Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C@:5]([C@@H:14]1[CH2:19][CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15]1)([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[CH:8]=1)[OH:6].[CH3:27][S:28](Cl)(=[O:30])=[O:29]>>[Cl:13][C:9]1[CH:8]=[C:7]([C@@:5]([OH:6])([C@@H:14]2[CH2:19][CH2:18][CH2:17][NH:16][CH2:15]2)[CH2:4][CH2:3][CH2:2][NH:1][S:28]([CH3:27])(=[O:30])=[O:29])[CH:12]=[CH:11][CH:10]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]([C@@](O)(CCCN)c2cccc(Cl)c2)C1
Reactant: CS(=O)(=O)Cl
Product: CS(=O)(=O)NCCC[C@@](O)(c1cccc(Cl)c1)[C@@H]1CCCNC1

Procedure:
N—((S)-4-(3-chlorophenyl)-4-hydroxy-4-((R)-piperidin-3-yl)butyl)methanesulfonamide was prepared by reaction of (R)-tert-butyl 3-((S)-4-amino-1-(3-chlorophenyl)-1-hydroxybutyl)piperidine-1-carboxylate with methanesulfonyl chloride followed by Boc removal using the conditions described in Example 83 Step 2.
Reaction SMILES: [CH3:1][N:2]([CH3:13])[CH2:3][CH2:4][N:5]1[CH:9]=[C:8]([N+:10]([O-])=O)[CH:7]=[N:6]1.Cl.O1CCOCC1>CO.O1CCOCC1>[CH3:1][N:2]([CH3:13])[CH2:3][CH2:4][N:5]1[CH:9]=[C:8]([NH2:10])[CH:7]=[N:6]1
Reactant: CN(C)CCn1cc([N+](=O)[O-])cn1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CN(C)CCn1cc(N)cn1
Reaction time: 8 h

Procedure:
N,N-dimethyl-2-(4-nitro-1H-pyrazol-1-yl)ethanamine (1.19 g, 6.46 mmol)was dissolved in methanol (65 ml) and the flask was equipped with a hydrogenation stopcock apparatus. The flask was purged with N2 and 10% Pd/C (100 mg) was added. The flask was again purged with N2, then flushed with H2 and left overnight stirring under H2 (1 atm). The reaction was purged with N2 and filtered through Celite, rinsing with methanol. The filtrate was concentrated in vacuo to give a viscous oil, which was dissolved in dioxane and treated with excess 4N HCl-dioxane, whereupon a thick and somewhat gummy precipitate formed. The mixture was concentrated to dryness and dried under vacuum.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH:14]([C:16]2[N:17]=[C:18]([C:22]3[CH:27]=[CH:26][C:25](Br)=[CH:24][CH:23]=3)[O:19][C:20]=2[CH3:21])[CH3:15])=[CH:8][C:7]=1[CH3:29].C([Sn](CCCC)(CCCC)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=1)CCC>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:30])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH:14]([C:16]2[N:17]=[C:18]([C:22]3[CH:27]=[CH:26][C:25]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=4)=[CH:24][CH:23]=3)[O:19][C:20]=2[CH3:21])[CH3:15])=[CH:8][C:7]=1[CH3:29]
Reactant: COC(=O)CCc1ccc(OCC(C)c2nc(-c3ccc(Br)cc3)oc2C)cc1C
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Solvent: Cc1ccccc1
Product: COC(=O)CCc1ccc(OCC(C)c2nc(-c3ccc(-c4ccccn4)cc3)oc2C)cc1C
Temperature: 25 °C

Procedure:
3-(4-{2-[2-(4-Bromo-phenyl)-5-methyl-oxazol-4-yl]-propoxy}-2-methylphenyl)-propionic acid methyl ester (592 mg, 1.25 mmol) is dissolved in anhydrous toluene (5 mL), degassed, and filled with nitrogen three times. Palladium tetrakis triphenyl phosphine [Pd(PPh3)4, 25 mg, 0.025 mmol] is added, and the degassing procedure is repeated. 2-tributylstannylpyridine (635 uL, 2.5 mmol) is then added via syringe and the reaction is heated to reflux. The reaction is monitored by HPLC. Upon complete consumption of starting material, the reaction is allowed to cool to room temperature and diluted with ethyl acetate. Celite is added and the mixture is filtered and rinsed with more ethyl acetate and water. The solution is further diluted with water and the two phases are separated. The organic layer is washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The pure 3-(2-Methyl-4-{2-[5-methyl-2-(4-pyridin-2-yl-phenyl)-oxazol-4-yl]-propoxy}-phenyl)-propionic acid methyl ester is obtained after column chromatography.
Reaction SMILES: [CH3:1][C@@:2]1([OH:13])[CH2:6][CH2:5][C@@H:4]([CH2:7][CH:8]=[CH:9][CH3:10])[C:3]1([CH3:12])[CH3:11].[C:14](Cl)(=[O:16])[CH3:15]>>[CH3:1][C@@:2]1([O:13][C:14](=[O:16])[CH3:15])[CH2:6][CH2:5][C@@H:4]([CH2:7][CH:8]=[CH:9][CH3:10])[C:3]1([CH3:12])[CH3:11]
Reactant: CC=CC[C@@H]1CC[C@@](C)(O)C1(C)C
Reactant: CC(=O)Cl
Product: CC=CC[C@@H]1CC[C@@](C)(OC(C)=O)C1(C)C

Procedure:
Using the procedure of Example 15, 2 g of (1R,S) 1,2,2-trimethyl-3-(2-butenyl)-cyclopentanol and 15 ml of acetyl chloride were reacted to obtain 1.8 g of (1R,S) 1,2,2-trimethyl-1-acetyloxy-3-(2-butenyl)-cyclopentane.
Reaction SMILES: [CH2:1]([C:3]1([CH2:17][CH3:18])[CH2:16][CH2:15][C:6]2=[C:7]([C:12]([OH:14])=O)[S:8][C:9]([S:10][CH3:11])=[C:5]2[CH2:4]1)[CH3:2].[CH3:19][Li]>C(OCC)C>[CH2:17]([C:3]1([CH2:1][CH3:2])[CH2:16][CH2:15][C:6]2=[C:7]([C:12](=[O:14])[CH3:19])[S:8][C:9]([S:10][CH3:11])=[C:5]2[CH2:4]1)[CH3:18]
Reactant: [Li]C
Reactant: CCC1(CC)CCc2c(C(=O)O)sc(SC)c2C1
Solvent: CCOCC
Product: CCC1(CC)CCc2c(C(C)=O)sc(SC)c2C1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 5,5-diethyl-3-methylsulfanyl-4,5,6,7-tetrahydro-benzo[c]thiophene-1-carboxylic acid (669 mg, 2.35 mmol) in diethyl ether (20 mL), a solution of methyllithium (2.6 mL, 1.6 M in diethyl ether) is added at rt. The reaction mixture is stirred at rt for 4 h, diluted with diethyl ether, washed with 1 N aq. K2HPO4 solution followed by 1 N aq. NaOH, dried over Na2SO4 and evaporated to give 1-(5,5-diethyl-3-methylsulfanyl-4,5,6,7-tetrahydro-benzo[c]thiophen-1-yl)-ethanone (458 mg) as a yellow oil, LC-MS: tR=1.15 min, [M+1]=283.1; 1H NMR(CDCl3): δ 2.96 (t, J=7.0 Hz, 2H), 2.53 (s, 3H), 2.45 (s, 3H), 2.32 (s, 2H), 1.56 (t, J=7.0 Hz, 2H), 1.35-1.20 (m, 4H), 0.83 (t, J=7.6 Hz, 6H).
Reaction SMILES: [OH:1][C:2]([CH3:27])([CH:9]=[CH:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:15][CH:14]=1)[CH2:3][C:4]([O:6]CC)=[O:5].[OH-].[Na+].[Br:30]Br.C(=O)([O-])O.[Na+]>CO>[OH:1][C:2]1([CH3:27])[CH:9]([Br:30])[CH:10]([CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:15][CH:14]=2)[O:6][C:4](=[O:5])[CH2:3]1
Reactant: BrBr
Reactant: CCOC(=O)CC(C)(O)C=CCCc1ccc(OCc2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC1(O)CC(=O)OC(CCc2ccc(OCc3ccccc3)cc2)C1Br
Yield: 52.9 %

Procedure:
The carboxylic acid (22.4 g) prepared by hydrolyzing 29.6 g of ethyl 3-hydroxy-3-methyl-7-(p-benzyloxyphenyl)-4-heptenoate with 80 ml of 4N sodium hydroxide solution in 500 ml of methanol, was treated with 9.73 g of bromine in an aqueous sodium hydrogen carbonate solution and the reaction mixture was worked up according to the method described in Example 1 (b). The product was recrystallized from a mixture of n-hexane and acetone (10:1) to yield 13.5 g of the desired compound melting at 155°-160° C.
Reaction SMILES: [CH2:1]([CH:3]([N:6]1[CH2:11][CH2:10][N:9]([C:12]([C:14]2[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=2)=[O:13])[CH2:8][CH2:7]1)[CH2:4][CH3:5])[CH3:2].[NH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1>>[CH2:1]([CH:3]([N:6]1[CH2:11][CH2:10][N:9]([C:12]([C:14]2[CH:21]=[CH:20][C:17]([CH2:18][N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)=[CH:16][CH:15]=2)=[O:13])[CH2:8][CH2:7]1)[CH2:4][CH3:5])[CH3:2]
Reactant: CCC(CC)N1CCN(C(=O)c2ccc(C=O)cc2)CC1
Reactant: C1CCNC1
Product: CCC(CC)N1CCN(C(=O)c2ccc(CN3CCCC3)cc2)CC1

Procedure:
Prepared from the product of Example 12 and pyrrolidine.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[N:9]1[C:16]2[N:12]([N:13]=[C:14]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[CH:15]=2)[CH:11]=[CH:10]1.[CH3:23][C:24]1[N:25]([C:29]2[CH:30]=[C:31]([CH:35]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:37]=2)[C:32](O)=[O:33])[CH:26]=[CH:27][N:28]=1>>[CH3:23][C:24]1[N:25]([C:29]2[CH:30]=[C:31]([CH:35]=[C:36]([C:38]([F:41])([F:39])[F:40])[CH:37]=2)[C:32]([NH:6][C:5]2[CH:7]=[CH:8][C:2]([CH3:1])=[C:3]([N:9]3[C:16]4[N:12]([N:13]=[C:14]([C:17]5[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=5)[CH:15]=4)[CH:11]=[CH:10]3)[CH:4]=2)=[O:33])[CH:26]=[CH:27][N:28]=1
Reactant: Cc1nccn1-c1cc(C(=O)O)cc(C(F)(F)F)c1
Reactant: Cc1ccc(N)cc1-n1ccn2nc(-c3cccnc3)cc12
Product: Cc1ccc(NC(=O)c2cc(-n3ccnc3C)cc(C(F)(F)F)c2)cc1-n1ccn2nc(-c3cccnc3)cc12

Procedure:
35 mg (0.12 mmol) of the compound of Example 6A and 33 mg (0.12 mmol) of 3-(2-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)benzoic acid [lit.: WO 2004/005281 A1, Example 91b] were reacted and worked up analogously to the procedure of Example 16. This gave 53 mg (81% of theory) of the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[S:10]([N:13]([CH2:28][C:29]1[CH:34]=[CH:33][C:32]([O:35]C2CCCCO2)=[C:31]([CH3:42])[CH:30]=1)[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][N:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)=[CH:16][CH:15]=1)(=[O:12])=[O:11].Cl>C(O)C.C(=O)(O)[O-].[Na+]>[OH:35][C:32]1[CH:33]=[CH:34][C:29]([CH2:28][N:13]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][N:23]3[CH2:24][CH2:25][CH2:26][CH2:27]3)=[CH:16][CH:15]=2)[S:10]([C:3]2[C:2]([CH3:1])=[CH:7][C:6]([CH3:8])=[CH:5][C:4]=2[CH3:9])(=[O:12])=[O:11])=[CH:30][C:31]=1[CH3:42]
Reactant: Cc1cc(C)c(S(=O)(=O)N(Cc2ccc(OC3CCCCO3)c(C)c2)c2ccc(OCCN3CCCC3)cc2)c(C)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Cc1cc(C)c(S(=O)(=O)N(Cc2ccc(O)c(C)c2)c2ccc(OCCN3CCCC3)cc2)c(C)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 52.4 %

Procedure:
To a solution of crude 2,4,6-trimethyl-N-[3-methyl-4-(tetrahydro-pyran-2-yloxy)-benzyl]-N-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-benzenesulfonamide (0.089 g, 0.15 mmol) prepared in Step A in 4 mL ethanol was added 0.8 mL of 1.2N HCl. The reaction mixture was stirred at room temperature for 2 days and was diluted with 10 mL saturated aqueous sodium bicarbonate. The aqueous solution was washed with methylene chloride (2×10 mL). The combined organic layers were dried (sodium sulfate), filtered, and concentrated in vacuo. The residue was purified by preparative TLC (1.0 mm silica gel layer, eluting with 10% methanol/ethyl acetate) to afford 0.040 g of the title compound. MS 509.1 (M+1)+
Reaction SMILES: [C:1]1([S:7][CH2:8][CH2:9][CH2:10][C:11]#[N:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:16])(=O)=O>C(Cl)Cl>[Cl:16][CH:8]([S:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH2:9][CH2:10][C:11]#[N:12]
Reactant: O=S(=O)(Cl)Cl
Reactant: N#CCCCSc1ccccc1
Solvent: ClCCl
Product: N#CCCC(Cl)Sc1ccccc1
Reaction time: 8 h
Yield: 102.9 %

Procedure:
To a solution of 50 g (0.28 mole) of 4-phenylthiobutyronitrile in 200 ml of methylene chloride is added 40.5 g (0.3 mole) of sulfuryl chloride dropwise during a period of six hours. Stirring is continued overnight. Solvent and excess sulfuryl chloride is then evaporated under vacuum to give 61 g of a crude product. This material is used in the next experiment without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[CH2:12]([O:14][C:15](=[O:33])[C:16]([O:23][C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=1[CH:31]=O)([CH2:20][CH2:21][CH3:22])[CH2:17][CH2:18][CH3:19])[CH3:13].N1CCCC1>CO>[CH2:12]([O:14][C:15](=[O:33])[C:16]([O:23][C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=1/[CH:31]=[C:6]1\[C:7](=[O:11])[NH:8][C:9]2[C:5]\1=[CH:4][CH:3]=[C:2]([Cl:1])[CH:10]=2)([CH2:20][CH2:21][CH3:22])[CH2:17][CH2:18][CH3:19])[CH3:13]
Reactant: O=C1Cc2ccc(Cl)cc2N1
Reactant: CCCC(CCC)(Oc1ccc(Cl)cc1C=O)C(=O)OCC
Solvent: CO
Solvent: C1CCNC1
Product: CCCC(CCC)(Oc1ccc(Cl)cc1/C=C1\C(=O)Nc2cc(Cl)ccc21)C(=O)OCC
Temperature: 80 °C
Yield: 20.6 %

Procedure:
To the mixture of 6-chlorooxindole (9.3 g, 55.7 mmol) and 2-(4-chloro-2-formyl-phenoxy)-2-propyl-pentanoic acid ethyl ester (14 g, 42.9 mmol) in methanol (100 mL) was added pyrrolidine (3.3 g, 47.2 mmol) dropwise. The mixture was then heated at 80° C. for 2 h. After cooled to room temperature, the mixture was concentrated. The residue was purified by flash column to give the title compound (4.2 g).
Reaction SMILES: Cl.Cl[C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[N:5][N:4]=1.[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[CH:15]=1>C(O)CCC>[CH3:20][C:16]1[CH:15]=[C:14]([CH:19]=[CH:18][CH:17]=1)[NH:13][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[N:5][N:4]=1
Reactant: Cc1cccc(N)c1
Reactant: Clc1nncc2ccccc12
Agent: Cl
Solvent: CCCCO
Product: Cc1cccc(Nc2nncc3ccccc23)c1
Temperature: 65 °C
Reaction time: 1 h

Procedure:
Under a N2 atmosphere, 30 g (149 mmol) 1-chlorophthalazine hydrochloride in 0.6 l n-butanol is mixed with 16.2 ml (149 mmol) m-toluidine and stirred for 1 h at 65° C. The solution is concentrated by evaporation and the residue distributed between dichloromethane/MeOH 10:1 and Na2CO3 solution (80 g in 0.5 l H2O). The aqueous phase is extracted twice with dichloromethane/MeOH 10:1, the organic phases are washed with Na2CO3 solution (80 g in 0.5 l H2O) and brine, dried (Na2SO4) and evaporated. The residue is taken up in 200 ml boiling dichloromethane/acetone 1:1, filtered hot, and partly evaporated. Then addition of DIPE leads to crystallization of the title compound, which is filtered off and washed with DIPE: m.p. 176-177° C.; 1H-NMR (DMSO-d6) 9.12 (s, HN), 9.08 (s, 1H), 8.59 (m, 1H), 7.99 (m, 3H), 7.76 (s, 1H), 7.73 (d, 1H), 7.24 (t, 1H), 6.86 (d, 1H), 2.32 (s, 3H); FAB-MS (M+H)+=236; an. calc. (C15H13N3.0.05 H2O) C, 76.28%; H, 5.59%; N, 17.79%; meas. C, 76.04%; H, 5.53%; N, 17.68%.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[CH:4][C:3]=1[C:10]1[N:14]([CH3:15])[N:13]=[CH:12][CH:11]=1.[NH2:16][C@@H:17]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:40])([F:39])[F:38])[CH:32]=1)[CH2:18][N:19]1[C:27](=[O:28])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]1=[O:29].C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)(Cl)Cl>[O:28]=[C:27]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20](=[O:29])[N:19]1[CH2:18][C@@H:17]([NH:16][C:7]([C:5]1[S:6][C:2]([CH3:1])=[C:3]([C:10]2[N:14]([CH3:15])[N:13]=[CH:12][CH:11]=2)[CH:4]=1)=[O:9])[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:39])([F:38])[F:40])[CH:32]=1
Reactant: Cc1sc(C(=O)O)cc1-c1ccnn1C
Reactant: N[C@@H](Cc1cccc(C(F)(F)F)c1)CN1C(=O)c2ccccc2C1=O
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1sc(C(=O)N[C@@H](Cc2cccc(C(F)(F)F)c2)CN2C(=O)c3ccccc3C2=O)cc1-c1ccnn1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.4 %

Procedure:
To a 50 mL round-bottomed flask was added 5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (201 mg, 0.91 mmol), 2-{(2S)-2-amino-3-[3-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione (301 mg, 0.87 mmol) [Prepared according to Preparation 6 except substituting N-{[(1,1-dimethylethyl)oxy]carbonyl}-3-(trifluoromethyl)-L-phenylalanine (4.98 g, 14.95 mmol) for N-{[(1,1-dimethylethyl)oxy]carbonyl}-2-(trifluoromethyl)-L-phenylalanine] and PyBrop (519 mg, 1.11 mmol) in chloroform (9 mL). DIEA (790 μL, 4.52 mmol) was added and the mixture stirred overnight at room temperature. The reaction mixture was adsorbed onto silica and purified via column chromatography (25-70% EtOAc/Hex) affording the title compound (247 mg, 45%): LC-MS (ES) m/z=553 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[C:19]([O:20][CH2:21][CH:22]([CH3:24])[CH3:23])=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][N:11]=1.NC(N)=[O:27].OO.FC(F)(F)C(OC(=O)C(F)(F)F)=O.C(=O)([O-])O.[Na+]>C(#N)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[C:19]([O:20][CH2:21][CH:22]([CH3:24])[CH3:23])=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][N+:11]=1[O-:27]
Reactant: COC(=O)c1cnc(-c2cc(OC)ccc2F)c(OCC(C)C)c1
Reactant: NC(N)=O
Agent: O=C([O-])O
Agent: OO
Agent: [Na+]
Solvent: CC#N
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: COC(=O)c1cc(OCC(C)C)c(-c2cc(OC)ccc2F)[n+]([O-])c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.4 %

Procedure:
Under a nitrogen atmosphere, to a solution of methyl 6-(2-fluoro-5-methoxyphenyl)-5-isobutoxynicotinate (758 mg) in acetonitrile (9.4 mL) were added urea-hydrogen peroxide adduct (555 mg) and trifluoroacetic anhydride (793 μL) at 0° C., and the mixture was gradually warmed to room temperature and stirred overnight. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the solvent was evaporated under reduced pressure. The residue was filtered, and the solvent in the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (631 mg) as a pale-yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:8][C:9]2[C:17]3[C:12](=[CH:13][C:14]([Cl:18])=[CH:15][CH:16]=3)[NH:11][CH:10]=2)[CH:5]=[CH:6][CH:7]=1.Br[C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1>>[Br:1][C:2]1[CH:3]=[C:4]([S:8][C:9]2[C:17]3[C:12](=[CH:13][C:14]([Cl:18])=[CH:15][CH:16]=3)[N:11]([C:20]3[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=3)[CH:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Brc1cccnc1
Reactant: Clc1ccc2c(Sc3cccc(Br)c3)c[nH]c2c1
Product: Clc1ccc2c(Sc3cccc(Br)c3)cn(-c3cccnc3)c2c1

Procedure:
Prepared according to the procedure described in Example 27, Step 1, using the following starting materials: 3-(3-bromo-phenylsulfanyl)-6-chloro-1H-indole and 3-bromopyridine.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]([CH:12]([NH:15][CH2:16][C:17]1[CH:33]=[CH:32][C:20]([O:21][C:22]([CH3:31])([CH3:30])[C:23]([O:25]C(C)(C)C)=[O:24])=[CH:19][CH:18]=1)[CH2:13][CH3:14])=[O:11].FC(F)(F)C(O)=O>ClCCl>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]([CH:12]([NH:15][CH2:16][C:17]1[CH:18]=[CH:19][C:20]([O:21][C:22]([CH3:30])([CH3:31])[C:23]([OH:25])=[O:24])=[CH:32][CH:33]=1)[CH2:13][CH3:14])=[O:11]
Reactant: CCC(NCc1ccc(OC(C)(C)C(=O)OC(C)(C)C)cc1)C(=O)Nc1ccc(C)cc1C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCC(NCc1ccc(OC(C)(C)C(=O)O)cc1)C(=O)Nc1ccc(C)cc1C
Yield: 75.8 %

Procedure:
Similarly to the procedure of Example 1-9, 170 mg (0.374 mmol) of tert-butyl 2-(4-{[(1-{[(2,4-dimethylphenyl)amino]carbonyl}propyl)amino]methyl}phenoxy)-2-methylpropionate (Example 1-7) are reacted with 0.72 ml (9.35 mmol) of trifluoroacetic acid in 3 ml of dichloromethane to give 113 mg (72%) of 2-(4-{[(1-{[(2,4-dimethylphenyl)amino]carbonyl}propyl)amino]methyl}phenoxy)-2-methyl-propionic acid.
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[CH:6][N:5]=[CH:4][CH:3]=1.[H-].[Na+].[C:13]([C:15]1[CH:22]=[CH:21][C:18]([CH2:19]Br)=[CH:17][CH:16]=1)#[N:14]>CN(C=O)C.O>[C:13]([C:15]1[CH:22]=[CH:21][C:18]([CH2:19][N:5]2[CH:4]=[CH:3][C:2](=[O:1])[C:7]([C:8]([OH:10])=[O:9])=[CH:6]2)=[CH:17][CH:16]=1)#[N:14]
Reactant: N#Cc1ccc(CBr)cc1
Reactant: O=C(O)c1cnccc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccc(Cn2ccc(=O)c(C(=O)O)c2)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 4-hydroxynicotinic acid (2.00 g, 14.4 mmol) in DMF (30 mL) is added sodium hydride (0.62 g, 55% dispersion in mineral oil, 14.2 mmol). After stirring for 10 min at room temperature, 4-cyanobenzyl bromide (2.88 g, 14.7 mmol) is added. After stirring for 2 h at room temperature, DMF (15 mL) is added and the reaction mixture is diluted with water. The formed precipitate is filtered off and dried. Yield: 2.57 g (56% of theory); ESI mass spectrum: [M+H]+=255; Retention time HPLC: 0.68 min (Z002—002).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][OH:5].CN(C)C=O.[CH3:11][O:12][C:13](=[O:21])[C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C>[CH3:11][O:12][C:13](=[O:21])[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:2][CH2:3][CH2:4][OH:5])=[CH:16][CH:15]=1
Reactant: COC(=O)c1ccc(O)cc1
Reactant: OCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OCCCO)cc1
Reaction time: 12 h
Yield: 29.7 %

Procedure:
To a 250 mL flask was added 3-bromo-1-propanol (4.17 g, 0.03 mol), anhydrous dimethylformamide (40 mL), methyl-4-hydroxybenzoate (3.0 g, 0.02 mol) and potassium carbonate (4.15 g, 0.03 mol). The flask was placed in a 50° C. oil bath and stirred for 12 hours. After cooling the reaction was diluted with ethyl acetate, transferred to separatory funnel, washed with aqueous 0.1 N hydrochloric acid, water then brine. The organic layer was dried with magnesium sulfate, filtered, and concentrated under reduced pressure to give 5.14 g of crude oil. Column chromatography [silica gel; eluent hexanes-ethyl acetate (1.68:1)] provided the desired product (1.25 g, 30%) as a white powder. 1H (CDCl3) δ(ppm): 2.04-2.08 (m, 2H); 3.86-3.88 (m, 5H); 4.17 (t, 2H); 6.91 (d, 2H); 7.98 (d, 2H); 13C (CDCl3) δ(ppm): 31.89, 51.81, 59.88, 65.50, 114.06, 122.67, 131.57, 162.60, 166.84.
Reaction SMILES: CS(O)(=O)=O.[NH2:6][CH2:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:17])[N:12]([CH:18]1[CH2:23][CH2:22][C:21](=[O:24])[NH:20][C:19]1=[O:25])[CH2:11]2.[C:26]1([N:36]=[C:37]=[O:38])[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=[CH:28][CH:27]=1.Cl>C(#N)C>[O:25]=[C:19]1[CH:18]([N:12]2[CH2:11][C:10]3[C:14](=[CH:15][CH:16]=[C:8]([CH2:7][NH:6][C:37]([NH:36][C:26]4[C:35]5[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=5)[CH:29]=[CH:28][CH:27]=4)=[O:38])[CH:9]=3)[C:13]2=[O:17])[CH2:23][CH2:22][C:21](=[O:24])[NH:20]1
Reactant: NCc1ccc2c(c1)CN(C1CCC(=O)NC1=O)C2=O
Reactant: O=C=Nc1cccc2ccccc12
Agent: CS(=O)(=O)O
Agent: Cl
Solvent: CC#N
Product: O=C1CCC(N2Cc3cc(CNC(=O)Nc4cccc5ccccc45)ccc3C2=O)C(=O)N1
Temperature: 25 °C
Reaction time: 3 h
Yield: 88.1 %

Procedure:
To a stirred mixture of 3-(5-aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione methanesulfonate (0.37 g, 1.00 mmol) and 1-naphthylisocyanate (0.17 g, 1.00 mmol) in acetonitrile (30 mL) at 0° C. was added TEA (0.20 g, 2.0 mmol) dropwise over 10 min. The mixture was stirred at ambient temperature for 3 h and then 10% aqueous HCl solution (30 mL) was added. The solid precipitate was filtered and dried in vacuo providing 1-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-3-naphthalen-1-yl-urea as a white solid (0.39 g, 89% yield); mp 250-252° C.; HPLC, Waters Symmetry C-18, 3.9×150 mm, 5 μm, 1 ml/min, 240 nm, 40/60 CH3CN/0.1% H3PO4, 6.96 (97.91%); 1H NMR (DMSO-d6) δ 1.94-2.06 (m, 1H, CHH), 2.29-2.47 (m, 1H, CHH), 2.54-2.67 (m, 1H, CHH), 2.84-3.00 (m, 1H, CHH), 4.26-4.46 (m, 2H, CHH), 4.50 (d, J=4.9 Hz, 2H, CH2 and CHH), 5.11 (dd, 1H, CH), 7.17 (t, 1H, NH), 7.38-7.62 (m, 6H, Ar), 7.72 (d, J=7.7 Hz, 1H, Ar), 7.90 (d, 1H, Ar), 8.01 (d, 1H, Ar), 8.12 (d, 1H, Ar), 8.69 (s, 1H, NH), 10.99 (s, 1H, NH); 13C NMR (DMSO-d6) δ 22.49, 31.20, 42.95, 47.13, 51.58, 116.73, 121.38, 121.98, 122.26, 123.00, 125.43, 125.61, 125.74, 125.89, 126.97, 128.34, 130.36, 133.69, 134.98, 142.45, 144.72, 155.66, 167.95, 170.99, 172.85; LCMS: MH=443; Anal. Calcd for C25H22N4O4: C, 67.86; H, 5.01; N, 12.66. Found: C, 67.50; H, 4.96; N, 12.34.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Br:13])[N:8]=1.N1C=CC=CC=1>ClCCl>[Br:13][C:9]1[N:8]=[C:7]([NH:6][S:2]([CH3:1])(=[O:4])=[O:3])[CH:12]=[CH:11][CH:10]=1
Reactant: Nc1cccc(Br)n1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1cccc(Br)n1
Reaction time: 4 h
Yield: 75.2 %

Procedure:
Methanesulphonyl chloride (0.74 g) in dichloromethane (5 ml) was added over 2 min to a stirred solution of 2-amino-6-bromopyridine (1.1 g) and pyridine (0.57 g) in dichloromethane (5 ml). After 4 h, the solvent was evaporated in vacuo to give an oil which was purified by FCC eluting with System A (95:5:1) to give the title compound as a white solid (1.2 g), m.p. 90°-94° C.