Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([OH:14])[CH:11]=[CH:12][CH:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[CH2:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]>CN(C)C=O>[N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:11]=[CH:12][CH:13]=2)[O:14][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Oc1cccc(CN2CCCCC2)c1
Reactant: CCOC(=O)CCCBr
Solvent: CN(C)C=O
Product: CCOC(=O)CCCOc1cccc(CN2CCCCC2)c1
Reaction time: 20 h
Yield: 94.5 %

Procedure:
A mixture of 3-(1-piperidinylmethyl)phenol (11.2 g) sodium hydride (1.5 g) and ethyl 4-bromobutyrate (11.7 g) in dimethylformamide (60 ml) was stirred at 25° during 20 h. The mixture was poured onto ice (300 g) and extracted with ethyl acetate (3×100 ml). The combined extracts were distilled to give the title compound as a colourless oil (16.9 g) b.p. 250°, 0.1 mm; tlc System B, Rf 0.9.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[N:6]=[C:5]2[C:17]1[N:22]=[C:21]([N:23]2[CH2:28][CH2:27][CH:26]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:25][CH2:24]2)[CH:20]=[N:19][CH:18]=1.[F:37][C:38]1[CH:39]=[C:40](B(O)O)[CH:41]=[CH:42][CH:43]=1.C([O-])([O-])=O.[Na+].[Na+].O1CCOCC1>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.O>[F:37][C:38]1[CH:43]=[C:42]([C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[N:7]([CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)[N:6]=[C:5]3[C:17]2[N:22]=[C:21]([N:23]3[CH2:28][CH2:27][CH:26]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:34])([CH3:35])[CH3:33])[CH2:25][CH2:24]3)[CH:20]=[N:19][CH:18]=2)[CH:41]=[CH:40][CH:39]=1
Reactant: CC(C)(C)OC(=O)NC1CCN(c2cncc(-c3nn(C4CCCCO4)c4ccc(Br)cc34)n2)CC1
Reactant: OB(O)c1cccc(F)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)NC1CCN(c2cncc(-c3nn(C4CCCCO4)c4ccc(-c5cccc(F)c5)cc34)n2)CC1
Temperature: 140 °C
Yield: 57.9 %

Procedure:
A glass microwave reaction vessel was charged with tert-butyl 1-(6-(5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)pyrazin-2-yl)piperidin-4-ylcarbamate (0.200 g, 0.359 mmol), 3-fluorophenylboronic acid (0.072 g, 0.515 mmol, Aldrich), Na2CO3 (0.210 g, 1.981 mmol, J. T. Baker) and trans-dichlorobis(triphenyl-phosphine)palladium (II) (0.022 g, 0.031 mmol, Strem). Dioxane (3 mL) and water (1 mL) were added and the reaction mixture was sealed under argon and heated in a Emrys Optmizer microwave reactor (Personal Chemistry, Biotage AB, Inc., Uppsala, Sweden) at 140° C. for 15 min. The mixture was partitioned between EtOAc/water. The aqueous layer was extracted with EtOAc (3×) and the combined organic layers were evaporated onto silica gel and purified by flash chromatography (Isco, (40 gram)) eluting with 2M NH3 in MeOH:DCM (0:1→1:49) to give 119 mg of tert-Butyl 1-(6-(5-(3-fluorophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)pyrazin-2-yl)piperidin-4-ylcarbamate as a yellow amorphous solid. MS (ESI, pos. ion) m/z: 573.2 (M+1). A solution of tert-butyl 1-(6-(5-(3-fluorophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)pyrazin-2-yl)piperidin-4-ylcarbamate (0.119 g, 0.208 mmol) in HCl, 5-6 N in IPA (5.00 mL, 25.00 mmol) and water (0.5 mL) was heated at 80° C. for 2.5 h. The reaction mixture was cooled to RT and the solid was filtered and washed with IPA. The material was dissolved in DMSO and purified by reverse-phase HPLC (Gilson; Gemini-NX 10μ C18 110 A AXIA, 100×50 mm column) eluting with 0.1% TFA-H2O:0.1% TFA ACN (9:1→1:9). The fractions containing the desired product were combined and concentrated in vacuo. The residue was dissolved in MeOH and loaded onto an SCX II cartridge eluting with MeOH then 2M NH3 in MeOH to give the title compound as a yellow crystalline solid. MS (ESI, pos. ion) m/z: 389.1 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][C:7]2[C:16]3[N:15]=[CH:14][C:13](=[O:17])[NH:12][C:11]=3[N:10]=[CH:9][CH:8]=2)=[CH:4][C:3]=1[F:20].[C:21]([C:25]1[CH:29]=[C:28]([N:30]=[C:31]=[O:32])[N:27]([C:33]2[CH:38]=[CH:37][C:36]([S:39]([CH3:42])(=[O:41])=[O:40])=[CH:35][CH:34]=2)[N:26]=1)([CH3:24])([CH3:23])[CH3:22].C(Cl)Cl>>[C:21]([C:25]1[CH:29]=[C:28]([NH:30][C:31]([NH:1][C:2]2[CH:19]=[CH:18][C:5]([O:6][C:7]3[C:16]4[N:15]=[CH:14][C:13](=[O:17])[NH:12][C:11]=4[N:10]=[CH:9][CH:8]=3)=[CH:4][C:3]=2[F:20])=[O:32])[N:27]([C:33]2[CH:38]=[CH:37][C:36]([S:39]([CH3:42])(=[O:41])=[O:40])=[CH:35][CH:34]=2)[N:26]=1)([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)(C)c1cc(N=C=O)n(-c2ccc(S(C)(=O)=O)cc2)n1
Reactant: Nc1ccc(Oc2ccnc3[nH]c(=O)cnc23)cc1F
Solvent: ClCCl
Product: CC(C)(C)c1cc(NC(=O)Nc2ccc(Oc3ccnc4[nH]c(=O)cnc34)cc2F)n(-c2ccc(S(C)(=O)=O)cc2)n1
Yield: 41 %

Procedure:
Method F2 was used with 8-(4-amino-3-fluorophenoxy)pyrido[2,3-b]pyrazin-3(4H)-one (56 mg, 0.206 mmol) and a 0.1 M solution of 3-tert-butyl-5-isocyanato-1-(4-(methylsulfonyl)phenyl)-1H-pyrazole in CH2Cl2 (5.8 mL, 0.58 mmol). The title compound was obtained as a yellow solid in 41% yield (50 mg) after chromatography on a Biotage 25+M column.
Reaction SMILES: [F:1][CH2:2][C:3]([N:17]1[C:21](=[O:22])[C:20]2=[CH:23][CH:24]=[CH:25][CH:26]=[C:19]2[C:18]1=[O:27])([CH2:6][CH2:7][CH2:8][O:9]CC1C=CC=CC=1)[C:4]#[N:5].[Si](I)(C)(C)C>ClCCl>[F:1][CH2:2][C:3]([N:17]1[C:21](=[O:22])[C:20]2=[CH:23][CH:24]=[CH:25][CH:26]=[C:19]2[C:18]1=[O:27])([CH2:6][CH2:7][CH2:8][OH:9])[C:4]#[N:5]
Reactant: N#CC(CF)(CCCOCc1ccccc1)N1C(=O)c2ccccc2C1=O
Agent: C[Si](C)(C)I
Solvent: ClCCl
Product: N#CC(CF)(CCCO)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 114.9 %

Procedure:
To a solution of 2-fluoromethyl-2-phthalimido-5-benzyloxypentanenitrile (49.4 g) in dry dichloromethane (400 ml) is added TMSI (45 ml, 2.2 equivalents, and the mixture is stirred at room temperature overnight. The solvent is removed under vacuum. The residue is evaporated two times more with dichloromethane and then dissolved in chloroform. After addition of triethylamine (60 ml), the mixture is refluxed for 3 hours. Washing with water, 1N HCl (2×), water again, drying, and evaporation gives 2-fluoromethyl-2-phthalimido-5-hydroxypentanenitrile as a brown oil (42.8 g).
Reaction SMILES: O[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]2[N:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:14]=[CH:15][C:3]=12.P(Cl)(Cl)([Cl:24])=O>>[Cl:24][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]2[N:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:14]=[CH:15][C:3]=12
Reactant: CCOC(=O)c1cnc2c(cnn2-c2ccccc2)c1O
Reactant: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1cnc2c(cnn2-c2ccccc2)c1Cl
Yield: 97.8 %

Procedure:
A mixture of 5.76 g (20.33 mmol) of ethyl 4-hydroxy-1-phenyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate and 15.58 g of phosphorus oxychloride was refluxed 1.5 hr, chilled and poured slowly onto crushed ice. The mixture was filtered and the solid washed with ice-water and dried to give 6.0 g of solid, m.p. 89-91° C.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:15]=[CH:14][C:10]3[O:11][CH2:12][O:13][C:9]=3[C:8]=2[C:16]2[C:17]3[NH:24][C:23]([CH3:25])=[C:22]([C:26]([NH:28][C@H:29]4[C@H:33]([OH:34])[CH2:32][NH:31][CH2:30]4)=[O:27])[C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:4][CH2:3]1.C([O:38][CH2:39][C:40](Cl)=[O:41])(=O)C>>[CH:2]1([CH2:5][O:6][C:7]2[CH:15]=[CH:14][C:10]3[O:11][CH2:12][O:13][C:9]=3[C:8]=2[C:16]2[C:17]3[NH:24][C:23]([CH3:25])=[C:22]([C:26]([NH:28][C@H:29]4[C@H:33]([OH:34])[CH2:32][N:31]([C:39](=[O:38])[CH2:40][OH:41])[CH2:30]4)=[O:27])[C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:4][CH2:3]1
Reactant: CC(=O)OCC(=O)Cl
Reactant: Cc1[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc2c1C(=O)N[C@@H]1CNC[C@H]1O
Agent: Cl
Product: Cc1[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc2c1C(=O)N[C@@H]1CN(C(=O)CO)C[C@H]1O

Procedure:
Starting from 4-[5-(cyclopropylmethoxy)-1,3-benzodioxol-4-yl]-N-[(3R*,4R*)-4-hydroxypyrrolidin-3-yl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f5) and commercially available 2-chloro-2-oxoethyl acetate the title compound is obtained as colorless solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][CH:9]2[C:28]([OH:30])=O)[CH:5]=[CH:6][CH:7]=1.[NH2:32][C:33]1[CH:42]=[CH:41][C:36]([O:37][CH2:38][CH2:39][OH:40])=[CH:35][CH:34]=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>C(Cl)Cl>[OH:40][CH2:39][CH2:38][O:37][C:36]1[CH:41]=[CH:42][C:33]([NH:32][C:28]([CH:9]2[CH:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:31])[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:25])([CH3:27])[CH3:26])[NH:10]2)=[O:30])=[CH:34][CH:35]=1
Reactant: Nc1ccc(OCCO)cc1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)CC1NC(C(=O)Nc2ccc(OCCO)cc2)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Yield: 77.2 %

Procedure:
In a manner similar to the method described in Examples 1e, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (0.4 g, 0.86 mmol) was reacted with 2-(4-amino-phenoxy)-ethanol (0.24 g, 1.5 mmol), HATU (0.58 g, 1.5 mmol) and iPr2NEt (0.3 mL, 1.7 mmol) in CH2Cl2 (20 mL) at room temperature for 20 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid [4-(2-hydroxy-ethoxy)-phenyl]-amide as a white solid (0.4 g, 78%).
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:8]=[C:7]([C:9]([OH:11])=[O:10])[CH:6]=[CH:5][CH:4]=1.[H-].[Na+].[CH3:14]I>C1COCC1.CCOC(C)=O>[CH3:14][O:1][CH2:2][C:3]1[N:8]=[C:7]([C:9]([OH:11])=[O:10])[CH:6]=[CH:5][CH:4]=1
Reactant: O=C(O)c1cccc(CO)n1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COCc1cccc(C(=O)O)n1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 300 mg (1.96 mmol) 6-hydroxymethyl-pyridine-2-carboxylic acid in 20 mL THF was added 188 mg (4.31 mmol) NaH in mineral oil (55%) at 0° C. After gas formation ceased, 310 μL (4.90 mmol) methyl iodide was added dropwise, then the mixture was stirred for 1 h at 0° C. and for 1 h at RT. The reaction mixture was diluted with EtOAc, extracted with water, washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[C:13]([N+:15]([O-])=O)[CH:12]=[CH:11][C:10]=2[O:18][CH3:19])=[CH:5][CH:4]=1.[H][H]>CO.[Pd]>[NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:14]=[C:13]([CH:12]=[CH:11][C:10]=2[O:18][CH3:19])[NH2:15])=[CH:7][CH:8]=1
Reactant: COc1ccc([N+](=O)[O-])cc1-c1ccc(CN)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COc1ccc(N)cc1-c1ccc(CN)cc1

Procedure:
A solution of 2-(4-aminomethylphenyl)-4-nitroanisole (4.50 g) in methanol (200 mL) was treated with 10% palladium on carbon (200 mg). The reaction mixture was stirred under one atmosphere of hydrogen for 2.5 hours. The reaction mixture filtered through Celite, and the filter cake was washed with methanol (3×25 mL). The filtrate was concentrated to dryness and the residue was purified by flash chromatography on silica gel (80 g) eluting with 0-6% methanol/0.5% triethylamine/dichloromethane. Pure fractions were combined and concentrated to give 3-(4-aminomethylphenyl)-4-methoxyaniline as an off white powder.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)#[N:2].[OH-].[Na+].O.Cl[CH:14]([F:16])[F:15]>O1CCCC1>[F:15][CH:14]([F:16])[O:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1
Reactant: FC(F)Cl
Reactant: N#Cc1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1ccc(OC(F)F)cc1
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 36.6 %

Procedure:
Under a dry argon atmosphere a mixture of 10.0 g (0.084 mole) of 4-cyanophenol, 33.6 g (0.84 mole) of sodium hydroxide, 110 ml of water, and 130 ml of tetrahydrofuran was stirred in a Morton flask and heated at reflux. During 1.25 hour, 8.6 g (0.99 mole) of chlorodifluoromethane was added to the reaction mixture. After complete addition, the mixture was allowed to cool to room temperature and was stirred for approximately 18 hours. The reaction mixture was poured into 500 g of ice water, the resulting mixture filtered, and the filtrate extracted with three 300 ml portions of diethyl ether. The ether extracts were combined, dried over anhydrous potassium carbonate, and filtered. The filtrate was evaporated under reduced pressure to give an oil which crystallized upon standing. The product was recrystallized from toluene/methylcyclohexane to give 5.2 g of 4-difluoromethoxybenzonitrile as a white solid, m.p. 36°-37° C.
Reaction SMILES: [C@@H:1]12[CH2:7][C@@H:4]([CH2:5][CH2:6]1)[CH2:3][C@@H:2]2[NH:8][C:9]1[S:10][CH:11]([CH2:15][CH2:16][OH:17])[C:12](=[O:14])[N:13]=1.[O:18]1[CH:23]=[CH:22][CH2:21][CH2:20][CH2:19]1>C(Cl)Cl>[C@@H:1]12[CH2:7][C@@H:4]([CH2:5][CH2:6]1)[CH2:3][C@@H:2]2[NH:8][C:9]1[S:10][CH:11]([CH2:15][CH2:16][O:17][CH:19]2[CH2:20][CH2:21][CH2:22][CH2:23][O:18]2)[C:12](=[O:14])[N:13]=1
Reactant: C1=COCCC1
Reactant: O=C1N=C(N[C@H]2C[C@@H]3CC[C@H]2C3)SC1CCO
Solvent: ClCCl
Product: O=C1N=C(N[C@H]2C[C@@H]3CC[C@H]2C3)SC1CCOC1CCCCO1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The mixture of 2-((1S,2S,4R)-bicyclo[2.2.1]heptan-2-ylamino)-5-(2-hydroxyethyl)thiazol-4(5H)-one (3.2 g, 12.6 mmol) and p-toulenesulfonic acid (500 mg) in 3,4-dihydro-2H-pyran (10 mL) was stirred for 2 h at room temperature. The resulting mixture was diluted with CH2Cl2 (100 mL), then washed with sat'd NaH2PO4, and dried over MgSO4. After being filtered and concentrated in vacuo, the crude residue was purified by flash chromatography (3:2; Hexane:EtOAc) to give the title compound as an oil. MS (ES+): 339 (M+H)+.
Reaction SMILES: [OH-].[Na+].Cl.[C:4](N)(=[NH:6])[CH3:5].[CH3:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[C:10]=1[NH:16][CH2:17][C:18]([NH:20][NH2:21])=O>CO.ClCCl>[CH3:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[C:10]=1[NH:16][CH2:17][C:18]1[N:6]=[C:4]([CH3:5])[NH:21][N:20]=1
Reactant: CC(=N)N
Reactant: Cc1cccc(C)c1NCC(=O)NN
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: Cc1nc(CNc2c(C)cccc2C)n[nH]1
Yield: 79.3 %

Procedure:
To a stirred solution of 8.8 g (0.022 mol) sodium hydroxide in 500 ml methanol was added 20 g (0.22 mol) acetamidine hydrochloride. After stirring for an additional 1/4 hour, 37.7 g (0.2 mol) alpha-(2,6-dimethylphenylamino)acethydrazide was added. The reaction mixture was heated under reflux for about 18 hours, cooled and filtered. The filtrate was evaporated under a reduced pressure to give a solid residue. The residue was diluted with dichloromethane, filtered, dried over magnesium sulfate and evaporated under reduced pressure to give a solid residue, which was triturated with ethyl ether/petroleum ether and dried to give 34.3 g of the product, m.p. 125°-126° C. The product is tabulated in Table I as Compound No. 2-A.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[O:32][CH3:33])=[CH:16][CH:15]=2)[C@@H:10]([O:34][CH2:35][C:36]2[CH:45]=[C:44]3[C:39]([CH2:40][CH2:41][CH2:42][N:43]3[CH2:46][CH2:47][CH2:48]OS(C)(=O)=O)=[CH:38][CH:37]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C-:54]#[N:55].[K+]>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:15]=[CH:16][C:17]([O:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[O:32][CH3:33])=[CH:18][CH:19]=2)[C@@H:10]([O:34][CH2:35][C:36]2[CH:45]=[C:44]3[C:39]([CH2:40][CH2:41][CH2:42][N:43]3[CH2:46][CH2:47][CH2:48][C:54]#[N:55])=[CH:38][CH:37]=2)[CH2:9]1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: [C-]#N
Reactant: COc1ccccc1COCCCOc1ccc([C@H]2CCN(C(=O)OC(C)(C)C)C[C@@H]2OCc2ccc3c(c2)N(CCCOS(C)(=O)=O)CCC3)cc1
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccccc1COCCCOc1ccc([C@H]2CCN(C(=O)OC(C)(C)C)C[C@@H]2OCc2ccc3c(c2)N(CCCC#N)CCC3)cc1
Temperature: 50 °C
Reaction time: 0.75 h
Yield: 71.4 %

Procedure:
To a well stirred solution of 0.200 g (0.266 mmol) of crude (3R,4R)-3-[1-(3-methanesulfonyloxy-propyl)-1,2,3,4-tetrahydro-quinolin-7-ylmethoxy]-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-piperidine-1-carboxylic acid tert-butyl ester [example 10(a)] in 1.8 ml of absolute N,N-dimethylformamide was added 0.026 (0.399 mmol, 1.5 equiv.) of potassium cyanide. After stirring for 45 min at 50° C., the reaction was allowed to warm to room temperature, poured into 50 ml of an ice/water mixture and extracted three times with 50 ml of ethyl acetate. The combined organic phases were washed twice with 20 ml of water, evaporated under reduced pressure and dried in a high vacuum. The thus-obtained crude product was purified by chromatography on silica gel using a 2:1 mixture of hexane and ethyl acetate as the eluent to yield 0.130 g (0.190 mmol, 71.4% of theory) of (3R,4R)-3-[1-(3-cyano-propyl)-1,2,3,4-tetrahydro-quinolin-7-ylmethoxy]-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-piperidine-1-carboxylic acid tert-butyl ester as a light yellow oil; MS: 684 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:29]=[CH:30][CH:31]=1)[CH2:6][N:7]1[CH2:11][CH2:10][C@H:9]([NH:12][S:13]([C:16]2[CH:25]=[CH:24][C:23]3[C:18](=[CH:19][C:20]([O:26][CH3:27])=[CH:21][CH:22]=3)[CH:17]=2)(=[O:15])=[O:14])[C:8]1=[O:28])#[N:2].[CH3:32][O:33][C:34]1[CH:35]=[C:36]([CH:39]=[CH:40][CH:41]=1)[CH2:37]Br>>[C:1]([C:3]1[CH:4]=[C:5]([CH:29]=[CH:30][CH:31]=1)[CH2:6][N:7]1[CH2:11][CH2:10][C@H:9]([N:12]([CH2:37][C:36]2[CH:39]=[CH:40][CH:41]=[C:34]([O:33][CH3:32])[CH:35]=2)[S:13]([C:16]2[CH:25]=[CH:24][C:23]3[C:18](=[CH:19][C:20]([O:26][CH3:27])=[CH:21][CH:22]=3)[CH:17]=2)(=[O:15])=[O:14])[C:8]1=[O:28])#[N:2]
Reactant: COc1ccc2ccc(S(=O)(=O)N[C@H]3CCN(Cc4cccc(C#N)c4)C3=O)cc2c1
Reactant: COc1cccc(CBr)c1
Product: COc1cccc(CN([C@H]2CCN(Cc3cccc(C#N)c3)C2=O)S(=O)(=O)c2ccc3ccc(OC)cc3c2)c1

Procedure:
The title compound is prepared as described in EXAMPLE 68, Part A using 7-methoxynaphthalene-2-sulfonic acid [1-(3-cyanobenzyl)-2-oxopyrrolidin-3-(S)-yl]amide, prepared as described in EXAMPLE 43, part A, and 3-methoxybenzyl bromide. The crude product is purified by column chromatography eluting with 50% EtOAc/hexanes to afford the title compound as a white foam.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][N:7]([C@H:12]([CH:17]([CH3:19])C)[C:13]([O:15][CH3:16])=[O:14])[C:8]2=[O:11])=[CH:4][CH:3]=1.Cl.N[C:22]1(C(OC)=O)CCC[CH2:23]1>>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][N:7]([C:12]3([C:13]([O:15][CH3:16])=[O:14])[CH2:17][CH2:19][CH2:23][CH2:22]3)[C:8]2=[O:11])=[CH:4][CH:3]=1
Reactant: COC(=O)[C@@H](C(C)C)N1Cc2ccc(Br)cc2C1=O
Reactant: COC(=O)C1(N)CCCC1
Agent: Cl
Product: COC(=O)C1(N2Cc3ccc(Br)cc3C2=O)CCCC1

Procedure:
The compound of example 341 was prepared analogous to compound of example 329 by reaction of the compound of example 328 and methyl 1-aminocyclopentanecarboxylate hydrochloride.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[NH:11][CH:10]=[CH:9]2)([O-:3])=[O:2].[Cl:13]N1C(=O)CCC1=O.C(=O)([O-])O.[Na+]>C(#N)C>[Cl:13][C:9]1[C:8]2[C:12](=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[CH:6][CH:7]=2)[NH:11][CH:10]=1
Reactant: O=[N+]([O-])c1cccc2cc[nH]c12
Reactant: O=C1CCC(=O)N1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: O=[N+]([O-])c1cccc2c(Cl)c[nH]c12
Temperature: 25 °C
Reaction time: 36 h
Yield: 91.9 %

Procedure:
7-Nitro-1H-indole (1.076 g, 6.64 mmol) was dissolved in 30 ml of acetonitrile, followed by the addition of 920 mg (6.89 mmol) of N-chlorosuccinimide. The obtained mixture was stirred at room temperature for 36 hours. A saturated aqueous solution of sodium hydrogencarbonate was added to the resulting mixture to form a precipitate. The precipitate was recovered by filtration and washed with water to give 1.2 g of powdery 3-chloro-7-nitro-1H-indole. This powder (863 mg, 4.39 mmol) was suspended in 10 ml of ethanol, followed by the addition of 4.95 g (21.9 mmol) of stannous chloride dihydrate and 100 μl of concentrated hydrochloric acid. The obtained mixture was heated under reflux for 30 minutes, followed by the addition of a saturated aqueous solution of sodium hydrogencarbonate. The obtained mixture was filtered to remove insolubles. Ethyl acetate was added to the filtrate to conduct extraction. The organic phase was dried over magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography to give 490 mg of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:25]#[N:26])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:10](=[O:24])[CH:9]=2)[CH:7]=1.FC(F)(F)S(O[CH2:33][CH:34]1[CH2:39][CH2:38][CH:37]([O:40][Si:41]([C:44]([CH3:47])([CH3:46])[CH3:45])([CH3:43])[CH3:42])[CH2:36][CH2:35]1)(=O)=O>C1COCC1>[Si:41]([O:40][CH:37]1[CH2:36][CH2:35][CH:34]([CH2:33][CH:16]([N:11]2[CH:12]=[C:13]([O:14][CH3:15])[C:8]([C:6]3[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=3[C:25]#[N:26])=[CH:9][C:10]2=[O:24])[C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])[CH2:39][CH2:38]1)([C:44]([CH3:47])([CH3:46])[CH3:45])([CH3:43])[CH3:42]
Reactant: COc1cn(CC(=O)OC(C)(C)C)c(=O)cc1-c1cc(Cl)ccc1C#N
Reactant: CC(C)(C)[Si](C)(C)OC1CCC(COS(=O)(=O)C(F)(F)F)CC1
Solvent: C1CCOC1
Product: COc1cn(C(CC2CCC(O[Si](C)(C)C(C)(C)C)CC2)C(=O)OC(C)(C)C)c(=O)cc1-c1cc(Cl)ccc1C#N

Procedure:
500 mg (1.26 mmol) of tert-butyl [4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]acetate, 712 mg (1.89 mmol) of (4-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl)methyl trifluoromethanesulphonate (trans/cis mixture) and 1.39 ml (1.39 mmol) of bis(trimethylsilyl)lithium amide (1M in THF) in 10 ml of THF were reacted according to General Method 7B. Purification by column chromatography (120 g silica cartridge, flow rate: 85 ml/min, cyclohexane/ethyl acetate gradient) gave the title compound. Yield: 479 mg (63% of theory)
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]2([C:19]3[CH:24]=[C:23]([CH3:25])[C:22]([O:26][CH3:27])=[C:21]([CH3:28])[N:20]=3)[C:16]3[C:11](=[C:12]([F:17])[CH:13]=[CH:14][CH:15]=3)[C:10]([NH2:18])=[N:9]2)[CH:5]=[CH:4][N:3]=1.[N:29]1[CH:34]=[C:33](B(O)O)[CH:32]=[N:31][CH:30]=1>>[F:17][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:11]=1[C:10]([NH2:18])=[N:9][C:8]2([C:19]1[CH:24]=[C:23]([CH3:25])[C:22]([O:26][CH3:27])=[C:21]([CH3:28])[N:20]=1)[C:6]1[CH:5]=[CH:4][N:3]=[C:2]([C:33]2[CH:34]=[N:29][CH:30]=[N:31][CH:32]=2)[CH:7]=1
Reactant: COc1c(C)cc(C2(c3ccnc(Br)c3)N=C(N)c3c(F)cccc32)nc1C
Reactant: OB(O)c1cncnc1
Product: COc1c(C)cc(C2(c3ccnc(-c4cncnc4)c3)N=C(N)c3c(F)cccc32)nc1C
Yield: 7 %

Procedure:
The title compound was synthesized as described in Example 33 in 7% yield starting from 1-(2-Bromopyridin-4-yl)-4-fluoro-1-(5-methoxy-4,6-dimethylpyridin-2-yl)-1H-isoindol-3-amine (200 mg, 0.45 mmol) and pyrimidin-5-ylboronic acid (61.8 mg, 0.50 mmol).
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[N:9]=1)[CH2:2][CH2:3][CH3:4].Br[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[C:29]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])=[CH:30][CH:31]=[CH:32][CH:33]=2)=[CH:24][CH:23]=1>>[C:37]([O:36][C:34]([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=1[C:25]1[CH:26]=[CH:27][C:22]([CH2:21][N:9]2[C:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:7]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:6]=[C:5]2[CH2:1][CH2:2][CH2:3][CH3:4])=[CH:23][CH:24]=1)=[O:35])([CH3:40])([CH3:39])[CH3:38]
Reactant: CCCCc1nc(C(=O)OCC)c(C(=O)OCC)[nH]1
Reactant: CC(C)(C)OC(=O)c1ccccc1-c1ccc(CBr)cc1
Product: CCCCc1nc(C(=O)OCC)c(C(=O)OCC)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Yield: 96.6 %

Procedure:
Following a procedure similar to that described in Example 1(a), but using 8.0 g of diethyl 2-butylimidazole-4,5-dicarboxylate (prepared as described in Preparation 3) and 10.41 g of t-butyl 4'-bromomethylbiphenyl-2-carboxylate, 15.4 g of the title compound were obtained as a gum.