Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH2:2]([O:9][C:10](=[O:22])[CH2:11][NH:12][CH:13]1[CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:29][CH2:30][C:31](Cl)=[O:32]>C(OCC)(=O)C>[CH2:2]([O:9][C:10](=[O:22])[CH2:11][N:12]([C:31](=[O:32])[CH2:30][Cl:29])[CH:13]1[CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14]1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=C(CNC1Cc2ccccc2C1)OCc1ccccc1
Reactant: O=C(Cl)CCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: O=C(CN(C(=O)CCl)C1Cc2ccccc2C1)OCc1ccccc1

Procedure:
N-(Indan-2-yl)glycine benzyl ester hydrochloride (6 g) is added to a mixture of 300 ml of ethyl acetate and 200 ml of 5% aqueous potassium carbonate, followed by vigorous stirring. To the resulting solution is added dropwise 6 ml of chloroacetyl chloride over 30 minutes with ice cooling. Thereafter, stirring is continued for an hour. The ethyl acetate layer is then separated, washed with water and dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. Addition of ether to the residue gives 6 g of N-chloroacetyl-N-(indan-2-yl)glycine benzyl ester as colorless scales melting at 99.5°-100.5° C.
Reaction SMILES: C(OC(=O)[N:7]([S:13]([C:16]1[C:21]([F:22])=[CH:20][C:19]([O:23][C@H:24]2[CH2:29][CH2:28][CH2:27][CH2:26][C@@H:25]2[C:30]2[C:31]([N+:41]([O-:43])=[O:42])=[N:32][N:33](C3CCCCO3)[CH:34]=2)=[CH:18][C:17]=1[F:44])(=[O:15])=[O:14])[C:8]1[N:9]=[CH:10][S:11][CH:12]=1)(C)(C)C.FC(F)(F)C(O)=O.ClCCl>CO>[F:22][C:21]1[CH:20]=[C:19]([O:23][C@H:24]2[CH2:29][CH2:28][CH2:27][CH2:26][C@@H:25]2[C:30]2[C:31]([N+:41]([O-:43])=[O:42])=[N:32][NH:33][CH:34]=2)[CH:18]=[C:17]([F:44])[C:16]=1[S:13]([NH:7][C:8]1[N:9]=[CH:10][S:11][CH:12]=1)(=[O:15])=[O:14]
Reactant: CC(C)(C)OC(=O)N(c1cscn1)S(=O)(=O)c1c(F)cc(O[C@H]2CCCC[C@@H]2c2cn(C3CCCCO3)nc2[N+](=O)[O-])cc1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CO
Product: O=[N+]([O-])c1n[nH]cc1[C@H]1CCCC[C@@H]1Oc1cc(F)c(S(=O)(=O)Nc2cscn2)c(F)c1
Yield: 54.1 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 22c by using the tert-butyl{[2,6-difluoro-4-({(1S*,2R*)-2-[3-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl]cyclohexyl}oxy)phenyl]sulfonyl}1,3-thiazol-4-ylcarbamate (426 mg, 0.636 mmol) prepared in Example 116b, trifluoroacetic acid (1.0 mL), dichloromethane (1.0 mL) and methanol (0.1 mL), to yield the title compound (167 mg, 54%) as a colorless solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:25][C@H:26]([NH:28][C:29](=[O:45])[C:30]([C:43]#[N:44])=[CH:31][C:32]([NH:35]C(=O)OC(C)(C)C)([CH3:34])[CH3:33])[CH3:27])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][C:12]=3[F:24])[C:3]=12.[ClH:46].C(OCC)C>CO.O1CCOCC1>[ClH:46].[NH2:35][C:32]([CH3:33])([CH3:34])[CH:31]=[C:30]([C:43]#[N:44])[C:29]([NH:28][C@H:26]([CH3:27])[CH2:25][N:8]1[C:4]2=[N:5][CH:6]=[N:7][C:2]([NH2:1])=[C:3]2[C:10]([C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:13][C:12]=2[F:24])=[N:9]1)=[O:45]
Reactant: C[C@H](Cn1nc(-c2ccc(Oc3ccccc3)cc2F)c2c(N)ncnc21)NC(=O)C(C#N)=CC(C)(C)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Solvent: CO
Product: C[C@H](Cn1nc(-c2ccc(Oc3ccccc3)cc2F)c2c(N)ncnc21)NC(=O)C(C#N)=CC(C)(C)N
Reaction time: 96 h
Yield: 95 %

Procedure:
To a solution of tert-butyl N-[4-[[(1R)-2-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]-1-methyl-ethyl]amino]-3-cyano-1,1-dimethyl-4-oxo-but-2-enyl]carbamate (71 mg, 0.12 mmol) in methanol (1 mL) was added 4N HCl in Dioxane (2 mL). The solution was stirred for 4 days and then it was added dropwise to stirring ethyl ether (70 mL). The suspension was stirred for 30 minutes and then filtered and rinse with ethyl ether (10 mL) to obtain 57 mg (95%) of the title compound as an HCl salt.
Reaction SMILES: CC1(C)COB([C:8]2[CH:13]=[CH:12][C:11]([C:14]([CH3:18])([CH3:17])[CH2:15][OH:16])=[CH:10][CH:9]=2)OC1.Br[C:21]1[C:22]([F:33])=[C:23]2[C:27](=[CH:28][C:29]=1[F:30])[NH:26][CH:25]=[C:24]2[CH:31]=[O:32].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.CCO.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:33][C:22]1[C:21]([C:8]2[CH:9]=[CH:10][C:11]([C:14]([CH3:17])([CH3:18])[CH2:15][OH:16])=[CH:12][CH:13]=2)=[C:29]([F:30])[CH:28]=[C:27]2[C:23]=1[C:24]([CH:31]=[O:32])=[CH:25][NH:26]2
Reactant: CC1(C)COB(c2ccc(C(C)(C)CO)cc2)OC1
Reactant: O=Cc1c[nH]c2cc(F)c(Br)c(F)c12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: CC(C)(CO)c1ccc(-c2c(F)cc3[nH]cc(C=O)c3c2F)cc1
Temperature: 25 °C
Yield: 31.5 %

Procedure:
To a solution of 2-[4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)phenyl]-2-methylpropan-1-ol (102 mg, 0.386 mmol) and 5-bromo-4,6-difluoro-1H-indole-3-carbaldehyde (100 mg, 0.386 mmol) in toluene (6 mL) and EtOH (2 mL) was added a solution of potassium carbonate (160 mg, 1.159 mmol) in water (1.0 mL) and Pd(dppf)Cl2 (15.8 mg, 0.019 mmol) at room temperature under N2. The reaction was cooled to room temperature, and extracted with ethyl acetate (10 mL×2). The organic layers were washed with brine (10 mL), and dried over sodium sulfate and concentrated to give a crude residue, which was purified by column chromatography to give the title compound (40 mg, 32%) as a yellow solid. 1H NMR (400 MHz, CD3OD) δ 10.0 (s, 1H), 8.13 (s, 1H), 7.51 (d, 2H), 7.40 (d, 2H), 7.19 (d, 1H), 3.63 (s, 2H), 1.36 (s, 6H).
Reaction SMILES: N1C=CC=CC=1.CS(O)(=O)=O.[CH:12]1([C:18]2[C:26]3[C:25](=[O:27])[NH:24][C:23]([C:28]4[CH:33]=[CH:32][C:31](N5CCC(O)CC5)=[CH:30][C:29]=4OC)=[N:22][C:21]=3[N:20]([CH3:43])[N:19]=2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.[Br:44]C1C=CC(C(Cl)=O)=CC=1.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[Br:44][C:31]1[CH:32]=[CH:33][C:28]([C:23]2[NH:24][C:25](=[O:27])[C:26]3[C:18]([CH:12]4[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]4)=[N:19][N:20]([CH3:43])[C:21]=3[N:22]=2)=[CH:29][CH:30]=1
Reactant: COc1cc(N2CCC(O)CC2)ccc1-c1nc2c(c(C3CCCCC3)nn2C)c(=O)[nH]1
Reactant: O=C(Cl)c1ccc(Br)cc1
Agent: CS(=O)(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: Cn1nc(C2CCCCC2)c2c(=O)[nH]c(-c3ccc(Br)cc3)nc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 15.2 %

Procedure:
To a 30 ml pyridine solution of 2.2 g (10 mmol) of the compound obtained in Example 32, 2.8 g (13 mmol) of p-bromobenzoyl chloride was added, and the mixture was stirred at room temperature for 3 hours. Further, 1.0 g (4.5 mmol) of p-bromobenzoyl chloride was added, and the mixture was stirred at room temperature for 4 hours. Then, an aqueous solution of sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of sodium chloride, and then dried over anhydrous sodium sulfate, followed by distilling off the solvent under reduced pressure. To the residue, 80 ml of ethanol and 40 ml of a 1M aqueous solution of sodium hydroxide were added, and the mixture was heated under reflux for 8 hours. Then, the reaction mixture was cooled to room temperature, and acetic acid was added. Precipitated solids were collected by filtration, the solids obtained were dissolved in chloroform, and the solution was washed with sodium hydrogen carbonate, water and a saturated aqueous solution of sodium chloride in this order. After the organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was recrystallized (ethanol) to obtain 590 mg (15%) of the captioned compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([O-:13])[O+:10]=[N:9]2)=[CH:4][CH:3]=1.C(Cl)(=O)C.[CH3:18][S:19](C)=O>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([S:19][CH3:18])=[C:11]([O-:13])[O+:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: CS(C)=O
Reactant: [O-]c1cn(-c2ccc(F)cc2)n[o+]1
Solvent: CC(=O)Cl
Product: CSc1c([O-])[o+]nn1-c1ccc(F)cc1
Reaction time: 8 h

Procedure:
Using the procedure of Masada and Okutani (Tetrahedron 30, 409-414 (1974)) the crude 3-(4-fluorophenyl)-3H-1,2,3-oxadiazol-1-ium-5-olate (1.95 g, 10.82 mmol) was dissolved in anhydrous DMSO (27 mL) and cooled in ice. Acetyl chloride (2.0 g, 25.5 mmol) was added dropwise. The reaction mixture was allowed to come to room temperature. After stiffing overnight, the mixture was partitioned between ether and saturated NaHCO3 solution. The organic layer was washed several times with water, dried and evaporated to dryness to afford 3-(4-fluorophenyl)-4-(methylthio)-3H-1,2,3-oxadiazol-1-ium-5-olate.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH:8]([S:17][C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)[C:9]2[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=2[F:16])[C:5]([Cl:25])=[CH:4][N:3]=1.[N:26]1([CH2:31][CH2:32][CH2:33][NH2:34])[CH:30]=[CH:29][N:28]=[CH:27]1>O1CCOCC1>[Cl:25][C:5]1[C:6]([CH:8]([S:17][C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)[C:9]2[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=2[F:16])=[CH:7][C:2]([NH:34][CH2:33][CH2:32][CH2:31][N:26]2[CH:30]=[CH:29][N:28]=[CH:27]2)=[N:3][CH:4]=1
Reactant: NCCCn1ccnc1
Reactant: Fc1ccc(F)c(C(Sc2ccc(Cl)cc2)c2cc(Cl)ncc2Cl)c1
Solvent: C1COCCO1
Product: Fc1ccc(F)c(C(Sc2ccc(Cl)cc2)c2cc(NCCCn3ccnc3)ncc2Cl)c1
Temperature: 25 °C
Yield: 39 %

Procedure:
A 1,4-dioxane (1.5 ml) solution of the 2,5-dichloro-4-[(4-chlorophenylthio)-(2,5-difluorophenyl)methyl]pyridine (200 mg, 0.48 mmol) obtained in Example 54 and 3-(imidazol-1-yl)propylamine (400 μl) was stirred at 120° C. for 5 days under an argon atmosphere. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue thus obtained was purified by silica gel chromatography (hexane:ethyl acetate=1:1) to give the title compound (94 mg, 39%) as an oil.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3](=O)[CH:4]=[CH:5][NH:6][CH:7]=[CH:8][C:9]#[N:10].[OH-].[Na+].CCCCCC.CC(C)=[O:24]>CO>[F:1][C:2]([F:13])([F:12])[C:3]1[C:8]([C:9]([NH2:10])=[O:24])=[CH:7][N:6]=[CH:5][CH:4]=1
Reactant: CC(C)=O
Reactant: N#CC=CNC=CC(=O)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: CO
Product: NC(=O)c1cnccc1C(F)(F)F
Yield: 65.6 %

Procedure:
3-[(4,4,4-Trifluoro-3-oxo-1-butenyl)amino]-2-propenenitrile (a low-polar compound IIa; 1.90 g, 10 mmol) was dissolved in methanol (15 ml), and sodium hydoxide (600 mg, 15 mmol) was added. The mixture was heated under reflux for 6 hours. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (a eluting solvent: hexane/acetone=1/1) to obtain 1.25 g (yield 65.6%) of the title compound.
Reaction SMILES: [C:1](OC1C2C(=CC=CC=2)N(CCC)C1=O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[N:29]([CH2:33][CH2:34][CH:35]([CH3:37])[CH3:36])[C:28](=[O:38])[C:27]2=[O:39]>>[C:1]([O:39][CH:27]1[C:26]2[C:30](=[CH:31][CH:32]=[C:24]([Cl:23])[CH:25]=2)[N:29]([CH2:33][CH2:34][CH:35]([CH3:36])[CH3:37])[C:28]1=[O:38])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)CCN1C(=O)C(=O)c2cc(Cl)ccc21
Reactant: CCCN1C(=O)C(OC(=O)c2ccccc2)c2ccccc21
Product: CC(C)CCN1C(=O)C(OC(=O)c2ccccc2)c2cc(Cl)ccc21

Procedure:
This compound was prepared in a similar way to 2-oxo-1-propylindolin-3-yl benzoate starting from 5-chloro-1-isopentylindoline-2,3-dione. 1H-NMR δ 8.11 (dd, 2H), 7.60 (dt, 1H), 7.47 (m, 2H) 7.45 (m, 3H), 7.33 (dd, 1H), 6.80 (d, 1H), 6.10 (d, 1H), 3.76 (m, 2H), 1.72 (m, 1H), 1.01 (dd, 6H).
Reaction SMILES: [F:1][C:2]1([C@@H:15]([OH:25])[CH:16]=[C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)C)S(=O)(=O)C2C=CC=CC=2S1(=O)=O.[I-].[Sm+2].[I-].O1CCCC1.[Cl-].[NH4+]>CO>[F:1][CH2:2][C@@H:15]([OH:25])/[CH:16]=[CH:17]/[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CC(=C[C@H](O)C1(F)S(=O)(=O)c2ccccc2S1(=O)=O)c1ccccc1
Agent: [Cl-]
Agent: [I-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CO
Product: O[C@@H](/C=C/c1ccccc1)CF
Reaction time: 1 h

Procedure:
A 5 ml round-bottomed flask provided with a stirrer was charged with the 2-fluoro-2-[(1S)-1-hydroxy-3-phenyl-2-butenyl]-1,3-benzodithiol 1,1,3,3-tetraoxide (41.2 mg, 0.11 mmol, 91% ee) prepared in Example 11 and MeOH (2.0 ml). The resultant mixture was cooled to 40° C. Samarium(II) iodide/tetrahydrofuran (0.1 M, 6.7 ml) was slowly added dropwise, and the mixture was stirred for 1 hour. Then, a saturated ammonium chloride aqueous solution was added. The aqueous layer was extracted with dichloromethane. A sodium thiosulfate aqueous solution was added to the organic layer, and the organic layer was extracted. Then, the organic layer was dried over anhydrous magnesium sulfate. The solvent was removed by distillation using an evaporator, and then the product was purified by silica gel column chromatography (dichloromethane:methanol=95:5) to obtain 15.0 mg (81%, 90% ee) of the target (3S)-(E)-4-fluoro-3-hydroxy-1-phenyl-1-butene.
Reaction SMILES: [CH2:1]1[C@@H:5]2[CH:6]3[C:11](=[O:12])[O:10][C:8](=[O:9])[CH:7]3[C@H:2]1[CH:3]=[CH:4]2.C1(C)C=CC=CC=1.COC1C=CC2N=CC=C([C@@H](O)[C@H]3N4C[C@H](C=C)[C@@H](CC4)C3)C=2C=1.[CH3:44][OH:45]>C(Cl)(Cl)(Cl)Cl>[CH3:44][O:45][C:11]([C@@H:6]1[C@@H:5]2[CH2:1][C@@H:2]([CH:3]=[CH:4]2)[C@@H:7]1[C:8]([OH:10])=[O:9])=[O:12]
Reactant: O=C1OC(=O)C2C1[C@@H]1C=C[C@H]2C1
Reactant: CO
Agent: C=C[C@H]1CN2CC[C@H]1C[C@H]2[C@H](O)c1ccnc2ccc(OC)cc12
Solvent: ClC(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: COC(=O)[C@H]1[C@@H](C(=O)O)[C@@H]2C=C[C@H]1C2
Temperature: -55 °C
Reaction time: 0.17 h
Yield: 99.5 %

Procedure:
The title compound was prepared as described in J. Org. Chem. 2000, 65, 6984-6991. cis-5-Norbornene-endo-2,3-dicarboxylic anhydride (5 g, 30.45 mmol) was suspended in a 1:1 mixture of toluene and carbon tetrachloride (610 mL). The mixture was stirred for 10 min. Quinine (10.87 g, 33.5 mmol) was added and the flask was degassed and backfilled with nitrogen. The solution was cooled to −55° C. While stirring, methanol (3.7 mL, 91.35 mmol) was added. The mixture was stirred at −55° C. for 16 h. Upon warming to 25° C., the mixture was concentrated in vacuo to a foam. The foam was dissolved in a mixture of ethyl acetate (400 mL) and 1.0 M aqueous hydrochloric acid solution (400 mL). The layers were separated and the organic layer was further washed with 1.0 M aqueous hydrochloric acid solution (2×200 mL), aqueous saturated brine solution (100 mL) and dried over magnesium sulfate, filtered, and concentrated in vacuo to afford the desired product, (1S,2S,3R,4R)-3-(methoxycarbonyl)bicyclo[2.2.1]hept-5-ene-2-carboxylic acid (5.95 g, 30.3 mmol, 99% yield) as a clear oil. 1H NMR (400 MHz, DMSO-d6) δ: 1.31 (1H, d, J=8.5 Hz), 1.98 (1H, d, J=8.6 Hz), 2.51 (2H, d, J=1.6 Hz), 2.95 (2H, bs), 3.52 (3H, s), 6.17-6.21 (2H, m), 12.16 (1H, s).
Reaction SMILES: [CH2:1]([C@@H:3]1[CH2:7][C@@H:6]([CH:8]2[CH2:10][N@@:9]2[S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N+:20]([O-:22])=[O:21])(=[O:13])=[O:12])[O:5][C:4]1=[O:23])[CH3:2].[CH3:24][C:25]1([CH3:39])[CH2:30][N:29]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[CH3:37])[C:28](=[O:38])[CH2:27][NH:26]1>C1(C)C=CC=CC=1>[CH3:24][C:25]1([CH3:39])[CH2:30][N:29]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[CH3:37])[C:28](=[O:38])[CH2:27][N:26]1[CH2:10][C@H:8]([NH:9][S:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N+:20]([O-:22])=[O:21])(=[O:13])=[O:12])[C@@H:6]1[CH2:7][C@@H:3]([CH2:1][CH3:2])[C:4](=[O:23])[O:5]1
Reactant: Cc1ccccc1N1CC(C)(C)NCC1=O
Reactant: CC[C@@H]1C[C@@H](C2C[N@@]2S(=O)(=O)c2ccccc2[N+](=O)[O-])OC1=O
Agent: CC[C@@H]1C[C@@H](C2C[N@]2S(=O)(=O)c2ccccc2[N+](=O)[O-])OC1=O
Solvent: Cc1ccccc1
Product: CC[C@@H]1C[C@@H]([C@H](CN2CC(=O)N(c3ccccc3C)CC2(C)C)NS(=O)(=O)c2ccccc2[N+](=O)[O-])OC1=O
Yield: 96.6 %

Procedure:
A solution of 770 mg of (3R,5S)-3-ethyl-5-[(S)-1-(2-nitrobenzenesulfonyl)aziridin-2-yl]dihydrofuran-2-one obtained in Example (106g) (2.26 mmol) and 593 mg of 5,5-dimethyl-1-(2-methylphenyl)piperazin-2-one obtained in Example (51d) (2.71 mmol) in toluene (23 ml) was stirred at 110° C. for five hours. After cooling, the reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent:methylene chloride/ethyl acetate=4/1) to obtain 1.22 g of the title compound (yield: 97%).
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[CH:5][C:4]([C:7](Cl)=[O:8])=[CH:3][CH:2]=1.[C:11]([NH2:15])([CH3:14])([CH3:13])[CH3:12].O>C(Cl)Cl>[C:11]([NH:15][C:7](=[O:8])[C:4]1[CH:5]=[CH:6][C:1]([CH3:10])=[CH:2][CH:3]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)N
Reactant: Cc1ccc(C(=O)Cl)cc1
Solvent: O
Solvent: ClCCl
Product: Cc1ccc(C(=O)NC(C)(C)C)cc1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 95 %

Procedure:
To a solution of p-toluoyl chloride (34.2 ml, 259 mmol) in DCM (250 ml), charged to a 500 mL round bottom, t-butylamine (57.3 ml, 543 mmol) was added slowly at 0° C. The reaction mixture was stirred at 0° C. for 45 min. The reaction mixture was then partioned between additional DCM and water. The organic layer was then washed with water 2 and brine. The organic layer was then dried over magnesium sulfate and concentrated under vacuum to give a white solid N-tert-butyl-4-methylbenzamide (47.07 g, 95.1% yield). MS (M+H)+ 192.
Reaction SMILES: C([O:3][C:4](=O)/[CH:5]=[CH:6]/[CH2:7][CH2:8][CH2:9][C:10]([CH3:32])([CH3:31])[CH2:11]/[CH:12]=[CH:13]\[C:14]([O:23][Si:24]([CH2:29][CH3:30])([CH2:27][CH3:28])[CH2:25][CH3:26])([C:19]([F:22])([F:21])[F:20])[C:15]([F:18])([F:17])[F:16])C>C1(C)C=CC=CC=1>[F:18][C:15]([F:16])([F:17])[C:14]([O:23][Si:24]([CH2:29][CH3:30])([CH2:27][CH3:28])[CH2:25][CH3:26])([C:19]([F:21])([F:22])[F:20])/[CH:13]=[CH:12]\[CH2:11][C:10]([CH3:31])([CH3:32])[CH2:9][CH2:8][CH2:7]/[CH:6]=[CH:5]/[CH2:4][OH:3]
Reactant: CCOC(=O)/C=C/CCCC(C)(C)C/C=C\C(O[Si](CC)(CC)CC)(C(F)(F)F)C(F)(F)F
Solvent: Cc1ccccc1
Product: CC[Si](CC)(CC)OC(/C=C\CC(C)(C)CCC/C=C/CO)(C(F)(F)F)C(F)(F)F
Reaction time: 0.5 h

Procedure:
To a solution of 10.09 g of (2E,9Z)-12,12,12-Trifluoro-7,7-dimethyl-11-triethylsilanyloxy-11-trifluoromethyl-dodeca-2,9-dienoic acid ethyl ester in 100 ml of toluene was added at −78° 40.0 ml of diisobutylalulminiumhydride (1.2 M in toluene) and stirring was continued for 30 min after which time t.l.c. indicated completion of the reaction. The mixture was washed with sat. aqueous NH4Cl-solution and water, the organic layer was dried over MgSO4 and evaporated to give 8.92 g of the pure (t.l.c.) title compound as a pale yellow oil. IR (neat): 3332 m, br. (OH), 1669 w (C═C).
Reaction SMILES: [CH2:1]([N:3]([N:6]([S:27]([N:30]([C@H:36]1[CH2:50][C@H:49]2[C@@H:39]([CH2:40][C:41]3[C:51]4[C:44](=[CH:45][CH:46]=[CH:47][C:48]2=4)[NH:43][C:42]=3[CH3:52])[N:38]([CH2:53][CH2:54][CH3:55])[CH2:37]1)[N:31]([CH2:34]C)[CH2:32]C)(=[O:29])=[O:28])[C@H:7]1[CH2:21][C@H:20]2[C@@H:10]([CH2:11][C:12]3[C:22]4[C:15](=[CH:16][CH:17]=[CH:18][C:19]2=4)[NH:14][C:13]=3[CH3:23])[N:9]([CH2:24][CH2:25][CH3:26])[CH2:8]1)[CH2:4]C)C.C(O)(=O)C(C(C(O)=O)O)O>CO>[CH3:32][N:31]([N:30]([S:27]([N:6]([C@H:7]1[CH2:21][C@H:20]2[C@@H:10]([CH2:11][C:12]3[C:22]4[C:15](=[CH:16][CH:17]=[CH:18][C:19]2=4)[NH:14][C:13]=3[CH3:23])[N:9]([CH2:24][CH2:25][CH3:26])[CH2:8]1)[N:3]([CH3:1])[CH3:4])(=[O:28])=[O:29])[C@H:36]1[CH2:50][C@H:49]2[C@@H:39]([CH2:40][C:41]3[C:51]4[C:44](=[CH:45][CH:46]=[CH:47][C:48]2=4)[NH:43][C:42]=3[CH3:52])[N:38]([CH2:53][CH2:54][CH3:55])[CH2:37]1)[CH3:34]
Reactant: CCCN1C[C@@H](N(N(CC)CC)S(=O)(=O)N([C@H]2C[C@@H]3c4cccc5[nH]c(C)c(c45)C[C@H]3N(CCC)C2)N(CC)CC)C[C@@H]2c3cccc4[nH]c(C)c(c34)C[C@H]21
Agent: O=C(O)C(O)C(O)C(=O)O
Solvent: CO
Product: CCCN1C[C@@H](N(N(C)C)S(=O)(=O)N([C@H]2C[C@@H]3c4cccc5[nH]c(C)c(c45)C[C@H]3N(CCC)C2)N(C)C)C[C@@H]2c3cccc4[nH]c(C)c(c34)C[C@H]21

Procedure:
Analogously, there is produced with diethylaminosulfonic acid chloride: (diethylamino)-(2-methyl-6-n-propyl-8alpha-ergolinylamino)-sulfone. Yield 25% as tartaric acid salt, [α]D =-34° (0.5% in methanol).
Reaction SMILES: [CH:1]1([NH:7][CH3:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:9]([N:14]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[C:17](=[O:24])OC1=O)[CH2:10][CH2:11][CH2:12][CH3:13]>>[CH:1]1([N:7]([CH3:8])[C:17](=[O:24])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[NH:14][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CNC1CCCCC1
Reactant: CCCCCn1c(=O)oc(=O)c2ccccc21
Product: CCCCCNc1ccccc1C(=O)N(C)C1CCCCC1
Yield: 67 %

Procedure:
The title compound (1 g, 67%) was obtained as a yellow solid from N-cyclohexyl-N-methylamine and 1-Pentyl-1H-benzo[d][1,3]oxazine-2,4-dione following the same procedure as described in Preparation 7.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[O:9][C:8]([C:10]3[N:11]=[C:12]4[CH:17]=[CH:16][C:15]([CH3:18])=[N:14][N:13]4[CH:19]=3)=[CH:7][C:6]2=[C:20]([OH:22])[CH:21]=1.Br[CH2:24][C:25]1[N:26]=[C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[S:28][CH:29]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:21]=[C:20]([O:22][CH2:24][C:25]2[N:26]=[C:27]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[S:28][CH:29]=2)[C:6]2[CH:7]=[C:8]([C:10]3[N:11]=[C:12]4[CH:17]=[CH:16][C:15]([CH3:18])=[N:14][N:13]4[CH:19]=3)[O:9][C:5]=2[CH:4]=1
Reactant: BrCc1csc(-c2ccccc2)n1
Reactant: COc1cc(O)c2cc(-c3cn4nc(C)ccc4n3)oc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1cc(OCc2csc(-c3ccccc3)n2)c2cc(-c3cn4nc(C)ccc4n3)oc2c1
Temperature: 22 °C
Reaction time: 18 h
Yield: 65.7 %

Procedure:
In a 100 mL round-bottom flask, a suspension of 6-methoxy-2-(6-methylimidazo[1,2-b]pyridazin-2-yl)benzofuran-4-ol (Example 39B, 0.190 g, 0.643 mmol) and 4-(bromomethyl)-2-phenylthiazole (Table of bromides, 0.180 g, 0.708 mmol) in DMF (5 mL) was purged under vacuum and N2 for 10 min. The reaction was treated with potassium carbonate (0.24 g, 1.737 mmol) and stirred at 22° C. for 18 hours, then diluted with DCM and washed with water (1×), brine (1×). The organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (2.5×10 cm, 0% to 50% EtOAc in CH2Cl2) to give the impure title material (0.198 g, 66%). The solid was triturated in hot ethyl acetate to provide the pure title material (0.176 g). LC (Method A): 2.414 min. HRMS (ESI) calcd for C26H21N4O3S [M+H]+ m/z 469.1329, found 469.1379. 1H NMR (CDCl3, 400 MHz) δ ppm: 2.57 (s, 3H), 3.84 (s, 3H), 5.39 (s, 2H), 6.46 (d, J=1.96 Hz, 1H), 6.74 (broad d, 1H), 6.91 (d, J=9.1 Hz, 1H), 7.34 (s, 1H), 7.36 (s, 1H), 7.39-7.46 (m, 3H), 7.80 (d, J=9.1 Hz, 1H), 7.90-8.0 (m, 2H), 8.19 (s, 1H).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][C@@H:13]2[CH3:18])(=[O:11])=[O:10])=[CH:5][CH:4]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[N:33]1([C:39]2[N:44]=[CH:43][C:42]([C:45](O)=[O:46])=[CH:41][CH:40]=2)[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1.C(N1CCOCC1)C>C(Cl)Cl.O>[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([S:9]([N:12]2[CH2:17][CH2:16][N:15]([C:45]([C:42]3[CH:41]=[CH:40][C:39]([N:33]4[CH2:38][CH2:37][O:36][CH2:35][CH2:34]4)=[N:44][CH:43]=3)=[O:46])[CH2:14][C@@H:13]2[CH3:18])(=[O:10])=[O:11])=[CH:7][CH:8]=1
Reactant: O=C(O)c1ccc(N2CCOCC2)nc1
Reactant: C[C@H]1CNCCN1S(=O)(=O)c1ccc(Cl)cc1
Agent: CCN1CCOCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCCl
Solvent: ClCCl
Product: C[C@H]1CN(C(=O)c2ccc(N3CCOCC3)nc2)CCN1S(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 56 %

Procedure:
To a suspension of (2S)-1-[(4-chlorophenyl)sulfonyl]-2-methylpiperazine hydrochloride (Description 4) (105 mg, 0.338 mmol), EDC (71.3 mg, 0.372 mmol), HOBT.H2O (56.9 mg, 0.372 mmol) and 6-(4-morpholinyl)-3-pyridinecarboxylic acid (77 mg, 0.372 mmol) in DCM (5 ml) was added N-ethyl morpholine (0.090 mL, 0.710 mmol). The reaction was stirred for 18 h at ambient temperature. To the reaction was added water (3 ml) and the organic layer collected via a hydrophobic frit. The organic layer was reduced in volume to approximately 2 ml then loaded onto a silica SP4 chromatography cartridge. The cartridge was eluted with a gradient from 60% ethyl acetate in iso-hexane to ethyl acetate then ethyl acetate. Fractions containing the desired product were combined and reduced in vacuo to yield the title compound as a white solid (88 mg).