Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li+].[C-:2]#[C:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.O(B(OC(C)C)OC(C)C)[CH:11](C)C.Br[C:24]1[CH:29]=[CH:28][C:27](C)=[CH:26][CH:25]=1>COCCOC.COCCOC.C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:7]1([CH3:11])[CH:8]=[CH:9][C:4]([C:3]#[C:2][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:5][CH:6]=1
Reactant: [C-]#Cc1ccccc1
Reactant: Cc1ccc(Br)cc1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Li+]
Solvent: C1CCOC1
Solvent: COCCOC
Product: Cc1ccc(C#Cc2ccccc2)cc1
Temperature: -78 °C
Reaction time: 1.5 h

Procedure:
General Procedure A. To a solution of lithium phenylacetylide (15.2 ml, 15.2 mmol) in DME (20 ml) under Argon at −78° C. was added triisopropoxylborane (3.5 ml, 15.2 mmol). The mixture was stirred at −78° C. for 1.5 hours. A solution of 1-bromo-4-methylbenzene (2 g, 11.7 mmol) in DME/THF (10 ml/10 ml) was degassed with dry argon, Pd(PPh3)4 (405 mg, 0.35 mmol) was added and the solution was degassed for another 5 min.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([S:10]([NH:13][C:14]2[N:15]=[N:16][CH:17]=[CH:18][CH:19]=2)(=[O:12])=[O:11])[CH:6]=[CH:7][C:8]=1[F:9])#[N:2].CCN(C(C)C)C(C)C.Cl[CH2:30][O:31][CH3:32]>C(Cl)Cl>[C:1]([C:3]1[CH:4]=[C:5]([S:10]([N:13]([CH2:30][O:31][CH3:32])[C:14]2[N:15]=[N:16][CH:17]=[CH:18][CH:19]=2)(=[O:11])=[O:12])[CH:6]=[CH:7][C:8]=1[F:9])#[N:2]
Reactant: COCCl
Reactant: N#Cc1cc(S(=O)(=O)Nc2cccnn2)ccc1F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCN(c1cccnn1)S(=O)(=O)c1ccc(F)c(C#N)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-cyano-4-fluoro-N-(pyridazin-3-yl)benzenesulfonamide (Preparation 6, 6.70 g, 24.1 mmol) in DCM (150 mL) at 0° C. was added DIPEA (6.48 mL, 35.18 mmol) followed by chloromethoxymethane (1.46 mL, 25.54 mmol) and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched by the addition of 1N NaOH (aq) solution, the organic layer was collected, washed with water, brine, and dried over Na2SO4 before concentrating in vacuo. The residue was purified using silica gel column chromatography eluting with EtOAc:Heptane 1:1 to afford the title compound as a mixture of isomers (3.85 g, 49%) that was used without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:15])[CH:9](C)[CH2:10][C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]([CH3:15])[CH2:9][CH2:10][C:11]([N:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1)=[O:13])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(CC(=O)O)N(C)C(=O)OC(C)(C)C
Reactant: C1COCCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CN(CCC(=O)N1CCOCC1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 106.4 %

Procedure:
To a mixture of N-t-butoxycarbonyl-N-methyl-β-methyl-β-alanine (1.02 g) and morpholine (0.48 g) in dry methylene chloride was added N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.05 g), and the mixture was stirred at ambient temperature overnight. After evaporation of the solvent, the residue was dissolved in ethyl acetate. The solution was washed with 1% citric acid aqueous solution, saturated sodium bicarbonate solution, and saturated sodium chloride solution. Then the solution was dried over magnesium sulfate and concentrated under reduced pressure to give 4-(N-t-butoxycarbonyl-N-methyl-β-alanyl)morpholine (1.36 g).
Reaction SMILES: [C:1]1([C:7]2[N:11]3[C:12](=[O:16])[NH:13][N:14]=[CH:15][C:10]3=[CH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:17]Br>C(Cl)(Cl)Cl>[Br:17][C:9]1[N:8]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:11]2[C:10]=1[CH:15]=[N:14][NH:13][C:12]2=[O:16]
Reactant: BrBr
Reactant: O=c1[nH]ncc2cnc(-c3ccccc3)n12
Solvent: ClC(Cl)Cl
Product: O=c1[nH]ncc2c(Br)nc(-c3ccccc3)n12
Temperature: 25 °C

Procedure:
A 3.0 gm. portion of 6-phenyl-imidazo[15-d]-as-triazin-4(3H)-one is stirred with 100 ml. of chloroform. The mixture is heated slightly and a solution of 1 ml. of bromine in 10 l ml. of chloroform is slowly dripped into the reaction mixture. The mixture is refluxed for 1 hour, cooled to room temperature, and filtered. To the solid is added aqueous Na2CO3 and chloroform and the mixture is shaken in a separatory funnel. The remaining solid and the organic phase are combined and evaporated on a steam bath. Methanol and 2-propanol are added and the mixture is treated twice with charcoal. Cooling gives the desired product as a solid, m.p. 192°-194° C.
Reaction SMILES: [F:1][C:2]1[CH:25]=[C:24]([F:26])[CH:23]=[C:22]([F:27])[C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([CH:15]2[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]2)=[O:14])[N:8]=1)=[O:5].NC1N=C(C(C2CCN(C)CC2)=O)C=CC=1.FC1C=C(F)C=C(F)C=1C(Cl)=O>ClC1C=CC=CC=1>[F:1][C:2]1[CH:25]=[C:24]([F:26])[CH:23]=[C:22]([F:27])[C:3]=1[C:4]([NH:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH:9]([C:13]([CH:15]2[CH2:16][CH2:17][N:18]([CH3:21])[CH2:19][CH2:20]2)=[O:14])[NH:8]1)=[O:5]
Reactant: CN1CCC(C(=O)c2cccc(NC(=O)c3c(F)cc(F)cc3F)n2)CC1
Agent: CN1CCC(C(=O)c2cccc(N)n2)CC1
Agent: O=C(Cl)c1c(F)cc(F)cc1F
Solvent: Clc1ccccc1
Product: CN1CCC(C(=O)C2CCCC(NC(=O)c3c(F)cc(F)cc3F)N2)CC1

Procedure:
The present invention is directed to a process for preparing 2,4,6-trifluoro-N-[6-(1-methyl-piperidine-4-carbonyl)-pyridin-2-yl]-benzamide or a pharmaceutically acceptable salt thereof e.g., the hemi-succinate salt comprising the step of: reacting (6-aminopyridin-2-yl)(1-methylpiperidin-4-yl)methanone (V) with 2,4,6-trifluorobenzoylchloride in the presence of chlorobenzene to yield 2,4,6-trifluoro-N-[6-(1-methyl-piperidin-4-ylcarbonyl)-piperidin-2-yl]benzamide (VI) hydrochloride.
Reaction SMILES: [I:1][C:2]1[C:3]([O:16][CH3:17])=[C:4]2[C:8](=[C:9]([O:12][CH3:13])[C:10]=1[I:11])[C:7](=[NH:14])[NH:6][C:5]2=N.[ClH:18].[CH2:19]([N:21]([CH2:28][CH3:29])[C:22]1[S:23][CH2:24][C:25](=[NH:27])[N:26]=1)[CH3:20].Cl.N1(C2SCC(=N)N=2)CCCCC1>>[ClH:18].[NH2:14][CH:7]1[C:8]2[C:4](=[C:3]([O:16][CH3:17])[C:2]([I:1])=[C:10]([I:11])[C:9]=2[O:12][CH3:13])[C:5](=[C:24]2[S:23][C:22]([N:21]([CH2:28][CH3:29])[CH2:19][CH3:20])=[N:26][C:25]2=[NH:27])[NH:6]1
Reactant: CCN(CC)C1=NC(=N)CS1
Reactant: COc1c(I)c(I)c(OC)c2c1C(=N)NC2=N
Agent: Cl
Agent: N=C1CSC(N2CCCCC2)=N1
Product: CCN(CC)C1=NC(=N)C(=C2NC(N)c3c(OC)c(I)c(I)c(OC)c32)S1

Procedure:
Following the procedure described in Example 9, part B above but using equivalent amounts of 5,6-diiodo-4,7-dimethoxy-1,3-diiminoisoindoline and 2-diethylamino-4-imino-2-thiazoline hydrochloride in place of 1,3-diiminoisoindoline and 2-piperidino-4-imino-2-thiazoline hydrochloride respectively, there is obtained as the product 1-amino-5,6-diiodo-4,7-dimethoxy-3-(2-diethylamino-4-imino-2-thiazolin-5-ylidene)isoindoline hydrochloride.
Reaction SMILES: C[O:2][C:3]1[C:4]2[N:5]([CH:15]=[N:16][N:17]=2)[C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([O:13][CH3:14])=[CH:8][CH:7]=2.Cl>C(O)(=O)C>[OH:2][C:3]1[C:4]2[N:5]([CH:15]=[N:16][N:17]=2)[C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([O:13][CH3:14])=[CH:8][CH:7]=2
Reactant: COc1ccc2c(c1)nc(OC)c1nncn12
Agent: Cl
Solvent: CC(=O)O
Product: COc1ccc2c(c1)nc(O)c1nncn12

Procedure:
A mixture consisting of 1.6 g. (0.0069 mole) of 4,7-dimethoxy-[1,2,4]triazolo[4,3-a]quinoxaline, 16 ml. of 1N hydrochloric acid and 48 ml. of glacial acetic acid was refluxed for a period of three hours. Upon completion of this step, the reaction mixture was poured over ice and filtered. The recovered product was then collected on the filter funnel and washed with diethyl ether to ultimately afford 1.19 g. (80%) of pure 4-hydroxy-7-methoxy[1,2,4]triazolo[4,3-a]quinoxaline, m.p. >250° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]=1[C:13](C)=[CH:14][C:15](O)=O.[C:19]([O:22]CC)(=[O:21])C>[Pd]>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]=1[CH2:13][CH2:14][CH2:15][C:19]([OH:22])=[O:21]
Reactant: CCOC(C)=O
Reactant: COc1ccc2ccccc2c1C(C)=CC(=O)O
Agent: [Pd]
Product: COc1ccc2ccccc2c1CCCC(=O)O
Reaction time: 15 h

Procedure:
The compound obtained in Step A (3.4 g, 1.40.10−2 mol) is solubilised in ethyl acetate (90 ml) in the presence of 5% palladium-on-carbon. The mixture is purged with argon and placed under a hydrogen atmosphere. After 15 hours' hydrogenation, the reaction mixture is filtered over Celite, rinsed and then evaporated under reduced pressure. The title product is isolated in the form of white crystals.
Reaction SMILES: [OH-].[Na+].Cl.[N+:4]([C:7]1[CH:15]=[CH:14][C:10]([C:11]([NH2:13])=[NH:12])=[CH:9][CH:8]=1)([O-:6])=[O:5].[Cl:16][C:17]([SH:20])(Cl)Cl.ClCCl>O>[Cl:16][C:17]1[S:20][N:13]=[C:11]([C:10]2[CH:9]=[CH:8][C:7]([N+:4]([O-:6])=[O:5])=[CH:15][CH:14]=2)[N:12]=1
Reactant: N=C(N)c1ccc([N+](=O)[O-])cc1
Reactant: SC(Cl)(Cl)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(-c2nsc(Cl)n2)cc1
Reaction time: 2 h
Yield: 40.3 %

Procedure:
A solution of 75.6 gm of sodium hydroxide in 100 ml of water was added to a stirred mixture of 101.4 gm of p-nitrobenzamidine hydrochloride, 70 gm of perchloromethyl mercaptan and 760 ml of dichloromethane, while keeping the temperature below -5° C. After additional 2 hours at -5° C., the resulting suspension was filtered, and the organic phase was separated, evaporated to dryness, and the residual solid was recrystallized from 95% ethanol, yielding 45 gm of the title compound, m.p. 143°-145° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([CH:17]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[CH2:18][OH:19])=[C:15]3[C:10]([CH:11]=[CH:12][CH:13]=[CH:14]3)=[N:9]2)=[CH:4][CH:3]=1.[CH3:26][O:27][C:28]([C:30]1([O:33][C:34]2[CH:39]=[CH:38][C:37](O)=[CH:36][CH:35]=2)[CH2:32][CH2:31]1)=[O:29].C(P(CCCC)CCCC)CCC.CN(C)C(N=NC(N(C)C)=O)=O>C1COCC1>[CH3:26][O:27][C:28]([C:30]1([O:33][C:34]2[CH:39]=[CH:38][C:37]([O:19][CH2:18][CH:17]([C:16]3[N:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)[N:9]=[C:10]4[C:15]=3[CH:14]=[CH:13][CH:12]=[CH:11]4)[CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)=[CH:36][CH:35]=2)[CH2:32][CH2:31]1)=[O:29]
Reactant: OCC(c1c2ccccc2nn1-c1ccc(Cl)cc1)C1CCCCC1
Reactant: COC(=O)C1(Oc2ccc(O)cc2)CC1
Agent: CCCCP(CCCC)CCCC
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Solvent: C1CCOC1
Product: COC(=O)C1(Oc2ccc(OCC(c3c4ccccc4nn3-c3ccc(Cl)cc3)C3CCCCC3)cc2)CC1

Procedure:
In analogy to the procedure described in example 29.2, 2-[2-(4-chloro-phenyl)-2H-indazol-3-yl]-2-cyclohexyl-ethanol (example 29.1) was reacted with 1-(4-hydroxy-phenoxy)-cyclopropanecarboxylic acid methyl ester (Hazeldine, Stuart T.; Polin, Lisa; Kushner, Juiwanna; White, Kathryn; Corbett, Thomas H.; Horwitz, Jerome P. Bioorganic & Medicinal Chemistry (2005), 13(12), 3910-3920) in the presence of tri-n-butylphosphine and N,N,N′,N′-tetramethylazodicarboxamide in THF at ambient temperature to give the title compound as off-white solid. MS: m/e=545.3 [M+H+].
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][N:15]([CH2:34][CH2:35][CH3:36])[CH:16]2[CH2:25][CH2:24][C:23]3[C:18](=[CH:19][C:20]([O:26][S:27]([C:30]([F:33])([F:32])[F:31])(=[O:29])=[O:28])=[CH:21][CH:22]=3)[CH2:17]2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[NH:8]1[CH2:13][CH2:12][CH:11]([CH2:14][N:15]([CH2:34][CH2:35][CH3:36])[CH:16]2[CH2:17][C:18]3[CH:19]=[C:20]([O:26][S:27]([C:30]([F:33])([F:31])[F:32])(=[O:29])=[O:28])[CH:21]=[CH:22][C:23]=3[CH2:24][CH2:25]2)[CH2:10][CH2:9]1
Reactant: CCCN(CC1CCN(C(=O)OC(C)(C)C)CC1)C1CCc2ccc(OS(=O)(=O)C(F)(F)F)cc2C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCN(CC1CCNCC1)C1CCc2ccc(OS(=O)(=O)C(F)(F)F)cc2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 64 %

Procedure:
To a solution of 4-{[propyl-(7-trifluoromethanesulfonyloxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-amino]-methyl}-piperidine-1-carboxylic acid tert-butyl ester, (220 mg, 0.41 mmol) in methylene chloride (5.0 mL) under an inert atmosphere was added trifluoroacetic acid (1.0 ml). The reaction was stirred at room temperature for 1 h. The reaction was concentrated in-vacuo and partitioned between 1 N NaOH (20 ml) and EtOAc (30 ml). The organic layer was separated, dried (MgSO4), and concentrated to afford trifluoro-methanesulfonic acid 7-(piperidin-4-ylmethyl-propyl-amino)-5,6,7,8-tetrahydro-naphthalen-2-yl ester (114mg).
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[H-].[Na+].[Br:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]2[C:27]3[C:22](=[CH:23][C:24]([O:30][CH2:31][CH:32]4[O:34][CH2:33]4)=[C:25]([O:28][CH3:29])[CH:26]=3)[N:21]=[CH:20][N:19]=2)=[C:13]([F:35])[CH:12]=1>CN(C=O)C>[Br:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]2[C:27]3[C:22](=[CH:23][C:24]([O:30][CH2:31][CH:32]([OH:34])[CH2:33][S:1][C:2]4[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=4)=[C:25]([O:28][CH3:29])[CH:26]=3)[N:21]=[CH:20][N:19]=2)=[C:13]([F:35])[CH:12]=1
Reactant: Sc1ccncc1
Reactant: COc1cc2c(Nc3ccc(Br)cc3F)ncnc2cc1OCC1CO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc2c(Nc3ccc(Br)cc3F)ncnc2cc1OCC(O)CSc1ccncc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 15.8 %

Procedure:
4-Mercaptopyridine (93 mg) was added to a suspension of sodium hydride 60% (12 mg) in DMF (2 ml) under nitrogen. After stirring for 15 minutes 4-(4-bromo-2-fluorophenylamino)-7-(2,3-epoxypropoxy)-6-methoxyquinazoline (100 mg) (from Example 5) was added and the mixture was stirred for 3 hours at ambient temperature. The volatiles were removed under vacuum. The residue was partitioned between methylene chloride and water and the pH of the aqueous layer was adjusted to 7 with 1N HCl. The organic layer was separated, washed with water, followed by brine, dried (MgSO4) and evaporated to give 4-(4-bromo-2-fluorophenylamino)-7-[2-hydroxy-3-(4-pyridylsulphanyl)propoxy]-6-methoxyquinazoline (20 mg).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[NH:4][CH2:3][CH:2]1[CH2:11][O:12][CH:13]1[CH:18]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][CH2:28][O:29][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[O:37][CH3:38])=[CH:21][CH:20]=2)[CH2:17][CH2:16][N:15]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:14]1.[CH3:46][O:47][CH2:48][CH2:49][CH2:50][C:51](Cl)=[O:52]>C(Cl)(Cl)Cl.C(N(CC)CC)C>[CH3:38][O:37][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=1[CH2:30][O:29][CH2:28][CH2:27][CH2:26][O:25][C:22]1[CH:23]=[CH:24][C:19]([CH:18]2[CH2:17][CH2:16][N:15]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:14][CH:13]2[O:12][CH2:11][CH:2]2[CH2:3][N:4]([C:51](=[O:52])[CH2:50][CH2:49][CH2:48][O:47][CH3:46])[C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[O:1]2)=[CH:20][CH:21]=1
Reactant: COCCCC(=O)Cl
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCC2CNc3ccccc3O2)cc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COCCCC(=O)N1CC(COC2CN(C(=O)OC(C)(C)C)CCC2c2ccc(OCCCOCc3ccccc3OC)cc2)Oc2ccccc21
Reaction time: 0.5 h

Procedure:
A solution of 0.33 g of tert-butyl 3-(3,4-dihydro-2H-benzo[1,4]oxazin-2(R,S)-ylmethoxy)-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate in 40 ml of chloroform and 0.23 ml of triethylamine is admixed at room temperature with 0.23 g of 4-methoxybutyryl chloride and stirred over 30 minutes. The reaction mixture is washed successively with 1N HCl and 1N NaOH, dried over sodium sulphate and concentrated by evaporation. The title compound is obtained as a colourless oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.27 (1:1.5 EtOAc-heptane); Rt=6.05.
Reaction SMILES: [OH:1][N:2]=[C:3]([NH2:10])[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][CH:5]=1.[C:11]([O:15][C:16]([NH:18][CH2:19][C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=1)[C:23](O)=O)=[O:17])([CH3:14])([CH3:13])[CH3:12].N>>[N:6]1[CH:7]=[CH:8][CH:9]=[C:4]([C:3]2[N:10]=[C:23]([C:22]3[CH:21]=[C:20]([CH:28]=[CH:27][CH:26]=3)[CH2:19][NH:18][C:16](=[O:17])[O:15][C:11]([CH3:14])([CH3:12])[CH3:13])[O:1][N:2]=2)[CH:5]=1
Reactant: NC(=NO)c1cccnc1
Reactant: CC(C)(C)OC(=O)NCc1cccc(C(=O)O)c1
Agent: N
Product: CC(C)(C)OC(=O)NCc1cccc(-c2nc(-c3cccnc3)no2)c1

Procedure:
The title compound was prepared according to the procedure of Example 8 using N′-hydroxynicotinimidamide (Aldrich) and 3-((tert-butoxycarbonylamino)methyl)benzoic acid (Fluka). 1H NMR (300 MHz, DMSO-d6) δ 1.42 (s, 9 H), 4.27 (d, J=6.1 Hz, 2 H), 7.51-7.72 (m, 4 H), 8.01-8.17 (m, 2 H), 8.45 (dt, J=8.1, 1.9 Hz, 1 H), 8.82 (dd, J=5.1, 1.7 Hz, 1H), 9.26 (dd, J=2.2, 0.8 Hz, 1 H) ppm; MS (DCI/NH3) m/z 353 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]1[CH:16]=[C:15]([CH3:17])[C:14]([OH:18])=[C:13]([CH3:19])[CH:12]=1)=[C:5]2[CH3:20].[Cu](C#N)[C:22]#[N:23].CN1CCCC1=O>C(OCC)(=O)C>[C:22]([C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]1[CH:16]=[C:15]([CH3:17])[C:14]([OH:18])=[C:13]([CH3:19])[CH:12]=1)=[C:5]2[CH3:20])#[N:23]
Reactant: Cc1cc(-c2[nH]c3ccc(Br)cc3c2C)cc(C)c1O
Reactant: N#C[Cu]C#N
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: Cc1cc(-c2[nH]c3ccc(C#N)cc3c2C)cc(C)c1O

Procedure:
1.32 g of 5-bromo-2-(4-hydroxy-3,5-dimethylphenyl)-3-methylindole and 0.54 g of copper cyanide were added to 10 ml of N-methylpyrrolidone, and the mixture was refluxed for 4 hours. To the reaction mixture was added ethyl acetate, and the mixture was washed with 20% aqueous ammonia solution and water, and dried. The solvent was evaporated, and the residue was purified by silica gel column chromatography. Recrystallization of the crude product from ether-petroleum ether gave 5-cyano-2-(4-hydroxy-3,5-dimethylphenyl)-3-methylindole.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH2:11]([O:14][C:15]([N:17]1[CH2:21][CH:20]([CH:22]([OH:24])[CH3:23])[CH2:19][N:18]1[C:25](=[O:29])[N:26]([CH3:28])[CH3:27])=[O:16])[CH:12]=[CH2:13].C(N(CC)CC)C>ClCCl>[C:22]([CH:20]1[CH2:19][N:18]([C:25](=[O:29])[N:26]([CH3:27])[CH3:28])[N:17]([C:15]([O:14][CH2:11][CH:12]=[CH2:13])=[O:16])[CH2:21]1)(=[O:24])[CH3:23]
Reactant: C=CCOC(=O)N1CC(C(C)O)CN1C(=O)N(C)C
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CCOC(=O)N1CC(C(C)=O)CN1C(=O)N(C)C
Temperature: 25 °C
Yield: 97.5 %

Procedure:
To a solution of oxalyl chloride (7.42 ml) in dichloromethane (250 ml) was added dropwise dimethyl sulfoxide (12.7 ml) at -70° C. To this reaction mixture was added dropwise a solution of 2-allyloxycarbonyl-1-dimethylcarbamoyl-4-(1-hydroxyethyl)pyrazolidine (22 g) in dichloromethane (40 ml), and then was added dropwise triethylamine (56.5 ml) at -70° C. The reaction mixture was allowed to warm to room temperature. The precipitate was filtered off and the filtrate was concentrated in vacuo. The residue was poured into a mixture of ethyl acetate and 1N-aqueous hydrochloric acid, and the organic layer was extracted, washed with brine, and dried over magnesium sulfate. Evaporation of the solvent gave a residual oil, which was chromatographed on silica gel eluting in turn with a mixture of hexane and ethyl acetate (1:2, V/V) and ethyl acetate to give 4-acetyl-2-allyloxycarbonyl-1-dimethylcarbamoylpyrazolidine (21.3 g).
Reaction SMILES: Br.[Br:2][CH:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.[CH2:9]([O:16][C:17](ON1C(=O)CCC1=O)=[O:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.CN1CCOCC1.O>O1CCCC1>[Br:2][CH:3]1[CH2:8][CH2:7][N:6]([C:17]([O:16][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:18])[CH2:5][CH2:4]1
Reactant: BrC1CCNCC1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Agent: Br
Solvent: O
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: O=C(OCc1ccccc1)N1CCC(Br)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 98.4 %

Procedure:
To a solution of 4-bromopiperidine hydrobromide (3.0 g, 12.2 mmol) in tetrahydrofuran (30 ml) were added 1-{[(benzyloxy)carbonyl]oxy}-2,5-pyrrolidinedione (3.20 g, 12.9 mmol), N-methylmorpholine (1.62 ml, 14.7 mmol) and 4-N,N-dimethylaminopyridine (30 mg) at room temperature, and stirred at room temperature for 16 hours. The reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed with a 1N-aqueous hydrochloric acid solution, dried over anhydrous magnesium sulfate and distilled under reduced pressure to remove the solvent, and the resulting residue was purified by a silica gel column chromatography (eluent: hexane/ethyl acetate=1/1) to obtain benzyl 4-bromo-1-piperidinecarboxylate (3.58 g, 98%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[OH:18])=[CH2:11])[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.C(=O)([O-])[O-].[K+].[K+].[Cl:25][CH2:26][CH2:27][CH2:28]Br>CC(C)=O>[Cl:25][CH2:26][CH2:27][CH2:28][O:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[C:10]([C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:4]=1[CH:3]=[CH:2][NH:1]2)=[CH2:11]
Reactant: ClCCCBr
Reactant: C=C(c1ccccc1O)c1cccc2[nH]ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=C(c1ccccc1OCCCCl)c1cccc2[nH]ccc12

Procedure:
Using the procedure of Step E of Example 1, 6.7 g of 2-[1-(1H-indol-4-yl)-ethenyl]-phenol of Step A of Example 22, 70 ml of acetone, 4 g of potassium carbonate and 11.5 ml of 1-chloro-3-bromo-propane were heated for 20 hours at reflux and after Chromatography and crystallization from petroleum ether (Eb=40-70° C.), 7.05 g of the desired product melting at 70 to 72° C. were obtained.
Reaction SMILES: [F:1][C:2]1[C:10]2[O:9][C:8]([NH:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[CH3:18])=[N:7][C:6]=2[CH:5]=[CH:4][C:3]=1[CH2:19][C:20](O)=[O:21].[F:23][C@@H:24]1[CH2:28][NH:27][C@H:26]([CH2:29][O:30][C:31]2[CH:40]=[CH:39][C:34]([C:35]([O:37][CH3:38])=[O:36])=[CH:33][CH:32]=2)[CH2:25]1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C>CN(C=O)C>[F:1][C:2]1[C:10]2[O:9][C:8]([NH:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[CH3:18])=[N:7][C:6]=2[CH:5]=[CH:4][C:3]=1[CH2:19][C:20]([N:27]1[CH2:28][C@@H:24]([F:23])[CH2:25][C@H:26]1[CH2:29][O:30][C:31]1[CH:40]=[CH:39][C:34]([C:35]([O:37][CH3:38])=[O:36])=[CH:33][CH:32]=1)=[O:21]
Reactant: COC(=O)c1ccc(OC[C@@H]2C[C@H](F)CN2)cc1
Reactant: Cc1ccccc1Nc1nc2ccc(CC(=O)O)c(F)c2o1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OC[C@@H]2C[C@H](F)CN2C(=O)Cc2ccc3nc(Nc4ccccc4C)oc3c2F)cc1
Temperature: 0 °C
Yield: 91.5 %

Procedure:
In DMF (5 ml), 7-fluoro-2-(2-methylphenylamino)-6-benzoxazolylacetic acid (300 mg, 1.0 mmol), methyl 4-((2S,4S)-4-fluoro-2-pyrrolidinylmethoxy)benzoate (253 mg, 1.0 mmol), EDC•HCl (288 mg, 1.5 mmol), HOBt (203 mg, 1.5 mmol) and triethylamine (0.70 ml, 5.0 mmol) were stirred at room temperature for 14 hours. After the reaction mixture was poured in ice water (20 ml), the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate and distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column (silica gel: 50 g), whereby from chloroform/acetone (10/1) eluate fractions, the title compound (490 mg, 92%) was obtained as a colorless amorphous substance.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]#[N:10].[CH3:11][Si]([N-][Si](C)(C)C)(C)C.[Na+].CC1[IH]C=CC=1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([CH3:11])[C:9]#[N:10]
Reactant: N#CCc1ccccc1Cl
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: CC1=CC=C[IH]1
Agent: [Na+]
Product: CC(C#N)c1ccccc1Cl
Yield: 85.5 %

Procedure:
Following the procedure outlined for Example 649, 2-(2-chlorophenyl)acetonitrile (15 g, 98.9 mmol) was reacted with NaHMDS (118 mL, 118 mmol), and methyl iodie (7.0 mL, 108 mmol) to afford the desired product (14 g, 87%) as a brown oil: ESI MS m/z 166 [C9H8ClN+H]+.