Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N-:1]=[N+]=[N-].[Na+].[Br:5][C:6]1[CH:14]=[C:13]2[C:9]([CH2:10][CH2:11][C:12]2=[O:15])=[CH:8][CH:7]=1.CS(O)(=O)=O>C(Cl)Cl>[Br:5][C:6]1[CH:14]=[C:13]2[C:9]([CH2:10][CH2:11][NH:1][C:12]2=[O:15])=[CH:8][CH:7]=1
Reactant: O=C1CCc2ccc(Br)cc21
Reactant: [N-]=[N+]=[N-]
Agent: CS(=O)(=O)O
Agent: [Na+]
Solvent: ClCCl
Product: O=C1NCCc2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 15 h
Yield: 60.7 %

Procedure:
Sodium azide (0.431 g, 6.63 mmol) was added slowly to a mixture of 6-bromo-2,3-dihydro-1H-inden-1-one (1 g, 4.74 mmol) and methanesulfonic acid (15 mL, 231 mmol) in DCM (30 mL) at 0° C. The mixture was stirred at rt for 15 hrs, then was carefully quenched with 1 M aqueous sodium hydroxide (50 mL). The aqueous layer was extracted with DCM (3×50 mL), and the combined organic layers were washed with water (20 mL) and brine (20 mL), dried and concentrated. The residue was purified by column chromatography (eluting with a gradient from 90:10 hexane-EtOAc to EtOAc) to give 7-bromo-3,4-dihydroisoquinolin-1(2H)-one as white solid (650 mg, 61%). 1H NMR (400 MHz, chloroform-d) δ 8.35 (1H, br. s.), 7.08-7.17 (1 H, m), 6.98-7.06 (1H, m), 6.95 (1H, d, J=1.98 Hz), 2.93 (2H, t, J=7.59 Hz), 2.49-2.68 (2H, m). Mass spectrum m/z 226, 228 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([I:23])=[CH:19][C:18]=2[F:24])=[C:4]([C:9]([N:11]2[CH2:14][CH:13]([OH:15])[CH2:12]2)=[O:10])[CH:5]=[CH:6][C:7]=1[F:8].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C(OCC)(=O)C>ClCCl>[F:1][C:2]1[C:3]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([I:23])=[CH:19][C:18]=2[F:24])=[C:4]([C:9]([N:11]2[CH2:12][C:13](=[O:15])[CH2:14]2)=[O:10])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C(c1ccc(F)c(F)c1Nc1ccc(I)cc1F)N1CC(O)C1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C1CN(C(=O)c2ccc(F)c(F)c2Nc2ccc(I)cc2F)C1
Temperature: 0 °C
Reaction time: 2 h
Yield: 92.5 %

Procedure:
1-({3,4-Difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol (132 mg, 0.295 mmol)ures similar to those in Example 1, was dissolved in dichloromethane (8 mL) and cooled to 0° C. Dess-Martin periodinane (187 mg, 0.441 mmol) was added and the mixture was stirred at ambient for 2 h. The mixture was quenched with saturated sodium bicarbonate solution: 10% sodium thiosulfate solution (1:1; 6 mL) and diluted with ethyl acetate. The organic portion was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Column chromatography (silica gel, 40-50% ethyl acetate in hexanes) gave 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-one (122 mg, 0.273 mmol, 93% yield): 1H NMR (400 MHz, CDCl3): 8.43 (br s, 1H), 7.44-7.38 (m, 1H), 7.36-7.32 (m, 1H), 7.27-7.20 (m, 1H), 6.86 (ddd, 1H), 6.64 (ddd, 1H), 4.94-4.93 (m, 4H); MS (EI) for C16H10F3IN2O2: 447 (MH+).
Reaction SMILES: [CH3:1][C:2]([NH2:11])([CH2:4][CH2:5][N:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1)[CH3:3].[C:12](ON1C(=O)CCC1=O)([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13]>C1COCC1>[CH3:3][C:2]([NH:11][C:12](=[O:13])[O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([CH2:4][CH2:5][N:6]1[CH2:7][CH2:8][CH2:9][CH2:10]1)[CH3:1]
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Reactant: CC(C)(N)CCN1CCCC1
Solvent: C1CCOC1
Product: CC(C)(CCN1CCCC1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 62.6 %

Procedure:
Crude 2-methyl-4-(pyrrolidin-1-yl)butan-2-amine (5.70 g, 31.7 mmol) was dissolved into THF (200 mL). To this solution was added CbzOSu (7.92 g, 1 equiv, 31.7 mmol) in one portion. The reaction was left to stir at room temperature for 16 h. The solvent was removed and the residue was taken up in a mixture of ethyl acetate (150 mL) and water (50 mL). The layers were separated and the organic layer washed with 1 M sodium carbonate (2×50 mL), 1 M HCl (50 mL) and brine (50 mL). The organic layer was dried over anhydrous MgSO4, filtered and concentrated to a pale yellow oil (9.0 g). The crude oil was purified on an ISCO purification system with gradient elution from 5-90% ethyl acetate in hexanes. The desired fraction was collected and concentrated to give a pale yellow oil (5.76 g, yield: 62.5%). 1H NMR (CDCl3, 400 MHz): δ 1.34 (s, 6H), 1.76-1.84 (m, 6H), 2.58-2.66 (m, 6H), 5.04 (s, 2H), 6.36 (bs, 1H), 7.27-7.39 (m, 5H). LRMS (ESI+) for C17H26N2O2 (290.2); Found: 291 (MH+).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][NH:5][CH2:6][CH2:7][CH2:8][CH2:9][NH:10][CH2:11][CH2:12][CH2:13][NH2:14].[OH-:15].[Na+].[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1>C(Cl)Cl>[S:23]([C:13]([S:23]([C:20]1[CH:21]=[CH:22][C:17]([CH3:27])=[CH:18][CH:19]=1)(=[O:25])=[O:24])([CH2:12][CH2:11][NH:10][CH2:9][CH2:8][CH2:7][CH2:6][NH:5][CH2:4][CH2:3][CH2:2][NH2:1])[N:14]([S:23]([C:20]1[CH:21]=[CH:22][C:17]([CH3:27])=[CH:18][CH:19]=1)(=[O:25])=[O:24])[S:23]([C:20]1[CH:21]=[CH:22][C:17]([CH3:27])=[CH:18][CH:19]=1)(=[O:24])=[O:15])([C:20]1[CH:21]=[CH:22][C:17]([CH3:27])=[CH:18][CH:19]=1)(=[O:25])=[O:24]
Reactant: [OH-]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: NCCCNCCCCNCCCN
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)N(C(CCNCCCCNCCCN)(S(=O)(=O)c2ccc(C)cc2)S(=O)(=O)c2ccc(C)cc2)S(=O)(=O)c2ccc(C)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
N1,N2, N3, N4 -Tetra-p-tosylspermine, To spermine tetrahydrocbloride (4.53 g, 13.0 mmol) and 10% aqueous NaOH (200 mL, 132 mmol) at 0° is added dropwise p-toluene-sulfonyl chloride (9.98 g, 52.3 mmol) in CH2Cl2 with rapid stirring. After 1 hr the mixture is allowed to warm to room temperature and to stir for 2 days. The organic phase is separated and washed with 0.5 N HCl, H2O, and brine, dried over Na2SO4 and purified on silica gel (450 g, 3% MeOH/CHCl3) to give 9.69 g, 91% yield of tetratosylspermine.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([CH:18]2[CH2:20][CH2:19]2)[NH:5][C:6]=1[C:7]1[CH:12]=[CH:11][N:10]=[C:9]([NH:13][CH2:14][C@@H:15]([NH2:17])[CH3:16])[N:8]=1.C1COCC1.O.C([O-])(O)=O.[Na+].Cl[C:33]([O:35][CH3:36])=[O:34]>O>[Br:1][C:2]1[N:3]=[C:4]([CH:18]2[CH2:20][CH2:19]2)[NH:5][C:6]=1[C:7]1[CH:12]=[CH:11][N:10]=[C:9]([NH:13][CH2:14][C@@H:15]([NH:17][C:33](=[O:34])[O:35][CH3:36])[CH3:16])[N:8]=1
Reactant: COC(=O)Cl
Reactant: C[C@H](N)CNc1nccc(-c2[nH]c(C3CC3)nc2Br)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)N[C@@H](C)CNc1nccc(-c2[nH]c(C3CC3)nc2Br)n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 88.3 %

Procedure:
A mixture of (S)—N1-(4-(4-bromo-2-cyclopropyl-1H-imidazol-5-yl)pyrimidin-2-yl)propane-1,2-diamine (13.3 g, 27.3 mmol, assumed theoretical yield) in 1:1 THF-water (200 mL) was cooled to 0° C. and solid NaHCO3 (20.6 g, 245 mmol) was added in portions. Methyl chloroformate (3.74 mL, 27.3 mmol) was added dropwise over 20 minutes and stirred for an additional 30 minutes. LCMS of an aliquot indicated complete reaction. Water (300 mL) was added and the resulting mixture was extracted with EtOAc (3×500 mL). The EtOAc layer was washed with brine (2×1 L), dried (Na2SO4) and concentrated. The resulting solid was suspended in a mixture of EtOAc (7 mL) and ethyl ether (25 mL) and the resulting suspension was allowed to settle at 0° C. The solids were collected and washed with cold Et2O (20 mL) to afford (S)-methyl 1-(4-(4-bromo-2-cyclopropyl-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate (9.56 g, 24.1 mmol, 89%) as an off-white solid: LCMS(m/z) 395.1 (MH+), tR=0.61 minute; 1H NMR (400 MHz, CDCl3) δ 0.91-1.03 (m, 2H), 1.08-1.19 (m, 2H), 1.22 (d, J=6.6 Hz, 3H), 1.77 (br s, 1H), 2.13-2.26 (m, 1H), 2.70-2.90 (m, 1H), 3.70 (s, 3H), 3.90-4.03 (m, 1H), 4.18-4.32 (m, 1H), 4.46-4.86 (m, 1H), 5.48-5.60 (m, 1H), 7.46 (d, J=5.5 Hz, 1H), 8.24 (d, J=5.4 Hz, 1H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.C(N=C=NCCCN(C)C)C.[CH3:19][O:20][C:21]1[C:22](=[O:49])[C:23]([CH3:48])=[C:24]([CH2:30][C:31]2[CH:32]=[CH:33][C:34]([O:40][CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)=[C:35]([CH:39]=2)[C:36](O)=[O:37])[C:25](=[O:29])[C:26]=1[O:27][CH3:28]>C(Cl)Cl>[CH3:19][O:20][C:21]1[C:22](=[O:49])[C:23]([CH3:48])=[C:24]([CH2:30][C:31]2[CH:32]=[CH:33][C:34]([O:40][CH2:41][C:42]3[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=3)=[C:35]([CH:39]=2)[C:36]([N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[O:37])[C:25](=[O:29])[C:26]=1[O:27][CH3:28]
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OCc3ccccc3)c(C(=O)O)c2)=C(C)C1=O
Reactant: C1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: COC1=C(OC)C(=O)C(Cc2ccc(OCc3ccccc3)c(C(=O)N3CCCCC3)c2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 43.3 %

Procedure:
Piperidine (0.025 g, 0.296 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.068 g, 0.355 mmol) were added to a methylene chloride solution (5 ml) of 5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-benzyloxybenzoic acid (0.050 g, 0.118 mmol) and the resulting solution was stirred at room temperature for 12 hours. The reaction solution was poured into ice water and then extracted with methylene chloride. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (chloroform:methanol=10:1) to obtain the titled compound (0.025 g, 0.0511 mmol, 43%).
Reaction SMILES: [N+:1]([C:4]1[C:10]([OH:11])=[CH:9][CH:8]=[CH:7][C:5]=1[OH:6])([O-])=O.C(N(CC)CC)C.[C:19](Cl)(=[O:21])[CH3:20].[OH-].[Na+]>CO.ClCCl.[Pd]>[OH:6][C:5]1[CH:7]=[CH:8][CH:9]=[C:10]([OH:11])[C:4]=1[NH:1][C:19](=[O:21])[CH3:20]
Reactant: CC(=O)Cl
Reactant: O=[N+]([O-])c1c(O)cccc1O
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CO
Product: CC(=O)Nc1c(O)cccc1O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 2-nitroresorcinol (1.0 g, 6.45 mmol) and 10% Pd—C (100 mg) in methanol (15 mL) was stirred under an atmosphere of hydrogen at ambient temperature for 4 hours. The reaction mixture was filtered through celite and the filtrate concentrated under reduced pressure. A mixture of the residue, triethylamine (1.8 mL, 12.9 mmol) and acetyl chloride (1.38 mL, 19.35 mmol) in dichloromethane (15 mL) was stirred at ambient temperature for 1 hour, poured into 1N NaOH (20 mL) and methanol (20 mL). After 10 minutes, the mixture was concentrated under reduced pressure and taken up in ethyl acetate and 1N HCl (50 mL, 1:1). The layers were separated and the organic phase was washed with brine, dried (MgSO4), filtered and concentrated to provide titled compound. MS (ESI (−)) m/e 166(M−H)+; 1H NMR (300 MHz, DMSO-d6) 9.31(s, 2H), 6.86 (t, 1H), 6.34 (d, 2H), 2.11(s, 3H).
Reaction SMILES: [F:1][B-](F)(F)F.N#[O+].N1C=CC=CC=1.[FH:14].C([O:18][C:19]1([C:33]2([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)SCCCS2)[CH2:24][CH2:23][CH2:22][CH:21]([NH:25]C(OC(C)(C)C)=O)[CH2:20]1)(=O)C.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl>[NH2:25][CH:21]1[CH2:22][CH2:23][CH2:24][C:19]([C:33]([F:1])([F:14])[C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)([OH:18])[CH2:20]1
Reactant: F
Reactant: CC(=O)OC1(C2(c3ccccc3)SCCCS2)CCCC(NC(=O)OC(C)(C)C)C1
Reactant: F[B-](F)(F)F
Agent: N#[O+]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: NC1CCCC(O)(C(F)(F)c2ccccc2)C1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of nitrosonium tetrafluoroborate (1.1 mmol, 128.5 mg) and hydrogen fluoride pyridine (0.5 mL) in DCM (2 mL) at 0° C. under argon was added a solution of 3-(tert-butoxycarbonylamino)-1-(2-phenyl-1,3-dithiaN-2-yl)cyclohexyl acetate (0.5 mmol, 226 mg) in DCM dropwise. The reaction mixture was stirred at 0° C. for 1 hour. Sodium carbonate (solid) was added until no further gas bubbling. The mixture and the methanol washings were filtered. The filtrate was concentrated. 3-Amino-1-(difluoro(phenyl)methyl)cyclohexanol was obtained after purification by reverse phase HPLC.
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][N:9]([C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:13])[CH2:8][CH2:7]2)[CH:5]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:4][NH:3]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].O1CCCC1.Br[CH2:44][C:45]1[CH:46]=[C:47]([CH:52]=[CH:53][CH:54]=1)[C:48]([O:50][CH3:51])=[O:49]>CN(C)C=O.C(OCC)(=O)C>[CH3:51][O:50][C:48]([C:47]1[CH:46]=[C:45]([CH:54]=[CH:53][CH:52]=1)[CH2:44][N:3]1[CH2:4][CH:5]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:6]2([CH2:11][CH2:10][N:9]([C:12]([O:14][CH2:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[O:13])[CH2:8][CH2:7]2)[C:2]1=[O:1])=[O:49]
Reactant: O=C(OCc1ccccc1)N1CCC2(CC1)C(=O)NCC2c1ccccc1
Reactant: COC(=O)c1cccc(CBr)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc(CN2CC(c3ccccc3)C3(CCN(C(=O)OCc4ccccc4)CC3)C2=O)c1
Yield: 86.3 %

Procedure:
A mixture of benzyl 1-oxo-4-phenyl-2,8-diazaspiro[4.5]decane-8-carboxylate (1 g, 3.03 mmol, 1 equiv), lithium bis(trimethylsilyl)amide, 1M in tetrahydrofuran (3.33 ml, 3.33 mmol, 1.1 equiv), and methyl 3-(bromomethyl)benzoate (694.08 g, 3.03 mmol, 1 equiv) in N,N-dimethylformamide was stirred for 16 h at ambient temperature. Reaction was diluted with ethyl acetate and the organic layer was washed with water and brine. The combined organic layers were dried over MgSO4 and concentrated in vacuo. The crude residue was purified using the Biotage flash chromatography system (SNAP 100 g cartridge, Rf=0.6, gradient—10%-50% ethyl acetate in hexanes) to afford the title compound as a cream solid (1.34 g, 92%); 1H NMR (400 MHz, DMSO-d6): δ 0.87-0.92 (m, 1H); 1.33 (s, 9H); 1.46-1.51 (m, 2H); 1.54-1.65 (m, 1H); 3.03-3.07 (m, 1H); 3.34-3.40 (m, 3H); 3.46-3.48 (m, 1H); 3.57-3.61 (m, 1H); 3.69-3.71 (m, 1H); 3.86 (s, 3H); 4.56 (s, 2H); 7.14-7.16 (m, 2H); 7.20-7.28 (m, 3H); 7.52-7.59 (m, 2H); 7.89-7.91 (m, 2H); MS for C31H32N2O5 m/z 513.23 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]1[CH2:8][C:7]2[CH:9]=[C:10]3[O:15][CH2:14][O:13][C:11]3=[CH:12][C:6]=2[C:5]([C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=2)=[N:4][N:3]1[C:25](=[S:27])[NH2:26].[CH2:28](OC(OCC)CBr)[CH3:29].CN(C)C=O>O>[CH3:1][CH:2]1[CH2:8][C:7]2[CH:9]=[C:10]3[O:15][CH2:14][O:13][C:11]3=[CH:12][C:6]=2[C:5]([C:16]2[CH:17]=[CH:18][C:19]([N+:22]([O-:24])=[O:23])=[CH:20][CH:21]=2)=[N:4][N:3]1[C:25]1[S:27][CH:28]=[CH:29][N:26]=1
Reactant: CC1Cc2cc3c(cc2C(c2ccc([N+](=O)[O-])cc2)=NN1C(N)=S)OCO3
Reactant: CCOC(CBr)OCC
Solvent: O
Solvent: CN(C)C=O
Product: CC1Cc2cc3c(cc2C(c2ccc([N+](=O)[O-])cc2)=NN1c1nccs1)OCO3
Temperature: 80 °C
Reaction time: 0.67 h
Yield: 80 %

Procedure:
A mixture of 1.00 g (2.60 mmol) of the starting material I, 2.54 g (12.89 mmol) of bromoacetaldehyde diethyl acetal and 10 ml of dimethylformamide was stirred at 80° C. for 40 min. Then the reaction mixture was diluted with water and the crude product obtained was recrystallized from ethanol to yield 0.85 g (80%) of the title compound. Mp.: 145-150° C.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(C)([O-])C.[K+].[F:14][C:15]1[C:20]([F:21])=[C:19](F)[N:18]=[CH:17][N:16]=1.O>O1CCCC1>[O:7]([C:19]1[C:20]([F:21])=[C:15]([F:14])[N:16]=[CH:17][N:18]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Oc1ccccc1
Reactant: Fc1ncnc(F)c1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: Fc1ncnc(Oc2ccccc2)c1F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 68.1 %

Procedure:
A solution of 42.4 g (0.45 mol) of phenol and 50.4 g (0.45 mol) of potassium tert-butoxide in 400 ml of tetrahydrofuran is added dropwise at 0° C. to a solution of 80 g (0.6 mol) of 4,5,6-trifluoropyrimidine in 1 l of tetrahydrofuran. When the addition was complete, the reaction mixture was stirred for 30 minutes at 0° C. and then poured into water and extracted using ethyl acetate. The organic phase is dried over sodium sulphate and concentrated in vacuo, and the residue is stirred with low-boiling petroleum ether. 63.8 g (68.1% of theory) of 4-phenoxy-5,6-difluoropyrimidine of melting point 65-66° C. are obtained.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6](O)[C:7](=[CH:11][CH:12]=1)[C:8]([OH:10])=[O:9].I[CH3:15].CN(C)[CH:18]=[O:19]>>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([C:8]([O:10][CH3:15])=[O:9])=[C:11]([O:19][CH3:18])[CH:12]=1
Reactant: CI
Reactant: O=C(O)c1ccc(Cl)cc1O
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Product: COC(=O)c1ccc(Cl)cc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.4 %

Procedure:
To a suspension of 60% sodium hydride oil (3.4 g) in dimethylformamide (25 ml) was added 4-chlorosalicylic acid (7.33 g) under ice-cooling, and the mixture was stirred for 1 hour at room temperature. After the stirring, iodomethane (25 g) was dropwise added to the mixture and the mixture was reacted for 1 hour at 50° C., which was followed by extraction with ether. The extract was washed with water and dried over magnesium sulfate. After the concentration, the residue was chromatographed on silica gel (hexane-ethyl acetate) to give 6.60 g of a colorless transparent liquid (yield 77.4%).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[C:7]([C:9]([OH:11])=O)[CH:6]=[CH:5][N:4]=1.[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][O:24][C@H:23]([C:27]2[CH:32]=[CH:31][C:30]([NH2:33])=[CH:29][C:28]=2[F:34])[CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15].C(N(C(C)C)C(C)C)C>C(Cl)Cl.CN(C=O)C>[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][O:24][C@H:23]([C:27]2[CH:32]=[CH:31][C:30]([NH:33][C:9]([C:7]3[CH:6]=[CH:5][N:4]=[C:3]([C:2]([F:1])([F:13])[F:12])[CH:8]=3)=[O:11])=[CH:29][C:28]=2[F:34])[CH2:22]1)=[O:20])([CH3:17])([CH3:15])[CH3:16]
Reactant: O=C(O)c1ccnc(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](c2ccc(N)cc2F)C1
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCO[C@H](c2ccc(NC(=O)c3ccnc(C(F)(F)F)c3)cc2F)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Under N2, 2-(trifluoromethyl)-4-pyridinecarboxylic acid (CAS 131747-41-6) (64.4 mg, 337 μmol, Eq: 1.00) was dissolved in CH2Cl2 (1 ml). 1-chloro-N,N2-trimethypropenylamine (51.8 mg, 51.3 μl, 388 μmol, Eq: 1.15) was added dropwise. After 30 minutes at RT, a solution contained (R)-2-(4-Amino-2-fluoro-phenyl)-morpholine-4-carboxylic acid tert-butyl ester (100 mg, 337 μmol, Eq: 1.00) and ethyldiisopropylamine (109 mg, 140 μl, 842 μmol, Eq: 2.5) in DMF (1.00 ml) was added. The RM was stirred at RT over 1 hour. Control with TLC: the reaction was finished. The RM was extracted with EtOAc and 1M citric acid solution; the organic phase was dried over MgSO4; filtered; concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 10 g, 10% to 50% EtOAc in heptane) leading to 149 mg (82%) of a white foam. MS (EIC): 468.1 ([M−H]−)
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7]N.C=O.[ClH:11].[CH3:12][N:13](C=O)C>>[ClH:11].[S:1]1[C:2]2=[CH:6][CH:7]=[CH:12][NH:13][CH:3]2[CH2:4][CH2:5]1
Reactant: CN(C)C=O
Reactant: NCCc1cccs1
Agent: C=O
Agent: Cl
Product: C1=CNC2CCSC2=C1

Procedure:
2-thienylethlamine was reacted with formaldehyde to give the corresponding formimine, which was then added to a solution of hydrochloric acid in DMF, resulting in cyclization to tetrahydrothienopyridine hydrochloride. The DMF used was anhydrous, KF≦0.05%, to avoid formimine hydrolysis.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](CC#N)=[C:4]([O:11][CH3:12])[CH:3]=1.[OH-:13].[K+].[CH2:15]([OH:18])[CH2:16]O>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:16][C:15]([OH:18])=[O:13])=[C:4]([O:11][CH3:12])[CH:3]=1
Reactant: OCCO
Reactant: [OH-]
Reactant: COc1cc(Cl)ccc1CC#N
Agent: [K+]
Product: COc1cc(Cl)ccc1CC(=O)O

Procedure:
141 g of 4-chloro-2-methoxyphenylacetonitrile are reacted with 83.2 g of potassium hydroxide in 280 ml of ethylene glycol. 148 g of solid are obtained (m.p.: 100° C.).
Reaction SMILES: [NH2:1][CH2:2][C:3]1([OH:16])[CH2:8][CH2:7][N:6]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:5][CH2:4]1.C(N(CC)CC)C.[Cl:24][CH2:25][C:26](Cl)=[O:27]>ClCCl.O>[CH2:9]([N:6]1[CH2:7][CH2:8][C:3]([CH2:2][NH:1][C:26](=[O:27])[CH2:25][Cl:24])([OH:16])[CH2:4][CH2:5]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: NCC1(O)CCN(Cc2ccccc2)CC1
Reactant: O=C(Cl)CCl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: O=C(CCl)NCC1(O)CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 78.4 %

Procedure:
To a solution of compound 397 (39.7 g, 180 mmol) in dichloromethane (350 mL) was added triethylamine (50.0 mL, 359 mmol), followed by dropwise addition of chloroacetyl chloride (16.5 mL, 207 mmol) over 15 minutes. The resulting solution was stirred at room temperature for 1.25 hours. The crude mixture was diluted with DCM and water, and extracted with DCM twice. The combined organics were dried over Na2SO4 and concentrated in vacuo to give compound 398 (41.9 g, 78%). LCMS-ESI (POS), M/Z, M+1: Found 297.1, Calculated 297.1.
Reaction SMILES: [CH2:1]([N:5]1[C:9](=[O:10])[C:8]2=[CH:11][C:12]([N+:15]([O-])=O)=[CH:13][CH:14]=[C:7]2[C:6]1=[O:18])[CH2:2][CH2:3][CH3:4].S(S([O-])=O)([O-])=O.[Na+].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>CO.O>[CH2:1]([N:5]1[C:9](=[O:10])[C:8]2=[CH:11][C:12]([NH2:15])=[CH:13][CH:14]=[C:7]2[C:6]1=[O:18])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN1C(=O)c2ccc([N+](=O)[O-])cc2C1=O
Agent: O=C([O-])[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCCCN1C(=O)c2ccc(N)cc2C1=O
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 59.2 %

Procedure:
A solution of N-butyl-4-nitrophthalimide (1.45 g, 5.8 mmol) in methanol (30 mL) was added drop wise to a well stirred solution of sodium dithionite (6.50 g, 37.1 mmol) and sodium carbonate (3.22 g, 30.5 mmol) in water (40 mL), while the temperature was maintained at 70° C. After addition, heating at 70° C. was continued for a further 30 minutes, then the reaction mixture was allowed to cool to room temperature. The reaction volume was reduced to one third by rotary evaporation, and the residual water solution was extracted with diethyl ether (2×50 mL). The combined organic phases were dried with anhydrous Na2SO4, and then taken to dryness. The residual oil was recrystallised from ethanol/water to give 750 mg (59%) of N-butyl-4-aminophthalimide.
Reaction SMILES: BrC1C=C[C:5]([OH:36])=[C:6]([C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:18]4[N:22]([CH:23]5[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]5)[C:21]5[CH:29]=[CH:30][C:31]([C:33]([OH:35])=[O:34])=[CH:32][C:20]=5[N:19]=4)[CH:14]=3)[N:9]=2)[CH:7]=1.C(C1C(=O)[NH:42][C:43](=[O:53])[N:44]([C:46]2[C:47]([Cl:52])=[N:48][CH:49]=[CH:50][CH:51]=2)C=1)(=O)C.[OH-].[K+]>C(O)C>[Cl:52][C:47]1[C:46]([N:44]2[CH:7]=[C:6]([C:8]3[CH:17]=[CH:16][C:15]4[C:10](=[CH:11][CH:12]=[C:13]([C:18]5[N:22]([CH:23]6[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]6)[C:21]6[CH:29]=[CH:30][C:31]([C:33]([OH:35])=[O:34])=[CH:32][C:20]=6[N:19]=5)[CH:14]=4)[N:9]=3)[C:5](=[O:36])[NH:42][C:43]2=[O:53])=[CH:51][CH:50]=[CH:49][N:48]=1
Reactant: CC(=O)c1cn(-c2cccnc2Cl)c(=O)[nH]c1=O
Reactant: O=C(O)c1ccc2c(c1)nc(-c1ccc3nc(-c4cc(Br)ccc4O)ccc3c1)n2C1CCCCC1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccc2c(c1)nc(-c1ccc3nc(-c4cn(-c5cccnc5Cl)c(=O)[nH]c4=O)ccc3c1)n2C1CCCCC1
Yield: 31 %

Procedure:
Following the procedure and workup for Compound 354, Compound 354e (100 mg, 0.256 mmol) was reacted with 5-acetyl-1-(2-chloro-pyridin-3-yl)-1H-pyrimidine-2,4-dione (0.256 mmol) in ethanol (2 mL) using 10% w/v KOH in ethanol (506 μL, 0.64 mmol) to produce the title compound 45 mg, 31% yield). MS: 593.17 (M+H+); HPLC Procedure A, retention time=10.02 min.