Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C:5]1[C:10](I)=[CH:9][C:8]([Br:12])=[C:7]([Cl:13])[N:6]=1)(=[O:3])[CH3:2].[C:14]([C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)#[CH:15]>C1COCC1.[Cu]I>[C:1]([O:4][C:5]1[C:10]([C:15]#[C:14][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[CH:9][C:8]([Br:12])=[C:7]([Cl:13])[N:6]=1)(=[O:3])[CH3:2]
Reactant: C#Cc1ccc(F)cc1
Reactant: CC(=O)Oc1nc(Cl)c(Br)cc1I
Agent: [Cu]I
Solvent: C1CCOC1
Product: CC(=O)Oc1nc(Cl)c(Br)cc1C#Cc1ccc(F)cc1
Temperature: 0 °C
Reaction time: 18 h
Yield: 82.3 %

Procedure:
5-bromo-6-chloro-3-iodopyridin-2-yl acetate (14.5 g, 38.5 mmol) was dissolved in THF (50 mL) and cooled to 0° C. TEA (2.5 mL), Copper(I)Iodide (0.514 g, 2.70 mmol), and bistriphenylphosphine palladiumdichloride (0.270 g, 0.385 mmol) were added to the reaction mixture. The mixture was degassed and charged with N2 (3×). Next, 1-ethynyl-4-fluorobenzene (5.55 g, 46.2 mmol) was added drop wise over the course of 1 h at 0° C. The reaction mixture was then allowed to slowly warm to rt and continue to stir for 18 h. LCMS and TLC show the reaction to be incomplete. An additional 2.5 mL of TEA was added. The mixture was then allowed to stir at rt over a long weekend (80 h). At this point, LCMS and TLC show no remaining starting material. The reaction mixture was concentrated to a dry solid. This solid was then taken up in DCM (50 mL) and washed with sat NH4Cl. The aq layer was extracted with DCM (2×20 mL). The combined organic extracts were washed with water, brine, dried over Na2SO4, filtered and concentrated to >15 g of a brown solid. This solid was dissolved in DCM, adsorbed onto Celite and then flashed on silica gel eluting with a 10-100% DCM in hexanes gradient over 15 column volumes to give 5-bromo-6-chloro-3-((4-fluorophenyl)ethynyl)pyridin-2-yl acetate (11.7 g, 31.7 mmol, 82% yield) as a tan solid. LCMS: m/e 369 (M+H)+ LCMS retention time: 3.74 min. (Column: Phenomenex-Luna 50×2.0 mm 3u. Solvent A=90% Water: 10% Methanol: 0.1% TFA. Solvent B=10% Water: 90% Methanol: 0.1% TFA. Start % B=0. Final % B=100. Gradient Time=4 min. Flow Rate=0.8 mL/min.). 1H NMR (500 MHz, CDCl3) δ ppm 8.13 (s, 1H), 7.48 (dd, J=8.7 Hz, 2H), 7.09 (dd, J=8.7 Hz, 2H), 2.39 (s, 3H).
Reaction SMILES: FC(F)(F)C(OI(C1C=CC=CC=1)OC(=O)C(F)(F)F)=[O:4].[CH3:22][C:23]([CH3:58])([CH2:56][CH3:57])[CH2:24][C:25]1[N:26]=[C:27]([CH:36]([OH:55])[C:37]2([C:43]3[CH:48]=[CH:47][C:46]([C:49]4[CH:54]=[CH:53][CH:52]=[CH:51][N:50]=4)=[CH:45][CH:44]=3)SCCCS2)[N:28]([S:30]([N:33]([CH3:35])[CH3:34])(=[O:32])=[O:31])[CH:29]=1>C(#N)C.O>[CH3:22][C:23]([CH3:58])([CH2:56][CH3:57])[CH2:24][C:25]1[N:26]=[C:27]([CH:36]([OH:55])[C:37](=[O:4])[C:43]2[CH:48]=[CH:47][C:46]([C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][N:50]=3)=[CH:45][CH:44]=2)[N:28]([S:30]([N:33]([CH3:35])[CH3:34])(=[O:32])=[O:31])[CH:29]=1
Reactant: CCC(C)(C)Cc1cn(S(=O)(=O)N(C)C)c(C(O)C2(c3ccc(-c4ccccn4)cc3)SCCCS2)n1
Reactant: O=C(OI(OC(=O)C(F)(F)F)c1ccccc1)C(F)(F)F
Solvent: CC#N
Solvent: O
Product: CCC(C)(C)Cc1cn(S(=O)(=O)N(C)C)c(C(O)C(=O)c2ccc(-c3ccccn3)cc2)n1
Temperature: 0 °C

Procedure:
[Bis(trifluoroacetoxy)iodo]benzene (184 mg, 0.48 mmol) was added to a 0° C. solution of 4-(2,2-dimethylbutyl)-2-{hydroxy[2-(4-pyridin-2-ylphenyl)-1,3-dithian-2-yl]methyl}-N,N-dimethyl-1H-imidazole-1-sulfonamide (110 mg, 0.20 mmol) in acetonitrile/water (3:1) (4 mL). After stirring at 0° C. until no further reaction (LCMS), the reaction mixture was quenched with saturated aqueous sodium thiosulfate/saturated aqueous sodium bicarbonate (1:1) and extracted with methylene chloride. The combined organic extracts were dried (magnesium sulfate) and concentrated in vacuo to afford 4-(2,2-dimethylbutyl)-2-[1-hydroxy-2-oxo-2-(4-pyridin-2-ylphenyl)ethyl]-N,N-dimethyl-1H-imidazole-1-sulfonamide which was used in the next step without further purification.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)[CH:6]=[C:7]([O:12]C)[C:8]=1[CH:9]([CH3:11])[CH3:10].Cl.N1C=CC=CC=1>>[CH:9]([C:8]1[C:3]([OH:2])=[CH:4][C:5]([CH:14]=[CH:15][C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)=[CH:6][C:7]=1[OH:12])([CH3:11])[CH3:10]
Reactant: COc1cc(C=Cc2cccs2)cc(OC)c1C(C)C
Agent: Cl
Solvent: c1ccncc1
Product: CC(C)c1c(O)cc(C=Cc2cccs2)cc1O
Yield: 24 %

Procedure:
This material was prepared from 2-[2-(3.5-dimethoxy-4-i-propylphenyl)ethenyl]thiophene obtained in example 17 and pyridine hydrochloride in 24% yield as the same way as described in example 2(b). 1HNMR (CDCl3, ppm): δ 1.40 (d, J=7.1 Hz), 3.47 (qint., J=7.1 Hz, 1H), 4.8 (b, 2H), 6.48 (s, 2H), 6.74 (d, J=16Hz, 1H), 7.0-7.1 (m, 3H), 7.2-7.3 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8](I)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:12].[CH2:13]([N:15]([CH2:18][CH3:19])[CH2:16][CH3:17])C>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:16]2[N:15]([CH3:13])[C:18]3[C:19]([CH:17]=2)=[CH:4][CH:3]=[CH:2][CH:10]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:12]
Reactant: O=C1NCc2c(Cl)ccc(I)c21
Reactant: CCN(CC)CC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Product: Cn1c(-c2ccc(Cl)c3c2C(=O)NC3)cc2ccccc21
Yield: 164.2 %

Procedure:
In a similar manner to Step 2 of Example 1, 4-chloro-7-iodoisoindolinone (84.0 mg, 0.286 mmol) was dissolved in acetonitrile (3 mL), and the solution was treated with Compound BK (100 mg, 0.571 mmol), palladium acetate (5.2 mg, 0.023 mmol) and triethylamine (0.400 mL, 2.87 mmol), followed by purification by flash column chromatography (hexane/ethyl acetate=7/3, 3/2, 1/1) to obtain Compound 156 (69.7 mg, yield 82%).
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=2)[N:8]=1)=O.[F:26][C:27]1[CH:28]=[C:29]2[C:34](=[CH:35][CH:36]=1)[N:33]=[C:32]([CH3:37])[CH:31]=[C:30]2[NH:38][NH2:39]>>[F:26][C:27]1[CH:28]=[C:29]2[C:34](=[CH:35][CH:36]=1)[N:33]=[C:32]([CH3:37])[CH:31]=[C:30]2[N:38]1[C:5]([C:7]2[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]3[CH:19]=[CH:18][C:17]([O:20][C:21]([F:23])([F:22])[F:24])=[CH:16][CH:15]=3)[N:8]=2)=[CH:4][CH:3]=[N:39]1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2ccc(OC(F)(F)F)cc2)ccc1=O
Reactant: Cc1cc(NN)c2cc(F)ccc2n1
Product: Cc1cc(-n2nccc2-c2nn(-c3ccc(OC(F)(F)F)cc3)ccc2=O)c2cc(F)ccc2n1

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(4-trifluoromethoxy-phenyl)-1H-pyridazin-4-one (A-8) and (6-fluoro-2-methyl-quinolin-4-yl)-hydrazine according to the method described for example 91. MS: M=482.2 (M+H)+
Reaction SMILES: [N+](C1C=CC(C[O:11][C:12]([C:14]2[N:15]3[CH:18]([CH:19]([CH3:36])[C:20]=2[S:21][CH:22]2[CH2:26][CH:25]([CH2:27][O:28][CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[O:24][CH2:23]2)[CH:17]([CH:37]([OH:39])[CH3:38])[C:16]3=[O:40])=[O:13])=CC=1)([O-])=O.C(=O)(O)[O-].[Na+:45].O>[Pd].O1CCOCC1>[Na+:45].[OH:39][CH:37]([CH:17]1[C:16](=[O:40])[N:15]2[CH:18]1[CH:19]([CH3:36])[C:20]([S:21][CH:22]1[CH2:26][CH:25]([CH2:27][O:28][CH2:29][C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[O:24][CH2:23]1)=[C:14]2[C:12]([O-:13])=[O:11])[CH3:38]
Reactant: CC(O)C1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(SC3COC(COCc4ccccc4)C3)C(C)C12
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(O)C1C(=O)N2C(C(=O)[O-])=C(SC3COC(COCc4ccccc4)C3)C(C)C12

Procedure:
The title compound is prepared by the procedure of Example 18 using 0.170 gof product from Example 81, 0.0277 g of sodium bicarbonate, 1.2 ml of water, 6.8 ml of dioxane, and 0.055 g of 10% palladium/carbon to give 0.045 g of desired product.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C:7]([CH3:28])([CH3:27])[CH2:8][C:9]1[N:10]([CH2:23][CH2:24][O:25][CH3:26])[N:11]=[C:12]2[C:21]=1[C:20]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N:14]=[C:13]2[NH2:22]>C(OCC)(=O)C>[NH2:22][C:13]1[C:12]2=[N:11][N:10]([CH2:23][CH2:24][O:25][CH3:26])[C:9]([CH2:8][C:7]([NH:6][S:2]([CH3:1])(=[O:4])=[O:3])([CH3:28])[CH3:27])=[C:21]2[C:20]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N:14]=1
Reactant: COCCn1nc2c(N)nc3ccccc3c2c1CC(C)(C)N
Reactant: CS(=O)(=O)Cl
Solvent: CCOC(C)=O
Product: COCCn1nc2c(N)nc3ccccc3c2c1CC(C)(C)NS(C)(=O)=O
Yield: 59.4 %

Procedure:
Using the method of Example 66, methanesulfonyl chloride (399 mg, 3.48 mmol) was reacted with 1-(2-amino-2-methylpropyl)-2-(2-methoxyethyl)-2H-pyrazolo[3,4-c]quinolin-4-amine (1.09 g, 3.48 mmol, prepared as described in Example 590). The crude product was purified by IFC (40M cartridge eluting with a gradient of 15 to 35% CMA in chloroform) to provide a white foam. The foam was refluxed with 35% ethyl acetate in hexanes (50 mL), ethyl acetate was added until a free flowing white solid appeared, and then the mixture was cooled on ice. The solid was isolated by filtration and dried to provide 809 mg of N-{2-[4-amino-2-(methoxyethyl)-2H-pyrazolo[3,4-c]quinolin-1-yl]-1,1-dimethylethyl}methanesulfonamide as a white solid, mp 211-213° C. MS (ESI) m/z 392 (M+H)+; Anal. Calcd for C18H25N5O3S: C, 55.22; H, 6.44; N, 17.89. Found: C, 55.05; H, 6.38; N, 17.98.
Reaction SMILES: [C:1]([N:6]1[C:10](=[O:11])[C:9]2=[CH:12][CH:13]=[CH:14][CH:15]=[C:8]2[C:7]1=[O:16])(OCC)=O.[NH:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]([CH2:26]CN)=[CH:18]1>>[NH:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]([CH2:26][CH2:1][N:6]2[C:7](=[O:16])[C:8]3[C:9](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]2=[O:11])=[CH:18]1
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Reactant: NCCc1c[nH]c2ccccc12
Product: O=C1c2ccccc2C(=O)N1CCc1c[nH]c2ccccc12
Temperature: 25 °C
Yield: 85.5 %

Procedure:
To a stirred suspension of 2-(1H-indol-3-yl)ethylamine (2.0 g in 20 mL of dry tetrahydrofuran) was added N-carbethoxyphthalimide (2.85 g) and the mixture heated to reflux on an oil bath. After 48 hours the reaction was cooled to room temperature, filtered and the filtrate concentrated in vacuo. The resulting solid was suspended in a mixture of hexane/methylene chloride (2.5:1) and filtered. Purification of the collected solids by flash chromatography on silica gel (methylene chloride:methanol, 97:3) gave the title compound (3.1 g).
Reaction SMILES: [C:1]([NH:9][CH2:10][C@@H:11]([C:35]([OH:37])=[O:36])[NH:12][C:13](=[O:34])[C:14]1[CH:19]=[CH:18][C:17]([C:20]([NH:22][CH2:23][C:24]2[CH:32]=[CH:31][CH:30]=[C:29]3[C:25]=2[CH:26]=[CH:27][NH:28]3)=[O:21])=[CH:16][C:15]=1[Cl:33])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1C=C(C(NCC2C3N=CNC=3C=CC=2)=O)C=CC=1C(N[C@H](C(O)=O)CNC(C1SC=CC=1)=O)=[O:42].ClC1C=C(C(NCC2C=CC=C3C=2C=CN3)=O)C=CC=1C(N[C@H](C(O)=O)CNC(C1SC=CC=1)=O)=O.ClC1C=C(C(NCC2C=CC=C3C=2CCN3)=O)C=CC=1C(N[C@H](C(O)=O)CNC(C1SC=CC=1)=O)=O.BrC1C=C(C(NCC2C=CC=C3C=2C=CN3)=O)C=CC=1C(N[C@H](C(O)=O)CNC(C1SC=CC=1)=O)=O.ClC1C=C(C(NCC2C=CC=C3C=2C=CN3)=O)C=CC=1C(N[C@H](C(O)=O)CNC(C1C=CSC=1)=O)=O.ClC1C=C(C(NCC2C=CC=C3C=2C=CN3)=O)C=CC=1C(N[C@H](C(O)=O)CNC(C1SC(C)=CC=1)=O)=O.ClC1C=C(C(NCC2C=CC=C3C=2C=NN3)=O)C=CC=1C(N[C@H](C(O)=O)CNC(C1SC=CC=1)=O)=O>>[C:1]([NH:9][CH2:10][C@@H:11]([C:35]([OH:37])=[O:36])[NH:12][C:13](=[O:34])[C:14]1[CH:19]=[CH:18][C:17]([C:20]([NH:22][CH2:23][C:24]2[CH:32]=[CH:31][CH:30]=[C:29]3[C:25]=2[CH2:26][C:27](=[O:42])[NH:28]3)=[O:21])=[CH:16][C:15]=1[Cl:33])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(NCc1cccc2[nH]ccc12)c1ccc(C(=O)N[C@@H](CNC(=O)c2ccccc2)C(=O)O)c(Cl)c1
Reactant: O=C(NCc1cccc2[nH]cnc12)c1ccc(C(=O)N[C@@H](CNC(=O)c2cccs2)C(=O)O)c(Cl)c1
Agent: Cc1ccc(C(=O)NC[C@H](NC(=O)c2ccc(C(=O)NCc3cccc4[nH]ccc34)cc2Cl)C(=O)O)s1
Agent: O=C(NCc1cccc2[nH]ccc12)c1ccc(C(=O)N[C@@H](CNC(=O)c2cccs2)C(=O)O)c(Br)c1
Agent: O=C(NCc1cccc2[nH]ccc12)c1ccc(C(=O)N[C@@H](CNC(=O)c2cccs2)C(=O)O)c(Cl)c1
Product: O=C1Cc2c(CNC(=O)c3ccc(C(=O)N[C@@H](CNC(=O)c4ccccc4)C(=O)O)c(Cl)c3)cccc2N1

Procedure:
3-(benzoylamino)-N-[2-chloro-4-[[(1H-indol-4-ylmethyl)amino]carbonyl]benzoyl]-L-alanine; N-[2-chloro-4-[[(1H-benzimidazol-4-ylmethyl)amino]carbonyl]benzoyl]-3-(thiophene-2-carbonyl)amino-L-alanine; N-[2-chloro-4-[[(1H-indol-4-ylmethyl)amino]carbony]benzoyl]-3-(thiophene-2-carbonyl)amino-L-alanine; N-[2-chloro-4-[[(2,3-dihydro-1H-indol-4-ylmethyl)amino]carbonyl]benzoyl]-3-(thiophene-2-carbonyl)amino-L-alanine; N-[2-bromo-4-[[(1H-indol-4-ylmethyl)amino]carbonyl]benzoyl]-3-(thiophene-2-carbonyl)amino-L-alanine; N-[2-chloro-4-[[(1H-indol-4-ylmethyl)amino]carbonyl]benzoyl]-3-(thiophene-3-carbonyl)anino-L-alanine; N-[2-chloro-4-[[(1H-indol-4-ylmethyl)amino]carbonyl]benzoyl]-3-[(5-methylthiophene-2-carbony)]amino-L-alanine), and N-[2-chloro-4-[[[(1H-indazol-4-yl)methyl]amino]carbonyl]benzoyl]-3-(thiophene-2-carbonyl)amino-L-alanine.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([Br:9])=[CH:4][C:3]=1[OH:10].[Yb+3].F[C:13](F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O.C(OC)(OC)OC>CCO.CC(=O)OCC.CCCCCC>[Br:9][C:5]1[C:6]([Cl:8])=[CH:7][C:2]2[N:1]=[CH:13][O:10][C:3]=2[CH:4]=1
Reactant: Nc1cc(Cl)c(Br)cc1O
Reactant: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CCO
Product: Clc1cc2ncoc2cc1Br
Temperature: 25 °C
Yield: 65.2 %

Procedure:
A mixture of 2-amino-5-bromo-4-chlorophenol (29). (865 mg, 3.89 mmol), trifluoromethanesulfonic acid Ytterbium (III) salt (24 mg, 1% mol) and trimethyl orthoformate (511 μl, 1.2 eq.) in 2 ml EtOH was heated at 90° C. for 2 h. After cooling down to r.t., the reaction mixture was taken up in EA, washed with aq. NaHCO3 and brine, dried over Na2SO4, concentrated to dryness. The resulting brown solid was dissolved in DCM and subjected to silica gel column purification using 0-100% B (A: hexane; B: 50% EA in hexane) to furnish 590 mg 30 as yellow solid (yield: 65.2%).
Reaction SMILES: C[O:2][C:3](=[O:39])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:12][CH2:13][CH2:14][N:15]([CH2:25][CH:26]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:18]=2[F:24])[CH:6]=1.[OH-].[Na+]>CO>[C:33]1([CH:26]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:25][N:15]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:18]=2[F:24])[CH2:14][CH2:13][CH2:12][O:11][C:7]2[CH:6]=[C:5]([CH2:4][C:3]([OH:39])=[O:2])[CH:10]=[CH:9][CH:8]=2)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: COC(=O)Cc1cccc(OCCCN(Cc2cccc(F)c2F)CC(c2ccccc2)c2ccccc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)Cc1cccc(OCCCN(Cc2cccc(F)c2F)CC(c2ccccc2)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
A solution of (3-{3-[(2,2-Diphenyl-ethyl)-(2,3-difluoro-benzyl)-amino]-propoxy}-phenyl)-acetic acid methyl ester (4b). (0.83 g, 0.0016 mol) in methanol (7.5 mL) was treated with 2N NaOH (5.0 ml) and the mixture stirred overnight at ambient temperature. After concentration to dryness, the residue was dissolved in EtOAc (25 mL) and water was added (10 mL), the solution acidified to pH 3 with concentrated hydrochloric acid, then extracted into EtOAc (3×20 mL). The combined organic extracts were dried over Na2SO4, and then concentrated in vacuo to provide the carboxylic acid as waxy oil. Solidification of the waxy oil from EtOAc gave white solid (5a) 0.73 g in 88% yield, mp: 148.4° C. 1H NMR (CD3OD) δ 7.18 (m, 1H), 6.99 (m, 1H), 6.81 (d, 2H), 6.76 (m, 1H), 6.72 (s, 1H), 6.55 (d, 1H), 4.17 (t, 1H), 3.67 (s, 2H), 3.55 (s, 2H), 3.54 (d, 2H), 3.07 (d, 2H), 2.62 (t, 2H), 1.77 (t, 2H); 13C NMR (CD3OD) δ 175.6, 160.5, 152.7, 151.5, 149.5, 149.4, 145.1, 137.3, 130.3, 130.1, 129.1, 127.6, 125.0, 124.9, 122.4, 129.3, 116.6, 114.1, 66.0, 60.9, 52.2, 51.3, 51.1, 42.2, 28.0. Anal. Calcd for C32H31F2NO3.21/2H2O: C, 68.55; H, 5.57; N, 2.50; F, 6.77. Found: C, 68.62; H, 5.27; N, 2.28; F, 6.52.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][C@@H:3]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)=[CH:9][CH:8]=2)[CH2:2]1.Cl[C:21]1[N:22]([CH3:34])[C:23](=[O:33])[CH:24]=[C:25]([C:27]2[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=2)[N:26]=1.C(N(CC)CC)C>O1CCCC1>[CH3:34][N:22]1[C:23](=[O:33])[CH:24]=[C:25]([C:27]2[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=2)[N:26]=[C:21]1[N:1]1[CH2:6][CH2:5][O:4][C@@H:3]([C:7]2[CH:8]=[CH:9][C:10]([NH:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)=[CH:11][CH:12]=2)[CH2:2]1
Reactant: c1ccc(Nc2ccc([C@H]3CNCCO3)cc2)nc1
Reactant: Cn1c(Cl)nc(-c2ccncc2)cc1=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cn1c(N2CCO[C@@H](c3ccc(Nc4ccccn4)cc3)C2)nc(-c2ccncc2)cc1=O
Yield: 36.6 %

Procedure:
A solution of N-{4-[(2S)-morpholin-2-yl]phenyl}pyridin-2-amine (0.2 g, 0.78 mmol), 2-chloro-1-methyl-6-oxo-4-(pyridin-4-yl)-1,6-dihydropyrimidine (0.13 g, 0.62 mmol), and triethylamine (0.23 g, 2.3 mmol) in tetrahydrofuran (10 ml) was stirred at 95° C. for 3 hours. The solvent was removed under reduced pressure and the residue was partitioned between water and dichloromethane. The organic layer was dried over anhydrous sodium sulfate and the solvent was concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel (chloroform-methanol, 10:1) to afford 3-Methyl-2-((2S)-2-(4-((pyridin-2-yl)amino)phenyl)morpholin-4-yl)-6-(pyridin-4-yl)-pyrimidin-4(3H)-one (100 mg, 37%) as a yellow oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:10]=[C:11]([C:13]([N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[O:14])[CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].[Br:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1.C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>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.O>[Br:20][C:21]1[CH:26]=[CH:25][C:24]([C:2]2[CH:12]=[C:11]([C:13]([N:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)=[O:14])[CH:10]=[C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH:3]=2)=[CH:23][CH:22]=1
Reactant: CCOC(=O)c1cc(Br)cc(C(=O)N2CCCC2)c1
Reactant: OB(O)c1ccc(Br)cc1
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: [Cs+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)c1cc(C(=O)N2CCCC2)cc(-c2ccc(Br)cc2)c1

Procedure:
To a mixture of ethyl 3-bromo-5-(pyrrolidine-1-carbonyl)benzoate (3.20 g, 9.81 mmol), 4-bromophenylboronic acid (2.17 g, 10.8 mmol), toluene (40 mL), cesium carbonate (3.52 g, 10.8 mmol), and water (5 mL) under argon was added tetrakis(triphenylphosphine)palladium(0) (567 mg, 0.49 mmol). The mixture was heated under reflux for 15 h. After cooling, the mixture was filtered through Celite and the filter cake was washed with EtOAc. The filtrate was washed with brine, dried (Na2SO4), and concentrated. The residue was purified by silica gel column (0-80% EtOAc/hexane) to afford a syrup. LC-MS: 404.0 [M+1]+.
Reaction SMILES: [C:1]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][CH2:16][C:17]([OH:19])=O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[Al+3].[Cl-].[Cl-].[Cl-].[Na+]>O>[C:1]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:10]=1[CH2:15][CH2:16][C:17]2=[O:19])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)CCc1ccccc1C(=O)c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: O=C1CCc2c1cccc2C(=O)c1ccccc1
Temperature: 160 °C

Procedure:
Five g. of o-benzoyl-β-phenylpropionic acid, 13 g. of anhydrous aluminum chloride and 1.3 g. of sodium chloride are admixed together and heated at 160°C for 1 hour. After cooling, water is added to the mixture, followed by extraction with chloroform. The extract is washed with a 5 % aqueous solution of sodium bicarbonate and water in that order and, then, dried. The solvent is distilled off under reduced pressure and the residue is dissolved in ethanol. The solution is decolorized with activated carbon and recrystallized from ethanol. The procedure yields 4-benzoylindan-1-one as crystals melting at 86°-88°C.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH2:8])[CH:7]=1.[OH:12][CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[NH2:8][C:6]1[CH:7]=[C:2]([N:16]2[CH2:17][CH2:18][CH:13]([OH:12])[CH2:14][CH2:15]2)[CH:3]=[CH:4][C:5]=1[N+:9]([O-:11])=[O:10]
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Reactant: OC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1cc(N2CCC(O)CC2)ccc1[N+](=O)[O-]
Temperature: 120 °C
Reaction time: 18 h

Procedure:
A mixture of 5-chloro-2-nitrophenylamine (1.3 g, 7.0 mmol), 4-hydroxypiperidine (2.2 g, 20 mmol), and K2CO3 (1.0 g, 7 mmol) in DMF (20 mL) was stirred at 120° C. for 18 h. The reaction mixture was cooled to room temperature, poured into water (50 mL) and extracted with EtOAc (3×50 mL). The combined organic extracts were dried over sodium sulfate, concentrated in vacuo, and the oily residue was triturated with 70/30 EtOAc/CHCl3 (8 mL) to yield a yellow solid. The solid product was collected by filtration, washed with 70:30 EtOAc/CHCl3 (8 mL), and dried in vacuo (0.63 g, 38%).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH2:13][C:14]1[CH:18]=[C:17]([CH3:19])[NH:16][N:15]=1.C(N(CC)CC)C>C(O)C>[Cl:1][C:2]1[N:11]=[C:10]([NH:13][C:14]2[NH:15][N:16]=[C:17]([CH3:19])[CH:18]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Clc1nc(Cl)c2ccccc2n1
Reactant: Cc1cc(N)n[nH]1
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1cc(Nc2nc(Cl)nc3ccccc23)[nH]n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2,4-dichloroquinazoline (12.69 g, 63 mmol) and 3-amino-5-methylpyrazole (6.18 g, 63 mmol) in ethanol (220 mL) is added triethylamine (8.13 mL, 63 mmol) and the reaction mixture is stirred for 3 hours at room temperature. The pale yellow precipitate is then collected by filtration, washed with cold ethanol and dried under vacuum to give (2-chloroquinazolin-4-yl)-(5-methyl-2H-pyrazol-3-yl)-amine.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:10]([I:11])=[N:9][NH:8][C:5]2=[N:6][CH:7]=1.[F:12][C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[CH2:15]Br.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:10]([I:11])=[N:9][N:8]([CH2:15][C:14]3[CH:17]=[CH:18][CH:19]=[CH:20][C:13]=3[F:12])[C:5]2=[N:6][CH:7]=1
Reactant: Fc1ccccc1CBr
Reactant: Fc1cnc2[nH]nc(I)c2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Fc1cnc2c(c1)c(I)nn2Cc1ccccc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
12.1 g (39.65 mmol) of the compound from Example 6A were initially charged in DMF (217 ml), and 8.25 g (43.62 mmol) of 2-fluorobenzyl bromide and 14.21 g (43.62 mmol) of cesium carbonate were then added. The mixture was stirred at RT for two hours. The reaction mixture was then poured onto water (1.17 l) and extracted twice with ethyl acetate (502 ml). The collected organic phases were washed with saturated aqueous sodium chloride solution (335 ml), dried, filtered and concentrated. The residue was chromatographed on silica gel (eluent: 97:3 petroleum ether/ethyl acetate) and the product fractions were concentrated. This gave 9.0 g (61% of theory) of the desired compound in solid form. The solid was taken up in ethyl acetate and washed with 10% aqueous sodium thiosulfate solution and then with saturated aqueous sodium chloride solution, dried and concentrated.