Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2](=[O:20])[C@H:3]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:4][C:5]1[CH:10]=[CH:9][C:8](I)=[CH:7][CH:6]=1.[CH3:21][S:22]([O-:24])=[O:23].[Na+].CNCCNC.O>CS(C)=O.CCOC(C)=O>[NH2:1][C:2](=[O:20])[C@H:3]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([S:22]([CH3:21])(=[O:24])=[O:23])=[CH:7][CH:6]=1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(I)cc1)C(N)=O
Reactant: CS(=O)[O-]
Agent: CNCCNC
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N[C@H](Cc1ccc(S(C)(=O)=O)cc1)C(N)=O
Reaction time: 3 h
Yield: 87.8 %

Procedure:
A mixture of (R)-tert-butyl 1-amino-3-(4-iodophenyl)-1-oxopropan-2-ylcarbamate (200 mg, 0.512 mmol), sodium methanesulfinate (200 mg, 85%, 1.66 mmol), CuOTf hemi-toluene complex (120 mg, 0.464 mmol) and N,N′-dimethylethylenediamine (0.030 mL, 0.279 mmol) in DMSO (5 mL) was stirred at 115 C for 3 h. Water and EtOAc were added. The organic phase was separated, washed with 5% NaHCO3, dried over Na2SO4, concentrated in vacuo to give (R)-tert-butyl 1-amino-3-(4-(methylsulfonyl)phenyl)-1-oxopropan-2-ylcarbamate (154 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[C:10]3[C:16]([C:17]4[CH:18]=[N:19][N:20]([CH2:22][C:23]5[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=5)[CH:21]=4)=[CH:15][N:14]([S:30]([C:33]4[CH:39]=[CH:38][C:36]([CH3:37])=[CH:35][CH:34]=4)(=[O:32])=[O:31])[C:11]3=[N:12][CH:13]=2)[CH:5]=[CH:4][C:3]=1[CH:40]1[CH2:45][CH2:44][N:43](C(OC(C)(C)C)=O)[CH2:42][CH2:41]1>CO.Cl.O1CCOCC1>[F:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[C:10]3[C:16]([C:17]4[CH:18]=[N:19][N:20]([CH2:22][C:23]5[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=5)[CH:21]=4)=[CH:15][N:14]([S:30]([C:33]4[CH:34]=[CH:35][C:36]([CH3:37])=[CH:38][CH:39]=4)(=[O:32])=[O:31])[C:11]3=[N:12][CH:13]=2)[CH:5]=[CH:4][C:3]=1[CH:40]1[CH2:41][CH2:42][NH:43][CH2:44][CH2:45]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(C5CCN(C(=O)OC(C)(C)C)CC5)c(F)c4)cnc32)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(C5CCNCC5)c(F)c4)cnc32)cc1
Yield: 98.5 %

Procedure:
Using similar reaction conditions as described in step-ii of example-7, tert-butyl 4-(2-fluoro-4-(3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperidine-1-carboxylate (product of step 1 of example 84) (130 mg, 0.179 mmol) was deprotected in methanol/HCl in dioxane (5/5 mL) to afford 110 mg (98.2% yield) of the titled compound. MS: m/z=624.4 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:6]=[C:5]([C:7]([OH:9])=O)[O:4][N:3]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C([O:33][C:34](=[O:54])[C:35]([CH3:53])([CH3:52])[CH2:36][C@H:37]([NH2:51])[CH2:38][C:39]1[CH:44]=[CH:43][C:42]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)=[CH:41][CH:40]=1)C.[Li+].[OH-]>CN(C=O)C.O.C1COCC1.CO>[C:42]1([C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=2)[CH:41]=[CH:40][C:39]([CH2:38][C@@H:37]([NH:51][C:7]([C:5]2[O:4][N:3]=[C:2]([OH:1])[CH:6]=2)=[O:9])[CH2:36][C:35]([CH3:53])([CH3:52])[C:34]([OH:54])=[O:33])=[CH:44][CH:43]=1
Reactant: CCOC(=O)C(C)(C)C[C@H](N)Cc1ccc(-c2ccccc2)cc1
Reactant: O=C(O)c1cc(O)no1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Agent: [Li+]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1cc(O)no1)C(=O)O
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
3-Hydroxyisoxazole-5-carboxylic acid (396 mg, 307 μmol, 1.0 eq.), EDCI (54.4 μL, 307 μmol, 1.0 eq.) and HOBt (41.5 mg, 307 μmol, 1.0 eq.) were combined in DMF (0.2 mL) and stirred for 5 minutes at room temperature. (R)-4-Amino-5-biphenyl-4-yl-2,2-dimethyl-pentanoic acid ethyl ester (100 mg, 307 μmol, 1.0 eq.) was added and the resulting mixture was stirred for 30 minutes. 1 M LiOH in water (1.2 mL) in THF (3 mL) was added and the mixture was maintained at 60° C. for 2 days. A small amount of MeOH was added to speed up the reaction. The reaction was then quenched with AcOH and the product was purified by preparative HPLC to yield the title compound (25 mg, 95% purity. MS m/z [M+H]+ calc'd for C23H24N2O5, 409.17; Found 409.4.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([NH:11][C:12]2[CH:13]=[N:14][CH:15]=[C:16]([C:18]([C:20]3[C:28]4[CH:27]=[N:26][CH:25]=[N:24][C:23]=4[N:22]([CH:29]([CH3:31])[CH3:30])[CH:21]=3)=[O:19])[CH:17]=2)=[O:10])=[N:6][CH:7]=1.[CH3:32][N:33](C=O)C>CCOC(C)=O.[C-]#N.[Zn+2].[C-]#N.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[C:32]([C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([NH:11][C:12]2[CH:13]=[N:14][CH:15]=[C:16]([C:18]([C:20]3[C:28]4[CH:27]=[N:26][CH:25]=[N:24][C:23]=4[N:22]([CH:29]([CH3:31])[CH3:30])[CH:21]=3)=[O:19])[CH:17]=2)=[O:10])=[N:6][CH:7]=1)#[N:33]
Reactant: CN(C)C=O
Reactant: CC(C)n1cc(C(=O)c2cncc(NC(=O)Cc3ccc(Br)cn3)c2)c2cncnc21
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)n1cc(C(=O)c2cncc(NC(=O)Cc3ccc(C#N)cn3)c2)c2cncnc21
Temperature: 100 °C
Yield: 18 %

Procedure:
Zinc cyanide (28 mg, 0.23 mmol) was added to 2-(5-Bromo-pyridin-2-yl)-N-[5-(7-(propan-2-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-pyridin-3-yl]-acetamide (Example 317, 75 mg, 0.16 mmol) in DMF (2 mL) and the mixture was degassed with argon for 10 minutes. Then tris(dibenzylideneacetone)dipalladium (3 mg, 0.003 mmol) and 1,1′-bis(diphenylphosphino)ferrocene (7 mg, 0.012 mmol) were added and the mixture was heated at 100° C. for 40 mins under microwave irradiation. The mixture was diluted with EtOAc (5 mL) and washed with water (2 mL), brine (2 mL) and dried over sodium sulphate. The filtrate was evaporated in vacuo and purified by preparative TLC (3% MeOH in DCM) to afford the title compound as a light brown solid in 18% yield, 12 mg.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[Cl:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=1.O>C1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Cl:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16][NH:1][C:2]2[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=2)=[CH:14][CH:13]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: Nc1ccc(C(=O)O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: O=C(O)c1ccc(NCc2ccc(Cl)cc2)cc1
Yield: 66.2 %

Procedure:
4-Aminobenzoic acid (13.7 g., 0.1 mole) and 4-chlorobenzaldehyde (14.05 g., 0.1 mole) were mixed in dry benzene (200 ml.), 4-toluenesulphonic acid (50 mg.) was added and the mixture was boiled under reflux in an apparatus incorporating a water-trap until the theoretical amount of water (1.8 ml) had been collected. The reaction mixture was cooled in iced water, the product filtered, dried and hydrogenated in NTP in ethanol (500 ml) in the presence of platinum oxide, (Adams catalyst), (100 mg). The catalyst was filtered off and the solution added to iced water. The product was filtered, dried and crystallised from 20% aqueous ethanol to give 4-[(4-chlorobenzyl)-amino]-benzoic acid (17.32 g., 78%) which melted at 206°-8° C.
Reaction SMILES: Cl.C(OCC)(=O)C.C([O:12][C:13]1[C:14]([CH2:19][N:20]2[CH2:25][CH2:24][CH:23]([CH:26]([CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[F:36])[C:27]#[N:28])[CH2:22][CH2:21]2)=[N:15][CH:16]=[CH:17][N:18]=1)(C)(C)C.[OH-].[Na+]>C(OCC)(=O)C>[F:36][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=1[CH2:29][CH:26]([CH:23]1[CH2:22][CH2:21][N:20]([CH2:19][C:14]2[C:13](=[O:12])[NH:18][CH:17]=[CH:16][N:15]=2)[CH2:25][CH2:24]1)[C:27]#[N:28]
Reactant: CC(C)(C)Oc1nccnc1CN1CCC(C(C#N)Cc2ccccc2F)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: N#CC(Cc1ccccc1F)C1CCN(Cc2ncc[nH]c2=O)CC1
Reaction time: 1 h
Yield: 79.9 %

Procedure:
After adding 3 ml of 4N hydrogen chloride/ethyl acetate to 188 mg of 2-[1-(3-tert-butoxy-2-pyrazinylmethyl)piperidin-4-yl]-3-(2-fluorophenyl)propionitrile while cooling on ice, the mixture was stirred 1 hour. A 2N sodium hydroxide solution was added to the reaction solution for neutralization, and extraction was performed with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. Diethyl ether was added to the residue and the mixture was filtered to obtain the title compound (129 mg, 80% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][C:7]2[N:8]=[C:9]([C:22]3[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=3)[S:10][C:11]=2[C:12]2[NH:16][N:15]=[C:14]([C:17]([O:19]CC)=[O:18])[CH:13]=2)=[CH:4][CH:3]=1.[Li+].[OH-].Cl>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2[N:8]=[C:9]([C:22]3[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=3)[S:10][C:11]=2[C:12]2[NH:16][N:15]=[C:14]([C:17]([OH:19])=[O:18])[CH:13]=2)=[CH:28][CH:29]=1
Reactant: CCOC(=O)c1cc(-c2sc(-c3ccncc3)nc2Cc2ccc(Cl)cc2)[nH]n1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)c1cc(-c2sc(-c3ccncc3)nc2Cc2ccc(Cl)cc2)[nH]n1
Reaction time: 72 h
Yield: 6.6 %

Procedure:
A solution of ethyl 5-(4-(4-chlorobenzyl)-2-(pyridin-4-yl)thiazol-5-yl)-1H-pyrazole-3-carboxylate (16.1 mg, 0.0379 mmol) in THF (0.50 mL) was treated with 1.0 M aqueous LiOH (0.0568 mL, 0568 mmol) and the solution was stirred at 40 degrees for 3 days. The reaction was then heated at 65 degrees for 6 hours. The reaction mixture was cooled and acidified with 1N HCl. The solution was extracted with EA (3×25 mL) and the combined organic layers were dried, filtered and concentrated in vacuo. The residue was purified by preparative reverse phase chromatography to give 1 mg (7% yield) of the title compound as a white solid. LC/MS (FA) ES+ 397, 399.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[C:11]([OH:13])=[O:12].S(Cl)(Cl)=O.N1C=CC=C[CH:19]=1.CO>CN(C=O)C.C(Cl)(Cl)(Cl)Cl>[CH3:19][O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([CH3:1])=[C:3]([C:11]([OH:13])=[O:12])[CH:4]=1
Reactant: c1ccncc1
Reactant: Cc1ccc(C(=O)O)cc1C(=O)O
Solvent: ClC(Cl)(Cl)Cl
Solvent: CN(C)C=O
Solvent: CO
Product: COC(=O)c1ccc(C)c(C(=O)O)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of compound (2) (2.83 g, 15.71 mmol), thionyl chloride (50 ml) and DMF (3 drops) was heated at reflux for 2 hours. After cooling to room temperature, excess thionyl chloride was removed under reduced pressure (rotary evaporator). The dark oil which was obtained was dissolved in carbon tetrachloride (30 ml), treated with pyridine (1 ml, 12.43 mmol) and methanol (20 ml) and stirred at ambient temperature for 2 hours. The solvents were evaporated and the residue purified by flash chromatography: silica, hexane/EtOAc (9:1).
Reaction SMILES: Cl[C:2]1[N:7]([CH2:8][CH:9]2[CH2:11][CH2:10]2)[C:6](=[O:12])[NH:5][C:4](=[O:13])[CH:3]=1.[NH2:14][NH2:15]>C(O)C>[CH:9]1([CH2:8][N:7]2[C:2]([NH:14][NH2:15])=[CH:3][C:4](=[O:13])[NH:5][C:6]2=[O:12])[CH2:11][CH2:10]1
Reactant: NN
Reactant: O=c1cc(Cl)n(CC2CC2)c(=O)[nH]1
Solvent: CCO
Product: NNc1cc(=O)[nH]c(=O)n1CC1CC1
Temperature: 82.5 °C

Procedure:
6-Chloro-1-cyclopropylmethyluracil (24.34 g, 0.12 mol) was suspended in absolute ethanol (245 mL) under nitrogen. Anhydrous hydrazine (11.69 g, 0.36 mol) was added via syringe in excess, resulting in a clear-yellow solution. The reaction mixture was heated at 80-85° C. for one hour; bright yellow crystals began forming within minutes of the application of heat. The reaction mixture was cooled to room temperature and then in an ice bath, and the crude product collected by filtration. N2H4×HCl was removed by triturating with cold water to give the product as a pale yellow solid, 20.47 g (86%). Mp 221° C. (dec).
Reaction SMILES: [C:1]([SiH2:5][O:6][C:7]([CH3:14])([CH3:13])[C@H:8]([NH2:12])[CH:9]([CH3:11])[CH3:10])([CH3:4])([CH3:3])[CH3:2].[Br:15][C:16]1[CH:17]=[N:18][CH:19]=[C:20](Br)[CH:21]=1>>[Br:15][C:16]1[CH:21]=[C:20]([NH:12][C@@H:8]([C:7]([CH3:13])([CH3:14])[O:6][SiH2:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH:9]([CH3:10])[CH3:11])[CH:19]=[N:18][CH:17]=1
Reactant: CC(C)[C@@H](N)C(C)(C)O[SiH2]C(C)(C)C
Reactant: Brc1cncc(Br)c1
Product: CC(C)[C@@H](Nc1cncc(Br)c1)C(C)(C)O[SiH2]C(C)(C)C

Procedure:
In analogy to the procedures described for the preparation of intermediate A-3 [B] and A-3 [C]: i) (R)-1-(tert-butyl-dimethyl-silanyloxymethyl)-2-methyl-propylamine has been reacted with 3,5-dibromopyridine to give (5-bromo-pyridin-3-yl)-[(R)-1-(tert-butyl-dimethyl-silanyloxymethyl)-2-methyl-propyl]-amine; ii) subsequent condensation with 1-methyl-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,4-dihydro-1H-quinolin-2-one (intermediate A-1) gave the title compound as light yellow amorphous solid. MS: 454.3 (M+H+).
Reaction SMILES: COC[O:4][C:5]1[CH:31]=[CH:30][C:8]([CH:9]=[C:10]2[CH2:15][CH2:14][CH2:13][C:12](=[CH:16][C:17]3[CH:22]=[CH:21][C:20]([O:23]COC)=[C:19]([O:27][CH3:28])[CH:18]=3)[C:11]2=[O:29])=[CH:7][C:6]=1[O:32][CH3:33]>CO.Cl>[OH:23][C:20]1[CH:21]=[CH:22][C:17]([CH:16]=[C:12]2[CH2:13][CH2:14][CH2:15][C:10](=[CH:9][C:8]3[CH:30]=[CH:31][C:5]([OH:4])=[C:6]([O:32][CH3:33])[CH:7]=3)[C:11]2=[O:29])=[CH:18][C:19]=1[O:27][CH3:28]
Reactant: COCOc1ccc(C=C2CCCC(=Cc3ccc(OCOC)c(OC)c3)C2=O)cc1OC
Agent: Cl
Solvent: CO
Product: COc1cc(C=C2CCCC(=Cc3ccc(O)c(OC)c3)C2=O)ccc1O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 64.5 %

Procedure:
2,6-Bis(4-methoxymethyloxy-3-methoxybenzylidene)cyclohexanone (38j, 0.49 g, 1.1 mmol) was dissolved in methanol (100 ml) and stirred for 15 min at room temperature. Concentrated hydrochloric acid (3 drops) was added and the mixture stirred for 3 hr at 60° C. The methanol was evaporated and the resulting residue extracted into ethyl acetate, washed with saturated sodium chloride, dried over magnesium sulfate, filtered and evaporated to afford a solid. The crude solid was recrystallized from ethanol to give 0.26 g (66%) of a yellow solid: mp 177-178° C. [expected mp 179-181° C.]; 1H NMR: δ 1.79 (m, 2H), 2.90 (t, 4H, J=5.4 Hz), 3.89 (s, 6H), 5.88 (s, 2H), 6.91 (s, 2H), 6.96 (d, 2H, J=4.8 Hz), 7.06 (d, 2H, J=8.0 Hz), 7.72 (s, 2H); 13C NMR: δ 23.1, 28.5, 56.0, 113.2, 114.4, 124.4, 128.5, 134.2, 136.9, 146.2, 146.4, 172.8.
Reaction SMILES: COC[NH:4][C:5]([C:7]1[S:15][C:14]2[C:9](=[N:10][CH:11]=[CH:12][C:13]=2[Cl:16])[CH:8]=1)=[S:6].Cl.[NH4+].[OH-]>C1COCC1>[Cl:16][C:13]1[CH:12]=[CH:11][N:10]=[C:9]2[CH:8]=[C:7]([C:5](=[S:6])[NH2:4])[S:15][C:14]=12
Reactant: COCNC(=S)c1cc2nccc(Cl)c2s1
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: NC(=S)c1cc2nccc(Cl)c2s1
Temperature: 0 °C
Yield: 84.8 %

Procedure:
To a solution of 7-Chloro-thieno[3,2-b]pyridine-2-carbothioic acid methoxymethyl-amide (93.9 g, 344 mmol) and 900 mL THF was added 1 N HCl (344 mL, 344 mmol). The reaction mixture was heated to reflux for seventy-two hours. The reaction mixture was cooled to 0° C., and 300 mL of concentrated NH4OH was added and stirred. The THF was removed under reduced pressure and the residue was suspended in ethyl acetate and stirred. The precipitate was filtered, washed with ethyl acetate and dried to give 7-chloro-thieno[3,2-b]pyridine-2-carbothioic acid amide (66.7 g) in 85% yield. C8H5ClN2S2: APCI m/z: 228.9/230.9 (MH+); 1H NMR (d6-DMSO): δ 10.24 (s, 1H), 9.94 (s, 1H), 8.65 (d, 1H, J=5.0 Hz), 8.19 (s, 1H), 7.62 (d, 1H, J=5.0 Hz) ppm.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([OH:18])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH3:15])[C:10](=[O:16])[C:9](Br)=[CH:8]2)=[O:4].[C:19]1([Sn](CCCC)(CCCC)CCCC)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.CCOC(C)=O.Cl>CN(C=O)C.[Cl-].[Na+].O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[C:6]([OH:18])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH3:15])[C:10](=[O:16])[C:9]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[CH:8]2)=[O:4]
Reactant: COC(=O)c1ncc2c(cc(Br)c(=O)n2C)c1O
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ncc2c(cc(-c3ccccc3)c(=O)n2C)c1O
Temperature: 120 °C
Yield: 59.4 %

Procedure:
A mixture of 3-bromo-5-hydroxy-1-methyl-2-oxo-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (60 mg, 0.19 mmol), PhSnBu3 (0.075 mL, 0.23 mmol), and PdCl2(PPh3)2 (27 mg, 0.038 mmol) in DMF (3 mL) was heated at 120° C. under nitrogen atmosphere for 2 h. After the mixture was cooled to r.t., brine and EtOAc were added. 1 M HCl was added until pH was about 2. The aqueous layer was extracted with additional EtOAc and the organic layers were combined, washed with water, and dried over MgSO4. After evaporating the solvent in vacuo, the crude product was chromatographed (0-60% EtOAc/hexanes+2% AcOH) to give 35 mg of the title compound. MS: (+) m/z 311.24 (M+1).
Reaction SMILES: F.[F:2]C1N=C(Cl)N=C(Cl)N=1.[F:11][C:12]1[N:17]=[C:16]([F:18])[N:15]=[C:14](Cl)[N:13]=1.FC1N=C(Cl)N=C(Cl)N=1.N1C(Cl)=NC(Cl)=NC=1Cl>>[N:13]1[C:14]([F:2])=[N:15][C:16]([F:18])=[N:17][C:12]=1[F:11]
Reactant: Fc1nc(Cl)nc(Cl)n1
Reactant: Fc1nc(F)nc(Cl)n1
Agent: Clc1nc(Cl)nc(Cl)n1
Agent: F
Product: Fc1nc(F)nc(F)n1

Procedure:
If 2,4-difluoro-6-chloro-s-triazine or 2-fluoro-4,6-dichloro-s-triazine is used in place of cyanuric chloride as the starting material, very good yields of pure cyanuric fluoride are possible even with molar ratios of hydrogen fluoride/cyanuric halide which are lower than those mentioned above. For example, when 2,4-difluoro-6-chloro-s-triazine is used the reaction is advantageously carried out with a molar ratio of hydrogen fluoride/2,4-difluoro-6-chloro-s-triazine of 1:1 to 4:1, preferably about 2:1; if 2-fluoro-4,6-dichloro-s-triazine is used as the starting material, advantageous results are obtained with a molar ratio of hydrogen fluoride/2-fluoro-4,6-dichloro-s-triazine of 2:1 to 5:1 and preferably the reaction is carried out using a molar ratio of hydrogen fluoride/2-fluoro-4,6-dichloro-s-triazine of 3:1. When 2,4-difluoro-6-chloro-s-triazine or 2-fluoro-4,6-dichloro-s-triazine is used as the starting material, the reaction is also carried out at temperatures betwen 150° C. and 300° C.; preferably the reaction is carried out at between 180° C. and 220° C., as when cyanuric chloride is used as the starting material. Pure cyanuric fluoride is likewise obtaining in high yield when a mixture of 2,4-difluoro-6-chloro-s-triazine and 2-fluoro-4,6-dichloro-s-triazine or a mixture of cyanuric chloride, 2,4-difluoro-6-chloro-s-triazine and 2-fluoro-4,6-dichloro-s-triazine is employed, in place of cyanuric chloride, 2,4-difluoro-6-chloro-s-triazine or 2-fluoro-4,6-dichloro-s-triazine, as the starting material. In this case the most advantageous molar ratio of hydrogen fluoride/cyanuric halide mixture depends on the mixing ratio of the two or the three cyanuric halide components in the starting mixture. The most advantageous temperature range for the reaction when a mixture of cyanuric halides is used is the same as that when pure cyanuric chloride is employed as the starting material.
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.Br[C:37]1[CH:42]=[C:41]([CH3:43])[N:40]=[C:39]([CH3:44])[CH:38]=1>>[CH3:43][C:41]1[CH:42]=[C:37]([C:16]2[CH:15]=[CH:14][C:13]([C@@H:11]([N:7]3[CH2:6][CH2:5][C@:4]([CH2:3][C:2]([OH:1])([CH3:34])[CH3:35])([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[O:9][C:8]3=[O:10])[CH3:12])=[CH:18][CH:17]=2)[CH:38]=[C:39]([CH3:44])[N:40]=1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: Cc1cc(Br)cc(C)n1
Product: Cc1cc(-c2ccc([C@H](C)N3CC[C@](CC(C)(C)O)(c4ccccc4)OC3=O)cc2)cc(C)n1

Procedure:
The title compound was prepared from (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one and 4-bromo-2,6-dimethylpyridine following a procedure analogous to that described in Example 1 Step 2. LC-MS Method 2 tR=1.049, m/z=459.1; 1H NMR (CD3OD) 0.94 (s, 3H), 1.24 (s, 3H), 1.55 (d, 3H), 2.15 (s, 2H), 2.23 (m, 1H), 2.45 (m, 1H), 2.51 (s, 6H), 3.05 (m, 1H), 5.57 (m, 1H), 7.04 (d, 2H), 7.24 (s, 2H), 7.26-7.38 (m, 5H), 7.45 (m, 1H).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[C:21]3=[N:22][CH:23]=[CH:24][CH:25]=[C:20]3[NH:19][C:18]2=[O:26])=[CH:13][CH:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.I[CH:28]([CH3:30])[CH3:29].[Cl-].[Cl-].[Ca+2]>CN(C=O)C.CO>[CH2:3]([O:10][C:11]1[CH:12]=[CH:13][C:14]([N:17]2[C:21]3=[N:22][CH:23]=[CH:24][CH:25]=[C:20]3[N:19]([CH:28]([CH3:30])[CH3:29])[C:18]2=[O:26])=[CH:15][CH:16]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=c1[nH]c2cccnc2n1-c1ccc(OCc2ccccc2)cc1
Reactant: CC(C)I
Agent: [Ca+2]
Agent: [Cl-]
Agent: [H-]
Solvent: CO
Solvent: CN(C)C=O
Product: CC(C)n1c(=O)n(-c2ccc(OCc3ccccc3)cc2)c2ncccc21

Procedure:
NaH (1.260 g) was added to a solution of 3-[4-(benzyloxy)phenyl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (5 g) and 2-iodopropane (3.15 mL) in DMF (50 mL) at room temperature. The mixture was stirred at room temperature under a dry atmosphere (CaCl2 tube) for 1 h. The reaction mixture was diluted with MeOH and concentrated in vacuo. The residue was purified by column chromatography (NH silica gel, eluted with 0%-50% EtOAc in hexane) to give 3-[4-(benzyloxy)phenyl]-1-(1-methylethyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (1.5 g) as dark yellow oil.
Reaction SMILES: S([C:5]1[N:6]=[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]2[C:13]=1C(OCC)=O)(C)(=O)=O.[CH:19]([SH:22])([CH3:21])[CH3:20]>>[CH:19]([S:22][C:5]1[N:6]=[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]2[CH:13]=1)([CH3:21])[CH3:20]
Reactant: CCOC(=O)c1c(S(C)(=O)=O)nc2ccccn12
Reactant: CC(C)S
Product: CC(C)Sc1cn2ccccc2n1

Procedure:
In a manner similar to the procedure in Reference Example 1, the oily title compound was prepared from ethyl 2-mesylimidazo[1,2-a]pyridine-3-carboxlate and isopropyl mercaptan. ##STR11##
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][C@H:8]1[CH2:13][CH2:12][C@@H:11]([N:14]=[N+:15]=[N-:16])[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH3:18][O:19][C:20](=[O:23])[C:21]#[CH:22].CCN(C(C)C)C(C)C>[Cu]I.C1COCC1>[CH3:18][O:19][C:20]([C:21]1[N:16]=[N:15][N:14]([C@H:11]2[CH2:12][CH2:13][C@@H:8]([NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:17])[CH2:9][CH2:10]2)[CH:22]=1)=[O:23]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](N=[N+]=[N-])CC1
Reactant: C#CC(=O)OC
Agent: [Cu]I
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)c1cn([C@H]2CC[C@@H](NC(=O)OC(C)(C)C)CC2)nn1
Temperature: 25 °C

Procedure:
To a THF (30 ml) solution under Ar of (cis-4-azido-cyclohexyl)carbamic acid tert-butyl ester (3.00 g) and propiolic acid methyl ester (1.05 g) were added CuI (2.38 g) and DIPEA (3.18 ml). The resulting slurry was stirred at RT over night. After dilution with EtOAc (200 ml) the mixture was washed with H2O (200 ml), dried over Na2SO4 and the solvent was evaporated. Chromatography (silica, CH2Cl2/MeOH 95:5) yielded 2.63 g (65%) of product. White crystals. MS 325.4 (95, [M+H]+), 269.4 (100, [M−tBu].+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:16]([OH:18])=O)[N:5]([C:7]2[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][CH:10]=[CH:9][N:8]=2)[CH:6]=1.[NH2:19][C:20]1[C:28]([Br:29])=[CH:27][C:26]([Br:30])=[CH:25][C:21]=1[C:22](O)=[O:23].BrC1C=C(C(O)=O)N(C2C(Cl)=CC=CN=2)C=1.NC1C(C)=CC(Cl)=CC=1C(O)=O>>[Br:30][C:26]1[CH:27]=[C:28]([Br:29])[C:20]2[N:19]=[C:16]([C:4]3[N:5]([C:7]4[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][CH:10]=[CH:9][N:8]=4)[CH:6]=[C:2]([Br:1])[CH:3]=3)[O:18][C:22](=[O:23])[C:21]=2[CH:25]=1
Reactant: Nc1c(Br)cc(Br)cc1C(=O)O
Reactant: O=C(O)c1cc(Br)cn1-c1ncccc1[N+](=O)[O-]
Agent: Cc1cc(Cl)cc(C(=O)O)c1N
Agent: O=C(O)c1cc(Br)cn1-c1ncccc1Cl
Product: O=c1oc(-c2cc(Br)cn2-c2ncccc2[N+](=O)[O-])nc2c(Br)cc(Br)cc12

Procedure:
According to the same manner as that of Reference Preparation Example 71-(5), 4-bromo-1-(3-nitro-2-pyridinyl)-1H-pyrrole-2-carboxylic acid and 2-amino-3,5-dibromobenzoic acid were used in place of 4-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrrole-2-carboxylic acid and 2-amino-5-chloro-3-methylbenzoic acid respectively to obtain 6,8-dibromo-2-[4-bromo-1-(3-nitro-2-pyridinyl)-1H-pyrrol-2-yl]-4H-3,1-benzoxazine-4-one of the formula: