Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6]([C:8]1[O:9][C:10]([CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:17][CH:16]=2)=[CH:11][CH:12]=1)=[O:7]>O.O1CCCC1>[C:18]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:17]=[CH:16][C:15]([O:14][CH2:13][C:10]2[O:9][C:8]([C:6]([OH:7])=[O:5])=[CH:12][CH:11]=2)=[CH:20][CH:19]=1
Reactant: COC(=O)c1ccc(COc2ccc(-c3ccccc3)cc2)o1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc(COc2ccc(-c3ccccc3)cc2)o1
Temperature: 25 °C
Reaction time: 72 h
Yield: 83.9 %

Procedure:
A solution of lithium hydroxide monohydrate (5.10 g, 121.5 mmol) in water (50 mL) was added to a solution of 5-(biphenyl-4-yloxymethyl)-furan-2-carboxylic acid methyl ester (15.00 g, 48.6 mmol) in tetrahydrofuran (450 mL). The reaction mixture was stirred at room temperature for 72 h. The solvents were evaporated and water was added. The mixture was extracted three times with ether. Insoluble white solid was filtered off. The pH of the aqueous solution was adjusted to 3 and the resulting mixture was extracted with ethyl acetate (3×500 mL). The combined organic layers were washed with 50% saturated brine and then evaporated under reduced pressure to give 5-(biphenyl-4-yloxymethyl)-furan-2-carboxylic acid (12.0 g, 84%) as a white solid.
Reaction SMILES: [CH2:1]([O:4][C@H:5]1[N:8]([C:9](=[C:26]([CH3:28])[CH3:27])[C:10]([O:12][CH:13]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[C:7](=[O:29])[C@@H:6]1[NH:30][C:31](=[O:39])[CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:2]#[CH:3].[OH2:40]>CO.S(=O)(=O)(O)O.C(OCC)(=O)C>[CH2:1]([O:4][C@H:5]1[N:8]([C:9](=[C:26]([CH3:28])[CH3:27])[C:10]([O:12][CH:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[O:11])[C:7](=[O:29])[C@@H:6]1[NH:30][C:31](=[O:39])[CH2:32][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[C:2]([CH3:3])=[O:40]
Reactant: O
Reactant: C#CCO[C@@H]1[C@@H](NC(=O)Cc2ccccc2)C(=O)N1C(C(=O)OC(c1ccccc1)c1ccccc1)=C(C)C
Agent: O=S(=O)(O)O
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(=O)CO[C@@H]1[C@@H](NC(=O)Cc2ccccc2)C(=O)N1C(C(=O)OC(c1ccccc1)c1ccccc1)=C(C)C

Procedure:
To a solution of diphenylmethyl α-[4(R)-propargyloxy-3(R)-phenylacetamido-2-oxo-azetidin-1-yl]-α-isopropylideneacetate (2.236 g; 4.28 mmole) in methanol (20 ml) is added water (2 ml). To this solution is added a saturated solution of mercuric sulfate in 10% sulfuric acid (0.8 ml), and the mixture is refluxed for 30 minutes. The reaction mixture is cooled, diluted with ethyl acetate, and washed with water. The ethyl acetate layer is dried over sodium sulfate, and concentrated under reduced pressure. Purification of the residue by chromatography over silica gel containing 10% water (100 g) using a mixture of benzene and ethyl acetate (2:1) as eluting solvent gives the product.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].CN(C)C=O.[Se:10]1(=[O:19])[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]=[CH:11]1.[C:20](Cl)(=[O:22])[CH3:21]>>[C:20]([C:16]1[CH:17]=[CH:18][C:13]2[N:12]=[CH:11][Se:10](=[O:19])[C:14]=2[CH:15]=1)(=[O:22])[CH3:21]
Reactant: CC(=O)Cl
Reactant: O=[Se]1C=Nc2ccccc21
Agent: [Al+3]
Agent: [Cl-]
Solvent: CN(C)C=O
Product: CC(=O)c1ccc2c(c1)[Se](=O)C=N2

Procedure:
12 grams (0.09 mol) of aluminum chloride are introduced into a ground-necked flask. 3.1 cm3 (0.04 mol) of dimethylformamide are added dropwise with stirring. After cooling, two grams (0.01 mol) of benzoselenazolinone are added and the mixture is homogenized. It is heated to 70°-80° C. on an oil bath with stirring, and 0.01 to 0.012 mol of acetyl chloride is then added. heating is maintained at a temperature of 80°-90° C. for a time T of approximately 4 h 30 min. The mixture is hydrolyzed on crushed ice. The product is drained, dried, and washed with boiling cyclohexane and recrystallized in toluene.
Reaction SMILES: C(N(CC)CC)C.Cl.[NH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14].Cl[C:19]1[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[S:21](=[O:29])(=[O:28])[N:20]=1>O1CCOCC1>[O:28]=[S:21]1(=[O:29])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[C:19]([NH:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[N:20]1
Reactant: O=S1(=O)N=C(Cl)c2ccccc21
Reactant: CCOC(=O)CCCN
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CCOC(=O)CCCNC1=NS(=O)(=O)c2ccccc21
Reaction time: 0.08 h

Procedure:
4.07 ml (29.2 mM) of triethylamine is added to 5.0 g. (29.2 mM) of ethyl 4-aminobutyrate hydrochloride, suspended in 75 ml of dioxane. After stirring for 5 minutes, 5.88 g. (29.2 mM) of 3-chloro-1,2-benzisothiazole 1,1-dioxide is added and the mixture is refluxed for one hour. The solvent is evaporated in vacuo and the residue is taken up in chloroform, washed with water, and evaporated to dryness. The residual 4-[(1,1-dioxo-1,2-benzisothiazol-3-yl)amino]-butanoic acid, ethyl ester is recrystallized from 40 ml. of methanol/water, yield 3.72 g., m.p. 125°-127°.
Reaction SMILES: I([O-])(=O)(=O)=O.[Na+].[OH:7][C@@H:8]1[C@H:12]([OH:13])[O:11][C@H:10]([CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)[C@@H:9]1[CH2:26][CH2:27][N:28]1[C:36](=[O:37])[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29]1=[O:38].O1CCCC1>CO>[CH:12]([O:11][C@H:10]([CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([F:23])([F:25])[F:24])=[CH:18][CH:17]=1)[C@@H:9]([CH:8]=[O:7])[CH2:26][CH2:27][N:28]1[C:36](=[O:37])[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29]1=[O:38])=[O:13]
Reactant: O=C1c2ccccc2C(=O)N1CC[C@@H]1[C@H](O)[C@H](O)O[C@@H]1CCc1ccc(C(F)(F)F)cc1
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: C1CCOC1
Solvent: CO
Product: O=CO[C@H](CCc1ccc(C(F)(F)F)cc1)[C@@H](C=O)CCN1C(=O)c2ccccc2C1=O
Reaction time: 2 h

Procedure:
A solution of sodium metaperiodate (0.313 g in 1 mL of water) was added to a solution of the compound obtained from step f above (0.22 g) in methanol:tetrahydrofuran (3 mL:1 mL) at 0° C. The reaction mixture was stirred for 2 hours at same temperature. After stirring the reaction mixture for an additional 6 hours at room temperature, the reaction mixture was evaporated on a rotary evaporator, and the residue was taken into water and extracted with ethyl acetate. The organic layer was washed with water and brine solution, and dried over anhydrous sodium sulphate. The solvent was evaporated under reduced pressure to afford the title compound (0.22 g).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH:5]([O:18][CH2:19][CH3:20])[CH2:6][C:7]1[C:16]2[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=2[C:10]([OH:17])=[CH:9][CH:8]=1)[CH3:2].C(OC(CC1C2SC=CC=2C(O[CH2:40][CH2:41][C:42]2[N:43]=[C:44]([C:48]3[CH:53]=[CH:52][C:51]([F:54])=[CH:50][C:49]=3[O:55][CH2:56][CH3:57])[O:45][C:46]=2[CH3:47])=CC=1)C(O)=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>>[CH2:1]([O:3][C:4](=[O:21])[CH:5]([O:18][CH2:19][CH3:20])[CH2:6][C:7]1[C:16]2[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=2[C:10]([O:17][CH2:40][CH2:41][C:42]2[N:43]=[C:44]([C:48]3[CH:53]=[CH:52][C:51]([F:54])=[CH:50][C:49]=3[O:55][CH2:56][CH3:57])[O:45][C:46]=2[CH3:47])=[CH:9][CH:8]=1)[CH3:2]
Reactant: CCOC(=O)C(Cc1ccc(O)c2c1CCCC2)OCC
Reactant: CCOc1cc(F)ccc1-c1nc(CCOc2ccc(CC(OCC)C(=O)O)c3sccc23)c(C)o1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CCOC(=O)C(Cc1ccc(OCCc2nc(-c3ccc(F)cc3OCC)oc2C)c2c1CCCC2)OCC

Procedure:
In analogy to the procedure described in example 17 a], [rac]-2-ethoxy-3-(4-hydroxy-5,6,7,8-tetrahydro-naphthalen-1-yl)-propionic acid ethyl ester (example 108 b]) was reacted with 2-[2-(2-ethoxy-4-fluoro-phenyl)-5-methyl-oxazol-4-yl]-ethanol (example 95) in the presence of triphenylphosphine and DEAD (diethyl azodicarboxylate) to yield [rac]-2-ethoxy-3-(4-{2-[2-(2-ethoxy-4-fluoro-phenyl)-5-methyl-oxazol-4-yl]-ethoxy}-5,6,7,8-tetrahydro-naphthalen-1-yl)-propionic acid ethyl ester, which was further saponified in analogy to the procedure described in example 91 e] to yield [rac]-2-ethoxy-3-(4-{2-[2-(2-ethoxy-4-fluoro-phenyl)-5-methyl-oxazol-4-yl]-ethoxy}-5,6,7,8-tetrahydro-naphthalen-1-yl)-propionic acid as colorless solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[NH:7][C:8]([CH3:28])([CH3:27])[CH2:9][C:10]1[C:18]2[C:13](=[C:14]([O:19]CC3C=CC=CC=3)[CH:15]=[CH:16][CH:17]=2)[NH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2]>[Pd].C(O)C>[C:1]([O:5][C:6](=[O:29])[NH:7][C:8]([CH3:28])([CH3:27])[CH2:9][C:10]1[C:18]2[C:13](=[C:14]([OH:19])[CH:15]=[CH:16][CH:17]=2)[NH:12][CH:11]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(Cc1c[nH]c2c(OCc3ccccc3)cccc12)NC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CCO
Product: CC(C)(Cc1c[nH]c2c(O)cccc12)NC(=O)OC(C)(C)C
Temperature: 50 °C
Reaction time: 0.67 h
Yield: 96.2 %

Procedure:
A mixture of [2-(7-benzyloxy-1H-indol-3-yl)-1,1-dimethyl-ethyl]-carbamic acid tert-butyl ester (20.75 g, 52.6 mmol), 5% Pd/C (1.00 g, 5 wt %), and 3A ethanol (200 mL) is pressurized to 55 psig with H2, and is heated to 50° C. After 40 minutes, the slurry is filtered, and the filtrate is concentrated to give 15.41 g of [2-(7-hydroxy-1H-indol-3-yl)-1,1-dimethyl-ethyl]-carbamic acid tert-butyl ester (96%). FDMS m/e=305 (M++1). To a solution of [2-(7-hydroxy-1H-indol-3-yl)-1,1-dimethyl-ethyl]-carbamic acid tert-butyl ester (6.04 g, 19.8 mmol) in dichloromethane (125 mL) is added triethylamine (14 mL, 99.2 mmol). The mixture is cooled to 0° C. and trifluoromethanesulfonyl anhydride (4.4 mL, 25.8 mmol) is added dropwise as a solution in dichloromethane (25 mL). The mixture is warmed to ambient and stirred overnight. The solution is diluted with brine and extracted three times with dichloromethane. The combined organics are dried over anhydrous sodium sulfate then filtered and evaporated. The residue is purified using silica gel chromatography (hexane/20% ethyl acetate in hexane gradient elution) to give 7.199 g of trifluoro-methanesulfonic acid 3-(2-tert-butoxycarbonylamino-2-methyl-propyl)-1H-indol-7-yl ester (83%). FDMS m/e=437 (M++1).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH:11]=[O:12])[CH:9]=2)[NH:4][N:3]=1.Br[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][C:16]=1[C:25]([F:28])([F:27])[F:26]>>[F:26][C:25]([F:27])([F:28])[C:16]1[CH:17]=[C:18]([C:21]([F:24])([F:22])[F:23])[CH:19]=[CH:20][C:15]=1[CH2:14][N:4]1[C:5]2[C:10](=[CH:9][C:8]([CH:11]=[O:12])=[CH:7][CH:6]=2)[C:2]([CH3:1])=[N:3]1
Reactant: FC(F)(F)c1ccc(CBr)c(C(F)(F)F)c1
Reactant: Cc1n[nH]c2ccc(C=O)cc12
Product: Cc1nn(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)c2ccc(C=O)cc12

Procedure:
1-(2,4-Bis-trifluoromethyl-benzyl)-3-methyl-1H-indazole-5-carbaldehyde was prepared from 3-Methyl-1H-indazole-5-carbaldehyde and 1-Bromomethyl-2,4-bis-trifluoromethyl-benzene following general procedure A.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][N:17]2[C:22](=[O:23])[C:21]3[S:24][CH:25]=[CH:26][C:20]=3[NH:19][C:18]2=[O:27])[CH2:11][CH2:10]1.[CH3:28]N(C)C=O>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][N:17]2[C:22](=[O:23])[C:21]3[S:24][CH:25]=[CH:26][C:20]=3[N:19]([CH3:28])[C:18]2=[O:27])[CH2:13][CH2:14]1
Reactant: CN(C)C=O
Reactant: COc1ccccc1N1CCN(CCn2c(=O)[nH]c3ccsc3c2=O)CC1
Product: COc1ccccc1N1CCN(CCn2c(=O)c3sccc3n(C)c2=O)CC1
Yield: 61 %

Procedure:
The title compound was produced following the procedure of Example 13 using dimethylformamide as the solvent and the thienopyrimidine-2,4-dione (1.82 g, 4.66 mmol) from Example 19. The title compound was isolated in 61% yield (1.13 g) after recrystallization from EtOH, mp 149°-151° C.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.I[C:7]1[CH:8]=[C:9]([CH3:14])[CH:10]=[C:11]([CH3:13])[CH:12]=1>CCCCCC.C(OCC)(=O)C>[CH3:14][C:9]1[CH:8]=[C:7]([N:1]2[CH:5]=[CH:4][CH:3]=[CH:2]2)[CH:12]=[C:11]([CH3:13])[CH:10]=1
Reactant: Cc1cc(C)cc(I)c1
Reactant: c1cc[nH]c1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Cc1cc(C)cc(-n2cccc2)c1
Yield: 99 %

Procedure:
Using general procedure B, pyrrole (83 μL, 1.2 mmol) was coupled with 5-iodo-m-xylene to give the crude product. Column chromatography (2×15 cm, hexane:ethyl acetate 9:1) provided 0.170 g (99% yield) of the product as a colorless oil. 1H NMR (400 MHz, CDCl3): δ 7.07 (t, J=7.0 Hz, 2H), 7.02 (s, 2H), 6.89 (s, 1H), 6.33 (t, J=7.0 Hz, 2H), 2.37 (s, 6H).
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([CH:14]([CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:15]([OH:17])[CH3:16])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:33](OC=C)(=[O:35])[CH3:34]>>[C:33]([O:17][C@@H:15]([C@H:14]([C:11]1[CH:12]=[CH:13][C:8]([O:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:9][CH:10]=1)[CH2:18][CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[CH3:16])(=[O:35])[CH3:34]
Reactant: CC(O)C(CCc1ccccc1)c1ccc(Oc2ccccc2)cc1
Reactant: C=COC(C)=O
Solvent: CCN(CC)CC
Product: CC(=O)O[C@H](C)[C@@H](CCc1ccccc1)c1ccc(Oc2ccccc2)cc1
Temperature: 30 °C
Reaction time: 48 h

Procedure:
47.2 g of (2RS,3SR)-3-(4-phenoxyphenyl)-5-phenylpentan-2-ol was dissolved in 470 ml of vinyl acetate, and 19.4 ml of triethylamine was added. Then, 4.7 g of immobilized lipase (Toyothium LIP) was added, followed by stirring at 30° C. for 2 days. The enzyme was filtered off and then, washed with ethyl acetate. The filtrate and the washing liquid were put together, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=10/1→5/1) to obtain 23.8 g of (2R,3S)-2-acetoxy-3-(4-phenoxyphenyl)-5-phenylpentane and 22.2 g of the above identified compound, respectively, as colorless oily substances. Further, the absolute configuration of the above-identified compound was determined by Mosher method (J. Am. Chem. Soc., vol. 113, p. 4092 (1991)).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([CH:19]3[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]3)=[CH:15][CH:14]=2)[N:3]=1.[C:32]([C:34]1[C:35]([CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42])=[N:36][CH:37]=[CH:38][N:39]=1)#[CH:33].C(N(CC)CC)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.CN(C=O)C>[CH2:44]([O:43][C:41](=[O:42])[CH2:40][C:35]1[C:34]([C:32]#[C:33][C:2]2[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]3[CH:18]=[CH:17][C:16]([CH:19]4[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]4)=[CH:15][CH:14]=3)[N:3]=2)=[N:39][CH:38]=[CH:37][N:36]=1)[CH3:45]
Reactant: C#Cc1nccnc1CC(=O)OCC
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(Nc3ncc(C(F)(F)F)c(Cl)n3)cc2)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1nccnc1C#Cc1nc(Nc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)cc2)ncc1C(F)(F)F
Temperature: 120 °C
Yield: 51.1 %

Procedure:
tert-Butyl 4-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate (I43) (140 mg, 0.306 mmol), ethyl 2-(3-ethynylpyrazin-2-yl)acetate (I101) (64 mg, 0.34 mmol), bis(triphenylphosphine)palladium(II) chloride (11 mg, 5 mol %) and DMF (2 mL) were loaded into a microwave tube and degassed with a nitrogen for ten minutes. Copper(I) iodide (3 mg, 5 mol %) and triethylamine (0.192 mL, 1.38 mmol) were added under nitrogen and the resulting mixture heated under microwave irradiation (120° C./15 minutes). The cooled mixture was concentrated, and the residue evaporated onto silica gel. Chromatography (12 g silica cartridge, 0-100% ethyl acetate/petroleum benzine 40-60° C.) gave the title compound (I102) (95.5 mg, 52% yield) as a yellow solid; 1H NMR (400 MHz, d6-DMSO) δ 10.47 (s, 1H), 8.87 (d, J=0.5 Hz, 1H), 8.76-8.71 (m, 2H), 7.63 (d, J=8.6 Hz, 2H), 7.23 (d, J=8.6 Hz, 2H), 4.15-3.99 (m, 6H), 2.80 (s, 2H), 2.70-2.63 (m, 1H), 1.80-1.70 (m, 2H), 1.55-1.44 (m, 2H), 1.42 (s, 9H), 1.14 (t, J=7.1 Hz, 3H). LCMS Method C: rt 6.73 min; m/z 633.1 [M+Na]+, 555.0 [M-tBu+2H]+, 511.1 [M-Boc+2H]+; m/z 609.1 [M−H]−.
Reaction SMILES: [BH4-].[Na+].[C:3]1([P:9]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[C:10]2[CH:44]=[CH:43][CH:42]=[CH:41][C:11]=2[CH:12]=[N:13][C@@H:14]2[CH2:19][CH2:18][CH2:17][CH2:16][C@H:15]2[N:20]=[CH:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[P:28]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.O>CO>[C:35]1([P:28]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[CH2:21][NH:20][C@@H:15]2[CH2:16][CH2:17][CH2:18][CH2:19][C@H:14]2[NH:13][CH2:12][C:11]2[CH:41]=[CH:42][CH:43]=[CH:44][C:10]=2[P:9]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=2)[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: C(=N[C@@H]1CCCC[C@H]1N=Cc1ccccc1P(c1ccccc1)c1ccccc1)c1ccccc1P(c1ccccc1)c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: c1ccc(P(c2ccccc2)c2ccccc2CN[C@@H]2CCCC[C@H]2NCc2ccccc2P(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C

Procedure:
1.14 g (30 mmol) of sodium borohydride are added a little at a time to a solution of 3.30 g (5.0 mmol) of trans-N,N′-bis(2-diphenylphosphanylbenzylidene)cyclohexane-1,2-diamine in 60 ml of methanol. The solution is refluxed for 24 hours and, after cooling to room temperature, admixed with 20 ml of water. The organic phase is extracted with 3×50 ml of dichloromethane and the combined organic phases are washed with 2×30 ml of 10% ammonium chloride solution and 30 ml of water. After drying over magnesium sulfate, the solvent is removed under reduced pressure and the residue is recrystallized from 30 ml of ethanol. The product precipitates in the form of light-yellow crystals in a yield of 2.68 g (4.0 mmol, 80%). 1H-NMR (400 MHz, CDCl3): δ=7.65–6.92 (m, 28 H, aromat. H), 4.11, 3.98 (2×d, J=13.4 Hz, 4 H, Ar—CH2), 2.21 (m, 2H, NCH), 1.63–1.27 (m, 8H, (CH2)4) ppm.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][N:13]([S:16]([CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)(=[O:18])=[O:17])[CH2:12][CH2:11]2)[C:5]([CH3:27])=[CH:4][N:3]=1.[H][H]>C(O)C.C(N(CC)CC)C.[Pd]>[CH3:27][C:5]1[C:6]([NH:8][CH2:9][CH:10]2[CH2:11][CH2:12][N:13]([S:16]([CH2:19][CH2:20][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)(=[O:17])=[O:18])[CH2:14][CH2:15]2)=[N:7][CH:2]=[N:3][CH:4]=1
Reactant: [H][H]
Reactant: Cc1cnc(Cl)nc1NCC1CCN(S(=O)(=O)CCc2ccccc2)CC1
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1cncnc1NCC1CCN(S(=O)(=O)CCc2ccccc2)CC1

Procedure:
EXAMPLE 92 was prepared from (2-chloro-5-methyl-pyrimidin-4-yl)-[1-(2-phenyl-ethanesulfonyl)-piperidin-4-ylmethyl]-amine by hydrogenation in ethanol-triethylamine over 5% palladium on carbon, 1 atm of hydrogen: MS (m+1)=375.5.
Reaction SMILES: C[C:2]1[C:7](C)=[CH:6][CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:14])[CH:11]=NO.CS(O)(=O)=[O:17]>>[NH:9]1[C:3]2[C:4](=[CH:5][CH:6]=[CH:7][CH:2]=2)[C:11](=[O:17])[C:10]1=[O:14]
Reactant: Cc1cccc(NC(=O)C=NO)c1C
Reactant: CS(=O)(=O)O
Product: O=C1Nc2ccccc2C1=O

Procedure:
Intermediate 3 (20 g, 0.1 mol) was added in small portions, with stirring, to 80 mL CH3SO3H at 70° C.-80° C. in one hour. After the addition was complete it was left at the same temperature for 15 more minutes and was then poured onto crushed ice in a beaker. Additional ice was added until the outside of the beaker felt cold to the touch. The precipitate was then collected and dissolved in 1N aqueous NaOH. Neutralization with acetic acid precipitated impurities which were removed by filtration, and acidification (HCl) of the filtrate gave isatin intermediate 4 as a solid (12.8 g, 70%). 1H NMR (400 MHz, DMSO-D6) δ ppm 2.09 (s, 3H) 2.27 (s, 3H) 6.89 (d, J=7.58 Hz, 1H) 7.25 (d, J=7.58 Hz, 1H) 11.02 (s, 1H).
Reaction SMILES: B(Br)(Br)Br.C([O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH:14]=[CH:15][S:16]([NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[S:26]([NH2:29])(=[O:28])=[O:27])(=[O:18])=[O:17])C.CO>ClCCl>[OH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH:14]=[CH:15][S:16]([NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[S:26]([NH2:29])(=[O:28])=[O:27])(=[O:17])=[O:18]
Reactant: CCOc1ccccc1C=CS(=O)(=O)Nc1ccccc1S(N)(=O)=O
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Product: NS(=O)(=O)c1ccccc1NS(=O)(=O)C=Cc1ccccc1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 16.2 %

Procedure:
Boron tribromide (1 M in dichloromethane, 5.4 mL, 5.44 mmol) was added dropwise over 5 min to a suspension of 2-[2-(2-ethoxy-phenyl)-ethenesulfonylamino]-benzenesulfonamide (example 222) (0.21 g, 0.54 mmol) in dichloromethane (10 mL) at −78° C. The reaction mixture was allowed to warm to room temperature and stirred overnight. Cooled to −20° C. and methanol (5 mL) was added slowly. The resulting solution was warmed up to room temperature and heated at 50° C. for 1 hour. The volatiles were removed under reduced pressure and the residue was taken up in methanol (5 mL). The mixture was concentrated in vacuo and the process was repeated once more. The residue was taken up in water (5 mL) and ethyl acetate (15 mL). The organic phase was separated, dried over magnesium sulfate and concentrated in vacuo. Purification by preparative HPLC gave 31 mg (16% yield) of the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[C:18]([C:20]#[C:21][CH2:22][N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[CH:17]=[C:16]([OH:29])[CH:15]=2)=[CH:9][C:8]=1[CH3:30])[CH3:2].[CH3:32][CH:33]([CH3:36])[CH2:34]O.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1COCC1>[CH2:1]([O:3][C:4](=[O:31])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[C:18]([C:20]#[C:21][CH2:22][N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[CH:17]=[C:16]([O:29][CH2:32][CH:33]([CH3:36])[CH3:34])[CH:15]=2)=[CH:9][C:8]=1[CH3:30])[CH3:2]
Reactant: CC(C)CO
Reactant: CCOC(=O)COc1ccc(Sc2cc(O)cc(C#CCN3CCOCC3)c2)cc1C
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: CCOC(=O)COc1ccc(Sc2cc(C#CCN3CCOCC3)cc(OCC(C)C)c2)cc1C
Reaction time: 16 h

Procedure:
{4-[3-Hydroxy-5-(3-morpholin-4-yl-prop-1-ynyl)-phenylsulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester (250 mg; 0.57 mmol), 2-methyl-propan-1-ol (0.078 mL; 0.85 mmol) and tributylphosphine (0.31 mL; 1.25 mmol) were dissolved in THF (15 mL) in a dried reaction flask under an atmosphere of nitrogen. 1,1′-(Azodicarbonyl)dipiperidine (0.31 g; 1.25 mmol) was dissolved in THF (10 mL) and added to the reaction mixture. After stirring for 16 h the reaction mixture was evaporated to dryness and purified by prep. HPLC (method B). Yield: 200 mg. HPLC-MS: m/z: 498.1 (M+); Rt: 2.03 min
Reaction SMILES: C1O[C:4]2([CH2:9][CH2:8][N:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[C:16]#[N:17])[CH2:6][CH2:5]2)[O:3]C1.Cl>CCOCC.C(=O)(O)[O-].[Na+]>[C:16]([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[N:7]1[CH2:8][CH2:9][C:4](=[O:3])[CH2:5][CH2:6]1)#[N:17]
Reactant: N#Cc1ccccc1N1CCC2(CC1)OCCO2
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Product: N#Cc1ccccc1N1CCC(=O)CC1
Temperature: 25 °C
Reaction time: 264 h

Procedure:
A solution of 4 (533 mg, 2.18 mmol) in ether (10 mL) was treated with 5% aqueous HCl (20 mL). The mixture was stirred at room temperature (11 d). The reaction was diluted with ether and neutralized with sodium bicarbonate solution. The aqueous layer was extracted with two additional portions of ether and the combined organic extracts were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. PCTLC (SiO2, 4 mm, 20% EtOAc-80% hexane) afforded the title compound (5).