Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH:2]([F:14])[C:3]1[NH:7][C:6]2[CH:8]=[CH:9][CH:10]=[C:11]([O:12][CH3:13])[C:5]=2[N:4]=1.[Cl:15][C:16]1[N:21]=[C:20](Cl)[N:19]=[C:18]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[N:17]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[Cl:15][C:16]1[N:17]=[C:18]([N:23]2[CH2:24][CH2:25][O:26][CH2:27][CH2:28]2)[N:19]=[C:20]([N:7]2[C:6]3[CH:8]=[CH:9][CH:10]=[C:11]([O:12][CH3:13])[C:5]=3[N:4]=[C:3]2[CH:2]([F:1])[F:14])[N:21]=1
Reactant: Clc1nc(Cl)nc(N2CCOCC2)n1
Reactant: COc1cccc2[nH]c(C(F)F)nc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(Cl)nc(N2CCOCC2)n1
Reaction time: 3 h
Yield: 85.9 %

Procedure:
A mixture of 3.96 g (20 mmol) of 2-difluoromethyl-4-methoxy-1H-benzimidazole, 4.70 g (20 mmol) of 2,4-dichloro-6-(4-morpholinyl)-1,3,5-triazine, and 22 g (80 mmol) of powdered K2CO3 in 150 mL of DMF was stirred rapidly for 3 hrs, and then diluted with water. The resulting precipitate was collected, washed with water and then with cold ethanol, and dried to give 6.82 g (86%) of 1-[4-chloro-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-4-methoxy-1H-benzimidazole: mp (CHCl3/EtOH) 263-266° C.; 1H NMR (CDCl3) δ 7.99 (d, J=8.4 Hz, 1H), 7.48 (t, JHF=53.4 Hz, 1H), 7.40 (t, J=8.3 Hz, 1H), 6.86 (d, J=8.1 Hz, 1H), 4.05 (s, 3H), 3.96 (m, 4H), 3.82 (m, 4H); Anal. Calcd. for C16H15ClF2N6O2: C, 48.4; H, 3.8; N, 21.2. Found: C, 48.3; H, 3.8; N, 21.1%.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][CH:10]=1)[NH2:7])([O-:3])=[O:2].C(N(CC)CC)C.[CH:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][C:19]=1[C:28](Cl)=[O:29].C(=O)(O)[O-].[Na+]>O1CCOCC1>[N+:1]([C:4]1[CH:5]=[C:6]([NH:7][C:28]([C:19]2[CH:20]=[CH:21][C:22]3[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:18]=2)=[O:29])[CH:8]=[CH:9][CH:10]=1)([O-:3])=[O:2]
Reactant: Nc1cccc([N+](=O)[O-])c1
Reactant: O=C(Cl)c1ccc2ccccc2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: O=C(Nc1cccc([N+](=O)[O-])c1)c1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68.9 %

Procedure:
To a mixture of 3-nitroaniline (2.07 g) and triethylamine (2.3 ml) in 1,4-dioxane (40 ml) was added 2-naphthoyl chloride (3.00 g) and the mixture was stirred at room temperature for 30 minutes. Then the mixture was poured into aqueous sodium bicarbonate and extracted with ethyl acetate three times. The combined organic phase was washed with aqueous sodium bicarbonate and brine, dried over magnesium sulfate and concentrated. The resultant solid was collected and washed with isopropyl ether to give N-(3-nitrophenyl)-2-naphthalenecarboxamide (3.02 g).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([CH3:30])[C:8]([CH:19]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C:20]([O:22]CC)=[O:21])=[C:9]2[C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.[C:31]([C:33]1([NH2:39])[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1)#[CH:32]>>[NH2:39][C:33]1([C:31]#[C:32][C:2]2[CH:11]=[C:10]3[C:5]([CH:6]=[C:7]([CH3:30])[C:8]([CH:19]([O:25][C:26]([CH3:28])([CH3:29])[CH3:27])[C:20]([OH:22])=[O:21])=[C:9]3[C:12]3[CH:13]=[CH:14][C:15]([Cl:18])=[CH:16][CH:17]=3)=[CH:4][CH:3]=2)[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1
Reactant: C#CC1(N)CCCCC1
Reactant: CCOC(=O)C(OC(C)(C)C)c1c(C)cc2ccc(Br)cc2c1-c1ccc(Cl)cc1
Product: Cc1cc2ccc(C#CC3(N)CCCCC3)cc2c(-c2ccc(Cl)cc2)c1C(OC(C)(C)C)C(=O)O

Procedure:
2-(7-((1-Aminocyclohexyl)ethynyl)-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyacetic acid (84) was prepared by the method of Example 67 from ethyl 2-(7-bromo-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyacetate using 1-ethynylcyclohexanamine. 1H-NMR: 400 MHz, (CD3OD) δ: 7.82 (d, J=8 Hz, 1H), 7.72 (s, 1H), 7.56 (m, 3H), 7.47 (d, J=8 Hz, 1H), 7.37 (s, 1H), 7.31 (d, J=8 Hz, 1H), 5.20 (s, 1H), 2.60 (s, 3H), 2.11 (m, 2H), 1.63-1.85 (m, 8H), 0.99 (s, 9H). LCMS-ESI+ (m/z): [M—NH2]+ calcd for C31H32ClO3: 487.2; found: 487.2.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9](Br)[C:8]([N+:12]([O-])=O)=[CH:7][C:6]=1[OH:15])([CH3:4])([CH3:3])[CH3:2].[CH3:16][O:17][C:18]([C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1)=[O:19]>CC#N>[C:1]([C:5]1[CH:10]=[C:9]([C:24]2[CH:23]=[CH:22][CH:21]=[C:20]([C:18]([O:17][CH3:16])=[O:19])[CH:25]=2)[C:8]([NH2:12])=[CH:7][C:6]=1[OH:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)c1cccc(B(O)O)c1
Reactant: CC(C)(C)c1cc(Br)c([N+](=O)[O-])cc1O
Solvent: CC#N
Product: COC(=O)c1cccc(-c2cc(C(C)(C)C)c(O)cc2N)c1

Procedure:
2-tert-Butyl-4-(3-methoxycarbonylphenyl)-5-aminophenol (C-17) was synthesized following the general scheme above starting from 2-tert-butyl-4-bromo-5-nitrophenol (C-14-a) and 3-(methoxycarbonyl)phenylboronic acid. HPLC ret. time 2.70 min, 10-99% CH3CN, 5 min run; ESI-MS 300.5 m/z (MH+).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:5]=[C:6](Br)[CH:7]=[C:8]([CH2:10][O:11][CH3:12])[CH:9]=1.[Mg].CN(C)[CH:17]=[O:18]>O1CCCC1>[CH3:1][O:2][CH2:3][C:4]1[CH:5]=[C:6]([CH:7]=[C:8]([CH2:10][O:11][CH3:12])[CH:9]=1)[CH:17]=[O:18]
Reactant: COCc1cc(Br)cc(COC)c1
Reactant: CN(C)C=O
Agent: [Mg]
Solvent: C1CCOC1
Product: COCc1cc(C=O)cc(COC)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 79 %

Procedure:
Grignard solution was prepared from 13.4 g (54.7 mmol) of 3,5-bis(methoxymethyl)bromobenzene, 3.25 g (134 mmol) of magnesium, and 60 ml of tetrahydrofuran (hereinafter abbreviated as “THF”) in a reaction vessel of 200 ml. Subsequently, 30 ml (387 mmol) of dimethylformamide (DMF) was added dropwise into this solution at 0° C. and further agitated at room temperature for 3 hours after completion of the addition. Solvent was removed from the obtained reaction liquid by reduced pressure and 2N hydrochloric acid was added. The obtained reaction mixture was extracted 3 times with 50 ml of diethyl ether and the organic layer was collected and dried with anhydrous magnesium sulfate after rinsing with water. Residues obtained by the removal of solvent were purified by silica gel column chromatography to obtain 8.36 g (43.0 mmol) of the target 3,5-bis(methoxymethyl)benzaldehyde as a viscous liquid.
Reaction SMILES: C[O:2][C:3](=[O:27])[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([F:14])=[CH:11][CH:12]=2)[C:7]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[S:22](Cl)(=[O:24])=[O:23])=[C:6]1[CH3:26].[OH-].[Na+].Cl>O1CCCC1>[F:14][C:10]1[CH:9]=[C:8]2[C:13](=[CH:12][CH:11]=1)[N:5]([CH2:4][C:3]([OH:2])=[O:27])[C:6]([CH3:26])=[C:7]2[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[S:22](=[O:24])(=[O:23])[NH:5][C:13]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: COC(=O)Cn1c(C)c(Cc2ccccc2S(=O)(=O)Cl)c2cc(F)ccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1c(Cc2ccccc2S(=O)(=O)Nc2ccccc2)c2cc(F)ccc2n1CC(=O)O
Temperature: 25 °C
Reaction time: 20 h
Yield: 127.7 %

Procedure:
A mixture of [3-(2-chlorosulfonylbenzyl)-5-fluoro-2-methylindol-1-yl]acetic acid methyl ester (0.078 g) and tetrahydrofuran (0.5 mL) was treated with 2.0 M aqueous sodium hydroxide solution (1.0 mL), and the resulting mixture was stirred at room temperature for 20 hours. The mixture was acidified by the addition of 2.0 M aqueous hydrochloric acid solution and concentrated under reduced pressure. The residue was purified by preparative reverse-phase HPLC, eluting with a mixture of acetonitrile and water (2:3 to 19:1 by volume) to afford the title compound as a white solid (0.055 g).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH2:7])[NH:5][N:6]=1.C([O:10][C:11](=O)[CH2:12][C:13](=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)C>CC(O)=O>[CH3:1][C:2]1[CH:3]=[C:4]2[NH:7][C:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:12][C:11](=[O:10])[N:5]2[N:6]=1
Reactant: Cc1cc(N)[nH]n1
Reactant: CCOC(=O)CC(=O)c1ccccc1
Solvent: CC(=O)O
Product: Cc1cc2[nH]c(-c3ccccc3)cc(=O)n2n1
Temperature: 25 °C

Procedure:
(prepared in a procedure analogous to that outlined in WO 2004/026229 A2) Step A: 5-Methyl-2H-pyrazol-3-ylamine (1 g, 0.0103 mol) was suspended in AcOH (7 ml), 3-oxo-3-phenylpropionic acid ethyl ester (1.95 ml, 1.1 eq) was added and the mixture heated at reflux for 3 h. The mixture was cooled to rt and concentrated under reduced pressure. The residue was stirred with EtOAc and the solid collected by filtration to give 1.83 g of 2-methyl-5-phenyl-4H-pyrazolo[1,5-a]pyrimidin-7-one. Step B: The product of step A (1.83 g) was dissolved in POCl3 (8.6 ml), pyridine (0.43 ml) was added and the mixture stirred for 3 days at rt. The resulting dark solution was diluted with Et2O and filtered. The filtrate was cooled to 0° C. and quenched with water; once the quench was complete, additional water was added and the organic layer removed. The aqueous layer was further extracted with Et2O, the combined organic layers were washed with NaHCO3 (sat), dried (Na2SO4), and concentrated under reduced pressure to give 1.92 g of 7-chloro-2-methyl-5-phenylpyrazolo[1,5-a]pyrimidine which was used without further purification. LCMS: MH+=244.1.
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[NH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19]>>[CH3:7][N:6]1[C:2]([NH:11][CH2:12][CH2:13][CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:20])([CH3:19])[CH3:21])=[C:3]([N+:8]([O-:10])=[O:9])[CH:4]=[N:5]1
Reactant: Cn1ncc([N+](=O)[O-])c1Cl
Reactant: CC(C)(C)OC(=O)NCCCN
Product: Cn1ncc([N+](=O)[O-])c1NCCCNC(=O)OC(C)(C)C
Yield: 85 %

Procedure:
Following Example 58, reaction of 5-chloro-1-methyl-4-nitro-1H-pyrazole and tert-butyl 3-aminopropylcarbamate gave tert-butyl 3-(1-methyl-4-nitro-1H-pyrazol-5-ylamino)propylcarbamate as a pale yellow gum (1.27 g, 85%). 1H NMR (400 MHz, CDCl3) δ 7.88 (s, 1H), 6.75 (s br, 1H), 4.67 (s br, 1H), 3.84 (s, 3H), 3.54 (q, J=6.6 Hz, 2H), 3.27 (q, J=6.6 Hz, 2H), 1.90-1.79 (m, 2H), 1.44 (s, 9H)
Reaction SMILES: O[C:2]1[C:11](C(O)=O)=[CH:10][C:9]2[C:4](=CC=CC=2)[C:3]=1[C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)C=C(C(O)=O)C=1O.C1([Li])C=CC=CC=1.[OH2:36].Cl>O1CCCC1>[C:3]1([C:15]([C:24]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[O:36])[CH:4]=[CH:9][CH:10]=[CH:11][CH:2]=1
Reactant: O
Reactant: O=C(O)c1cc2ccccc2c(-c2c(O)c(C(=O)O)cc3ccccc23)c1O
Agent: Cl
Agent: [Li]c1ccccc1
Solvent: C1CCOC1
Product: O=C(c1ccccc1)c1ccccc1
Temperature: -78 °C

Procedure:
With stirring under dry nitrogen, 2,2′-dihydroxy-1,1′-binaphthalene-3,3′-dicarboxylic acid (8.42 g, 22.5 mmol) was dissolved in dry tetrahydrofuran (500 mL) then cooled to −78° C. with a dry ice/acetone bath. Phenyllithium (100 mL of 1.8 M in 70/30 cyclohexane/ether, 0.18 mol) was added dropwise, then the solution was allowed to warm to ambient temperature. After stirring overnight, deionized water (50 mL) was slowly added to the reaction solution at 0° C. With vigorous stirring, 1 M hydrochloric acid was added dropwise until the water phase became strongly acidic (pH=2). The organic phase was washed with water in a separatory funnel, then dried over magnesium sulfate and evaporated. The orange residue was redissolved in dichloromethane and eluted through a silica gel plug. The orange filtrate was evaporated to yield 2,2′-dihydroxy-1,1′-binaphthalene-3,3′-bis (phenylketone) as a yellow solid (10.5 gm).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[C:11](=[O:15])[N:10]([C:16]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]3[CH:29]=[C:28]([NH:30][C:31]4[CH:36]=[CH:35][C:34]([C:37]([N:39]5[CH2:44][CH2:43][O:42][CH2:41][CH2:40]5)=[O:38])=[CH:33][N:32]=4)[C:27](=[O:45])[N:26]([CH3:46])[CH:25]=3)[C:17]=1[CH:18]=[O:19])[N:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].C(Cl)Cl.[BH4-].[Na+]>CO>[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[C:11](=[O:15])[N:10]([C:16]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]3[CH:29]=[C:28]([NH:30][C:31]4[CH:36]=[CH:35][C:34]([C:37]([N:39]5[CH2:40][CH2:41][O:42][CH2:43][CH2:44]5)=[O:38])=[CH:33][N:32]=4)[C:27](=[O:45])[N:26]([CH3:46])[CH:25]=3)[C:17]=1[CH2:18][OH:19])[N:9]=[CH:8]2)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cn1cc(-c2cccc(-n3ncc4cc(C(C)(C)C)ccc4c3=O)c2C=O)cc(Nc2ccc(C(=O)N3CCOCC3)cn2)c1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: Cn1cc(-c2cccc(-n3ncc4cc(C(C)(C)C)ccc4c3=O)c2CO)cc(Nc2ccc(C(=O)N3CCOCC3)cn2)c1=O
Yield: 76.5 %

Procedure:
121 mg (0.20 mmol) of 2-(6-tert-butyl-1-oxo-1H-phthalazin-2-yl)-6-{1-methyl-5-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridin-3-yl}-benzaldehyde was weighed into a 20 mL reaction vial fitted with a stir bar and septum. Added 4 mL of CH2Cl2 and 2 mL MeOH and stirred to obtain a clear amber solution. Added 1.1 mL (0.29 mmol) of a freshly prepared 10 mg/mL solution of sodium borohydride in MeOH. Stirred at room temperature for 3 hr. Quenched the reaction with 5 mL of saturated aqueous NH4Cl. Added 5 mL of CH2Cl2 to the reaction mixture and separated phases. Washed the organic phase with 5 mL brine, dried over Na2SO4, and removed the solvent on rotavap. Added 2 mL acetonitrile to the residue and immersed the vial in an ultrasonic bath. The residue dissolved momentarily, then a white precipitate rapidly crystallized out of solution. Added 5 mL Et2O to the mixture and collected the precipitate by filtration. Dried under high vacuum to obtain 95 mg of the title compound as an off-white solid. MS (ESI) 621 (M+H)+.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:20]([NH:21][C:22]3[CH:23]=[CH:24][CH:25]=[C:26]([C:28]#[CH:29])[CH:27]=3)=[N:19][CH:18]=[N:17][C:9]2=[CH:10][C:11]=1[O:12][CH2:13][CH2:14][O:15][CH3:16].N#N.C(Cl)[Cl:33]>C(#N)C>[C:28]([C:26]1[CH:27]=[C:22]([NH:21][C:20]2[C:8]3[C:9](=[CH:10][C:11]([O:12][CH2:13][CH2:14][O:15][CH3:16])=[C:6]([O:5][CH2:4][CH2:3][O:2][CH3:1])[CH:7]=3)[N:17]=[CH:18][N:19]=2)[CH:23]=[CH:24][C:25]=1[Cl:33])#[CH:29]
Reactant: C#Cc1cccc(Nc2ncnc3cc(OCCOC)c(OCCOC)cc23)c1
Reactant: ClCCl
Agent: N#N
Solvent: CC#N
Product: C#Cc1cc(Nc2ncnc3cc(OCCOC)c(OCCOC)cc23)ccc1Cl
Reaction time: 0.5 h

Procedure:
300 mg erlotinib was dissolved in 200 mL CH2Cl2 at −78° C. cooled by dry-ice/acetone bath. A mixture of F2 and N2 gas containing 20% F2/80% N2 was passed through the reaction vessel continuously at a flow rate of 2 L/min. Reaction was stopped after 30 min and the solvent was removed under vacuum. Dried reaction products were dissolved in 3 mL acetonitrile and was separated on an Agilent Zorbax C8 250×4.6 mm column, gradient elution from 30% MeOH/70% 0.1% formic acid in dd-H2O to 90% MeOH/10% 0.1% formic acid in dd-H2O, 1 ml/min total flow rate. Each fraction was analyzed by mass spectrometry. Fractions containing reaction products without excess amount of the starting material erlotinib, were mixed to form the modified erlotinib mixture compound library for drug property screening to identify components with improved properties over erlotinib. A component with m/z value corresponding to mono-chlorinated erlotinib was isolated and purified by successive preparative HPLC separations. The purified compound was analyzed by LC-MS/MS and NMR to provide the structure of the title compound. The observed m/z value 428.1374 (Thermo Finnigan LTQ Orbitrap, positive ion mode), is consistent with calculated m/z of protonated mono-chlorinated erlotinib (m/z(calc)=428.1372), molecular formula: C22H23ClN3O4+. High resolution MSn (n=2-4) experiments on LTQ orbitrap indicate the fluorine substitution is on the 3-ethynylphenyl ring (or ethynyl group) of erlotinib (fragment at m/z 152.0259, calc: 152.0261 for C8H7ClN+). 1H-NMR spectra data indicate the chlorine substitution is at the 4-position of the 3-ethynylphenyl ring of erlotinib. 1H-NMR (400 MHz, DMSO-d6) δ ppm 3.36 (s, 6H), 3.78 (m, 4H), 4.36 (m, 4H), 4.68 (s, 1H), 7.39 (s, 1H), 7.66 (d, J=8.8, 1H), 7.86 (dd, J=8.8, 2.4, 1H), 8.06 (d, J=2.4, 1H), 8.46, (s, 1H), 8.89 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.[C:10](#[N:14])[CH2:11][C:12]#[N:13].N1CCCCC1>O1CCOCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:11]([C:10]#[N:14])[C:12]#[N:13])[CH:7]=[CH:8][CH:9]=1
Reactant: O=Cc1cccc(Br)c1
Reactant: N#CCC#N
Solvent: C1COCCO1
Solvent: C1CCNCC1
Product: N#CC(C#N)=Cc1cccc(Br)c1

Procedure:
In this situation the aldehyde, such as 3-bromobenzaldehyde as a representative example, is reacted with malononitrile in the presence of catalytic piperidine in a solvent such as dioxane to afford the 2-[(3-bromophenyl)methylene]malononitrile. Epoxide formation proceeds readily with commercial bleach at a pH of 5 to 6. Treatment with hydrobromic acid in methanol then affords the required methyl 2-bromo-2-(3-bromophenyl)acetate. Similarly prepared was methyl 2-bromo-2-(3-cyanophenyl)acetate
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([C:9]([O-:11])=[O:10])[C:6]([I:12])=[C:5]([O:13][CH3:14])[N:4]=1.[OH-].[Na+]>CO.O>[CH3:1][O:2][C:3]1[N:8]=[C:7]([C:9]([OH:11])=[O:10])[C:6]([I:12])=[C:5]([O:13][CH3:14])[N:4]=1
Reactant: COc1nc(OC)c(I)c(C(=O)[O-])n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1nc(OC)c(I)c(C(=O)O)n1
Reaction time: 8 h

Procedure:
18.0 g of methyl, 2,6-dimethoxy-5-iodopyrimidine-4-carboxylate are introduced in portions into a stirred solution of 2.4 g of sodium hydroxide in 70 ml of methanol and 4 ml of water. Stirring is allowed to continue overnight at room temperature, the methanol is distilled off and the residue is taken up in water. The aqueous phase is extracted using ethyl acetate, acidified to pH 2-3 using conc. hydrochloric acid and extracted using dichloromethane. The combined dichloromethane extracts are dried over sodium sulfate and the solvent is distilled off in vacuo. 10.1 g of 2,6-dimethoxy-5-iodopyrimidine-4-carboxylic acid of melting point 125°-126° C. are obtained in this way.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:7]=[C:8]([CH:13]=[CH:14][CH:15]=1)[C:9]([O:11][CH3:12])=[O:10])=[O:4].Cl.[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH:30]=[CH:31][C:32]=1[O:33][CH3:34])[C:22]([N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)=[O:23].C(N(CC)CC)C>C(#N)C>[CH3:12][O:11][C:9]([C:8]1[CH:7]=[C:6]([CH:15]=[CH:14][CH:13]=1)[NH:5][C:3](=[O:4])[CH2:2][N:27]1[CH2:28][CH2:29][N:24]([C:22](=[O:23])[C:21]2[CH:30]=[CH:31][C:32]([O:33][CH3:34])=[C:19]([O:18][CH3:17])[CH:20]=2)[CH2:25][CH2:26]1)=[O:10]
Reactant: COc1ccc(C(=O)N2CCNCC2)cc1OC
Reactant: COC(=O)c1cccc(NC(=O)CCl)c1
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)c1cccc(NC(=O)CN2CCN(C(=O)c3ccc(OC)c(OC)c3)CC2)c1

Procedure:
5 Grams of methyl m-(α-chloroacetylamino)benzoate, 7.56 g of N-(3,4-dimethoxybenzoyl)piperazine monohydrochloride, 7.76 g of triethylamine and 30 ml of acetonitrile were mixed together and reacted at 45° to 50° C. for 5 hours. After completion of the reaction, the reaction mixture was ice-cooled, and the crystals formed were removed by filtration. The mother liquor was concentrated to dryness, and extracted by adding 1 N-sodium hydroxide aqueous solution and chloroform. The chloroform layer was washed with water, dried and removed by distillation. The oily substance obtained was purified by a silica gel column chromatography to obtain 10.08 g of m-methoxycarbonyl-α-[4-(3,4-dimethoxybenzoyl)-1-piperazinyl]acetanilide in the form of colorless oily substance.
Reaction SMILES: [Na].[NH2:2][C:3]1[N:8]=[C:7]([NH2:9])[C:6](I)=[C:5]([CH3:11])[N:4]=1.[CH3:12][C:13]([C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=1)([CH3:19])/[CH:14]=[CH:15]/B(O)O>C(O)C>[NH2:2][C:3]1[N:8]=[C:7]([NH2:9])[C:6](/[CH:15]=[CH:14]/[C:13]([C:20]2[CH:21]=[CH:22][C:23]([C:26]([F:27])([F:29])[F:28])=[CH:24][CH:25]=2)([CH3:12])[CH3:19])=[C:5]([CH3:11])[N:4]=1
Reactant: CC(C)(/C=C/B(O)O)c1ccc(C(F)(F)F)cc1
Reactant: Cc1nc(N)nc(N)c1I
Agent: [Na]
Solvent: CCO
Product: Cc1nc(N)nc(N)c1/C=C/C(C)(C)c1ccc(C(F)(F)F)cc1
Temperature: 80 °C
Reaction time: 28 h
Yield: 56.5 %

Procedure:
Sodium metal, 4.1 grams (0.18 mole), was stirred with 250 mL of ethanol for 30 minutes. After this time 20.0 grams (0.08 mole) of 2,4-diamino-5-iodo-6-methylpyrimidine (prepared in Step B of Example 3), 27.6 grams (0.11 mole) of trans-3-methyl-3-(4-trifluoromethylphenyl)-1-butenylboronic acid, and 9.2 grams (0.008 mole) of tetrakistriphenylphosphine palladium(0) were added. The reaction miXture was purged with nitrogen, and then heated to 80° C. where it stirred for about 28 hours. After this time the reaction mixture was concentrated under reduced pressure to about 20% of the original volume and then poured into 300 mL of water. The mixture was cooled in an ice-bath, and a solid was collected by filtration. The solid was triturated with a mixture of 1:1 petroleum ether:diethyl ether, and then subjected to column chromatography on silica gel using 5% methanol in methylene chloride as the eluant. The product-containing fractions were combined and concentrated under reduced pressure to a solid residue. The solid was recrystallized from 1-propanol and water, yielding 15.2 grams of trans-2,4-diamino-6-methyl-5-[3-(4-trifluoromethylphenyl)-3-methyl-1-butenyl]pyrimidine, mpt 82°-185° C. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[F:11][C:12]([F:16])([F:15])[CH2:13][OH:14].[OH-].[Li+].CS(C)=O>O>[F:11][C:12]([F:16])([F:15])[CH2:13][O:14][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: OCC(F)(F)F
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ccc(OCC(F)(F)F)nc1

Procedure:
2-Chloro-5-nitropyridine (9.5 grams), 2,2,2-trifluoroethanol (6.0 grams), and lithium hydroxide (4.0 grams) were mixed in 50 ml. of DMSO and stirred overnight (about 18 hours) at room temperature. The reaction mixture was then poured into water and the product was separated by filtration. It was crystallized from ethyl acetate-hexanes, yield 5.0 grams, m.p., 35°-37° C.
Reaction SMILES: [N:1]1([C:7]2[C:8]3[S:28][C:27]([CH2:29][N:30]4[CH2:35][CH2:34][N:33]([C:36]([CH3:41])([CH3:40])[C:37]([NH2:39])=[O:38])[CH2:32][CH2:31]4)=[CH:26][C:9]=3[N:10]=[C:11]([Sn](CCCC)(CCCC)CCCC)[N:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Br[C:43]1[CH:48]=[N:47][CH:46]=[C:45]2[NH:49][CH:50]=[CH:51][C:44]=12>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.[Cu]I>[CH3:40][C:36]([N:33]1[CH2:32][CH2:31][N:30]([CH2:29][C:27]2[S:28][C:8]3[C:7]([N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)=[N:12][C:11]([C:43]4[CH:48]=[N:47][CH:46]=[C:45]5[NH:49][CH:50]=[CH:51][C:44]=45)=[N:10][C:9]=3[CH:26]=2)[CH2:35][CH2:34]1)([CH3:41])[C:37]([NH2:39])=[O:38]
Reactant: Brc1cncc2[nH]ccc12
Reactant: CCCC[Sn](CCCC)(CCCC)c1nc(N2CCOCC2)c2sc(CN3CCN(C(C)(C)C(N)=O)CC3)cc2n1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: CC(C)(C(N)=O)N1CCN(Cc2cc3nc(-c4cncc5[nH]ccc45)nc(N4CCOCC4)c3s2)CC1
Temperature: 140 °C
Yield: 27.5 %

Procedure:
A mixture of 2-[4-(4-morpholin-4-yl-2-(tributlystannanyl)thieno[3,2-d]pyrimidin-6-ylmethyl)piperazin-1-yl]isobutyramide (1.17 g, 1.69 mmol), 4-bromo-1H-pyrrolo[2,3-c]pyridine (432 mg, 2.19 mmol), tetrakis(triphenylphosphine)palladium (194 mg, 10 mol %) and CuI (385 mg, 2.02 mmol) in dioxane (20 mL) was purged with argon gas then heated at 140° C., for 20 min, in a microwave reactor. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge, washed with MeOH/DCM then eluted with 2 M NH3 in MeOH/DCM. The resulting residue was purified by column chromatography (Si—PPC, MeOH:DCM, gradient 0:100 to 20:80). The resulting solid was dissolved in MeOH, loaded onto an Isolute® SCX-2 cartridge, washed with MeOH then eluted with 2 M NH3 in MeOH to afford 105 as a pale yellow solid (242 mg, 39%). LCMS (Method F): RT 4.51 min, [M+H]+ 521.2. 1H NMR (DMSO, 400 MHz): δ 11.75 (s, 1H); 9.13 (s, 1 H); 8.81 (s, 1 H); 7.71 (t, J=2.7 Hz, 1 H); 7.45 (s, 1 H); 7.40-7.37 (m, 1 H); 7.07 (d, J=3.5 Hz, 1 H); 6.95 (d, J=3.5 Hz, 1 H); 4.01 (t, J=4.6 Hz, 4 H); 3.87 (s, 2 H); 3.83 (t, J=4.6 Hz, 4 H); 2.58 (s, 4 H); 2.49 (s, 4 H); 1.10 (s, 6 H)