Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[O:6][C:5]([C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1>O1CCOCC1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[O:6]1[C:5]([C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=2)=[CH:4][CH:3]=[C:2]1[C:5]1[O:6][CH:2]=[CH:3][CH:4]=1
Reactant: N#Cc1ccc(-c2ccc(Br)o2)cc1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: N#Cc1ccc(-c2ccc(-c3ccco3)o2)cc1
Temperature: 105 °C
Yield: 79.5 %

Procedure:
A mixture of 2 (2.48 g, 10 mmol), 2-tributyltin furan (3.58 g, 10 mmol), and tetrakis(triphenylphosphine) palladium (200 mg) in dry dioxane (60 mL) was heated under nitrogen at reflux (100-110° C.) for 24 h. The solvent was evaporated under reduced pressure and the resulting solid was dissolved in ethyl acetate. This solution was passed through celite to remove Pd. The solution was evaporated, and the solid was collected via filtration and washed with hexanes to furnish compound 3 in 79.5% yield, mp 104-105° C. 1H NMR (CDCl3); δ 6.51 (dd, J=3.6 Hz, J=1.8 Hz, 1H), 6.68 (m, 2H), 6.87 (d, J=3.6 Hz, 1H), 7.46 (d, J=1.8 Hz, 1H), 7.66 (d, J=8.4 Hz, 2H), 7.77 (d, J=8.4 Hz, 2H). 13C NMR (CDCl3); δ 150.9, 147.5, 145.8, 142.4, 134.1, 132.5, 123.7, 118.9, 111.6, 110.1, 107.5, 106.3. EIMS (m/z, rel.int.); 235 (M+, 100), 206 (10), 178 (15). Calcd for C15H9NO2: C, 76.59; H, 3.86; N, 5.95. Found. C, 76.35; H, 3.88; N, 5.92.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:9](O)=[O:10])=[CH:4][CH:3]=1.[NH3:19]>O=S(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:9]([NH2:19])=[O:10])=[CH:4][CH:3]=1
Reactant: N
Reactant: O=C(O)C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Solvent: O=S(Cl)Cl
Product: NC(=O)C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.2 %

Procedure:
A suspension of 2,2-bis-(4-chloro-phenyl)-acetic acid (0.50 g, 1.8 mmol) in SOCl2 (5 mL) was heated at reflux for 1 h. The mixture was concentrated, and the residue was azeotroped with toluene (3×). The crude acid chloride was stirred in DCM (10 mL) at rt and treated with NH3 (0.5 M in dioxane, 14 mL, 7.5 mmol). After 1 h, the reaction mixture was concentrated, and the residue was diluted with satd. aq. NaHCO3 and extracted with DCM (3×). The combined organics were dried (Na2SO4) and concentrated to provide the amide as a white solid (0.50 g, 100%). The amide was used without further purification. 1H NMR (400 MHz, CDCl3): 7.35-7.28 (m, 4H), 7.23-7.17 (m, 4H), 5.69 (br s, 1H), 5.53 (br s, 1H), 4.87 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([N+:13]([O-])=O)[C:11]=1[CH3:12])[N:8]=[CH:7][N:6]=[C:5]2[NH:16][C:17]1[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=1.N.CO>CCO.[Pd]>[NH2:13][C:10]1[C:11]([CH3:12])=[CH:2][CH:3]=[C:4]2[C:9]=1[N:8]=[CH:7][N:6]=[C:5]2[NH:16][C:17]1[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=1
Reactant: Cc1c(Br)cc2c(Nc3ccc(C#N)cc3)ncnc2c1[N+](=O)[O-]
Agent: [Pd]
Agent: N
Solvent: CCO
Solvent: CO
Product: Cc1ccc2c(Nc3ccc(C#N)cc3)ncnc2c1N
Reaction time: 8 h
Yield: 83.1 %

Procedure:
A mixture of 4-(6-bromo-7-methyl-8-nitroquinazolin-4-ylamino)benzonitrile (400 mg, 1.04 mmol) and Pd/C (10%˜30 mg) in EtOH (20 mL) was stirred under H2 gas (1 atm) overnight. 30 mL of NH3/MeOH (2 M) was added and the mixture was filtered through celite and washed with MeOH/DCM (˜1:1). After removal of solvent the product was purified by flash chromatography eluting with MeOH/DCM (1-5%) to give 4-(8-amino-7-methylquinazolin-4-ylamino)benzonitrile (238 mg, 83%). MS (ESI, pos. ion) m/z: 276 [M+H]+
Reaction SMILES: [N:1]1[O:2][N:3]=[C:4]2[CH2:9][CH2:8][C:7]3[S:10][C:11]([NH:13][C:14]([C:16]45[CH2:23][CH:22]6[CH2:24][CH:18]([CH2:19][CH:20]4[CH2:21]6)[CH2:17]5)=[O:15])=[N:12][C:6]=3[C:5]=12.[CH3:25][O:26][CH2:27][CH2:28]Br>>[CH3:25][O:26][CH2:27][CH2:28][N:12]1[C:6]2[C:5]3=[N:1][O:2][N:3]=[C:4]3[CH2:9][CH2:8][C:7]=2[S:10]/[C:11]/1=[N:13]\[C:14]([C:16]12[CH2:17][CH:18]3[CH2:24][CH:22]([CH2:21][CH:20]1[CH2:19]3)[CH2:23]2)=[O:15]
Reactant: O=C(Nc1nc2c(s1)CCc1nonc1-2)C12CC3CC(CC1C3)C2
Reactant: COCCBr
Product: COCCn1c2c(s/c1=N\C(=O)C13CC4CC(CC1C4)C3)CCc1nonc1-2

Procedure:
The product from Example 71B and 2-bromoethyl methyl ether were processed according to the method of Example 1B to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.44-1.70 (m, 4 H), 1.70-1.87 (m, 4 H), 2.14 (d, J=11.2 Hz, 2 H), 2.29 (s, 2 H), 2.59 (t, J=6.8 Hz, 1 H), 3.13 (t, J=7.1 Hz, 2 H), 3.21-3.30 (m, 5 H), 3.63-3.85 (m, 2 H), 4.69 (t, J=5.8 Hz, 2 H); MS (ESI+) m/z 401 (M+H)+; Anal. Calculated for C20H24N4O3S: C, 59.98; H, 6.04; N, 13.99. Found: C, 59.90; H, 6.09; N, 13.95.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][C:5](=[O:7])[C:4]([CH2:8][CH:9]=[CH2:10])=[C:3]1[CH3:11].N1C=CN=C1.[C:17]([Si:21]([CH3:24])([CH3:23])Cl)([CH3:20])([CH3:19])[CH3:18].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C)C=O>[Si:21]([O:1][CH:2]1[CH2:6][C:5](=[O:7])[C:4]([CH2:8][CH:9]=[CH2:10])=[C:3]1[CH3:11])([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:24])[CH3:23]
Reactant: C=CCC1=C(C)C(O)CC1=O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: C=CCC1=C(C)C(O[Si](C)(C)C(C)(C)C)CC1=O
Temperature: 0 °C
Yield: 96.9 %

Procedure:
1 (RS)-4-hydroxy-3-methyl-2-(2-propenyl)-cyclopent-2-ene-1-one (5.0 g) and imidazole (2.91 g) were dissolved in dry dimethylformamide (20 ml), and tert-butyldimethylchlorosilane (5.45 g) was added thereto at room temperature and the resulting mixture was allowed to react for 14 hours at room temperature. The reaction solution was poured into an ice-cooled aqueous citric acid solution, and extracted three times with diethyl ether. The organic layers were combined, and the combined layer was washed with saturated aqueous sodium bicarbonate solution and brine in sequence, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The resultant residue was subjected to column chromatography (eluent; n-hexane: ethy acetate=4:1) to afford (RS)-4-tert-butyldimethylsilyloxy-3-methyl-2-(2-propenyl)cyclopent-2-ene-1-one (8.48 g, yield 97.0%) as a pale yellow oil.
Reaction SMILES: [CH3:1][C:2]([NH:5][S:6]([C:9]1[S:10][C:11]([S:14]([NH2:17])(=[O:16])=[O:15])=[CH:12][CH:13]=1)(=[O:8])=[O:7])([CH3:4])[CH3:3].[H-].[Na+].Cl.Cl[CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>CN(C)C=O>[CH3:4][C:2]([NH:5][S:6]([C:9]1[S:10][C:11]([S:14]([NH:17][CH2:22][CH2:23][N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)(=[O:16])=[O:15])=[CH:12][CH:13]=1)(=[O:8])=[O:7])([CH3:1])[CH3:3]
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(S(N)(=O)=O)s1
Reactant: ClCCN1CCOCC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)NS(=O)(=O)c1ccc(S(=O)(=O)NCCN2CCOCC2)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 22.1 %

Procedure:
A solution of the product from Step B (1.05 g, 3.52 mmol), sodium hydride (60% dispersion in mineral oil, 310 mg, 7.75 mmol) and 4-(2-chloroethyl)morpholine hydrochloride (0.721 g, 3.88 mmol) in anhydrous dimethylformamide (DMF) (20 mL) was heated at 110° C. for 2.5 h and then stirred at ambient temperature overnight. The reaction mixture was extracted with ethyl acetate (3×100 mL), washed with brine, dried over molecular sieves and concentrated. The residue was chromatographed (silica, elution with 50% ethyl acetate-hexane) to yield 0.32 g (22%) of the desired product.
Reaction SMILES: [NH2:1][C@H:2]([C:7]([O:9][CH3:10])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].Cl.C(N(CC)CC)C.[NH:19]([C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28])[C@H:20]([C:24](O)=[O:25])[CH:21]([CH3:23])[CH3:22].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O>[NH:19]([C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28])[C@H:20]([C:24]([NH:1][C@H:2]([C:7]([O:9][CH3:10])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5])=[O:25])[CH:21]([CH3:23])[CH3:22]
Reactant: COC(=O)[C@@H](N)CC(C)C
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](CC(C)C)NC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 19.9 g (110 mmols) of H-Leu-OMe.HCl in 120 ml of dimethylformamide is mixed at 0° C. with 14.6 ml (105 mmols) of triethylamine. The precipitated triethylamine hydrochloride is filtered off, the filtrate added to a solution of 25.1 g (100 mmols) of Z-Val-OH in 200 ml of dimethylformamide at 0° C. and then 22.6 g (110 mmols) of dry dicyclohexylcarbodiimide are added. The batch is stirred for 1 hour at 0° C., then kept overnight in a refrigerator, filtered, and the filtrate is evaporated under a high vacuum at 40° C. The oily residue is taken up in 30 ml of ethyl acetate, the solution cooled to 0° C. and the precipitated dicyclohexylurea is filtered off. On addition of n-hexane the product crystallizes overnight out of the filtrate; it melts at 102°-105° C. Optical rotation [α]D20 =-41° (c=2.88 in methanol).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][N:10]2[C:18]3[C:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:16][NH:15][C:14](=O)[C:13]=3[CH:12]=[CH:11]2)=[CH:5][CH:4]=1.P(Cl)([Cl:34])(OC1C=CC=CC=1)=O>>[Cl:34][C:14]1[C:13]2[CH:12]=[CH:11][N:10]([CH2:9][C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[C:18]=2[C:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:16][N:15]=1
Reactant: CCOC(=O)c1c[nH]c(=O)c2ccn(Cc3ccc(OC)cc3)c12
Reactant: O=P(Cl)(Cl)Oc1ccccc1
Product: CCOC(=O)c1cnc(Cl)c2ccn(Cc3ccc(OC)cc3)c12

Procedure:
Prepared in a similar manner to Example 243(e) using ethyl 1-{[4-(methyloxy)phenyl]methyl}-4-oxo-4,5-dihydro-1H-pyrrolo[3,2-c]pyridine-7-carboxylate (14.45 g) and phenyl dichlorophosphate (100 ml) to afford the title compound as a yellow oil (7.2 g).
Reaction SMILES: [CH2:1]([O:8][N:9]([CH2:12][CH:13]1[C:18](=[O:19])[N:17]([CH2:20][C:21](O)=[O:22])[C:16]2[CH:24]=[CH:25][CH:26]=[CH:27][C:15]=2[S:14]1)[CH:10]=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:28]([NH2:31])[CH2:29][CH3:30].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH2:1]([O:8][N:9]([CH2:12][CH:13]1[C:18](=[O:19])[N:17]([CH2:20][C:21]([NH:31][CH2:28][CH2:29][CH3:30])=[O:22])[C:16]2[CH:24]=[CH:25][CH:26]=[CH:27][C:15]=2[S:14]1)[CH:10]=[O:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCN
Reactant: O=CN(CC1Sc2ccccc2N(CC(=O)O)C1=O)OCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCCNC(=O)CN1C(=O)C(CN(C=O)OCc2ccccc2)Sc2ccccc21
Reaction time: 8 h

Procedure:
To a solution of {2-[(benzyloxy-formyl-amino)-methyl]-3-oxo-2,3-dihydro-benzo[1,4]thiazin-4-yl}-acetic acid (0.13 mmol) in anhydrous DMF, propylamine (0.13 mmol) is added followed by DIEA (0.13 mmol) and HATU (0.13 mmol). The reaction mixture is stirred overnight and the desired product 2-{2-[(benzyloxy-formyl-amino)-methyl]-3-oxo-2,3-dihydro-benzo[1,4]thiazin-4-yl}-N-propyl-acetamide is obtained and used in the next step without further purification. MS: (ES+): 428.2 [M+1].
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[C:11]([O:15][C:16](=[O:38])[CH2:17][N:18]1[C:22]2[CH:23]=[CH:24][C:25]([NH:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:26][C:21]=2[N:20]=[C:19]1[CH2:35][CH2:36][CH3:37])([CH3:14])([CH3:13])[CH3:12].CCN(C(C)C)C(C)C>CN(C1C=CN=CC=1)C.C(Cl)Cl.Cl>[C:11]([O:15][C:16](=[O:38])[CH2:17][N:18]1[C:22]2[CH:23]=[CH:24][C:25]([N:27]([CH2:28][C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:6](=[O:7])[C:5]3[CH:9]=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=3)=[CH:26][C:21]=2[N:20]=[C:19]1[CH2:35][CH2:36][CH3:37])([CH3:14])([CH3:13])[CH3:12]
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: CCCc1nc2cc(NCc3ccccc3)ccc2n1CC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCc1nc2cc(N(Cc3ccccc3)C(=O)c3ccc(Cl)cc3)ccc2n1CC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-Chloro-benzoyl chloride (46 μL, 0.36 mmol) was added to a solution of (5-benzylamino-2-propyl-benzoimidazol-1-yl)-acetic acid tert-butyl ester (45 mg, 0.12 mmol), DIEA (41 μL, 0.24 mmol) and DMAP (15 mg, 0.12 mmol) in CH2Cl2 (1 mL), and stirred overnight at room temperature. The reaction solution was diluted with aqueous HCl (1.0 M) and filtered through an Extrelut column. The Extrelut column was washed with CH2Cl2, and the filtrate was concentrated to afford the subtitle compound that was used without further purification. MS calculated for C30H32ClN3O3+H: 518, observed: 518.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:19][CH2:18][CH2:17][C:16]3=[O:20])=[CH:11][CH:10]=2)O1.Cl[C:23]1[CH:24]=[CH:25][C:26]2[N:27]=[C:28]([NH:36]C(=O)C)[N:29]=[C:30]([CH:33]3[CH2:35][CH2:34]3)[C:31]=2[N:32]=1>>[NH2:36][C:28]1[N:29]=[C:30]([CH:33]2[CH2:35][CH2:34]2)[C:31]2[N:32]=[C:23]([C:9]3[CH:10]=[CH:11][C:12]([N:15]4[CH2:19][CH2:18][CH2:17][C:16]4=[O:20])=[CH:13][CH:14]=3)[CH:24]=[CH:25][C:26]=2[N:27]=1
Reactant: CC(=O)Nc1nc(C2CC2)c2nc(Cl)ccc2n1
Reactant: CC1(C)OB(c2ccc(N3CCCC3=O)cc2)OC1(C)C
Product: Nc1nc(C2CC2)c2nc(-c3ccc(N4CCCC4=O)cc3)ccc2n1

Procedure:
The experimental procedure of example 2 was repeated, except for the use of 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-pyrrolidin-2-one instead of 4-fluorophenylboronic acid and N-(6-chloro-4-cyclopropyl-pyrido[3,2-d]pyrimidin-2-yl)-acetamide instead of 6-chloro-4-propyl-pyrido[3,2-d]pyrimidin-2-ylamine. The resulting compound was characterized as follows: MS (m/z) 346.2 [M+H]+; HPLC Rt=2.67 minutes (Method B).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:43])[CH2:4][C:5]1[C:6]([C:11]#[C:12][C:13]2[C:18]([C:19]([F:22])([F:21])[F:20])=[CH:17][N:16]=[C:15]([NH:23][C:24]3[CH:29]=[CH:28][C:27]([CH:30]4[CH2:35][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:32][CH2:31]4)=[CH:26][CH:25]=3)[N:14]=2)=[N:7][CH:8]=[CH:9][CH:10]=1>CN(C=O)C.[Pd]>[CH3:1][O:2][C:3](=[O:43])[CH2:4][C:5]1[C:6]([CH2:11][CH2:12][C:13]2[C:18]([C:19]([F:22])([F:20])[F:21])=[CH:17][N:16]=[C:15]([NH:23][C:24]3[CH:29]=[CH:28][C:27]([CH:30]4[CH2:35][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:41])([CH3:40])[CH3:42])=[O:37])[CH2:32][CH2:31]4)=[CH:26][CH:25]=3)[N:14]=2)=[N:7][CH:8]=[CH:9][CH:10]=1
Reactant: COC(=O)Cc1cccnc1C#Cc1nc(Nc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)cc2)ncc1C(F)(F)F
Agent: [Pd]
Solvent: CN(C)C=O
Product: COC(=O)Cc1cccnc1CCc1nc(Nc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)cc2)ncc1C(F)(F)F
Temperature: 25 °C
Reaction time: 24 h
Yield: 74.7 %

Procedure:
A solution of tert-butyl 4-(4-((4-((3-(2-methoxy-2-oxoethyl)pyridin-2-yl)ethynyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate (I121) (81.5 mg, 0.137 mmol) in DMF (10 mL) was added to a solution of 10% Pd/C (170 mg) in DMF (7 mL). The reaction was stirred at room temperature for 24 hours under an atmosphere of hydrogen. The reaction was filtered through a pad of celite, washing with EtOAc (100 mL). The solvent was removed in vacuo to afford an oil which was purified on by column chromatography on silica gel (0-40% EtOAc in petroleum benzine 40-60° C.) to yield the title compound (I122) (61.4 mg, 75%) as a viscous oil; 1H NMR (400 MHz, CDCl3) δ 8.51 (s, 1H), 8.46 (dd, J=4.8, 1.7 Hz, 1H), 7.56-7.50 (m, 3H), 7.49 (s, 1H), 7.19-7.14 (m, 2H), 7.12 (dd, J=7.7, 4.8 Hz, 1H), 4.23 (bs, 2H), 3.72 (s, 2H), 3.70 (s, 3H), 3.40-3.33 (m, 2H), 3.32-3.23 (m, 2H), 2.80 (t, J=12.1 Hz, 2H), 2.62 (tt, J=12.1, 3.5 Hz, 1H), 1.81 (d, J=12.9 Hz, 2H), 1.65-1.55 (m, 2H), 1.48 (s, 9H). LCMS Method C: rt 6.01 min; m/z 622 [M+Na]+, 600 [M+H]+, 544 [M-tButyl+2H]+.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([NH:14][C:15](=[O:35])[C:16]3[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[CH:18][C:17]=3[N+:32]([O-])=O)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.O.O.Cl[Sn]Cl>CO>[CH:10]1[C:11]2[CH:12]([NH:14][C:15](=[O:35])[C:16]3[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[CH:18][C:17]=3[NH2:32])[C:13]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: COc1cc(C(=O)NC2c3ccccc3-c3ccccc32)c([N+](=O)[O-])cc1OCc1ccccc1
Agent: Cl[Sn]Cl
Solvent: CO
Solvent: O
Product: COc1cc(C(=O)NC2c3ccccc3-c3ccccc32)c(N)cc1OCc1ccccc1
Yield: 84 %

Procedure:
N1-(9H-9-fluorenyl)-4-(benzyloxy)-5-methoxy-2-nitrobenzamide of formula (7e) (500 mg, 1.07 mmol) was dissolved in methanol (10 mL), SnCl2.2H2O (839 mg, 3.2 mmol) was added and refluxed until the TLC indicated the completion of the reaction. The methanol was evaporated by vacuum and the aqueous layer was then adjusted to pH 8 with 10% NaHCO3 solution and extracted with ethyl acetate (2×30 mL). The combined organic phase was dried over Na2SO4 and evaporated under vacuum to afford the crude N1-(9H-9-fluorenyl)-2-amino-4-(benzyloxy)-5-methoxybenzamide (450 mg, 95% yield). This was further purified by column chromatography using ethyl acetate:hexane (6:4) as a solvent system to obtain the pure product (8e) (610 mg, 84% yield). 1H NMR (CDCl3) δ 3.95 (s, 3H), 5.20 (s, 2H), 5.70 (s, 1H), 6.70 (s, 1H), 7.00-7.41 (m, 5H), 7.45-7.706 (m, 9H); FABMS: 436 (M+H)+.
Reaction SMILES: [C:1]([C:3]1([OH:9])[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1)#[CH:2].[F:10][C:11]1[C:12](I)=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][C:15](=[O:20])/[C:14]/2=[CH:21]\[C:22]1[NH:23][CH:24]=[CH:25][C:26]=1[O:27][CH3:28]>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.CN(C=O)C.CCN(CC)CC>[F:10][C:11]1[C:12]([C:2]#[C:1][C:3]2([OH:9])[CH2:8][CH2:7][O:6][CH2:5][CH2:4]2)=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][C:15](=[O:20])/[C:14]/2=[CH:21]\[C:22]1[NH:23][CH:24]=[CH:25][C:26]=1[O:27][CH3:28]
Reactant: C#CC1(O)CCOCC1
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(I)c21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(C#CC3(O)CCOCC3)c21

Procedure:
Using Method C above, 4-ethynyl-tetrahydro-pyran-4-ol (41.1 mg, 0.33 mmol) (Example 85A) was coupled with (Z)-1,3-dihydro-5-fluoro-4-iodo-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (50 mg, 0.13 mmol) (Starting Material 6) using (Ph3P)4Pd (15 mg) and Cul (2.5 mg) as catalyst in DMF (4 mL) and Et3N (4 mL) as solvent at 85° C. for 7 h to yield (Z)-1,3-Dihydro-5-fluoro-4-[(4-hydroxy-tetrahydro-pyran-4-yl)ethynyl]-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one. (Yield 36 mg, 75%).
Reaction SMILES: CCN=C=NCCCN(C)C.Cl.[N:13]1([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:20][CH2:19][CH2:18][C@H:14]1[C:15]([OH:17])=O.[NH:28]1[CH2:41][CH2:40][CH2:39][C@H:29]1[C:30]([NH:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:31]>C1COCC1>[N:13]1([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:20][CH2:19][CH2:18][C@H:14]1[C:15]([N:28]1[CH2:41][CH2:40][CH2:39][C@H:29]1[C:30]([NH:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:31])=[O:17]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Reactant: O=C(Nc1ccccc1)[C@@H]1CCCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 73.6 %

Procedure:
201 mg (1.05 mmol) of EDCl was added to 5 ml of THF solution of 100 mg (0.526 mmol) of Boc-Pro-OH (manufactured by Tokyo Chemical Industry Co., Ltd), and 113 mg (0.526 mmol) of H-Pro-NHPh (manufactured by Tokyo Chemical Industry Co., Ltd), followed by stirring for 6 hours at room temperature. After a reaction mixture was concentrated under reduced pressure, the concentrate was extracted by adding water and ethyl acetate. After an organic layer was washed sequentially with a diluted hydrochloric acid, an aqueous solution of sodium hydrogen carbonate and water (one time for each), it was concentrated under reduced pressure, thereby obtaining crude amide. The obtained amide compound was purified by a silica gel column chromatography (hexane/ethyl acetate=5/1 to 1/1 (volume ratio)), thereby obtaining 150 mg of the product with a yield of 73.6%.
Reaction SMILES: S(Cl)([Cl:3])=O.[C:5]([C:8]1[CH:16]=[CH:15][C:11]([C:12](O)=[O:13])=[CH:10][CH:9]=1)(=[O:7])[CH3:6]>C1(C)C=CC=CC=1>[C:5]([C:8]1[CH:16]=[CH:15][C:11]([C:12]([Cl:3])=[O:13])=[CH:10][CH:9]=1)(=[O:7])[CH3:6]
Reactant: CC(=O)c1ccc(C(=O)O)cc1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: CC(=O)c1ccc(C(=O)Cl)cc1

Procedure:
120 mmol of thionyl chloride are added to 600 mmol of 4-acetylbenzoic acid in 150 ml of toluene. The reaction mixture is heated at reflux for 3 hours and then cooled. The solvent is evaporated off. The product is used without any other treatment.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:15]=[C:14]([C:16]([O:18]CCCC)=[O:17])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+].O>O1CCOCC1>[CH2:1]([O:5][C:6]1[CH:15]=[C:14]([C:16]([OH:18])=[O:17])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)c1cc(OCCCC)nc2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CCCCOc1cc(C(=O)O)c2ccccc2n1
Temperature: 25 °C
Yield: 87.9 %

Procedure:
A mixture of 2.67 g (8.86 mmols) of Compound b, 1.77 g of sodium hydroxide, 60 ml of water and 60 ml of dioxane was stirred at room temperature for an hour. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluting solvent: chloroform/methanol=5/1) to give 1.91 g (yield 90%) of Compound a.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][CH2:9][C:10]2[N:14]3[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:13]3=[N:12][C:11]=2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:3]=1.[CH3:26][C:27]1([OH:33])[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>CC(O)(C)C.C(OCC)(=O)C>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]2[N:14]([C:10]([CH2:9][NH:8][C:4]3[N:3]=[C:2]([N:30]4[CH2:31][CH2:32][C:27]([CH3:26])([OH:33])[CH2:28][CH2:29]4)[CH:7]=[CH:6][N:5]=3)=[C:11]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:12]=2)[CH:15]=1
Reactant: CC1(O)CCNCC1
Reactant: Clc1ccc2nc(-c3ccccc3)c(CNc3nccc(Cl)n3)n2c1
Solvent: CCOC(C)=O
Solvent: CC(C)(C)O
Product: CC1(O)CCN(c2ccnc(NCc3c(-c4ccccc4)nc4ccc(Cl)cn34)n2)CC1
Temperature: 95 °C

Procedure:
A mixture of 4-chloro-N-((6-chloro-2-phenylimidazo[1,2-a]pyridin-3-yl)methyl)pyrimidin-2-amine (50 mg, 0.135 mmol) and 4-methylpiperidin-4-ol (200 mg, 1.74 mmol) in t-BuOH (0.5 ml) was heated 95° C. until the reaction was completed. The mixture was diluted with ethyl acetate and the resulting mixture was washed with saturated NaHCO3 and brine, dried over Na2SO4 and concentrated by evaporation. The crude product was purified by silica gel chromatography (methanol/methylene chloride gradient) to title compound. M/e+ 449 for C24H26ClN6O (M+H)+; 1H-NMR (400 MHz, CDCl3) δ 8.47 (s, 1H), 7.89 (d, J=5.8 Hz, 1H), 7.76 (d, J=6.9 Hz, 2H), 7.57 (d, J=9.5 Hz, 1H), 7.47 (m, 3H), 7.39 (d, J=7.7 Hz, 1H), 7.16 (dd, J=9.5, 1.8 Hz, 1H), 5.99 (d, J=6.2 Hz, 1H), 5.05 (d, J=5.5 Hz, 2H), 5.00 (bs, 1H), 4.00 (m, 2H), 3.40 (m, 2H), 1.62 (m, 4H), 1.29 (s, 3H) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[CH2:10][C:11]([OH:13])=[O:12].OS(O)(=O)=O.[CH3:19]O>>[CH3:19][O:12][C:11](=[O:13])[CH2:10][C:3]1[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=1[Cl:1]
Reactant: COc1ccc(Cl)c(CC(=O)O)c1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1cc(OC)ccc1Cl

Procedure:
2-Chloro-5-methoxy-benzeneacetic acid (10 g, CAS Reg. No. 91367-10-1) was dissolved in MeOH (210 mL) and H2SO4 (0.7 mL) was added. The mixture was then refluxed over night. Methanol was removed in vacuo and the residue was dissolved in ethyl acetate. The organic layer was washed with sat. NaHCO3 and brine, dried over Na2SO4 and evaporated. The title compound was obtained as a light brown oil (10.16 g) and was used without further purification. 1H-NMR (□, CDCl3): 7.27 (d, 1H), 6.83 (d, 1H), 6.77 (dd, 1H), 3.79 (s, 3H), 3.74 (s, 2H), 3.72 (s, 3H).