Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][CH:14]=1)([CH3:12])[CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].C([O-])=O.[NH4+]>CCO.[Pd]>[CH3:12][C:2]([C:13]1[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=1)([CH3:1])[CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:8])([CH3:9])[CH3:10]
Reactant: CC(C)(C)OC(=O)NCC(C)(C)c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: CC(C)(C)OC(=O)NCC(C)(C)c1ccc(N)cc1
Yield: 83.2 %

Procedure:
To a refluxing solution of tert-butyl 2-methyl-2-(4-nitrophenyl)propylcarbamate (725 mg, 2.5 mmol) and ammonium formate (700 mg, 10.9 mmol) in EtOH (25 mL) was added Pd-5% wt on carbon (400 mg). The mixture was refluxed for 1 h, cooled and filtered through Celite. The filtrate was concentrated to give tert-butyl 2-methyl-2-(4-aminophenyl)propylcarbamate (G-3) (550 mg, 83%), which was used without further purification. 1H NMR (400 MHz, DMSO-d6) δ 6.99 (d, J=8.5 Hz, 2H), 6.49 (d, J=8.6 Hz, 2H), 4.85 (s, 2H), 3.01 (d, J=6.3 Hz, 2H), 1.36 (s, 9H), 1.12 (s, 6H); HPLC ret. time 2.02 min, 10-99% CH3CN, 5 min run; ESI-MS 265.2 m/z (MH+).
Reaction SMILES: O[CH2:2][CH2:3][N:4]([CH:38]([CH3:40])[CH3:39])[C:5]([C:7]1[C:12]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:11]([OH:21])[N:10]=[C:9]([CH2:22][C:23]2(C3C=CC4C(=CC=CC=4)C=3)[CH2:27][CH2:26][CH2:25][CH2:24]2)[N:8]=1)=[O:6].C(OC1C(=O)N=C(C[C:57]2([C:62]3[CH:67]=[C:66](Cl)[CH:65]=[CH:64][C:63]=3Cl)[CH2:61][CH2:60][CH2:59]C2)N2CCN(C(C)C)C(=O)C=12)C1C=CC=CC=1>>[CH2:14]([O:13][C:12]1[C:11](=[O:21])[N:10]=[C:9]([CH2:22][C:23]2([C:61]3[CH:60]=[CH:59][C:63]4[C:62](=[CH:67][CH:66]=[CH:65][CH:64]=4)[CH:57]=3)[CH2:27][CH2:26][CH2:25][CH2:24]2)[N:8]2[CH2:2][CH2:3][N:4]([CH:38]([CH3:40])[CH3:39])[C:5](=[O:6])[C:7]=12)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC(C)N(CCO)C(=O)c1nc(CC2(c3ccc4ccccc4c3)CCCC2)nc(O)c1OCc1ccccc1
Reactant: CC(C)N1CCn2c(CC3(c4cc(Cl)ccc4Cl)CCCC3)nc(=O)c(OCc3ccccc3)c2C1=O
Product: CC(C)N1CCn2c(CC3(c4ccc5ccccc5c4)CCCC3)nc(=O)c(OCc3ccccc3)c2C1=O
Yield: 41.33 %

Procedure:
9-Benzyloxy-2-isopropyl-6-(1-naphthalen-2-yl-cyclopentylmethyl)-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (221) (90.0 mg, 41.33%) was synthesized as a white solid from 5-benzyloxy-6-hydroxy-2-(1-naphthalen-2-yl-cyclopentylmethyl)-pyrimidine-4-carboxylic acid (2-hydroxyethyl)-isopropylamide (220) (225.0 mg, 0.417 mmol) following the procedure described for 9-benzyloxy-6-[1-(2,5-dichlorophenyl)-cyclopentylmethyl]-2-isopropyl-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (208).
Reaction SMILES: Cl([O-])=O.[Na+].[CH3:5][O:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:17][CH3:18])[CH:13]=2)[C:8]=1[CH:19]=[O:20].C1(C=CC=C(O)C=1)[OH:22]>O.C(O)(C)(C)C.O1CCOCC1.C(O)(=O)C>[CH3:5][O:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:17][CH3:18])[CH:13]=2)[C:8]=1[C:19]([OH:22])=[O:20]
Reactant: Oc1cccc(O)c1
Reactant: COc1ccc2c(C=O)c(OC)ccc2c1
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CC(C)(C)O
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc2c(C(=O)O)c(OC)ccc2c1
Temperature: 85 °C
Yield: 83.6 %

Procedure:
A solution of sodium chlorite (15.7 g, 80%, 0.139 mol) in 45 mL of water was added rapidly to a warm solution of 2,6-dimethoxy-1-naphthalenecarboxaldehyde [25.76 g, 0.119 mol, described by N. P. Buu-Hoi et al, J. Chem. Soc., 2776 (1955)], resorcinol (17.8 g, 0.162 mol) and acetic acid (0.25 g) in tert-butanol (115 mL) and p-dioxane (95 mL). The reaction temperature was maintained at about 85° C. for 10 minutes then allowed to cool and the mixture was concentrated under vacuum. The residue was partitioned between 1M KOH and dichloromethane. The phases were separated and the aqueous solution was acidified with 6N HCl and washed three times with dichloromethane. The acidic dichloromethane extracts were combined and washed with water and then with saturated sodium chloride and then dried over Na2SO4. After filtration and concentration, the residue was recrystallized from ethanol-water to give 23.1 g (84% yield) of 2,6-dimethoxy-1-naphthalenecarboxylic acid as an off-white solid, m.p. 153°-155° C.
Reaction SMILES: [CH:1]([O:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1B(O)O)=[O:6])([CH3:3])[CH3:2].Cl[C:17]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][N:18]=1>C1(C)C=CC=CC=1.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>[CH:1]([O:4][C:5](=[O:6])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:17]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][N:18]=1)([CH3:3])[CH3:2]
Reactant: CC(C)OC(=O)c1ccccc1B(O)O
Reactant: FC(F)(F)c1ccc(Cl)nc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CC(C)OC(=O)c1ccccc1-c1ccc(C(F)(F)F)cn1
Yield: 70 %

Procedure:
2-(Isopropylcarboxy)-phenylboronic acid (S. Caron and J. M. Hawkins, J. Org. Chem. 1998, 63, 2054-2055) (2.2 g, 10.6 mmol) and 2-chloro-5-trifluoromethylpyridine (500 mg, 2.75 mmol) were dissolved in toluene. Tetrakis(triphenylphosphine)palladium (160 mg, 0.14 mmol) was added and the reaction vessel purged by alternating vacuum and nitrogen gas three times. 8 ml of a 10% sodium carbonate solution was added and the reaction mixture was heated at reflux for 1.5 h. The resulting mixture was extracted with ethyl acetate, the combined organic layers dried (magnesium sulfate), filtered and concentrated under vacuum. Purification of the residue by column chromatography eluting with 10% ethyl acetate in hexanes provided the title compound in approximately 70% yield.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N:11]1[C:15]2=[N:16][CH:17]=[CH:18][C:19]([N:20]3[CH:24]=[C:23]([C:25]4[CH:26]=[N:27][N:28]([CH3:30])[CH:29]=4)[N:22]=[CH:21]3)=[C:14]2[C:13]([C:31]([F:34])([F:33])[F:32])=[N:12]1)[C:5]([NH2:7])=[O:6].[C:35]1(B(O)O)[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(Cl)(Cl)Cl>[CH3:30][N:28]1[CH:29]=[C:25]([C:23]2[N:22]=[CH:21][N:20]([C:19]3[CH:18]=[CH:17][N:16]=[C:15]4[N:11]([C:10]5[C:2]([C:35]6[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=6)=[CH:3][C:4]([C:5]([NH2:7])=[O:6])=[CH:8][CH:9]=5)[N:12]=[C:13]([C:31]([F:32])([F:33])[F:34])[C:14]=34)[CH:24]=2)[CH:26]=[N:27]1
Reactant: Cn1cc(-c2cn(-c3ccnc4c3c(C(F)(F)F)nn4-c3ccc(C(N)=O)cc3Cl)cn2)cn1
Reactant: OB(O)c1ccccc1
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Solvent: O
Product: Cn1cc(-c2cn(-c3ccnc4c3c(C(F)(F)F)nn4-c3ccc(C(N)=O)cc3-c3ccccc3)cn2)cn1
Yield: 6.1 %

Procedure:
Compound (153) (0.030 g), phenylboronic acid (0.014 g), palladium acetate (0.001 g), tricyclohexylphosphine (0.004 g), and potassium phosphate (0.050 g) were dissolved in toluene (0.5 mL) and water (0.025 mL), followed by stirring using microwaves at 130° C. for 10 min. The reaction solution was distributed between chloroform and water, and the organic layer was washed with saturated saline and then dried over anhydrous sodium sulfate. The solvent was distilled away, and the residue was purified by neutral silica gel column chromatography (chloroform/methanol) to obtain compound (172) (0.002 g, 6%) as a white solid.
Reaction SMILES: C[N+]([O-:5])(C)C.Br[CH2:7][CH2:8][CH2:9][CH2:10][C:11]([CH3:15])([CH3:14])[C:12]#[N:13]>CS(C)=O>[CH3:14][C:11]([CH3:15])([CH2:10][CH2:9][CH2:8][CH:7]=[O:5])[C:12]#[N:13]
Reactant: CC(C)(C#N)CCCCBr
Reactant: C[N+](C)(C)[O-]
Solvent: CS(C)=O
Product: CC(C)(C#N)CCCC=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of trimethylamine oxide (1.5 g, 19.6 mmol, Aldrich) in DMSO (10 mL) was added 6-bromo-2,2-dimethylhexanenitrile (0.84 mL, 4.9 mmol, Aldrich). After stirring at room temperature overnight, the reaction mixture was quenched with water (10 mL) and extracted with hexanes (4×10 mL). The combined organic extracts were washed with brine (20 mL), dried (NaSO4), filtered and concentrated to afford 0.65 g (80% pure) of the title compound. MS (ESI+) m/z 157 (M+NH4)+.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:11]=[N:10][C:9]([N:12]([CH2:20][C:21]2([C:25]3[C:30]([F:31])=[CH:29][CH:28]=[CH:27][N:26]=3)[CH2:24][CH2:23][CH2:22]2)C(=O)OC(C)(C)C)=[CH:8][CH:7]=1)=[CH2:5])C.Cl/[C:33](=[N:39]/O)/[C:34]([O:36][CH2:37][CH3:38])=[O:35].C(O)(C(F)(F)F)=O>C1COCC1>[F:31][C:30]1[C:25]([C:21]2([CH2:20][NH:12][C:9]3[N:10]=[N:11][C:6]([C:4]4[O:3][N:39]=[C:33]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH:5]=4)=[CH:7][CH:8]=3)[CH2:24][CH2:23][CH2:22]2)=[N:26][CH:27]=[CH:28][CH:29]=1
Reactant: C=C(OCC)c1ccc(N(CC2(c3ncccc3F)CCC2)C(=O)OC(C)(C)C)nn1
Reactant: CCOC(=O)/C(Cl)=N\O
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(-c2ccc(NCC3(c4ncccc4F)CCC3)nn2)on1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 102.4 %

Procedure:
To t-butyl 6-(1-ethoxyvinyl)pyridazin-3-yl((1-(3-fluoropyridin-2-yl)cyclobutyl)methyl)carbamate (439 mg, 1.02 mmol) in THF (5.0 mL) was added (E)-ethyl 2-chloro-2-(hydroxyimino)acetate (465 mg, 3.06 mmol) and TEA (1.4 mL, 10.2 mmol). The reaction mixture was stirred at rt for 30 min followed by addition of TFA (5 mL) and then heated to reflux overnight. The mixture was then concentrated and purified by reverse phase chromatography to give 415 mg of the title compound as a colorless oil, LRMS (M+H+) m/z 398.3.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[CH2:4][C:5]1[S:9][C:8]([NH2:10])=[N:7][CH:6]=1.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2([C:26](O)=[O:27])[CH2:25][CH2:24]2)=[CH:19][CH:18]=1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>C(#N)C>[Cl:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[CH2:4][C:5]1[S:9][C:8]([NH:10][C:26]([C:23]2([C:20]3[CH:19]=[CH:18][C:17]([O:16][CH3:15])=[CH:22][CH:21]=3)[CH2:25][CH2:24]2)=[O:27])=[N:7][CH:6]=1
Reactant: COc1ccc(C2(C(=O)O)CC2)cc1
Reactant: Nc1ncc(Cc2ccccc2Cl)s1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1ccc(C2(C(=O)Nc3ncc(Cc4ccccc4Cl)s3)CC2)cc1
Reaction time: 16 h
Yield: 54.4 %

Procedure:
5-(2-Chloro-benzyl)-thiazol-2-ylamine (0.250 g, 1.11 mmol) and 1-(4-methoxy-phenyl)-cyclopropanecarboxylic acid (0.213 g, 1.11 mmol) were dissolved in acetonitrile (20 mL) containing triethylamine (0.28 mL, 2.0 mmol). O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU, 0.494 g, 1.3 mmol) was added and the solution was allowed to stir for 16 hours. The crude product was evaporated to dryness and purified by column chromatography on silica gel using a gradient of 5-40% ethyl acetate in hexanes. The pure fractions were combined and evaporated to dryness to yield a white solid (0.2408 g, 0.6036 mmol, 54.4%). ESI-MS m/z calc. 398.1. found 399.0 (M+1)+. Retention time of 3.77 minutes. 1H NMR (400 MHz, CD3CN) d 1.21 (q, J=3.6 Hz, 2H), 1.59 (q, J=3.6 Hz, 2H), 3.78 (s, 3H), 4.19 (s, 2H), 6.88-6.96 (m, 2H), 7.07 (s, 1H), 7.23-7.46 (m, 6H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[C:11]([OH:27])=[CH:12][C:13]([O:16][Si:17]([CH:24]([CH3:26])[CH3:25])([CH:21]([CH3:23])[CH3:22])[CH:18]([CH3:20])[CH3:19])=[CH:14][CH:15]=1.C(N(CC)C(C)C)(C)C.[CH3:37][O:38][CH2:39]Cl.[Cl-].[NH4+]>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([O:16][Si:17]([CH:21]([CH3:23])[CH3:22])([CH:24]([CH3:26])[CH3:25])[CH:18]([CH3:20])[CH3:19])=[CH:12][C:11]=1[O:27][CH2:37][O:38][CH3:39]
Reactant: COCCl
Reactant: COc1ccc(F)c(-c2ccc(O[Si](C(C)C)(C(C)C)C(C)C)cc2O)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COCOc1cc(O[Si](C(C)C)(C(C)C)C(C)C)ccc1-c1cc(OC)ccc1F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2′-fluoro-5′-methoxy-4-((triisopropylsilyl)oxy)biphenyl-2-ol (4.01 g) and N,N-diisopropylethylamine (5.4 mL) in DMF (30 mL) was added chloromethyl methyl ether (1.5 mL), and the mixture was stirred at room temperature for 3 hr. The mixture was further stirred at 50° C. for 1 hr, and saturated aqueous ammonium chloride solution was added to the reaction mixture. The mixture was extracted with ethyl acetate, and the extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, the residue was dissolved in DMF (30 mL), and N,N-diisopropylethylamine (2.7 mL) and chloromethyl methyl ether (1.0 mL) were added. The reaction mixture was stirred at room temperature for 2 hr, and saturated aqueous ammonium chloride solution was added. The reaction mixture was extracted with ethyl acetate, and the extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (3.50 g) as a colorless oil.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[Cl:13][C:14]1[CH:31]=[C:30]([F:32])[C:29]([N:33]2[C:38](=[O:39])[CH:37]=[C:36]([C:40]([F:43])([F:42])[F:41])[N:35]([CH3:44])[C:34]2=[O:45])=[CH:28][C:15]=1[O:16][C:17]1[C:18]([O:23][CH2:24][C:25](O)=[O:26])=[N:19][CH:20]=[CH:21][CH:22]=1.Cl.[CH3:47][O:48][NH2:49].C(N(CC)CC)C>O.CN(C)C=O>[Cl:13][C:14]1[CH:31]=[C:30]([F:32])[C:29]([N:33]2[C:38](=[O:39])[CH:37]=[C:36]([C:40]([F:43])([F:42])[F:41])[N:35]([CH3:44])[C:34]2=[O:45])=[CH:28][C:15]=1[O:16][C:17]1[C:18]([O:23][CH2:24][C:25]([NH:49][O:48][CH3:47])=[O:26])=[N:19][CH:20]=[CH:21][CH:22]=1
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(Oc3cccnc3OCC(=O)O)c(Cl)cc2F)c1=O
Reactant: CON
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CONC(=O)COc1ncccc1Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl
Reaction time: 2 h
Yield: 28.3 %

Procedure:
0.13 g of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride was added to a mixture of 0.30 g of 3-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-2-carboxymethoxypyridine [present compound 7-6], 56 mg of O-methylhydroxylamine hydrochloride, 68 mg of triethylamine and 2 ml of N,N-dimethylformamide at room temperature, and stirred for 2 hours. Then the mixture was poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 90 mg of 3-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-2-[(methoxyaminocarbonyl)methoxy]pyridine [present compound 7-84].
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[N:14]([CH2:15][C:16]3[O:17][CH:18]=[C:19]([C:21]([O:23]C)=[O:22])[N:20]=3)[C:13](=[O:25])[N:12]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=3)[C:11]([CH3:36])=[C:10]2[C:37]([CH:39]2[CH2:41][CH2:40]2)=[O:38])=[CH:5][CH:4]=1)#[N:2].[OH-].[Li+].Cl.CO>O1CCCC1.O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[N:14]([CH2:15][C:16]3[O:17][CH:18]=[C:19]([C:21]([OH:23])=[O:22])[N:20]=3)[C:13](=[O:25])[N:12]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:33])([F:34])[F:35])[CH:27]=3)[C:11]([CH3:36])=[C:10]2[C:37]([CH:39]2[CH2:40][CH2:41]2)=[O:38])=[CH:7][CH:8]=1)#[N:2]
Reactant: COC(=O)c1coc(CN2C(=O)N(c3cccc(C(F)(F)F)c3)C(C)=C(C(=O)C3CC3)C2c2ccc(C#N)cc2)n1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC1=C(C(=O)C2CC2)C(c2ccc(C#N)cc2)N(Cc2nc(C(=O)O)co2)C(=O)N1c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of methyl 2-{[6-(4-cyanophenyl)-5-(cyclopropylcarbonyl)-4-methyl-2-oxo-3-[3-(trifluoromethyl)phenyl]-3,6-dihydropyrimidin-1(2H)-yl]methyl}-1,3-oxazole-4-carboxylate (Example 43) (50 mg, 0.09 mmol) in tetrahydrofuran (1.5 ml) is added a solution of lithium hydroxide (4.24 mg, 0.18 mmol) in water (1.5 ml). The reaction solution is stirred at room temperature overnight (16 h). The pH of the solution is adjusted to less than pH 7 with 1 N hydrochloric acid (500 μl). After 5 minutes stirring, a precipitate is obtained. Methanol (3 ml) is added, and the crude reaction solution is purified directly by preparative HPLC (RP18 column; eluent: acetonitrile/0.1% aq. formic acid 30:70→90:10). The title compound is isolated as a colourless solid.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([S:13]([C:16]2[N:23]3[C:19]([S:20][CH:21]=[CH:22]3)=[N:18][C:17]=2[Cl:24])(=[O:15])=[O:14])[CH:5]=1.[CH3:25][NH2:26]>C1COCC1>[Cl:24][C:17]1[N:18]=[C:19]2[N:23]([C:16]=1[S:13]([N:6]1[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:4]([CH2:3][CH2:2][NH:26][CH3:25])=[CH:5]1)(=[O:14])=[O:15])[CH:22]=[CH:21][S:20]2
Reactant: O=S(=O)(c1c(Cl)nc2sccn12)n1cc(CCBr)c2ccccc21
Reactant: CN
Solvent: C1CCOC1
Product: CNCCc1cn(S(=O)(=O)c2c(Cl)nc3sccn23)c2ccccc12
Temperature: 50 °C

Procedure:
A solution of 3-(2-bromoethyl)-1-(6-chloroimidazo[2,1-b]thiazole-5-sulfonyl) indole (92 mg, 0.20 mmol) in THF is treated with methyl amine (2M in methanol, 0.4 mL, 2 eq.), heated at 50° C. for 24 h, cooled and concentrated in vacuo. The resultant residue is purified by HPLC1 to give the title product as a white solid, 18.5 mg, identified by HPLC2 and mass spectral analyses. 1HPLC conditions (preparative): Gilson Preparative HPLC system; YMC Pro C18, 20 mm×50 mm ID, 5 uM column; 2 mL injection; Solvent A: 0.02% TFA/water; Solvent B: 0.02% TFA/acetonitrile; Gradient: Time 0: 95% A; 2 min: 95% A; 14 min: 10% A, 15 min: 10% A, 16 min: 95% A; Flow rate 22.5 mL/min; Detection: 254 nm DAD.2HPLC conditions (analytical): Hewlett Packard 1100 HPLC system; Waters Xterra C18, 2 mm×30 mm ID, 3 uM column; 5 uL injection; Solvent A: 0.02% TFA/water; Solvent B: 0.02% TFA/acetonitrile; Gradient: Time 0: 95% A; 0.2 min: 95% A; 3 min: 5% A; Flow rate 1.2 mL/min; Detection: 254 nm DAD.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](S(C)(=O)=O)[C:5]([C:12]#[N:13])=[C:4]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=2)[N:3]=1.[CH:26]1([NH2:32])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([NH:32][CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)[C:5]([C:12]#[N:13])=[C:4]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=2)[N:3]=1
Reactant: NC1CCCCC1
Reactant: COc1cc(-c2nc(N)nc(S(C)(=O)=O)c2C#N)cc(OC)c1OC
Solvent: COCCOC
Product: COc1cc(-c2nc(N)nc(NC3CCCCC3)c2C#N)cc(OC)c1OC

Procedure:
From 2-amino-4-methanesulfonyl-6-(3,4,5-trimethoxy-phenyl)-pyrimidine-5-carbonitrile and cyclohexylamine in DME. ES-MS m/e (%): 384 (M+H+, 100).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][CH2:6][C@H:7]([OH:18])[C:8]([NH:10][C:11]1[CH:16]=[N:15][C:14]([CH3:17])=[CH:13][N:12]=1)=[O:9])[CH3:4].Cl[C:20]1[N:25]=[CH:24][N:23]=[C:22]2[N:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[C:35]([F:38])([F:37])[F:36])[N:27]=[CH:28][C:21]=12.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1>[CH2:3]([O:5][CH2:6][C@H:7]([O:18][C:20]1[C:21]2[CH:28]=[N:27][N:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[C:35]([F:37])([F:38])[F:36])[C:22]=2[N:23]=[CH:24][N:25]=1)[C:8]([NH:10][C:11]1[CH:16]=[N:15][C:14]([CH3:17])=[CH:13][N:12]=1)=[O:9])[CH3:4]
Reactant: FC(F)(F)c1ccccc1-n1ncc2c(Cl)ncnc21
Reactant: CCOC[C@H](O)C(=O)Nc1cnc(C)cn1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC[C@H](Oc1ncnc2c1cnn2-c1ccccc1C(F)(F)F)C(=O)Nc1cnc(C)cn1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 90.3 %

Procedure:
60% Sodium hydride (60.0 mg, 1.50 mmol) was added in one portion to (S)-3-ethoxy-2-hydroxy-N-(5-methylpyrazin-2-yl)propanamide (Intermediate H1) (225 mg, 1.00 mmol) in anhydrous THF (5 mL) and the mixture was cooled to 0° C. under nitrogen. The resulting suspension was stirred at 0° C. for 10 minutes and then 4-chloro-1-(2-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4-d]pyrimidine (Intermediate P1) (298.6 mg, 1.00 mmol) as suspension in dry THF (4 mL) added dropwise over 1 minute. The mixture was stirred at 0° C. for 15 mins, allowed to warm to ambient temperature and stirred for 2 hours. 1M Citric acid (2 mL) was added and the mixture extracted with ethyl acetate (2×20 mL). The organic extracts were washed with water (15 mL) and brine (15 mL), dried (MgSO4) and evaporated. The residue was purified by flash silica chromatography, eluting with 60 to 100% ethyl acetate in isohexane to give the product (440 mg, 88%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].C([O-])([O-])=O.[K+].[K+].CN(C=O)C.Br[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25]>O.C(Cl)(Cl)Cl.CO>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CCOC(=O)CBr
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: O
Product: CCOC(=O)COc1ccc([N+](=O)[O-])cc1
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 92.7 %

Procedure:
Into a 50 mL 3-neck RBF equipped with a magnetic stirrer, reflux condenser, and thermo pocket were sequentially charged 4-nitro phenol (1.00 g), K2CO3 (1.98 g) and DMF (7 mL). The reaction mixture was heated to 70° C. for 15 minutes. Ethyl bromoacetate (1.44 g) was added at 70° C. and the reaction mixture was stirred at the same temperature for 30 minutes. The reaction was monitored on TLC using CHCl3:methanol (9.5:0.5) as mobile phase. After completion of the reaction, the mixture was cooled to room temperature and poured into cold water. Solid precipitate was filtered and washed with water. The solid was dried under reduced pressure at 45° C. for 1 hr to give 1.50 g of ethyl 2-(4-nitrophenoxy)acetate. The obtained solid was taken for the next step without further purification.
Reaction SMILES: [O:1]=[C:2]([C:26]1[C:35]2[C:30](=[CH:31][CH:32]=[C:33]([O:36][CH3:37])[CH:34]=2)[N:29]=[CH:28][C:27]=1[F:38])[CH2:3][CH2:4][C@@H:5]1[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][S:13][C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=2[F:21])[CH2:7][C@@H:6]1[C:22]([O:24]C)=[O:23].[OH-].[Na+]>Cl>[O:1]=[C:2]([C:26]1[C:35]2[C:30](=[CH:31][CH:32]=[C:33]([O:36][CH3:37])[CH:34]=2)[N:29]=[CH:28][C:27]=1[F:38])[CH2:3][CH2:4][C@@H:5]1[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][S:13][C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=2[F:21])[CH2:7][C@@H:6]1[C:22]([OH:24])=[O:23]
Reactant: COC(=O)[C@H]1CN(CCSc2cc(F)ccc2F)CC[C@H]1CCC(=O)c1c(F)cnc2ccc(OC)cc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: COc1ccc2ncc(F)c(C(=O)CC[C@@H]3CCN(CCSc4cc(F)ccc4F)C[C@@H]3C(=O)O)c2c1
Temperature: 20 °C
Reaction time: 5 h
Yield: 73.9 %

Procedure:
A mixture of 0.1 g of methyl (3R,4R)-4-[3-oxo-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(2,5-difluorophenylsulfanyl)ethyl]piperidine-3-carboxylate in 2 cm3 of 5N hydrochloric acid is brought to a temperature in the region of 80° C. with stirring and under an inert atmosphere for 5 hours. After cooling to around 20° C., the reaction medium is neutralized with 1.8 cm3 of 5N sodium hydroxide until a pH of 6 is obtained, and is then extracted with 20 cm3 of dichloromethane. The organic phase is dried over magnesium sulfate, filtered, and then evaporated to dryness under reduced pressure (2 kPa) at a temperature in the region of 30° C. The residue obtained is purified by chromatography on a column of silica gel (particle size 70–200 μm; diameter 2 cm), eluting with a mixture of dichloromethane-methanol-aqueous ammonia (28%) (40/5/0.5 by volume) and collecting fractions of 10 cm3. The fractions containing the expected product are pooled and then evaporated according to the conditions described above. 0.072 g of (3R,4R)-4-[3-oxo-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(2,5-difluorophenylsulfanyl)ethyl]piperidine-3-carboxylic acid, in the form of a beige-colored solid, is obtained.