Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][N:5]1[C:13]2[C:8](=[C:9]([N+:14]([O-:16])=[O:15])[CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6]1.C(=O)([O-])[O-].[K+].[K+].[NH:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>CN(C=O)C.O>[N+:14]([C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:8]=1[CH:7]=[CH:6][N:5]2[CH2:4][CH2:3][CH2:2][N:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1)([O-:16])=[O:15]
Reactant: O=[N+]([O-])c1cccc2c1ccn2CCCBr
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cccc2c1ccn2CCCN1CCOCC1
Temperature: 80 °C
Reaction time: 12 h

Procedure:
To a solution of 1-(3-bromopropyl)-4-nitro-1H-indole (8.18 g, 28.9 mmol) in anhydrous N,N′-dimethylformamide (200 mL) was added grounded potassium carbonate (12 g, 87 mmol) in portions. Then a solution of morpholine (12.6 g, 144.8 mmol) in N,N′-dimethylformamide was added dropwise. The mixture was stirred at 80° C. for 12 hours, diluted with water and extracted with ethyl acetate. The organic phases were combined, washed by brine, dried over anhydrous sodium sulfate, filtrated and evaporated to afford the product 4-(3-(4-nitro-1H-indol-1-yl)propyl)morpholine, which was used for the next step without purification.
Reaction SMILES: [CH:1]1[N:9]2[C:4]([NH:5][NH:6][C:7]3[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=32)=[N:3][N:2]=1.[C:14]1([CH2:20][C:21](Cl)=[O:22])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[C:14]1([CH2:20][C:21]([N:5]2[C:4]3=[N:3][N:2]=[CH:1][N:9]3[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[N:6]2[C:21](=[O:22])[CH2:20][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:22])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: c1ccc2c(c1)NNc1nncn1-2
Reactant: O=C(Cl)Cc1ccccc1
Product: O=C(Cc1ccccc1)N1c2ccccc2-n2cnnc2N1C(=O)Cc1ccccc1
Yield: 63.9 %

Procedure:
5 g (0.028 mole) of 4,5-dihydro-s-triazolo[3,4-c]benzo-as-triazine are reacted with 9.8 g (0.064 mole) of phenylacetyl chloride as described in Example 12. 7.33 g (64%) of the title compound are obtained; m.p.: 150°-151° C.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH3:15][C:16]1[CH:17]=[C:18]([CH:26]=[C:27]([CH3:29])[CH:28]=1)[O:19][CH:20]([CH2:24][CH3:25])[C:21](Cl)=[O:22]>C1C=CC=CC=1>[CH2:1]([NH:8][C:21](=[O:22])[CH:20]([O:19][C:18]1[CH:17]=[C:16]([CH3:15])[CH:28]=[C:27]([CH3:29])[CH:26]=1)[CH2:24][CH3:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCC(Oc1cc(C)cc(C)c1)C(=O)Cl
Reactant: NCc1ccccc1
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: CCC(Oc1cc(C)cc(C)c1)C(=O)NCc1ccccc1
Reaction time: 5 h
Yield: 62.1 %

Procedure:
In 30 ml of benzene were dissolved 1.8 g (0.017 mole) of benzylamine and 1.2 g (0.015 mole) of pyridine, and thereto was added dropwise 3.0 g (0.013 mole) of 2-(3,5-dimethylphenoxy)-butyroyl chloride at room temperature with stirring. After the reaction was carried out for 5 hours, the reaction mixture was washed with water, dilute hydrochloric acid, dilute aqueous sodium hydroxide and then water successively. After the benzene layer was dried, the benzene was removed by distillation. The resultant crude crystals were recrystallized from n-hexane to give 2.4 g of N-benzyl-2-(3,5-dimethylphenoxy)-butyramide melting at 93°-94° C. as colorless needles.
Reaction SMILES: [C:1]([C:3]1[O:7][C:6]([C:8](Cl)=[O:9])=[CH:5][CH:4]=1)#[N:2].[CH3:11][N:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:23]=[CH:22][C:21]([NH2:24])=[C:20]([C:25]3[C:29]([CH3:30])=[CH:28][S:27][CH:26]=3)[CH:19]=2)[CH2:14][CH2:13]1.CCN(C(C)C)C(C)C>>[CH3:11][N:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:23]=[CH:22][C:21]([NH:24][C:8]([C:6]3[O:7][C:3]([C:1]#[N:2])=[CH:4][CH:5]=3)=[O:9])=[C:20]([C:25]3[C:29]([CH3:30])=[CH:28][S:27][CH:26]=3)[CH:19]=2)[CH2:14][CH2:13]1
Reactant: N#Cc1ccc(C(=O)Cl)o1
Reactant: Cc1cscc1-c1cc(N2CCN(C)CC2)ccc1N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cscc1-c1cc(N2CCN(C)CC2)ccc1NC(=O)c1ccc(C#N)o1
Yield: 24 %

Procedure:
Using a procedure similar to Example 9, step (c), 5-cyano-furan-2-carbonyl chloride (64 mg, 0.41 mmol, as prepared in Example 9, step (c)) was allowed to react with 4-(4-methyl-piperazin-1-yl)-2-(4-methyl-thiophen-3-yl)-phenylamine (80 mg, 0.27 mmol, as prepared in the previous step) in the presence of DIEA (0.10 mL, 0.59 mmol) to afford 25.8 mg (24%) of the title compound as a yellow solid. 1H-NMR (CDCl3; 400 MHz): δ 2.09 (s, 3H), 2.37 (s, 3H), 2.59-2.60 (m, 4H), 3.24-3.26 (m, 4H), 6.83 (d, 1H, J=2.9 Hz), 6.98-7.06 (m, 2H), 7.14-7.21 (m, 3H), 7.96 (s, 1H), 8.32 (d, 1H, J=9.0 Hz). Mass spectrum (ESI, m/z): Calcd. for C22H22N4O2S, 407.1 (M+H). found 407.1.
Reaction SMILES: [CH3:1][CH:2]([O:6][C:7]1[N:15]=[C:14]2[C:10]([N:11]=[C:12]([O:22][CH3:23])[N:13]2C2CCCCO2)=[C:9]([NH2:24])[N:8]=1)[CH2:3][CH2:4][CH3:5].[C:25]([OH:31])([C:27]([F:30])([F:29])[F:28])=[O:26]>CO>[F:28][C:27]([F:30])([F:29])[C:25]([OH:31])=[O:26].[CH3:1][CH:2]([O:6][C:7]1[N:15]=[C:14]2[C:10]([N:11]=[C:12]([O:22][CH3:23])[NH:13]2)=[C:9]([NH2:24])[N:8]=1)[CH2:3][CH2:4][CH3:5]
Reactant: CCCC(C)Oc1nc(N)c2nc(OC)n(C3CCCCO3)c2n1
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: CCCC(C)Oc1nc(N)c2nc(OC)[nH]c2n1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 2-[(1-methylbutyl)oxy]-8-methoxy-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (313 mg) in dry MeOH (3.13 mL) was added TFA (0.313 mL) and the mixture was stirred at room temperature for 48 h. The reaction mixture was concentrated in vacuo to give a yellow residue which was triturated with Et2O and filtered to give the title compound as an off-white solid (218 mg).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:18]=[CH:17][C:13]([C:14](O)=[O:15])=[CH:12][CH:11]=3)=[CH:7][C:6]=2[CH:19]=1.Cl>C1COCC1>[OH:15][CH2:14][C:13]1[CH:12]=[CH:11][C:10]([C:8]2[O:9][C:5]3[CH:4]=[CH:3][C:2]([OH:1])=[CH:19][C:6]=3[CH:7]=2)=[CH:18][CH:17]=1
Reactant: O=C(O)c1ccc(-c2cc3cc(O)ccc3o2)cc1
Agent: Cl
Solvent: C1CCOC1
Product: OCc1ccc(-c2cc3cc(O)ccc3o2)cc1
Yield: 55.5 %

Procedure:
To a solution of 128 (0.15 g, 0.6 mmol), in THF (20 ml) was added BH3 (3 ml of 1.0 M in THF) and the reaction was heated to reflux for 3 hr. The reaction was then cooled and poured into 2N HCl and extracted with EtOAc. The EtOAc was dried over MgSO4, filtered and concentrated and triturated with CH2Cl2 and filtered to give 129 as a solid (0.08 g, 57%); 1H NMR (DMSO-d6) δ 9.21 (br s, 1 H), 7.82 (d, 2 H, J=8.1 Hz), 7.43–7.38 (m, 3 H), 7.24 (s, 1 H), 6.92 (d, 1 H, J=2.1 Hz), 6.73 (dd, 1 H, J=8.5 Hz, 2.6 Hz), 5.28 (t, 1 H, J=5.7 Hz), 4.54 (d, 2 H, J=5.5 Hz); MS 239 (M−H)−.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:12][CH2:11][CH2:10][NH:9]2)=[CH:4][CH:3]=1.[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[S:20](Cl)(=[O:22])=[O:21]>>[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[S:20]([N:9]1[CH2:10][CH2:11][CH2:12][CH:8]1[C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)(=[O:22])=[O:21]
Reactant: Fc1ccc(C2CCCN2)cc1
Reactant: O=S(=O)(Cl)c1ccccc1F
Product: O=S(=O)(c1ccccc1F)N1CCCC1c1ccc(F)cc1

Procedure:
The title compound, off-white solid, m.p.91° C. and MS: m/e=323 (M+) was prepared in accordance with the general method of example 1e from (RS)-2-(4-fluoro-phenyl)-pyrrolidine and 2-fluoro-benzenesulfonyl chloride.
Reaction SMILES: [CH:1]([Si:4]([O:11][C:12]1[CH:17]=[C:16]([CH3:18])[C:15](Br)=[C:14]([CH3:20])[CH:13]=1)([CH:8]([CH3:10])[CH3:9])[CH:5]([CH3:7])[CH3:6])([CH3:3])[CH3:2].C([Li])CCC.[CH2:26]([O:33][C:34]1[CH:41]=[CH:40][C:37]([CH:38]=[O:39])=[CH:36][C:35]=1[S:42]([C:45]1[CH:50]=[CH:49][C:48]([F:51])=[CH:47][CH:46]=1)(=[O:44])=[O:43])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.[Cl-].[NH4+]>O1CCCC1>[CH2:26]([O:33][C:34]1[CH:41]=[CH:40][C:37]([CH:38]([C:15]2[C:16]([CH3:18])=[CH:17][C:12]([O:11][Si:4]([CH:8]([CH3:10])[CH3:9])([CH:5]([CH3:7])[CH3:6])[CH:1]([CH3:3])[CH3:2])=[CH:13][C:14]=2[CH3:20])[OH:39])=[CH:36][C:35]=1[S:42]([C:45]1[CH:46]=[CH:47][C:48]([F:51])=[CH:49][CH:50]=1)(=[O:44])=[O:43])[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: O=Cc1ccc(OCc2ccccc2)c(S(=O)(=O)c2ccc(F)cc2)c1
Reactant: Cc1cc(O[Si](C(C)C)(C(C)C)C(C)C)cc(C)c1Br
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1cc(O[Si](C(C)C)(C(C)C)C(C)C)cc(C)c1C(O)c1ccc(OCc2ccccc2)c(S(=O)(=O)c2ccc(F)cc2)c1
Reaction time: 1 h

Procedure:
810 mg (2.27 mmol) of 4-bromo-3,5-dimethylphenyl triisopropylsilyl ether (Example VII) are dissolved in 10 ml of tetrahydrofuran. At −78° C., 147.3 mg (2.3 mmol) of butyllithium (2.4 molar in hexane) are added dropwise. At the same temperature, stirring is continued for one hour, and 600 mg (1.62 mmol) of 4-(benzyloxy)-3-[(4-fluorophenyl)sulphonyl]benzaldehyde (Example VI), dissolved in 4 ml of tetrahydrofuran, are then added dropwise. The mixture is stirred at −78° C. for one hour, and saturated ammonium chloride solution is then added. The mixture is extracted three times with ethyl acetate and the combined organic phases are dried with sodium sulphate and concentrated. This gives 580 mg (55% of theory) of {4-(benzyloxy)-3-[(4-fluorophenyl)sulphonyl]phenyl}{2,6-dimethyl-4-(triisopropylsilyl)oxy]phenyl}methanol.
Reaction SMILES: [C:1]([C:3]([C:12]#[N:13])=[C:4]([NH:6][C:7](=[O:11])[N:8]([CH3:10])[CH3:9])[SH:5])#[N:2].[OH:14]O>O>[C:1]([C:3]1[C:12]([OH:14])=[N:13][S:5][C:4]=1[NH:6][C:7](=[O:11])[N:8]([CH3:10])[CH3:9])#[N:2]
Reactant: CN(C)C(=O)NC(S)=C(C#N)C#N
Reactant: OO
Solvent: O
Product: CN(C)C(=O)Nc1snc(O)c1C#N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 3-(2,2-Dicyano-1-mercapto-vinyl)-1,1-dimethyl-urea (sodium salt) (30 g, 137 mmol) in water (300 mL) was treated at ambient temperature with hydrogen peroxide (14 mL of a 10 M solution). The reaction warmed and thickened with solid formation and so was treated with additional water (100 mL). The mixture was heated to reflux for 15 minutes, effecting complete dissolution and then cooled to ambient temperature. After 1 hour at ambient temperature, the mixture was concentrated to a constant weight (35 g, >100% due to water content) and was used immediately in the next step.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:24](=[CH:25][CH:26]=1)[C:8]1=[N:9][O:10][C:11]([C:12]3[CH:13]=[CH:14][C:15]([O:20][CH:21]([CH3:23])[CH3:22])=[C:16]([CH:19]=3)[C:17]#[N:18])=[C:7]1[CH2:6][CH2:5]2.[CH2:27]([Sn](CCCC)(CCCC)C=C)[CH2:28]CC.[Cl-].[Li+]>O1CCOCC1.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>[CH:21]([O:20][C:15]1[CH:14]=[CH:13][C:12]([C:11]2[O:10][N:9]=[C:8]3[C:24]4[C:4]([CH2:5][CH2:6][C:7]=23)=[CH:3][C:2]([CH:27]=[CH2:28])=[CH:26][CH:25]=4)=[CH:19][C:16]=1[C:17]#[N:18])([CH3:22])[CH3:23]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: CC(C)Oc1ccc(-c2onc3c2CCc2cc(Br)ccc2-3)cc1C#N
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: C1COCCO1
Product: C=Cc1ccc2c(c1)CCc1c-2noc1-c1ccc(OC(C)C)c(C#N)c1
Temperature: 100 °C
Yield: 67.3 %

Procedure:
5-(7-Bromo-4,5-dihydronaphtho[1,2-c]isoxazol-3-yl)-2-isopropoxybenzonitrile (Preparation 15B, 0.15 g, 0.367 mmol) dissolved in dioxane (3 mL) was transferred to a 15 mL sealed tube. Tributyl(vinyl)stannane (0.118 mL, 0.403 mmol) was added followed by lithium chloride (0.047 g, 1.100 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.042 g, 0.037 mmol). The contents were purged with nitrogen gas for 5 min., immersed in an oil bath, and heated at 100° C. for 14 h. The reaction mixture was concentrated and to the red-brown oil was added ethyl acetate (10 mL). The contents were sonicated for 5 min. and filtered. The filter cake was washed with ethyl acetate (2×5 mL). The filtrate was concentrated under reduced pressure and the resulting oil was subjected to silica gel column chromatography (hexane/ethyl acetate). Fractions corresponding to the product were collected and concentrated to yield 2-isopropoxy-5-(7-vinyl-4,5-dihydronaphtho[1,2-c]isoxazol-3-yl)benzonitrile (0.088 g, 0.247 mmol, 67% yield) as a pale yellow solid. LC/MS M+1=357.1.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5](B2OC(C)(C)C(C)(C)O2)[C:4]([C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=2)=[N:3]1.Br[C:26]1[CH:31]=[CH:30][N:29]=[C:28]2[N:32]([S:49]([C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)(=[O:51])=[O:50])[C:33]([C:35]3([OH:48])[CH2:40][CH2:39][N:38]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:37][CH2:36]3)=[CH:34][C:27]=12>>[OH:48][C:35]1([C:33]2[N:32]([S:49]([C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)(=[O:51])=[O:50])[C:28]3=[N:29][CH:30]=[CH:31][C:26]([C:5]4[C:4]([C:16]5[CH:17]=[CH:18][C:19]([N+:22]([O-:24])=[O:23])=[CH:20][CH:21]=5)=[N:3][N:2]([CH3:1])[CH:6]=4)=[C:27]3[CH:34]=2)[CH2:36][CH2:37][N:38]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:39][CH2:40]1
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2cc3c(Br)ccnc3n2S(=O)(=O)c2ccccc2)CC1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)c(-c2ccc([N+](=O)[O-])cc2)n1
Product: Cn1cc(-c2ccnc3c2cc(C2(O)CCN(C(=O)OC(C)(C)C)CC2)n3S(=O)(=O)c2ccccc2)c(-c2ccc([N+](=O)[O-])cc2)n1

Procedure:
Following the procedure described for Intermediate 100 using 1-methyl-3-(4-nitrophenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole and 1,1-dimethylethyl 4-[4-bromo-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]-4-hydroxy-1-piperidinecarboxylate provided the title compound. ESMS [M+H]+: 659.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[O:10][CH2:11][C:12](=[O:14])[N:13]=2)[CH:6]=[CH:7][CH:8]=1.N1C(C)=CC=CC=1C.[O:23](S(C(F)(F)F)(=O)=O)[S:24]([C:27]([F:30])([F:29])[F:28])(=O)=[O:25]>C(Cl)Cl>[F:28][C:27]([F:30])([F:29])[S:24]([O:14][C:12]1[N:13]=[C:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)[O:10][CH:11]=1)(=[O:25])=[O:23]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: COc1cccc(C2=NC(=O)CO2)c1
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: COc1cccc(-c2nc(OS(=O)(=O)C(F)(F)F)co2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 75 %

Procedure:
Compound 16 (516 mg, 1 eq) was dissolved in CH2Cl2. To the resulting solution, at 0° C., was added 501 μL (1.6 eq) of 2,6-lutidine, followed by the dropwise addition of Tf2O (681 ml, 1.5 eq). The resulting mixture was stirred for 4 h at RT, then an additional 501 μL (1.6 eq) of 2,6-lutidine and 681 ml (1.5 eq) of Tf2O were added. After 1 h, the mixture was evaporated and the residue purified by flash chromatography (SiO2, CH2Cl2/hexane, 9/1) giving 17 as a red oil in 75% yield.
Reaction SMILES: [CH2:1]([N:3]=[C:4]=[O:5])[CH3:2].C([O:8][C:9](=O)[C:10]1[C:15]([O:16][CH3:17])=[C:14]([O:18][CH3:19])[CH:13]=[CH:12][C:11]=1[NH2:20])C>N1C=CC=CC=1.[OH-].[Na+]>[CH2:1]([N:3]1[C:9](=[O:8])[C:10]2[C:11](=[CH:12][CH:13]=[C:14]([O:18][CH3:19])[C:15]=2[O:16][CH3:17])[NH:20][C:4]1=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(N)ccc(OC)c1OC
Reactant: CCN=C=O
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Product: CCn1c(=O)[nH]c2ccc(OC)c(OC)c2c1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 80.5 %

Procedure:
To ethyl isocyanate (1.65 ml, 1.48 g, 20.8 mM) in pyridine (9.2 ml) at 0° C. was added a cold solution of 2-amino-5,6-dimethoxybenzoic acid ethyl ester (3.0 g, 20.8 mM) in pyridine (16.7 ml). The solution was stirred at 0° C. for thirty minutes, then kept at room temperature for one hour. During this time, a precipitate formed. The mixture was concentrated to dryness to give an off-white solid. This was dissolved in 69.9 ml of 1N NaOH (4:1 MeOH-H2O) and heated at reflux for two hours. The solvent was removed in vacuo and the residue dissolved in H2O (150 ml). The mixture was taken to pH 6 with acetic acid and the resulting white solid filtered, washed with H2O (50 ml), and dried to give crude product as a white solid; 3.12 g; mp 208°-211° C. Recrystallization from isopropanol (100 ml) and drying afforded the title compound as a white solid; 2.09 g; mp 212°-214° C., total yield 80.5%, CF3COOH(TMS), 7.60 (d, 1H, J7,8 =9.0 Hz, 7-H), 7.13 (d, 1H, J8,7 =9.0 Hz, 8-H), 4.20 (9, 2H, J=6.0 Hz, 9-H), 4.19 (s, 3H, 5 or 6-OCH3), 4.05 (s, 3H, 5 or 6-OCH3), 1.40 (t, 3H, J=6.0 Hz, 10-H). M+ 250.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([N:8]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[CH2:11][O:10][C:9]2=[O:18])[CH2:4][CH2:3]1.Cl[C:20]1[N:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[C:23]([C:30]([OH:32])=[O:31])=[CH:22][N:21]=1>>[O:18]=[C:9]1[O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:8]1[CH:5]1[CH2:4][CH2:3][N:2]([C:20]2[N:25]=[C:24]([C:26]([F:28])([F:29])[F:27])[C:23]([C:30]([OH:32])=[O:31])=[CH:22][N:21]=2)[CH2:7][CH2:6]1
Reactant: O=C1OCc2ccccc2N1C1CCNCC1
Reactant: O=C(O)c1cnc(Cl)nc1C(F)(F)F
Agent: Cl
Product: O=C(O)c1cnc(N2CCC(N3C(=O)OCc4ccccc43)CC2)nc1C(F)(F)F

Procedure:
The title compound was prepared from 1-piperidin-4-yl-1,4-dihydro-2H-3,1-benzoxazin-2-one hydrochloride (0.70 g) and 2-chloro-4-(trifluoromethyl)pyrimidine-5-carboxylic acid (1.8 g) using the method of example 115 step (ii). Yield 1.1 g.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[C:16]([Cl:35])[C:17]=1[C:18]([N:20]1[C:28]2[CH:27]=[CH:26][N:25]=[C:24]([NH:29][C:30]([CH:32]3[CH2:34][CH2:33]3)=[O:31])[C:23]=2[CH:22]=[CH:21]1)=[O:19])[C:5]([NH:7][C@H:8]([C:10]([O:12]CC)=[O:11])[CH3:9])=[O:6].[OH-].[Na+]>O1CCCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[C:16]([Cl:35])[C:17]=1[C:18]([N:20]1[C:28]2[CH:27]=[CH:26][N:25]=[C:24]([NH:29][C:30]([CH:32]3[CH2:34][CH2:33]3)=[O:31])[C:23]=2[CH:22]=[CH:21]1)=[O:19])[C:5]([NH:7][C@H:8]([C:10]([OH:12])=[O:11])[CH3:9])=[O:6]
Reactant: CCOC(=O)[C@H](C)NC(=O)c1cc(Cl)c(C(=O)n2ccc3c(NC(=O)C4CC4)nccc32)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: C[C@H](NC(=O)c1cc(Cl)c(C(=O)n2ccc3c(NC(=O)C4CC4)nccc32)c(Cl)c1)C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.5 %

Procedure:
A mixture of ethyl N-[3,5-dichloro-4-({4-[(cyclopropylcarbonyl)amino]-1H-pyrrolo[3,2-c]pyridin-1-yl}carbonyl)benzoyl]alaninate (20 mg, 0.038 mmol) in tetrahydrofuran and water (1:1, 1 mL) was treated with sodium hydroxide (1.5 mg) and stirred at room temperature for about 1 hour. Tetrahydrofuran was removed under vaccuo and the residue was acidified with hydrochloric acid solution (1N, upto pH 2). The solid was filtered and dried to get pure N-[3,5-dichloro-4-({4-[(cyclopropylcarbonyl)amino]-1H-pyrrolo[3,2-c]pyridin-1-yl}carbonyl)benzoyl]alanine (12 mg, 66%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[C:5](=O)[NH:6][NH:7][C:8]([N:10]1[CH2:15][CH2:14][N:13]([C:16](=[O:27])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[C:23]([F:26])([F:25])[F:24])[CH2:12][CH2:11]1)=[S:9])[CH3:2].CS(O)(=O)=O>C1(C)C=CC=CC=1.CN1CCCC1=O>[CH2:1]([O:3][C:4]([C:5]1[S:9][C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16](=[O:27])[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]([F:26])([F:25])[F:24])[CH2:12][CH2:11]2)=[N:7][N:6]=1)=[O:29])[CH3:2]
Reactant: CCOC(=O)C(=O)NNC(=S)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1
Agent: CS(=O)(=O)O
Solvent: Cc1ccccc1
Solvent: CN1CCCC1=O
Product: CCOC(=O)c1nnc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)s1
Yield: 68 %

Procedure:
Oxo-{N′-[4-(2-trifluoromethylbenzoyl)piperazine-1-carbothioyl]hydrazino}-acetic acid ethyl ester (2.88 g, 6.56 mmol) was dissolved in a mixture of 50 mL of toluene and 10 mL of N-methyl-2-pyrrolidone. Methanesulfonic acid (0.723 mL, 11.15 mmol) was then added dropwise over 5 minutes to the stirred solution. The mixture was refluxed for 1.5 hours, then evaporated to 10 mL, and then 20 mL of water was added. The pH of the solution was adjusted to 8 by saturated NaHCO3. The mixture was extracted with ethyl acetate (2×50 mL). The combined organic phase was washed with brine, dried over anhydrous Na2SO4, and concentrated. The residue was purified by flash chromatography to give the title compound in 68% yield (1.84 g). 1H NMR (500 MHz, CDCl3) δ 7.74 (d, J=7.8 Hz, 1H), 7.64 (dd, J=7.5, 7.5 Hz, 1H), 7.60 (dd, J=7.5, 7.5 Hz, 1H), 7.35 (d, J=7.3 Hz, 1H), 4.44 (q, J=7.1 Hz, 2H), 4.06-4.11 (m, 1H), 3.86-3.91 (m, 1H), 3.56-3.77 (m, 4H), 3.35 (t, J=5.4 Hz, 2H), 1.41 (t, J=7.1 Hz, 3H). MS (ES+) m/z 415.5 (M+1).
Reaction SMILES: C[O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][C@H:7]([N:13]([CH2:21][CH2:22][CH3:23])[CH2:14][CH2:15][C:16]1[S:17][CH:18]=[CH:19][CH:20]=1)[CH2:8]2.B(Br)(Br)Br.C(=O)(O)[O-].[Na+]>ClCCl>[CH3:23][CH2:22][CH2:21][N:13]([C@@H:7]1[CH2:8][C:9]2[CH:10]=[CH:11][CH:12]=[C:3]([OH:2])[C:4]=2[CH2:5][CH2:6]1)[CH2:14][CH2:15][C:16]1[S:17][CH:18]=[CH:19][CH:20]=1
Reactant: CCCN(CCc1cccs1)[C@H]1CCc2c(cccc2OC)C1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCCN(CCc1cccs1)[C@H]1CCc2c(O)cccc2C1
Temperature: 0 °C
Yield: 100 %

Procedure:
To a three-necked flask, the (S)-5-methoxy-N-propyl-N-(2′-(thien-2-yl-)ethyl)-tetralin-2-amine (20 g, 61 mmol) prepared above in Example 6 and DCM (300 mL) were added at room temperature, and then cooled to about 0° C. Thereafter, a solution of boron tribromide (73.2 mmol) in dichloromethane (concentration: 1 g/3.8 mL) was added dropwise to the reaction liquid. After the addition, the temperature was warmed up to room temperature to react. After the reaction being complete, the mixture was neutralized by the addition of saturated aqueous sodium bicarbonate solution. The organic phase was separated out and concentrated to give crude rotigotine free base. Yield: 100%, Purity: 91%.
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:10]([C:14]1[CH:19]=[CH:18][C:17]([C:20]2[O:21][CH:22]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH:23]([OH:26])[CH2:24][N:25]=2)=[CH:16][CH:15]=1)([CH3:13])([CH3:12])[CH3:11]>O1CCCC1>[C:10]([C:14]1[CH:15]=[CH:16][C:17]([C:20]2[O:21][CH:22]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH:23]([O:26][C:8](=[O:9])[NH:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:24][N:25]=2)=[CH:18][CH:19]=1)([CH3:13])([CH3:11])[CH3:12]
Reactant: O=C=Nc1ccccc1
Reactant: CC(C)(C)c1ccc(C2=NCC(O)C(c3ccccc3)O2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(C2=NCC(OC(=O)Nc3ccccc3)C(c3ccccc3)O2)cc1
Temperature: 50 °C
Yield: 31.6 %

Procedure:
Phenyl isocyanate (2 g) is added at a temperature in the region of 20° C. to a solution, maintained under an argon atmosphere, of (5RS, 6SR)-2-(4-tert-butylphenyl)-6-phenyl-5,6-dihydro-4H-1,3-oxazin-5-ol (3.2 g) in anhydrous tetrahydrofuran (35 cc). The solution obtained is heated to 50° C. for 5 hours and then concentrated to dryness under reduced pressure (2.7 kPa). The solid obtained is purified by chromatography on silica (0.063-0.2 mm; 200 g) contained in a column 3.5 cm in diameter, collecting 20-cc fractions. Fractions 22 to 29, eluted with a mixture of cyclohexane and ethyl acetate (7:3 by volume), are concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. The solid obtained is again purified by chromatography on silica (0.063-0.2 mm; 200 g) contained in a column 2.5 cm in diameter, collecting 10-cc fractions. Fractions 19 to 25, eluted with a mixture of dichloromethane and methanol (98:2 by volume), are concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. After recrystallization in ethyl acetate, (5RS, 6SR)-2-(4-tert-butylphenyl)-6-phenyl-5-phenylcarbamoyloxy-5,6-dihydro-4H-1,3-oxazine (1.4 g), m.p. 80° C., is obtained.