Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:11][CH2:12][CH3:13])[C:9]=1[OH:10])[CH:5]=[O:6].[H-].[Na+].[CH2:16](Cl)[O:17][CH3:18].CCOC(C)=O>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:11][CH2:12][CH3:13])[C:9]=1[O:10][CH2:16][O:17][CH3:18])[CH:5]=[O:6]
Reactant: COCCl
Reactant: CCOc1cc(C=O)cc(Br)c1O
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOc1cc(C=O)cc(Br)c1OCOC
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 59.1 %

Procedure:
A solution of 3-bromo-5-ethoxy-4-hydroxybenzaldehyde (1.0 g, 4.1 mmol) in DMF (10 mL) was cooled at 0° C., NaH (180 mg, 4.5 mmol) was added, and the mixture was stirred for 15 minutes. MOM-Cl (360 mg, 4.5 mmol) was added, and the mixture was warmed to room temperature in two hours. TLC (PE:EtOAc=5:1) indicated that the starting material was consumed. Ice water was added to quench the reaction, and aqueous layer was extracted with EtOAc (30 mL×3). The combined organic layer was washed with brine (20 mL), dried over Na2SO4, filtered, concentrated, and purified by column chromatograph to give 3-bromo-5-ethoxy-4-(methoxymethoxy)benzaldehyde (0.7 g, yield: 59.3%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:28][CH2:29][N:30]3[CH2:35][CH2:34][C:33]([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)([C:36]([OH:38])=O)[CH2:32][CH2:31]3)[CH2:13][CH2:12][N:11]([C:14](=[O:27])[C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[O:46]1[CH2:51][CH2:50][N:49]([CH2:52][CH2:53][NH:54]C(C2(C3C=CC=CC=3)CCNCC2)=O)[CH2:48][CH2:47]1>CO.ClCCl>[ClH:1].[O:46]1[CH2:51][CH2:50][N:49]([CH2:52][CH2:53][NH:54][C:36]([C:33]2([C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=3)[CH2:32][CH2:31][N:30]([CH2:29][CH2:28][C:9]3([C:4]4[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=4)[CH2:13][CH2:12][N:11]([C:14](=[O:27])[C:15]4[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=4)[CH2:10]3)[CH2:35][CH2:34]2)=[O:38])[CH2:48][CH2:47]1
Reactant: COc1cc(C(=O)N2CCC(CCN3CCC(C(=O)O)(c4ccccc4)CC3)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC
Reactant: O=C(NCCN1CCOCC1)C1(c2ccccc2)CCNCC1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: COc1cc(C(=O)N2CCC(CCN3CCC(C(=O)NCCN4CCOCC4)(c4ccccc4)CC3)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC

Procedure:
Prepare by the method of Example 26FH.5 using 1-[2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylic acid (0.16 g, 0.625 mmol) and 4-phenyl-piperidine-4-carboxylic acid (2-morpholino-ethyl)-amide hydrochloride (0.07 mL, 0.5 mmol). Chromatograph on silica gel eluting with 6% methanol/dichloromethane to give the title compound: Rf =0.34 (silica gel, 10% methanol/dichloromethane). Exact mass (FAB+): calculated for C40H51Cl2N4O6 calculated 753.3191. Found 753.3186.
Reaction SMILES: Cl.[CH3:2][C@H:3]1[O:8][CH2:7][CH2:6][NH:5][CH2:4]1.C(N(C(C)C)C(C)C)C.[Br:18][C:19]1[CH:20]=[C:21]([C:35]([O:37][CH3:38])=[O:36])[CH:22]=[C:23]2[C:28]=1[O:27][C:26](S(CC)(=O)=O)=[CH:25][C:24]2=[O:34]>C(Cl)Cl>[Br:18][C:19]1[CH:20]=[C:21]([C:35]([O:37][CH3:38])=[O:36])[CH:22]=[C:23]2[C:28]=1[O:27][C:26]([N:5]1[CH2:6][CH2:7][O:8][C@H:3]([CH3:2])[CH2:4]1)=[CH:25][C:24]2=[O:34]
Reactant: C[C@@H]1CNCCO1
Reactant: CCS(=O)(=O)c1cc(=O)c2cc(C(=O)OC)cc(Br)c2o1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)c1cc(Br)c2oc(N3CCO[C@H](C)C3)cc(=O)c2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 87.6 %

Procedure:
A mixture of (R)-2-methylmorpholine hydrochloride (0.436 g, 3.17 mmol) and N-ethyl-N-isopropylpropan-2-amine (1.184 mL, 6.80 mmol) in DCM (5 mL) was added dropwise to a stirred solution of methyl 8-bromo-2-(ethylsulfonyl)-4-oxo-4H-chromene-6-carboxylate (0.85 g, 2.27 mmol) in DCM (10 mL) at 10° C. under argon. The resulting solution was stirred at RT for 3 hrs. The reaction mixture was quenched with 1M HCl, the phases were separated, the organic phase was washed with brine dried over magnesium sulfate and concentrated to afford the crude product which was purified by flash chromatography on silica gel eluting with 0 to 10% MeOH in DCM. The solvent was evaporated to dryness to afford after a trituration with ether, methyl 8-bromo-2-((R)-2-methylmorpholino)-4-oxo-4H-chromene-6-carboxylate (0.760 g, 88%) as a pale yellow foam. Mass Spectrum: M+H+ 382. The reaction was repeated on a similar scale before proceeding to the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:30])[N:19]([C@@H:23]5[CH2:28][CH2:27][NH:26][CH2:25][C@H:24]5[F:29])[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:33]([F:36])([F:35])[F:34])[CH:3]=1.[CH3:37][C:38]([CH3:40])=O>>[Cl:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:30])[N:19]([C@@H:23]5[CH2:28][CH2:27][N:26]([CH:38]([CH3:40])[CH3:37])[CH2:25][C@H:24]5[F:29])[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:33]([F:36])([F:35])[F:34])[CH:3]=1
Reactant: O=C1S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C(=O)N1[C@@H]1CCNC[C@H]1F
Reactant: CC(C)=O
Product: CC(C)N1CC[C@@H](N2C(=O)S/C(=C\c3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)C2=O)[C@H](F)C1

Procedure:
(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-[(3R,4R)-3-fluoro-1-(1-methylethyl)piperidin-4-yl]-1,3-thiazolidine-2,4-dione was prepared from (5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-[(3R,4R)-3-fluoropiperidin-4-yl]-1,3-thiazolidine-2,4-dione (Example 381) and acetone (in place of formaldehyde) following General Procedure R2.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].Br[C:15]([CH3:22])([CH3:21])[C:16]([O:18][CH2:19][CH3:20])=[O:17]>>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:15]([CH3:22])([CH3:21])[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(C)(C)Br
Reactant: Nc1ccc(Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Product: CCOC(=O)C(C)(C)Nc1ccc(Cl)cc1
Temperature: 140 °C
Yield: 31.6 %

Procedure:
A mixture of 4-chloroaniline (2 g, 15.7 mmol), sodium bicarbonate (1.58 g, 18.8 mmol) and ethyl 2-bromo-2-methylpropanoate (6.12 g, 31.4 mmol) was heated at 140° C. in microwave reactor for 2 h. The reaction was cooled to rt and filtered. The filtrate was concentrated and purified by flash column chromatography using 0-40% EtOAc in heptanes as eluent. The product containing fractions were collected, concentrated, and dried under high vacuum overnight to give ethyl 2-(4-chlorophenylamino)-2-methylpropanoate (1.2 g, 32% yield) as an brown oil.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.[CH2:11]([O:13][C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[C:16]([N+:21]([O-:23])=[O:22])[CH:15]=1)[CH3:12]>>[CH3:1][C:2]1[N:3]=[CH:4][C:5]([C:6]([NH:18][C:17]2[CH:19]=[CH:20][C:14]([O:13][CH2:11][CH3:12])=[CH:15][C:16]=2[N+:21]([O-:23])=[O:22])=[O:8])=[CH:9][CH:10]=1
Reactant: CCOc1ccc(N)c([N+](=O)[O-])c1
Reactant: Cc1ccc(C(=O)O)cn1
Product: CCOc1ccc(NC(=O)c2ccc(C)nc2)c([N+](=O)[O-])c1

Procedure:
The title compound was prepared from 6-methylnicotinic acid and 4-ethoxy-2-nitroaniline and was obtained as a yellow solid as described in Example 15. 1H NMR (CDCl3): 11.09 (s, 1H), 9.12 (d, J=2.1, 1H), 8.85 (d, J=9.3, 1H), 8.16-8.13 (m, 1H), 7.73 (d, J=3.0, 1H), 7.34-7.29 (m, 2H), 4.11 (q, J=6.9, 2H), 2.67 (s, 3H), 1.46 (t, J=6.9, 3H).
Reaction SMILES: [C:1](=[O:15])([O-])[O:2][C:3]1([C:12]#[N:13])[CH:8]=CC=C[CH:4]1C(C)C.[OH:16][CH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>>[C:12]([C:3]([CH3:4])([O:2][C:1]([N:20]1[CH2:21][CH2:22][CH:17]([OH:16])[CH2:18][CH2:19]1)=[O:15])[CH3:8])#[N:13]
Reactant: OC1CCNCC1
Reactant: CC(C)C1C=CC=CC1(C#N)OC(=O)[O-]
Product: CC(C)(C#N)OC(=O)N1CCC(O)CC1
Yield: 98.1 %

Procedure:
50 g of 1-cyano-1-methylethylphenyl carbonate and 25 g of 4-hydroxypiperidine were heated at 130° C. After completion of the reaction, the resulting product was purified by silica gel column chromatography (elution solvent: hexane:ethyl acetate=1:1-1:2-0:1), thereby obtaining 50.5 g of the intended compound.
Reaction SMILES: Cl.[CH3:2][O:3][NH2:4].C(N(CC)CC)C.[S:12]1[CH:16]=[CH:15][C:14]2[CH:17]([N:21]=[C:22]=[O:23])[CH2:18][CH2:19][CH2:20][C:13]1=2>C(Cl)Cl>[CH3:2][O:3][NH:4][C:22]([NH:21][CH:17]1[C:14]2[CH:15]=[CH:16][S:12][C:13]=2[CH2:20][CH2:19][CH2:18]1)=[O:23]
Reactant: O=C=NC1CCCc2sccc21
Reactant: CON
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CONC(=O)NC1CCCc2sccc21
Temperature: 15 °C
Reaction time: 0.33 h

Procedure:
A mixture of 5 grams of methoxyamine hydrochloride in 60 ml. of methylene chloride is stirred and cooled to 15°C., and 6 grams of triethylamine in 15 ml. of methylene chloride is added. After 20 minutes of stirring, 5.38 grams of 4,5,6,7-tetrahydrobenzo[b]thien-4-yl isocyanate is added dropwise. After stirring an additional 0.5 hour at 15°C. to 20°C., the mixture is stirred at room temperature for 0.5 hour. The mix is then filtered, and the filtrate is washed with water and saturated sodium bicarbonate solution. The filtrate is dried (magnesium sulfate) and evaporated to dryness to afford the title compound which is recrystallized from acetone/hexane to give the product with melting point 138.5°C. to 141°C.
Reaction SMILES: [OH:1][CH2:2][C:3]([CH2:8][OH:9])([CH2:6][OH:7])[CH2:4][OH:5].[SH:10][CH:11]([CH3:15])[C:12]([OH:14])=O.S(=O)(=O)(O)O>O.C1(C)C=CC=CC=1>[SH:10][CH:11]([CH3:15])[C:12]([O:1][CH2:2][C:3]([CH2:8][O:9][C:12](=[O:14])[CH:11]([SH:10])[CH3:15])([CH2:6][O:7][C:12](=[O:14])[CH:11]([SH:10])[CH3:15])[CH2:4][O:5][C:12](=[O:14])[CH:11]([SH:10])[CH3:15])=[O:14]
Reactant: OCC(CO)(CO)CO
Reactant: CC(S)C(=O)O
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Solvent: O
Product: CC(S)C(=O)OCC(COC(=O)C(C)S)(COC(=O)C(C)S)COC(=O)C(C)S
Temperature: 25 °C
Reaction time: 48 h
Yield: 88 %

Procedure:
To a 500-milliliter round-bottom flask equipped with a magnetic stirring bar, a water separator, and a condenser were added 27.23 grams (0.200 mol) of pentaerythritol, 90.22 grams (0.850 mol) of 2-mercaptopropionic acid, 100 milliliters of toluene, and 0.5 milliliter of concentrated sulfuric acid. The mixture was heated under reflux with stirring. After about 2 days, the solid material had disappeared, and about 17 milliliters (0.94 mol) of water had been collected by the water separator. Upon cooling to room temperature, the mixture was extracted with 30 milliliters of saturated NaHCO3 solution and washed with two 50-milliliter portions of water. The organic layer was dried over anhydrous MgSO4, and most of the toluene and residual 2-mercaptopropionic acid were removed by distillation under vacuum. Recrystallization of the residue from ethanol gave 86.0 grams (88.4%, calcd. 97.3 grams) of pentaerythritol tetrakis(2-mercaptopropionate) as a white solid, mp 93-96° C.; 1H NMR (in CDCl3 w/TMS, ppm): 4.17-4.30 (AB m, 8H, CH2O), 3.50 (pentuplet, 4H, CHSH), 2.17 (d of d, 4H, SH), 1.51 (d, 12H, CH3); {1H}13C NMR (in CDCl3 w/TMS, ppm): 172.79 (C═O), 62.47 (CH2O), 43.05 [C(CH2)4], 35.43 (CCHSH), 20.94 (CH3).
Reaction SMILES: [CH:1]([C:3]1[S:4][CH:5]=[CH:6][C:7]=1[S:8]([N:11]([CH3:26])[C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:20]=1[NH:19][C:18]([C:21]1[S:22][CH:23]=[CH:24][N:25]=1)=[CH:17]2)(=[O:10])=[O:9])=[O:2].[CH3:27][Mg]Br.O>O1CCCC1>[OH:2][CH:1]([C:3]1[S:4][CH:5]=[CH:6][C:7]=1[S:8]([N:11]([CH3:26])[C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:20]=1[NH:19][C:18]([C:21]1[S:22][CH:23]=[CH:24][N:25]=1)=[CH:17]2)(=[O:10])=[O:9])[CH3:27]
Reactant: CN(c1cccc2cc(-c3nccs3)[nH]c12)S(=O)(=O)c1ccsc1C=O
Reactant: C[Mg]Br
Solvent: O
Solvent: C1CCOC1
Product: CC(O)c1sccc1S(=O)(=O)N(C)c1cccc2cc(-c3nccs3)[nH]c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 33 %

Procedure:
To a solution of 2-formyl-N-methyl-N-[2-(1,3-thiazol-2-yl)-1H-indol-7-yl]thiophene-3-sulfonamide (790 mg) in tetrahydrofuran (20 mL) was added methylmagnesium bromide (3.0 M, 1.5 mL), and the mixture was stirred at room temperature for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography (ethyl acetate:hexane=1:1) to give the title compound (272 mg, yield 33%) as white crystals. melting point 193° C.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:25][CH2:26][C:27]1[C:28]([F:44])=[C:29]([O:34][C:35]2[CH:36]=[C:37]([CH:40]=[C:41]([Cl:43])[CH:42]=2)[C:38]#[N:39])[C:30]([Cl:33])=[CH:31][CH:32]=1.[Cl:45][C:46]1[CH:50]=[CH:49][NH:48][C:47]=1[C:51](O)=[O:52].CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:45][C:46]1[CH:50]=[CH:49][NH:48][C:47]=1[C:51]([NH:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[C:29]([O:34][C:35]2[CH:36]=[C:37]([C:38]#[N:39])[CH:40]=[C:41]([Cl:43])[CH:42]=2)[C:28]=1[F:44])=[O:52]
Reactant: O=C(O)c1[nH]ccc1Cl
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CN)c2F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CNC(=O)c3[nH]ccc3Cl)c2F)c1
Reaction time: 2 h
Yield: 26.6 %

Procedure:
HATU (0.061 g, 0.16 mmole) was added to a DMF (2 ml) solution of 3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-chlorobenzonitrile (0.050 g, 0.16 mmole) and 3-chloro-1H-pyrrole-2-carboxylic acid (0.023 g, 0.16 mmole) in DMF. DIPEA (0.021 g, 0.16 mmole) was added and the solution stirred for 2 h. The mixture was partitioned between EtOAc and water. The organic layer was separated and washed with 15% NaHCO3 and dried over MgSO4 and the EtOAc evaporated. The residue was purified on silica with EtOAc and Hexanes to afford the title compound (0.0187 g, 26%) as a white solid. 1H NMR (400 MHz, Acetone-d6): δ ppm 10.93 (br. s., 1H), 7.62-7.67 (m, 1H), 7.56-7.62 (m, 1H), 7.37-7.48 (m, 4H), 7.02 (t, 1H), 6.23 (t, 1H), 4.72 (d, 2H). MS: m/z 438.1 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@:11]([F:14])([CH3:13])[CH2:10][C@H:9]1[C:15]([OH:17])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:18][C@@H:19]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:24]=1[F:30])[CH2:20][CH2:21][OH:22]>CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@:11]([F:14])([CH3:13])[CH2:10][C@H:9]1[C:15](=[O:17])[NH:18][C@@H:19]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:24]=1[F:30])[CH2:20][CH2:21][OH:22])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1C[C@](C)(F)C[C@H]1C(=O)O
Reactant: N[C@H](CCO)c1cccc(Cl)c1F
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1C[C@](C)(F)C[C@H]1C(=O)N[C@H](CCO)c1cccc(Cl)c1F

Procedure:
was prepared according to Scheme B9 (Step A) from (2S,4R)-4-fluoro-4-methyl-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (prepared as described Scheme B18) and (R)-3-amino-3-(3-chloro-2-fluoro-phenyl)-propan-1-ol. TLC, Rf (EtOAc)=0.55; MS (UPLC/MS): 433.3 [M+H]+, 477.3 [M+HCOO]−; tR (HPLC conditions a): 3.26 min.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:21])=[C:6]([NH:8][C:9]2[N:14]=[C:13]([C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)[CH:12]=[CH:11][N:10]=2)[CH:7]=1.[Cl:22][CH2:23][C:24]1[CH:32]=[CH:31][C:27]([C:28](Cl)=[O:29])=[CH:26][CH:25]=1>O>[Cl:22][CH2:23][C:24]1[CH:32]=[CH:31][C:27]([C:28]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([CH3:21])=[C:6]([NH:8][C:9]3[N:14]=[C:13]([C:15]4[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=4)[CH:12]=[CH:11][N:10]=3)[CH:7]=2)=[O:29])=[CH:26][CH:25]=1
Reactant: O=C(Cl)c1ccc(CCl)cc1
Reactant: Cc1ccc(N)cc1Nc1nccc(-c2cccnc2)n1
Solvent: O
Product: Cc1ccc(NC(=O)c2ccc(CCl)cc2)cc1Nc1nccc(-c2cccnc2)n1

Procedure:
In certain embodiments of the invention, after condensing N-(5-amino-2-methylphenyl)-4-(3-pyridinyl)-2-pyrimidine-amine with 4-chloromethylbenzoyl chloride in the presence of an inorganic base to obtain 4-chloromethyl-N-(4-methyl-3-(4-(pyridin-3-yl)pyrimidin-2-ylamino)phenyl)benzamide, water is added, and 4-chloromethyl-N-(4-methyl-3-(4-(pyridin-3-yl)pyrimidin-2-ylamino)phenyl)benzamide is isolated by filtration.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[O:7][CH:6]([C:8]([NH:10][CH2:11][CH2:12][C:13]([OH:15])=O)=[O:9])[C:5]([CH3:17])([CH3:16])[CH2:4][O:3]1.[CH:19]1[C:24]([NH2:25])=[CH:23][CH:22]=[C:21]([OH:26])[CH:20]=1>>[OH:26][C:21]1[CH:22]=[CH:23][C:24]([NH:25][C:13](=[O:15])[CH2:12][CH2:11][NH:10][C:8]([CH:6]2[C:5]([CH3:17])([CH3:16])[CH2:4][O:3][C:2]([CH3:1])([CH3:18])[O:7]2)=[O:9])=[CH:19][CH:20]=1
Reactant: CC1(C)OCC(C)(C)C(C(=O)NCCC(=O)O)O1
Reactant: Nc1ccc(O)cc1
Product: CC1(C)OCC(C)(C)C(C(=O)NCCC(=O)Nc2ccc(O)cc2)O1
Yield: 97.5 %

Procedure:
3-[N-(2,2,5,5-Tetramethyl-1,3-dioxane-4-carbonyl)amino]propionic acid (1.04 g) and 0.665 g of p-aminophenol were reacted in the same manner as in Reference Example 15 to obtain 1.37 g of the objective compound (yield: 98%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](/[C:11](=[CH:14]/[C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)/[C:12]#[N:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[Cl-].[CH2:23]([O:25][C:26](=[O:32])[CH2:27][CH2:28][C:29](O)=[O:30])[CH3:24]>N1C=CC=CC=1>[C:29]([O:21][C:18]1[CH:17]=[CH:16][C:15](/[CH:14]=[C:11](\[C:12]#[N:13])/[C:5]2[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)=[CH:20][CH:19]=1)(=[O:30])[CH2:28][CH2:27][C:26]([O:25][CH2:23][CH3:24])=[O:32]
Reactant: CCOC(=O)CCC(=O)O
Reactant: COc1ccc(/C(C#N)=C/c2ccc(O)cc2)cc1OC
Agent: [Cl-]
Solvent: c1ccncc1
Product: CCOC(=O)CCC(=O)Oc1ccc(/C=C(\C#N)c2ccc(OC)c(OC)c2)cc1
Yield: 90 %

Procedure:
Compound 1 (50 mg) and succinic acid monoethyl ester chloride (51 μL) were dissolved in pyridine (1 mL), followed by stirring for a whole day and night. After completion of reaction, the resultant reaction mixture was concentrated to dryness under reduced pressure, followed by purification by means of silica gel chromatography employing a chloroform/methanol system, to thereby produce the target product (73 mg, yield: 90%).
Reaction SMILES: [CH2:1]([N:8]([CH3:27])[C:9]1[C:14]2[N:15]=[C:16](Cl)[N:17]=[C:18]([N:19]3[CH2:24][CH2:23][S:22](=[O:25])[CH2:21][CH2:20]3)[C:13]=2[N:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:28][CH2:29][CH2:30][NH2:31]>O>[CH2:1]([N:8]([CH3:27])[C:9]1[C:14]2[N:15]=[C:16]([NH:31][CH2:30][CH2:29][OH:28])[N:17]=[C:18]([N:19]3[CH2:24][CH2:23][S:22](=[O:25])[CH2:21][CH2:20]3)[C:13]=2[N:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCCO
Reactant: CN(Cc1ccccc1)c1ncnc2c(N3CCS(=O)CC3)nc(Cl)nc12
Solvent: O
Product: CN(Cc1ccccc1)c1ncnc2c(N3CCS(=O)CC3)nc(NCCO)nc12

Procedure:
8.1 gm (0.02 mol) of 8-(N-benzyl-methylamino)-2-chloro-4-(1-oxido-thiomorpholino)-pyrimido[5,4-d]pyrimidine (melting point: 158°-160° C.) were heated at about 90° C. for one hour with 12.2 gm (0.2 mol) of 2-hydroxyethyl-amine. The mixture thus obtained was taken up in about 250 ml of water, whereby the reaction product separated out as a precipitate which soon solidified. It was filtered off, washed with water and dried at about 60° C. Yield: 8.2 gm (96% of theory).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:9][CH3:10])=[C:6]([OH:8])[CH:7]=1.Cl[CH2:12][C:13]([CH3:15])=[CH2:14].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>C1(C)C=CC=CC=1>[CH3:14][C:13](=[CH2:12])[CH2:15][O:8][C:6]1[CH:7]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=1[O:9][CH3:10]
Reactant: COc1ccc(Br)cc1O
Reactant: C=C(C)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: C=C(C)COc1cc(Br)ccc1OC
Temperature: 80 °C
Reaction time: 2 h

Procedure:
A mixture of 5-bromo-2-methoxyphenol (17.8 g), 3-chloro-2-methyl-1-propene (13.0 ml), potassium carbonate (18.2 g), and DMF (150 ml) was stirred at 80° C. for 2 hours. The mixture was diluted with toluene, washed with a saturated saline and dried over anhydrous magnesium sulfate, and the solvent was distilled off to give Compound IIa-a (22.2 g, 98.4%) as a colorless oily substance.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[CH:9][N:10]([C:12]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li]CCCC.[Si:36]([O:43][C:44]1[C:45]([F:55])=[C:46]([CH:49]=[C:50]([O:52][CH2:53][CH3:54])[CH:51]=1)[CH:47]=[O:48])([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:38])[CH3:37].[NH4+].[Cl-]>C1COCC1.CCOC(C)=O>[Si:36]([O:43][C:44]1[C:45]([F:55])=[C:46]([CH:47]([C:9]2[N:10]([C:12]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:11]=[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[N:8]=2)[OH:48])[CH:49]=[C:50]([O:52][CH2:53][CH3:54])[CH:51]=1)([C:39]([CH3:40])([CH3:42])[CH3:41])([CH3:38])[CH3:37]
Reactant: CCOc1cc(C=O)c(F)c(O[Si](C)(C)C(C)(C)C)c1
Reactant: c1ccc(-c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOc1cc(O[Si](C)(C)C(C)(C)C)c(F)c(C(O)c2nc(-c3ccccc3)cn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 84.6 %

Procedure:
To a solution of intermediate 8.1 (1.00 g, 2.59 mmol) in 20 mL THF at 0° C., was added BuLi (1.4 M, 2.03 mL, 2.85 mmol). The mixture was stirred for 30 min at 0° C., then a solution of 3-(tert-butyldimethylsilyloxy)-5-ethoxy-2-fluorobenzaldehyde (773 mg, 2.59 mmol) in 2 mL THF was added dropwise. The mixture was stirred at 0° C. for 30 min, quenced with sat. NH4Cl and diluted with EtOAc. The organic phase was washed with H2O and brine, dried (Na2SO4) and concentrated. The crude product was purified by flash chromatography (0 to 30% EtOAc/hexanes, gradient) to afford 1.50 g (80%) of Intermediate 123.1 as a pale yellow solid.
Reaction SMILES: Br[CH:2]([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[Cl:9][C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([Cl:20])[CH:18]=2)[CH:13]=[C:12]([N:21]([C:23]2[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=2)[CH3:22])[N:11]=1.C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[Cl:9][C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([Cl:20])[CH:18]=2)[CH:13]=[C:12]([N:21]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH:2]([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4])=[CH:25][CH:24]=2)[CH3:22])[N:11]=1
Reactant: CCOC(=O)C(C)Br
Reactant: CN(c1ccc(O)cc1)c1cc2ccc(Cl)cc2c(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOC(=O)C(C)Oc1ccc(N(C)c2cc3ccc(Cl)cc3c(Cl)n2)cc1
Yield: 85.5 %

Procedure:
A mixture of ethyl 2-bromopropionate (1.6 g), 4-[N-(1,7-dichloroisoquinolin-3-yl)-N-methylamino]phenol (2.76 g), anhydrous potassium carbonate (1.19 g) and methyl ethyl ketone was heated under reflux for a period of 3 hours. The mixture was cooled, washed with water and was dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure to give an oil which was purified by column chromatography over silica gel (eluant dichloromethane) to give ethyl 2-{4-[N-(1,7-dichloroisoquinolin-3-yl)-N-methylamino]phenoxy}propionate (3.10 g) as a yellow oil which crystallised from ethanol, mp 86° C. The assigned structure was confirmed by proton magnetic resonance spectroscopy and mass spectrometry. Proton magnetic resonance spectrum (CDCl3 ; δ in ppm): 1.3 (3H, t); 1.65 (3H, d); 3.45 (3H, s); 4.25 (2H, q); 4.75 (1H, q); 6.40 (1H, s); 6.85-7.35 (6H, m); 8.00 (1H, s).