Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(NCC)C.C(O)=O.CC1(C)[O:17][C:15](=[O:16])[CH2:14][C:12](=O)O1.C(=O)[C:20]1[CH:29]=[CH:28][C:25]([O:26][CH3:27])=[C:22]([O:23][CH3:24])[CH:21]=1>>[CH3:24][O:23][C:22]1[CH:21]=[C:20]([CH2:12][CH2:14][C:15]([OH:17])=[O:16])[CH:29]=[CH:28][C:25]=1[O:26][CH3:27]
Reactant: COc1ccc(C=O)cc1OC
Reactant: CC1(C)OC(=O)CC(=O)O1
Solvent: O=CO
Solvent: CCNCC
Product: COc1ccc(CCC(=O)O)cc1OC

Procedure:
After dropwise adding 17.55 g (25 ml, 0.24 mol) of diethylamine to 27.6 g (22.6 ml, 0.6 mol) of formic acid under stirring and cooling, 7.2 g (0.05 mol) of Meldrum's acid and 8.3 g (0.05 mol) of veratraldehyde were added to the above mixture, then the procedure of Example 35 was followed.
Reaction SMILES: O1CCOCC1.Cl.C(OC([NH:15][CH2:16][C:17]([NH:19][C:20]1[N:28]=[C:27]2[C:23]([C:24]([C:36]3[CH:41]=[CH:40][N:39]=[CH:38][CH:37]=3)=[C:25]([C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)[NH:26]2)=[CH:22][CH:21]=1)=[O:18])=O)(C)(C)C.C1(OC)C=CC=CC=1>O1CCOCC1>[NH2:15][CH2:16][C:17]([NH:19][C:20]1[N:28]=[C:27]2[C:23]([C:24]([C:36]3[CH:37]=[CH:38][N:39]=[CH:40][CH:41]=3)=[C:25]([C:29]3[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=3)[NH:26]2)=[CH:22][CH:21]=1)=[O:18]
Reactant: CC(C)(C)OC(=O)NCC(=O)Nc1ccc2c(-c3ccncc3)c(-c3ccc(F)cc3)[nH]c2n1
Agent: Cl
Solvent: C1COCCO1
Solvent: COc1ccccc1
Product: NCC(=O)Nc1ccc2c(-c3ccncc3)c(-c3ccc(F)cc3)[nH]c2n1
Reaction time: 0.5 h

Procedure:
An HCl dioxane solution (4N, anhydrous, 0.27 mL) was added to 6-(2′-t-butoxycarbonylamino-1′-oxo-ethylamino)-3-(4-pyridyl)-2-(4-fluoro-phenyl)-7-aza-indole (54) (50.0 mg, 0.11 mmol), anisole (59 ml, 0.55 mmol), and dioxane (4 mL) in one portion. After 30 min at 23° C., the reaction was concentrated with a stream of nitrogen in a hood. The residue was diluted with saturated bicarbonate (30 mL), extracted with ethyl acetate (3×50 mL), and dried (Na2SO4). After concentration in vacuo, the residue was purified by application of preparative plate chromatography (two 2 mm silica gel plates, ethyl acetate:methanol 19:1) to afford 6-(2′-amino-1′-oxo-ethylamino)-3-(4-pyridyl)-2-(4-fluoro phenyl)-7-aza-indole (55): Mass Spectrum (CI) 362 (MH+).
Reaction SMILES: C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(OC([NH:41][C:42]1[S:46][C:45]([C:47]2[C:52]([F:53])=[CH:51][CH:50]=[CH:49][C:48]=2[F:54])=[N:44][C:43]=1[C:55]([OH:57])=O)=O)(C)(C)C.[NH2:58][C:59]1[CH:60]=[N:61][N:62]([CH3:78])[C:63]=1[N:64]1[CH2:69][CH2:68][N:67](C(OC(C)(C)C)=O)[CH2:66][C@H:65]1[CH3:77].CCN(C(C)C)C(C)C>C(Cl)Cl>[NH2:41][C:42]1[S:46][C:45]([C:47]2[C:48]([F:54])=[CH:49][CH:50]=[CH:51][C:52]=2[F:53])=[N:44][C:43]=1[C:55]([NH:58][C:59]1[CH:60]=[N:61][N:62]([CH3:78])[C:63]=1[N:64]1[CH2:69][CH2:68][NH:67][CH2:66][C@H:65]1[CH3:77])=[O:57]
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1c1c(N)cnn1C
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2c(F)cccc2F)nc1C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[C@@H]1CNCCN1c1c(NC(=O)c2nc(-c3c(F)cccc3F)sc2N)cnn1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 22 %

Procedure:
A solution of PyBOP (313 mg, 0.60 mmol) and 5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid from Example 25 (153 mg, 0.43 mmol) in DCM (10 mL) was stirred at room temperature for 30 min. A solution of (R)-tert-butyl 4-(4-amino-1-methyl-1H-pyrazol-5-yl)-3-methylpiperazine-1-carboxylate (133 mg, 0.45 mmol) and DIPEA (0.12 mL, 0.68 mmol) in DCM (10 mL) were added and the mixture stirred at room temperature for 16 hr. The mixture was diluted with DCM (50 mL) and washed with water (20 mL). The organic layer was separated, passed through a phase separation cartridge and concentrated under reduced pressure. The isolated intermediate was re-dissolved in DCM (6 mL) and TFA (2 mL) added. The mixture was stirred at room temperature for 4 hr. The mixture was concentrated under reduced pressure and the residue re-dissolved in DCM (50 mL) and washed with saturated aqueous NaHCO3 (2×10 mL). The organic layer was separated, passed through a phase separation cartridge and concentrated under reduced pressure. Purification by preparative HPLC gave 112 as a white solid (41 mg, 22% over two steps). 1H NMR (400 MHz, CDCl3) δ 8.66 (s, 1H), 7.92 (s, 1H), 7.38-7.25 (m, 1H), 7.03 (t, J=9.0 Hz, 2H), 6.20 (s, 2H), 3.77 (s, 3H), 3.27-3.15 (m, 2H), 3.10-2.93 (m, 4H), 2.59 (dd, J=12.5, 9.5 Hz, 1H), 0.88 (d, J=6.3 Hz, 3H). Alkyl NH not observed. LCMS (ES+) m/z 434 (M+1).
Reaction SMILES: Cl.Cl.[C:3]1([CH:9]([NH2:19])[C:10]2[NH:18][C:13]3=[CH:14][N:15]=[CH:16][CH:17]=[C:12]3[CH:11]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(CC)C(C)C)(C)C.[C:29](O)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[N:32][CH:31]=1.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl.CN(C)C1C=CN=CC=1>[C:3]1([CH:9]([C:10]2[NH:18][C:13]3=[CH:14][N:15]=[CH:16][CH:17]=[C:12]3[CH:11]=2)[NH:19][C:29](=[O:36])[C:30]2[CH:35]=[CH:34][CH:33]=[N:32][CH:31]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=C(O)c1cccnc1
Reactant: NC(c1ccccc1)c1cc2ccncc2[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(NC(c1ccccc1)c1cc2ccncc2[nH]1)c1cccnc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 32.2 %

Procedure:
To a solution of 1-phenyl-1-(1H-pyrrolo[2,3-c]pyridin-2-yl)methylamine dihydrochloride (Example 40) (51 mg, 0.17 mmol), N,N-diisopropylethylamine (DIPEA) (0.15 mL, 0.85 mmol) and nicotinic acid (22 mg, 0.18=mmol) in methylene chloride (2.0 mL) was added 1-ethyl-3-dimethylaminopropylcarbodiimide hydrochloride (EDC-HCl) (30 mg, 0.20 mmol) followed by a catalytic amount of 4-dimethylaminopyridine (DMAP). The reaction mixture was stirred at room temperature overnight (20 h) under a N2 atmosphere. TLC analysis showed the starting amine, therefore the reaction mixture was heated to reflux. After refluxing overnight, the reaction mixture was concentrated to dryness. The residue was dissolved in EtOAc and water. The organic layer was washed with water, 1 M citric acid, saturated NaHCO3, and saturated NaCl. TLC analysis showed that the majority of desired product was extracted into the 1 M citric acid washing. The citric acid extracts were made basic with 15% NaOH solution and extracted with methylene chloride. The organic extracts were dried over Na2SO4, filtered and concentrated to dryness. Trituration with Et2O/CH2Cl2 (1:1) provided N-[phenyl(1H-pyrrolo[2,3-c]pyridin-2-yl)methyl]nicotinamide (18 mg, 32%) as a light yellow solid after drying: mp 178-188° C.; 1H NMR (300 MHz, CD3OD) δ6.30 (1H, s), 6.67 (1H, s), 7.35-7.55 (7H, m), 8.03 (1H, d, J=5.5 Hz), 8.30-8.38 (1H, m), 8.61 (1H, s), 8.69-8.71 (1H, m), 9.05-9.07 (1H, m); ESI MS m/z 329 [C20H16N4O+H]+; HPLC (Method A) >99% (AUC) tR=13.3 min.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[N:4][NH:5][N:6]=1.Br[CH2:13][CH:14]([CH3:16])[CH3:15].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(#N)C.O>[CH2:13]([N:5]1[N:4]=[C:3]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:2]([CH3:1])=[N:6]1)[CH:14]([CH3:16])[CH3:15]
Reactant: CC(C)CBr
Reactant: CCOC(=O)c1n[nH]nc1C
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CCOC(=O)c1nn(CC(C)C)nc1C
Temperature: 60 °C
Yield: 43.3 %

Procedure:
To av solution of ethyl 5-methyl-2H-1,2,3-triazole-4-carboxylate (0.5 g, 3.2 mmol) in acetonitrile (40 mL) were added 1-bromo-2-methylpropane (1.25 mL, 11.5 mmol), potassium carbonate (2.66 g, 19.2 mmol) and a catalytic amount of potassium iodide. The reaction mixture was heated to 60° C. for 22 h. The reaction mixture was allowed to cool to ambient temperature and was diluted with water (50 mL) and extracted with ethyl acetate (3×50 mL). The organic layer was dried over sodium sulfate and concentrated in vacuo to yield 293 mg (43%) of the title compound; MS (APPI/APCI) m/z 212[M+H+].
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][C:8]=2[O:10][C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][C:12]=2[F:18])[CH:3]=[CH:2]1.N1C2C(=NC=CC=2OC2C=CC(NC(NC(=O)CC3C=CC=CC=3)=S)=CC=2F)C=C1.[N-]=C=S.[Cl:52][C:53]1[CH:58]=[CH:57][CH:56]=[C:55]([Cl:59])[C:54]=1[CH2:60][C:61]([N:63]=[C:64]=[S:65])=[O:62].[ClH:66]>CO>[ClH:52].[ClH:66].[NH:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][C:8]=2[O:10][C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:64]([NH:63][C:61](=[O:62])[CH2:60][C:54]3[C:53]([Cl:52])=[CH:58][CH:57]=[CH:56][C:55]=3[Cl:59])=[S:65])=[CH:13][C:12]=2[F:18])[CH:3]=[CH:2]1
Reactant: Nc1ccc(Oc2ccnc3cc[nH]c23)c(F)c1
Reactant: O=C(Cc1c(Cl)cccc1Cl)N=C=S
Agent: Cl
Agent: O=C(Cc1ccccc1)NC(=S)Nc1ccc(Oc2ccnc3cc[nH]c23)c(F)c1
Agent: [N-]=C=S
Solvent: CO
Product: O=C(Cc1c(Cl)cccc1Cl)NC(=S)Nc1ccc(Oc2ccnc3cc[nH]c23)c(F)c1
Yield: 48 %

Procedure:
Starting from the compound 268 and following the procedure described above for the synthesis of compound 269a (example 221) but replacing 2-phenylacethyl isothiocyanate with 2-(2,6-dichlorophenyl)acetyl isothiocyanate, a white solid was obtained. This material was dissolved in MeOH and treated with HCl (1 mL, 1.0M in ether). Solvents were removed under the reduced pressure and the residue was lyophilized, to afford the title compound 269b (48% yield) as a yellowish solid. 1H NMR (DMSO-d6) δ (ppm): 13.29 (s, 1H), 12.32 (s, 1H), 12.05(s, 1H), 8.52(d, 1H), 8.14 (m, 2H), 7.64 (m, 2H), 7.51(d, 1H), 7.37(dd, 1H), 6.86 (m, 1H), 6.81(dd, 1H), 4.22 (s, 2H), MS (m/z): 489.1 (M+H) (found).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([CH3:13])=[CH:11][CH:10]=[CH:9][C:8]=2[CH3:14])[N:5]=[CH:4][C:3]=1[C:15]#[N:16].[OH:17]O.N>C(O)C.ClCCl>[NH2:1][C:2]1[N:6]([C:7]2[C:12]([CH3:13])=[CH:11][CH:10]=[CH:9][C:8]=2[CH3:14])[N:5]=[CH:4][C:3]=1[C:15]([NH2:16])=[O:17]
Reactant: OO
Reactant: Cc1cccc(C)c1-n1ncc(C#N)c1N
Agent: N
Solvent: CCO
Solvent: ClCCl
Product: Cc1cccc(C)c1-n1ncc(C(N)=O)c1N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2 g (9.4 mmol) of 5-amino-1-(2,6-dimethylphenyl)-1H-pyrazole-4-carbonitrile (Example 1A) are dissolved in 25 ml of ethanol, and a mixture of 20 ml of 30% strength hydrogen peroxide and 40 ml of 25% strength ammonia is added. The solution is stirred at room temperature overnight and then concentrated to about 15 ml in a rotary evaporator. The oily emulsion resulting thereby is taken up in dichloromethane. It is washed several times with water and saturated sodium thiosulphate solution. Drying over magnesium sulphate is followed by removal of the solvent in vacuo. The residue is purified by preparative HPLC (YMC Gel ODS-AQ S 5/15 μm; eluent A: water, eluent B: acetonitrile; gradient: 0 min 30% B, 5 min 30% B, 50 min 95% B). 0.88 g (40% of theory) of the product is obtained as colourless solid.
Reaction SMILES: [CH2:1]([NH:3][C:4]([C:6]1[C:11]([F:12])=[CH:10][C:9]([N:13]2[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]2)=[C:8]([F:26])[CH:7]=1)=[O:5])[CH3:2].[ClH:27]>O1CCOCC1.C(OCC)C>[ClH:27].[CH2:1]([NH:3][C:4](=[O:5])[C:6]1[CH:7]=[C:8]([F:26])[C:9]([N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[CH:10][C:11]=1[F:12])[CH3:2]
Reactant: CCNC(=O)c1cc(F)c(N2CCN(C(=O)OC(C)(C)C)CC2)cc1F
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: CCNC(=O)c1cc(F)c(N2CCNCC2)cc1F
Reaction time: 0.5 h
Yield: 98 %

Procedure:
tert-butyl 4-(4-(ethylcarbamoyl)-2,5-difluorophenyl)piperazine-1-carboxylate (0.020 g, 0.054 mmol) was diluted with 4.0M HCl in dioxane (3 mL) and stirred for 30 min. The thick white precipitate that formed was diluted with ethyl ether (10 mL) and stirred until a fine suspension resulted. The precipitate was filtered under nitrogen and dried in vacuum to afford N-ethyl-2,5-difluoro-4-(piperazin-1-yl)benzamide hydrochloride (16.2 mg, 0.053 mmol, 98% yield) as a white solid. ESI-MS:m/z 270 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C@H:19]([NH2:21])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[C:28](Cl)(=[O:31])[O:29][CH3:30]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[C@@H:19]([NH:21][C:28](=[O:31])[O:29][CH3:30])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: C[C@@H](N)[C@@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccccc1
Reactant: COC(=O)Cl
Product: COC(=O)N[C@@H](C)[C@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccccc1

Procedure:
Prepared as described in Example 1 using (1S,2R)-1-{[1-(4-fluorophenyl)-1H-indazol-5-yl]oxy}-1-phenylpropan-2-amine (1a, 14 mg, 38 μmol) and methyl chlorocarbonate (11 mg, 114 μmol). Yield 14 mg (90%).
Reaction SMILES: F[C:2]1[CH:9]=[C:8]([C:10]2[CH:15]=[C:14]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][C@H:17]3[CH3:22])[N:13]=[C:12]([NH:23][CH3:24])[N:11]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[NH2:25][NH2:26].CCN(C(C)C)C(C)C>C(O)C>[CH3:24][NH:23][C:12]1[N:11]=[C:10]([C:8]2[CH:7]=[C:6]3[C:3]([C:4]([NH2:5])=[N:25][NH:26]3)=[CH:2][CH:9]=2)[CH:15]=[C:14]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][C@H:17]2[CH3:22])[N:13]=1
Reactant: CNc1nc(-c2ccc(C#N)c(F)c2)cc(N2CCOC[C@H]2C)n1
Reactant: NN
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CNc1nc(-c2ccc3c(N)n[nH]c3c2)cc(N2CCOC[C@H]2C)n1
Temperature: 150 °C
Yield: 41.8 %

Procedure:
To a 5-mL microwave vial was added 2-fluoro-4-{2-(methylamino)-6-[(3R)-3-methyl-4-morpholinyl]-4-pyrimidinyl}benzonitrile (270 mg, 0.824 mmol), hydrazine (0.31 mL, 9.9 mmol), Hunig's base (0.576 mL, 3.30 mmol), and ethanol (3 mL). The reaction mixture was heated at 150° C. for 70 minutes in a microwave reactor. LCMS analysis indicated good conversion, so the reaction mixture was concentrated, dissolved in DMSO and purified by RP-HPLC (8-32% CH3CN in water, 0.1% TFA). The product fractions were pooled, then basified with NaHCO3 and extracted with EtOAc. The organic layer was dried and concentrated to afford the title compound (117 mg). LC-MS (ES) m/z=340 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 1.17-1.23 (m, 3H), 2.84 (d, J=4.0 Hz, 3H), 3.02-3.20 (m, 1H), 3.38-3.51 (m, 1H), 3.56-3.66 (m, 1H), 3.67-3.78 (m, 1H), 3.87-3.98 (m, 1H), 4.07-4.19 (m, 1H), 4.45-4.57 (m, 1H), 5.38 (s, 2H), 6.55 (bs, 2H), 7.61 (s, 1H), 7.71 (d, J=8.3 Hz, 1H), 7.98 (bs, 1H), 11.51 (s, 1H).
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][C:4]([OH:6])=[O:5].[CH2:10](O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.O.[C:19]1([CH3:29])[CH:24]=[CH:23][C:22]([S:25]([OH:28])(=[O:27])=[O:26])=[CH:21][CH:20]=1.C1C=CC=CC=1>O>[C:19]1([CH3:29])[CH:20]=[CH:21][C:22]([S:25]([OH:28])(=[O:26])=[O:27])=[CH:23][CH:24]=1.[NH2:1][C@H:2]([C:7]([O:9][CH2:29][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:8])[CH2:3][C:4]([O:6][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:5]
Reactant: OCc1ccccc1
Reactant: N[C@@H](CC(=O)O)C(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: N[C@@H](CC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Temperature: 25 °C

Procedure:
A stirred mixture of L-aspartic acid (399 g.; 3.00 moles), benzyl alcohol (1.95 kg.; 18.0 moles), p-toluenesulfonic acid monohydrate (582 g.; 3.06 moles), and dry benzene (1.2 l.) was heated at reflux for 16 hours. The water formed in the reaction (145 ml.) was removed by means of a Dean-Stark trap. The resulting solution was cooled to room temperature, then diluted with benzene (1.2 l.) and ether (3.6 l.). The resulting solid was collected on a filter, washed with ether (7.0 l.), and dried; yield, 1195 g. (82%). The crude product was recrystallized from methanol (1720 ml.) to give 959 g. (80% recovery) of purified (I); m.p., 158°-159.5°; literature m.p., 158°-160°. Additional reactions were carried out to give a total of 4.27 kg. of product suitable for further transformation.
Reaction SMILES: CN(C=O)C.Br[C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:17])[O:12][C@H:11]([CH3:18])[CH2:10]2.Br[Zn][CH2:21][CH:22]1[O:26][CH2:25][CH2:24][O:23]1>CCOC(C)=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[O:23]1[CH2:24][CH2:25][O:26][CH:22]1[CH2:21][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:17])[O:12][C@H:11]([CH3:18])[CH2:10]2
Reactant: Br[Zn]CC1OCCO1
Reactant: C[C@@H]1Cc2cc(Br)ccc2C(=O)O1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C[C@@H]1Cc2cc(CC3OCCO3)ccc2C(=O)O1
Temperature: 110 °C

Procedure:
A sealed tube was charged with aryl bromide, palladium(II) acetate (0.028 g, 0.124 mmol) and commercially available tri-t-butylphosphine-BF4 complex (0.072 g, 0.25 mmol) and sealed. The tube was evacuated and refilled with nitrogen before DMF (12 ml) and (3R)-6-bromo-3-methyl-3,4-dihydro-1H-isochromen-1-one (0.75 g, 3.1 mmol) were added followed by commercially available bromo(1,3-dioxolan-2-ylmethyl)zinc (6.2 ml, 3.1 mmol). The tube was heated to 110° C. in the microwave for 75 minutes, after which it was cooled, diluted with EtOAc, filtered, concentrated and purified via MPLC (20-50% E/H) to afford (3R)-6-(1,3-dioxolan-2-ylmethyl)-3-methyl-3,4-dihydro-1H-isochromen-1-one.
Reaction SMILES: Br[C:2]1[C:7]([C:8]2[C:9](=[O:29])[N:10]([CH:26]([CH3:28])[CH3:27])[C:11](=[O:25])[N:12]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=3)[C:13]=2[CH3:14])=[CH:6][CH:5]=[CH:4][N:3]=1.[C:30]([C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1)#[N:31].O.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.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>[CH:26]([N:10]1[C:9](=[O:29])[C:8]([C:7]2[C:2]([C:35]3[CH:36]=[CH:37][C:32]([C:30]#[N:31])=[CH:33][CH:34]=3)=[N:3][CH:4]=[CH:5][CH:6]=2)=[C:13]([CH3:14])[N:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=2)[C:11]1=[O:25])([CH3:28])[CH3:27]
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: Cc1c(-c2cccnc2Br)c(=O)n(C(C)C)c(=O)n1-c1cccc(C(F)(F)F)c1
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: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1c(-c2cccnc2-c2ccc(C#N)cc2)c(=O)n(C(C)C)c(=O)n1-c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Yield: 85.3 %

Procedure:
5-(2-Bromopyridin-3-yl)-3-isopropyl-6-methyl-1-(3-(trifluoromethyl)phenyl)pyrimidin-2,4(1H,3H)-dione (prepared in Reference Example 189) (132 mg) and 4-cyanophenylboronic acid (166 mg) were dissolved in 1,4-dioxane (10 ml). Thereto were added under nitrogen atmosphere water (1 ml), sodium carbonate (239 mg) and tetrakis(triphenylphosphine)palladium (33 mg) and the resulting mixture was stirred with heating under reflux for one and a half hours. The reaction mixture was cooled to room temperature, and thereto was then water and the resulting mixture was extracted with ethyl acetate (50 ml). The organic layer was washed with saturated saline (50 ml), dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: firstly hexane/ethyl acetate, secondly chloroform/methanol) to afford 4-(3-(3-isopropyl-6-methyl-2,4-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)pyridin-2-yl)benzonitrile (118 mg).
Reaction SMILES: ClCC([C:5]1[C:15]2[CH2:14][CH2:13][C:12]3[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=3[NH:10][C:9]=2[CH:8]=[CH:7][CH:6]=1)=O.[F:20][C:21]1[CH:35]=[CH:34][C:24]2[C:25]([CH:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)=[N:26][O:27][C:23]=2[CH:22]=1.C([O-])([O-])=O.[K+].[K+].[C:42]([OH:49])(=[O:48])/[CH:43]=[CH:44]/[C:45]([OH:47])=[O:46]>C(#N)C.C(O)C>[C:42]([OH:49])(=[O:48])/[CH:43]=[CH:44]/[C:45]([OH:47])=[O:46].[F:20][C:21]1[CH:35]=[CH:34][C:24]2[C:25]([CH:28]3[CH2:29][CH2:30][N:31]([CH2:44][C:45]([N:10]4[C:11]5[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=5[CH2:13][CH2:14][C:15]5[CH:5]=[CH:6][CH:7]=[CH:8][C:9]4=5)=[O:46])[CH2:32][CH2:33]3)=[N:26][O:27][C:23]=2[CH:22]=1
Reactant: O=C(CCl)c1cccc2c1CCc1ccccc1N2
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Agent: O=C(O)/C=C/C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: CC#N
Product: O=C(CN1CCC(c2noc3cc(F)ccc23)CC1)N1c2ccccc2CCc2ccccc21

Procedure:
A stirred mixture of 2-chloroacetyl-10,11-dihydro-5H-dibenz[b,f]azepine (6.6 g, 4.3 mmol), 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine (5 g, 22.7 mmol) and K2CO3 (3.5 g, 40 mmol) in acetonitrile (300 ml) was heated at reflux for 4 hours. The insolubles were filtered, and the solvent was removed on a rotary evaporator. The crude product was purified by flash chromatography over a silica gel column (100 g of SiO2 ; eluted with dichloromethane (DCM) and 1-2% CH3OH in DCM). The product thus obtained weighed 8.7 g as a yellow oil. A sample (1.5 g) of this material was dissolved in ethanol and was treated with a solution of fumaric acid in ethanol (360 mg/3 ml). The solids collected were recrystallized from acetonitrile to yield 90 mg of white crystals, m.p. 182°-183° C.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[NH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1>CS(C)=O.O>[O:13]1[CH2:14][CH2:15][N:10]([C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=2)[CH2:11][CH2:12]1
Reactant: N#Cc1ccc(F)cc1
Reactant: C1COCCN1
Solvent: CS(C)=O
Solvent: O
Product: N#Cc1ccc(N2CCOCC2)cc1
Temperature: 120 °C
Reaction time: 4 h
Yield: 79.4 %

Procedure:
Into a 50-mL 3-necked round-bottom flask, was placed a solution of 4-fluorobenzonitrile (500 mg, 4.13 mmol, 1.00 equiv) in DMSO (5 mL), and morpholine (1070 mg, 12.30 mmol, 3.00 equiv). The resulting solution was stirred for 4 h at 120° C. in an oil bath. The resulting solution was diluted with 100 mL of H2O. The solids were collected by filtration. The product was obtained as 617 mg (79%) of a yellow solid.
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]=[O:9])=[C:6]([N:10]2[C:22](=[O:23])[C:14]3=[CH:15][N:16]4[C:21]([CH2:20][CH2:19][CH2:18][CH2:17]4)=[C:13]3[CH:12]=[N:11]2)[N:5]=[CH:4][CH:3]=1.C([CH:26]1[CH2:31][N:30]([CH:32]2[CH2:35][O:34][CH2:33]2)[CH2:29][CH2:28][N:27]1[C:36]1[CH:37]=[CH:38][C:39]([NH:42][C:43]2[C:44](=[O:59])[N:45]([CH3:58])[CH:46]=[C:47](B3OC(C)(C)C(C)(C)O3)[CH:48]=2)=[N:40][CH:41]=1)C.C([O-])([O-])=O.[Na+].[Na+].CN(C=O)C>O>[CH3:58][N:45]1[C:44](=[O:59])[C:43]([NH:42][C:39]2[CH:38]=[CH:37][C:36]([N:27]3[CH2:28][CH2:29][N:30]([CH:32]4[CH2:33][O:34][CH2:35]4)[CH2:31][CH2:26]3)=[CH:41][N:40]=2)=[CH:48][C:47]([C:2]2[C:7]([CH:8]=[O:9])=[C:6]([N:10]3[C:22](=[O:23])[C:14]4=[CH:15][N:16]5[C:21]([CH2:20][CH2:19][CH2:18][CH2:17]5)=[C:13]4[CH:12]=[N:11]3)[N:5]=[CH:4][CH:3]=2)=[CH:46]1
Reactant: CCC1CN(C2COC2)CCN1c1ccc(Nc2cc(B3OC(C)(C)C(C)(C)O3)cn(C)c2=O)nc1
Reactant: O=Cc1c(Cl)ccnc1-n1ncc2c3n(cc2c1=O)CCCC3
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1cc(-c2ccnc(-n3ncc4c5n(cc4c3=O)CCCC5)c2C=O)cc(Nc2ccc(N3CCN(C4COC4)CC3)cn2)c1=O
Temperature: 50 °C
Yield: 40.8 %

Procedure:
A 50-mL round bottomed flask equipped with a reflux condenser was charged with 4-chloro-2-(4-oxo-7,8,9,10-tetrahydropyridazino[4,5-a]indolizin-3(4H)-yl)nicotinaldehyde 192c (118 mg, 0.36 mmol), 1-methyl-3-(5-(4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-yl-amino)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one 101l (171 mg, 0.36 mmol), Na2CO3 (78 mg, 0.72 mmol), Pd (dppf)Cl2 (30 mg, 0.036 mmol), DMF (10 mL), and water (1 mL). After bubbling nitrogen through the mixture for 30 minutes, it was heated at 50° C. for 10 hours under N2 protection. It was then cooled to room temperature and evaporated under reduced pressure. The residue was purified by silica-gel column chromatography eluting with 20:1 dichloromethane/methanol to afford 198a (93 mg, 40%) as a brown solid. MS-ESI: [M+H]+ 634.3.