Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:18][C@@H:19]([CH3:23])[C:20]([OH:22])=O)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[N:57]([CH2:60][CH2:61][CH2:62][C:63]1([C:76]2[CH:81]=[CH:80][CH:79]=[CH:78][CH:77]=2)[NH:67][N:66]=[C:65]([C:68]2[CH:73]=[C:72]([F:74])[CH:71]=[CH:70][C:69]=2[F:75])[S:64]1)=[N+:58]=[N-:59]>C(#N)C>[N:57]([CH2:60][CH2:61][CH2:62][C@:63]1([C:76]2[CH:81]=[CH:80][CH:79]=[CH:78][CH:77]=2)[N:67]([C:20](=[O:22])[C@@H:19]([O:18][Si:1]([C:14]([CH3:16])([CH3:15])[CH3:17])([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH3:23])[N:66]=[C:65]([C:68]2[CH:73]=[C:72]([F:74])[CH:71]=[CH:70][C:69]=2[F:75])[S:64]1)=[N+:58]=[N-:59]
Reactant: C[C@H](O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)C(=O)O
Reactant: [N-]=[N+]=NCCCC1(c2ccccc2)NN=C(c2cc(F)ccc2F)S1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)C(=O)N1N=C(c2cc(F)ccc2F)S[C@@]1(CCCN=[N+]=[N-])c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 25.1 %

Procedure:
To a solution of (S)-2-(t-butyldiphenylsilyloxy)propanoic acid (339 mg, 1.09 mmol) in acetonitrile (6 mL) was added HATU (550 mg, 1.45 mmol) followed by DIEA (0.378 mL, 2.17 mmol). After stirring at room temperature for 15 minutes, a solution of 2-(3-azidopropyl)-5-(2,5-difluorophenyl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazole (260 mg, 0.72 mmol) in acetonitrile (4 mL) was added. After stirring at room temperature for 16 hours, the mixture was concentrated under reduced pressure and partitioned between saturated NaHCO3 (50 mL) and ethyl acetate (50 mL). The aqueous layer was extracted with ethyl acetate, and the combined organic phases were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The brown oil was chromatographed (9:1 hexanes/ethyl acetate) to provide the less polar diastereomer, (S)-1-((S)-2-(3-azidopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-(t-butyldiphenylsilyloxy)propan-1-one (121 mg) and the more polar diastereomer, (S)-1-((R)-2-(3-azidopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-(t-butyldiphenylsilyloxy)propan-1-one (175 mg) as pale yellow oils. Absolute stereochemistry was assigned by examination of a protein inhibitor co-crystal structure of Eg5 and (S)-1-((S)-2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-methoxypropan-1-one.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH:7]=[CH2:8])[CH:2]1[O:4][CH2:3]1.[H-].[O-2:10].[Al+3].[O-2].[O-2].[Al+3]>C1(C)C=CC=CC=1.O=[Pt]=O>[CH2:1]([O:5][CH2:6][CH:7]1[O:10][CH2:8]1)[CH:2]1[O:4][CH2:3]1
Reactant: [O-2]
Reactant: C=CCOCC1CO1
Agent: O=[Pt]=O
Agent: [Al+3]
Agent: [H-]
Solvent: Cc1ccccc1
Product: C(OCC1CO1)C1CO1
Temperature: 90 °C
Yield: 87.2 %

Procedure:
Allyl glycidyl ether (13.2 mL, 0.111 mol) was added to HMS-501 (10.0 g, 0.0741 mol) in toluene. A catalytic amount of PtO2 was added, and the mixture was heated at 90° C., overnight. An NMR spectrum taken the following day showed there to be substantially no remaining hydride (peak at approx. 4.7 ppm). The reaction mixture was then cooled and passed through a bed of aluminum oxide layered on top of a fitted glass filter. The frit was washed with additional toluene. The eluent was collected in a round-bottom flask. The solvent and residual allyl glycidyl ether were then removed in vacuo at 50° C., to yield the epoxy-PDMS as a thick clear liquid (16.09 g, 87.2%).
Reaction SMILES: [Cl-].[NH4+].[Cl:3][C:4]1[CH:19]=[CH:18][C:7]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[N+:15]([O-])=O)=[CH:6][CH:5]=1>C(O)C.O.[Fe]>[Cl:3][C:4]1[CH:19]=[CH:18][C:7]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[NH2:15])=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1cnccc1Oc1ccc(Cl)cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Nc1cnccc1Oc1ccc(Cl)cc1
Yield: 74.6 %

Procedure:
To a refluxing mixture of iron powder (1.91 g, 34.43 mmol) and ammonium chloride (230 mg, 4.30 mmol) in ethanol (45 μL) and water (8 mL) was added 4-(4-chlorophenoxy)-3-nitropyridine (AMR01116, 1.57 g, 6.26 mmol) and the resulting mixture was stirred at reflux for 1 h. After removal of the solvent, the residue was diluted in aqueous sodium hydrogen carbonate (40 mL) and extracted with DCM (3×20 mL). The organic layer was dried (MgSO4), filtered and evaporated. Flashmaster chromatography of the crude product using DCM/MeOH 9:1 as eluent gave 4-(4-chlorophenoxy)-pyridin-3-ylamin (1.03 g, 75%) as a white solid, mp 104-106° C.
Reaction SMILES: [CH3:1][N:2]([CH3:20])[C:3]1[N:8]=[C:7]2[N:9]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[C:10](=[O:13])[N:11]([CH3:12])[C:6]2=[CH:5][CH:4]=1.[CH3:21][S:22]([N:25]1[CH2:30][CH2:29][C:28]2[N:31]([CH2:44][C@@H:45]3[CH2:47][O:46]3)[N:32]=[C:33]([C:34]3[CH:39]=[CH:38][C:37]([C:40]([F:43])([F:42])[F:41])=[CH:36][CH:35]=3)[C:27]=2[CH2:26]1)(=[O:24])=[O:23]>CCO.ClC(Cl)C>[CH3:1][N:2]([CH3:20])[C:3]1[N:8]=[C:7]2[N:9]([CH:14]3[CH2:19][CH2:18][N:17]([CH2:47][C@H:45]([OH:46])[CH2:44][N:31]4[C:28]5[CH2:29][CH2:30][N:25]([S:22]([CH3:21])(=[O:24])=[O:23])[CH2:26][C:27]=5[C:33]([C:34]5[CH:39]=[CH:38][C:37]([C:40]([F:42])([F:43])[F:41])=[CH:36][CH:35]=5)=[N:32]4)[CH2:16][CH2:15]3)[C:10](=[O:13])[N:11]([CH3:12])[C:6]2=[CH:5][CH:4]=1
Reactant: CN(C)c1ccc2c(n1)n(C1CCNCC1)c(=O)n2C
Reactant: CS(=O)(=O)N1CCc2c(c(-c3ccc(C(F)(F)F)cc3)nn2C[C@@H]2CO2)C1
Solvent: CCO
Solvent: CC(Cl)Cl
Product: CN(C)c1ccc2c(n1)n(C1CCN(C[C@H](O)Cn3nc(-c4ccc(C(F)(F)F)cc4)c4c3CCN(S(C)(=O)=O)C4)CC1)c(=O)n2C
Temperature: 80 °C
Reaction time: 16 h
Yield: 112.3 %

Procedure:
To a stirring solution of 0.24 g (0.0009 mol) of 5-dimethylamino-1-methyl-3-piperidin-4-yl-1,3-dihydro-imidazo[4,5-b]pyridin-2-one in EtOH/Dichloroethane (1.5 mL/1.5 mL) was added 0.23 g (0.0005 mol) of (R)-5-methanesulfonyl-1-oxiranylmethyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine. The reaction mixture was heated to 80° C. and stirred for 16 h and concentrated. The crude product was then dissolved in CH2Cl2 (40 mL) and purified using flash chromatography (0-6% MeOH/CH2Cl2) affording 0.38 g (97%) of the desired product as a white solid. MS (electrospray): exact mass calculated for C31H39F3N8O4S, 676.28; m/z found, 677.28 [M+H]+. 1H NMR (400 MHz, CDCl3): 7.71 and 7.67 (A and B of AA′BB′ quartet, Jab=8.3 Hz, 4H), 7.03 (d, J=8.6 Hz, 1H), 6.16 (d, J=8.6 Hz, 1H), 4.58 and 4.56 (A and B of AB quartet, Jab=14.5 Hz, 2H), 4.36 (ft, J=12.1 Hz, 4.04 Hz, 1H), 4.25-4.01 (m, 4H), 3.77-3.60 (m, 2H), 3.33 (s, 3H), 3.16-3.04 (m, 2H), 3.03 (s, 6H), 2.99-2.90 (m, 2H), 2.88 (s, 3H), 2.77 (qd, J=12.1 Hz, 3.54 Hz, 2H), 2.56-2.42 (m, 3H), 2.21 (t, J=11.6 Hz, 1H), 1.75 (d, J=11.6 Hz, 2H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:16][C:15]2([C:17]([O:19][CH3:20])=[O:18])[CH:10]([C:11](=O)[CH2:12][CH2:13][CH:14]2[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[O:27][CH3:28])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH2:31][NH2:32]>CO>[CH2:1]([N:8]1[CH2:16][C:15]2([C:17]([O:19][CH3:20])=[O:18])[CH:10]([C:11](=[N:31][NH2:32])[CH2:12][CH2:13][CH:14]2[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[O:27][CH3:28])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NN
Reactant: COC(=O)C12CN(Cc3ccccc3)CC1C(=O)CCC2c1ccccc1OC
Solvent: CO
Solvent: O
Product: COC(=O)C12CN(Cc3ccccc3)CC1C(=NN)CCC2c1ccccc1OC
Yield: 101.4 %

Procedure:
A solution of 166.6 g (0.424 mol) of methyl (3aRS,4SR,7aRS)-2-benzyl-4-(2-methoxyphenyl)-7-oxo-octahydroisoindole-3a-carboxylate and of 84.5 g (1.69 mol) of hydrazine hydrate in 2.8 dm3 of methanol is brought to reflux for two hours. After concentrating the methanol under reduced pressure, the residue was taken up in 2 dm3 of dichloromethane, washed with four times 1 dm3 of distilled water, dried over magnesium sulphate and concentrated under reduced pressure. 175.2 g of methyl (3aRS,4SR,7aRS)-2-benzyl-7-hydrazono-4-(2-methoxyphenyl)octahydroisoindole-3a-carboxylate were thus obtained in the form of a yellow oil, the characteristics of which were as follows:
Reaction SMILES: CS([O:5][CH:6]([CH3:35])[CH:7]([N:9]1[C:13](=[O:14])[N:12]([C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH2:26][CH2:25][N:24]([C:27]4[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=4)[CH2:23][CH2:22]3)=[CH:17][CH:16]=2)[CH:11]=[N:10]1)[CH3:8])(=O)=O.[OH-].[K+]>CO.O1CCCC1>[OH:5][CH:6]([CH3:35])[CH:7]([N:9]1[C:13](=[O:14])[N:12]([C:15]2[CH:16]=[CH:17][C:18]([N:21]3[CH2:22][CH2:23][N:24]([C:27]4[CH:28]=[CH:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=4)[CH2:25][CH2:26]3)=[CH:19][CH:20]=2)[CH:11]=[N:10]1)[CH3:8]
Reactant: COc1ccc(N2CCN(c3ccc(-n4cnn(C(C)C(C)OS(C)(=O)=O)c4=O)cc3)CC2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(N2CCN(c3ccc(-n4cnn(C(C)C(C)O)c4=O)cc3)CC2)cc1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
According to the precedure described in Nakamura et al. (J.A.C.S. 1985, 107 p2138), intermediate 5d (0.001 mol) was added to a solution of KOH (0.03 g) in CH3OH (7 ml) and tetrahydrofuran (3 ml). The mixture was stirred at 100° C. for 4 hours, yielding [S-(R*,R*)]-2,4-dihydro-2-(2-hydroxy-1-methylpropyl)-4-[4-[4-(4-methoxyphenyl)-1-piperazinyl]phenyl]-3H-1,2,4-triazol-3-one (interm. 5c).
Reaction SMILES: [OH:1][CH2:2][C:3]([CH2:10][OH:11])([CH2:7][CH:8]=[CH2:9])[C:4]([OH:6])=[O:5].[C:12]([O-])([O-])=O.[K+].[K+].CI>CC(C)=O>[OH:1][CH2:2][C:3]([CH2:10][OH:11])([CH2:7][CH:8]=[CH2:9])[C:4]([O:6][CH3:12])=[O:5]
Reactant: O=C([O-])[O-]
Reactant: C=CCC(CO)(CO)C(=O)O
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: C=CCC(CO)(CO)C(=O)OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 23.2 %

Procedure:
A mixture of crude 2,2-bis(hydroxymethyl)pent-4-enoic acid (1 eq., 8.72 g), K2CO3 (3 eq., 22.9 g) and acetone (109 ml) was stirred at room temperature for 30 min. MeI (6 eq., 46.4 g) was added at 0° C. The mixture was stirred at room temperature for 2 days and concentrated. Water and EtOAc were added. The aqueous layer was extracted with 3×EtOAc. The organic layers were dried over MgSO4. Silica gel chromatography using 4-40% ACN (containing 5% MeOH)-DCM yields the title compound as colorless oil (2.2 g, 23% for two steps).
Reaction SMILES: [C:1]([OH:10])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][C:6](O)=O.[CH3:11][NH2:12]>O>[CH3:11][N:12]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]1=[O:10]
Reactant: CN
Reactant: O=C(O)CCCCC(=O)O
Solvent: O
Product: CN1CCCCCC1=O

Procedure:
This example illustrates that adipic acid may be successfully hydrogenated in the presence of water and methyl amine to produce N-methyl-caprolactam.
Reaction SMILES: [Cl-:1].[Cl-:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[C:23]1[CH:28]=[CH:27][C:26]([C:29]([C:38]2[CH:43]=[CH:42][C:41](O)=[CH:40][CH:39]=2)([C:34]([F:37])([F:36])[F:35])[C:30]([F:33])([F:32])[F:31])=[CH:25][CH:24]=1>ClCCl>[Cl:1][C:23]1[CH:28]=[CH:27][C:26]([C:29]([C:38]2[CH:43]=[CH:42][C:41]([Cl:2])=[CH:40][CH:39]=2)([C:34]([F:37])([F:36])[F:35])[C:30]([F:33])([F:32])[F:31])=[CH:25][CH:24]=1
Reactant: Oc1ccc(C(c2ccc(O)cc2)(C(F)(F)F)C(F)(F)F)cc1
Reactant: [Cl-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: FC(F)(F)C(c1ccc(Cl)cc1)(c1ccc(Cl)cc1)C(F)(F)F
Reaction time: 4 h

Procedure:
To a slurry of triphenylphosphine dichloride (0.2 moles) in dichloromethane (250 ml) under argon is added 2,2-bis(4-hydroxyphenyl)hexafluoropropane (0.1 mole). The solvent is removed by distillation to form an essentially solid reaction mixture in the reaction vessel. The reaction vessel is heated in a molten metal bath to form a molten reaction mixture and the mixture agitated for approximately four hours before cooling to obtain a solid reaction product. The resulting solid is dissolved in dichloromethane and washed first with dilute sodium hydroxide and second with deionized water. The resulting organic fraction is collected and purified passing it through a silica gel chromatographic column using hexane as the eluting solvent. The hexane is removed from the eluate with a rotary evaporator to yield 2,2-bis(4-chlorophenyl)hexafluoropropane.
Reaction SMILES: [CH:1]1([C:6]2([CH3:19])[CH2:14][C:13]3[C:8](=[C:9]([Cl:17])[C:10]([Cl:16])=[C:11]([OH:15])[CH:12]=3)[C:7]2=[O:18])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:20]1(=[O:24])[O:23][CH2:22][CH2:21]1.Cl>[OH-].[Na+]>[O:18]=[C:7]1[C:8]2[C:13](=[CH:12][C:11]([O:15][CH2:22][CH2:21][C:20]([OH:24])=[O:23])=[C:10]([Cl:16])[C:9]=2[Cl:17])[CH2:14][C:6]1([CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5]1)[CH3:19]
Reactant: CC1(C2CCCC2)Cc2cc(O)c(Cl)c(Cl)c2C1=O
Reactant: O=C1CCO1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CC1(C2CCCC2)Cc2cc(OCCC(=O)O)c(Cl)c(Cl)c2C1=O

Procedure:
2-Cyclopentyl-2-methyl-5-hydroxy-6,7-dichloro-1-indanone (15.5 g., 0.05 mole) is dissolved in a 10% sodium hydroxide solution (50 ml.). The solution is heated to reflux and beta-propiolactone (36.0 g., 0.5 mole) is added at such a rate as to keep the reaction mixture refluxing. The reaction mixture is kept basic by the addition of 10% sodium hydroxide. The reaction mixture is cooled and acidified with dilute hydrochloric acid. The product is extracted with ether and extracted from the ether solution with a 5% solution of sodium bicarbonate. Acidification affords the desired product.
Reaction SMILES: [C:1]1([C:7]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:8]2[CH:12]=[C:11]([CH:13]=[CH:14][CH:15]3[CH2:20][CH2:19][N:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[C:17](=[O:27])[CH2:16]3)[N:10]=[CH:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>CO.[H][H].[Pd]>[C:34]1([C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[N:8]2[CH:12]=[C:11]([CH2:13][CH2:14][CH:15]3[CH2:20][CH2:19][N:18]([C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)[C:17](=[O:27])[CH2:16]3)[N:10]=[CH:9]2)[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: O=C1CC(C=Cc2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)CCN1c1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: O=C1CC(CCc2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)CCN1c1ccccc1

Procedure:
The product from Step I is dissolved in methanol and hydrogenated at 60 psi hydrogen with 10% palladium on carbon. When reaction is complete, the catalyst is filtered and the title compound obtained after evaporation of solvent.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].O=[C:8]1[CH2:14][CH:13]2[N:15]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH:10]([CH2:11][CH2:12]2)[CH2:9]1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1.CCCCCC>[CH2:1]=[C:8]1[CH2:14][CH:13]2[N:15]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH:10]([CH2:11][CH2:12]2)[CH2:9]1
Reactant: CC(C)(C)[O-]
Reactant: CC(C)(C)OC(=O)N1C2CCC1CC(=O)C2
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C=C1CC2CCC(C1)N2C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.6 %

Procedure:
Potassium tert-butoxide (0.62 g, 5.5 mmol) was added to a suspension of methyltriphenylphosphonium bromide (1.98 g, 5.5 mmol) in tetrahydrofuran (20 mL) and the resulting mixture was stirred at room temperature for one hour. A solution of tert-butyl 3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate (0.50 g, 2.2 mmol) in tetrahydrofuran (5 mL) was then added and the resulting mixture was stirred at 35° C. for two hours. The mixture was cooled, diluted with hexane (100 mL), filtered, and the filtrate was washed with water then brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (20% ethyl acetate in hexanes) to give tert-butyl 3-methylene-8-azabicyclo[3.2.1]octane-8-carboxylate (0.45 g, 91% yield). GC-MS (EI) for C13H21NO2: 223 (M+).
Reaction SMILES: C([O:8][C:9]1[C:14]([C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:13][CH:12]=[CH:11][C:10]=1[C:19]([C:21]1[CH:22]=[C:23]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[O:33][CH3:34])[CH:24]=[CH:25][CH:26]=1)=[CH2:20])C1C=CC=CC=1>CO.C(OCC)(=O)C.[Pd]>[C:15]([C:14]1[CH:13]=[CH:12][CH:11]=[C:10]([CH:19]([C:21]2[CH:22]=[C:23]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[O:33][CH3:34])[CH:24]=[CH:25][CH:26]=2)[CH3:20])[C:9]=1[OH:8])([CH3:16])([CH3:17])[CH3:18]
Reactant: C=C(c1cccc(-c2ccccc2OC)c1)c1cccc(C(C)(C)C)c1OCc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1ccccc1-c1cccc(C(C)c2cccc(C(C)(C)C)c2O)c1
Reaction time: 3 h
Yield: 59.3 %

Procedure:
A solution of 28 (1.3 g, 2.9 mmol) in methanol (20 mL) and ethyl acetate (30 mL) was treated with 20% palladium on activated carbon (50% wet, 0.10 g) and was hydrogenated at 40 psi in a Parr shaker for 3 hr. The catalyst was filtered out and washed with ethyl acetate. The filtrate was stripped and the crude product was purified by chromatography on silica (60 g) with 2% ethyl acetate in hexane (3 L) to afford pure D3 (0.62 g, 59%).
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[F:12][C:13]([F:17])([F:16])[CH2:14][OH:15].[OH-].[Na+].OS(O)(=O)=O>C1(C)C=CC=CC=1.O>[F:8][C:6]1[CH:5]=[CH:4][C:3]([N+:9]([O-:11])=[O:10])=[C:2]([O:15][CH2:14][C:13]([F:17])([F:16])[F:12])[CH:7]=1
Reactant: OCC(F)(F)F
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1ccc(F)cc1OCC(F)(F)F
Temperature: 47.5 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2,4-difluoronitrobenzene (300.0 g, 1.89 mol) and 2,2,2-trifluoroethanol (245.0 g, 2.45 mol) in toluene (600 mL) was added sodium hydroxide (90.5 g, 2.26 mol) in portions over 30 min to keep the temperature between 30 and 40° C. After the temperature had dropped to 30° C., the reaction mixture was heated to 45-50° C. using an oil bath for additional 16 h. After cooling, water (500 mL) and 2.5 N H2SO4 (200-300 mL, for adjustment of pH to 5) were added and the organic layer was separated. The water layer was extracted with EtOAc (2×300 mL). The combined organic layers were washed with saturated sodium chloride solution (100 mL) and dried over magnesium sulfate. The solvent was evaporated to give a yellow oil, which solidified after 30 min to give a yellowish solid (450.0 g, quantitative). The crude product was used in the next step without purification. 1H NMR (300 MHz, CDCl3/TMS): δ 8.03-7.98 (m, 1H), 6.93-6.82 (m, 2H), 4.49 (q, J=7.7 Hz, 2H). 13C NMR (75 MHz, CDCl3/TMS): δ 165.0 (d, 1JCF=259.6 Hz), 152.3 (d, 3JCF=13.1 Hz), 128.2 (d, 3JCF=11.9 Hz), 122.4 (d, 1JCF=273.4 Hz), 110.1 (d, 2JCF=22.5 Hz), 105.9 (q, 1JCF=242.6 Hz), 104.3 (d, 2JCF=26.1 Hz), 67.6 (q, 1JCF=36.7 Hz).
Reaction SMILES: CO.[CH3:3][NH2:4].CO.F[C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=1>O>[CH3:3][NH:4][C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=1
Reactant: N#Cc1ccc(F)cc1
Reactant: CN
Solvent: CO
Solvent: O
Product: CNc1ccc(C#N)cc1

Procedure:
A 40% methylamine methanol solution (7.5 mL) was added to a methanol (2.5 mL) solution of 4-fluorobenzonitrile (2.00 g) and the mixture was heated under reflux for fifteen hours under nitrogen atmosphere. After the solvent was removed under reduced pressure, to the residue obtained was added water (15 mL) and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine successively, and dried over anhydrous sodium sulfate. The oil obtained by removal of the solvent under reduced pressure was purified by silica gel column chromatography (eluent; hexane:ethyl acetate=2:1) to obtain the titled compound (0.48 g) as crystals.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[C:16]([S:21]([CH3:24])(=[O:23])=[O:22])[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:25][C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[N:31]([CH3:35])[C:30]([S:36](Cl)(=[O:38])=[O:37])=[CH:29]2>ClCCCl.CN(C1C=CN=CC=1)C.ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][S:36]([C:30]3[N:31]([CH3:35])[C:32]4[C:28]([CH:29]=3)=[CH:27][C:26]([F:25])=[CH:34][CH:33]=4)(=[O:38])=[O:37])=[C:16]([S:21]([CH3:24])(=[O:23])=[O:22])[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cn1c(S(=O)(=O)Cl)cc2cc(F)ccc21
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(N)c(S(C)(=O)=O)c2)CC1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Product: Cn1c(S(=O)(=O)Nc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)cc2S(C)(=O)=O)cc2cc(F)ccc21
Temperature: 80 °C
Reaction time: 72 h
Yield: 24.8 %

Procedure:
To a solution of 4-(4-amino-3-methanesulfonyl-phenyl)-piperidine-1-carboxylic acid tert-butyl ester (cf. Example 24e, 0.048 g) in 1,2-dichloroethane (3.0 ml) was added 5-fluoro-1-methyl-1H-indole-2-sulfonyl chloride (0.035 g) and DMAP (0.025 g). The reaction mixture was stirred at 80° C. for 72 h, diluted with dichloromethane (2 ml) and chromatographed on silica gel using dichloromethane/ethyl acetate as eluent to obtain the title compound (0.019 g) as an off-white foam. MS (ISN): 564.3 (M−H)−
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](/[CH:8]=[CH:9]/[C:10](OCC)=[O:11])[CH:5]=[CH:6][CH:7]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4](/[CH:8]=[CH:9]/[CH2:10][OH:11])[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)/C=C/c1cccc(Br)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: Cc1ccccc1
Product: OC/C=C/c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.7 %

Procedure:
A vigorously stirred solution of ethyl trans-3-(3-bromophenyl)-2-propenoate (26.71 g, 0.105 mol) in dry toluene (150 ml) at -5° C. (ice-EtOH) under nitrogen was treated with lithium aluminium hydride (3.98 g, 0.105 mol) in one portion. The reaction temperature was allowed to gradually warm to room temperature over 30 min., at 25° C. the reaction became quite exothermic (25-40° C.) with the formation of a grey gelatinous precipitate. Stirring was continued for 1 h, after which the reaction was carefully quenched with water (300 ml) and ice (200 g) then allowed to stand at 25° C. for 30 min. The mixture was filtered through Celite (Registered Trade Mark) and the residue was washed with ethyl acetate (2×200 ml). The filtrate was extracted with the organic washings, the combined organic phases were washed with brine (3×300 ml), water (300 ml), dried (Na2SO4) and evaporated to give the title compound as a pale yellow oil (21.42 g, 96%). Distillation at 120° C. at 0.05 mmHg. gave a colourless oil. (Found C, 50.73; H, 4.12; Br, 37.53. C9H9BrO requires C, 50.73; H, 4.26; Br, 37.50%); Vmax (thin film)/cm-1 3325.5 (br. OH), 2862.0, 1653.0, 1591.0, 1562.5; δH (270 MHz) 2.15 (1H, bs, 1-OH), 4.30 (2H, dd, 2×1H, 3J1,2 =5.5, 4J1,3 =1.5 Hz), 6.33 (1H, dt, 2-H, 3J2,3 =15.8, 3J2,1 =5.3 Hz), 6.53 (1H, dt, 3-H, 3J3,2 =16.2, 4J3,1 =1.3 Hz), 7.15 (1H, t, 5'-H, Jo =7.8 Hz), 7.26 (1H, dt, 6'-H, Jo =7.6, Jm =1.3 Hz), 7.35 (1H, dt, 4'-H, Jo =7.9, Ja =1.6 Hz), 7.50 (1H, t, 2'-H, Jm =1.6 Hz). δC (67.8 MHz) 63.2 (1-C), 122.7 (3'-C), 125.0 (2-C), 129.2 95'-H), 138.8 (1'-C). The remaining signals fall in the narrow range 130.0 to 130.4 ppm; m/z 214.1, 212.1 (44.86,49.78, M+), 196.0, 194.0 (1.47, 1.03), 185.0, 183.0 (10.81, 12.19), 172.0, 170.0 (46.47, 49.07), 158.0, 156.0 (15.47, 15.80), 133.1, 131.1 (36.29, 25.66), 104.1 (100).