
Reaction SMILES: CCC[N:4]([C@@H:12]1[CH2:17][C:16]2[CH:18]=[CH:19][CH:20]=[C:21]([OH:22])[C:15]=2[CH2:14][CH2:13]1)[CH2:5][CH2:6][C:7]1[S:11][CH:10]=[CH:9][CH:8]=1.Cl.[CH3:24]OC1C=CC=C2C=1CCC(=O)C2.S1C=CC=C1CCN.C1(C)C=CC(S(O)(=O)=O)=CC=1.C([BH3-])#N.[Na+]>>[CH3:24][O:22][C:21]1[CH:20]=[CH:19][CH:18]=[C:16]2[C:15]=1[CH2:14][CH2:13][CH:12]([NH:4][CH2:5][CH2:6][C:7]1[S:11][CH:10]=[CH:9][CH:8]=1)[CH2:17]2
Reactant: COc1cccc2c1CCC(=O)C2
Reactant: CCCN(CCc1cccs1)[C@H]1CCc2c(O)cccc2C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Agent: NCCc1cccs1
Product: COc1cccc2c1CCC(NCCc1cccs1)C2

Procedure:
The preparation of racemic rotigotine hydrochloride is disclosed in U.S. Pat. No. 4,564,628. The process, which is depicted in Scheme 1, comprises reacting 5-methoxy-2-tetralone (Compound I) with β-(2-thienyl)ethylamine in presence of p-toluenesulfonic acid and sodium cyanoborohydride to obtain 1,2,3,4-tetrahydro-5-methoxy-N-[2-(thienyl)-ethyl]-2-naphthaleneamine (Compound II), which is reacted with propionyl chloride in presence of triethylamine to obtain N-(1,2,3,4-tetrahydro-5-methoxy-2-naphthenyl)-N-[2-(2-thienyl)ethyl)]propaneamide (Compound III). This propanamide is reduced with lithium aluminum hydride to obtain 1,2,3,4-tetrahydro-5-methoxy-N-propyl-N-[2-(2-thienyl)ethyl]-2-naphthaleneamine (Compound IV), which is subsequently reacted with boron tribromide, then hydrochloric acid (HCl) to form the racemic rotigotine hydrochloride (Compound V).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[O:11][N:10]=[C:9]([CH3:12])[N:8]=2)=[C:5]([CH3:13])[N:4]=[CH:3]1.[Br:14]Br>C(Cl)(Cl)Cl>[Br:14][C:3]1[N:2]([CH3:1])[C:6]([C:7]2[O:11][N:10]=[C:9]([CH3:12])[N:8]=2)=[C:5]([CH3:13])[N:4]=1
Reactant: Cc1noc(-c2c(C)ncn2C)n1
Reactant: BrBr
Solvent: ClC(Cl)Cl
Product: Cc1noc(-c2c(C)nc(Br)n2C)n1
Temperature: 25 °C
Reaction time: 26 h
Yield: 51.5 %

Procedure:
To a stirred solution of 5-(3,5-dimethyl-3H-imidazol-4-yl)-3-methyl-[1,2,4]oxadiazol (0.7 g, 3.93 mmol) in chloroform (7 ml) was added dropwise at RT a solution of bromine (0.94 g, 0.30 ml, 5.89 mmol) in chloroform (7 ml). The reaction mixture was stirred at RT for 26 h, evaporated, poured into sat. NaHCO3 solution (40 ml) and extracted with dichloromethane (2×30 ml). The combined organic layers were washed with brine (40 ml), dried (MgSO4) and evaporated to give the crude product as yellow oil (0.84 g). Purification by column chromatography on silica gel (ethyl acetate/MeOH 98:2) gave the title compound (0.52 g, 51%) as a white solid, m.p. 89° C. and MS: m/e=256, 258 (M+).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][C:5]=1[OH:12])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:20][CH2:21][CH2:22][Cl:23].Cl>CN(C)C=O>[Cl:23][CH2:22][CH2:21][CH2:20][O:12][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:4]=1[O:3][CH2:1][CH3:2])[CH:8]=[O:9]
Reactant: CCOc1ccc(C=O)cc1O
Reactant: ClCCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1ccc(C=O)cc1OCCCCl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
4-Ethoxy-3-hydroxybenzaldehyde (74.3 g) and potassium carbonate (111.3 g) were suspended in N,N-dimethylformamide (350 mL). To the mixture was added dropwise 1-bromo-3-chloropropane (79.6 mL) under ice-cooling, and the mixture was stirred at room temperature for 16 hours. To the reaction mixture was added dropwise 2 mol/L hydrochloric acid (300 mL), and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by column chromatography on silica gel (eluent: ethyl acetate/hexane=1/5) to give the title compound (69.8 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH:7]=[C:6](I)[C:5]2=[O:13].[NH:14]1[CH:18]=[CH:17][CH:16]=[N:15]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[NH:14]1[CH:18]=[CH:17][C:16]([C:7]2[O:8][C:9]3[C:4]([C:5](=[O:13])[CH:6]=2)=[CH:3][C:2]([Cl:1])=[CH:11][CH:10]=3)=[N:15]1
Reactant: O=c1c(I)coc2ccc(Cl)cc12
Reactant: c1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=c1cc(-c2cc[nH]n2)oc2ccc(Cl)cc12
Temperature: 0 °C
Yield: 34 %

Procedure:
A mixture of 6-chloro-3-iodochromone (153 mg) prepared in Example 28, pyrazole (136 mg), potassium carbonate (1382 mg), and dimethylformamide (15 ml) was reacted at 80° C. for 2 hours with stirring. The reaction mixture was added to ice water and extracted from chloroform. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purifiedby the silica gel column chromatography, and recrystallized from benzene/hexane to give the titled compound (41.9 mg; yield=34.0%) as orange crystals. Melting point: 217°-219° C. Mass spectrum (M+): 246.5.
Reaction SMILES: [C:1]([C:4]1[N:5]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([C:29](=O)[CH3:30])=[CH:25][CH:24]=2)[C:6](=[O:21])[C:7]2[C:12]([C:13]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[CH:11][C:10]([Br:20])=[CH:9][CH:8]=2)(=[O:3])[CH3:2].Cl.[NH2:33][OH:34].C([O-])(=O)C.[Na+]>C(O)C>[C:1]([C:4]1[N:5]([CH2:22][C:23]2[CH:24]=[CH:25][C:26]([C:29](=[N:33][OH:34])[CH3:30])=[CH:27][CH:28]=2)[C:6](=[O:21])[C:7]2[C:12]([C:13]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[CH:11][C:10]([Br:20])=[CH:9][CH:8]=2)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc(Cn2c(C(C)=O)c(-c3ccccc3)c3cc(Br)ccc3c2=O)cc1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CC(=O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc(C(C)=NO)cc1
Yield: 85.7 %

Procedure:
To a solution of 3-acetyl-2-(4-acetylbenzyl)-6-bromo-4-phenyl-2H-isoquinolin-1-one (95 mg) in ethanol (10 ml) were added hydroxylamine hydrochloride (17 mg) and sodium acetate (29 mg) at room temperature and the mixture was heated under reflux for 6 hrs. The solvent was evaporated under reduced pressure and the residue was partitioned between ethyl acetate and saturated aqueous sodium hydrogen carbonate solution, washed with saturated brine and dried by adding sodium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=4/1→3/2) to give the title compound (84 mg, 86%).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([N:10]([C@H:29]2[CH2:34][CH2:33][C@H:32]([CH3:35])[CH2:31][CH2:30]2)[C:11]([NH:13][C:14]2[S:15][C:16]([S:19][CH2:20][C:21](=[O:28])[N:22]3[CH2:27][CH2:26]C[CH2:24][CH2:23]3)=[CH:17][N:18]=2)=[O:12])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[C:36]([N:39]1CCC(N([C@H]2CC[C@H](C)CC2)C(=O)NC2SC(SCC(O)=O)=CN=2)CC1)(=O)C.CN1CCNCC1>>[C:1]([N:4]1[CH2:5][CH2:6][CH:7]([N:10]([C@H:29]2[CH2:30][CH2:31][C@H:32]([CH3:35])[CH2:33][CH2:34]2)[C:11]([NH:13][C:14]2[S:15][C:16]([S:19][CH2:20][C:21]([N:22]3[CH2:27][CH2:26][N:39]([CH3:36])[CH2:24][CH2:23]3)=[O:28])=[CH:17][N:18]=2)=[O:12])[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCC(N(C(=O)Nc2ncc(SCC(=O)N3CCCCC3)s2)[C@H]2CC[C@H](C)CC2)CC1
Reactant: CC(=O)N1CCC(N(C(=O)Nc2ncc(SCC(=O)O)s2)[C@H]2CC[C@H](C)CC2)CC1
Agent: CN1CCNCC1
Product: CC(=O)N1CCC(N(C(=O)Nc2ncc(SCC(=O)N3CCN(C)CC3)s2)[C@H]2CC[C@H](C)CC2)CC1

Procedure:
Prepared in a similar manner to 1-(1-acetyl-piperidin-4-yl)-1-(trans-4-methyl-cyclohexyl)-3-[5-(2-oxo-2-piperidin-1-yl-ethylsulfanyl)-thiazol-2-yl]-urea using {2-[3-(1-acetyl-piperidin-4-yl)-3-(trans-4-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid and N-methylpiperazine.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:31]=[CH:30][C:8]([CH2:9][N:10]2[CH:14]=[C:13]([CH:15]3[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]3)[C:12]([CH2:28][CH3:29])=[N:11]2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[C:32]([OH:38])([C:34]([F:37])([F:36])[F:35])=[O:33]>>[OH:38][C:32]([C:34]([F:37])([F:36])[F:35])=[O:33].[OH:38][C:32]([C:34]([F:37])([F:36])[F:35])=[O:33].[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([CH2:9][N:10]2[CH:14]=[C:13]([CH:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)[C:12]([CH2:28][CH3:29])=[N:11]2)=[CH:30][CH:31]=1)(=[O:3])=[O:4]
Reactant: CCc1nn(Cc2ccc(S(C)(=O)=O)cc2)cc1C1CCN(C(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Product: CCc1nn(Cc2ccc(S(C)(=O)=O)cc2)cc1C1CCNCC1

Procedure:
4-((1-(4-Methylsulfonylbenzyl)-3-ethyl)-(1H)-pyrazol4-yl)-N-t-butoxylcarbonylpiperidine from Step C was treated with TFA for 1 h and evaporated to afford the title compound as the TFA salt.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[N:14]=[CH:15][NH:16][CH:17]=3)=[C:11]([CH2:18][O:19][CH3:20])[O:10][N:9]=2)=[CH:4][CH:3]=1.F[C:22]1[CH:27]=[CH:26][C:25]([C:28](=[O:30])[CH3:29])=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[N:14]=[CH:15][N:16]([C:22]4[CH:27]=[CH:26][C:25]([C:28](=[O:30])[CH3:29])=[CH:24][CH:23]=4)[CH:17]=3)=[C:11]([CH2:18][O:19][CH3:20])[O:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: COCc1onc(-c2ccc(F)cc2)c1-c1c[nH]cn1
Reactant: CC(=O)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COCc1onc(-c2ccc(F)cc2)c1-c1cn(-c2ccc(C(C)=O)cc2)cn1
Temperature: 120 °C
Reaction time: 16 h
Yield: 84.3 %

Procedure:
A mixture of 3-(4-fluoro-phenyl)-4-(1H-imidazol-4-yl)-5-methoxymethyl-isoxazole (273 mg, 1.0 mmol), 1-(4-fluorophenyl)-ethanone (212 mg, 1.5 mmol), and potassium carbonate (276 mg, 2.0 mmol) in DMF (4 mL) was stirred at 120° C. for 16 h. After cooling to room temperature, the resulting solution was poured into cold water and stirred for 15 min. The precipitate was collected by filtration, washed with water, hexane, and dried to afford the title compound (330 mg, 79%) which was obtained as light brown solid. MS: m/e=392.5[M+H]+.