Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([CH3:13])=[C:11]2[C:6]([C:7]([O:22][CH:23]3[CH2:40][CH:39]4[CH:25]([C:26](=[O:46])[N:27]([CH3:45])[CH2:28][CH2:29][CH2:30][CH2:31][CH:32]=[CH:33][CH:34]5[C:36]([C:42](O)=[O:43])([NH:37][C:38]4=[O:41])[CH2:35]5)[CH2:24]3)=[N:8][C:9]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)=[N:10]2)=[CH:5][CH:4]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.C1CCN2C(=NCCC2)CC1.[CH:70]1([S:73]([NH2:76])(=[O:75])=[O:74])[CH2:72][CH2:71]1>C1COCC1.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[C:12]([CH3:13])=[C:11]2[C:6]([C:7]([O:22][CH:23]3[CH2:40][CH:39]4[CH:25]([C:26](=[O:46])[N:27]([CH3:45])[CH2:28][CH2:29][CH2:30][CH2:31][CH:32]=[CH:33][CH:34]5[C:36]([C:42]([NH:76][S:73]([CH:70]6[CH2:72][CH2:71]6)(=[O:75])=[O:74])=[O:43])([NH:37][C:38]4=[O:41])[CH2:35]5)[CH2:24]3)=[N:8][C:9]([C:14]3[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=3)=[N:10]2)=[CH:5][CH:4]=1
Reactant: NS(=O)(=O)C1CC1
Reactant: COc1ccc(-c2nc(OC3CC4C(=O)NC5(C(=O)O)CC5C=CCCCCN(C)C(=O)C4C3)c3ccc(OC)c(C)c3n2)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCOC(C)=O
Product: COc1ccc(-c2nc(OC3CC4C(=O)NC5(C(=O)NS(=O)(=O)C6CC6)CC5C=CCCCCN(C)C(=O)C4C3)c3ccc(OC)c(C)c3n2)cc1
Temperature: 60 °C

Procedure:
The acid 137 (130 mg, 0.207 mmol) and N,N,-carbonyldiimidazole (43 mg, 0.26 mmol) in THF (7 mL) were heated to reflux for 2 hours. DBU (29 μl), and cyclopropanesulfonamide, prepared as described in WO03/053349, (28 mg, 0.23 mmol) was then added and the mixture was stirred at 60° C. over-night. The reaction mixture was diluted with ethyl acetate (25 mL) and washed with 0.5 M citric acid. Purification by HPLC gave 30 mg of the title compound. MS (M+H)+ 732.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][C:14]=1[C:15]1[O:16][C:17]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][C:18]=2[N:19]=1)C1C=CC=CC=1.[H][H]>[Pd].C(O)(=O)C>[F:26][C:24]([F:25])([F:27])[C:21]1[CH:22]=[CH:23][C:17]2[O:16][C:15]([C:14]3[CH:13]=[CH:12][N:11]=[CH:10][C:9]=3[OH:8])=[N:19][C:18]=2[CH:20]=1
Reactant: FC(F)(F)c1ccc2oc(-c3ccncc3OCc3ccccc3)nc2c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Product: Oc1cnccc1-c1nc2cc(C(F)(F)F)ccc2o1
Yield: 96.9 %

Procedure:
A mixture of 4.69 g of 2-(3-benzyloxypyridin-4-yl)-5-(trifluoromethyl)benzoxazole, 1.0 g of 5% palladium on carbon and 70 ml of acetic acid was stirred under about one atmosphere of hydrogen at room temperature for nine hours. The reaction mixture was filtered through Celite™. The filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 3.44 g of 4-[5-(trifluoromethyl)benzoxazole-2-yl]pyridin-3-ol (hereinafter, referred to as “active compound 114”).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[C:12]([C:25]#[CH:26])[N:13]=[C:14]([C:18]([NH:20][CH2:21][C:22]([OH:24])=[O:23])=[O:19])[C:15]=3[OH:17])[S:10][N:9]=2)=[CH:4][CH:3]=1.[OH:27]S(O)(=O)=O>O>[C:25]([C:12]1[N:13]=[C:14]([C:18]([NH:20][CH2:21][C:22]([OH:24])=[O:23])=[O:19])[C:15]([OH:17])=[C:16]2[C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)=[N:9][S:10][C:11]=12)(=[O:27])[CH3:26]
Reactant: C#Cc1nc(C(=O)NCC(=O)O)c(O)c2c(-c3ccc(Cl)cc3)nsc12
Reactant: O=S(=O)(O)O
Solvent: O
Product: CC(=O)c1nc(C(=O)NCC(=O)O)c(O)c2c(-c3ccc(Cl)cc3)nsc12
Temperature: 25 °C
Yield: 22.9 %

Procedure:
To the solution of {[3-(4-chloro-phenyl)-7-ethynyl-4-hydroxy-isothiazolo[5,4-c]pyridine-5-carbonyl]-amino}-acetic acid (0.28 mmol) in actone/water=4:1 (2.8 mL) was added conc. H2SO4 (36.2 mg, 0.37 mmol) and HgSO4 (84.3 mg, 0.28 mmol). The reaction mixture was refluxed for 2 h. After cooling to r.t. the mixture was concentrated in vacuo. The residue was dissolved in DMSO (2.5 mL) and purified by flash column chromatography on C18 (40 g), eluting with 30-80% CH3CN/H2O in 0.1% HCOOH to give the title compound (26 mg) as a brown solid: MS (m/z) 406.0 (M+1).
Reaction SMILES: [C:1]([S:4][CH2:5][C@@H:6]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:17])[C:7]([OH:9])=O)(=[O:3])[CH3:2].Cl.[CH2:19]([O:21][C:22](=[O:27])[C@@H:23]([OH:26])[CH2:24][NH2:25])[CH3:20].C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>CN(C=O)C.C(Cl)CCl>[CH2:19]([O:21][C:22](=[O:27])[C@@H:23]([OH:26])[CH2:24][NH:25][C:7](=[O:9])[C@@H:6]([CH2:5][S:4][C:1](=[O:3])[CH3:2])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:17])[CH3:20]
Reactant: CCOC(=O)[C@@H](O)CN
Reactant: CC(=O)SC[C@@H](Cc1ccccc1C)C(=O)O
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CCOC(=O)[C@@H](O)CNC(=O)[C@@H](CSC(C)=O)Cc1ccccc1C

Procedure:
Combine 2(S)-acetylthiomethyl-3-(2-methylphenyl)propionic acid (1.65 g) and (S)-isoserine ethyl ester hydrochloride (1.10 g), EDC (1.51 g), HOBT (0.99 g) and N-methylmorpholine (1.50 ml) in DMF (10 ml), and stir the resulting mixture for 20 hours. Concentrate the reaction mixture in vacuo and partition the residue between dichloromethane/water. Concentrate the dried (MgSO4) dichloromethane solution in vacuo. Chromatograph the resulting residue on a column of flash silica gel (300 ml) using ethyl acetate:hexane (1:3); ethyl acetate; ethyl acetate:methanol (9:1) as eluant to give the title compound, a colorless oil, [α]D26 =0° (MeOH).
Reaction SMILES: [H-].[Na+].[CH:3]12[C:11](=[O:12])[NH:10][C:9](=[O:13])[CH:4]1[CH2:5][CH2:6][CH2:7][CH2:8]2.[O:14]1[CH2:34][CH:15]1[CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][CH:21]([C:24]2[C:28]3[CH:29]=[CH:30][C:31]([F:33])=[CH:32][C:27]=3[O:26][N:25]=2)[CH2:20][CH2:19]1>CN(C)C=O>[F:33][C:31]1[CH:30]=[CH:29][C:28]2[C:24]([CH:21]3[CH2:22][CH2:23][N:18]([CH2:17][CH2:16][CH:15]([OH:14])[CH2:34][N:10]4[C:9](=[O:13])[CH:4]5[CH2:5][CH2:6][CH2:7][CH2:8][CH:3]5[C:11]4=[O:12])[CH2:19][CH2:20]3)=[N:25][O:26][C:27]=2[CH:32]=1
Reactant: Fc1ccc2c(C3CCN(CCC4CO4)CC3)noc2c1
Reactant: O=C1NC(=O)C2CCCCC12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1C2CCCCC2C(=O)N1CC(O)CCN1CCC(c2noc3cc(F)ccc23)CC1
Yield: 49.1 %

Procedure:
To a mixture of 60% sodium hydride (0.12 g) and dimethylformamide (5 ml), cyclohexane-1,2-dicarboximide (0.5 g) was portionwise added. A solution of 1-(3,4-epoxybutyl)-4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine (0.8 g) in dimethylformamide (10 ml) was dropwise added thereto at room temperature, and the resultant mixture was kept at an inner temperature of 90 to 100° C. for 16.5 hours. Insoluble materials were removed by filtration, and the residue was combined with water and extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution, dried over magnesium sulfate and concentrated under reduced pressure. The resulting crude crystals were recrystallized from a mixture of isopropyl ether and isopropanol to give the objective compound (0.6 g).
Reaction SMILES: [F:1][C:2]1([F:9])[CH2:5][CH:4]([CH2:6][CH2:7][OH:8])[CH2:3]1.CC(C)=[O:12].OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O>[F:1][C:2]1([F:9])[CH2:5][CH:4]([CH2:6][C:7]([OH:12])=[O:8])[CH2:3]1
Reactant: OCCC1CC(F)(F)C1
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Product: O=C(O)CC1CC(F)(F)C1
Reaction time: 2 h
Yield: 92 %

Procedure:
A solution of 2-(3,3-difluorocyclobutyl)ethanol (270 mg, 2.0 mmol, prepared as described in Bogen, S. et al., Bioorg. Med. Chem. Lett., 18:4219 (2008)) in acetone (5 mL) was treated with Jones reagent (2.7 mmol, 1 mL of 2.7 M solution) over a period of 30 minutes at room temperature. After 2 hours, additional Jones reagent (0.25 mL) was added. After 1 hour, the reaction mixture was filtered through CELITE®, and concentrated under reduced pressure. The reaction mixture was re-dissolved in ethyl acetate (10 mL), washed with water (2×20 mL), brine (20 mL), and then dried over MgSO4, The mixture was then filtered and concentrated to isolate Intermediate S-9A (275 mg, 92% yield) as a tan solid. 1H NMR (500 MHz, chloroform-d) δ 2.74-2.87 (2H, m), 2.57-2.62 (2H, m), 2.48-2.56 (1H, m, J=8.60, 4.30, 4.30, 1.94 Hz), 2.23-2.35 (2H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]1[C:23](=[O:24])[N:22]([CH3:25])[C:13]2[N:14]([CH3:21])[C:15]3[C:20]([C:12]=2[CH:11]=1)=[CH:19][CH:18]=[CH:17][CH:16]=3.[C:26](Cl)(=[O:28])[CH3:27]>>[C:26]([C:18]1[CH:19]=[C:20]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH3:21])[C:13]1[N:22]([CH3:25])[C:23](=[O:24])[C:10]([C:3]3[CH:4]=[CH:5][C:6]([O:8][CH3:9])=[CH:7][C:2]=3[Cl:1])=[CH:11][C:12]2=1)(=[O:28])[CH3:27]
Reactant: CC(=O)Cl
Reactant: COc1ccc(-c2cc3c4ccccc4n(C)c3n(C)c2=O)c(Cl)c1
Product: COc1ccc(-c2cc3c4cc(C(C)=O)ccc4n(C)c3n(C)c2=O)c(Cl)c1

Procedure:
The process is carried out as indicated in Example 60 above, using compound B: 3-(2-chloro-4-methoxyphenyl)-1,9-dimethyl-1,9-dihydropyrido[2,3-b]indol-2-one and acetyl chloride.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH:12]=[O:13])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[CH2:14]([Mg]Br)[CH3:15]>C1COCC1>[NH2:1][C:2]1[C:3]([CH:12]([OH:13])[CH2:14][CH3:15])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2
Reactant: Nc1c(C=O)ccc2cccnc12
Reactant: CC[Mg]Br
Solvent: C1CCOC1
Product: CCC(O)c1ccc2cccnc2c1N
Yield: 76.3 %

Procedure:
In a similar fashion using route 27 general procedure 66, 8-amino-quinoline-7-carbaldehyde 404 (1 g, 5.83 mmol), ethyl magnesium bromide (3M in THF; 5.81 ml, 17.44 mmol) and THF (30 ml) gave the title compound (900 mg, 91%) after purification by column chromatography with DCM/MeOH (99:1) as the eluent.
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=O.[CH3:16][C:17]([C:19]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=1[Cl:26])=O.O.C1(C)C(S(O)(=O)=O)=CC=CC=1.C>C(O)C>[Cl:26][C:20]1[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:19]=1[C:17]1[CH:16]=[C:4]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:3]2[C:2](=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:1]=1
Reactant: Nc1ccccc1C(=O)c1ccccc1
Reactant: CC(=O)c1cc(Cl)ccc1Cl
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: O
Solvent: CCO
Product: Clc1ccc(Cl)c(-c2cc(-c3ccccc3)c3ccccc3n2)c1
Reaction time: 24 h
Yield: 65 %

Procedure:
2-Aminobenzophenone (33 g) and 2,5-dichloroacetophenone (32 g) were placed in a flask together with 2.5 g of toluenesulfonic acid monohydrate. The mixture was heated and stirred at 160°-170° C. for 24 hours. The resulting mixture was diluted with ethanol (300 ml). The crystals was filtered to give 63 g crude product, which was treated with charcoal and recrystallized first from ethanol, followed by recrystallization from hexane and ethyl acetate to give monomer as white crystals (65%).
Reaction SMILES: [OH-].[Na+].[OH:3][CH2:4][CH:5]1[CH2:10]C[CH2:8][N:7]([C:11]2[CH:12]=[CH:13][C:14]([CH3:32])=[C:15]([CH:31]=2)[C:16]([NH:18][C:19]2[C:20]([CH3:30])=[C:21]([CH:26]=[CH:27][C:28]=2[CH3:29])[C:22]([O:24]C)=[O:23])=[O:17])[CH2:6]1>CO>[OH:3][CH2:4][CH:5]1[CH2:10][CH2:8][N:7]([C:11]2[CH:12]=[CH:13][C:14]([CH3:32])=[C:15]([CH:31]=2)[C:16]([NH:18][C:19]2[C:20]([CH3:30])=[C:21]([CH:26]=[CH:27][C:28]=2[CH3:29])[C:22]([OH:24])=[O:23])=[O:17])[CH2:6]1
Reactant: COC(=O)c1ccc(C)c(NC(=O)c2cc(N3CCCC(CO)C3)ccc2C)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1ccc(N2CCC(CO)C2)cc1C(=O)Nc1c(C)ccc(C(=O)O)c1C
Reaction time: 5 h
Yield: 18.8 %

Procedure:
A solution of aqueous 5N NaOH (5.00 ml) is added to a stirred solution of methyl 3-[[5-[3-(hydroxymethyl)-1-piperidyl]-2-methyl-benzoyl]amino]-2,4-dimethyl-benzoate (0.4 g, 0.975 mmol) in MeOH (5 ml). After 5 hours at ambient temperature, the organic solvent is removed under reduced pressure and the residue is diluted with water, acidified to pH 4 with 1N HCl, and extracted twice with 10% IPA in CH2Cl2. The organic layers are combined and dried over anhydrous sodium sulfate. The solvent is removed under reduced pressure and the resulting precipitate is triturated with diethyl ether and filtered to afford the title compound as a brown solid (70 mg, 56%). Mass spectrum (m/z): 381.2 (M−1).
Reaction SMILES: [NH2:1][C:2]1[C:11]([C:12]([O:14][CH3:15])=[O:13])=[C:10]2[C:5]([CH:6]3[CH2:16][CH:7]3[CH2:8][O:9]2)=[CH:4][CH:3]=1.[CH2:17]([N:19]1[CH2:23][CH2:22][C@H:21]([CH2:24][C:25]2[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=2[S:32](Cl)(=[O:34])=[O:33])[CH2:20]1)[CH3:18]>C(Cl)Cl.N1C=CC=CC=1>[CH2:17]([N:19]1[CH2:23][CH2:22][C@H:21]([CH2:24][C:25]2[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=2[S:32]([NH:1][C:2]2[C:11]([C:12]([O:14][CH3:15])=[O:13])=[C:10]3[C:5]([C@@H:6]4[CH2:16][C@@H:7]4[CH2:8][O:9]3)=[CH:4][CH:3]=2)(=[O:33])=[O:34])[CH2:20]1)[CH3:18]
Reactant: CCN1CC[C@H](Cc2cc(F)ccc2S(=O)(=O)Cl)C1
Reactant: COC(=O)c1c(N)ccc2c1OCC1CC21
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCN1CC[C@H](Cc2cc(F)ccc2S(=O)(=O)Nc2ccc3c(c2C(=O)OC)OC[C@H]2C[C@@H]32)C1
Temperature: 40 °C
Yield: 25.8 %

Procedure:
A solution of methyl 5-amino-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (Intermediate 42, 0.19 g) in DCM (10 mL) and pyridine (3.5 mL) was treated with a solution of 2-((S)-1-ethylpyrrolidin-3-ylmethyl)-4-fluorobenzenesulfonyl chloride (Intermediate 114, 0.26 g) in DCM (5 mL) and the mixture was stirred and heated at 40° C. for 1 hour. The resultant mixture was evaporated to dryness and the residue was purified by chromatography on silica, eluting with a mixture of DCM and methanol with a gradient of 0-25%, then flushed with 100% methanol to give methyl (1aS,7bR)-5-[2-((S)-1-ethylpyrrolidin-3-ylmethyl)-4-fluoro-benzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (0.107 g) as a gum.
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[CH:2]=O.[CH3:8][S:9]([C:12]1[CH:13]=[C:14]([CH:16]=[CH:17][CH:18]=1)[NH2:15])(=[O:11])=[O:10].C([BH3-])#N.[Na+].C(OC(C)=O)(C)C>C1(C)C=CC=CC=1.CO.C(O)(=O)C>[CH2:6]([O:5][C:1](=[O:4])[CH2:2][NH:15][C:14]1[CH:16]=[CH:17][CH:18]=[C:12]([S:9]([CH3:8])(=[O:11])=[O:10])[CH:13]=1)[CH3:7]
Reactant: CCOC(=O)C=O
Reactant: CS(=O)(=O)c1cccc(N)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CCOC(=O)CNc1cccc(S(C)(=O)=O)c1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 56 %

Procedure:
A 0.5 M solution of ethyl glyoxalate in toluene (0.95 ml, 5 mmol; CAS Reg. No. 924-44-7) and acetic acid (0.4 ml) were added to an ice cold solution of 3-(methylsulfonyl)aniline (500 mg, 2 mmol; CAS Reg. No. 5470-49-5) in methanol (6.3 ml) under an argon atmosphere. Sodium cyanoborohydride (356 mg, 5 mmol) was added in 3 portions within 10 min. The reaction mixture was stirred for 45 min at 0° C. and then at ambient temperature over night. The reaction mixture was poured onto ice water (100 ml). iPrOAc (100 ml) was added and the layers were separated. The aqueous layer was extracted one more time with iPrOAc (100 ml). The combined extracts were washed two times with ice water/brine 1/1 and dried over sodium sulfate. After filtering the solvent was removed under reduced pressure to give the crude product as yellow foam which was purified by column chromatography (silica gel, iPrOAc/n-heptane) to obtain the title compound (350 mg, 1 mmol; 56%) as white solid. MS (ESI): m/z=258.2 [M+H]+.
Reaction SMILES: N[C:2]1[C:3]([I:21])=[C:4]([C:9]([I:20])=[C:10]([N:13](CCO)C(=O)C)[C:11]=1[I:12])[C:5]([NH:7][CH3:8])=[O:6].[Cl-].O.C[C:25]([N:27](C)[CH3:28])=[O:26]>>[NH2:13][C:10]1[C:9]([I:20])=[C:4]([C:5]([NH:7][CH3:8])=[O:6])[C:3]([I:21])=[C:2]([C:11]=1[I:12])[C:25]([NH:27][CH3:28])=[O:26]
Reactant: CC(=O)N(C)C
Reactant: CNC(=O)c1c(I)c(N)c(I)c(N(CCO)C(C)=O)c1I
Agent: [Cl-]
Solvent: O
Product: CNC(=O)c1c(I)c(N)c(I)c(C(=O)NC)c1I
Temperature: 25 °C
Reaction time: 144 h

Procedure:
To a solution of 3-amino-5-[N-(2-hydroxyethyl)acetamido]-2,4,6-triiodo-N-methylbenzamide (II; 50.32 g.; 0.08 mole) dissolved in dimethylacetamide (252 ml.) was added in one portion 2,3,4,5,6-O-pentaacetylgluconyl chloride (101.88 g.; 0.24 mole; prepared by the method of C. E. Braun and C. D. Cook, Org. Syn., 41, 79 (1961)). After being stirred for six days at room temperature, the reaction mixture was poured into a mixture of dimethylacetamide (510 ml.) and water (680 ml.). The mixture was stirred for 2 hours, after which it was extracted with chloroform (3×340 ml.). The combined chloroform extracts were washed with 5% aqueous bicarbonate (2×340 ml.) and water (340 ml.), dried over sodium sulfate and evaporated under reduced pressure to give III as an oil, 132.75 g. (>100% due to the presence of dimethylacetamide as shown by the nuclear magnetic resonance spectrum). The product was homogeneous by thin-layer chromatography (ethyl acetate-acetic acid, 98:2), and the nuclear magnetic resonance spectrum was consistent with the assigned structure. The product was hydrolyzed without further purification.
Reaction SMILES: [CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1.[C:16]1([CH2:22][C:23](Cl)=[O:24])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][N:5]([C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1)[C:23](=[O:24])[CH2:22][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: CN(C)CCNc1ccc([N+](=O)[O-])cc1
Product: CN(C)CCN(C(=O)Cc1ccccc1)c1ccc([N+](=O)[O-])cc1

Procedure:
Prepared from 4-(2-dimethylamino-ethylamino)-nitrobenzene and phenylacetyl-chloride
Reaction SMILES: N#N.[Br:3][C:4]1[CH:9]=[C:8](Br)[CH:7]=[CH:6][N:5]=1.[Li]CCCC.CN(C)[C:18](=[O:20])[CH3:19]>CCOCC>[Br:3][C:4]1[CH:9]=[C:8]([C:18](=[O:20])[CH3:19])[CH:7]=[CH:6][N:5]=1
Reactant: Brc1ccnc(Br)c1
Reactant: CC(=O)N(C)C
Agent: N#N
Agent: [Li]CCCC
Solvent: CCOCC
Product: CC(=O)c1ccnc(Br)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a suspension of commercially available 2,4-dibromo-pyridine (3.30 g, 13.9 mmol) in dry Et2O (75 mL) was treated with n-BuLi (5.85 mL of a 2.5M solution in hexanes, 14.6 mmol) at −78° C. The reaction mixture was stirred at this temperature for 30 min. N,N-Dimethyl-acetamide (2.6 mL, 27.9 mmol) was then added and the mixture allowed to warm to rt over a period of 1 h and stirred at this temperature for 30 min. The reaction was quenched by the addition of sat. aq. NH4Cl (50 mL). The layers were separated and the aq. layer extracted with Et2O (2×50 mL). The combined org. extracts were dried over Na2SO4, filtered, and the solvent was removed under reduced pressure. Purification of the residue by FC (20:1 to 5:1 hept-EA) gave the title compound as a white solid. TLC:rf (1:1 hept-EA)=0.41. LC-MS-conditions 02: tR=0.81 min; [M+H]+=200.61.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:13]3[S:21][C:20]([CH2:22][CH3:23])=[N:19][C:14]=3[CH:15]=[N:16][C:17]=2[CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1C=C(C=CC=1)C(OO)=[O:29]>C(Cl)(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:13]3[S:21][C:20]([CH2:22][CH3:23])=[N:19][C:14]=3[CH:15]=[N+:16]([O-:29])[C:17]=2[CH:18]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCc1nc2cnc3cc(OCc4ccccc4)ccc3c2s1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: CCc1nc2c[n+]([O-])c3cc(OCc4ccccc4)ccc3c2s1
Temperature: 25 °C
Yield: 97.8 %

Procedure:
To a stirred solution of 7-benzyloxy-2-ethylthiazolo[4,5-c]quinoline (15.0 g, 46.8 mmol) in chloroform (150 mL), 3-chloroperoxybezoic acid (m-CPBA. 50% w/w, 16.15 g, 46.8 mmol) was slowly added in small portions. The reaction was maintained at room temperature overnight. The reaction mixture was transferred to a separatory funnel and washed with 10% aqueous sodium carbonate (2×50 mL). The chloroform layer was concentrated to provide 15.4 g of 7-benzyloxy-2-ethylthiazolo[4,5-c]quinoline 5-oxide as a light tan solid. MS (ACPI) m/z=337 (M+H)+. This material was carried on without further purification to the next step.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]2[C:18]3[CH2:17][N:16]([CH2:19][C:20]4[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=4)[C:15](=[O:28])[NH:14][C:13]=3[N:12]=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[F:29][C:30]1[CH:35]=[CH:34][C:33]([N:36]2[CH:41]=[CH:40][CH:39]=[C:38]([C:42](O)=[O:43])[C:37]2=[O:45])=[CH:32][CH:31]=1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH3:27][O:26][C:23]1[CH:24]=[CH:25][C:20]([CH2:19][N:16]2[CH2:17][C:18]3[C:9]([O:8][C:5]4[CH:4]=[CH:3][C:2]([NH:1][C:42]([C:38]5[C:37](=[O:45])[N:36]([C:33]6[CH:32]=[CH:31][C:30]([F:29])=[CH:35][CH:34]=6)[CH:41]=[CH:40][CH:39]=5)=[O:43])=[N:7][CH:6]=4)=[CH:10][CH:11]=[N:12][C:13]=3[NH:14][C:15]2=[O:28])=[CH:21][CH:22]=1
Reactant: O=C(O)c1cccn(-c2ccc(F)cc2)c1=O
Reactant: COc1ccc(CN2Cc3c(Oc4ccc(N)nc4)ccnc3NC2=O)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(CN2Cc3c(Oc4ccc(NC(=O)c5cccn(-c6ccc(F)cc6)c5=O)nc4)ccnc3NC2=O)cc1
Yield: 31.8 %

Procedure:
A solution of 5-[(6-aminopyridin-3-yl)oxy]-3-(4-methoxybenzyl)-3,4-dihydropyrido[2,3-d]pyrimidin-2(1H)-one (100.00 mg; 0.26 mmol; 1.00 eq.), 1-(4-fluoro-phenyl)-2-oxo-1,2-dihydro-pyridine-3-carboxylic acid (67.97 mg; 0.29 mmol; 1.10 eq.), pybop (179.26 mg; 0.34 mmol; 1.30 eq.), DMF (4.00 ml), and N,N-diisopropylethylamine (0.13 μl; 0.79 mmol; 3.00 eq.) was stirred at room temperature under N2 for 14 hours. The reaction was concentrated, redissolved in DMSO, and purified via prep HPLC to afford 49 mg (26%) of 282 as a peach-colored solid. LC-MS (M+H=593, obsd.=593).
Reaction SMILES: [F:1][C:2]1([CH2:9][C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:11])[CH:7]=[CH:6][N:5]=[C:4]([F:8])[CH2:3]1.[Br:18]Br>C(O)(=O)C>[F:1][C:2]1([CH:9]([Br:18])[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:11])[CH:7]=[CH:6][N:5]=[C:4]([F:8])[CH2:3]1
Reactant: BrBr
Reactant: O=C(CC1(F)C=CN=C(F)C1)c1ccccc1
Solvent: CC(=O)O
Product: O=C(c1ccccc1)C(Br)C1(F)C=CN=C(F)C1
Yield: 101.6 %

Procedure:
4-Fluoro-2-(2-fluoropyridin-4-yl)acetophenone (0.5 g; 2.1 mmol) dissolved in acetic acid (4 ml) is treated with bromine (0.34 g; 2.1 mmol) in acetic acid (1 ml) at room temperature for 2.5 h under stirring. The light brown solution is evaporated to dryness, dissolved in ether and extracted three times with diethyl ether. The combined organic phases are washed with a saturated solution of NaHCO3, dried over Na2SO4, filtered and evaporated to dryness to yield the title compound as pale yellow oil (0.67 g; 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][N:7]2[C:12](=[O:13])[NH:11][C:10](=[O:14])[CH2:9][NH:8]2)=[CH:4][CH:3]=1.[Cl:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](Cl)=[O:23])=[CH:20][CH:19]=1>C1C=CC=CC=1>[Cl:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([N:8]2[CH2:9][C:10](=[O:14])[NH:11][C:12](=[O:13])[N:7]2[CH2:6][C:5]2[CH:15]=[CH:16][C:2]([Cl:1])=[CH:3][CH:4]=2)=[O:23])=[CH:20][CH:19]=1
Reactant: O=C1CNN(Cc2ccc(Cl)cc2)C(=O)N1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Solvent: c1ccccc1
Product: O=C1CN(C(=O)c2ccc(Cl)cc2)N(Cc2ccc(Cl)cc2)C(=O)N1
Yield: 60 %

Procedure:
Into a 100 ml round bottomed flask equipped with a reflux condenser sealed with a calcium chloride tube, were placed 100 ml of dry benzene, 1 g of 2-(4'-chlorobenzyl)-hexahydro-1,2,4-triazine-3,5-dione and 2 ml of p-chlorobenzoylchloride. The mixture was refluxed for 18 hours, the solution obtained was then cooled and the precipitated crystals were filtered off by suction to yield 1 g (60%) of 1-(4'-chlorobenzoyl)-2-(4'-chlorobenzyl)-hexahydro-1,2,4-triazine-3,5-dione; m.p. 205°.
Reaction SMILES: Cl.[NH2:2][N:3]1[CH2:7][C:6](=[O:8])[NH:5][C:4]1=[O:9].[N:10]1[C:19]2[C:14](=[CH:15][C:16]([CH2:20][N:21]3[C:25]4=[N:26][C:27]([C:30](=O)[CH3:31])=[CH:28][N:29]=[C:24]4[N:23]=[N:22]3)=[CH:17][CH:18]=2)[CH:13]=[CH:12][CH:11]=1>>[N:10]1[C:19]2[C:14](=[CH:15][C:16]([CH2:20][N:21]3[C:25]4=[N:26][C:27](/[C:30](=[N:2]/[N:3]5[CH2:7][C:6](=[O:8])[NH:5][C:4]5=[O:9])/[CH3:31])=[CH:28][N:29]=[C:24]4[N:23]=[N:22]3)=[CH:17][CH:18]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: NN1CC(=O)NC1=O
Reactant: CC(=O)c1cnc2nnn(Cc3ccc4ncccc4c3)c2n1
Agent: Cl
Product: C/C(=N\N1CC(=O)NC1=O)c1cnc2nnn(Cc3ccc4ncccc4c3)c2n1
Yield: 58 %

Procedure:
The title compound was prepared in 58% yield as a light yellow solid in analogy to the synthesis of example 52 from 1-aminoimidazolidine-2,4-dione hydrochloride and 1-(1-(quinolin-6-ylmethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl)ethanone. 1H-NMR (400 MHz, DMSO-d6) δ ppm 11.45 (s, 1H), 9.41 (s, 1H), 8.89 (d, 1H), 8.35 (d, 1H), 8.02 (m, 2H), 7.84 (d, 1H), 7.53 (dd, 1H), 6.23 (s, 2H), 4.56 (s, 2H), 2.49 (s, 3H). LCMS (method B): [MH]+=402, tR=1.81 min.