Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:4]1[CH:12]=[N:11][C:10]2[C:5]1=[N:6][C:7](N)=[N:8][C:9]=2[Cl:13])(=O)C.[Br:15][Si](C)(C)C.N(OCCC(C)C)=O>O1CCCC1>[Br:15][C:7]1[N:6]=[C:5]2[C:10]([NH:11][CH:12]=[N:4]2)=[C:9]([Cl:13])[N:8]=1
Reactant: CC(=O)n1cnc2c(Cl)nc(N)nc21
Reactant: C[Si](C)(C)Br
Agent: CC(C)CCON=O
Solvent: C1CCOC1
Product: Clc1nc(Br)nc2nc[nH]c12
Temperature: 22.5 °C
Reaction time: 19 h

Procedure:
9-Acetyl-2-amino-6-chloropurine (1.00 g, 4.72 mmol), bromotrimethylsilane (2.17 g, 14.2 mmol) and isoamyl nitrite (0.83 g, 5.67 mmol) were added to tetrahydrofuran (5 ml), and the mixture was stirred at 20-25° C. for 19 hr to give 2-bromo-6-chloropurine.
Reaction SMILES: [CH3:1][CH:2]([NH:4][CH2:5][C:6]1[S:10][C:9](B(O)O)=[CH:8][CH:7]=1)[CH3:3].Br[C:15]1[CH:16]=[C:17]2[C:21](=[C:22]([C:24]([NH2:26])=[O:25])[CH:23]=1)[NH:20][CH:19]=[C:18]2[CH:27]1[CH2:32][CH2:31][N:30]([S:33]([CH2:36][CH3:37])(=[O:35])=[O:34])[CH2:29][CH2:28]1.C(=O)([O-])[O-].[K+].[K+]>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>[CH2:36]([S:33]([N:30]1[CH2:29][CH2:28][CH:27]([C:18]2[C:17]3[C:21](=[C:22]([C:24]([NH2:26])=[O:25])[CH:23]=[C:15]([C:9]4[S:10][C:6]([CH2:5][NH:4][CH:2]([CH3:3])[CH3:1])=[CH:7][CH:8]=4)[CH:16]=3)[NH:20][CH:19]=2)[CH2:32][CH2:31]1)(=[O:35])=[O:34])[CH3:37]
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(Br)cc23)CC1
Reactant: CC(C)NCc1ccc(B(O)O)s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccc(CNC(C)C)s4)cc23)CC1
Yield: 37 %

Procedure:
Following the general procedure of 5-{5-[(ethylamino)methyl]-2-thienyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide, (5-formyl-2-thienyl)boronic acid (50 mg, 0.32 mmol), isopropylamine (0.027 mL, 0.32 mmol), and NaCNBH3 (40 mg, 0.64 mmol) were reacted to give 41 mg of crude (5-{[(1-methylethyl)amino]methyl}-2-thienyl)boronic acid. The crude (5-{[(1-methylethyl)amino]methyl}-2-thienyl)boronic acid was then reacted with 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide (80 mg, 0.193 mmol), potassium carbonate (160 mg, 1.16 mmol), and tetrakis(triphenylphosphine)palladium(0) (5 mg, 0.004 mmol) to give 74 mg of the title compound (37%).
Reaction SMILES: [N:1]1[C:6]2[NH:7][CH:8]=[CH:9][C:5]=2[C:4]([N:10]2[CH2:17][C:14]3([CH2:16][CH2:15]3)[N:13]([S:18]([NH2:21])(=[O:20])=[O:19])[CH2:12][CH2:11]2)=[N:3][CH:2]=1.S(N[CH2:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)(=O)(=O)N>>[CH2:27]([NH:21][S:18]([N:13]1[CH2:12][CH2:11][N:10]([C:4]2[C:5]3[CH:9]=[CH:8][NH:7][C:6]=3[N:1]=[CH:2][N:3]=2)[CH2:17][C:14]21[CH2:16][CH2:15]2)(=[O:20])=[O:19])[CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: NS(=O)(=O)N1CCN(c2ncnc3[nH]ccc23)CC12CC2
Reactant: NS(=O)(=O)NCCc1ccccc1
Product: O=S(=O)(NCCc1ccccc1)N1CCN(c2ncnc3[nH]ccc23)CC12CC2

Procedure:
Prepared in a way similar to intermediate 1, using 2-(sulfamoylamino)-ethylbenzene instead of sulfamide.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@@H:5]([NH:8][C:9]2[C:14]([C:15]#[N:16])=[CH:13][N:12]=[C:11](S(C)(=O)=O)[N:10]=2)[CH2:4][C:3]1([CH3:22])[CH3:21].[F:23][C:24]([F:37])([CH3:36])[CH2:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][CH2:34][NH2:35])=[CH:29][CH:28]=1.CCN(C(C)C)C(C)C>C1COCC1>[F:23][C:24]([F:37])([CH3:36])[CH2:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][CH2:34][NH:35][C:11]2[N:10]=[C:9]([NH:8][C@@H:5]3[CH2:6][CH2:7][C@H:2]([OH:1])[C:3]([CH3:22])([CH3:21])[CH2:4]3)[C:14]([C:15]#[N:16])=[CH:13][N:12]=2)=[CH:29][CH:28]=1
Reactant: CC(F)(F)COc1ccc(CCN)cc1
Reactant: CC1(C)C[C@H](Nc2nc(S(C)(=O)=O)ncc2C#N)CC[C@@H]1O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(F)(F)COc1ccc(CCNc2ncc(C#N)c(N[C@@H]3CC[C@H](O)C(C)(C)C3)n2)cc1
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 30 %

Procedure:
A mixture of 4-(((1R,4S)-4-hydroxy-3,3-dimethylcyclohexyl)amino)-2-(methylsulfonyl)pyrimidine-5-carbonitrile (90 mg, 0.28 mmol), 2-(4-(2,2-difluoropropoxyl)phenyl)ethanamine (70 mg crude) and DIEA (85 mg, 0.66 mmol) in THF (2 mL) was stirred at 100° C. in a microwave reactor for 1.5 h. After cooling to room temperature, the reaction mixture was concentrated and the residue was purified by standard methods to give the title product (38.6 mg, 0.084 mmol, 28% yield). 1H NMR (400 MHz, CD3OD) δ (ppm) 8.15-7.97 (m, 1H), 7.15 (d, J=8.4 Hz, 2H), 6.87 (d, J=8.4 Hz, 2H), 4.39-4.22 (m, 1H), 4.12 (t, J=11.6 Hz, 2H), 3.66-3.49 (m, 2H), 3.41-3.35 (m, 1H), 2.88-2.77 (t, J=7.2 Hz, 2H), 1.96-1.82 (m, 1H), 1.80-1.42 (m, 8H), 1.03-0.95 (m, 6H). MS (ESI) m/z 460.2 [M+H]+.
Reaction SMILES: [C:1]([C:4]1[CH:28]=[CH:27][C:7]2[N:8]3[CH:26]=[CH:25][CH:24]=[C:9]3[C:10]3([CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]3)[O:11][C:6]=2[CH:5]=1)(=O)[NH2:2].N1C(Cl)=NC(Cl)=NC=1Cl.O>CN(C=O)C>[C:1]([C:4]1[CH:28]=[CH:27][C:7]2[N:8]3[CH:26]=[CH:25][CH:24]=[C:9]3[C:10]3([CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]3)[O:11][C:6]=2[CH:5]=1)#[N:2]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)Oc1cc(C(N)=O)ccc1-n1cccc12
Agent: Clc1nc(Cl)nc(Cl)n1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC2(CC1)Oc1cc(C#N)ccc1-n1cccc12
Yield: 42.4 %

Procedure:
A solution of tert-butyl 7′-carbamoylspiro[piperidine-4,4′-pyrrolo[2,1-c][1,4]benzoxazine]-1-carboxylate (2.7 g, 7.1 mmol) and cyanuric chloride (1.3 g, 7.1 mmol) in DMF (10 mL) was stirred at room temperature for 1 hour. The reaction was poured into water and the product was extracted into ethyl acetate. The organics were dried over sodium sulfate, filtered and evaporated to yield a crude mixture that was purified by silica gel chromatography eluting with 0-100% EtOAc in Hexanes. Pure fractions were combined and concentrated to yield tert-butyl 7-cyanospiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′-carboxylate (1.1 g, 44%). ESI-MS m/z calc. 365.4. found 366.3 (M+1)+. Retention time: 2.00 minutes (3 min run).
Reaction SMILES: [NH2:1][C@H:2]([C:5]1[N:14]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:22][C:23]([F:26])([F:25])[F:24])[CH:16]=2)[C:13](=[O:27])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[F:28])[N:6]=1)[CH2:3][CH3:4].Cl[C:30]1[C:31]2[CH:38]=[CH:37][NH:36][C:32]=2[N:33]=[CH:34][N:35]=1.C(N(C(C)C)CC)(C)C>CC(O)(C)C>[N:33]1[C:32]2[NH:36][CH:37]=[CH:38][C:31]=2[C:30]([NH:1][C@H:2]([C:5]2[N:14]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:22][C:23]([F:26])([F:24])[F:25])[CH:16]=3)[C:13](=[O:27])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][C:11]=3[F:28])[N:6]=2)[CH2:3][CH3:4])=[N:35][CH:34]=1
Reactant: CC[C@H](N)c1nc2cccc(F)c2c(=O)n1-c1cccc(OCC(F)(F)F)c1
Reactant: Clc1ncnc2[nH]ccc12
Solvent: CC(C)(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CC[C@H](Nc1ncnc2[nH]ccc12)c1nc2cccc(F)c2c(=O)n1-c1cccc(OCC(F)(F)F)c1
Temperature: 120 °C
Reaction time: 14 h
Yield: 17.4 %

Procedure:
Under nitrogen, to (S)-2-(1-aminopropyl)-5-fluoro-3-(3-(2,2,2-trifluoroethoxy)phenyl)quinazolin-4(3H)-one (22 mg, 0.056 mmol, 1.0 equiv) in t-BuOH (0.11 mL) at 23° C. was added 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (10 mg, 0.067 mmol, 1.2 equiv) and diisopropylethylamine (19 μL, 0.11 mmol, 2.0 equiv). After stirring for 14 hr at 120° C. in a sealed tube, the reaction mixture was concentrated in vacuo and the residue was purified by preparative TLC eluting with CH2Cl2/MeOH to afford 5.0 mg of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([CH2:13][C:14]([OH:16])=[O:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CI.[C:19]([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:19][O:15][C:14](=[O:16])[CH2:13][CH:10]1[CH2:11][CH2:12][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(CC(=O)O)C1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)CC1CCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of 2-(1-(tert-butoxycarbonyl)pyrrolidin-3-yl)acetic acid (500 mg, 2.18 mmol, Astatec Pharmaceutical Technology Co.) in DMF (10 mL) was added methyl iodide (163 μL, 2.62 mmol, Sigma-Aldrich) and K2CO3 (904 mg, 6.53 mmol). These ingredients were stirred at a temperature of about 25° C. for 1 h after which the reaction mixture was quenched with water (20 mL), extracted three times with EtOAc (20 mL for each extraction), washed twice with water (20 mL for each wash), washed with saturated aqueous NaCl (10 mL), dried (MgSO4), and concentrated under reduced pressure to provide tert-butyl 3-(2-methoxy-2-oxoethyl)pyrrolidine-1-carboxylate as an oil. To a mixture of tert-butyl 3-(2-methoxy-2-oxoethyl)pyrrolidine-1-carboxylate (2.18 mmol) in dioxane (10 mL) at a temperature of about 25° C. was added 4N HCl in dioxane (10.8 mmol). Then the reaction mixture was stirred at 50° C. for 2 h. Thereafter, the mixture was concentrated under reduced pressure to provide 380 mg of the hydrochloride of methyl 2-(pyrrolidin-3-yl)acetate as a colorless oil (yield 96% for two steps), the identity of which was confirmed using 1H NMR and LC/MS.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.Cl.[CH3:8][N:9]1[CH2:14][CH2:13][CH:12]([C:15]([OH:17])=[O:16])[CH2:11][CH2:10]1.CN(C=O)C.[C:23]1([CH:29](O)[CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(Cl)Cl>[CH3:8][N:9]1[CH2:14][CH2:13][CH:12]([C:15]([O:17][CH:29]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:16])[CH2:11][CH2:10]1
Reactant: CN1CCC(C(=O)O)CC1
Reactant: OC(Cc1ccccc1)c1ccccc1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CN1CCC(C(=O)OC(Cc2ccccc2)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 37 %

Procedure:
Oxalyl dichloride (141 μl, 1.67 mmol) was added dropwise to a solution of 1-methylpiperidine-4-carboxylic acid hydrochloride (300 mg, 1.67 mmol) in DCM (20 ml) and few drops of DMF (catalytic amount). The reaction was stirred at room temperature for 2 hours. The volatiles were removed under vacuum, and the crude was taken up with pyridine (20 ml). 1,2-Diphenylethanol (331 mg, 1.67 mmol) was added, and the resulting suspension was heated under microwave irradiation at 140° C. for 1 hour. Pyridine was removed under vacuum, and the crude was purified by flash chromatography (DCM/MeOH=97/3 to 94/6) to obtain 1,2-diphenylethyl 1-methylpiperidine-4-carboxylate (200 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[N:11][C:12]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)=[N:13][CH:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[F:22][C:23]([F:51])([C:47]([F:50])([F:49])[F:48])[C:24]([F:46])([F:45])[C:25]([F:44])([F:43])[O:26][C:27]([F:42])([F:41])[C:28]([F:40])([F:39])[O:29][C:30]([F:38])([F:37])[CH2:31][O:32][CH2:33][CH2:34][CH2:35]Br>O>[CH2:1]([O:8][C:9]1[CH:14]=[N:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]([O:21][CH2:35][CH2:34][CH2:33][O:32][CH2:31][C:30]([O:29][C:28]([F:39])([F:40])[C:27]([F:41])([F:42])[O:26][C:25]([F:43])([F:44])[C:24]([F:45])([F:46])[C:23]([F:22])([F:51])[C:47]([F:50])([F:49])[F:48])([F:38])[F:37])=[CH:19][CH:20]=2)=[N:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: FC(F)(COCCCBr)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: CCCCCCCOc1cnc(-c2ccc(O)cc2)nc1
Solvent: O
Product: CCCCCCCOc1cnc(-c2ccc(OCCCOCC(F)(F)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)cc2)nc1

Procedure:
The title compound was prepared essentially as described in Example 1 by combining 5-heptyloxy-2-(4-hydroxyphenyl)pyrimidine (3.0 g, 10.0 mmol) and 3-(2-(2-(nonafluorobutoxy)tetrafluoroethoxy)-2,2-difluoroethoxy)-1-bromopropane (6.6 g, 12.0 mmol, Example 10). The product was isolated by addition of water (60 mL) to the resulting mixture, followed by filtration and recrystallization from ethanol. The recrystallized precipitate was dried at about 130° C., and the resulting product was further purified by Kugelrohr distillation (b.p. 180-190° C. at 2 torr; yield 5.6 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:16][S:17][CH2:18][C:19]([O:21]CC)=[O:20])[O:13][CH2:12][C:11]([CH3:15])([CH3:14])[CH2:10][O:9]2)=[CH:4][CH:3]=1.[Li+].[OH-]>C1COCC1.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:16][S:17][CH2:18][C:19]([OH:21])=[O:20])[O:9][CH2:10][C:11]([CH3:15])([CH3:14])[CH2:12][O:13]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)CSCC1(c2ccc(Cl)cc2)OCC(C)(C)CO1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)COC(CSCC(=O)O)(c2ccc(Cl)cc2)OC1
Temperature: 0 °C
Reaction time: 18 h
Yield: 96.2 %

Procedure:
Ethyl ({[2-(4-chlorophenyl)-5,5-dimethyl-1,3-dioxan-2-yl]methyl}thio)acetate (3.36 g, 9.36 mmol) was dissolved in THF (45 ml) and cooled to 0° C. LiOH (0.79 g, 18.8 mmol) in water (12 ml) was added and the mixture was stirred for 18 h at room temperature. The solvents were evaporated. The crude product was extracted between water and diethyl ether. The aqueous layer was acidified using 2M HCl to pH 6 and extracted twice with CH2Cl2. The combined CH2Cl2 layers were dried (Na2SO4) and concentrated under reduced pressure to afford 2.98 g (96%) of the title compound as an yellow oil. 1H-NMR (CDCl3, 300 MHz): δ 0.62 (s, 3H), 1.34 (s, 3H), 2.95 (s, 2H), 3.34 (s, 2H), 3.45 (s, 4H), 7.4 (m, 4H)
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([NH:14][C:15]([C:17]3[CH:18]=[C:19]4[C:24](=[CH:25][CH:26]=3)[C:23](Cl)=[N:22][N:21]=[C:20]4[Cl:28])=[O:16])[CH:11]=[CH:12][CH:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].[O:31]1CCOCC1.Cl>O>[N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([NH:14][C:15]([C:17]3[CH:18]=[C:19]4[C:24](=[CH:25][CH:26]=3)[C:23](=[O:31])[NH:22][N:21]=[C:20]4[Cl:28])=[O:16])[CH:11]=[CH:12][CH:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1COCCO1
Reactant: O=C(Nc1cccc(CN2CCCCC2)c1)c1ccc2c(Cl)nnc(Cl)c2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(Nc1cccc(CN2CCCCC2)c1)c1ccc2c(=O)[nH]nc(Cl)c2c1
Temperature: 50 °C

Procedure:
A mixture of 1,4-dichloro-phthalazine-6-carboxylic acid (3-piperidin-1-ylmethyl-phenyl)-amide (257 mg, 0.619 mmol), 2N NaOH (3.1 mL, 6.19 mmol) and dioxane (5 mL) was heated to 50° C. for 1 h. The reaction was diluted with water, acidified with conc. HCl to ˜pH 6. The reaction mixture was concentrated to low volume and filtered through celite. Preparatory HPLC afforded the desired regioisomer 4-chloro-1-oxo-1,2-dihydro-phthalazine-6-carboxylic acid (3-piperidin-1-ylmethyl-phenyl)-amide hydroformate (16 mg) as a pale yellow solid, 1H NMR (400 MHz, d6-DMSO) δ: 1.54 (m, 2H), 1.44 (m, 4H), 2.28 (m, 4H), 3.37 (s, 2H), 7.00 (m, 1H), 7.25 (m, 1H), 7.67 (m, 2H), 8.06 (d, 1H), 8.10 (s, 1H), 8.47 (dd, 1H), 8.82 (d, 1H), 10.63 (1H), 12.95 (s, 1H) ppm; m/z (M+1) 396.95.
Reaction SMILES: [NH:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]1=[O:7].[OH:8][C:9]1C(=O)N(CC2C=CC(OC)=CC=2)CCC=1C(=O)CC.COS(OC)(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[CH3:9][O:8][C:3]1[C:2](=[O:7])[NH:1][CH:6]=[CH:5][CH:4]=1
Reactant: O=c1cccc[nH]1
Reactant: CCC(=O)C1=C(O)C(=O)N(Cc2ccc(OC)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: COS(=O)(=O)OC
Product: COc1ccc[nH]c1=O
Reaction time: 16 h

Procedure:
said pyridinone compound of Formula (6.0.0) by methylation with dimethylsulfate; wherein a reaction mixture is established with dimethylformamide (DMF) solvent in the presence of cesium carbonate, Cs2CO3, with gradual addition of said dimethylsulfate over a period of 30 minutes, while said reaction mixture temperature is kept at from 20° to 25° C.; and thereafter, said reaction mixture is maintained at said temperature and stirred for 16 hours; whereby there is produced a 3-methoxy-pyridinone compound N-protected by p-methoxybenzyl, of Formula (7.0.0):
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[C:5]1[C:10](Br)=[CH:9][CH:8]=[N:7][C:6]=1[Cl:12])[CH3:2].[CH3:14][O-:15].[Na+]>CO.CCOC(C)=O>[CH2:1]([O:3][C:4](=[O:13])[C:5]1[C:10]([O:15][CH3:14])=[CH:9][CH:8]=[N:7][C:6]=1[Cl:12])[CH3:2]
Reactant: C[O-]
Reactant: CCOC(=O)c1c(Br)ccnc1Cl
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(OC)ccnc1Cl
Temperature: 40 °C
Reaction time: 4 h

Procedure:
To a solution of 4-bromo-2-chloronicotinic acid ethyl ester (5.06 mmol) in 15 mL MeOH was added 1.0 mL of a solution of NaOMe (30% in MeOH). The reaction mixture was stirred at 40° C. for 4 h, cooled to RT, diluted with EtOAc and then quenched with sat. aq. NH4Cl solution. The organic layers was dried over MgSO4 and concentrated in vacuo to give the desired compound as brown oil;
Reaction SMILES: [CH3:1][Mg+].[Br-].[Cl:4][C:5]1[C:13]2[CH:12]=[C:11]([C:14](N(OC)C)=[O:15])[S:10][C:9]=2[CH:8]=[CH:7][CH:6]=1>C1COCC1>[Cl:4][C:5]1[C:13]2[CH:12]=[C:11]([C:14](=[O:15])[CH3:1])[S:10][C:9]=2[CH:8]=[CH:7][CH:6]=1
Reactant: CON(C)C(=O)c1cc2c(Cl)cccc2s1
Reactant: C[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Product: CC(=O)c1cc2c(Cl)cccc2s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.5 %

Procedure:
Add a solution of CH3MgBr (3 M in THF, 1.7 ml, 4.99 mmol) to a suspension of 4-chloro-N-methoxy-N-methylbenzo[b]thiophene-2-carboxamide (0.85 g, 3.33 mmol) in dry THF (10 mL) at 0° C. Then stir the mixture for overnight at ambient temperature. Quench the reaction with saturated NH4Cl aqueous solution (15 mL) and extract the aqueous mixture with EtOAc (10 mL×3). The combined organic layers are washed with brine, dried over anhydrous Na2SO4 and concentrated under vacuum. Purify the residue by silica gel chromatograph (PE:EtOAc=6:1) to afford 1-(4-chlorobenzo[b]thiophen-2-yl)ethanone as white solid (0.6 g, 86.9%). 1H NMR (400 MHz, CDCl3) δ 8.10-8.07 (s, 1H), 7.75 (d, J=5.2, 1H), 7.47-7.36 (m, 2H), 2.72-2.68 (s, 3H).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.CCCCCC.C([Li])CCC.O([Si:25]([CH:32]([CH3:34])[CH3:33])([CH:29]([CH3:31])[CH3:30])[CH:26]([CH3:28])[CH3:27])S(C(F)(F)F)(=O)=O>C1COCC1>[CH:26]([Si:25]([CH:32]([CH3:34])[CH3:33])([CH:29]([CH3:31])[CH3:30])[C:2]1[O:1][CH:5]=[CH:4][N:3]=1)([CH3:28])[CH3:27]
Reactant: c1cocn1
Reactant: CC(C)[Si](OS(=O)(=O)C(F)(F)F)(C(C)C)C(C)C
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)[Si](c1ncco1)(C(C)C)C(C)C
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a solution of oxazole (2.1 g) in THF (90 mL) was added dropwise n-butyllithium hexane solution (1.6M, 19.7 mL) at −78° C. The reaction mixture was stirred at 0° C. for 10 min under nitrogen atmosphere, and triisopropylsilyl triflate (8.5 mL) was added thereto. The reaction mixture was stirred at room temperature for 2 hr, and the solvent was evaporated under reduced pressure. To the residue was added ethyl acetate, and the mixture was washed with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (6.7 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[C:4]([N+:9]([O-])=O)[C:3]=1[NH:12][C:13]([CH:15]1[CH2:19][CH2:18][O:17][CH2:16]1)=[O:14].[H][H]>C(OCC)(=O)C.[Ni]>[NH2:9][C:4]1[CH:5]=[C:6]([OH:8])[CH:7]=[C:2]([Cl:1])[C:3]=1[NH:12][C:13]([CH:15]1[CH2:19][CH2:18][O:17][CH2:16]1)=[O:14]
Reactant: O=C(Nc1c(Cl)cc(O)cc1[N+](=O)[O-])C1CCOC1
Reactant: [H][H]
Agent: [Ni]
Solvent: CCOC(C)=O
Product: Nc1cc(O)cc(Cl)c1NC(=O)C1CCOC1

Procedure:
0.60 g (2.09 mmol) N-(2-chloro-4-hydroxy-6-nitrophenyl)tetrahydrofuran-3-carboxamide were placed in 10 mL ethyl acetate and hydrogenated under a hydrogen atmosphere and with the addition of 0.20 g Raney nickel at RT and a hydrogen pressure of 3 bar until all the hydrogen had been taken up. The catalyst was filtered off and the filtrate was evaporated down i.vac.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][C@H:10]([O:13][C:14]2[C:15]3[CH2:23][N:22]([CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH2:21][CH2:20][C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:24]([N:22]1[CH2:21][CH2:20][C:16]2[N:17]=[CH:18][N:19]=[C:14]([O:13][C@H:10]3[CH2:11][CH2:12][NH:8][CH2:9]3)[C:15]=2[CH2:23]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](Oc2ncnc3c2CN(Cc2ccccc2)CC3)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: c1ccc(CN2CCc3ncnc(O[C@H]4CCNC4)c3C2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.2 %

Procedure:
To a solution of (S)-3-(6-benzyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy)-pyrrolidine-1-carboxylic acid tert-butyl ester (560 mg, 1.364 mmol) in 2 mL of CH2Cl2 was added TFA (1.576 mL, 20.46 mmol). The reaction mixture was stirred at rt for 1 h, concentrated and then eluted through an Isolute SCX-2 cartridge (10 g) to remove excess TFA with (i) MeOH (ii) NH3/MeOH and the basic fraction evaporated in vacuum to give 6-benzyl-4-((S)-pyrrolidin-3-yloxy)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine (420 mg, quantitative yield) as a yellow gum. LCMS: [M+H]+=311.2, Rt(3)=0.11.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][C:9]1([C:15]([OH:17])=O)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.CN(C(O[N:26]1N=[N:33][C:28]2C=CC=N[C:27]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.NCC#N.CCN(CC)CC>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][C:9]1([C:15]([NH:33][CH2:28][C:27]#[N:26])=[O:17])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: O=C(O)C1(Sc2ccccc2Br)CCCCC1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: N#CCN
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: N#CCNC(=O)C1(Sc2ccccc2Br)CCCCC1
Reaction time: 8 h

Procedure:
To a mixture of 1-[(2bromophenyl)sulfanyl]cyclohexanecarboxylic acid (77 mg, 0.24 mmol), HATU (99 mg, 0.26 mmol) and aminoacetonitrile hydrochloride (33 mg, 0.35 mmol) in DMF (3 mL) was added Et3N (0.1 mL, 0.72 mmol). The mixture was stirred overnight, then partitioned between ethyl acetate and 1 M HCl. The organic phase was washed with water, 1 M NaOH and brine, then dried over MgSO4 and concentrated to give 1-[(2-bromophenyl)sulfanyl]-N-(cyanomethyl)cyclohexanecarboxamide.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Br:12]Br>>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([CH2:11][Br:12])=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(C(C)(C)C)cc1
Reactant: BrBr
Product: CC(C)(C)c1ccc(CBr)cc1

Procedure:
In another known process in which a Cu salt is likewise used, i.e. Cu(NO3)2, p-tert.butyltoluene is the starting material, which is first reacted with an approximately equivalent amount of bromine to give p-tert.butylbenzyl bromide which is then boiled for a prolonged period of time in combination with a Cu(NO3)2 solution. p-tert.Butylbenzaldehyde is obtained in this manner in a yield of about 42% of the theory (cf. J. Chem. Soc., 1935, page 1848).
Reaction SMILES: Br[CH:2](Br)[C:3]1[C:12]2[O:11][C:10]([CH3:13])=[CH:9][C:8](=[O:14])[C:7]=2[C:6]([C:15]#[N:16])=[CH:5][CH:4]=1.C[N+]1([O-])CC[O:22]CC1>C(#N)C>[CH:2]([C:3]1[C:12]2[O:11][C:10]([CH3:13])=[CH:9][C:8](=[O:14])[C:7]=2[C:6]([C:15]#[N:16])=[CH:5][CH:4]=1)=[O:22]
Reactant: Cc1cc(=O)c2c(C#N)ccc(C(Br)Br)c2o1
Reactant: C[N+]1([O-])CCOCC1
Solvent: CC#N
Product: Cc1cc(=O)c2c(C#N)ccc(C=O)c2o1

Procedure:
260 mg (0.72 mmol) of 8-(dibromomethyl)-2-methyl-4-oxo-4H-chromene-5-carbonitrile are heated with 187 mg (1.6 mmol) of N-methylmorpholine N-oxide with the addition of molecular sieves in 15 ml of acetonitrile under reflux overnight. After filtration through kieselguhr, the solvent is removed in vacuo, and the residue is purified by preparative HPLC. 23 mg (15% of theory) of the title compound are obtained.