Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7](=[O:8])[N:6]([CH3:9])[CH:5]=[C:4]([C:10]2[C:11]([CH3:28])=[C:12]([NH:16][C:17]([C:19]3[S:23][C:22]4[CH2:24][CH2:25][CH2:26][CH2:27][C:21]=4[CH:20]=3)=[O:18])[CH:13]=[CH:14][CH:15]=2)[CH:3]=1.Cl[C:30]1[N:35]=[CH:34][C:33]([CH:36]2[N:41]([CH3:42])[CH2:40][CH2:39][N:38]([CH3:43])[C:37]2=[O:44])=[CH:32][CH:31]=1.CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:42][N:41]1[CH2:40][CH2:39][N:38]([CH3:43])[C:37](=[O:44])[CH:36]1[C:33]1[CH:32]=[CH:31][C:30]([NH:1][C:2]2[C:7](=[O:8])[N:6]([CH3:9])[CH:5]=[C:4]([C:10]3[C:11]([CH3:28])=[C:12]([NH:16][C:17]([C:19]4[S:23][C:22]5[CH2:24][CH2:25][CH2:26][CH2:27][C:21]=5[CH:20]=4)=[O:18])[CH:13]=[CH:14][CH:15]=3)[CH:3]=2)=[N:35][CH:34]=1
Reactant: CN1CCN(C)C(c2ccc(Cl)nc2)C1=O
Reactant: Cc1c(NC(=O)c2cc3c(s2)CCCC3)cccc1-c1cc(N)c(=O)n(C)c1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Cc1c(NC(=O)c2cc3c(s2)CCCC3)cccc1-c1cc(Nc2ccc(C3C(=O)N(C)CCN3C)cn2)c(=O)n(C)c1
Temperature: 95 °C
Yield: 33.5 %

Procedure:
A 48-mL sealed tube equipped with a magnetic stirring bar was charged with 43 (0.20 g, 0.5 mmol), 3-(6-chloropyridin-3-yl)-1,4-dimethylpiperazin-2-one (0.185 g, 0.8 mmol), Pd2(dba)3 (0.032 g, 0.035 mmol), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (0.030 g, 0.05 mmol), and Cs2CO3 (0.326 g, 1.0 mmol) in dioxane (10 mL). After the mixture was degassed for 15 min., it was heated at 95° C. for 16 h. Then, the reaction mixture was cooled to room temperature and poured into H2O (10 mL). To this was added dichloromethane (10 mL) and the layers were separated. The aqueous phase was extracted with dichloromethane (3×10 mL), and the combined organic extracts were washed with H2O (5 mL) and brine (5 mL), dried (Na2SO4), and concentrated. The crude mixture was purified by column chromatography, gradient 0-10%, MeOH in dichloromethane/ether (1/1), to afford 0.10 g (34%) of 44 as a solid; MS (ESI+) m/z 596 (M+H).
Reaction SMILES: C[O-].[Na+].[C:4]([O:12][CH2:13][CH3:14])(=[O:11])[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].CS(O[C@@H:20]([CH3:24])[CH2:21][CH2:22][CH3:23])(=O)=O.[Cl-].[NH4+]>C(OCC)(=O)C.C(Cl)Cl>[CH3:24][C@@H:20]([CH:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[C:4]([O:12][CH2:13][CH3:14])=[O:11])[CH2:21][CH2:22][CH3:23]
Reactant: CCC[C@H](C)OS(C)(=O)=O
Reactant: CCOC(=O)CC(=O)OCC
Agent: C[O-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCC[C@@H](C)C(C(=O)OCC)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96 %

Procedure:
At room temperature, a three-neck flask with internal thermometer, dropping funnel and stirrer was initially charged under protective nitrogen gas with 33.1 g of sodium methoxide (95% pure, 0.583 mol) in 250 ml of dry ethyl acetate. Subsequently, 97.5 g of diethyl malonate (0.609 mol) were added dropwise at from 20 to 30° C. The clear mixture was stirred at 25° C. for 30 min, and 85.7 g of (S)-1-methylbutyl methanesulfonate (0.516 mol) were added undiluted. The mixture was heated to 79° C. and stirred for 7 h. After cooling to 25° C., the suspension was admixed with 800 ml of methylene chloride and 500 ml of 5% by weight ammonium chloride solution. After phase separation, the organic phase was washed with 150 ml of water and then dried over sodium sulfate. After distillative removal of solvent, diethyl [(R)-1-methylbutyl]malonate was obtained in a yield of 105 g. The product contains dimethyl ester and ethyl methyl ester, formed by transesterification (GC purity: sum of Me/Me, Me/Et, Et/Et: 96%). The corrected yield is 96% of theory.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@@H:6]1[O:24][C@@H:25]1[C@@H:30]([CH2:31][O:32][C:33](=[O:35])[CH3:34])[O:29][C@H:28]([O:36][C@@H:37]2[C@@H:42]([CH2:43][O:44][C:45](=[O:47])[CH3:46])[O:41][C@H:40](Br)[C@H:39]([O:49][C:50](=[O:52])[CH3:51])[C@H:38]2[O:53][C:54](=[O:56])[CH3:55])[C@H:27]([O:57][C:58](=[O:60])[CH3:59])[C@H:26]1[O:61][C:62](=[O:64])[CH3:63])(=[O:3])[CH3:2].[N-:65]=[N+:66]=[N-:67].[Na+]>CCOC(C)=O.C([O-])(O)=O.[Na+].[N+](CCCC)(CCCC)(CCCC)CCCC.[Br-]>[C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@@H:6]1[O:24][C@@H:25]1[C@@H:30]([CH2:31][O:32][C:33](=[O:35])[CH3:34])[O:29][C@H:28]([O:36][C@@H:37]2[C@@H:42]([CH2:43][O:44][C:45](=[O:47])[CH3:46])[O:41][C@@H:40]([N:65]=[N+:66]=[N-:67])[C@H:39]([O:49][C:50](=[O:52])[CH3:51])[C@H:38]2[O:53][C:54](=[O:56])[CH3:55])[C@H:27]([O:57][C:58](=[O:60])[CH3:59])[C@H:26]1[O:61][C:62](=[O:64])[CH3:63])(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@H](Br)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1O[C@H]1O[C@H](COC(C)=O)[C@@H](O[C@H]2O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]2OC(C)=O)[C@H](OC(C)=O)[C@H]1OC(C)=O
Reactant: [N-]=[N+]=[N-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: [Br-]
Solvent: CCOC(C)=O
Product: CC(=O)OC[C@H]1O[C@@H](N=[N+]=[N-])[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1O[C@H]1O[C@H](COC(C)=O)[C@@H](O[C@H]2O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]2OC(C)=O)[C@H](OC(C)=O)[C@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The bromide 72 (˜200 mg) was taken up in a mixture of EtOAc (5 mL) and NaHCO3 (sat.) (5 mL). NaN3 (500 mg) was added, followed by Bu4NBr (cat.). The mixture was stirred vigorously overnight at r.t. The solution was diluted with EtOAc and washed with NaHCO3(sat.) (×2) and brine (×1), before being dried (Na2SO4) and the solvent evaporated to yield the azide 73 as white solid (198.9 mg, 100%, two steps) which was reacted on without further purification or characterisation.
Reaction SMILES: CC1C=C(C)C=C(C)C=1S([O-])(=O)=O.[NH2:14][N+:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[O:21][CH2:22][C:23]1[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:24]=1[F:30].[C:31]([O:36][CH2:37][CH3:38])(=[O:35])[C:32]#[C:33][CH3:34].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH2:37]([O:36][C:31]([C:32]1[C:33]([CH3:34])=[N:14][N:15]2[C:16]([O:21][CH2:22][C:23]3[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:24]=3[F:30])=[CH:17][CH:18]=[CH:19][C:20]=12)=[O:35])[CH3:38]
Reactant: CC#CC(=O)OCC
Reactant: N[n+]1ccccc1OCc1c(F)cccc1F
Agent: Cc1cc(C)c(S(=O)(=O)[O-])c(C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1c(C)nn2c(OCc3c(F)cccc3F)cccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A stirred solution of 540 mg (1.00 mmol, 81% pure) of 1-amino-2-[(2,6-difluorobenzyl)oxy]pyridinium-2,4,6-trimethylbenzenesulphonate from Example 128A in DMF (10 ml) at 0° C. was admixed with 0.35 ml (3.06 mmol) of ethyl 2-butynoate and 623 mg (4.51 mmol) of potassium carbonate. The reaction mixture was stirred at room temperature overnight and added dropwise to 20 ml of water while stirring. The resulting suspension was extracted with ethyl acetate (2×20 ml). The combined organic phases were dried with a phase separation cartridge and concentrated under reduced pressure. The residue was purified by flash chromatography using a prepacked silica gel cartridge (eluent:cyclohexane-ethyl acetate 10:1 to 1:1), which gave 200 mg (25% of theory, 43% pure) of the target compound.
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:7][C:8]([C:10]2[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=2)[C:13]#[N:14])=O)[CH:4]=[CH:5][N:6]=1.[N:18]1[CH:23]=[CH:22][N:21]=[CH:20][C:19]=1[NH:24][C:25]([NH2:27])=[S:26].II.N1C=CC=CC=1>O>[CH3:1][C:2]1[N:3]([C:7]2[S:26][C:25]([NH:24][C:19]3[CH:20]=[N:21][CH:22]=[CH:23][N:18]=3)=[N:27][C:8]=2[C:10]2[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=2)[C:13]#[N:14])[CH:4]=[CH:5][N:6]=1
Reactant: NC(=S)Nc1cnccn1
Reactant: Cc1nccn1CC(=O)c1cccc(C#N)c1
Agent: II
Solvent: O
Solvent: c1ccncc1
Product: Cc1nccn1-c1sc(Nc2cnccn2)nc1-c1cccc(C#N)c1
Temperature: 25 °C

Procedure:
3-(2-Methylimidazol-1-yl-acetyl)-benzonitrile (13.8 g, 0.06 mol) is mixed with pyrazinyl-2-thiourea (9.4 g, 0.06 mol), iodine (15.6 g, 0.06 mol) and pyridine (60 ml). The mixture is stirred, initially at room temperature and then at 60° C. overnight (17.5 hours). The mixture obtained is allowed to cool to room temperature and water (50 ml) added. The solid obtained is filtered off, stirred in water (50 ml) for 30 minutes, and filtered off again. The resulting solid is dried at 40° C. in vacuo over P2O5 to give the title compound.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[C:7]([O:11][C:12]([N:14]([C:28]1[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=1)[CH2:15][CH2:16][O:17][C:18]1[CH:19]=[C:20]([CH:24]=[C:25]([Cl:27])[CH:26]=1)[C:21](O)=[O:22])=[O:13])([CH3:10])([CH3:9])[CH3:8].[F:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[NH:41][CH2:42][CH2:43][C:44]#[N:45].CCN(C(C)C)C(C)C>ClCCl.CN(C=O)C.CN(C1C=CN=CC=1)C>[C:7]([O:11][C:12](=[O:13])[N:14]([CH2:15][CH2:16][O:17][C:18]1[CH:19]=[C:20]([C:21](=[O:22])[N:41]([CH2:42][CH2:43][C:44]#[N:45])[C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=2[F:34])[CH:24]=[C:25]([Cl:27])[CH:26]=1)[C:28]1[CH:29]=[CH:30][N:31]=[CH:32][CH:33]=1)([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)(C)OC(=O)N(CCOc1cc(Cl)cc(C(=O)O)c1)c1ccncc1
Reactant: N#CCCNc1ccccc1F
Agent: CN(C)c1ccncc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N(CCOc1cc(Cl)cc(C(=O)N(CCC#N)c2ccccc2F)c1)c1ccncc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 34.6 %

Procedure:
2M Oxalyl chloride solution in dichloromethane (0.090 ml) and DMF (0.001 ml) were added to a suspension of 3-[2-(tert-butoxycarbonyl-pyridin-4-yl-amino)-ethoxy]-5-chloro-benzoic acid (0.059 g) in anhydrous dichloromethane (1 ml). The reaction was stirred at room temperature for 1.5 h then a solution of 3-(2-fluoro-phenylamino)propionitrile (0.026 g) in dichloromethane (1 ml), DMAP (0.002 g) and DIPEA (0.078 m l) were added. The reaction mixture was stirred at room temperature for 66 h. The reaction mixture was partitioned between ethyl acetate and 1M aqueous hydrochloric acid. The aqueous layer was removed and the organic phase washed with further 1M aqueous hydrochloric acid, saturated aqueous sodium bicarbonate solution, water and dried with brine and over sodium sulphate and concentrated under reduced pressure. The residue was purified by flash column chromatography, eluting with ethyl acetate:cyclohexane (4:1 v/v), to give the title compound as a colourless gum (0.028 g).
Reaction SMILES: [O:1]=[C:2]1[CH:6]2[CH2:7][N:8](C(OC(C)(C)C)=O)[CH2:9][CH2:10][N:5]2[C:4](=[O:18])[N:3]1[C@@H:19]1[CH2:21][C@H:20]1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:22]1([C@@H:20]2[CH2:21][C@H:19]2[N:3]2[C:2](=[O:1])[CH:6]3[CH2:7][NH:8][CH2:9][CH2:10][N:5]3[C:4]2=[O:18])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CC(C)(C)OC(=O)N1CCN2C(=O)N([C@@H]3C[C@H]3c3ccccc3)C(=O)C2C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1C2CNCCN2C(=O)N1[C@@H]1C[C@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
A solution of A4 in DCM (0.5 M) was cooled to 0° C. (ice bath) and TFA (9 eq.) was added and the reaction was stirred at RT overnight. The solvent was removed under reduced pressure. The crude material was treated with Et2O (20 mL) and HCl (1N, 12 mL). The two layers were separated, and organic phase washed with water (2×15 mL). To the combined organic extracts was added solid K2CO3 in small portion until pH 9-10. The mixture was extracted with DCM and combined extracts were dried and evaporated under reduced pressure to yield (100%) the desired compound that was used crude in the next step. 1H NMR (400 MHz, DMSO-d6, 300K) δ 7.29-7.20 (5H, m), 3.90 (1H, m), 3.78 (1H, m), 3.15 (1H, m), 2.85 (3H, m), 2.65 (1H, m), 2.50-2.30 (3H, m), 1.5 (1H, m), 1.35 (1H, m). MS (ES+) C15H17N3O2 requires 271, found: 272 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([Cl:11])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[H-].[Na+].[CH3:14]I>CN(C=O)C>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([Cl:11])=[CH:7][N:8]2[CH3:14])=[CH:4][CH:3]=1
Reactant: CI
Reactant: Clc1c[nH]c2cc(Br)ccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1cc(Cl)c2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 87.6 %

Procedure:
A solution of 6-bromo-3-chloro-1H-indole (D72) (894 mg, 3.88 mmol) in DMF (16 mL) was cooled to 0° C. under an atmosphere of nitrogen. Sodium hydride (60% in mineral oil) (163 mg, 4.07 mmol) was added portionwise followed by methyl iodide (0.243 mL, 3.88 mmol). The mixture was stirred for 1.5 hour, slowly allowing to warm to RT. The mixture was quenched with saturated aq. NH4Cl and extracted with ethyl acetate (2×150 mL). The organic extracts were combined, dried with anhydrous sodium sulfate, filtered and evaporated to dryness. The residues were purified on silica, eluting with cyclohexane and ethyl acetate (0-50%). The appropriate fractions were combined and evaporated to dryness to give title compound (831 mg). LCMS (A): m/z (M−H)− 242/244, C9H7BrClN requires 243/245 (acidic).
Reaction SMILES: C([Li])CCC.CCCCCC.C[Si](C)(C)[N:14]1[CH2:19][CH2:18][C:17]2[S:20][CH:21]=[CH:22][C:16]=2[CH2:15]1.[B:25](OCCCC)([O:31]CCCC)[O:26]CCCC.Cl>C1COCC1.CN(P(N(C)C)(N(C)C)=O)C>[S:20]1[C:17]2[CH2:18][CH2:19][NH:14][CH2:15][C:16]=2[CH:22]=[C:21]1[B:25]([OH:31])[OH:26]
Reactant: C[Si](C)(C)N1CCc2sccc2C1
Reactant: CCCCOB(OCCCC)OCCCC
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: OB(O)c1cc2c(s1)CCNC2
Temperature: -20 °C
Reaction time: 2 h

Procedure:
45.4 cc. of a 12% solution of butyl lithium in hexane (0.084 mol) are added dropwise, under an atmosphere of nitrogen, to a solution, cooled to -20° C., of 15 g. (0.07 mol) 5-trimethylsilyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine, prepared as in Example 7, in 150 cc. of THF. The reaction mixture is allowed to return to 0° C. and 3 cc. HMPT are added thereto. After cooling this mixture to -50° C., a solution of 19.3 g. (0.084 mol) tributyl borate in 30 cc. THF is added dropwise. Stirring is continued for 2 hours, whilst allowing the mixture to return to ambient temperature. 28 cc. 3N hydrochloric acid (0.084 mol) are then added and the precipitate formed is filtered off. The crystals are washed with acetone and with diisopropyl ether and then dried in vacuo. Off white crystals are obtained in quantitative yield; m.p.>260° C.; NMR (D2O): 6.75 (s,1H); 4.10 (m,2H); 2.80-3.50 (m,4H).
Reaction SMILES: [CH2:1]1[O:12][C:11]2[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH2:8])=[CH:4][C:3]=2[O:2]1.Cl[C:14]1[C:15]2[CH:28]=[C:27]([CH2:29][CH3:30])[S:26][C:16]=2[N:17]=[C:18]([C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)[N:19]=1>>[N:23]1[CH:22]=[CH:21][C:20]([C:18]2[N:19]=[C:14]([NH:8][CH2:7][CH2:6][C:5]3[CH:9]=[CH:10][C:11]4[O:12][CH2:1][O:2][C:3]=4[CH:4]=3)[C:15]3[CH:28]=[C:27]([CH2:29][CH3:30])[S:26][C:16]=3[N:17]=2)=[CH:25][CH:24]=1
Reactant: NCCc1ccc2c(c1)OCO2
Reactant: CCc1cc2c(Cl)nc(-c3ccncc3)nc2s1
Product: CCc1cc2c(NCCc3ccc4c(c3)OCO4)nc(-c3ccncc3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of 3,4-methylenedioxyphenethylamine with 4-chloro-2-(pyridin-4-yl)-6-ethyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-4-yl)-4-(3,4-methylenedioxyphenethylamino)-6-ethyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: C([C:3](C)=[O:4])C.[C:6]([O:11][C:12]1([CH2:22]C)C2CC3CC(C[CH:13]1C3)C2)(=[O:10])[C:7](C)=C.N(C(C)(C)C#N)=NC(C)(C)C#N>CO>[CH3:13][CH:12]([O:11][C:6]([CH3:7])=[O:10])[CH2:22][O:4][CH3:3]
Reactant: C=C(C)C(=O)OC1(CC)C2CC3CC(C2)CC1C3
Reactant: CCC(C)=O
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: CO
Product: COCC(C)OC(C)=O
Temperature: 80 °C
Reaction time: 4 h

Procedure:
A monomer solution was prepared by placing 4800 g of methyl ethyl ketone (hereinafter inscribed as “MEK”) in a tank kept at a nitrogen atmosphere, and dissolving 2080 g of 5-acryloyloxy-2,6-norbornanecarbolactone (hereinafter inscribed as “NLA”) as a repeat unit (B) having a polar group for enhancing adhesion to a semiconductor substrate {hereinafter (B) on a head of the compounds in the examples has the same meaning as this} and 2480 g of 2-ethyl-2-adamantyl methacrylate (hereinafter inscribed as “EAM”) as a repeat unit (A) which is decomposed by an acid to become alkali soluble (hereinafter (A) on a head in the compounds in the examples has the same meaning as this). A polymerization initiator was prepared by placing 700 g of MEK and 80 g of azobisisobutyronitrile (hereinafter inscribed as “AIBN”) in another container kept at a nitrogen atmosphere and dissolving. Into a polymerization tank kept at the nitrogen atmosphere, 3500 g of MEK was put and the temperature was raised to 80° C. with stirring. Subsequently, the monomer solution and the polymerization initiator solution kept at the temperature of 25 to 30° C. were fed into the polymerization tank kept at 80° C. over 4 hours, respectively. After the completion of feed, the polymerized solution was matured for 2 hours with keeping the polymerization temperature at 80° C., then cooled to room temperature and taken out. Polymer was precipitated from the resulting polymerized solution by dropping in 70 kg of aqueous methanol and filtrated. The resultant wet cake was washed with 70 kg of methanol, filtrated subsequently dissolved in MEK again, and passed through a filter 40QSH supplied from Cuno Incorporated to remove a trace amount of metals. Then, the solvent was replaced by PGMEA with removing MEK by heating under reduced pressure to prepare PGMEA solution containing 15% polymer. The features of the resultant polymer, the content of high polymer and the evaluation results of storage stability of PGMEA solution are shown in Table 1.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[CH3:7][NH:8][C:9]1[S:10][C:11]([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)=[C:12]([CH:14]=O)[N:13]=1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CS(C)=O>[CH3:7][NH:8][C:9]1[S:10][C:11]([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)=[C:12]([CH:14]=[CH2:1])[N:13]=1
Reactant: CNc1nc(C=O)c(-c2ccncc2)s1
Reactant: CC(C)(C)[O-]
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: CS(C)=O
Product: C=Cc1nc(NC)sc1-c1ccncc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 27.1 %

Procedure:
Potassium tert-butoxide (1.46 g) was added to a solution of 2-methylamino-5-(4-pyridyl)-4-thiazolecarbaldehyde (1.9 g) and methyltriphenylphosphonium bromide (4.66 g) in dimethyl sulfoxide (87 ml) and the mixture was stirred for 5 hours at ambient temperature. The reaction mixture was poured into ice-water (300 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed with a saturated aqueous solution of sodium chloride (100 ml) and dried over magnesium sulfate. Solvent was distilled off and the residue was subjected to column chromatography on silica gel (120 g) and eluted with a mixture of chloroform and methanol (40:1). The fractions containing the object compound were combined and concentrated until the volume was about 15 ml. The resultant white needles were collected by filtration and washed with cold ethyl acetate and dried under reduced pressure to give white needles of 2-methylamino-5-(4-pyridyl)-4-vinylthiazole (510 mg).
Reaction SMILES: CCN=C=NCCCN(C)C.Cl.[CH3:13][O:14][C:15]1[N:20]=[C:19]([C:21]2[CH:22]=[C:23]([C:27]3([C:33](O)=[O:34])[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[CH:24]=[CH:25][CH:26]=2)[CH:18]=[C:17]([NH:36][CH2:37][CH2:38][C:39]2[CH:44]=[CH:43][C:42]([O:45][C:46]([F:49])([F:48])[F:47])=[CH:41][CH:40]=2)[N:16]=1.[CH3:50][S:51]([NH2:54])(=[O:53])=[O:52]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:13][O:14][C:15]1[N:20]=[C:19]([C:21]2[CH:22]=[C:23]([C:27]3([C:33]([NH:54][S:51]([CH3:50])(=[O:53])=[O:52])=[O:34])[CH2:28][CH2:29][O:30][CH2:31][CH2:32]3)[CH:24]=[CH:25][CH:26]=2)[CH:18]=[C:17]([NH:36][CH2:37][CH2:38][C:39]2[CH:44]=[CH:43][C:42]([O:45][C:46]([F:49])([F:48])[F:47])=[CH:41][CH:40]=2)[N:16]=1
Reactant: CS(N)(=O)=O
Reactant: COc1nc(NCCc2ccc(OC(F)(F)F)cc2)cc(-c2cccc(C3(C(=O)O)CCOCC3)c2)n1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: COc1nc(NCCc2ccc(OC(F)(F)F)cc2)cc(-c2cccc(C3(C(=O)NS(C)(=O)=O)CCOCC3)c2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.1 %

Procedure:
N-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride (39 mg, 0.2 mmol) is added to a stirred ice cold solution of N-[4-(3-{2-methoxy-6-[2-(4-trifluoromethoxy-phenyl)-ethylamino]-pyrimidin-4-yl}-phenyl)-tetrahydro-pyran-4-carboxylic acid (100 mg, 0.19 mmol), methanesulfonamide (19.3 mg, 0.2 mmol) and 4-dimethylaminopyridine (23.6 mg, 0.19 mmol) in dry DCM under nitrogen. The reaction mixture is stirred overnight at room temperature and concentrated in vacuo. The residue is dissolved in ethyl acetate, washed with 0.1 N HCl, brine and water, dried over sodium sulfate, filtered and concentrated in vacuo. The residue is purified by chromatography (SiO2 packed column), eluting with ethyl acetate/heptane to afford N-[4-(3-{2-methoxy-6-[2-(4-trifluoromethoxy-phenyl)-ethylamino]-pyrimidin-4-yl}-phenyl)-tetrahydro-pyran-4-carbonyl]-methanesulfonamide [86 mg, Example 84(a)]. LCMS: RT=2.52 minutes, LCMS: 595 (M+H). IC50=0.7 nM
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]([C:17]1[CH:18]=[N:19][C:20]([N:23]2[CH2:28][CH2:27][N:26]([CH2:29][CH3:30])[CH2:25][CH2:24]2)=[CH:21][CH:22]=1)=[O:16].[IH:31]>O>[I:31][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]([C:17]1[CH:18]=[N:19][C:20]([N:23]2[CH2:28][CH2:27][N:26]([CH2:29][CH3:30])[CH2:25][CH2:24]2)=[CH:21][CH:22]=1)=[O:16]
Reactant: I
Reactant: CCN1CCN(c2ccc(C(=O)NCCCCCCCCCCCCO)cn2)CC1
Solvent: O
Product: CCN1CCN(c2ccc(C(=O)NCCCCCCCCCCCCI)cn2)CC1

Procedure:
A solution of 2.09 g of N-(12-hydroxydodecyl)-6-(4-ethyl-1-piperazinyl)pyridine-3-carboxamide in 57% hydriodic acid was stirred at 120° C. for 30 minutes. The reaction solution was diluted with water and extracted with chloroform. The chloroform layer was washed with a saturated aqueous solution of sodium hydrogen carbonate and a saturated aqueous solution of sodium chloride, then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue thus obtained was chromatographed over a silica gel column to afford 1.94 g of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][C:12](=[O:14])[NH:11][C:10](=[O:15])[CH2:9]2)=[CH:4][C:3]=1Br.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[CH3:25][C:26]1([CH3:35])[CH2:31][CH2:30][C:29](B(O)O)=[CH:28][CH2:27]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1>C1(C)C=CC=CC=1.O1CCOCC1.CCOC(C)=O.CC([O-])=O.CC([O-])=O.[Pd+2]>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][C:12](=[O:14])[NH:11][C:10](=[O:15])[CH2:9]2)=[CH:4][C:3]=1[C:29]1[CH2:30][CH2:31][C:26]([CH3:35])([CH3:25])[CH2:27][CH:28]=1
Reactant: Nc1ccc(C2CC(=O)NC(=O)C2)cc1Br
Reactant: CC1(C)CC=C(B(O)O)CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=P([O-])([O-])[O-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: CC1(C)CC=C(c2cc(C3CC(=O)NC(=O)C3)ccc2N)CC1
Temperature: 80 °C
Yield: 21.1 %

Procedure:
A solution of 600 mg (2.12 mmol) of 4-(4-amino-3-bromo-phenyl)-piperidine-2,6-dione (as prepared in Example 1, step (j)) in toluene (20 mL) and dioxane (20 mL) was treated with 900 mg (4.24 mmol) of K3PO4, 424 mg (2.76 mmol) of 4,4-dimethyl-cyclohex-1-enylboronic acid, and 297 mg (0.848 mmol) of 2-(dicyclohexylphosphino)biphenyl. The mixture was degassed via sonication, placed under Ar, treated with 47.6 mg (0.212 mmol) of Pd(OAc)2, and heated to 80° C. for 2.5 h. The mixture was diluted with EtOAc (100 mL) and washed with water (2×70 mL). The aqueous layer was extracted with EtOAc (100 mL), the combined organic layers were dried (MgSO4) and concentrated in vacuo. Silica gel chromatography of the residue on a 50-g Varian MegaBond Elut SPE column with 25-50% EtOAc-hexane afforded 140 mg (21%) of the title compound as a tan solid: Mass spectrum (ESI, m/z): Calcd. for C19H24N2O2, 313.2 (M+H). found 313.1.