Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I([O-])(=O)(=O)=O.[Na+].[I:7]I.S(=O)(=O)(O)O.[Br:14][C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1>C(O)(=O)C.C(OC(=O)C)(=O)C.O>[I:7][C:19]1[CH:20]=[C:15]([Br:14])[CH:16]=[CH:17][C:18]=1[CH3:21]
Reactant: II
Reactant: Cc1ccc(Br)cc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Solvent: O
Product: Cc1ccc(Br)cc1I
Temperature: 10 °C
Reaction time: 8 h
Yield: 197.9 %

Procedure:
Sodium periodate (0.5 molar equivalent, 102.5 g, 0.48 mol) and iodine (0.3 molar equivalent, 81.6 g, 0.32 mol) are suspended in acetic acid (700 ml) and acetic anhydride (340 ml). The batch is then cooled to 10° C., and sulfuric acid (2.9 molar equivalents, 142 ml, 2.66 mol) is slowly added dropwise at this temperature. 4-Bromotoluene 5 (1 molar equivalent, 160.7 g, 0.94 mol) is subsequently slowly added dropwise at room temperature, and the batch is stirred overnight. After addition of cooled water (1000 ml) and a solution of Na2SO3 (169 g in 1000 ml), the mixture is extracted by shaking with dichloromethane (DCM). The organic phase is washed with water, dried and evaporated in a rotary evaporator. The product 6 (188.0 g, 67%) is obtained in the form of a liquid by vacuum distillation.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([CH3:25])([S:21]([CH3:24])(=[O:23])=[O:22])[C:11]([NH:13][O:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][O:16]2)=[O:12])=[C:4]([CH3:26])[CH:3]=1.[C:27]1(B(O)O)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(=O)([O-])[O-].[Na+].[Na+].BrC1C=CC(CCC(C)(S(C)(=O)=O)C(O)=O)=CC=1.Cl>O.O1CCOCC1>[CH3:25][C:10]([S:21]([CH3:24])(=[O:23])=[O:22])([CH2:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:3][C:4]=1[CH3:26])[C:11]([NH:13][O:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][O:16]1)=[O:12]
Reactant: Cc1cc(Br)ccc1CCC(C)(C(=O)NOC1CCCCO1)S(C)(=O)=O
Reactant: OB(O)c1ccccc1
Agent: CC(CCc1ccc(Br)cc1)(C(=O)O)S(C)(=O)=O
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(-c2ccccc2)ccc1CCC(C)(C(=O)NOC1CCCCO1)S(C)(=O)=O
Reaction time: 0.17 h
Yield: 68.4 %

Procedure:
4-(4-Bromo-2-methylphenyl)-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide (250 mg, 0.558 mmol), phenyl boronic acid (102 mg, 0.837 mmol), sodium carbonate (181 mg, 1.71 mmol), Pd (II) EnCat (144 mg, 0.056 mmol, 0.39 mmol/g loading) were combined in a 2-5 mL microwave vial followed by the addition of 2 mL of dioxane, and 2 mL of water. The reaction was irradiated in a microwave at 120° C. for 40 minutes, followed by neutralization through the addition of 5 mL of aqueous 4N HCl and the mixture was extracted with ethyl acetate (3×15 mL). The organics were combined, dried over magnesium sulfate, filtered and concentrated onto silica gel. Silica chromatography (30% ethyl acetate 70% heptane for 10 minutes, then 30% ethyl acetate 70% heptane to 60% ethyl acetate 40% heptane for 40 minutes) afforded the title compound as a white solid (170 mg, 68%). LC-MS m/z 444.2 (M−1)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:21])[CH2:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19]C)=[CH:15][CH:14]=2)=[CH:4][C:3]=1[C:22]([F:25])([F:24])[F:23].B(Br)(Br)Br.[NH4+].[OH-]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:21])[CH2:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)=[CH:4][C:3]=1[C:22]([F:23])([F:24])[F:25]
Reactant: COc1ccc(CCCC(=O)Nc2ccc(Cl)c(C(F)(F)F)c2)cc1
Agent: BrB(Br)Br
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Product: O=C(CCCc1ccc(O)cc1)Nc1ccc(Cl)c(C(F)(F)F)c1
Temperature: 25 °C
Yield: 80.9 %

Procedure:
To a solution of N-[4-chloro-3-(trifluoromethyl)phenyl]-4-(4-methoxyphenyl)butanamide (460 mg, 1.23 mmol) in DCM (6 mL) at 0° C. was added BBr3 (1.0 M in DCM, 0.40 mL, 0.4 mmol) dropwise. The solution was allowed to warm to rt. Upon reaction completion, the solution was poured onto ice and neutralized with NH4OH. The yellow solid was filtered off and rinsed with hexanes and Et2O to give the product as a white solid (356 mg, 81%). LCMS, AA: Rt=1.94 min, [MH− 356.1].
Reaction SMILES: C([O:8][C:9]1[CH:10]=[CH:11][C:12]2[O:39][CH2:38][C:15]3([C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[N:17]([CH:24]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[C:16]3=[O:37])[C:13]=2[CH:14]=1)C1C=CC=CC=1.C(OC1C=CC2C3(COC=2C=1)C1C(=CC=CC=1)N(C(C1C=CC=CC=1)C1C=CC=CC=1)C3=O)C1C=CC=CC=1>>[C:31]1([CH:24]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:17]2[C:18]3[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:15]3([C:13]4[CH:14]=[C:9]([OH:8])[CH:10]=[CH:11][C:12]=4[O:39][CH2:38]3)[C:16]2=[O:37])[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: O=C1N(C(c2ccccc2)c2ccccc2)c2ccccc2C12COc1ccc(OCc3ccccc3)cc12
Agent: O=C1N(C(c2ccccc2)c2ccccc2)c2ccccc2C12COc1cc(OCc3ccccc3)ccc12
Product: O=C1N(C(c2ccccc2)c2ccccc2)c2ccccc2C12COc1ccc(O)cc12

Procedure:
Following the procedure as described in EXAMPLE 2.68 and making non-critical variations using 5-(benzyloxy)-1′-(diphenylmethyl)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one to replace 6-(benzyloxy)-1′-(diphenylmethyl)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one, 1′-(diphenylmethyl)-5-hydroxyspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one was obtained (78%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ8.22 (br s, 1H), 7.30-7.08 (m, 10H), 7.02-6.93 (m, 1H), 6.88 (s, 1H), 6.85-6.75 (m, 2H), 6.65-6.49 (m, 2H), 6.38-6.26 (m, 1H), 6.13-6.02 (m, 1H), 4.65 (ABq, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[C:11]([F:19])[CH:10]=2)=[N:4][C:5](Br)=[CH:6][N:7]=1.C(=O)([O-])[O-].[Na+].[Na+].CC1(C)C(C)(C)OB([C:34]2[CH2:35][CH2:36][CH2:37][N:38]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH:39]=2)O1.C(Cl)Cl>COCCOC.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:36]2[CH2:35][CH2:34][CH2:39][N:38]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH:37]=2)=[N:4][C:3]=1[C:9]1[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[C:11]([F:19])[CH:10]=1
Reactant: CC(C)(C)OC(=O)N1C=C(B2OC(C)(C)C(C)(C)O2)CCC1
Reactant: COC(=O)c1ccc(-c2nc(Br)cnc2N)cc1F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: COCCOC
Product: COC(=O)c1ccc(-c2nc(C3=CN(C(=O)OC(C)(C)C)CCC3)cnc2N)cc1F
Temperature: 110 °C
Yield: 60.2 %

Procedure:
To a mixture of methyl 4-(3-amino-6-bromopyrazin-2-yl)-2-fluorobenzoate (240 mg, 0.70 mmol) in DME (6 mL) and 2 M sodium carbonate (1.0 mL, 2.0 mmol) was added tert-butyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydropyridine-1(2H)-carboxylate(180 mg, 0.582 mmol) followed by PdCl2(dppf).CH2Cl2 adduct (14.4 mg, 17.5 μmol). The reaction mixture was heated in microwave at 110° C. for 20 min. The reaction mixture was partitioned between ethylacetate and water. The organic layer was separated, and washed with water and brine. The organic was dried over sodium sulfate, filtered and evaporated. The residue was purified by flash chromatography eluting with 0-50-80% EtOAc in heptane to yield the desired product as a yellow solid (150 mg, 60%). LCMS (m/z): 429.2 (MH+), 1.03 min.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7]([C:11]([O:13][CH3:14])=[O:12])[CH2:6][CH2:5]2.C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC(S(O[CH2:31][CH2:32][Cl:33])(=O)=O)=CC=1>C(C(C)=O)C>[Cl:33][CH2:32][CH2:31][O:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7]([C:11]([O:13][CH3:14])=[O:12])[CH2:6][CH2:5]2
Reactant: COC(=O)C1CCc2cc(O)ccc21
Reactant: Cc1ccc(S(=O)(=O)OCCCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: COC(=O)C1CCc2cc(OCCCl)ccc21
Reaction time: 0.5 h

Procedure:
In a 20-liter reactor provided with a mechanical stirrer and reflux cooler, 1078 g of methyl 2,3-dihydro-5-hydroxy-1H-inden-1-carboxylate were dissolved with 9 l of dry methyl ethyl ketone, 1162 g of anhydrous potassium carbonate were added and stirred for 30 minutes; then 1448 h of 2-chloroethyl p-toluensulphonate were added and refluxed in oil bath for 50 hours. The mixture was allowed to cool, the insoluble solid was filtered and washed twice with acetone over the same filter. The filtrate was evaporated and dried at vacuum, the residue was dissolved in 4.7 l of toluene and extracted with 1.8 l of 3N sodium hydroxyde solution through the decantation funnel and mechanical stirring for 15 minutes; then it was neutralized with water and dried. After evaporation of solvent at vacuum, the residue as reddish liquid weighed 1419 g (99%). Thin-layer chromatography (silica-gel) showed a major spot and a slight shadow at lower Rf. Cl analysis correct. It was used for the following synthesis step without further purification.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:17]=[C:16]3[C:10]([CH2:11][CH2:12][N:13]([CH:18]4[CH2:21][CH2:20][CH2:19]4)[CH2:14][CH2:15]3)=[N:9]2)=[CH:4][CH:3]=1.[NH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1>O1CCOCC1.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]>[CH:18]1([N:13]2[CH2:14][CH2:15][C:16]3=[CH:17][N:8]([C:5]4[CH:6]=[CH:7][C:2]([N:22]5[CH2:27][CH2:26][O:25][CH2:24][CH2:23]5)=[CH:3][CH:4]=4)[N:9]=[C:10]3[CH2:11][CH2:12]2)[CH2:21][CH2:20][CH2:19]1
Reactant: Brc1ccc(-n2cc3c(n2)CCN(C2CCC2)CC3)cc1
Reactant: C1COCCN1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: c1cc(-n2cc3c(n2)CCN(C2CCC2)CC3)ccc1N1CCOCC1
Temperature: 100 °C

Procedure:
A mixture of 2-(4-bromophenyl)-6-cyclobutyl-2,4,5,6,7,8-hexahydropyrazolo[3,4-d]azepine (may be prepared as described in Example 35) (80 mg, 0.23 mmol), morpholine (40 μl, 0.46 mmol), cesium carbonate (115 mg, 0.35 mmol), tris(dibenzylideneacetone)dipalladium(0) (10 mg, 0.01 mmol) and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane) (20 mg, 0.035 mmol) in dioxane (2 ml) was heated in the microwave (normal absorption) at 100° C. for 2 hours. The same amounts again of morpholine, cesium carbonate, tris(dibenzylideneacetone)dipalladium(0) and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane) were added and the mixture heated in the microwave at 150° C. for 2 hours. The reaction mixture was purified by SCX cartridge, followed by Mass Directed Autopreparation and column chromatography on silica gel, eluting with a mixture of 2M ammonia in methanol/dichloromethane (0-5%) to afford the title compound (E39). MS (ES+) m/e 353 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:19]2[C:20](=[O:33])[N:21]([CH3:32])[C:22]([NH:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[N:23][CH:24]=2)[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16](I)[S:17][C:10]=12.[CH3:34][NH:35][C:36]([C:38]1[CH:43]=[CH:42][C:41](B(O)O)=[CH:40][CH:39]=1)=[O:37].[Li+].[Cl-]>O1CCOCC1.C([O-])([O-])=O.[Na+].[Na+].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>[F:1][C:2]1[CH:3]=[C:4]([C:19]2[C:20](=[O:33])[N:21]([CH3:32])[C:22]([NH:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[N:23][CH:24]=2)[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([C:41]3[CH:42]=[CH:43][C:38]([C:36]([NH:35][CH3:34])=[O:37])=[CH:39][CH:40]=3)[S:17][C:10]=12
Reactant: Cn1c(Nc2ccccc2)ncc(-c2ccc(Oc3ccnc4cc(I)sc34)c(F)c2)c1=O
Reactant: CNC(=O)c1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: C1COCCO1
Product: CNC(=O)c1ccc(-c2cc3nccc(Oc4ccc(-c5cnc(Nc6ccccc6)n(C)c5=O)cc4F)c3s2)cc1
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
A suspension of 5-(3-fluoro-4-(2-iodothieno[3,2-b]pyridin-7-yloxy)phenyl)-3-methyl-2-(phenylamino)pyrimidin-4(3H)-one (0.018 g, 0.032 mmol), 4-(methylcarbamoyl)phenylboronic acid (0.007 g, 0.038 mmol), Pd(PPh3)4 (0.002 g, 0.002 mmol) and LiCl (0.005 g, 0.126 mmol) in dioxane (1 mL) and 2M aqueous Na2CO3 (1 mL) was stirred at 100° C. for 30 minutes. The reaction mixture was cooled to room temperature and then partitioned between EtOAc and H2O. The layers were separated and the aqueous layer was re-extracted with EtOAc (1×). The combined organic layers were dried over Na2SO4, filtered and concentrated. The crude product was purified by flash column chromatography, eluting with 10:1 CH2Cl2/MeOH. The product was obtained (9.5 mg; 52%) as a pale yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 9.04 (br s, 1H), 8.60-8.53 (m, 2H), 8.20 (s, 1H), 8.11 (s, 1H), 8.04-7.94 (m, 4H), 7.89 (dd, 1H), 7.69 (m, 1H), 7.57-7.48 (m, 3H), 7.38 (m, 2H), 7.17 (m, 1H), 6.70 (dd, 1H), 3.59 (s, 3H), 2.82 (d, 3H). LRMS (APCI pos) m/e 578 (M+1).
Reaction SMILES: [CH2:1]([C:3]1[O:7][C:6]([C:8]([O:10]C)=[O:9])=[CH:5][C:4]=1[C:12]1[N:16]([CH3:17])[N:15]=[CH:14][CH:13]=1)[CH3:2].[Cl:18]N1C(=O)CCC1=O.[OH-].[Na+]>O1CCCC1>[Cl:18][C:13]1[CH:14]=[N:15][N:16]([CH3:17])[C:12]=1[C:4]1[CH:5]=[C:6]([C:8]([OH:10])=[O:9])[O:7][C:3]=1[CH2:1][CH3:2]
Reactant: CCc1oc(C(=O)OC)cc1-c1ccnn1C
Reactant: O=C1CCC(=O)N1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCc1oc(C(=O)O)cc1-c1c(Cl)cnn1C
Reaction time: 1 h
Yield: 62.8 %

Procedure:
A solution of methyl 5-ethyl-4-(1-methyl-1H-pyrazol-5-yl)-2-furancarboxylate (950 mg, 4.06 mmol) and N-chlorosuccinimide (542 mg, 4.06 mmol) in tetrahydrofuran (20 ml) was stirred in a sealed tube for 1 h at 70° C. 6N sodium hydroxide (13.5 ml, 81 mmol) was added in one portion and the solution stirred an additional 1 h. The reaction mixture was then partitioned between H2O-DCM and the pH of the aqueous phase was adjusted to ˜4 and washed several times with DCM. The combined organic fractions were dried over Na2SO4, concentrated and used directly without further purification yielding 4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-ethyl-2-furancarboxylic acid (683 mg, 2.55 mmol, 62.8% yield) as a yellow oil: LCMS (ES) m/e 254, 256 (M, M+2)+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C([S:9][C:10](=S)[CH2:11][C:12](=[O:27])[C:13]1[C:26]2[S:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[S:18][C:17]=2[CH:16]=[CH:15][CH:14]=1)C>C(O)C>[N:1]1([C:10](=[S:9])[CH2:11][C:12]([C:13]2[C:26]3[S:25][C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[S:18][C:17]=3[CH:16]=[CH:15][CH:14]=2)=[O:27])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: C1COCCN1
Reactant: CCSC(=S)CC(=O)c1cccc2c1Sc1ccccc1S2
Solvent: CCO
Product: O=C(CC(=S)N1CCOCC1)c1cccc2c1Sc1ccccc1S2
Temperature: 25 °C
Yield: 82.1 %

Procedure:
Morpholine (0.96 ml, 11 mmol) was added to a solution of 3-oxo-3-thianthren-1-yl-dithiopropionic acid ethyl ester (3.99 g, 11 mmol) in ethanol (20 ml). The reaction was refluxed for 8 hours and was then cooled to room temperature. The precipitate formed was filtered and dried to give the desired product as a bright orange solid (3.50 g, 82%). m/z (LC-MS, ESP), RT=4.81 and 5.33 min same (M+1)=388
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4]([OH:6])=[O:5].N[C:13]1N=[CH:20][CH:19]=[CH:18][C:14]=1[C:15](O)=[O:16]>>[Cl:11][C:7]1[CH:8]=[CH:9][N:10]2[C:15](=[O:16])[C:14]3[CH2:13][CH2:20][CH2:19][C:18]=3[N:1]=[C:2]2[C:3]=1[C:4]([OH:6])=[O:5]
Reactant: Nc1nccc(Cl)c1C(=O)O
Reactant: Nc1ncccc1C(=O)O
Product: O=C(O)c1c(Cl)ccn2c(=O)c3c(nc12)CCC3

Procedure:
by substituting 2-amino-4-chloronicotinic acid for the 2-aminonicotinic acid in Example 4, there is obtained the named compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([O:10][CH3:11])=[O:9])=[CH:4][C:3]=1[OH:12].C(OCC)(=O)C.C(=O)([O-])O.[Na+].Br[CH:25]([CH2:29][CH3:30])[C:26](Br)=[O:27]>O>[CH2:29]([CH:25]1[C:26](=[O:27])[NH:1][C:2]2[CH:7]=[CH:6][C:5]([C:8]([O:10][CH3:11])=[O:9])=[CH:4][C:3]=2[O:12]1)[CH3:30]
Reactant: CCC(Br)C(=O)Br
Reactant: COC(=O)c1ccc(N)c(O)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: CCC1Oc2cc(C(=O)OC)ccc2NC1=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 87 %

Procedure:
To a solution of 2-amino-5-methoxycarbonylphenol [Tetrahedron, 46(15), 5177-5186 (1990)] (9.80 g) in a mixed solvent of ethyl acetate (200 ml) and water (200 ml) were added sodium hydrogen carbonate (7.30 g) and 2-bromobutyryl bromide (13.70 g) and the mixture was stirred at room temperature for 10 minutes. The organic layer was separated and the solvent was distilled off under reduced pressure. The resulting residue was dissolved in dimethylformamide (500 ml), to the solution was added potassium carbonate (8.90 g) and the mixture was stirred at room temperature for a day. The reaction solution was poured into water to give precipitates, which were taken by filtration and dried to give 2-ethyl-7-methoxycarbonyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine (12.0 g).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[C:5]([C:10](=[O:26])[CH2:11][CH2:12][CH:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]2)=[CH:4][CH:3]=1.[Cl:27]N1C(=O)CCC1=O>CN(C)C=O.C(OCC)C>[NH2:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[C:5]([C:10](=[O:26])[CH2:11][CH2:12][CH:13]2[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:23])([CH3:25])[CH3:24])=[O:20])[CH2:17][CH2:18]2)=[CH:4][C:3]=1[Cl:27]
Reactant: O=C1CCC(=O)N1Cl
Reactant: COc1nc(N)ccc1C(=O)CCC1CCN(C(=O)OC(C)(C)C)CC1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COc1nc(N)c(Cl)cc1C(=O)CCC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 80 °C
Reaction time: 4 h
Yield: 55.4 %

Procedure:
A mixture of 1,1-dimethylethyl 4-{3-[6-amino-2-(methyloxy)-3-pyridinyl]-3-oxopropyl}-1-piperidinecarboxylate (step 3, 300 mg, 0.825 mmol) and N-chlorosuccinimide (115.7 mg, 0.866mmol) in N,N-dimethylformamide (5 ml) was stirred at 80° C. for 4 h. After cooling to room temperature, the mixture was diluted with diethylether (150 ml), washed with water (50 ml×2) and brine (150 ml), and dried over magnesium sulfate. Removal of solvent gave a brown oil, which was chromatographed on a column of silica gel eluting with ethyl acetate/hexane (2:1) to afford 182 mg (56%) of the title compound as a colorless oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[CH:20][C:19]([F:22])=[C:18]([Br:23])[CH:17]=1)[C:10]([CH3:25])([CH3:24])[CH:9]2O)=[O:5])[CH3:2].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[CH:20][C:19]([F:22])=[C:18]([Br:23])[CH:17]=1)[C:10]([CH3:24])([CH3:25])[CH2:9]2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc2c(c1)C(O)C(C)(C)C(c1ccc(F)c(Br)c1)N2
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1ccc(F)c(Br)c1)N2
Temperature: 25 °C
Reaction time: 1 h
Yield: 33.9 %

Procedure:
To a mixture of 2-(3-bromo-4-fluoro-phenyl)-4-hydroxy-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (1.93 g, 4.57 mmol) and triethylsilane (5 mL) at 25° C. was added trifluoroacetic acid (1 mL) dropwise. The resulting mixture was stirred at 25° C. for 1 h. Then the reaction mixture was concentrated in vacuo and the residue was extracted with ethyl acetate (2×50 mL), washed with saturated aqueous sodium bicarbonate solution (2×20 mL), dried over anhydrous sodium sulfate and concentrated in vacuo. Purification on flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company) (10% ethyl acetate/hexanes) to afford 2-(3-bromo-4-fluoro-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (0.63 g, 34%) as a white solid: LC/MS m/e calcd for C20H21BrFNO2 M+: 406.3, observed: 406.2, 408.2.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[CH3:11][N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[CH3:11][N:12]1[CH2:17][CH2:16][N:15]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)[CH2:14][CH2:13]1
Reactant: CN1CCNCC1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CN1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 60 °C

Procedure:
To a solution of 25.0 g (0.18 mol) of 1-fluoro-4-nitrobenzene and 19.5 g (0.2 mol) of 1-methylpiperazine in 300 mL of acetonitrile, add 48.9 g (0.35 mol) of anhydrous potassium carbonate. Heat the reaction mixture to 60° C. for 20 h under nitrogen. After this time, add 100 mL of water and concentrate mixture to 200 mL volume. Add another 100 mL of water and extract with 3×200 mL of methylene chloride. Extract the combined methylene chloride extracts with 100 mL of 6N hydrochloric acid solution and 3×200 mL of water. Make the combined aqueous extracts basic (pH=14) with 50% sodium hydroxide solution and extract with 3×200 mL of methylene chloride. Dry the extracts over anhydrous sodium sulfate. Remove the drying agent by filtration and evaporate the solvent in vacuo. Dissolve the residue in 150 mL of methanol and bubble hydrogen chloride gas through the solution until pH=1. Precipitate the product by addition of diethyl ether to obtain the title compound.
Reaction SMILES: C1COCC1.[CH2:6]([Mg]Cl)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[NH2:15][C:16]1[C:21](Br)=[N:20][C:19]([Br:23])=[C:18]([Cl:24])[N:17]=1>[Cl-].[Zn+2].[Cl-].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.O>[NH2:15][C:16]1[C:21]([CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:20][C:19]([Br:23])=[C:18]([Cl:24])[N:17]=1
Reactant: Cl[Mg]Cc1ccccc1
Reactant: Nc1nc(Cl)c(Br)nc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: C1CCOC1
Solvent: O
Product: Nc1nc(Cl)c(Br)nc1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.8 %

Procedure:
Under an argon atmosphere, to anhydrous THF (40 mL) was added zinc chloride (1.0 M in diethyl ether) (23.7 mL, 23.7 mmol), and to the mixture was added benzyl magnesium chloride (2.0 M in THF) (10.4 mL, 20.8 mmol). After stirring at room temperature for 30 minutes, to the mixture were successively added dichlorobis(triphenylphosphine)palladium(II) (488 mg, 695 μmol) and 2-amino-3,5-dibromo-6-chloropyrazine (4) (4.00 g, 13.9 mmol) at room temperature. The mixture was stirred overnight (15 hours and a half) at room temperature as it was. After to the mixture was added water, the product was extracted with ethyl acetate (×3). The combined organic extract was washed successively with water (×1) and brine (×1), followed by drying over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the residue was purified by silica gel flash column chromatography (n-hexane/ethyl acetate=5/1) to give 2-amino-3-benzyl-5-bromo-6-chloropyrazine (5) (3.64 g, 12.2 mmol, 87.6%) as a yellow solid. TLC Rf=0.25 (n-hexane/ethyl acetate=4/1); 1H NMR (500 MHz, CDCl3) δ 4.08 (s, 2H), 4.50 (s, 2H), 7.19-7.24 (m, 2H), 7.27-7.37 (m, 3H); 13C NMR (126 MHz, CDCl3) δ 40.1, 123.8, 127.5, 128.4, 129.3, 135.3, 139.5, 144.9, 151.3.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[N:12]([CH2:13][CH2:14]S)[CH2:11][C@@H:10]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:9]([S:23]([CH2:26][CH2:27][CH3:28])(=[O:25])=[O:24])[CH2:8][C:7]=2[CH:29]=1)#[N:2].[N-:30]=[N+:31]=[N-:32].[Na+]>CN(C=O)C.O>[N:30]([CH2:14][CH2:13][N:12]1[C:6]2[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:29][C:7]=2[CH2:8][N:9]([S:23]([CH2:26][CH2:27][CH3:28])(=[O:24])=[O:25])[C@H:10]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:11]1)=[N+:31]=[N-:32]
Reactant: [N-]=[N+]=[N-]
Reactant: CCCS(=O)(=O)N1Cc2cc(C#N)ccc2N(CCS)C[C@H]1Cc1ccccc1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCS(=O)(=O)N1Cc2cc(C#N)ccc2N(CCN=[N+]=[N-])C[C@H]1Cc1ccccc1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
A mixture of Compound B of Example 27 (95.2 mg, 0.2 mmol) and sodium azide (15 mg, 0.23 mmol) in DMF (0.5 mL) was stirred at 70° C. overnight. The mixture was cooled to rt and diluted with water. The solid was collected, washed with water and dried to afford the title compound, 83 mg (95%) LC/MS: m/e (M+H)+=439.