Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:36])[CH2:4][CH2:5][CH2:6][N:7]([CH2:9][CH:10]([O:12][C:13]1[C:14]2[C:21]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)=[C:20]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[O:19][C:15]=2[N:16]=[CH:17][N:18]=1)[CH3:11])[CH3:8].[OH-].[Na+]>C1COCC1>[CH3:29][O:28][C:25]1[CH:24]=[CH:23][C:22]([C:21]2[C:14]3[C:13]([O:12][CH:10]([CH3:11])[CH2:9][N:7]([CH3:8])[CH2:6][CH2:5][CH2:4][C:3]([OH:36])=[O:2])=[N:18][CH:17]=[N:16][C:15]=3[O:19][C:20]=2[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[CH:27][CH:26]=1
Reactant: COC(=O)CCCN(C)CC(C)Oc1ncnc2oc(-c3ccccc3)c(-c3ccc(OC)cc3)c12
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(OC(C)CN(C)CCCC(=O)O)c23)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Put 20 mg (0.027 mmol) (+/−)-4-[(2-{[5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidin-4-yl]oxy}propyl)(methyl)amino]butanoic acid methyl ester in 0.8 ml THF. Add 0.27 ml (0.27 mmol) 1 N sodium hydroxide solution and stir overnight at RT. Then concentrate by evaporation and purify the residue by thick-layer chromatography on silica gel (solvent: dichloromethane/methanol 9:1). Extract the product zone with dichloromethane/methanol 7:3. 8.5 mg (66.3% of theor.) of the target compound is obtained.
Reaction SMILES: C(N(CC)CC)C.[Br:8][C:9]1[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=1.[Cl:16][C:17]1[CH:18]=[C:19]([CH2:23][CH2:24][C:25](O)=[O:26])[CH:20]=[CH:21][CH:22]=1.CCN=C=NCCCN(C)C.C([O-])(O)=O.[Na+]>C(Cl)Cl.O>[Br:8][C:9]1[CH:15]=[CH:14][C:12]([NH:13][C:25](=[O:26])[CH2:24][CH2:23][C:19]2[CH:20]=[CH:21][CH:22]=[C:17]([Cl:16])[CH:18]=2)=[CH:11][CH:10]=1
Reactant: Nc1ccc(Br)cc1
Reactant: O=C(O)CCc1cccc(Cl)c1
Agent: CCN=C=NCCCN(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CCc1cccc(Cl)c1)Nc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Triethylamine (1.01 mL, 7.27 mmol) was added slowly to a mixture of 4-bromoaniline (0.500 g, 2.91 mmol), 3-(3-chlorophenyl)propanoic acid (0.643 g, 2.91 mmol), and EDCI (0.669 g, 3.49 mmol) in CH2Cl2 (20 mL). The mixture was stirred at room temperature for 48 hours and saturated aqueous NaHCO3 was added. Water (50 mL) was added followed by additional CH2Cl2. The mixture as stirred for 10 minutes and layers were separated. The CH2Cl2 layer was dried over Na2SO4, then filtered. The solvent was removed under reduced pressure and the residual oil chromatographed (CH2Cl2/EtOAc) to provide the title compound as a white fluffy solid.
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:9])[NH:4][C:5](=[S:8])[NH:6][CH:7]=1.[OH-].[K+].[CH3:12]I>C(O)C>[CH3:1][C:2]1[C:3](=[O:9])[N:4]=[C:5]([S:8][CH3:12])[NH:6][CH:7]=1
Reactant: CI
Reactant: Cc1c[nH]c(=S)[nH]c1=O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CSc1nc(=O)c(C)c[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.9 %

Procedure:
5-methyl-2-thiouracil (2 g, 98%, 13.78 mmol, 1 eq) and KOH, 85%, (1.05 eq, 995 mg) were suspended in 25 ml of absolute ethanol and the mixture was stirred for 1 hour at room temperature. In the suspension was then added MeI (1.05 eq, 905 μl) dropwise and the suspension was heated at 65° C. (temperature on display of heating device) for 2 hours. Solvent was then evaporated. In the rest was added 100 ml of water and using ultrasound was suspended. The obtained precipitate was collected by filtration, it was dried and obtained was 5-methyl-2-methylsulfanyl-1H-pyrimidin-4-one (1.7 g, yield=71.9%, purity=93%) in form of a white powder. MS: [M+H]+=157.08 1H NMR (300 MHz; DMSO-d6) δ/ppm 1.90 (s, 3H), 2.50 (s, 3H), 7.78 (s, 1H)
Reaction SMILES: C([O:7][CH2:8][C@@H:9]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:10]1[C:11]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)=[C:12]2[C:17](=[CH:18][C:19]=1[CH3:20])[N:16]=[C:15]([N:21]1[CH:25]=[CH:24][N:23]=[CH:22]1)[CH:14]=[CH:13]2)(=O)C(C)(C)C.[OH-].[Na+]>O1CCCC1.CO.O>[C:34]([O:33][C@@H:9]([C:10]1[C:11]([C:26]2[CH:27]=[CH:28][C:29]([Cl:32])=[CH:30][CH:31]=2)=[C:12]2[C:17](=[CH:18][C:19]=1[CH3:20])[N:16]=[C:15]([N:21]1[CH:25]=[CH:24][N:23]=[CH:22]1)[CH:14]=[CH:13]2)[CH2:8][OH:7])([CH3:37])([CH3:35])[CH3:36]
Reactant: Cc1cc2nc(-n3ccnc3)ccc2c(-c2ccc(Cl)cc2)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Cc1cc2nc(-n3ccnc3)ccc2c(-c2ccc(Cl)cc2)c1[C@@H](CO)OC(C)(C)C
Temperature: 45 °C
Yield: 98.2 %

Procedure:
To a solution of (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-2-(1H-imidazol-1-yl)-7-methylquinolin-6-yl)ethyl pivalate (39.2 mg, 0.075 mmol) in tetrahydrofuran and methanol (5:1, 1 mL) was added 1 M sodium hydroxide (2 mL) and the reaction was heated to 45° C. overnight. The reaction was cooled to room temperature, diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated. The crude extract was co-evaporated two times with acetonitrile to give a clear white oil (32.1 mg). LCMS-ER+ (m/z): [M+H]+ calcd for C25H27ClN3O2: 436.17. found: 436.86.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([O:26][CH3:27])[C:5]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=2)=[C:6]2[C:11]=1[N:10]=[C:9]([O:12][CH3:13])[CH:8]=[C:7]2[CH3:14].C(NC(C)C)(C)C.I[CH:36]([CH3:51])[CH2:37][CH2:38][CH2:39][N:40]1[C:44](=[O:45])[C:43]2=[CH:46][CH:47]=[CH:48][CH:49]=[C:42]2[C:41]1=[O:50]>CC#N.O>[CH3:13][O:12][C:9]1[CH:8]=[C:7]([CH3:14])[C:6]2[C:11](=[C:2]([NH:1][CH:36]([CH3:51])[CH2:37][CH2:38][CH2:39][N:40]3[C:44](=[O:45])[C:43]4=[CH:46][CH:47]=[CH:48][CH:49]=[C:42]4[C:41]3=[O:50])[CH:3]=[C:4]([O:26][CH3:27])[C:5]=2[O:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:23])([F:24])[F:25])[CH:17]=2)[N:10]=1
Reactant: CC(I)CCCN1C(=O)c2ccccc2C1=O
Reactant: COc1cc(C)c2c(Oc3cccc(C(F)(F)F)c3)c(OC)cc(N)c2n1
Solvent: O
Solvent: CC(C)NC(C)C
Solvent: CC#N
Product: COc1cc(C)c2c(Oc3cccc(C(F)(F)F)c3)c(OC)cc(NC(C)CCCN3C(=O)c4ccccc4C3=O)c2n1
Reaction time: 24 h

Procedure:
A mixture of 8-amino-2,6-dimethoxy-4-methyl-5-(3-trifluoromethylphenoxy)quinoline (8.0 g, 21.2 mmol), diisopropylamine (2.14 g, 21.2 mmol) and 4-iodo-1-phthalimidopentane (IPP) (7.26 g, 21.2 mmol) in CH3CN (40 mL) was refluxed for 24 hours after which time additional diisopropylamine (2.14 g, 21.2 mmol) and IPP (7.26 g, 21.2 mmol) were added. After refluxing a further 24 hours, more diisopropylamine (1.07 g, 10.6 mmol) and IPP (3.63 g, 10.6 mmol) were added and refluxing was continued a further 24 hours. The cooled mixture was diluted with H2O (20 mL) and stirred in an ice bath until crystallization was complete. Filtration and recrystallization from IPA gave 8.4 g (67%) of 1st crop title compound, mp 120°-124° C. Further recrystallization raised the mp to 121°-124° C.
Reaction SMILES: [CH2:1]([N:8]([CH2:21][C:22]1[CH:39]=[CH:38][C:25]([O:26][C:27]2[CH:32]=[CH:31][C:30]([CH2:33][CH2:34][C:35]([OH:37])=O)=[CH:29][CH:28]=2)=[CH:24][CH:23]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[C:10]=1[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C([O:43][C:44](=[O:48])[CH2:45][CH2:46][NH2:47])C>>[CH2:1]([N:8]([CH2:21][C:22]1[CH:39]=[CH:38][C:25]([O:26][C:27]2[CH:28]=[CH:29][C:30]([CH2:33][CH2:34][C:35]([NH:47][CH2:46][CH2:45][C:44]([OH:48])=[O:43])=[O:37])=[CH:31][CH:32]=2)=[CH:24][CH:23]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[C:10]=1[CH3:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CCN
Reactant: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2ccc(CCC(=O)O)cc2)cc1
Agent: Cl
Product: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2ccc(CCC(=O)NCCC(=O)O)cc2)cc1

Procedure:
The product from Example 104A and β-alanine ethyl ester hydrochloride were processed as described in Example 104B to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ8.97 (s, 1 H), 7.90 (t, 1 H), 7.14-7.34 (m, 8 H), 7.01 (m, 4 H), 6.87 (d, 4 H), 4.06 (s, 2 H), 4.02 (s, 2 H), 7.71 (br s, 1H), 3.22 (dd, 2 H), 2.91 (s, 3 H), 2.77 (t, 2 H), 2.34 (m, 7 H); MS (APCI) m/z 616 (M+H+).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[C:11]([CH2:15][C:16]([OH:18])=[O:17])[CH:12]=[CH:13][CH:14]=2)O1.Br[C:21]1[N:22]=[C:23]([C:28]2[O:29][C:30]3[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:31]=3[N:32]=2)[C:24]([NH2:27])=[N:25][CH:26]=1>C1(C)C=CC=CC=1.O1CCOCC1.C(=O)([O-])[O-].[Na+].[Na+]>[NH2:27][C:24]1[N:25]=[CH:26][C:21]([C:9]2[CH:10]=[C:11]([CH2:15][C:16]([OH:18])=[O:17])[CH:12]=[CH:13][CH:14]=2)=[N:22][C:23]=1[C:28]1[O:29][C:30]2[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:31]=2[N:32]=1
Reactant: Nc1ncc(Br)nc1-c1nc2ccc(F)cc2o1
Reactant: CC1(C)OB(c2cccc(CC(=O)O)c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: Nc1ncc(-c2cccc(CC(=O)O)c2)nc1-c1nc2ccc(F)cc2o1
Temperature: 85 °C
Yield: 12.7 %

Procedure:
A mixture of 2-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetic acid (85 mg), 5-bromo-3-(6-fluoro-1,3-benzoxazol-2-yl)pyrazin-2-amine (100 mg) in toluene-dioxane (1 ml-1.5 ml) and 2M aqueous sodium carbonate (5 ml) was degassed. Pd(dppf)Cl2 (24 mg) was added. The resulting mixture was heated to 85° C. for 6 hours. 1-Butanol (5 ml) was added to the mixture and the mixture was washed with brine (3×5 ml). The resulting organic layer was concentrated and purified by chromatography on silica gel eluting with a gradient of methanol in ethyl acetate to give the title compound (15 mg) as a solid. NMR Spectrum: (DMSOd6, 400 MHz) 7.25 (m, 2H), 7.30 (m, 1H), 7.40 (m, 1H), 7.90 (m, 6H), 8.80 (s, 1H); Mass spectrum: M+H+ 365.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][CH:13]([N:21]([CH2:33][C:34]1[CH:43]=[CH:42][CH:41]=[CH:40][C:35]=1[C:36]([O:38]C)=[O:37])[S:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[O:31][CH3:32])(=[O:24])=[O:23])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[OH-].[Na+].Cl>O.CO>[O:11]=[C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2](=[O:1])[N:3]1[CH2:12][CH:13]([N:21]([CH2:33][C:34]1[CH:43]=[CH:42][CH:41]=[CH:40][C:35]=1[C:36]([OH:38])=[O:37])[S:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[O:31][CH3:32])(=[O:24])=[O:23])[CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: COC(=O)c1ccccc1CN(C(Cc1ccccc1)CN1C(=O)c2ccccc2C1=O)S(=O)(=O)c1ccccc1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1ccccc1S(=O)(=O)N(Cc1ccccc1C(=O)O)C(Cc1ccccc1)CN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Yield: 80.5 %

Procedure:
To the solution of compound 2d (100 mg, 0.17 mmol) in H2O (2 mL) and MeOH (10 mL) was added aqueous NaOH (33 mg, 0.84 mmol). The resulting mixture was heated to reflux for 2 hr. Then the mixture was cooled to rt and acidified to pH=3 with 3.5N aqueous HCl, concentrated in vacuo to remove the volatile solvent. The resulting mixture was extracted with EA (2×30 mL). The organic extracts were combined and dried over anhydrous Na2SO4, concentrated in vacuo to give compound 2e as a white solid (80 mg, 80% yield).
Reaction SMILES: [C:1]1([CH3:16])[CH:6]=[CH:5][C:4]([C:7]2[N:15]=[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][N:9]3[N:8]=2)=[CH:3][CH:2]=1.[Br:17]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:17][CH2:16][C:1]1[CH:2]=[CH:3][C:4]([C:7]2[N:15]=[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][N:9]3[N:8]=2)=[CH:5][CH:6]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(-c2nc3ccccn3n2)cc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1ccc(-c2nc3ccccn3n2)cc1
Temperature: 20 °C

Procedure:
41.85 g of 2-(p-tolyl)-s-triazolo[1,5-a]pyridine (26) are dissolved at 50° C. in 1,200 ml of dry carbon tetrachloride. 37.4 g of N-bromosuccinimide and 1 g of dibenzoyl peroxide are then added and the mixture is warmed gradually to the boil while stirring well and with exposure to a 400 W lamp. The reaction mixture is kept under reflux for 4 hours and is then cooled to 20° C. and the product which has precipitated is filtered off with suction. The succinimide is removed by washing with a large amount of water and the material on the suction filter is dried. This gives 39.2 g (58% of theory) of compound (I) in the form of a pale beige powder with a melting point of 192° to 193° C. After recrystallising twice from toluene, 32.3 g (56.1% of theory) of small, virtually colourless, glossy needles with a melting point of 195.5° to 196° C. are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)[N:12]=[C:11]([C:20]([OH:22])=[O:21])[CH:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.[Cl:23]C1N=C(NN)C=CC=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([Cl:23])[N:15]=3)[N:12]=[C:11]([C:20]([OH:22])=[O:21])[CH:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: O=C(O)c1cc(-c2cc(F)cc(Cl)c2)n(-c2ccccn2)n1
Reactant: NNc1cccc(Cl)n1
Product: O=C(O)c1cc(-c2cc(F)cc(Cl)c2)n(-c2cccc(Cl)n2)n1

Procedure:
1.30 g (3.97 mmol) of the compound of Example 1A is reacted analogously to the synthesis of the compound of Example 20A with 854 mg (5.95 mmol) of 6-chloropyridin-2-yl-hydrazine. After hydrolysis, 815 mg (58% of theory) of the title compound is obtained.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:13][CH3:14])=[C:4]([Cl:12])[C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[C:15](Cl)(=O)C(Cl)=O>ClCCl.CN(C=O)C>[Br:1][C:2]1[C:3]([O:13][CH3:14])=[C:4]([Cl:12])[C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([O:9][CH3:15])=[O:8]
Reactant: O=C(Cl)C(=O)Cl
Reactant: COc1c(Br)cc(C(=O)O)c(O)c1Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Br)c(OC)c(Cl)c1O
Temperature: 13 °C
Reaction time: 1 h
Yield: 99.8 %

Procedure:
To a solution of 5-bromo-3-chloro-2-hydroxy-4-methoxybenzoic acid (10.4 g) in dichloromethane (150 mL) were added a solution of oxalyl chloride (7.05 g) in dichloromethane (10 mL) and DMF (3 drops) under ice-cooling, and the mixture was stirred at 13° C. for 1 hr. The solvent was evaporated under reduced pressure, and the residue was dissolved in THF (50 mL). This solution was added dropwise to a solution of triethylamine (1.20 g) in methanol (150 mL) under ice-cooling, and the mixture was stirred at 13° C. for 16 hr. The solvent was evaporated under reduced pressure from the reaction mixture, and the residue was diluted with ethyl acetate and water. 1N Hydrochloric acid was added thereto, and the mixture was partitioned. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (10.9 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](B(O)O)=[CH:5][C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2.[F:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1Br.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC>[CH3:1][O:2][C:3]1[C:4]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[F:16])=[CH:5][C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:12]=1
Reactant: COc1cc2ccccc2cc1B(O)O
Reactant: Fc1ccccc1Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COc1cc2ccccc2cc1-c1ccccc1F
Temperature: 25 °C
Yield: 75 %

Procedure:
In the atmosphere of argon, 14.3 g of 3-methoxynaphthalene-2-boronic acid, 12.4 g of 2-fluorobromobenzene, 1.64 g of tetrakistriphenylphosphine palladium (0), 220 mL of 1,2-dimethoxyethane, 110 mL of a 2M aqueous solution of sodium carbonate were placed in a flask, and the resulting mixture was stirred with heating under reflux for 8 hours. After cooling to room temperature, the reaction solution was extracted with toluene. An aqueous phase was removed, and then an organic phase was washed with saturated saline. The organic phase was dried with magnesium sulfate and then concentrated. Residues were purified by silica gel column chromatography, whereby 13.4 g (yield: 75%) of 2-methoxy-3-(2-fluorophenyl)naphthalene was obtained.
Reaction SMILES: [OH:1][N:2]=[C:3](Cl)[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][CH:5]=1.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]#[CH:19])=[CH:14][CH:13]=1.N>>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[O:1][N:2]=[C:3]([C:4]3[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=3)[CH:19]=2)=[CH:14][CH:13]=1
Reactant: C#Cc1ccc(Cl)cc1
Reactant: ON=C(Cl)c1cccnc1
Agent: N
Product: Clc1ccc(-c2cc(-c3cccnc3)no2)cc1

Procedure:
The titled compound was prepared as the hydrochloride salt according to Method CB using the product of Example 1A (78 mg, 0.5 mmol) and 1-chloro-4-ethynylbenzene (Aldrich, 68 mg, 0.5 mmol). 1H NMR (300 MHz, DMSO-d6) δ 7.62-7.75 (m, 3H), 7.79 (s, 1H), 7.89-8.01 (m, 2H), 8.40 (dt, J=8.1, 1.7 Hz, 1H), 8.78 (dd, J=5.1, 1.4 Hz, 1H), 9.16 (d, J=2.0 Hz, 1H) ppm; MS (DCI/NH3) m/z 259 (M+H)+, 257 (M+H)+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C@@H:2]1[CH2:7][O:8][C:9]1[C:17]2[C:16]3[CH:18]=[C:19]([C:22]#[N:23])[N:20]=[CH:21][C:15]=3[N:14]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:13]=2[N:12]=[CH:11][CH:10]=1.C=O.[C:34](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(#N)C.O.C(=O)(O)[O-].[Na+].C(Cl)Cl>[CH3:34][N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C@@H:2]1[CH2:7][O:8][C:9]1[C:17]2[C:16]3[CH:18]=[C:19]([C:22]#[N:23])[N:20]=[CH:21][C:15]=3[N:14]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:13]=2[N:12]=[CH:11][CH:10]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: C[Si](C)(C)CCOCn1c2cnc(C#N)cc2c2c(OC[C@H]3CCCCN3)ccnc21
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC#N
Solvent: O
Product: CN1CCCC[C@@H]1COc1ccnc2c1c1cc(C#N)ncc1n2COCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of (R)-4-(piperidin-2-ylmethoxy)-9-(2-trimethylsilanyl-ethoxymethyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile (220 mg, 0.50 mmol) in acetonitrile (2.2 mL) and water (0.45 mL) was added Formalin (41 uL, 1.5 mmol) followed by sodium triacetoxyborohydride (210 mg, 1.0 mmol), and the reaction mixture was stirred at ambient temperature for 20 minutes. The mixture diluted with saturated aqueous sodium bicarbonate solution (50 mL) and methylene chloride (50 mL). The organic layer was separated, dried over sodium sulfate, filtered, concentrated in vacuo, and purified flash chromatography (silica, 4 g, ISCO, 1-20% methanol in methylene chloride) to afford the title compound as a yellow solid, which was used in the next step without any further purification (197 mg, 87%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=1.Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[N:31]1[CH2:35][CH2:34][CH2:33][S:32]1(=[O:37])=[O:36]>>[O:36]=[S:32]1(=[O:37])[CH2:33][CH2:34][CH2:35][N:31]1[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[C:6]1[CH:5]=[CH:4][C:3]([C:17]2[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=2)=[C:2]([F:1])[CH:7]=1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)cn3)c(F)c2)OC1(C)C
Reactant: O=S1(=O)CCCN1c1ccccc1Br
Product: Nc1cnc(-c2ccc(-c3ccccc3N3CCCS3(=O)=O)cc2F)cn1

Procedure:
Title compound was prepared using conditions analogous to those described in Example 1 using 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-pyrazin-2-amine and 2-(2-bromophenyl)isothiazolidine 1,1-dioxide. MS (ESI): mass calcd. for C19H17FN4O2S, 384.11; m/z found, 385.2 [M+H]+. 1H NMR (500 MHz, CDCl3) δ 8.62-8.58 (m, 1H), 8.12 (d, J=1.5, 1H), 7.99 (m, 1H), 7.76-7.71 (m, 1H), 7.49-7.45 (m, 1H), 7.46-7.38 (m, 4H), 4.69 (s, 2H), 3.30-3.04 (m, 4H), 2.39-2.11 (m, 2H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([C:21](=O)[CH2:22][CH2:23][CH2:24][CH3:25])[C:17](OC)=[O:18])=[C:11]([F:27])[CH:10]=1)#[N:2].[O:28]1[C:32]2([CH2:37][CH2:36][CH:35]([NH:38][C:39]3[NH:43][CH:42]=[N:41][N:40]=3)[CH2:34][CH2:33]2)[O:31][CH2:30][CH2:29]1.N12CCCN=C1CCCCC2.C(N(CC)C1C=CC=CC=1)C>Cl>[CH2:22]([C:21]1[N:40]2[N:41]=[CH:42][N:43]=[C:39]2[N:38]([CH:35]2[CH2:34][CH2:33][C:32]3([O:28][CH2:29][CH2:30][O:31]3)[CH2:37][CH2:36]2)[C:17](=[O:18])[C:16]=1[CH2:15][C:12]1[CH:13]=[CH:14][C:9]([C:4]2[C:3]([C:1]#[N:2])=[CH:8][CH:7]=[CH:6][CH:5]=2)=[CH:10][C:11]=1[F:27])[CH2:23][CH2:24][CH3:25]
Reactant: c1nnc(NC2CCC3(CC2)OCCO3)[nH]1
Reactant: CCCCC(=O)C(Cc1ccc(-c2ccccc2C#N)cc1F)C(=O)OC
Agent: Cl
Solvent: CCN(CC)c1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Product: CCCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n(C2CCC3(CC2)OCCO3)c2ncnn12
Temperature: 180 °C
Reaction time: 8 h
Yield: 59.6 %

Procedure:
A mixture of methyl 2-[(2′-cyano-3-fluorobiphenyl-4-yl)methyl]-3-oxoheptanoate (6.55 g), N-(1,4-dioxaspiro[4.5]dec-8-yl)-4H-1,2,4-triazol-3-amine (2.00 g), 1,8-diazabicyclo[5.4.0]undec-7-ene (0.5 mL) and N,N-diethylaniline (20 mL) was stirred at 180° C. overnight, allowed to cool, and poured into 1 M hydrochloric acid (100 mL), and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a pale-yellow oil (2.88 g, 60%).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[C:5]([O:9][C:10]([N:12]1[CH2:17][C@@H:16]([CH3:18])[NH:15][C@@H:14]([CH3:19])[CH2:13]1)=[O:11])([CH3:8])([CH3:7])[CH3:6]>C(Cl)Cl>[C:5]([O:9][C:10]([N:12]1[CH2:17][C@@H:16]([CH3:18])[N:15]([C:1](=[O:3])[CH3:2])[C@@H:14]([CH3:19])[CH2:13]1)=[O:11])([CH3:8])([CH3:6])[CH3:7]
Reactant: CC(=O)Cl
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H](C)N1
Solvent: ClCCl
Product: CC(=O)N1[C@H](C)CN(C(=O)OC(C)(C)C)C[C@@H]1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.9 %

Procedure:
Acetyl chloride (0.216 ml, 3.04 mmol) was added to a stirred solution of (3S,5R)-3,5-dimethyl-piperazine-1-carboxylic acid tert-butyl ester (500 mg, 2.34 mmol) and TEA (0.49 ml, 3.51 mmol) in DCM (20 ml). The mixture was stirred at room temperature overnight, then the solvent was evaporated and the residue was partitioned between Et2O and 5% citric acid. The organic phase was dried over Na2SO4 and evaporated in vacuo to give 545 mg of (3S,5R)-4-acetyl-3,5-dimethyl-piperazine-1-carboxylic acid tert-butyl ester as a colourless oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[F:25][C:26]1[CH:34]=[CH:33][C:29]([C:30](Cl)=[O:31])=[CH:28][CH:27]=1>>[F:25][C:26]1[CH:34]=[CH:33][C:29]([C:30]([NH:1][C:2]2[N:7]=[C:6]3[C:8]([CH:11]4[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C:19]5[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=5)[CH2:13][CH2:12]4)=[CH:9][NH:10][C:5]3=[CH:4][CH:3]=2)=[O:31])=[CH:28][CH:27]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: Nc1ccc2[nH]cc(C3CCN(CCc4ccccc4)CC3)c2n1
Product: O=C(Nc1ccc2[nH]cc(C3CCN(CCc4ccccc4)CC3)c2n1)c1ccc(F)cc1

Procedure:
Beginning with 0.015 gm (0.047 mMol) 5-amino-3-(1-(2-phenyleth-1-yl)piperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.007 mL (0.061 mMol) 4-fluorobenzoyl chloride, the title compound was prepared essentially by the procedure described in Example 7.
Reaction SMILES: [C:1]1([PH:7](=[O:9])[OH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO.[CH3:12]CN=C=NCCCN(C)C>CN(C)C1C=CN=CC=1.C1COCC1>[C:1]1([PH:7](=[O:8])[O:9][CH3:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=[PH](O)c1ccccc1
Reactant: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CO
Solvent: C1CCOC1
Product: CO[PH](=O)c1ccccc1
Reaction time: 24 h
Yield: 22.6 %

Procedure:
To a solution of phenylphosphinic acid (5.00 g, 35.2 mmol), anhydrous methanol (7.0 mL, 170 mmol) and 4-dimethylaminopyridine (425 mg, 3.48 mmol) in 50 mL of THF (distilled from ketyl) was added EDAC (8.05 g, 42 mmol) at room temperature. The reaction was stirred for 24 hours then partitioned between HCl solution (75 mL of 1M aq) and ethyl acetate (75 mL). The organic layer was separated, washed with HCl solution (75 mL of 1M aq), sodium bicarbonate solution (75 mL of 5% aq) then dried (sodium sulfate) and concentrated in vacuo to afford the crude title compound as a colorless liquid (1.24 g, 7.95 mmol, 23%).