Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:25])[CH2:5][N:6]1[C:12](=[O:13])[CH:11]([N:14]2[C:22](=[O:23])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]2=[O:24])[CH2:10][CH2:9][S:8][CH2:7]1)C.[Li+].[OH-]>C1COCC1>[O:23]=[C:22]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15](=[O:24])[N:14]1[CH:11]1[CH2:10][CH2:9][S:8][CH2:7][N:6]([CH2:5][C:4]([OH:25])=[O:3])[C:12]1=[O:13]
Reactant: CCOC(=O)CN1CSCCC(N2C(=O)c3ccccc3C2=O)C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)CN1CSCCC(N2C(=O)c3ccccc3C2=O)C1=O
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of ethyl[5-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-4-oxo-1,3-thiazepan-3-yl]acetate (181 mg, 0.50 mmol) [Karanewsky U.S. Pat. No. 4,460,579] in THF (2 mL) is added 1.0 N aqueous LiOH (0.55 mL, 0.55 mmol) and the reaction mixture is stirred at ambient temperature for 6 h. The reaction mixture is purified directly by HPLC using a reversed phase C18 column and eluting with a gradient of H2O:CH3CN:CF3CO2H—90:10:0.1 to 5:95:0.1. The pure, product-containing fractions are combined and concentrated in vacuo to provide the title compound.
Reaction SMILES: C([O-])(=O)C.[Na+].BrN1C(C)(C)C(=O)N(Br)C1=O.C([O:20][C:21]1[CH2:38][CH2:37][C@H:36]2[C:23](=[CH:24][CH2:25][C@@H:26]3[C@@H:35]2[C@H:34]([O:39][C:40](=[O:42])[CH3:41])[CH2:33][C@@:31]2([CH3:32])[C@H:27]3[CH2:28][CH2:29][C:30]2=[O:43])[CH:22]=1)(=O)C.S([O-])([O-])=O.[Na+].[Na+].[Br-].[Li+].C(=O)([O-])[O-].[Li+].[Li+]>CN1CCCC1=O.C(Cl)Cl>[C:40]([O:39][C@@H:34]1[CH2:33][C@@:31]2([CH3:32])[C@@H:27]([CH2:28][CH2:29][C:30]2=[O:43])[C@H:26]2[C@H:35]1[C@@H:36]1[C:23]([CH:24]=[CH:25]2)=[CH:22][C:21](=[O:20])[CH2:38][CH2:37]1)(=[O:42])[CH3:41]
Reactant: CC(=O)OC1=CC2=CC[C@@H]3[C@H]([C@H](OC(C)=O)C[C@]4(C)C(=O)CC[C@@H]34)[C@H]2CC1
Agent: CC(=O)[O-]
Agent: CC1(C)C(=O)N(Br)C(=O)N1Br
Agent: O=C([O-])[O-]
Solvent: CN1CCCC1=O
Solvent: ClCCl
Product: CC(=O)O[C@@H]1C[C@]2(C)C(=O)CC[C@H]2[C@@H]2C=CC3=CC(=O)CC[C@@H]3[C@H]21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 59.7 %

Procedure:
48 ml of a 10% aqueous sodium acetate solution and, in portions, 22.3 g of 1,3-dibromo-5,5-dimethylhydantoin are added to 57 g of 3,11α-diacetoxy-estra-3,5-dien-17-one in 470 ml of N-methyl-2-pyrrolidinone while being cooled with ice. After 30 minutes, 16.7 g of sodium sulfite is added, it is stirred for 15 minutes at 0° C., then mixed with 20 g of lithium bromide and 16 g of lithium carbonate and stirred at 100° C. After 2 hours, the reaction mixture is added to ice/water. The precipitated product is suctioned off, dissolved in methylene chloride, washed neutral with water and dried. The crude product is recrystallized from 200 ml of ethyl acetate. 30 g of 11α-acetoxy-estra-4,6-diene-3,17-dione with a melting point of 246-248° C. is obtained.
Reaction SMILES: [CH2:1]([C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[CH:17]=[C:16]([O:21]C)[C:15]([S:23][CH3:24])=[CH:14]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].B(Br)(Br)Br>ClCCl>[CH2:1]([C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[CH:17]=[C:16]([OH:21])[C:15]([S:23][CH3:24])=[CH:14]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCCc1ccc2cc(OC)c(SC)cc2c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCCCCCCCCCc1ccc2cc(O)c(SC)cc2c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 67.6 %

Procedure:
A dichloromethane (50 ml) solution of 6-decyl-3-methylthio-2-methoxynaphthalene (compound (4)-64) (28 g, 81 mmol) was added to a dichloromethane solution of BBr3 (ca.2 M 70 ml, 140 mmol) at −78° C. The solution was stirred at room temperature for 12 hours. Ice (approximately 20 g) was added to the mixture. The reaction solution was extracted with dichloromethane (20 ml×3). The organic layers obtained by repeating the extraction three times were collected, washed with saturated saline water (30 ml×3), dried with MgSO4, and condensed. The residue was refined by column chromatography (silica gel, developed at dichloromethane:hexane=1:1), and recrystallized with hexane to obtain 6-decyl-3-methylthio-2-hydroxynaphthalene (18.1 g, 72%) as white crystals.
Reaction SMILES: [CH2:1]([S:3]([C:5]1[CH:6]=[C:7]([C:21]2[N:26]=[C:25]([CH3:27])[N:24]=[C:23]([N:28]([CH2:38][C:39]3[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=3)[CH2:29][C:30]3[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=3)[N:22]=2)[C:8]([NH:11][C:12]2[CH:13]=[N:14][C:15]([O:19][CH3:20])=[C:16]([F:18])[CH:17]=2)=[N:9][CH:10]=1)=[O:4])[CH3:2].O.S(O)([O-])(=O)=[O:49].S(O)(OO)(=O)=O.[K+]>CO.O1CCOCC1>[CH2:1]([S:3]([C:5]1[CH:6]=[C:7]([C:21]2[N:26]=[C:25]([CH3:27])[N:24]=[C:23]([N:28]([CH2:29][C:30]3[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=3)[CH2:38][C:39]3[CH:40]=[CH:41][C:42]([O:45][CH3:46])=[CH:43][CH:44]=3)[N:22]=2)[C:8]([NH:11][C:12]2[CH:13]=[N:14][C:15]([O:19][CH3:20])=[C:16]([F:18])[CH:17]=2)=[N:9][CH:10]=1)(=[O:49])=[O:4])[CH3:2]
Reactant: CCS(=O)c1cnc(Nc2cnc(OC)c(F)c2)c(-c2nc(C)nc(N(Cc3ccc(OC)cc3)Cc3ccc(OC)cc3)n2)c1
Reactant: O=S(=O)([O-])O
Agent: O=S(=O)(O)OO
Agent: [K+]
Solvent: CO
Solvent: C1COCCO1
Solvent: O
Product: CCS(=O)(=O)c1cnc(Nc2cnc(OC)c(F)c2)c(-c2nc(C)nc(N(Cc3ccc(OC)cc3)Cc3ccc(OC)cc3)n2)c1
Reaction time: 8 h
Yield: 71.4 %

Procedure:
To a slurry of 4-(5-(ethylsulfinyl)-2-(5-fluoro-6-methoxypyridin-3-ylamino)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (0.090 g, 0.140 mmol) in 2 mL MeOH, 2 mL dioxane, and 1 mL water was added potassium peroxymonosulfate sulfate (0.172 g, 0.280 mmol). The bright yellow slurry was stirred rapidly overnight. The reaction was partitioned between satd NaHCO3 and DCM. The aqueous layer was extracted with DCM 3 times, and the combined organics were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The material was treated with DCM and purified by silica gel chromatography (25 g column) using 20 to 100% EtOAc/hexane. The product-containing fractions were concentrated to afford 4-(5-(ethylsulfonyl)-2-(5-fluoro-6-methoxypyridin-3-ylamino)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (0.066 g, 0.100 mmol, 71.6% yield) as a yellow solid. m/z (ESI, +ve ion) 660 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 11.91 (s, 1H), 8.80 (d, J=2.7 Hz, 1H), 8.43 (d, J=2.7 Hz, 1H), 8.15-8.33 (m, 2H), 7.14-7.25 (m, 4H), 6.80-6.93 (m, 4H), 4.87 (s, 2H), 4.83 (s, 2H), 4.02 (s, 3H), 3.82 (s, 3H), 3.79 (s, 3H), 3.07-3.22 (m, 1H), 2.82-2.94 (m, 1H), 2.62 (s, 3H), 1.28 (t, J=7.4 Hz, 3H).
Reaction SMILES: [Br:1][C:2]1[C:10]2[S:9][C:8]([NH:11][C@@H:12]3[CH2:17][CH2:16][CH2:15][CH2:14][C@H:13]3[OH:18])=[N:7][C:6]=2[CH:5]=[CH:4][C:3]=1[OH:19].Cl[C:21]1[CH:26]=[CH:25][N:24]=[C:23]([C:27]([NH:29][CH3:30])=[O:28])[CH:22]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN1C(=O)CCC1>[Br:1][C:2]1[C:10]2[S:9][C:8]([NH:11][C@@H:12]3[CH2:17][CH2:16][CH2:15][CH2:14][C@H:13]3[OH:18])=[N:7][C:6]=2[CH:5]=[CH:4][C:3]=1[O:19][C:21]1[CH:26]=[CH:25][N:24]=[C:23]([C:27]([NH:29][CH3:30])=[O:28])[CH:22]=1
Reactant: CNC(=O)c1cc(Cl)ccn1
Reactant: Oc1ccc2nc(N[C@@H]3CCCC[C@H]3O)sc2c1Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: CNC(=O)c1cc(Oc2ccc3nc(N[C@@H]4CCCC[C@H]4O)sc3c2Br)ccn1
Temperature: 80 °C
Reaction time: 12 h

Procedure:
To the solution of 7-bromo-2-((1R,2R)-2-hydroxycyclohexylamino)benzo[d]thiazol-6-ol (50 mg, 0.145 mmol, 1.0 eq) in 1 mL of NMP was added 4-chloro-N-methylpicolinamide (29 mg, 0.174 mmol, 1.2 eq) and cesium carbonate (165 mg, 0.507 mmol, 3.5 eq) at room temperature. The reaction mixture was stirred at 80° C. for ca. 12 hours, thereafter the mixture was purified on the reverse phase HPLC. LC/MS (m/z) [479.0] (MH+)
Reaction SMILES: [H-].[Na+].[CH3:3][NH:4][C:5](=[O:14])[O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.CS(O[CH2:20][C@H:21]1[CH2:26][O:25][CH2:24][CH2:23][O:22]1)(=O)=O>CN(C)C=O.C(OCC)C>[CH2:7]([O:6][C:5](=[O:14])[N:4]([CH2:20][C@H:21]1[CH2:26][O:25][CH2:24][CH2:23][O:22]1)[CH3:3])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CS(=O)(=O)OC[C@H]1COCCO1
Reactant: CNC(=O)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CN(C[C@H]1COCCO1)C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
Sodium hydride (29 mg, 0.74 mmol) was suspended in 2 mL of N,N-dimethylformamide (DMF) and cooled to 0° C. A solution of benzyl methylcarbamate (81 mg, 0.49 mmol) in 2 mL of DMF was added via syringe. After 20 minutes, a solution of (2R)-1,4-dioxan-2-ylmethyl methanesulfonate (191 mg, 0.97 mmol) in 2 mL of DMF was added by syringe and the mixture was heated to 70° C. After 2 h the mixture was cooled to ambient temperature, then diluted in diethyl ether, washed with water and brine, then dried over sodium sulfate and concentrated. The residue was purified by flash column chromatography (silica, ethylacetate/hexanes) to afford the title compound. LRMS (APCI) calc'd for (C14H20NO4) [M+H]+, 266.1; found, 266.2.
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH2:7][C@H:8]([NH:11][C:12]1[CH:17]=[CH:16][N:15]=[C:14](O)[C:13]=1[N+:19]([O-:21])=[O:20])[CH2:9][CH3:10].CCN(C(C)C)C(C)C.Cl.P(Cl)(Cl)([Cl:34])=O.[Cl-].[Na+]>C1(C)C=CC=CC=1>[Cl:34][C:14]1[C:13]([N+:19]([O-:21])=[O:20])=[C:12]([NH:11][C@@H:8]([CH2:7][C:3]2[S:4][CH:5]=[CH:6][C:2]=2[Cl:1])[CH2:9][CH3:10])[CH:17]=[CH:16][N:15]=1
Reactant: CC[C@H](Cc1sccc1Cl)Nc1ccnc(O)c1[N+](=O)[O-]
Reactant: O=P(Cl)(Cl)Cl
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: CC[C@H](Cc1sccc1Cl)Nc1ccnc(Cl)c1[N+](=O)[O-]
Temperature: 60 °C

Procedure:
A toluene solution of (R)-N-[1-[(3-chloro-2-thienyl)methyl]propyl]-2-hydroxy-3-nitro-4-pyridinamine (Compound IV) (0.1 mole in 100 mL of toluene) containing 2 equivalents of DIPEA hydrochloride is heated to 60° C. and 20.6 grams of phosphorus oxychloride is added over 10 minutes with stirring. The reaction is stirred at 60° C. until complete (3 hours). After cooling to 0° C., 245 grams of 2N sodium chloride is added at such a rate so as to maintain the reaction temperature below 10° C. The biphasic mixture is stirred 1-2 hours at 0° C. before it is allowed to warm to room temperature overnight. The bottom aqueous layer is separated from the organic layer. The organic layer is concentrated in vacuo and the residue purified by flash chromatography eluting with 25.75 ethyl acetate:heptane to give Compound V. MS (EI) m/z 345 (10%). 1HNMR (500 Mhz, CDCl3 /CD3OD)δ1.0 (2H, t); 1.5-1.8 (2H, m); 2.9-3.2 (2H, m); 3.8 (1H, m); 6.5 (1H, bd); 6.6 (1H, d); 7.15 (1H, d); 7.9 (1H, d).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[C:8]([CH3:11])[CH:7]=[C:6]([CH3:12])[CH:5]=2.BrC(C)C(OCC)OCC.CC1C=C(C=C(C)C=1)N>>[CH3:1][CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][C:6]([CH3:12])=[CH:7][C:8]=2[CH3:11])[NH:3]1
Reactant: Cc1cc(C)c2cc(C)[nH]c2c1
Agent: CCOC(OCC)C(C)Br
Agent: Cc1cc(C)cc(N)c1
Product: Cc1cc(C)c2c(c1)NC(C)C2

Procedure:
Using a similar procedure to that described in Example 16, 1-acetyl-2,4,6-trimethyl-5-(nitromethylsulphonyl)indoline was obtained in 22% yield as a cream solid, m.p. 175° C.; microanalysis, found: C,51.7; H,5.3; N,8.5%; C14H18N2O5S requires: C,51.5; H,5.6; N,8.6%; NMR (d6 -DMSO): 1.2(3H,d), 2.25(3H,s), 2.4(3H,s), 2.6(3H,s), 2.6-2.8(1H,d), 3.2-3.4(1H,dd), 4.6-4.8(1H,m), 6.4(2H,s), 7.7-8.0(1H,br). The original starting material 2,4,6-trimethylindole, was itself obtained as a yellow oily solid, NMR: 2.39(3H,s), 2.40(3H,s), 2.46(3H,s), 6.15(1H,s), 6.7(1H,s), 6.9(1H,s), 7.6(1H,br) using a similar procedure to that described in J. Org. Chem., 1981, 46(4), 781, starting from 2-bromo-1,1-diethoxypropane and 3,5-dimethylaniline. The intermediate 2,4,6-trimethylindoline was obtained by a similar procedure to that described in connection with 4,6-dimethylindoline in Example 17. It was converted to the corresponding 1-acetyl derivative, m.p. 75° C. without characterisation.
Reaction SMILES: NC(N)=S.F[C:6]1[CH:7]=[C:8]([NH:13][C:14]([NH2:16])=[S:15])[CH:9]=[C:10](F)[CH:11]=1.FC1C=C(F)C2SC(N)=NC=2C=1>>[NH2:16][C:14]1[S:15][C:9]2[CH:10]=[CH:11][CH:6]=[CH:7][C:8]=2[N:13]=1
Reactant: NC(=S)Nc1cc(F)cc(F)c1
Agent: NC(N)=S
Agent: Nc1nc2cc(F)cc(F)c2s1
Product: Nc1nc2ccccc2s1

Procedure:
In certain cases the requisite 2-amino-1,3-benzothiazole was prepared from the corresponding thiourea as described above for the preparation of N-(3,5-difluorophenyl) thiourea and 5,7-difluoro-1,3-benzothiazol-2-amine.
Reaction SMILES: CC(C)([O-])C.[Na+].C1COCC1.CN(C=O)C.[F:17][C:18]([F:22])([F:21])[CH2:19][OH:20].[Br:23][C:24]1[CH:29]=[CH:28][C:27](F)=[CH:26][C:25]=1[C:31]([F:34])([F:33])[F:32]>CC(OC)(C)C>[Br:23][C:24]1[CH:29]=[CH:28][C:27]([O:20][CH2:19][C:18]([F:22])([F:21])[F:17])=[CH:26][C:25]=1[C:31]([F:32])([F:33])[F:34]
Reactant: Fc1ccc(Br)c(C(F)(F)F)c1
Reactant: OCC(F)(F)F
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: COC(C)(C)C
Solvent: C1CCOC1
Product: FC(F)(F)COc1ccc(Br)c(C(F)(F)F)c1
Temperature: 80 °C
Reaction time: 7 h
Yield: 99.1 %

Procedure:
To a 2.4 M solution of sodium-tert-butoxide in THF (156.3 mL, 375 mmol, Chemetall) was added DMF (38.5 mL, 500 mmol) and then 2,2,2-trifluoroethanol (41.27 g, 413 mmol). After the addition of 2-bromo-5-fluorobenzotrifluoride (60.8 g, 250 mmol) the reaction mixture was heated to reflux and stirred at ˜80° C. for 7 h. After cooling to 25° C., TBME (800 mL) was added and the reaction mixture was washed with 1M HCl (400 mL), 5% NaHCO3 (400 mL) and 10% brine (400 mL). The organic layer was dried (Na2SO4), filtered and evaporated to dryness (60° C./≧5 mbar), affording the crude title product (80.0 g, 99.1%) as a yellow oil which was used without purification in the next step 1H NMR (CDCl3, 400 MHz) δ 4.38 (q, J=7.9 Hz, 2H), 6.98 (dd, J1=8.6 Hz, J2=2.7 Hz, 1H), 7.28 (d, J=2.7 Hz, 1H), 7.65 (d, J=8.9 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]([NH:12][C:13]2[C:14]3[CH:39]=[CH:38][N:37](S(C4C=CC(C)=CC=4)(=O)=O)[C:15]=3[N:16]=[C:17]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([N:26]4[CH2:31][CH2:30][N:29]([CH:32]([CH3:34])[CH3:33])[CH2:28][CH2:27]4)=[CH:22][C:21]=3[O:35][CH3:36])[N:18]=2)[C:3]=1[C:4]([NH2:6])=[O:5].[OH-].[K+]>O1CCOCC1.CC(O)C.C(OCC)(=O)C>[F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]([NH:12][C:13]2[N:18]=[C:17]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([N:26]4[CH2:27][CH2:28][N:29]([CH:32]([CH3:33])[CH3:34])[CH2:30][CH2:31]4)=[CH:22][C:21]=3[O:35][CH3:36])[NH:16][C:15]3=[N:37][CH:38]=[CH:39][C:14]=23)[C:3]=1[C:4]([NH2:6])=[O:5]
Reactant: COc1cc(N2CCN(C(C)C)CC2)ccc1Nc1nc(Nc2cc(F)cc(F)c2C(N)=O)c2ccn(S(=O)(=O)c3ccc(C)cc3)c2n1
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COc1cc(N2CCN(C(C)C)CC2)ccc1Nc1nc(Nc2cc(F)cc(F)c2C(N)=O)c2ccnc-2[nH]1
Yield: 85.9 %

Procedure:
To a solution of 2,4-difluoro-6-({2-{[4-[4-(1-methylethyl)-1-piperazinyl]-2-(methyloxy)phenyl]amino}-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)benzamide (1.5 g, 2.17 mmols) in 1,4-dioxane (100 ml) and 2-propanol (2 ml) was added 1.0M potassium hydroxide (21 ml, 21.7 mmol) and the reaction was heated at 80C overnight. The resulting solution was diluted with ethyl acetate, washed with water, adsorbed onto silica gel and purified by LC (DCM to 10% MeOH/DCM) to afford 2,4-difluoro-6-[(2-{[4-[4-(1-methylethyl)-1-piperazinyl]-2-(methyloxy)phenyl]amino}-1H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]benzamide (1.0 g, 86%). ESIMS (M+H)+=537. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.00 (d, J=6.60 Hz, 6H) 2.54-2.60 (m, 4H) 2.64-2.72 (m, 1H) 3.05-3.11(m, 4H) 3.78 (s, 3H) 6.18 (dd, J=3.48, 2.02 Hz, 1H) 6.45 (dd, J=8.62, 2.38 Hz, 1H) 6.61 (d, J=2.57 Hz, 1H) 6.86-6.92 (m, 1H) 6.96 (dd, J=3.67, 2.20 Hz, 1H) 7.59 (s, 1H) 7.68 (d, J=8.80 Hz, 1H) 8.01 (br. s., 1H) 8.16 (s, 1H) 8.53-8.59 (m, 1H) 11.08 (s, 1H) 11.32 (s, 1H).
Reaction SMILES: [ClH:1].C[O:3][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH2:6][CH2:7][C@H:8]([N:14]([CH2:22][CH2:23][CH3:24])[CH2:15][CH2:16][C:17]1[S:18][CH:19]=[CH:20][CH:21]=1)[CH2:9]2.B(Br)(Br)Br.C(=O)(O)[O-].[Na+]>ClCCl>[CH3:24][CH2:23][CH2:22][N:14]([C@@H:8]1[CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[C:4]([OH:3])[C:5]=2[CH2:6][CH2:7]1)[CH2:15][CH2:16][C:17]1[S:18][CH:19]=[CH:20][CH:21]=1.[ClH:1]
Reactant: CCCN(CCc1cccs1)[C@H]1CCc2c(cccc2OC)C1
Agent: BrB(Br)Br
Agent: Cl
Agent: O=C([O-])O
Solvent: ClCCl
Product: CCCN(CCc1cccs1)[C@H]1CCc2c(O)cccc2C1
Temperature: 25 °C
Yield: 79.5 %

Procedure:
To a 10 L three-necked flask, the (S)-5-methoxy-N-propyl-N-(2′-(thien-2-yl-)ethyl)-tetralin-2-amine hydrochloride (295 g, 0.9 mol) prepared above in Example 7 and 5.5 kg DCM were added at room temperature, and then cooled to a temperature of 0° C.-5° C. Thereafter, a 1 M solution of boron tribromide (1.08 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 perform the reaction. After the reaction being complete, the mixture was neutralized by the addition of saturated aqueous sodium bicarbonate solution, and left alone and partitioned. The organic phase was adjusted to be acidic by the addition of an aqueous hydrochloride solution or an organic solution of hydrogen chloride or by the introduction of hydrochloride gas. The mixture was filtered, and the filter cake was washed with DCM and dried overnight to give crude rotigotine hydrochloride. Yield: 79.5%, Purity: 98.2%.
Reaction SMILES: C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.O1CCCCC1[O:24][CH2:25][C:26]#[C:27][CH2:28][O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C(O)C>[O:29]([CH2:28][C:27]#[C:26][CH2:25][OH:24])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: C(#CCOC1CCCCO1)COc1ccccc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCO
Product: OCC#CCOc1ccccc1
Temperature: 55 °C
Reaction time: 2 h

Procedure:
1.02 g (0.004 mol) of pyridinium p-toluenesulfonate was added to a solution of 2 g of 4-phenoxy-but-2-yn-1-ol tetrahydropyranyl ether in 20 ml of 96% ethanol. The reaction mixture was stirred for 2 hours at 55° C.; the solvent was then removed in vacuo and the residue diluted with 20 ml of water and extracted with methylene chloride (3×20 ml). The combined extracts were dried over sodium sulfate and the solvent evaporated in vacuo. The residue was purified by column chromatography on 30 g of silica gel, using hexane-ethyl acetate (90:10) as eluant, to yield 4-phenoxy-but-2-yn-1-ol, as an oil.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([N:9](S(C2C=CC(C)=CC=2)(=O)=O)[CH2:10][CH2:11][CH2:12][N:13](C(OC(C)(C)C)=O)[CH2:14][CH2:15][CH2:16][N:17]([C:28]2[CH:33]=[CH:32][C:31]([S:34][CH3:35])=[CH:30][CH:29]=2)S(C2C=CC(C)=CC=2)(=O)=O)=[CH:5][CH:4]=1>Br>[CH3:35][S:34][C:31]1[CH:30]=[CH:29][C:28]([NH:17][CH2:16][CH2:15][CH2:14][NH:13][CH2:12][CH2:11][CH2:10][NH:9][C:6]2[CH:7]=[CH:8][C:3]([S:2][CH3:1])=[CH:4][CH:5]=2)=[CH:33][CH:32]=1
Reactant: CSc1ccc(N(CCCN(CCCN(c2ccc(SC)cc2)S(=O)(=O)c2ccc(C)cc2)C(=O)OC(C)(C)C)S(=O)(=O)c2ccc(C)cc2)cc1
Agent: Br
Product: CSc1ccc(NCCCNCCCNc2ccc(SC)cc2)cc1

Procedure:
Dissolve 1,9-bis(4-methylmercaptophenyl)-1,9-bis[(4-methylphenyl)sulfonyl]-5-(t-butyloxycarbonyl)-1,5,9-triazanonane (783 mg, 1 mmol) in 48% hydrobromic acid (mL). Stir for several hours and evaporate the solvent in vacuo. Dissolve the residue in water and neutralize with saturated sodium hydrogen carbonate and extract with ethyl acetate. Dry (MgSO4) and evaporate the solvent in vacuo. Purify by silica gel chromatography to give the title compound.
Reaction SMILES: [CH:1]12B[CH:5]([CH2:6][CH2:7][CH2:8]1)[CH2:4][CH2:3][CH2:2]2.[CH2:10]([N:17]1[CH2:22][CH2:21][N:20]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:19][C@@H:18]1[CH:30]=[CH2:31])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrC=CC1C=CC=CC=1.[OH-].[Na+]>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>[CH2:10]([N:17]1[CH2:22][CH2:21][N:20]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:19][C@@H:18]1[CH2:30][CH2:31][CH:1]=[CH:8][C:7]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: C=C[C@H]1CN(Cc2ccccc2)CCN1Cc1ccccc1
Reactant: B1C2CCCC1CCC2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: BrC=Cc1ccccc1
Agent: [Na+]
Product: C(=Cc1ccccc1)CC[C@H]1CN(Cc2ccccc2)CCN1Cc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 27.8 %

Procedure:
Combine 9-borabicyclo[3.3.1]nonane (81.6 mL, 40.3 mmol, 0.5 M in THF) and (S)-1,4-dibenzyl-2-vinyl-piperazine (2.0 g, 6.8 mmol)and stir at ambient temperature. After 16 hours, take half volume of it, add triphenylphosphine (143 mg, 0.55 mmol), tetrakis(triphenylphosphine)palladium(0) (78.5 mg, 0.068 mmol), and beta-bromostyrene (0.93 g, 5.08 mmol). Add 3N NaOH (2.8 mL, 8.8 mmol) slowly, gas evolution will occur. Heat to reflux. After 24 hours, cool to ambient temperature. Remove the solvent under reduced pressure, dilute with diethyl ether, wash with 1N HCl, 1N NaOH, H2O and brine, dry the organic layer over Na2SO4, filter and concentrate under reduced pressure. Purification by flash chromatography on silica gel using 2N ammonia in methanol-methylene chloride (0.5%–3%) as the eluent, collect compound and pass through 10 g SCX column, using MeOH, 0.2 N NH3 in MeOH as eluent to give the title compound (750 mg, 56%): mass spectrum (electrospray): m/z=397.3 (M+1); 1H NMR (300 MHz, CDCl3): δ7.35–7.16 (m, 15H), 6.36–6.12 (m, 2H), 4.01 (d, 1H, J=13.2), 3.56–3.43 (m, 2H), 3.25 (d, 1H, J=13.4 Hz), 2.75–2.68 (m, 2H), 2.56–2.48 (m, 2H), 2.29–2.13 (m, 5H), 1.82–1.76 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[S:9]([N:12]1[C:17]2[CH:18]=[C:19]([C:22]([NH:24][C:25]3[CH:33]=[CH:32][C:28]([C:29]([OH:31])=[O:30])=[C:27]([F:34])[CH:26]=3)=[O:23])[CH:20]=[CH:21][C:16]=2[O:15][CH2:14][CH2:13]1)(=[O:11])=[O:10].F[C:36]1C=CC(F)=C[C:37]=1S(Cl)(=O)=O>>[CH2:36]([O:30][C:29](=[O:31])[C:28]1[CH:32]=[CH:33][C:25]([NH:24][C:22]([C:19]2[CH:20]=[CH:21][C:16]3[O:15][CH2:14][CH2:13][N:12]([S:9]([C:3]4[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=4[F:1])(=[O:10])=[O:11])[C:17]=3[CH:18]=2)=[O:23])=[CH:26][C:27]=1[F:34])[CH3:37]
Reactant: O=C(Nc1ccc(C(=O)O)c(F)c1)c1ccc2c(c1)N(S(=O)(=O)c1cc(F)ccc1F)CCO2
Reactant: O=S(=O)(Cl)c1cc(F)ccc1F
Product: CCOC(=O)c1ccc(NC(=O)c2ccc3c(c2)N(S(=O)(=O)c2cc(F)ccc2F)CCO3)cc1F

Procedure:
4-{[4-(2,5-Difluoro-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-2-fluoro-benzoic acid, MS (ISP): m/e=491.1 (M−H), was prepared as described for example 21, steps 1 to 8. Step 7 was performed using 2,5-difluoro-benzenesulfonyl chloride and yielded 4-{[4-(2,5-difluoro-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-2-fluoro-benzoic acid ethyl ester, which was hydrolyzed in step 8.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[O:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1.[CH3:14][C:15]([S@:18]([NH2:20])=[O:19])([CH3:17])[CH3:16]>ClCCCl.S([O-])([O-])(=O)=O.[Cu+2]>[CH3:14][C:15]([S@:18](/[N:20]=[CH:8]/[C:7]1[CH:10]=[CH:11][C:4]([O:3][C:2]([F:13])([F:12])[F:1])=[CH:5][CH:6]=1)=[O:19])([CH3:17])[CH3:16]
Reactant: CC(C)(C)[S@](N)=O
Reactant: O=Cc1ccc(OC(F)(F)F)cc1
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: ClCCCl
Product: CC(C)(C)[S@@](=O)/N=C/c1ccc(OC(F)(F)F)cc1
Temperature: 55 °C
Yield: 102.3 %

Procedure:
To a cloudy solution of 4-(trifluoromethoxy)benzaldehyde (5 g, 26.3 mmol) and (R)-2-methylpropane-2-sulfinamide (3.51 g, 28.9 mmol) in DCE (52 mL), under N2, was added copper (II) sulfate (6.30 g, 39.4 mmol), and the resulting mixture heated in a preheated oil bath at 55° C. for 22 hours. The reaction mixture was filtered through a pad of celite, eluting with DCM. The filtrate was concentrated to afford a viscous yellow oil of (R,E)-2-methyl-N-(4-(trifluoromethoxy)benzylidene)propane-2-sulfinamide (7.9 g, 26.9 mmol, 102% yield). Material was taken onto next step without further purification. 1H NMR (400 MHz, CDCl3) δ ppm 1.27 (s, 9H) 7.32 (d, J=8.07 Hz, 2H) 7.91 (d, J=8.75 Hz, 2H) 8.59 (s, 1H). LCMS m/z 294.1 (M+H)+, Rt 1.01 min.