Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([C:11]([F:14])([F:13])[F:12])=[N:10][C:5]2=[N:4][CH:3]=1.[F:15][C:16]1[C:21]([C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)=[C:20]([F:28])[CH:19]=[CH:18][C:17]=1B(O)O>>[F:28][C:20]1[C:21]([C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)=[C:16]([F:15])[CH:17]=[CH:18][C:19]=1[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([C:11]([F:14])([F:13])[F:12])=[N:10][C:5]2=[N:4][CH:3]=1
Reactant: FC(F)(F)c1ccn2c(Br)cnc2n1
Reactant: OB(O)c1ccc(F)c(-c2cccnc2)c1F
Product: Fc1ccc(-c2cnc3nc(C(F)(F)F)ccn23)c(F)c1-c1cccnc1

Procedure:
3-Bromo-7-trifluoromethylimidazo[1,2-α]pyrimidine was coupled with 2,4-difluoro-3-(pyridin-3-yl)benzeneboronic acid as described in Example 1 to give 3-[2,4-difluoro-3-(pyridin-3-yl)phenyl]-7-trifluoromethylimidazo[1,2-α]pyrimidine as an off-white solid. Bis-hydrochloride salt (from ethyl acetate/ethanol): δH (400 MHz, DMSO) 7.60-7.65 (2H, m), 7.90-7.96 (2H, m), 8.34 (1H, s), 8.47 (1H, d, J 8), 8.87 (1H, dd, J 5 and 1), 9.08 (1H, s), 9.32 (1H, dd, J 7 and 3).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7](Cl)=[O:8])=[CH:5][C:4]([CH3:10])=[N:3]1.[NH2:11][C:12]1[CH:29]=[CH:28][C:15]([C:16]([C:18]2[CH:26]=[C:25]3[C:21]([CH2:22][C:23](=[O:27])[NH:24]3)=[CH:20][CH:19]=2)=[O:17])=[CH:14][CH:13]=1>C1COCC1>[O:27]=[C:23]1[CH2:22][C:21]2[C:25](=[CH:26][C:18]([C:16]([C:15]3[CH:14]=[CH:13][C:12]([NH:11][C:7]([C:6]4[N:2]([CH3:1])[N:3]=[C:4]([CH3:10])[CH:5]=4)=[O:8])=[CH:29][CH:28]=3)=[O:17])=[CH:19][CH:20]=2)[NH:24]1
Reactant: Nc1ccc(C(=O)c2ccc3c(c2)NC(=O)C3)cc1
Reactant: Cc1cc(C(=O)Cl)n(C)n1
Solvent: C1CCOC1
Product: Cc1cc(C(=O)Nc2ccc(C(=O)c3ccc4c(c3)NC(=O)C4)cc2)n(C)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.7 %

Procedure:
A dry 25 mL flask was charged with 2,5-Dimethyl-2H-pyrazole-3-carbonyl chloride (0.820 g, 5.15 mmol) and THF (10 mL). 6-(4-Amino-benzoyl)-1,3-dihydro-indol-2-one (as prepared in Example 15, 1.00 g, 3.97 mmol) was added to the THF solution of the acid chloride, and the mixture was allowed to reflux for 4 h. The reaction mixture was then allowed to cool to room temperature. The room temperature reaction mixture was concentrated in vacuo, and the crude residue was dissolved in EtOH (5 mL). The ethanolic solution was treated with 1M NaOH(aq) (2 mL) and stirred for 30 min. The basic solution was acidified to a pH of 1 with 1M HCl(aq) yielding a tan precipitate. The solids were filtered to afford the pure 2,5-Dimethyl-2H-pyrazole-3-carboxylic acid [4-(2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (1.35 g, 3.60 mmol, 91%).
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([OH:9])[CH2:2]2.[CH3:10][S:11](Cl)(=[O:13])=[O:12].N1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>ClCCl>[CH3:10][S:11]([O:9][CH:3]1[CH:4]2[CH2:7][CH2:8][N:1]([CH2:6][CH2:5]2)[CH2:2]1)(=[O:13])=[O:12]
Reactant: OC1CN2CCC1CC2
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CS(=O)(=O)OC1CN2CCC1CC2
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 97.8 %

Procedure:
Quinuclidin-3-ol (10.0 g, 0.0787 mol) was dissolved under N2 in dry dichloromethane (200 ml) and cooled in an ice bath to 0° C. Methanesulphonyl chloride (7.3 ml, 10.8 g, 0.094 mol, 1.2 eq) and dry pyridine (7.64 ml, 7.46 g, 0.094 mol, 1.2 eq) were added and the mixture stirred at 0° C. for 20 min. The solution was then warmed to r.t. and stirred under N2 for 1 h. Saturated aqueous potassium carbonate solution (150 ml) was added, and the organic layer extracted and collected. The aqueous layer was re-extracted with EtOAc (3×200 ml), the organic solutions dried (Na2SO4), filtered, and evaporated to dryness under reduced pressure to yield a pale yellow oil which was pumped under high vacuum to remove any last traces of pyridine to yield the title compound (D8) (15.8 g, 98%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Br[CH2:8][CH2:9][CH2:10][Cl:11]>C1(C)C=CC=CC=1>[Cl:11][CH2:10][CH2:9][CH2:8][N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: C1COCCN1
Reactant: ClCCCBr
Solvent: Cc1ccccc1
Product: ClCCCN1CCOCC1
Temperature: 70 °C
Reaction time: 4 h
Yield: 33.7 %

Procedure:
To a solution of morpholine (2.00 g, 23.0 mmol) in toluene (200 mL), was added 1-bromo-3-chloropropane (4.55 mL, 45.9 mmol) and the mixture was stirred for 4 h at 70° C. Insoluble materials were removed by filtration and the filtrate has been concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc/hexane=70/30→100/0) to give the title compound (1.27 g, 68%) as a colorless oil.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:24][C@@H:23]([CH3:25])[N:13]2[C:14]3[CH:15]=[C:16]([CH2:21][OH:22])[CH:17]=[CH:18][C:19]=3[CH2:20][C@@H:12]2[CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].I[CH3:27]>CN(C)C=O>[C:3]([O:7][C:8]([N:10]1[CH2:24][C@@H:23]([CH3:25])[N:13]2[C:14]3[CH:15]=[C:16]([CH2:21][O:22][CH3:27])[CH:17]=[CH:18][C:19]=3[CH2:20][C@@H:12]2[CH2:11]1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: CI
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]2Cc3ccc(CO)cc3N21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCc1ccc2c(c1)N1[C@H](C2)CN(C(=O)OC(C)(C)C)C[C@H]1C
Temperature: 50 °C
Reaction time: 2 h
Yield: 52 %

Procedure:
Sodium hydride (55-65% dispersion in mineral oil, 27 mg, 0.67 mmol) was added to a solution of (4R,10aR)-7-hydroxymethyl-4-methyl-3,4,10,10a-tetrahydro-1H-pyrazino[1,2-a]indole-2-carboxylic acid tert-butyl ester (200 mg, 0.63 mmol) in N,N-dimethylformamide (5 mL) at r.t., then after 1 h iodomethane (89 mg, 0.63 mmol) was added and the reaction mixture was stirred 2 h at 50° C. After cooling another portion of sodium hydride (27 mg, 0.67 mmol) was added, then after the addition of a second equivalent of iodomethane (89 mg, 0.63 mmol) the reaction mixture was stirred 2 h at 50° C. After cooling the reaction mixture was poured onto ice and extracted with ether (30 mL), the organic layer was washed with half-saturated brine, dried (MgSO4), and concentrated. Chromatography on SiO2 (Hexane/EtOAc 3:1) yielded the title compound (109 mg, 52%). Light yellow oil, ISP-MS: m/e=333.3 ([M+H]+).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([CH2:14][CH2:15][CH3:16])[CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.Cl[CH2:18][C:19]1[CH:20]=[CH:21][C:22]([C:34]([CH3:37])([CH3:36])[CH3:35])=[C:23]([C:25]2[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:26]=2[F:33])[CH:24]=1>>[CH3:37][C:34]([C:22]1[C:23]([C:25]2[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:26]=2[F:33])=[CH:24][C:19]([CH2:18][O:1][C:2]2[CH:3]=[CH:4][C:5]([C@@H:8]([CH2:14][CH2:15][CH3:16])[CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:6][CH:7]=2)=[CH:20][CH:21]=1)([CH3:35])[CH3:36]
Reactant: CCC[C@@H](CC(=O)OC)c1ccc(O)cc1
Reactant: COc1ccc(F)c(-c2cc(CCl)ccc2C(C)(C)C)c1
Product: CCC[C@@H](CC(=O)OC)c1ccc(OCc2ccc(C(C)(C)C)c(-c3cc(OC)ccc3F)c2)cc1
Yield: 50.7 %

Procedure:
Compound 7.1 (0.051 g, 0.2 mmol) was alkylated by reaction with compound A (0.08 g, 0.3 mmol) according to the method given in Example 1 to give compound 7.2 as a clear oil (0.05 g, 44% yield). MS ESI (pos.) m/e: 515.2 (M+Na)+, 510.2 (M+H2O)+.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[O:7]1[CH2:12][C:11](=O)[NH:10][C:9]2[CH:14]=[CH:15][CH:16]=[CH:17][C:8]1=2>O1CCCC1>[O:7]1[CH2:12][CH2:11][NH:10][C:9]2[CH:14]=[CH:15][CH:16]=[CH:17][C:8]1=2
Reactant: O=C1COc2ccccc2N1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: c1ccc2c(c1)NCCO2
Reaction time: 0.25 h

Procedure:
Into a 250 mL 3-necked round bottom flask was placed a solution of lithium aluminum hydride (3.6 g, 94.74 mmol) in tetrahydrofuran (80 mL). The mixture was stirred for 15 minutes. This was followed by the addition of a solution of 2H-benzo[b][1,4]oxazin-3(4H)-one (5.7 g, 38.22 mmol) in tetrahydrofuran (21 mL), which was added dropwise with stirring. The resulting solution was allowed to react, with stirring, overnight while the temperature was maintained at reflux in a bath of oil. The reaction progress was monitored by TLC (ethyl acetate/petroleum ether=1:1). The reaction mixture was then quenched by the adding 3.6 mL of H2O and 10.8 mL 15% NaOH. A filtration was performed. The filter cake was washed 1 time with 30 mL of tetrahydrofuran. The resulting solution was extracted two times with 100 mL of ethyl acetate and the organic layers combined and dried over Na2SO4 and concentrated by evaporation under vacuum using a rotary evaporator. This resulted in 4.8 g (79%) of 3,4-dihydro-2H-benzo[b][1,4]oxazine as red oil.
Reaction SMILES: [C:1]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7]([NH:10][C:11](=[N:14][C:15]1[N:20]=[C:19]([O:21][CH3:22])[N:18]=[C:17]([O:23][CH3:24])[N:16]=1)SC)(=[O:9])=[O:8].[CH3:31][O:32][NH2:33]>O1CCOCC1>[C:1]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7]([NH:10][C:11]([NH:14][C:15]1[N:20]=[C:19]([O:21][CH3:22])[N:18]=[C:17]([O:23][CH3:24])[N:16]=1)=[N:33][O:32][CH3:31])(=[O:9])=[O:8]
Reactant: COc1nc(N=C(NS(=O)(=O)c2ccccc2-c2ccccc2)SC)nc(OC)n1
Reactant: CON
Solvent: C1COCCO1
Product: CON=C(Nc1nc(OC)nc(OC)n1)NS(=O)(=O)c1ccccc1-c1ccccc1
Yield: 69.8 %

Procedure:
4.45 g of 1-(2-biphenylylsulfonyl) 3-(4,6-dimethoxy-1,3,5-triazin-2-yl) 2-methylisothiourea were dissolved in 50 ml of dioxane, and 2.35 g of O-methylhydroxylamine were added to the solution. The mixture was heated under reflux for 5 hours. After cooling, the solvent was distilled off under reduced pressure, and the residue was recrystallized from ethanol to give 3.1 g of N-(2-biphenylylsulfonyl) N'-(4,6-dimethoxy-1,3,5-triazin-2-yl) N"-(methoxy)guanidine represented by the following formula: ##STR30##
Reaction SMILES: CC(=[N:4][N:5]=[C:6]1[N:10]([CH3:11])[C:9]([CH3:12])=[CH:8][S:7]1)C.[ClH:13]>>[ClH:13].[CH3:11][N:10]1[C:9]([CH3:12])=[CH:8][S:7][C:6]1=[N:5][NH2:4]
Reactant: CC(C)=NN=c1scc(C)n1C
Agent: Cl
Product: Cc1csc(=NN)n1C

Procedure:
3.5 g (19 mmol) of 3,4-dimethyl-2(3H)thiazolone-(1-methylethylidene) hydrazone from step A in 60 mL of 6 M hydrochloric acid was heated at 50° C. for 30 minutes. The reaction mixture was then concentrated, and the crude product was recrystallized from ethanol. This gave 2 g (60% of the theoretical) of a pink-colored powder.
Reaction SMILES: P(=[S:5])([O-])([O-])[O-].[Na+].[Na+].[Na+].Cl.[C:10]([CH:13]1[CH2:18][CH2:17][CH2:16][N:15]([C:19](=[NH:22])[CH2:20][Cl:21])[CH2:14]1)(=[O:12])[NH2:11].Cl>O>[ClH:21].[C:10]([CH:13]1[CH2:18][CH2:17][CH2:16][N:15]([C:19](=[NH:22])[CH2:20][SH:5])[CH2:14]1)(=[O:12])[NH2:11]
Reactant: N=C(CCl)N1CCCC(C(N)=O)C1
Reactant: [O-]P([O-])([O-])=S
Agent: Cl
Agent: [Na+]
Solvent: O
Product: N=C(CS)N1CCCC(C(N)=O)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 105.9 %

Procedure:
1.43 g of trisodium phosphorothioate were added to an ice-cooled solution of 2.04 g of 2-[(3RS)-3-carbamoylpiperidin-1-yl]-2-iminoethylchloride hydrochloride in 9.7 ml of water, and the mixture was stirred at room temperature for one hour. 7.9 ml of 1N hydrochloric acid were then added, and the mixture was heated at 50° C. for 30 minutes. The reaction mixture was then worked up in the same manner as in Example 3(2) to give 2.0 g of 2-[(3RS)-3-carbamoylpiperidin-1-yl]-2-iminoethylmercaptan hydrochloride.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:14]=[CH:13][C:6]2[CH2:7][CH2:8][CH2:9][NH:10][C:11](=[O:12])[C:5]=2[CH:4]=1.[H-].[Na+].[CH2:17](Br)[CH:18]=[CH2:19]>CN(C)C=O.[Cl-].[Na+].O>[CH2:19]([N:10]1[CH2:9][CH2:8][CH2:7][C:6]2[CH:13]=[CH:14][C:3]([O:2][CH3:1])=[CH:4][C:5]=2[C:11]1=[O:12])[CH:18]=[CH2:17]
Reactant: C=CCBr
Reactant: COc1ccc2c(c1)C(=O)NCCC2
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCN1CCCc2ccc(OC)cc2C1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 83 %

Procedure:
A solution of 8-methoxy-2,3,4,5-tetrahydro-1H-2-benzazepin-1-one (10.0 g 0.052 mol) in N,N-dimethylformamide (30 mL) and allylbromide (23 mL, 0.260 mL) was treated with NaH (60% by wt. dispersion in oil, 2.50 g, 0.063 mol) and the resulting grey suspension stirred at room temperature under an atmosphere of argon. Gas evolution was noted. After 15 minutes, the solution was diluted with brine and partitioned between ethyl acetate and brine. The combined organic layers were concentrated in vacuo and purified by chromatography over silica gel eluting with a gradient of hexane to 1:1 ethyl acetate/hexane to yield 8 g (83%) of 2-allyl-8-methoxy-2,3,4,5-tetrahydro-1H-2-benzazepin-1-one as a colorless oil: 1H NMR(CDCl3) d7.23(m, 1H), 7.03(d, J=9 Hz, 1H), 6.90(dd, J=3, 9 Hz, 1H), 5.91(m, 1H), 5.23(m, 2H), 4.20(d, J=6 Hz, 2H), 3.82(s, 3H), 3.18(t, J=6 Hz, 2H), 2.72(t, J=6 Hz, 2H), 1.96(pentet, J=6 Hz, 2H); 13C NMR(CDCl3) d170.59(CO), 158.42(NCO), 136.88, 133.81, 129.43, 129.35, 129.33, 117.56, 117.54, 112.98, 55.26, 49.43, 45.37, 29.57, 29.22; MS(FAB) m/z=232.1(MH+).
Reaction SMILES: [CH3:1][N:2]1[C:7](=[S:8])[NH:6][C:5]2[CH:9]=[CH:10][N:11]=[CH:12][C:4]=2[S:3]1(=[O:14])=[O:13].[C:15](=O)([O-])[O-].[K+].[K+].CI>C(#N)C>[CH3:1][N:2]1[C:7]([S:8][CH3:15])=[N:6][C:5]2[CH:9]=[CH:10][N:11]=[CH:12][C:4]=2[S:3]1(=[O:14])=[O:13]
Reactant: CN1C(=S)Nc2ccncc2S1(=O)=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC#N
Product: CSC1=Nc2ccncc2S(=O)(=O)N1C
Reaction time: 1 h

Procedure:
A solution of 2-methyl-3-thioxo-2,3-dihydro-4H-pyrido[4,3-e]-1,2,4-thiadiazine 1,1-dioxide (1.0 g) in acetonitrile (20 mL) was supplemented with potassium carbonate (1.0 g), then with methyl iodide (1 mL). After 1 h at room temperature, the solvent was removed by distillation under reduced pressure. The residue was dispersed in water (50 mL) and the suspension was adjusted to pH 5 with formic acid. The insoluble material was collected by filtration, washed with water and dried (yield: 0.8 g); m.p. 135°-138° C. (Compound V).
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[Cl:13][C:14]1[C:23]2[C:18](=[CH:19][C:20]([O:25][CH3:26])=[C:21]([OH:24])[CH:22]=2)[N:17]=[CH:16][N:15]=1.[CH3:27][N:28]1[CH2:32][CH2:31][CH:30](O)[CH2:29]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl.CO.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cl:13][C:14]1[C:23]2[C:18](=[CH:19][C:20]([O:25][CH3:26])=[C:21]([O:24][CH:30]3[CH2:31][CH2:32][N:28]([CH3:27])[CH2:29]3)[CH:22]=2)[N:17]=[CH:16][N:15]=1
Reactant: CN1CCC(O)C1
Reactant: COc1cc2ncnc(Cl)c2cc1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CO
Product: COc1cc2ncnc(Cl)c2cc1OC1CCN(C)C1
Reaction time: 1 h
Yield: 29.6 %

Procedure:
Diethyl azodicarboxylate (793 mg, 4.56 mmol) was added portionwise at room temperature to a stirred suspension of 4-chloro-7-methoxyquinazolin-6-ol (800 mg, 3.80 mmol), 1-methylpyrrolidin-3-ol (422 mg, 4.18 mmol) and triphenylphosphine (1.3 g, 4.96 mmol) in dichloromethane (16 ml). The reaction mixture was stirred for 1 hour and then a further portion of diethyl azodicarboxylate (360 ul) and triphenylphosphine (0.65 mg) were added. The mixture was stirred for 1 hour and the resulting orange solution was purified directly by silica gel chromatography eluting with a 0-10% mixture of methanol in dichloromethane to 4-chloro-7-methoxy-6-[(1-methylpyrrolidin-3-yl)oxy]quinazoline (330 mg, 28% yield) as a tan coloured solid:
Reaction SMILES: C[O-].[Na+].[C:4]([C:7]1[CH:14]=[CH:13][C:10]([CH:11]=O)=[CH:9][CH:8]=1)([OH:6])=[O:5].[C:15]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)(=[O:17])[CH3:16]>CO>[O:17]=[C:15]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH:16]=[CH:11][C:10]1[CH:13]=[CH:14][C:7]([C:4]([OH:6])=[O:5])=[CH:8][CH:9]=1
Reactant: O=Cc1ccc(C(=O)O)cc1
Reactant: CC(=O)c1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=C(O)c1ccc(C=CC(=O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 71.6 %

Procedure:
Sodium methoxide (1.8 g, 33.3 mmol) was added to a stirred suspension of 4-carboxybenzaldehyde (2.5 g, 16.6 mmol) and acetophenone (2.0 g uL, 16.6 mmol) in methanol (50 mL) at room temperature. The mixture was stirred at room temperature for 16 hours, and half of the volume of methanol was removed under reduced pressure. The mixture was poured into HCl 1M (50 mL) (until pH=2) and ethyl acetate was added. The separated aqueous layer was extracted with ethyl acetate (3×30 mL) dried (MgSO4 anh.), filtered and evaporated. The residue was triturated with dichloromethane-hexanes (1:1) to afford 3 g of 43 (72% yield).
Reaction SMILES: C([Li])CCC.[NH2:6][C:7]1[C:12]([F:13])=[CH:11][C:10]([F:14])=[CH:9][N:8]=1.[I:15]I.S([O-])([O-])(=O)=S.[Na+].[Na+]>C1COCC1>[F:13][C:12]1[C:7]([NH2:6])=[N:8][CH:9]=[C:10]([F:14])[C:11]=1[I:15]
Reactant: Nc1ncc(F)cc1F
Reactant: II
Agent: O=S([O-])([O-])=S
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: Nc1ncc(F)c(I)c1F
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
n-Butyllithium (41 ml, 1.6 M solution in hexanes, 66 mmol) was added drop wise to a solution of 2-amino-3,5-difluoropyridine (3.4 g, 26 mmol) in THF (100 ml) at −78° C. The mixture was allowed to stir at that temperature for 1.5 hr, then a solution of iodine (20 g, 78 mmol) in THF (30 ml) was added. The mixture was stirred at −78° C. for 15 min, then it was allowed to warm to rt. Saturated aqueous sodium thiosulfate was added, and the mixture was extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography (0-25% ethyl acetate in hexanes eluant) to provide the title compound. MS m/z: 297.9 (M+MeCN+1).
Reaction SMILES: Cl.[CH3:2][C:3]1([CH2:9][CH2:10][NH:11][C:12](=[O:24])[O:13][CH2:14][C:15]2[O:19][N:18]=[C:17]([C:20](=[O:23])[NH:21][CH3:22])[CH:16]=2)[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.Cl[C:26]1[N:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[CH:28][N:27]=1.C(N(CC)C(C)C)(C)C>C(#N)C>[CH3:2][C:3]1([CH2:9][CH2:10][NH:11][C:12](=[O:24])[O:13][CH2:14][C:15]2[O:19][N:18]=[C:17]([C:20](=[O:23])[NH:21][CH3:22])[CH:16]=2)[CH2:4][CH2:5][N:6]([C:26]2[N:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[CH:28][N:27]=2)[CH2:7][CH2:8]1
Reactant: FC(F)(F)c1ccnc(Cl)n1
Reactant: CNC(=O)c1cc(COC(=O)NCCC2(C)CCNCC2)on1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CNC(=O)c1cc(COC(=O)NCCC2(C)CCN(c3nccc(C(F)(F)F)n3)CC2)on1
Yield: 74.3 %

Procedure:
The process is performed according to the procedure described in Example 12 (step 12.5.). Starting with 0.30 g (0.83 mmol) of 3-methylcarbamoylisoxazol-5-ylmethyl [2-(4-methylpiperidin-4-yl)ethyl]carbamate hydrochloride, 0.23 g (1.25 mmol) of 2-chloro-4-trifluoromethylpyrimidine and 430 μL (2.49 mmol) of N,N-diisopropylethylamine, dissolved in 2.77 mL of acetonitrile, 0.29 g of expected product is obtained in the form of a powder.
Reaction SMILES: [O:1]=[C:2]1[C@@H:6]([N:7]2[C:13](=[O:14])[CH2:12][CH2:11][N:10]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=3)[CH2:9][CH2:8]2)[CH2:5][CH2:4][O:3]1.[CH3:25][NH:26][CH3:27]>>[OH:3][CH2:4][CH2:5][C@H:6]([N:7]1[C:13](=[O:14])[CH2:12][CH2:11][N:10]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:23])([F:22])[F:24])[CH:16]=2)[CH2:9][CH2:8]1)[C:2]([N:26]([CH3:27])[CH3:25])=[O:1]
Reactant: O=C1OCC[C@@H]1N1CCN(c2cccc(C(F)(F)F)c2)CCC1=O
Reactant: CNC
Product: CN(C)C(=O)[C@H](CCO)N1CCN(c2cccc(C(F)(F)F)c2)CCC1=O

Procedure:
In analogy to the procedure described in example 17A, 4-((S)-2-oxo-tetrahydro-furan-3-yl)-1-(3-trifluoromethyl-phenyl)-[1,4]diazepan-5-one (example 7) and dimethylamine (5.6 M in EtOH) gave the title compound in quantitative yield as an yellow oil. MS: 388.1 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:12]=[N:13][C:14](S(C)=O)=[N:15][CH:16]=2)=[O:10])=[CH:4][CH:3]=1.[C:20]([O:30][CH3:31])(=[O:29])[C@H:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[OH:22].C1CCN2C(=NCCC2)CC1>C1COCC1>[CH3:31][O:30][C:20](=[O:29])[C@@H:21]([O:22][C:14]1[N:13]=[CH:12][C:11]([C:9](=[O:10])[NH:8][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[CH:16][N:15]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CS(=O)c1ncc(C(=O)Nc2ccc(F)cc2)cn1
Reactant: COC(=O)[C@@H](O)c1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: COC(=O)[C@@H](Oc1ncc(C(=O)Nc2ccc(F)cc2)cn1)c1ccccc1
Yield: 10.9 %

Procedure:
A suspension of 2-methanesulfinylpyrimidine-5-carboxylic acid (4-fluorophenyl)amide (100 mg, 0.36 mmol) and (S)-(+)-methyl mandelate (86 mg, 0.52 mmol) in 3.6 mL of THF was treated dropwise with DBU (80 μL, 0.54 mmol) at room temperature. The reaction mixture clarified and turned yellow over the course of 5 min. The reaction was quenched after 24 hours by the addition of 5 mL 1 M HCl, followed by 25 mL of 1:1 (v:v) ethyl acetate:water. The mixture was extracted with 2×25 mL portions of ethyl acetate. The organic extracts were combined, dried using Na2SO4 and concentrated in vacuo. The crude material was dissolved in 30% (v/v)-ethyl acetate/hexanes and chromatographed through 15 g silica gel, followed by a second chromatography through 20 g silica gel. The product fractions were concentrated to yield 15 mg (11%) of the titled compound as a white solid. ESI-MS z/z 382 (MH+), 380 (M−H−).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH3:9])[C:3]=1[N+:10]([O-:12])=[O:11].Br[CH2:14][C:15]#[N:16].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:14][C:15]#[N:16])=[C:4]([CH3:9])[C:3]=1[N+:10]([O-:12])=[O:11]
Reactant: N#CCBr
Reactant: Cc1c(O)ccc(Cl)c1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: Cc1c(OCC#N)ccc(Cl)c1[N+](=O)[O-]
Temperature: 80 °C

Procedure:
A mixture of 4-chloro-2-methyl-3-nitrophenol (7.6 g), bromoacetonitrile (3.4 mL), and potassium carbonate (16.8 9) in 2-butanone (80 mL) was heated at 80° C. for 2 hr under an atmosphere of nitrogen. The reaction mixture was cooled to room temperature, then filtered to remove the salts. The filtrate was diluted with ethyl ether (200 mL), washed with saturated sodium chloride solution, and dried over magnesium sulfate. Evaporation of the solvent afforded a yellow solid (9.1 g).
Reaction SMILES: [CH3:1][CH:2]([CH3:7])[CH2:3][C:4](O)=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:41][N:42]1[C:51]2[C:46](=[CH:47][N:48]=[C:49]([CH3:52])[CH:50]=2)[CH:45]=[C:44]([C:53]2[CH:54]=[C:55]([NH:60]/[C:61](/[NH2:64])=[N:62]/[OH:63])[CH:56]=[CH:57][C:58]=2[CH3:59])[C:43]1=[O:65]>CN(C=O)C>[CH2:3]([C:4]1[O:63][N:62]=[C:61]([NH:60][C:55]2[CH:56]=[CH:57][C:58]([CH3:59])=[C:53]([C:44]3[C:43](=[O:65])[N:42]([CH3:41])[C:51]4[C:46]([CH:45]=3)=[CH:47][N:48]=[C:49]([CH3:52])[CH:50]=4)[CH:54]=2)[N:64]=1)[CH:2]([CH3:7])[CH3:1]
Reactant: CC(C)CC(=O)O
Reactant: Cc1cc2c(cn1)cc(-c1cc(N/C(N)=N/O)ccc1C)c(=O)n2C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc2c(cn1)cc(-c1cc(Nc3noc(CC(C)C)n3)ccc1C)c(=O)n2C
Temperature: 100 °C
Reaction time: 1 h

Procedure:
3-Methylbutanoic acid (13 mg, 0.12 mmol), HATU (50 mg, 0.12 mmol), and DIPEA (0.023 mL, 0.12 mmol) were stirred in dry DMF (3 mL) for 1 h before 17 (40 mg, 0.118 mmol) was added at rt. The stirring was continued for 1 h before it was heated at 100° C. for 5 h. After cooling and filtration, the mixture was purified by preparative LC/MS to give 3-(5-(5-isobutyl-1,2,4-oxadiazol-3-ylamino)-2-methylphenyl)-1,7-dimethyl-1,6-naphthyridin-2(1H)-one (A68) as a solid. 1H NMR (400 MHz, d4-MeOH) δ 8.92 (s, 1H), 7.92 (s, 1H), 7.73 (s, 1H), 7.33 (d, J=1 Hz, 1H), 7.24 (dd, J=8, 4 Hz, 1H), 7.14 (d, J=4 Hz, 1H), 3.72 (s, 3H), 2.72 (s, 3H), 2.60 (d, J=8 Hz, 2H), 2.10-2.01 (m, 1H), 2.06 (s, 3H), 0.92 (d, J=8 Hz, 6H). MS m/z 403.4, 404.5 (M+1).