Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][O:11][C@H:10]([C@@H:14]([OH:26])[C:15]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][CH:19]=3)=[O:16])[C:9]2=[O:27])=[CH:4][CH:3]=1.[S:28](Cl)([CH3:31])(=[O:30])=[O:29]>CN(C=O)C.N1C=CC=CC=1.O>[C:24]([C:21]1[CH:22]=[CH:23][C:18]([NH:17][C:15](=[O:16])[C@H:14]([OH:26])[C@H:10]2[O:11][CH2:12][CH2:13][N:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:1][S:28]([CH3:31])(=[O:30])=[O:29])=[CH:3][CH:4]=3)[C:9]2=[O:27])=[CH:19][CH:20]=1)#[N:25]
Reactant: CS(=O)(=O)Cl
Reactant: N#Cc1ccc(NC(=O)[C@H](O)[C@H]2OCCN(c3ccc(N)cc3)C2=O)cc1
Solvent: CN(C)C=O
Solvent: O
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1ccc(N2CCO[C@H]([C@@H](O)C(=O)Nc3ccc(C#N)cc3)C2=O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of compound 26-5 (70 mg) in DMF-pyridine (2 mL-2 mL), was added mesyl chloride (16.3 microL). The reaction mixture was stirred at room temperature overnight. The mixture was diluted with water then it was extracted with EtOAc. The extract was washed with water, 1N HCl and brine. The organic layer was dried with anhyd. Na2SO4 and the solvent was removed under reduced pressure to obtain compound 28-1 (30 mg) as a pale yellow amorphous solid.
Reaction SMILES: C([O:5][C:6](=[O:32])[C:7]([CH3:31])([NH:9][C:10]([C:12]1[CH:20]=[CH:19][C:15]2[S:16][CH:17]=[CH:18][C:14]=2[C:13]=1[O:21][CH2:22]COC1C=CC=CC=1)=[O:11])[CH3:8])(C)(C)C.[F:33][C:34]([F:39])([F:38])[C:35](O)=O>ClCCl>[CH3:8][C:7]([NH:9][C:10]([C:12]1[CH:20]=[CH:19][C:15]2[S:16][CH:17]=[CH:18][C:14]=2[C:13]=1[O:21][CH2:22][C:12]1[CH:20]=[CH:19][C:35]([C:34]([F:39])([F:38])[F:33])=[CH:14][CH:13]=1)=[O:11])([CH3:31])[C:6]([OH:5])=[O:32]
Reactant: CC(C)(C)OC(=O)C(C)(C)NC(=O)c1ccc2sccc2c1OCCOc1ccccc1
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(NC(=O)c1ccc2sccc2c1OCc1ccc(C(F)(F)F)cc1)C(=O)O

Procedure:
113 mg of 2-Methyl-2-{[4-(2-phenoxy-ethoxy)-benzo[b]thiophene-5-carbonyl]-amino}-propionic acid tert-butyl ester were dissolved in 2 ml dichloromethane and treated with 1 ml trifluoroacetic acid. After 6h at room temperature the volatiles were evaporated. The residue was treated with ethanol and 2 M HCl and evaporated three times. The resulting residue was crystallized from diethylether/heptane to afford 50 mg of 2-Methyl-2-{[4-(4-trifluoromethyl-benzyloxy)-benzo[b]thiophene-5-carbonyl]-amino}-propionic acid.
Reaction SMILES: [F:1][C:2]([F:17])([CH:11]([F:16])[C:12]([F:15])([F:14])[F:13])[CH2:3][O:4][C:5](=[O:10])[CH:6]([F:9])[CH2:7]F.C1(C=CC(O)=CC=1)O.N12CCCC1=NCCC2>C(OCC)C>[F:9][C:6](=[CH2:7])[C:5]([O:4][CH2:3][C:2]([F:1])([F:17])[CH:11]([F:16])[C:12]([F:15])([F:14])[F:13])=[O:10]
Reactant: O=C(OCC(F)(F)C(F)C(F)(F)F)C(F)CF
Agent: C1CN=C2CCCN2C1
Agent: Oc1ccc(O)cc1
Solvent: CCOCC
Product: C=C(F)C(=O)OCC(F)(F)C(F)C(F)(F)F
Yield: 45.3 %

Procedure:
To a solution of 55.5 g (0.2 mole) of 2,3-difluoropropionic acid-2,2,3,4,4,4-hexafluorobutylester and a spatula tipful of hydroquinone in 550 ml of dry diethyl ether there was added dropwise at -10° C. a solution of 23 g (0.19 mole) of 1,5-diazabicyclo[4.3.0]non-5-ene in 140 ml of dry diethyl ether. The solvent was then distilled off in vacuo in the cold and the residue remaining was fractionated. In this way, 23 g of 2,2,3,4,4,4-hexafluorobutyl α-fluoroacrylate were obtained having a boiling point of 53° to 54° C. at 20 mbar and a purity of 98%.
Reaction SMILES: [CH:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][C:2]=1[O:11][CH2:12][CH2:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=1.[C:23]([O:30][CH3:31])(=[O:29])[CH2:24][C:25]([O:27][CH3:28])=[O:26].C([O-])(=O)C.[NH2+]1CCCCC1>C1(C)C=CC=CC=1>[CH:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][C:2]=1[O:11][CH2:12][CH2:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=[C:24]([C:23]([O:30][CH3:31])=[O:29])[C:25]([O:27][CH3:28])=[O:26])=[CH:17][CH:16]=1
Reactant: O=Cc1ccc(OCCOc2ccc3c(c2)CCCC3)cc1
Reactant: COC(=O)CC(=O)OC
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Product: COC(=O)C(=Cc1ccc(OCCOc2ccc3c(c2)CCCC3)cc1)C(=O)OC
Temperature: 25 °C
Yield: 96.1 %

Procedure:
To a solution of 4-[2-(5,6,7,8,-tetrahydro-2-naphthoxy)ethoxy]benzaldehyde (1.26 g, 4.26 mmol) and dimethyl malonate (1.69 g, 12.78 mmol) in toluene (30 ml) is added a catalytic quantity of piperidinium acetate. Then the mixture is refluxed in a Dean-Stark trap for 8 hours. After cooled to room temperature, the solution was concentrated under a vacuum to give title compound (1.68 g, 96%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[NH2:8].Cl.C(ONC([CH:16](C)[C:17]([O:19][CH2:20][CH3:21])=[O:18])=N)C>C(O)(=O)C>[NH:8]1[C:7]2[CH:6]=[CH:5][N:4]=[CH:3][C:2]=2[N:1]=[C:16]1[C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: Nc1ccncc1N
Reactant: CCONC(=N)C(C)C(=O)OCC
Agent: Cl
Solvent: CC(=O)O
Product: CCOC(=O)c1nc2cnccc2[nH]1
Temperature: 120 °C
Reaction time: 18 h
Yield: 68.7 %

Procedure:
A mixture comprising 3,4-diaminopyridine (51.7 g, 0.46 mol), ethyl 2-(N-ethoxyamidino)propionoate hydrochloride (125 g, 0.69 mol) and glacial acetic acid (200 mL) was heated at 85° C. and stirred for 18 hours and then heated at 120° C. and stirred for an additional hour. The mixture was cooled to room temperature and concentrated in vacuo. The residue was neutralized by addition of an excess of 5M aqueous ammonium hydroxide and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate and then saturated aqueous sodium chloride, dried (MgSO4), filtered and concentrated in vacuo to provide ethyl 1H-imidazo[4,5-c]pyridine-2-carboxylate (60.4 g, 58% yield); 1H NMR (300 MHz, CDCl3): 9.00 (s, 1H), 8.45 (d, 1H), 7.50 (d, 1H), 4.25 (q, 2H), 3.90 (q, 1H), 1.75 (d, 3H), 1.25 (tr, 3H).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:5]=[C:6]([OH:11])[CH:7]=[C:8]([CH3:10])[CH:9]=1.[Cl:12][CH:13]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:14](Cl)=[O:15].O>CN(C=O)C>[Cl:12][CH:13]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:14]([O:11][C:6]1[CH:7]=[C:8]([CH3:10])[CH:9]=[C:4]([CH3:3])[CH:5]=1)=[O:15]
Reactant: O=C(Cl)C(Cl)c1ccccc1
Reactant: Cc1cc(C)cc(O)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(C)cc(OC(=O)C(Cl)c2ccccc2)c1
Reaction time: 0.5 h
Yield: 7.3 %

Procedure:
Sodium hydride (2 g) was added portionwise to a solution of 3,5-dimethylphenol (6.1 g) in DMF (50 ml). The mixture was stirred for 30 minutes and added dropwise at a temperature below 30° C. to a solution of 2-chloro-2-phenylacetylchloride (9.45 g) in DMF (50 ml). The mixture was stirred overnight, decomposed with water (5 ml) and the solvent was evaporated. Water was added and the mixture was extracted with DCM. The separated organic layer was dried, filtered and the solvent was evaporated. The residue was purified over silica gel on a glass filter (eluent: hexane/DIPE 100/0, 98/2 and 95/5). The pure fractions were collected and the solvent was evaporated [residue; yielding 10.82 g (79%)]. A small amount of the obtained residue was crystallized from DIPE, the precipitate was filtered off and the solvent was evaporated, yielding 1 g of (±)-3,5-dimethylphenyl α-chlorobenzeneacetate (intermediate 5; mp. 79.0° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:8]([OH:39])[CH2:9][NH:10][C:11]2[CH:16]=[CH:15][NH:14][C:13](=[O:17])[C:12]=2[C:18]2[NH:19][C:20]3[C:28]([N:29]=2)=[CH:27][C:26]2[C:25](=[O:30])[N:24]([CH:31]4[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]4)[C:23](=O)[C:22]=2[CH:21]=3)[CH:5]=[CH:6][CH:7]=1>CC(O)=O.[Zn]>[Cl:1][C:2]1[CH:3]=[C:4]([C@H:8]([OH:39])[CH2:9][NH:10][C:11]2[CH:16]=[CH:15][NH:14][C:13](=[O:17])[C:12]=2[C:18]2[NH:29][C:28]3[C:20](=[CH:21][C:22]4[CH2:23][N:24]([CH:31]5[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]5)[C:25](=[O:30])[C:26]=4[CH:27]=3)[N:19]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CN1CCC(N2C(=O)c3cc4nc(-c5c(NC[C@@H](O)c6cccc(Cl)c6)cc[nH]c5=O)[nH]c4cc3C2=O)CC1
Agent: [Zn]
Solvent: CC(=O)O
Product: CN1CCC(N2Cc3cc4nc(-c5c(NC[C@@H](O)c6cccc(Cl)c6)cc[nH]c5=O)[nH]c4cc3C2=O)CC1
Temperature: 90 °C

Procedure:
2-{4-[(S)-2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-6-(1-methyl-piperidin-4-yl)-1H-1,3,6-triaza-s-indacene-5,7-dione (36.1 mg, 0.066 mmol) was mixed with zinc dust (100 mg) in AcOH (4 mL) and the reaction mixture was heated at 90° C. for 2 h. After it was cooled to the room temperature, the upper clear layer of the reaction mixture was evaporated and the residue was subjected to HPLC purification to afford the title compound in TFA salt form (9.2 mg, 22%). 1H NMR (DMSO-d6) δ 1.90-2.15 (4H), 2.75 (s, 3H, CH3), 3.21 (m, 2H), 3.42-3.60 (2H), 3.65 (m, 1H), 4.31 (m, 1H), 4.50 (s, 2H), 4.98 (m, 1H), 6.19 (d, J=6 Hz, 1H), 7.31-7.41 (3H), 7.51 (d, J=6 Hz, 1H), 7.63 (s, 1H), 7.78 (s, 1H), 7.90 (s, 1H), 9.60 (br s, 1H), 11.06 (br s, 1H, NH), 11.23 (br d, J=6 Hz, 1H, NH); ESI-MS m/z 533.5 (MH+).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1B(O)O)=[O:2].Br[C:13]1[CH:17]=[CH:16][S:15][CH:14]=1.C(=O)([O-])[O-].[Na+].[Na+]>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.C(#N)C>[S:15]1[CH:16]=[CH:17][C:13]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[CH:1]=[O:2])=[CH:14]1
Reactant: O=Cc1ccccc1B(O)O
Reactant: Brc1ccsc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: O=Cc1ccccc1-c1ccsc1
Temperature: 150 °C
Yield: 56 %

Procedure:
A microwave vial (20 ml) was charged with 2-formylphenylboronic acid (290 mg, 2.0 mmol), 3-bromo-thiophene (326 mg, 2.0 mmol), and 8 ml of acetonitrile. To this mixture was added 4 ml of aqueous sodium carbonate (1M), followed by 50 mg of dichlorobis-(triphenylphosphine)-palladium(II). The reaction vessel was sealed and heated at 150° C. for 5 minutes with microwave irradiation. After cooling, the reaction mixture was extracted with ethylacetate. The organic layer was evaporated to provide a crude material, which was purified by ISCO to give 211 mg of 2-thiophen-3-yl-benzaldehyde.
Reaction SMILES: [CH2:1](O)[CH2:2][CH3:3].CC1C=CC=C(C)N=1.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[CH2:28]([O:35][NH2:36])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C(Cl)Cl>[CH2:28]([O:35][NH:36][CH2:1][CH2:2][CH3:3])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: NOCc1ccccc1
Reactant: CCCO
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CCCNOCc1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 81.5 %

Procedure:
To a solution of propan-1-ol (6.25 mL, 83.2 mmol) and 2,6-dimethylpyridine (11.6 mL, 99.8 mmol) in CH2Cl2 (500 mL) under a nitrogen atmosphere at −78° C. was added dropwise trifluoromethanesulfonic anhydride (14.0 mL, 83.2 mmol). After stirring for 30 min at −78° C., a solution of O-benzylhydroxylamine (10.7 ml, 91.5 mmol) in CH2Cl2 (10 mL) was added dropwise. The resulting mixture was stirred at −78° C. for 1 h, then warmed to room temperature, and stirred for additional 2 h. The reaction mixture was diluted with ice water (250 mL) and the organic layer was separated, washed with saturated aq. NaHCO3 (100 mL) and brine (100 mL). The aqueous layers were extracted again with EtOAc (1×200 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure to give the crude material that was purified by silica gel flash column chromatography (CH2Cl2). To the fraction containing product and 2,6-dimethylpyridine was added 2 M aq KOH (100 mL), that was then washed with MTBE. The aqueous layer was then brought to a pH of ˜5 with 1 M aq HCl and then extracted with MTBE (3×50 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure to afford 11.2 g (75%) of O-benzyl-N-propylhydroxylamine.
Reaction SMILES: [NH2:1][C:2]1[C:15]([O:16][CH3:17])=[CH:14][C:5]2[CH2:6][CH2:7][N:8]([CH2:11][CH2:12][OH:13])[CH2:9][CH2:10][C:4]=2[CH:3]=1.Cl[C:19]1[N:24]=[C:23]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[S:32]([N:35]2[CH2:39][CH2:38][C@H:37]([CH3:40])[CH2:36]2)(=[O:34])=[O:33])[C:22]([Cl:41])=[CH:21][N:20]=1>>[Cl:41][C:22]1[C:23]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[S:32]([N:35]2[CH2:39][CH2:38][C@H:37]([CH3:40])[CH2:36]2)(=[O:34])=[O:33])=[N:24][C:19]([NH:1][C:2]2[C:15]([O:16][CH3:17])=[CH:14][C:5]3[CH2:6][CH2:7][N:8]([CH2:11][CH2:12][OH:13])[CH2:9][CH2:10][C:4]=3[CH:3]=2)=[N:20][CH:21]=1
Reactant: C[C@H]1CCN(S(=O)(=O)c2ccccc2Nc2nc(Cl)ncc2Cl)C1
Reactant: COc1cc2c(cc1N)CCN(CCO)CC2
Product: COc1cc2c(cc1Nc1ncc(Cl)c(Nc3ccccc3S(=O)(=O)N3CC[C@H](C)C3)n1)CCN(CCO)CC2

Procedure:
The title compound was prepared from 2-(7-Amino-8-methoxy-1,2,4,5-tetrahydro-3-benzazepin-3-yl)-ethanol and (2,5-Dichloro-pyrimidin-4-yl)-[2-((S)-3-methyl-pyrrolidine-1-sulfonyl)-phenyl]-amine in an analogous manner to Example 61e. Product isolated as an off-white foam (0.035 g, 29%). MP: 65-85° C. 1H NMR (400 MHz, CDCl3, δ, ppm): 9.37 (s, 1H), 8.49 (d, J=8.3 Hz, 1H), 8.15 (s, 1H), 8.01 (s, 1H), 7.94 (dd, J=8.0 Hz and 1.4 Hz, 1H), 7.57-7.50 (m, 2H), 7.25-7.20 (m, 1H), 6.65 (s, 1H), 3.87 (s, 3H), 3.64 (t, J=5.4 Hz, 2H), 3.43 (dd, J=9.5 Hz and 7.2 Hz, 1H), 3.40-3.34 (m, 1H), 3.30-3.22 (m, 1H), 2.90-2.86 (m, 2H), 2.80 (dd, J=9.5 Hz and 7.5 Hz, 1H), 2.24-2.11 (m, 1H), 1.96-1.87 (m, 1H), 1.43-1.33 (m, 1H), 0.86 (d, J=6.6 Hz, 3H). MS: 587.16 (MH)+.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[Br:26][C:27]1[CH:35]=[CH:34][C:30]([C:31](Cl)=[O:32])=[CH:29][CH:28]=1>>[Br:26][C:27]1[CH:35]=[CH:34][C:30]([C:31]([N:20]2[CH2:21][CH2:22][CH:17]([N:15]3[C:14](=[O:23])[C:13]([CH3:25])([CH3:24])[C:12]([C:6]4[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:4]([O:3][CH3:2])[CH:5]=4)=[N:16]3)[CH2:18][CH2:19]2)=[O:32])=[CH:29][CH:28]=1
Reactant: O=C(Cl)c1ccc(Br)cc1
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OC
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(C(=O)c4ccc(Br)cc4)CC3)C(=O)C2(C)C)cc1OC

Procedure:
The title compound is prepared analogously as described for GP1 using 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one hydrochloride (compound B1*HCl) and 4-bromobenzoyl chloride as starting compounds. The crude product is purified by crystallization from EA and diethyl ether to yield the title compound.
Reaction SMILES: [C:1]([C:5]1[S:9][C:8]([C:10]([NH:12][CH:13]([C:18]2[CH:23]=[CH:22][C:21](B3OC(C)(C)C(C)(C)O3)=[CH:20][CH:19]=2)[C:14]([O:16]C)=[O:15])=[O:11])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Br:33][C:34]1[CH:35]=[N:36][C:37](I)=[N:38][CH:39]=1.C([O-])(O)=O.[Na+].CC(O)=O>C1COCC1.CC#N>[Br:33][C:34]1[CH:35]=[N:36][C:37]([C:21]2[CH:20]=[CH:19][C:18]([CH:13]([NH:12][C:10]([C:8]3[S:9][C:5]([C:1]([CH3:3])([CH3:4])[CH3:2])=[CH:6][CH:7]=3)=[O:11])[C:14]([OH:16])=[O:15])=[CH:23][CH:22]=2)=[N:38][CH:39]=1
Reactant: Brc1cnc(I)nc1
Reactant: COC(=O)C(NC(=O)c1ccc(C(C)(C)C)s1)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC#N
Solvent: CC(=O)O
Product: CC(C)(C)c1ccc(C(=O)NC(C(=O)O)c2ccc(-c3ncc(Br)cn3)cc2)s1
Temperature: 120 °C
Yield: 47.5 %

Procedure:
Prepared using General Procedure 10. A mixture of methyl 2-(5-(tert-butyl)thiophene-2-carboxamido)-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl)acetate (320 mg, 0.71 mmol) and 5-bromo-2-iodopyrimidine (220 mg, 0.78 mmol) in THF (2 mL) and MeCN (2 mL) was treated with saturated aq. NaHCO3 (1600 μl, 1.40 mmol) and de-gassed (N2 bubbling). PdCl2dppf (26 mg, 0.04 mmol) was added and the mixture was heated at 120° C. for 30 min in a microwave reactor. The mixture was poured onto H2O (30 mL), acidified with AcOH and extracted with EA (3×15 mL). The combined organics were dried over MgSO4, evaporated, and purified by chromatography (EA/hexane with 1% AcOH) to provide 160 mg (46%) of 2-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-2-carboxamido)acetic acid as a white solid. LCMS-ESI (m/z) calculated for C21H20BrN3O3S: 473.0; found 474.0 [M+H]+, tR=2.68 min (Method 8).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([CH3:7])[N:4]=[CH:3]1.C([Li])CCC.C=O.[OH:15][CH2:16]C1N2CCCCC2=CN=1>>[CH3:1][N:2]1[CH:6]=[C:5]([CH3:7])[N:4]=[C:3]1[CH2:16][OH:15]
Reactant: Cc1cn(C)cn1
Reactant: OCc1ncc2n1CCCC2
Agent: C=O
Agent: [Li]CCCC
Product: Cc1cn(C)c(CO)n1

Procedure:
The reaction of 1,4-dimethylimidazole (5.65 g.) with n-butyl lithium followed by treatment with formaldehyde (according to the method described for the preparation of 3-hydroxymethyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine in Example 243) gave 1,4-dimethyl-2-hydroxymethylimidazole (2.71 g.), m.p. 125°-126° (ethyl acetate-petroleum ether).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[CH:9][C:10](=[O:20])[C:11]=2[C:12]2[C:17]([F:18])=[CH:16][CH:15]=[CH:14][C:13]=2[F:19])[N:7]=1.[C:21]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1B(O)O>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:21]1([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[CH:9][C:10](=[O:20])[C:11]=2[C:12]2[C:17]([F:18])=[CH:16][CH:15]=[CH:14][C:13]=2[F:19])[N:7]=1
Reactant: OB(O)c1ccccc1-c1ccccc1
Reactant: O=c1ccn2nc(Cl)ccc2c1-c1c(F)cccc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: O=c1ccn2nc(-c3ccccc3-c3ccccc3)ccc2c1-c1c(F)cccc1F
Temperature: 90 °C

Procedure:
2-chloro-5-(2,6-difluorophenyl)-6H-pyrido[1,2-b]pyridazin-6-one (50 g, 0.17 mmol), biphenyl-2-ylboronic acid (51.4 mg, 0.26 mmol), and Tetrakis (19.6 g, 0.017 mmol) were added to a flask and purged with N2 (3×). After the addition of toluene (5 mL), ethanol (0.5 mL), and 2M Na2CO3 (0.5 mL) the resulting mixture was heated to 90° C. for 1 hour. The reaction was concentrated in vacuo and the crude residue was dissolved in H2O/EtOAc (1:1) and extracted with H2O, 1N HCl (2×), brine (2×), dried over MgSO4, and concentrated in vacuo to yield an oil. The crude material was purified via silica gel chromatography (CH2Cl2/EtOAc/MeOH) to yield the title compound.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:12](=[O:29])[N:13]([C@H:15]3[CH2:20][CH2:19][CH2:18][CH2:17][C@@H:16]3[O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[CH2:14][C:9]2=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[CH:30]([B-](F)(F)F)=[CH2:31].[K+].C(=O)([O-])[O-].[K+].[K+].C(=O)(O)[O-].[Na+]>C1COCC1.O.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[Si:22]([O:21][C@H:16]1[CH2:17][CH2:18][CH2:19][CH2:20][C@@H:15]1[N:13]1[CH2:14][C:9]2[C:10](=[CH:11][C:2]([CH:30]=[CH2:31])=[C:3]3[C:8]=2[N:7]=[CH:6][CH:5]=[CH:4]3)[C:12]1=[O:29])([C:25]([CH3:27])([CH3:26])[CH3:28])([CH3:24])[CH3:23]
Reactant: C=C[B-](F)(F)F
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CCCC[C@@H]1N1Cc2c(cc(Br)c3cccnc23)C1=O
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1CCOC1
Product: C=Cc1cc2c(c3ncccc13)CN([C@H]1CCCC[C@@H]1O[Si](C)(C)C(C)(C)C)C2=O
Temperature: 50 °C

Procedure:
To a solution of 5-bromo-8-[(1S,2S)-2-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl]-8,9-dihydro-7H-pyrrolo[3,4-h]quinolin-7-one (see Example 18, 2.00 g, 4.21 mmol) in a mixture of 20 mL of THF and 2 mL of water under an atmosphere of nitrogen was added potassium vinyltrifluoroborate (0.789 g, 5.89 mmol), potassium carbonate (1.45 g, 10.5 mmol), and bis(tri-tert-butylphosphine)palladium(0) (0.215 g, 0.421 mmol). The mixture was heated at 50° C. for 2 hr, cooled to ambient temperature, poured into saturated aqueous sodium bicarbonate and extracted 2× with ethyl acetate. The combined organic extracts were dried with sodium sulfate, filtered, and concentrated in vacuo. The residue was purified via silica gel chromatography, eluting with 0-60% ethyl acetate in hexanes to provide 8-[(1S,2S)-2{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl]-5-ethenyl-8,9-dihydro-7H-pyrrolo[3,4-h]quinolin-7-one that gave a proton NMR spectra consistent with theory and a mass ion (ES+) of 424.4.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:15]=[CH:14][N:13]([CH3:16])[N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[CH3:17][N:18]([CH3:50])[C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[C:25](=[O:29])[N:24]([C:30]1[CH:40]=[CH:39][CH:38]=[C:37](B3OC(C)(C)C(C)(C)O3)[C:31]=1[CH2:32][O:33]C(=O)C)[CH2:23][CH2:22]2.C(=O)([O-])[O-].[Na+].[Na+].[OH-].[Li+]>COCCOC.O.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>[CH3:17][N:18]([CH3:50])[C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[C:25](=[O:29])[N:24]([C:30]1[CH:40]=[CH:39][CH:38]=[C:37]([C:2]3[CH:3]=[C:4]([NH:10][C:11]4[CH:15]=[CH:14][N:13]([CH3:16])[N:12]=4)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=3)[C:31]=1[CH2:32][OH:33])[CH2:23][CH2:22]2
Reactant: Cn1ccc(Nc2cc(Br)cn(C)c2=O)n1
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cccc1N1CCc2cc(N(C)C)ccc2C1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Li+]
Solvent: COCCOC
Solvent: O
Product: CN(C)c1ccc2c(c1)CCN(c1cccc(-c3cc(Nc4ccn(C)n4)c(=O)n(C)c3)c1CO)C2=O
Reaction time: 3 h
Yield: 60 %

Procedure:
5-Bromo-1-methyl-3-(1-methyl-1H-pyrazol-3-ylamino)-1H-pyridin-2-one (35 mg, 0.13 mmol), acetic acid 2-(6-dimethylamino-1-oxo-3,4-dihydro-1H-isoquinolin-2-yl)-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzyl ester (58 mg, 0.13 mmol), tetrakis(triphenylphosphine)palladium(0) (14 mg, 0.012 mmol), and sodium carbonate (40 mg, 0.38 mmol) were dissolved in 2 mL 1,2-dimethoxyethane and 1 mL water. This was microwaved at 120° C. for 30 minutes. This was partitioned between ethylacetate and water. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. This was dissolved in 3 mL tetrahydrofuran, 1.5 mL methanol, and 1.5 mL water. 1M aq. Lithium hydroxide solution (0.38 mL, 0.38 mmol) was added. This stirred for 3 hours. This was partitioned between ethylacetate and water. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, concentrated in vacuo, and purified by preparative TLC (5% methanol/dichloromethane) to yield 6-Dimethylamino-2-{2-hydroxymethyl-3-[1-methyl-5-(1-methyl-1H-pyrazol-3-ylamino)-6-oxo-1,6-dihydro-pyridin-3-yl]-phenyl}-3,4-dihydro-2H-isoquinolin-1-one (39 mg, 0.078 mmol). MS (ESI) 499.2 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[N:11]([CH2:12][CH:13]=C)[C:10]2[N:9]=[C:8]([C:15]#[N:16])[CH:7]=[CH:6][C:5]=2[CH:4]=[CH:3]1.I([O-])(=O)(=O)=[O:18].[Na+]>O1CCOCC1.O.[Os](=O)(=O)(=O)=O>[O:1]=[C:2]1[N:11]([CH2:12][CH:13]=[O:18])[C:10]2[N:9]=[C:8]([C:15]#[N:16])[CH:7]=[CH:6][C:5]=2[CH:4]=[CH:3]1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=CCn1c(=O)ccc2ccc(C#N)nc21
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: N#Cc1ccc2ccc(=O)n(CC=O)c2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 111.9 %

Procedure:
7-Oxo-8-(2-propen-1-yl)-7,8-dihydro-1,8-naphthyridine-2-carbonitrile (374 mg, 1.773 mmol) was dissolved in 1,4-dioxane (10 ml) and water (10 ml). Sodium periodate (948 mg, 4.433 mmol) was added, followed by osmium tetroxide (0.38 ml of 4% aqueous solution). The mixture stirred at rt for 1 h, water (40 ml) was added the mixture was stirred for a further 1 h. The reaction was concentrated to about 50 ml and extracted with 20% MeOH/DCM (3×100 ml). The organic extracts were combined, dried over anhydrous magnesium sulphate, filtered and evaporated under reduced pressure to give 7-oxo-8-(2-oxoethyl)-7,8-dihydro-1,8-naphthyridine-2-carbonitrile as an impure brown solid (423 mg, 112%).