Azzindani/Open_Reaction_Data huggingface dataset:
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: OB(O)c1cccc(F)c1
Reactant: CC(C)(C)OC(=O)NC1CCN(c2cncc(-c3nn(C4CCCCO4)c4ccc(Br)cc34)n2)CC1
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: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:15]2[N:16]=[N:17][N:18]3[CH:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:22][CH2:21][CH2:20][C:19]=23)[CH:6]=[CH:7][C:8]=1[C:9]1[O:13][C:12]([CH3:14])=[N:11][CH:10]=1.C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[Cl:39]N1C(=O)CCC1=O>C1COCC1.C(OCC)(=O)C>[Cl:39][C:23]1([C:24]([O:26][CH2:27][CH3:28])=[O:25])[N:18]2[N:17]=[N:16][C:15]([C:5]3[CH:6]=[CH:7][C:8]([C:9]4[O:13][C:12]([CH3:14])=[N:11][CH:10]=4)=[C:3]([O:2][CH3:1])[CH:4]=3)=[C:19]2[CH2:20][CH2:21][CH2:22]1
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCOC(=O)C1CCCc2c(-c3ccc(-c4cnc(C)o4)c(OC)c3)nnn21
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)C1(Cl)CCCc2c(-c3ccc(-c4cnc(C)o4)c(OC)c3)nnn21
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 128.4 %

Procedure:
To a mixture of ethyl 3-[3-methoxy-4-(2-methyl-1,3-oxazol-5-yl)phenyl]-4,5,6,7-tetrahydro[1,2,3]triazolo[1,5-a]pyridine-7-carboxylate (1.00 g) in THF (52 mL) was added lithiumhexamethyl disilazide (1M THF solution, 3.14 mL) at −78° C. under an argon atmosphere. The reaction mixture was stirred at −78° C. for 20 min, and at 0° C. for 20 min. To the reaction mixture was added N-chlorosuccinimide (419 mg) at 0° C., and the mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with ethyl acetate, the mixture was washed with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (1.40 g).
Reaction SMILES: [SH:1][C:2]1[NH:3][C:4]2[CH:10]=[C:9]([O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13])[CH:8]=[CH:7][C:5]=2[N:6]=1.[H-].[Na+].[N+]([C:24]1[O:28][C:27]([CH:29]=[O:30])=[CH:26][CH:25]=1)([O-])=O.O>O1CCCC1>[C:15]([Si:12]([CH3:13])([CH3:14])[O:11][C:9]1[CH:8]=[CH:7][C:5]2[NH:6][C:2]([S:1][C:24]3[O:28][C:27]([CH:29]=[O:30])=[CH:26][CH:25]=3)=[N:3][C:4]=2[CH:10]=1)([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc2nc(S)[nH]c2c1
Reactant: O=Cc1ccc([N+](=O)[O-])o1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)[Si](C)(C)Oc1ccc2[nH]c(Sc3ccc(C=O)o3)nc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 50.7 %

Procedure:
Aldehyde intermediate preparation: A solution of 2-mercapto-5-(tert-butyl-dimethyl-silanyloxy)-benzimidazole (2.07 g, 7.38 mmol) in tetrahydrofuran (15 ml) is added dropwise to a mixture of sodium hydride (60% dispersion in mineral oil, 0.472 g, 11.8 mmol) and tetrahydrofuran (5 ml) at 0° C. The mixture is stirred at room temperature for 3 hours. A solution of 5-nitro-2-furaldehyde (1.04 g, 7.38 mmol) in tetrahydrofuran (10 ml) is then added dropwise over a 15 minute period and the mixture is stirred for 16 hours at room temperature. Water (10 ml) is then added and the reaction mixture is concentrated under reduced pressure. The residue is dissolved in a minimal volume of ethyl acetate and is filtered through a silica gel plug (20 ml) that is eluted with 500 ml of ethyl acetate. The organic filtrates are concentrated under reduced pressure and are purified on a silicagel column (120 g) eluted with a mixture of cyclohexane and ethyl acetate (7/3, v/v) to yield 1.4 g of 5-[5-(tert-butyl-dimethyl-silanyloxy)-1H-benzimidazol-2-ylsulfanyl]-furan-2-carbaldehyde as a brown oil. Yield=51%. Analytical LC/MS (method B): retention time=4.62 min., m/z=375.05 (positive ion mode).
Reaction SMILES: [S:1]1[CH2:5][C:4](=[O:6])[NH:3][C:2]1=[O:7].[OH:8][C:9]1[CH:10]=[C:11]([CH:14]=[C:15]([Cl:18])[C:16]=1[OH:17])[CH:12]=O.N1CCCCC1>C(O)(=O)C>[OH:8][C:9]1[CH:10]=[C:11]([CH:12]=[C:5]2[S:1][C:2](=[O:7])[NH:3][C:4]2=[O:6])[CH:14]=[C:15]([Cl:18])[C:16]=1[OH:17]
Reactant: O=Cc1cc(O)c(O)c(Cl)c1
Reactant: O=C1CSC(=O)N1
Solvent: CC(=O)O
Solvent: C1CCNCC1
Product: O=C1NC(=O)C(=Cc2cc(O)c(O)c(Cl)c2)S1
Temperature: 100 °C

Procedure:
A solution containing 1.33 g of thiazolidine-2,4-dione, 1.72 g of 3,4-dihydroxy-5-chlorobenzaldehyde and 2 ml of piperidine in 20 ml of acetic acid was heated for five hours at 100 ° C. Yield 1.9 g (70%), mp 299°-301° C.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[CH:28]1([CH2:33][CH:34]([C:38]2[CH:43]=[CH:42][C:41]([C:44]3[CH:45]=[N:46][CH:47]=[CH:48][CH:49]=3)=[CH:40][CH:39]=2)[C:35](O)=[O:36])[CH2:32][CH2:31][CH2:30][CH2:29]1.[NH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][N:52]=1>C(Cl)Cl>[CH:28]1([CH2:33][CH:34]([C:38]2[CH:43]=[CH:42][C:41]([C:44]3[CH:45]=[N:46][CH:47]=[CH:48][CH:49]=3)=[CH:40][CH:39]=2)[C:35]([NH:50][C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][N:52]=2)=[O:36])[CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: O=C(O)C(CC1CCCC1)c1ccc(-c2cccnc2)cc1
Reactant: Nc1ccccn1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=C(Nc1ccccn1)C(CC1CCCC1)c1ccc(-c2cccnc2)cc1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
A solution of triphenylphosphine (133 mg, 0.51 mmol) in methylene chloride (5 mL) was cooled to 0° C. and then slowly treated with N-bromosuccinimide (90 mg, 0.51 mmol). The reaction mixture was stirred at 0° C. for 20 min and then treated with 3-cyclopentyl-2-(4-pyridin-3-yl-phenyl)-propionic acid (125 mg, 0.42 mmol). The resulting reaction mixture was stirred at 0° C. for 5 min and then allowed to warm to 25° C. where it was stirred for 20 min. The reaction mixture was then treated with 2-aminopyridine (88 mg, 0.93 mmol). The resulting reaction mixture was stirred at 25° C. for 15 h. The crude reaction mixture was then directly purified by flash chromatography (Merck Silica gel 60, 230-400 mesh, 1/2 hexanes/ethyl acetate) to afford impure 3-cyclopentyl-N-pyridin-2-yl-2-(4-pyridin-3-yl-phenyl)-propionamide as a pink foam. The impure foam was dissolved in methylene chloride (40 mL) and washed with a saturated aqueous sodium bicarbonate solution (1×40 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo to afford pure 3-cyclopentyl-N-pyridin-2-yl-2-(4-pyridin-3-yl-phenyl)-propionamide (75 mg, 48%) as a pink foam: mp 139-140° C.; EI-HRMS m/e calcd for C24H25N3O (M+) 371.1998, found 371.2006.
Reaction SMILES: [OH:1][CH:2]([CH3:12])[CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].CCN(CC)CC.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>C(Cl)Cl>[CH3:20][S:21]([O:1][CH:2]([CH3:12])[CH2:3][NH:4][C:5]([O:6][C:7]([CH3:8])([CH3:10])[CH3:9])=[O:11])(=[O:23])=[O:22]
Reactant: CS(=O)(=O)Cl
Reactant: CC(O)CNC(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(CNC(=O)OC(C)(C)C)OS(C)(=O)=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 94.2 %

Procedure:
To a solution of tert-butyl 2-hydroxypropylcarbamate (14.3 g, 81.7 mmol) and Et3N (35.6 ml, 245.1 mmol) in CH2Cl2 (250 mL) at 0° C. was slowly added a solution of methanesulfonyl chloride (9.5 mL, 122.6 mmol) in CH2Cl2 (250 mL). The mixture was stirred at 0° C. for 2 h, diluted with CH2Cl2 (300 mL) and washed with water, 1 N HCl, 5% NaHCO3 and brine. The organic layer was dried over MgSO4 and concentrated under reduced pressure to afford 1-(tert-butoxycarbonylamino)propan-2-yl methanesulfonate (19.5 g, 94%) as a light yellow oil. Mass calculated for C9H19NO5S=253.32; found: [M+H]+=254.2.
Reaction SMILES: [CH2:1]([C@H:3]1[C@@H:7]([C:8]2[N:12]3[C:13]4[C:19](I)=[CH:18][N:17]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:14]=4[N:15]=[CH:16][C:11]3=[N:10][N:9]=2)[CH2:6][C@@H:5]([NH:29][S:30]([CH:33]2[CH2:35][CH2:34]2)(=[O:32])=[O:31])[CH2:4]1)[CH3:2].[C-:36]#[N:37].[K+]>CN(C=O)C.[Cu]I.C1OCCOCCOCCOCCOCCOC1>[C:36]([C:19]1[C:13]2[N:12]3[C:8]([C@@H:7]4[C@H:3]([CH2:1][CH3:2])[CH2:4][C@H:5]([NH:29][S:30]([CH:33]5[CH2:35][CH2:34]5)(=[O:32])=[O:31])[CH2:6]4)=[N:9][N:10]=[C:11]3[CH:16]=[N:15][C:14]=2[N:17]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:27])([CH3:26])[CH3:28])[CH:18]=1)#[N:37]
Reactant: [C-]#N
Reactant: CC[C@@H]1C[C@H](NS(=O)(=O)C2CC2)C[C@@H]1c1nnc2cnc3c(c(I)cn3COCC[Si](C)(C)C)n12
Agent: [Cu]I
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: CN(C)C=O
Product: CC[C@@H]1C[C@H](NS(=O)(=O)C2CC2)C[C@@H]1c1nnc2cnc3c(c(C#N)cn3COCC[Si](C)(C)C)n12
Temperature: 110 °C
Reaction time: 4 h
Yield: 81.4 %

Procedure:
To a solution of N-((1S,3R,4S)-3-ethyl-4-(8-iodo-6-((2-(trimethylsilyl)ethoxy)methyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)cyclopropanesulfonamide (0.1 g, 0.16 mmol, prepared using KK from Preparation #GGG.1) in DMF (1.2 mL) was added potassium cyanide (0.03 g, 0.40 mmol), copper(I) iodide (0.076 g, 0.40 mmol), tetrakis(triphenyl-phosphine)palladium(0) (0.002 g, 0.002 mmol) and 18-crown-6 (0.003 g, 0.01 mmol). The reaction mixture was stirred at about 110° C. for about 4 h and cooled to ambient temperature. The solvent was removed under reduced pressure. The residue was partitioned between EtOAc (15 mL) and water (8 mL). The aqueous layer was further extracted with EtOAc (15 mL). The combined organic layers were dried with MgSO4, filtered, and concd under reduced pressure to give N-((1S,3S,4R)-3-(8-cyano-6-((2-(trimethylsilyl)ethoxy)methyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-4-ethylcyclopentyl)cyclopropanesulfonamide (0.069 g, 82%): LC/MS (Table 1, Method b) Rt=2.50 min; MS m/z: 530 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[CH2:6][N:7]([CH2:14][C:15]1[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[CH:19][C:16]=1[C:17]#[N:18])[C:8]1[N:9]=[N:10][N:11]([CH3:13])[N:12]=1.[CH2:36]([Mg]Br)[CH3:37].[BH4-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1(C)C=CC=CC=1.CCOCC>[NH2:18][CH:17]([C:16]1[CH:19]=[CH:20][C:21]([C:23]([F:26])([F:25])[F:24])=[CH:22][C:15]=1[CH2:14][N:7]([CH2:6][C:5]1[CH:4]=[C:3]([C:2]([F:1])([F:34])[F:35])[CH:29]=[C:28]([C:30]([F:31])([F:32])[F:33])[CH:27]=1)[C:8]1[N:9]=[N:10][N:11]([CH3:13])[N:12]=1)[CH2:36][CH3:37]
Reactant: Cn1nnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)Cc2cc(C(F)(F)F)ccc2C#N)n1
Reactant: CC[Mg]Br
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CCC(N)c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1
Reaction time: 2.5 h
Yield: 87 %

Procedure:
To a solution of 2-{[(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-methyl}-4-trifluoromethyl-benzonitrile (Preparation 7) (300.0 mg, 0.590 mmoles) in toluene (1.2 mL) was added ethyl magnesium bromide (0.59 mL, 1.77 mmoles of a 3M solution in ether) dropwise at room temperature and the reaction mixture was stirred for 2.5 hours. The reaction was quenched by adding methanol (0.98 mL) dropwise with stirring until methanol and toluene were thoroughly mixed. To this mixture sodium borohydride (22.3 mg, 0.590 mmoles) was added in one portion and the reaction stirred for 1.5 hours. A 10% aqueous citric acid (1.5 mL) solution was added drop wise at room temperature until bubbling stopped. The reaction mixture was made basic to pH 10 with 1 N NaOH solution. The organic layer was dried over sodium sulfate, filtered and concentrated. The crude product was purified using cation exchange resin (Waters Oasis MCX 6CC 500 mg LP Extraction Cartridge, Waters, Milford, Mass., USA) to yield the title compound (278.4 mg, 87% yield) as yellow gum. MS (ES+) Calc: 608.5, Found: 609.1 (M+1).
Reaction SMILES: [BH4-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([O:15][CH3:16])[C:12]=1[O:13][CH3:14])[CH:8]=[O:9].O>O1CCCC1>[CH3:16][O:15][C:11]1[CH:10]=[C:7]([CH:6]=[C:5]([O:4][CH3:3])[C:12]=1[O:13][CH3:14])[CH2:8][OH:9]
Reactant: COc1cc(C=O)cc(OC)c1OC
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(CO)cc(OC)c1OC
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 94.4 %

Procedure:
To a 500 ml round-bottom flask under nitrogen were added 15.32 g (0.41 mol) of sodium borohydride and 100 ml of dry tetrahydrofuran. The mixture was stirred for 10 min., then 20 g (0.108 mol) of 3,4,5-trimethoxybenzaldehyde dissolved in 100 ml of tetrahydrofuran was added dropwise to the solution described above. After stirring at room temperature for 16 hr, the solution was cooled to 0° C., 5 ml of distilled water was added dropwise, and the ice-bath was removed. The mixture was stirred overnight. Tetrahydrofuran was concentrated. The mixture was then diluted with 200 ml of water, and extracted twice with 200 ml of diethyl ether. The extract was dried over magnesium sulfate, concentrated after filtration, and dried in vacuum overnight. 3,4,5-Trimethoxybenzyl alcohol (20.2 g, 100% yield) was obtained as a colorless oil, which can be used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14](=[O:19])[CH2:13][CH2:12]2.C([Li])CCC.CCCCCC.[CH2:31](Br)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>O1CCCC1>[CH2:31]([N:15]1[C:16]2[C:11](=[CH:10][C:9]([C:3]3[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=3[F:1])=[CH:18][CH:17]=2)[CH2:12][CH2:13][C:14]1=[O:19])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: BrCc1ccccc1
Reactant: O=C1CCc2cc(-c3ccc(F)cc3F)ccc2N1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=C1CCc2cc(-c3ccc(F)cc3F)ccc2N1Cc1ccccc1
Temperature: 25 °C
Yield: 36 %

Procedure:
To a solution of 6-(2,4-difluorophenyl)-3,4-dihydroquinolin-2(1H)-one (130 mg, 0.50 mmol) in anhydrous tetrahydrofuran (5 mL) at 0° C. in a dry flask equipped with an inlet of dry nitrogen was added fresh 1.6 M n-butyl lithium in n-hexane (0.6 mL, 0.96 mmol) with stirring. The reaction mixture was stirred at 0° C. for 2 hours, followed by addition of a second portion of 1.6 M n-butyl lithium in n-hexane (0.6 mL, 0.96 mmol), and the mixture stirred for another 2 hours. To this mixture was added slowly a solution of benzyl bromide (855 mg, 5.00 mmol) in anhydrous tetrahydrofuran (3 mL) at 0° C., stirred overnight, and allowed to warm to room temperature. The reaction was followed by LCMS and stirring was continued until all of the starting material was consumed. The reaction mixture was quenched by slow addition of saturated aqueous ammonium chloride (10 mL) with stirring, concentrated under reduced pressure, diluted with ethyl acetate (20 mL) and dilute aqueous ammonium chloride (10 mL). The aqueous phase was extracted with ethyl acetate (3×20 mL), and the combined organic phase successively washed with 2N sodium carbonate (20 mL), 30% ammonium chloride (20 mL), brine (20 mL), and dried over magnesium sulfate. Evaporation of the solvent under reduced pressure gave a crude mixture, which was purified by reverse phase HPLC with a gradient of acetonitrile/water (2% to 98%) to afford 1-benzyl-6-(2,4-difluorophenyl)-3,4-dihydroquinolin-2(1H)-one (62 mg, 0.18 mmol, 35%). LCMS mz 350.0 (M+H), 372.0 (M+Na), anal HPLC>98% in purity. 1H NMR (400 MHz; CDCl3) δ7.10-7.40 (m, 8H); 6.80-7.00 (m, 3H); 5.22 (s, 2H); 3.05 (m, 2H); 2.85 (m, 2H).
Reaction SMILES: [F:1][C:2]1[C:3]2[N:4]([CH:12]=[CH:13][N:14]=2)[CH:5]=[CH:6][C:7]=1[C:8]([OH:11])([CH3:10])[CH3:9].Br[C:16]1[CH:17]=[CH:18][C:19]([F:27])=[C:20]([N:22]2[CH:26]=[CH:25][N:24]=[CH:23]2)[CH:21]=1>>[F:1][C:2]1[C:3]2[N:4]([C:12]([C:16]3[CH:17]=[CH:18][C:19]([F:27])=[C:20]([N:22]4[CH:26]=[CH:25][N:24]=[CH:23]4)[CH:21]=3)=[CH:13][N:14]=2)[CH:5]=[CH:6][C:7]=1[C:8]([OH:11])([CH3:10])[CH3:9]
Reactant: CC(C)(O)c1ccn2ccnc2c1F
Reactant: Fc1ccc(Br)cc1-n1ccnc1
Product: CC(C)(O)c1ccn2c(-c3ccc(F)c(-n4ccnc4)c3)cnc2c1F
Yield: 24 %

Procedure:
2-(8-Fluoroimidazo[1,2-α]pyridin-7-yl)propan-2-ol was coupled to 1-(5-bromo-2-fluorophenyl)-1H-imidazole as described in Example 6 to give 2-{8-fluoro-3-[4-fluoro-(3-imidazol-1-yl)phenyl]imidazo[1,2-α]pyridin-7-yl}propan-2-ol as a pale yellow solid (83 mg, 24%): m/z (ES+) 355 [MH+].
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][NH2:6])=[O:4].[CH3:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]=[C:16]2[CH2:21][CH2:20][CH2:19][CH2:18][C:17]2=O)=[CH:11][CH:10]=1>C1C=CC=CC=1.CO>[CH3:1][O:2][C:3]([NH:5][N:6]=[C:17]1[CH2:18][CH2:19][CH2:20][CH2:21][C:16]1=[CH:15][C:12]1[CH:11]=[CH:10][C:9]([O:8][CH3:7])=[CH:14][CH:13]=1)=[O:4]
Reactant: COc1ccc(C=C2CCCCC2=O)cc1
Reactant: COC(=O)NN
Solvent: CO
Solvent: c1ccccc1
Product: COC(=O)NN=C1CCCCC1=Cc1ccc(OC)cc1
Reaction time: 1 h
Yield: 95.1 %

Procedure:
To a solution of 22.68 g (0.252 moles) of N-methoxycarbonyl hydrazine in 100 ml of benzene a solution of 50.0 g (0.23 moles) of 2-(p-methoxyphenylmethylene)-cyclohexan-1-one in 300 ml of anhydrous methanol is added, under stirring. The reaction mixture is boiled for one hour, clarified with activated carbon, filtered and the filtrate is cooled. 63.05 g of the desired compound are obtained. Yield: 94.65%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](O)=O)=[N:6][CH:7]=1.Cl.CN(C)CCCN=C=NCC.N1C=CC=CC=1.[NH2:29][C:30]1[C:35]([NH2:36])=[CH:34][C:33]([CH:37]2[CH2:41][CH2:40][CH2:39][N:38]2C(OC(C)(C)C)=O)=[C:32]([O:49][C:50]2[CH:55]=[CH:54][C:53]([S:56]([CH3:59])(=[O:58])=[O:57])=[CH:52][CH:51]=2)[CH:31]=1>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[NH:36][C:35]3[CH:34]=[C:33]([CH:37]4[CH2:41][CH2:40][CH2:39][NH:38]4)[C:32]([O:49][C:50]4[CH:55]=[CH:54][C:53]([S:56]([CH3:59])(=[O:58])=[O:57])=[CH:52][CH:51]=4)=[CH:31][C:30]=3[N:29]=2)=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCCC1c1cc(N)c(N)cc1Oc1ccc(S(C)(=O)=O)cc1
Reactant: O=C(O)c1ccc(Br)cn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CS(=O)(=O)c1ccc(Oc2cc3nc(-c4ccc(Br)cn4)[nH]c3cc2C2CCCN2)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
220 mg of 5-bromopyridine-2-carboxylic acid and 260 mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide monohydrochloride were added in order to a pyridine (10 ml) solution of 500 mg of t-butyl 2-(4,5-diamino-2-(4-methanesulfonyl-phenoxy)-phenyl)-pyrrolidine-1-carboxylate, and the reaction liquid was stirred at room temperature for 12 hours. The reaction liquid was diluted with chloroform, washed with water and saturated saline in order, and dried with anhydrous magnesium sulfate. The solvent was evaporated away under reduced pressure, the resulting residue was dissolved in 10 ml of trifluoroacetic acid, and the reaction liquid was heated under reflux for 3 hours. After cooled, the reaction liquid was distilled under reduced pressure, and the resulting residue was diluted with chloroform, and then made basic with aqueous saturated sodium bicarbonate added thereto. Then, the organic layer was washed with saturated saline and dried with anhydrous magnesium sulfate. The solvent was evaporated away under reduced pressure, and the resulting residue was purified through silica gel column chromatography (developing solvent: chloroform/methanol/aqueous ammonia=50/1/0.1) to obtain the entitled compound as a colorless oily substance.
Reaction SMILES: [CH3:1][C:2]([N:9]1[CH:13]=[C:12]([NH:14][C:15]2[NH:16][C:17](=O)[CH:18]=[CH:19][N:20]=2)[CH:11]=[N:10]1)([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].P(Cl)(Cl)([Cl:24])=O.[OH-].[Na+]>C(#N)C>[Cl:24][C:17]1[CH:18]=[CH:19][N:20]=[C:15]([NH:14][C:12]2[CH:11]=[N:10][N:9]([C:2]([CH3:8])([CH3:1])[C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH:13]=2)[N:16]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)C(C)(C)n1cc(Nc2nccc(=O)[nH]2)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Product: CCOC(=O)C(C)(C)n1cc(Nc2nccc(Cl)n2)cn1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a solution of ethyl 2-methyl-2-(4-((6-oxo-1,6-dihydropyrimidin-2-yl)amino)-1H-pyrazol-1-yl)propanoate (2.0 g) obtained in Step C of Example 347 in acetonitrile (20 mL) was added phosphorus oxychloride (4.0 mL), and the mixture was stirred at 80° C. for 2 hr. To the reaction mixture was added 8 M aqueous sodium hydroxide solution (25 mL), and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (2.0 g).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[CH3:27][N:28]1[CH:33]=[CH:32][CH:31]=[C:30]([CH3:34])[C:29]1=[O:35]>C(Cl)(Cl)(Cl)Cl>[Br:1][CH2:34][C:30]1[C:29](=[O:35])[N:28]([CH3:27])[CH:33]=[CH:32][CH:31]=1
Reactant: Cc1cccn(C)c1=O
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Cn1cccc(CBr)c1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 44.6 %

Procedure:
N-Bromosuccinimide (2.17 g, 12.2 mmol) and benzoic peroxyanhydride (0.295 g, 1.22 mmol) were added to a flask containing a solution of 1,3-dimethylpyridin-2(1H)-one (1.50 g, 12.2 mmol) in carbon tetrachloride (250 mL, degassed with flowing N2 for 5 minutes). The mixture was heated at reflux for 3 hours. The reaction mixture was cooled to ambient temperature, filtered through filter paper, and the filtrate was concentrated under vacuum. The residue was suspended in diethyl ether (20 mL), stirred for 15 minutes, and the liquid was decanted. The solids were rinsed with diethyl ether (3×5 mL), then dried under vacuum to give 3-(bromomethyl)-1-methylpyridin-2(1H)-one as a yellow solid (1.1 g).