Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([O-])([CH3:4])[CH3:3].[K+].[C:7]([C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[NH:12][CH:11]=1)(=[O:9])[CH3:8].[C:19]1(C)[C:20]([S:25](Cl)(=[O:27])=[O:26])=[CH:21]C=CC=1.C(OC(C)=O)C.O>CN(C=O)C>[C:2]1([CH3:4])[CH:3]=[CH:21][C:20]([S:25]([N:12]2[C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:10]([C:7](=[O:9])[CH3:8])=[CH:11]2)(=[O:27])=[O:26])=[CH:19][CH:1]=1
Reactant: CC(C)(C)[O-]
Reactant: CC(=O)c1c[nH]c2ccccc12
Reactant: Cc1ccccc1S(=O)(=O)Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CC(=O)c1cn(S(=O)(=O)c2ccc(C)cc2)c2ccccc12
Reaction time: 0.5 h
Yield: 78 %

Procedure:
Add 1.0 M t-BuOK (3.0 mL, 0.003 mol) to a stirring solution of 3-acetyl indole (0.478 g, 0.0030 mol) in dry DMF (20 mL) under N2 at ambient temperature and stir for 30 min. Add toluenesulfonyl chloride to this solution and stir the resulting mixture overnight. Pour the reaction into EtOAc—H2O, separate the organic layer and extract several times with H2O, wash with brine, dry (MgSO4), filter, and evaporate on the rotary evaporator. Chromatograph on the ISCO eluting with a gradient hexane-EtOAc (0-100%) over 30 minutes to give 0.73 g (78%) of the title compound as a solid: 1H (CDCl3).δ 7.8 (d, 1H), 8.2(s, 1H), 7.9(d,1H), 7.7 (d,2H), 7.4 (m, 2H), 7.3(d,2H), 2.6 (s, 3H), 2.4(s, 3H).
Reaction SMILES: [S:1]1[C:10]2[C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[N:7]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:33])[C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[C:26]=4[CH3:32])=[CH:19][CH:18]=3)=[O:16])[CH2:6][CH2:5][C:4]=2[CH:3]=[CH:2]1.[Cl:34]N1C(=O)CCC1=O>C(OCC)(=O)C>[Cl:34][C:2]1[S:1][C:10]2[C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[N:7]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:33])[C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[C:26]=4[CH3:32])=[CH:19][CH:18]=3)=[O:16])[CH2:6][CH2:5][C:4]=2[CH:3]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cc1c(F)cccc1C(=O)Nc1ccc(C(=O)N2CCc3ccsc3-c3ccccc32)cc1
Solvent: CCOC(C)=O
Product: Cc1c(F)cccc1C(=O)Nc1ccc(C(=O)N2CCc3cc(Cl)sc3-c3ccccc32)cc1
Reaction time: 8 h

Procedure:
To a solution of 0.457 g (1.0 mmol) of N-[4-[(4,5-dihydro-6H-thieno[3,2-d][1]benzazepin-6-yl)carbonyl]phenyl]-2-methyl-3-fluorobenzamide in 25 ml of ethyl acetate is added 1.0 mmol of N-chlorosuccinimide. The mixture is stirred overnight and filtered. The filtrate is washed with water, 1N HCl, 1M NaHCO3, H2O and dried (Na2SO4). The solvent is removed to give the product as a solid.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][C:12]([NH:14][NH2:15])=O)=[CH:8][CH:9]=2)[CH:4]=[N:3][CH:2]=1.Cl[C:17]1[N:18]=[N:19][C:20]([C:23]2[CH:24]=[N:25][N:26]([CH3:28])[CH:27]=2)=[CH:21][CH:22]=1>C(O)CCC>[CH3:28][N:26]1[CH:27]=[C:23]([C:20]2[CH:21]=[CH:22][C:17]3[N:14]([C:12]([CH2:11][C:7]4[CH:6]=[C:5]5[C:10](=[CH:9][CH:8]=4)[N:1]=[CH:2][N:3]=[CH:4]5)=[N:19][N:18]=3)[N:15]=2)[CH:24]=[N:25]1
Reactant: Cn1cc(-c2ccc(Cl)nn2)cn1
Reactant: NNC(=O)Cc1ccc2ncncc2c1
Solvent: CCCCO
Product: Cn1cc(-c2ccc3nnc(Cc4ccc5ncncc5c4)n3n2)cn1
Temperature: 25 °C
Yield: 5.7 %

Procedure:
Quinazolin-6-yl-acetic acid hydrazide (0.032 g, 0.158 mmol) and 3-chloro-6-(1-methyl-1H-pyrazol-4-yl)-pyridazine (0.031 g, 0.158 mmol) were heated to 165° C. in butanol (2 mL) for five hours. The reaction was cooled to room temperature, evaporated in vacuo and purified via silica gel column chromatography eluting with 5% methanol in dichloromethane to give 0.0031 g (7%) of 6-[6-(1-methyl-1H -pyrazol-4-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-ylmethyl]-quinazoline. 1H NMR (400 MHz, CD3OD) δ 8.45 (s, 1H), 8.29 (s, 1H), 8.06 (d, 2H, J=9.6 Hz), 7.60 (d, 2H, J=9.6 Hz), 7.55 (m, 1H), 7.17 (d, 1H, J=8.0 Hz), 6.08 (s, 1H), 4.58 (m, 2H), 3.89 (s, 3H). Mass spectrum (LCMS, ESI pos.): Calcd for C18H14N8; found: 343.3 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][CH:31]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([C:24]#[C:25][CH2:26][OH:27])[CH:22]=3)[N:17]=[CH:16][N:15]=2)=[CH:9][C:8]=1[Cl:28].C(N(CC)CC)C.[CH3:39][S:40](Cl)(=[O:42])=[O:41]>ClCCl>[CH3:39][S:40]([O:27][CH2:26][C:25]#[C:24][C:21]1[CH:22]=[C:23]2[C:18](=[CH:19][CH:20]=1)[N:17]=[CH:16][N:15]=[C:14]2[NH:13][C:10]1[CH:11]=[CH:12][C:7]([O:6][CH2:5][C:4]2[CH:29]=[CH:30][CH:31]=[C:2]([F:1])[CH:3]=2)=[C:8]([Cl:28])[CH:9]=1)(=[O:42])=[O:41]
Reactant: OCC#Cc1ccc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c2c1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCC#Cc1ccc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c2c1
Temperature: 25 °C
Yield: 43 %

Procedure:
To a solution of 3-(4-(4-(3-fluorobenzyloxy)-3-chlorophenylamino)quinazolin-6-yl)prop-2-yn-1-ol (compound 10.1, 800 mg), triethyl amine (0.4 mL) in dichloromethane (20 mL) at 0° C. was added MsCl (0.16 mL) and the reaction mixture was warmed to room temperature. The reaction was washed with saturated NaHCO3 aqueous solution and extracted with dichloromethane. The combined organic layer and extracts were dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography, eluting with EtOAc to give the desired product. LCMS ESI(+) m/z: 513 (M+1). Yield: 43%.
Reaction SMILES: [C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][C:23](I)=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:26]([O-:29])([O-])=O.[K+].[K+].[S:32]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33]1.C(OCC)(=O)C>C1(OC)C=CC=CC=1.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:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][C:23]([C:26]([C:34]5[CH:35]=[CH:36][S:32][CH:33]=5)=[O:29])=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C([O-])[O-]
Reactant: OB(O)c1ccsc1
Reactant: C[C@H](Nc1nccc(-n2cnc3cc(I)ccc32)n1)c1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [K+]
Solvent: COc1ccccc1
Solvent: CCOC(C)=O
Product: C[C@H](Nc1nccc(-n2cnc3cc(C(=O)c4ccsc4)ccc32)n1)c1ccccc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 10.8 %

Procedure:
A mixture of 2-[(S)-1-phenylethylamino]-4-[5-iodobenzimidazol-1-yl]pyrimidine (EXAMPLE 271) (66 mg), K2CO3 (103 mg), 3-thiopheneboronic acid (58 mg) and Pd(PPh3)2Cl2 (1 mg) in anisole (6 mL) was stirred overnight at 100° C. under 1 Atm CO. The reaction mixture was poured into a separatory funnel containing 100 mL ethyl acetate and was washed with water and brine. The organic extracts were combined, dried over anhydrous MgSO4, filtered and concentrated. The product was purified by silica gel chromatography (eluted with a gradient of 100% CH2Cl2 going to 5% MeOH in CH2Cl2) followed by reverse phase chromatography (eluted with a gradient going from 50% water in methanol (with 0.1% TFA) to 100% methanol (with 0.1% TFA)). The resulting salt was then subjected to preparative thin layer chromatography (eluted with 5% (2N NH3 in MeOH) in CH2Cl2) to give 6.9 mg of the title compound. Mass spectrum (ESI): 426.0 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][C:8](=[O:11])[NH:7][C:6]=2[CH:12]=1.C(N(CC)C(C)C)(C)C.[I-].[Na+].Cl[CH2:25][O:26][CH3:27]>ClCCCl.ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][C:8](=[O:11])[N:7]([CH2:25][O:26][CH3:27])[C:6]=2[CH:12]=1
Reactant: O=C1COc2ccc(Br)cc2N1
Reactant: COCCl
Agent: [I-]
Agent: [Na+]
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCN1C(=O)COc2ccc(Br)cc21
Temperature: 70 °C
Reaction time: 3 h
Yield: 87.7 %

Procedure:
A suspension of 6-bromo-2H-1,4-benzoxazin-3(4H)-one (13 g, 57 mmol) in 1,2-dichloroethane (350 ml) was cooled in an ice bath to which N,N-diisopropylethylamine (119 ml), sodium iodide (10.25 g, 68.4 mmol) and chloromethylmethyl ether (43.3 ml, 570 mmol) were added, and the mixture was stirred at 70° C. for 3 hours. After cooling, the reaction mixture was diluted with dichloromethane, washed with cold water, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform/methanol) to yield 13.6 g (88%) of the title compound in the form of a light brown solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C([Li])CCC.[NH2:13][C:14]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:15]=1[C:16](O)=[O:17].Cl[Si](C)(C)C.Cl>CCOCC.C1COCC1>[NH2:13][C:14]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:15]=1[C:16]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1)=[O:17]
Reactant: Nc1ccc(Cl)cc1C(=O)O
Reactant: Brc1ccccn1
Agent: C[Si](C)(C)Cl
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: Nc1ccc(Cl)cc1C(=O)c1ccccn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 45.1 %

Procedure:
To a solution of 2-bromopyridine (5 ml, 52 mmol) in Et2O (60 ml) was added 40 ml of a n-butyllithium (1.6M in hexane, 64 mmol) drop wise at −40° C. over 30 min under a nitrogen atmosphere. The resulting yellow solution was stirred for a further 1 hr at −50° C. to −30° C. In a separate flask, a solution of 2-amino-5-chlorobenzoic acid (2.05 g, 12 mmol) in dry THF (90 ml), under nitrogen atmosphere and with ice-cooling, was added in one portion to the solution prepared as described above. The reaction mixture was stirred for 2 hrs at 0° C. and then chlorotrimethylsilane (30 ml) was added at 0° C. with stirring. The reaction mixture was allowed to warm to room temperature and 1 N HCl aq (100 ml) was added. The resulting two-phase system was separated. The aqueous phase was adjusted to pH 12 with 6N NaOH solution and extracted with ethyl acetate (2×150 ml). The combined organic extractions were dried over Na2SO4. After removal of solvent, the residue was purified by the flash chromatography using ethyl acetate/hexane (1:4) as eluent. Crystallization of the product from Et2O/hexane mixture gave 1.26 g (45%) of desired product as yellow solid. 1H-NMR (DMSO-d6, 500 MHz): δ 6.90 (1H, d, J=9 Hz), 7.31 (1H, dd, J=9 and 2.5 Hz), 7.40 (2H, br), 7.53 (1H, d, J=2.5 Hz), 7.61 (1H, m), 7.79 (1H, d, J=8 Hz), 8.03 (1H, m), 8.69 (1H, m). MS: (ESI+): 233.2 (M+1).
Reaction SMILES: [N:1]1[C:10]2[C:9](=[O:11])[CH:8]=[CH:7][C:6](=[O:12])[C:5]=2[N:4]=[CH:3][CH:2]=1.[CH2:13]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>O1CCOCC1>[C:14]1([CH2:13][N:20]2[CH2:21][CH2:22][N:23]([C:8]3[C:9](=[O:11])[C:10]4[N:1]=[CH:2][CH:3]=[N:4][C:5]=4[C:6](=[O:12])[CH:7]=3)[CH2:24][CH2:25]2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=C1C=CC(=O)c2nccnc21
Reactant: c1ccc(CN2CCNCC2)cc1
Solvent: C1COCCO1
Product: O=C1C=C(N2CCN(Cc3ccccc3)CC2)C(=O)c2nccnc21
Reaction time: 3 h
Yield: 32.9 %

Procedure:
A mixture of 160 mg of 5,8-quinoxalinedione and 352 mg of 1-benzylpiperazine in 10 ml of dioxane was stirred or 3 hours. The solvent was then removed and the residue triturated with ether. This solid was collected, washed with ether and dried, giving 110 mg of the desired product, mp 165°-168° C. (dec.).
Reaction SMILES: C1(N2C(=O)C3=CNC4C=CC(N5CCNCC5)=NC=4C3=N2)C=CC=CC=1.F[C:28]1[CH:37]=[CH:36][C:35]2[NH:34][CH:33]=[C:32]3[C:38](=[O:47])[N:39]([C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][N:42]=4)[N:40]=[C:31]3[C:30]=2[N:29]=1.[CH3:48][CH:49]1[CH2:54][NH:53][CH2:52][CH2:51][NH:50]1.N1CCNCC1>>[CH3:48][CH:49]1[NH:50][CH2:51][CH2:52][N:53]([C:28]2[CH:37]=[CH:36][C:35]3[NH:34][CH:33]=[C:32]4[C:38](=[O:47])[N:39]([C:41]5[CH:46]=[CH:45][CH:44]=[CH:43][N:42]=5)[N:40]=[C:31]4[C:30]=3[N:29]=2)[CH2:54]1
Reactant: CC1CNCCN1
Reactant: O=c1c2c[nH]c3ccc(F)nc3c-2nn1-c1ccccn1
Agent: C1CNCCN1
Agent: O=c1c2c[nH]c3ccc(N4CCNCC4)nc3c-2nn1-c1ccccc1
Product: CC1CN(c2ccc3[nH]cc4c(=O)n(-c5ccccn5)nc-4c3n2)CCN1

Procedure:
The title compound was prepared following the procedure described for 6a using 5b and 2-methylpiperazine instead of 5a and piperazine respectively. 1H-NMR (DMSO-d6) δ (ppm): 1.07 (3H, d, J=6.87 Hz), 2.78 (3H, m), 3.00 (2H, m), 4.31 (2H, m), 7.14 (2H, m), 7.83 (2H, m), 8.22 (1H, dt, J=7.96, 7.64 Hz), 8.49 (2H, m). m/z 362.4 (MH+).
Reaction SMILES: [C:1]1([CH2:7][C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:10](OC)=[O:11].[H-].[Na+]>>[OH:11][CH:10]=[C:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:8]#[N:9]
Reactant: COC=O
Reactant: N#CCc1ccccc1
Agent: [H-]
Agent: [Na+]
Product: N#CC(=CO)c1ccccc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Phenylacetonitrile (10 g, 85.4 mmol) and methyl formate (67 ml) were dissolved in TIIF (250 ml) in a reaction vessel, and then NaH (2.6 g, 106.7 mmol) was added thereto at 0° C. The solution was stirred at room temperature for 12 hr. After completion of the reaction, the reaction mixture was washed with distilled water and acidified with 1 N HCl to adjust the pH to 5 or less. Thereafter, the resulting solution was extracted with dichloromethane. The organic layer was dried over anhydrous Na2SO4, followed by filtration. The filtrate was concentrated under reduced pressure to give 12.3 g (84.7 mmol, quant.) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]=1[C:13]([OH:15])=[O:14].C(Cl)(=O)C(Cl)=O.[CH:22](O)([CH3:24])[CH3:23].N1C=CC=CC=1>ClCCl.CN(C)C=O>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]=1[C:13]([O:15][CH:22]([CH3:24])[CH3:23])=[O:14]
Reactant: CC(C)O
Reactant: COc1ccc2ccccc2c1C(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccc2ccccc2c1C(=O)OC(C)C
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a solution of 2-methoxynaphthoic acid (458 mg, 2.3 mmol) in dry dichloromethane (9 mL) at 0° C. under a N2 atmosphere was added oxalyl chloride (1.4 mL of a 2M solution in dichloromethane, 2.8 mmol) and 4 drops of N,N-dimethyl formamide. The mixture was stirred at 0° C. for 20 minutes then allowed to warm to room temperature and stirred for one hour. The mixture was concentrated in vacuo. To this dry powder was added isopropanol (9 mL) and pyridine (367 μL, 4.5 mmol), with stirring. After stirring for 2 hours at room temperature, the mixture was concentrated and partitioned between H2O (10 mL) and ethyl acetate (3×10 mL) and the combined organic layers was washed with saturated NaCl (10 mL). The organic layer was dried over Na2SO4, and the crude product was purified by column chromatography on silica gel using 10% ethyl acetate in hexane. The title compound was obtained as a colorless solid (260 mg, 47%).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([O:11][C:12]2[C:17]([CH3:18])=[CH:16][C:15]([CH:19]3[CH2:21][CH2:20]3)=[CH:14][C:13]=2[CH3:22])[C:5]2[NH:10][CH:9]=[CH:8][C:6]=2[N:7]=1.[NH2:23][C:24]1[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][CH:25]=1.C(O)(C(F)(F)F)=O>O>[CH:19]1([C:15]2[CH:16]=[C:17]([CH3:18])[C:12]([O:11][C:4]3[C:5]4[NH:10][CH:9]=[CH:8][C:6]=4[N:7]=[C:2]([NH:23][C:24]4[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][CH:25]=4)[N:3]=3)=[C:13]([CH3:22])[CH:14]=2)[CH2:21][CH2:20]1
Reactant: Cc1cc(C2CC2)cc(C)c1Oc1nc(Cl)nc2cc[nH]c12
Reactant: N#Cc1ccc(N)cc1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C2CC2)cc(C)c1Oc1nc(Nc2ccc(C#N)cc2)nc2cc[nH]c12
Temperature: 90 °C
Reaction time: 16 h
Yield: 41.5 %

Procedure:
In a sealed tube was placed 2-chloro-4-(4-cyclopropyl-2,6-dimethylphenoxy)-5H-pyrrolo[3,2-d]pyrimidine (20 mg, 0.064 mmol), 4-aminobenzonitrile (31 mg, 0.26 mmol), TFE (0.21 mL) and TFA (0.04 mL, 0.51 mmol). The reaction mixture was stirred at 90° C. for 16 h. Upon completion of the reaction, the resulting mixture was diluted with water and washed with EtOAc. The combined organic layers were washed with NaHCO3, brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by preparative TLC TLC, eluting with 5% Acetone/CH2Cl2 to give the product as a light yellow solid (10.5 mg, 45%).
Reaction SMILES: C([O:3][C:4](=[O:29])[CH:5](C(OCC)=O)[CH:6]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH3:23])[CH:15]=1)[CH:7]([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10])C.[OH-].[K+].O.Cl>C(O)C>[CH3:23][O:22][C:16]1[CH:15]=[C:14]([CH:6]([CH:7]([O:8][CH2:9][CH3:10])[O:11][CH2:12][CH3:13])[CH2:5][C:4]([OH:29])=[O:3])[CH:19]=[CH:18][C:17]=1[O:20][CH3:21]
Reactant: CCOC(=O)C(C(=O)OCC)C(c1ccc(OC)c(OC)c1)C(OCC)OCC
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCOC(OCC)C(CC(=O)O)c1ccc(OC)c(OC)c1
Yield: 85.2 %

Procedure:
3-(3,4-dimethoxyphenyl)-4,4-diethoxy-2-ethoxycarbonyl butyric acid ethyl ester (3.07 g, 7.44 mM) and potassium hydroxide (3.41 g) were refluxed in ethanol (40 ml) for 4 hours. To this solution water was poured, acidified with concentrated hydrochloric acid, and extracted with diethylether. The organic extract was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to obtain a brown oil of 3-(3,4-dimethoxyphenyl)-4,4-diethoxy butyric acid (1.98 g). The brown oil (1.98 g) thus obtained and hydrazine hydrate (0.90 ml) were added to a mixture of acetic acid (8.3 ml) and water (6.3 ml), refluxed for 5 hours, poured into an aqueous solution of sodium bicarbonate, extracted with methylene chloride, dried, and the solvent was evaporated under reduced pressure to obtain a yellow solid residue. The residue was purified with flash chromatography (SiO2: eluted with a gradient of 60% ethyl acetate/hexane to 70% ethyl acetate/hexane). The solvent was evaporated under reduced pressure, and the residue was dried to obtain the pale yellow solid of title compound (0.92 g, yield 53.0%).
Reaction SMILES: Cl.[CH:2]([C:5]1[CH:6]=[C:7]([C@@H:11]([NH2:13])[CH3:12])[CH:8]=[CH:9][CH:10]=1)([CH3:4])[CH3:3].[Cl:14][C:15]1[CH:16]=[C:17]([CH:33]=[CH:34][C:35]=1[O:36][C@@H:37]([CH3:42])[C:38]([O:40][CH3:41])=[O:39])[CH2:18][N:19]1[C:27]2[C:22](=[CH:23][C:24]([C:28](O)=[O:29])=[CH:25][CH:26]=2)[C:21]([CH3:31])=[C:20]1[CH3:32]>>[Cl:14][C:15]1[CH:16]=[C:17]([CH2:18][N:19]2[C:27]3[C:22](=[CH:23][C:24]([C:28](=[O:29])[NH:13][C@H:11]([C:7]4[CH:8]=[CH:9][CH:10]=[C:5]([CH:2]([CH3:4])[CH3:3])[CH:6]=4)[CH3:12])=[CH:25][CH:26]=3)[C:21]([CH3:31])=[C:20]2[CH3:32])[CH:33]=[CH:34][C:35]=1[O:36][C@@H:37]([CH3:42])[C:38]([O:40][CH3:41])=[O:39]
Reactant: COC(=O)[C@H](C)Oc1ccc(Cn2c(C)c(C)c3cc(C(=O)O)ccc32)cc1Cl
Reactant: CC(C)c1cccc([C@H](C)N)c1
Agent: Cl
Product: COC(=O)[C@H](C)Oc1ccc(Cn2c(C)c(C)c3cc(C(=O)N[C@@H](C)c4cccc(C(C)C)c4)ccc32)cc1Cl

Procedure:
The title compound was prepared following the same protocol as described in Step 5, Example 36, using the (S)-1-(3-isopropylphenyl)ethanamine hydrochloride instead of the (S)-1-(3-cyclopropylphenyl)ethanamine hydrochloride and the (S)-1-(3-chloro-4-((1-methoxy-1-oxopropan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylic acid instead of the 1-(4-(2-methoxy-2-oxoethoxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylic acid.
Reaction SMILES: [C:1]1([NH:11][CH2:12][C:13]([OH:15])=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[C:16]([O:20][C:21](=[N:35][NH:36][C:37]([NH2:39])=[O:38])[CH2:22][C@H:23]([NH:26][C:27](=[O:34])[C@H:28]([CH2:30][CH:31]([CH3:33])[CH3:32])[NH2:29])[CH:24]=[O:25])([CH3:19])([CH3:18])[CH3:17].O.OC1C2N=NNC=2C=CC=1.Cl.C(N=C=NC(N)CC(C)C)C>CN1CCCC1=O.C(Cl)Cl>[C:16]([O:20][C:21](=[N:35][NH:36][C:37]([NH2:39])=[O:38])[CH2:22][C@H:23]([NH:26][C:27](=[O:34])[C@H:28]([CH2:30][CH:31]([CH3:33])[CH3:32])[NH:29][C:13](=[O:15])[CH2:12][NH:11][C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1)[CH:24]=[O:25])([CH3:18])([CH3:19])[CH3:17]
Reactant: O=C(O)CNc1cccc2ccccc12
Reactant: CC(C)C[C@H](N)C(=O)N[C@H](C=O)CC(=NNC(N)=O)OC(C)(C)C
Agent: CCN=C=NC(N)CC(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CN1CCCC1=O
Solvent: O
Solvent: ClCCl
Product: CC(C)C[C@H](NC(=O)CNc1cccc2ccccc12)C(=O)N[C@H](C=O)CC(=NNC(N)=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 16 h
Yield: 100.4 %

Procedure:
To a solution of (1-naphthylamino)acetic acid (0.076 g, 0.38 mmol) and (3S)-3-(leucinyl)amino-4-oxobutanoic acid tert-butyl ester semicarbazone (see Example 1, Part B, 0.180 g, ca 0.41 mmol) in N-methylpyrrolidone(1.0 mL)-CH2Cl2(1.0 mL) at 0° C. (ice bath) under nitrogen was added hydroxybenzotriazole hydrate (0.075 g) followed by 1-ethyl-3-(3′,3′-dimethyl-1′-aminopropyl)carbodiimide hydrochloride (0.100 g, 0.52 mmol). After stirring at 0° C. for 3 hrs and at room temperature for 16 hrs, the mixture was partitioned between EtOAc-water. The organic phase was washed with water, 5% KHSO4, saturated NaHCO3 and saturated NaCl solutions, dried over anhydrous Na2SO4 and evaporated to dryness. The crude product was purified by flash chromatography eluting with MeOH-CH2Cl2 (1:30 then 1:15) to give the title compound (0.201 g, 100%) as a pale yellow foam. TLC(MeOH-CH2Cl2; 5:95) Rf=0.29.
Reaction SMILES: [CH:1]([C:3]1[NH:7][C:6]([C:8]([O:10][CH3:11])=[O:9])=[CH:5][CH:4]=1)=[CH2:2].[C:12]([NH:18][C:19]1[N:20]=[C:21]([OH:30])[C:22]2[CH:28]=[C:27](Br)[CH:26]=[N:25][C:23]=2[N:24]=1)(=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:12]([NH:18][C:19]1[N:20]=[C:21]([OH:30])[C:22]2[CH:28]=[C:27]([CH:2]=[CH:1][C:3]3[NH:7][C:6]([C:8]([O:10][CH3:11])=[O:9])=[CH:5][CH:4]=3)[CH:26]=[N:25][C:23]=2[N:24]=1)(=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14]
Reactant: C=Cc1ccc(C(=O)OC)[nH]1
Reactant: CC(C)(C)C(=O)Nc1nc(O)c2cc(Br)cnc2n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(C=Cc2cnc3nc(NC(=O)C(C)(C)C)nc(O)c3c2)[nH]1
Temperature: 25 °C
Yield: 89.3 %

Procedure:
A mixture of methyl 5-vinylpyrrole-2-carboxylate (298 mg, 2.0 mmol), 2-pivaloylamino4-hydroxy-6-bromopyrido[2,3-d]pyrimidine (683 mg, 2.1 mmol), palladium acetate (22.5 mg, 0.1 mmol), tri-o-tolylphosphine (60.9 mg, 0.2 mmol), and triethylamine (7.0 mL) in acetonitrile (20 mL) was heated overnight at reflux. The reaction mixture was cooled to room temperature, and the solid which formed collected by filtration, washed with cold acetonitrile, and dried to give methyl 5-[2-(2-pivaloylamino-4-hydroxypyrido[2,3-d]pyrimidin-6-yl)ethenyl]pyrrole-2-carboxylate as a yellow solid (706 mg, 89%). The product can be used in the next step without further purification. An analytical sample, mp >260° C., was obtained by recrystallization from methanol: 1H NMR (DMSO-d6) δ 12.28 (s, 1H), 12.08 (s, 1H), 11.40 (s, 1H), 8.93 (s, 1H), 8.40 (s, 1H), 7.36 (d, 1H, J=16.6 Hz), 7.27 (d, 1H, J=16.6 Hz), 6.81 (m, 1H), 6.48 (m, 1H), 3.76 (s, 3H), 1.23 (s, 9H).
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([SH:20])[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl[C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[C:29]([O:32][CH3:33])[CH:30]=2)[N:25]=[CH:24][N:23]=1>>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20][C:22]3[C:31]4[C:26](=[CH:27][CH:28]=[C:29]([O:32][CH3:33])[CH:30]=4)[N:25]=[CH:24][N:23]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc2ncnc(Cl)c2c1
Reactant: CC(C)(C)c1cc(NC(=O)Nc2cccc(S)c2)no1
Product: COc1ccc2ncnc(Sc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)c2c1

Procedure:
The title compound was prepared from 1-(5-tert-butylisoxazol-3-yl)-3-(3-mercaptophenyl)urea described in Example 44A (87 mg, 0.3 mmol) and 4-chloro-6-methoxyquinazoline (59 mg, 0.3 mmol) as described in Example 46 and its corresponding hydrochloride salt was prepared as described in Example 4B Step 2 to give 1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-methoxyquinazolin-4-ylthio)phenyl)urea as the mono-hydrochloride (76 mg, 0.15 mmol, 50%). 1H NMR (300 MHz, DMSO-d6) δ 9.75 (s, 1H), 9.49 (s, 1H), 8.80 (s, 1H), 7.95 (d, 1H), 7.87 (s, 1H), 7.71 (dd, 1H), 7.55 (d, 1H), 7.49-7.42 (m, 2H), 7.29 (d, 1H), 6.50 (s, 1H), 4.00 (s, 3H), 1.28 (s, 9H); LC-MS (ESI) m/z 450 (M+H)+.