Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([Cl:16])[CH:14]=2)[NH:9][C:8](=[O:17])[CH:7]=1)[CH2:2][CH:3]=[CH2:4]>C1C=CC=CC=1>[Cl:16][C:13]1[CH:12]=[CH:11][C:10]2[NH:9][C:8](=[O:17])[CH:7]3[CH2:4][CH:3]4[CH2:2][CH2:1][O:5][C:6]34[C:15]=2[CH:14]=1
Reactant: C=CCCOc1cc(=O)[nH]c2ccc(Cl)cc12
Solvent: c1ccccc1
Product: O=C1Nc2ccc(Cl)cc2C23OCCC2CC13
Reaction time: 96 h

Procedure:
A solution of 4-(but-3-enyloxy)-6-chloroquinolin-2(1H)-one (600 mg, 2.403 mmol) in benzene (240 mL) was placed under a 450 W Hg UV lamp (fitted with a condenser for cooling) and stirred for 4 days (96 hours). The mixture was then cooled, concentrated in vacuo, and taken up in ˜75 mL of methylene chloride (with mild heating to dissolve as much as possible). The sample, which was a mixture of regioisomers, was purified by column chromatography. Concentration of the compound that eleuted second provided the title compound.
Reaction SMILES: [CH3:1][C:2]1[C:3]2[CH:16]=[CH:15][CH:14]=[CH:13][C:4]=2[S:5][C:6]=1[CH:7]1[CH2:12][NH:11][CH2:10][CH2:9][NH:8]1.Cl[C:18]1[CH:27]=[C:26]2[C:21]([C:22](=[O:33])[C:23]([C:30]([OH:32])=[O:31])=[CH:24][N:25]2[CH2:28][CH3:29])=[CH:20][C:19]=1[F:34]>N1C=CC=CC=1>[CH2:28]([N:25]1[C:26]2[C:21](=[CH:20][C:19]([F:34])=[C:18]([N:11]3[CH2:10][CH2:9][NH:8][CH:7]([C:6]4[S:5][C:4]5[CH:13]=[CH:14][CH:15]=[CH:16][C:3]=5[C:2]=4[CH3:1])[CH2:12]3)[CH:27]=2)[C:22](=[O:33])[C:23]([C:30]([OH:32])=[O:31])=[CH:24]1)[CH3:29]
Reactant: Cc1c(C2CNCCN2)sc2ccccc12
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(Cl)cc21
Solvent: c1ccncc1
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCNC(c4sc5ccccc5c4C)C3)cc21

Procedure:
A 2 g portion of 2-(3-methylbenzo[b]thien-2-yl)piperazine was added to 7 ml of pyridine. A 780 mg portion of 7-chloro-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid was added and the mixture was heated in a pressure bottle, under argon at 120°-130° C. for 18 hours. The solid was collected, washed with pyridine, then ether and recrystallized from dimethylformamide, giving 540 mg of the desired product, mp 302°-304° C. (dec.).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([OH:18])([CH3:17])[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH3:16])[CH:5]=[CH:4][N:3]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1.[Li+].C[Si]([N-:49][Si](C)(C)C)(C)C.[NH4+].[Cl-]>C1COCC1.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].O>[NH2:49][C:2]1[CH:7]=[C:6]([C:8]([OH:18])([CH3:17])[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH3:16])[CH:5]=[CH:4][N:3]=1
Reactant: Cc1ccccc1CC(C)(O)c1ccnc(Cl)c1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [Cl-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccccc1CC(C)(O)c1ccnc(N)c1
Yield: 28.3 %

Procedure:
2-(2-Chloro-pyridin-4-yl)-1-o-tolyl-propan-2-ol (141 mg, 0.54 mmol), tris(dibenzylideneacetone)dipalladium(0) (99 mg, 0.11 mmol) and 2-(dicyclohexylphosphino)biphenyl (99 mg, 0.28 mmol) are mixed in dry THF (5 mL). Then Argon is bubbled through the solution for 5 min and 1.0 M LiHMDS (2.2 mL, 2.2 mmol) is added. Then the reaction mixture is heated at 65° C. for 16 hrs before the saturated NH4Cl aqueous solution (10 mL) is added along with water (20 mL). The mixture is extracted with EtOAc (3×25 mL) and the organic layers are combined and concentrated to give the crude product. Purification by silica flash column chromatography using MeOH in DCM (gradient from 0% to 10%) affords 37 mg of the desired product.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:13][O:12][C:11](=[O:14])[NH:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[Cl:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20](Cl)=[O:21]>>[Cl:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([N:10]1[CH:9]([C:4]2[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[CH:3]=2)[CH2:13][O:12][C:11]1=[O:14])=[O:21]
Reactant: O=C1NC(c2ccc(F)c(F)c2)CO1
Reactant: O=C(Cl)CCCCCl
Product: O=C(CCCCCl)N1C(=O)OCC1c1ccc(F)c(F)c1

Procedure:
Prepared by Procedure AF and Scheme H using 4-(3,4-difluorophenyl)-1,3-oxazolidin-2-one and 5-chloropentanoyl chloride.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[I-].[Na+].[OH:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][C:17]=1[OH:18])[CH:13]=[O:14].[CH2:19](Br)[CH2:20][CH2:21][CH3:22]>CC(=O)CC.O>[OH:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][C:17]=1[O:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH:13]=[O:14]
Reactant: CCCCBr
Reactant: O=Cc1ccc(O)c(O)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CCC(C)=O
Product: CCCCOc1ccc(C=O)cc1O
Yield: 40.1 %

Procedure:
Anhydrous potassium carbonate (5.9 g, 0.0434 mmol) and sodium iodide (0.434 g, 2.9 mmol) were added to 3,4-dihydroxybenzaldehyde (4.0 g, 28.9 mmol), in butanone (100 ml), at room temperature. The reaction was stirred for 10 min after which butyl bromide (3.11 ml, 28.9 mmol) was added dropwise and the reaction was refluxed for 3 h. The reaction mixture was diluted with water and the product was extracted with dichloromethane (3×50 ml), the combined organic layers were dried over magnesium sulphate and reduced in vacuo. Purification by column chromatography (SiO2, petroleum:ether (40:60 v/v) with an increasing gradient of ethyl acetate) afforded 2.25 g (58%) of 3-hydroxy-4-butoxybenzaldehyde as an off-white solid.
Reaction SMILES: [C:1]([C:4]1[N:5]=[CH:6][C:7]2[CH2:8][CH2:9][CH2:10][CH2:11][C:12]=2[CH:13]=1)(=[O:3])[CH3:2].[BrH:14].BrBr>C(O)(=O)C>[Br:14][CH2:2][C:1]([C:4]1[N:5]=[CH:6][C:7]2[CH2:8][CH2:9][CH2:10][CH2:11][C:12]=2[CH:13]=1)=[O:3]
Reactant: Br
Reactant: CC(=O)c1cc2c(cn1)CCCC2
Agent: BrBr
Solvent: CC(=O)O
Product: O=C(CBr)c1cc2c(cn1)CCCC2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of 3-acetyl-5,6,7,8-tetrahydroisoquinoline (287.7 mg, 1.64 mmol) and hydrobromic acid (25% solution in acetic acid, 3.1 ml) was added a solution of bromine (93.3 μl, 1.81 mmol) in acetic acid (0.4 ml) at 0° C. The mixture was stirred at room temperature for an additional 3 h. and concentrated. The residue was made basic with saturated aqueous hydrogen bicarbonate and extracted with diethyl ether (150 ml). The organic layer dried (MgSO4) and concentrated to afford 524.9 mg of the crude title compound as an brown oil.
Reaction SMILES: [O:1]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]([C:19]2[O:20][C:21]([C:24]3[N:29]=[C:28]([C:30]([O:32]C)=[O:31])[CH:27]=[CH:26][CH:25]=3)=[CH:22][N:23]=2)=[O:18])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].[OH-].Cl>C1COCC1.O.CCOC(C)=O>[O:1]([CH2:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][CH2:16][C:17]([C:19]2[O:20][C:21]([C:24]3[N:29]=[C:28]([C:30]([OH:32])=[O:31])[CH:27]=[CH:26][CH:25]=3)=[CH:22][N:23]=2)=[O:18])=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1cccc(-c2cnc(C(=O)CCc3ccc(COc4ccccc4)cc3)o2)n1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cccc(-c2cnc(C(=O)CCc3ccc(COc4ccccc4)cc3)o2)n1
Yield: 80.6 %

Procedure:
Methyl 6-(2-(3-(4-(phenoxymethyl)phenyl)propanoyl)oxazol-5-yl)pyridine-2-carboxylate (109 mg, 0.246 mmol) was dissolved in THF/H2O (3:2, 15 mL) and LiOH (18 mg, 0.75 mmol) was added. The reaction solution was stirred at room temperature under an atmosphere of Ar for 15 min before the addition of 1 N HCl to adjust the solution to an acidic pH to quench the reaction. The reaction solution was diluted with EtOAc and the organic and aqueous layers were separated. The aqueous layer was extracted with EtOAc (3×). The organic phases were combined and washed with saturated aqueous NaCl, dried over Na2SO4, and concentrated in vacuo. The crude product was purified by tritration in ether to provide 6-(2-(3-(4-(phenoxymethyl)phenyl)propanoyl)oxazol-5-yl)pyridine-2-carboxylic acid as a pale yellow solid (85 mg, 81%): 1H NMR (THF-d8, 600 MHz) δ 8.11-8.04 (m, 4H), 7.35 (d, 2H, J=7.9 Hz), 7.29 (d, 2H, J=7.9 Hz), 7.22 (dd, 2H, J=8.5, 7.5 Hz), 6.95 (d, 2H, J=7.8 Hz), 6.87 (t, 1H, J=7.3 Hz), 5.02 (s, 2H), 3.43 (t, 2H, J=7.6 Hz), 3.06 (t, 2H, J=7.6 Hz); 13C NMR (THF-d8, 150 MHz) δ 187.1, 165.6, 160.1, 158.7, 153.4, 150.0, 147.0, 141.4, 139.6, 136.4, 130.0, 129.3, 128.6, 128.4, 125.3, 123.5, 121.3, 115.5, 70.2, 41.3, 30.0; HR ESI-TOF m/z 429.1444 (M+H+, C25H20N2O5, requires 429.1445).
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].[C:14]1([CH2:20][CH2:21]Br)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CN(C)C=O.C(OCC)C>[C:14]1([CH2:20][CH2:21][CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:1]([O:9][CH2:10][CH3:11])=[O:8])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: BrCCc1ccccc1
Reactant: CCOC(=O)CC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCOC(=O)C(CCc1ccccc1)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 71.4 %

Procedure:
A solution of diethyl malonate (6.07 ml, 40 mmol) in dimethyl formamide (60 ml) at 0° C. was treated portionwise with sodium hydride (1.6 g, 40 mmol, 60% dispersion in oil) and stirred for 0.25 h. 2-Phenylethyl bromide (5.48 ml, 40 mmol) in dimethylformarnmide (30 ml) was added dropwise. The mixture was warmed to room temperature and stirred for 1 h. The mixture was diluted with diethyl ether (300 ml), washed with water (4×200 ml), saturated brine (100 ml), dried (MgSO4) and evaporated. Flash chromatography on silica, eluting with 1% ethyl acetate in hexane, gave the title compound as a colourless oil (7.55 g, 71%); νmax (CH2Cl2), 1726 cm-1 ;
Reaction SMILES: Cl[Si:2](Cl)([CH3:4])[CH3:3].[CH:6]([C:23]1[CH:28]=[C:27]([C:29]([CH3:32])([CH3:31])[CH3:30])[CH:26]=[C:25]([C:33]([CH3:36])([CH3:35])[CH3:34])[C:24]=1[OH:37])([C:8]1[CH:13]=[C:12]([C:14]([CH3:17])([CH3:16])[CH3:15])[CH:11]=[C:10]([C:18]([CH3:21])([CH3:20])[CH3:19])[C:9]=1[OH:22])[CH3:7].C(N(CC)CC)C>>[C:29]([C:27]1[CH:26]=[C:25]([C:33]([CH3:34])([CH3:36])[CH3:35])[C:24]2[O:37][Si:2]([CH3:4])([CH3:3])[O:22][C:9]3[C:10]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:11][C:12]([C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:13][C:8]=3[CH:6]([CH3:7])[C:23]=2[CH:28]=1)([CH3:32])([CH3:30])[CH3:31]
Reactant: C[Si](C)(Cl)Cl
Reactant: CC(c1cc(C(C)(C)C)cc(C(C)(C)C)c1O)c1cc(C(C)(C)C)cc(C(C)(C)C)c1O
Solvent: CCN(CC)CC
Product: CC1c2cc(C(C)(C)C)cc(C(C)(C)C)c2O[Si](C)(C)Oc2c1cc(C(C)(C)C)cc2C(C)(C)C
Yield: 78.5 %

Procedure:
Utilizing the procedure of Example 1, this compound is prepared from 25.8 grams (0.20 mole) of dichlorodimethylsilane, 87.7 grams (0.20 mole) of 2,2'-ethylidene-bis(4,6-di-t-butylphenol) and 40.5 grams (0.40 mole) of triethylamine. Recrystallization from acetonitrile-toluene yields 77.7 g (79% yield) of product as white needles, mp 171°-177° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([O:12][CH3:13])=[C:10]([O:14][CH3:15])[CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=[O:6].[CH3:16]O>S(=O)(=O)(O)O>[CH3:1][O:2][C:3]1[C:11]([O:12][CH3:13])=[C:10]([O:14][CH3:15])[CH:9]=[CH:8][C:4]=1[C:5]([O:7][CH3:16])=[O:6]
Reactant: COc1ccc(C(=O)O)c(OC)c1OC
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(OC)c(OC)c1OC

Procedure:
To a solution of 2,3,4-trimethoxybenzoic acid (25 g) in dry methanol (250 ml), concentrated sulfuric acid (2.4 ml) was added. The reaction solution was refluxed for 20 hr, concentrated to half its volume by evaporation, and poured into a mixture of ice and water. The solution was extracted with methylene chloride and the organic extract was washed with cold aqueous sodium carbonate solution and water, dried over sodium sulfate and evaporated to give 25.4 g of 2,3,4-trimethoxybenzoic acid, methyl ester: ir (CHCl3) 1720 cm-1 ; and nmr (CDCl3) δ 3.85 (s, 3H), 3.87 (s, 3H), 3.92 (s, 6H), 6.65 (d, 1H) and 7.55 (d, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].I[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].O>CN(C=O)C>[CH2:17]([O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCCCCCCCI
Reactant: O=Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCCCCCOc1ccc(C=O)cc1
Yield: 97.2 %

Procedure:
To a solution of 4-hydroxybenzaldehyde (732 mg, 6 mmol) in anhydrous DMF (13 ml), under nitrogen atmosphere, K2CO3 (1658 mg, 12 mmol), and, after 10 minutes, iododecane (1785 mg, 7.2 mmol) were added. The mixture was heated to reflux for 3 hours, then water was added and the product was extracted with CH2Cl2. The organic layers were washed with water and with NaCl saturated solution, dried with Na2SO4. After evaporation of the solvent, the crude product was purified by chromatography on silica gel (Petroleum ether/Ethyl acetate 11/1) and 1530 mg (yield 97%) of the pure product of the title were obtained.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:23]([CH2:28][CH3:29])[CH2:24][C:25]([NH2:27])=O)=[CH:4][CH:3]=1.C(N(CC)CC)C.FC(F)(F)C(OC(=O)C(F)(F)F)=O>O1CCCC1.C(OCC)(=O)C>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:23]([CH2:28][CH3:29])[CH2:24][C:25]#[N:27])=[CH:4][CH:3]=1
Reactant: CCC(CC(N)=O)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCC(CC#N)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Reaction time: 0.5 h

Procedure:
To a stirred solution of 3-[9-chloro-1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]pentanamide (60.1 mg, 0.133 mmol) and triethylamine (112 μL, 0.800 mmol) in tetrahydrofuran (1.5 mL) was added trifluoroacetic anhydride (55.6 μL, 0.400 mmol) at 0° C. After 0.5 h, the reaction mixture was diluted with ethyl acetate, washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 0-70% ethyl acetate/n-hexane gradient mixture give the title compound as a colorless amorphous (45.1 mg, 0.104 mmol, 78%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)[N:6]=[C:5]2[NH:18][C:19]1[CH:24]=[CH:23][C:22]([F:25])=[C:21]([Cl:26])[CH:20]=1.[CH3:27][O:28][C:29]1[N:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1.O.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.O>[Cl:26][C:21]1[CH:20]=[C:19]([NH:18][C:5]2[C:4]3[C:9](=[CH:10][CH:11]=[C:2]([C:32]4[CH:33]=[N:34][C:29]([O:28][CH3:27])=[CH:30][CH:31]=4)[CH:3]=3)[N:8]=[C:7]([C:12]3[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=3)[N:6]=2)[CH:24]=[CH:23][C:22]=1[F:25]
Reactant: COc1ccc(B(O)O)cn1
Reactant: Fc1ccc(Nc2nc(-c3cccnc3)nc3ccc(Br)cc23)cc1Cl
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(-c2ccc3nc(-c4cccnc4)nc(Nc4ccc(F)c(Cl)c4)c3c2)cn1
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 54.4 %

Procedure:
A 2.0 dram reaction vial was charged with 6-bromo-N-(3-chloro-4-fluorophenyl)-2-(pyridin-3-yl)quinazolin-4-amine (synthesized as described in Scheme 1 and 4, substituting 5-bromo-2-nitrobenzoic acid for 2-nitro-5-propoxy-benzoic acid and 3-chloro-4-fluoroaniline for 2-aminobenzamide) (100 mg, 0.233 mmol, 1.0 equiv), 6-methoxypyridin-3-ylboronic acid (44.5 mg, 0.291 mmol, 1.25 equiv), Pd(APhos)2Cl2 (6.6 mg, 0.0093 mmol, 4 mol %) and potassium phosphate monohydrate (69 mg, 0.70 mmol, 3.0 equiv). The mixture was suspended in dioxane/water (9:1, 4 mL), and the reaction was heated at 90° C. for 14 h. The reaction mixture was cooled to room temperature, diluted with water (15 mL) and the resultant precipitate was collected by filtration. The crude product was purified by stirring in methanol for 30 min at 60° C. to give the desired product as a pale yellow solid (58 mg, 54%) LCMS m/z=458.1 (M+1) (Method C) (retention time=2.56 min). 1H NMR (300 MHz, DMSO) δ 10.12 (s, 1H), 9.53 (s, 1H), 8.82 (s, 1H), 8.70 (dd, J=16.9, 5.4 Hz, 3H), 8.25 (d, J=8.6 Hz, 3H), 8.01-7.87 (m, 2H), 7.57 (dd, J=11.2, 6.0 Hz, 2H), 7.03 (d, J=8.6 Hz, 1H), 3.94 (s, 3H).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[N:2]1.Br[CH2:14][CH2:15][N:16]1[C:20](=[O:21])[C:19]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:18]2[C:17]1=[O:26].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[O:26]=[C:17]1[C:18]2[C:19](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20](=[O:21])[N:16]1[CH2:15][CH2:14][N:1]1[CH:5]=[CH:4][C:3]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[N:2]1
Reactant: O=C1c2ccccc2C(=O)N1CCBr
Reactant: CC(C)(C)OC(=O)c1cc[nH]n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)c1ccn(CCN2C(=O)c3ccccc3C2=O)n1
Reaction time: 12 h
Yield: 32.2 %

Procedure:
To a solution of 2.31 g of tert-butyl 1H-pyrazole-3-carboxylate and 6.98 g of N-(2-bromoethyl)phthalimide in DMF (65 mL) was added 8.95 g of cesium carbonate at room temperature, followed by stirring for 12 hours. The reaction solution was diluted with water, followed by extraction with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: chloroform-hexane) to obtain 1.51 g of tert-butyl 1-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-1H-pyrazole-3-carboxylate as a colorless solid.
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][NH2:13])=[CH:7][CH:6]=1)([O-:4])=[O:3].C(=O)([O-])O.[Na+].[C:19](Cl)(=[O:23])[C:20]([CH3:22])=[CH2:21]>O.C(OCC)(=O)C>[N+:2]([C:5]1[CH:6]=[CH:7][C:8]([CH2:11][CH2:12][NH:13][C:19](=[O:23])[C:20]([CH3:22])=[CH2:21])=[CH:9][CH:10]=1)([O-:4])=[O:3]
Reactant: C=C(C)C(=O)Cl
Reactant: NCCc1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: C=C(C)C(=O)NCCc1ccc([N+](=O)[O-])cc1

Procedure:
2-(4-Nitrophenyl)ethylamine hydrochloride (1.72 g) and sodium hydrogencarbonate (5.00 g) were dissolved in water (25 mL), to which ethyl acetate (25 mL) was added, followed by being stirred in an ice bath. Methacryloyl chloride (1.79 g) was added dropwise thereto. After stirring for 10 minutes, the organic layer was separated. The aqueous layer was extracted with ethyl acetate, the organic layers were combined, washed with water and brine, dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The recrystallization was performed by using a mixture solvent of hexane and ethyl acetate. N-[2-(4-Nitrophenyl)ethyl]methacrylamide was obtained as pale yellowish crystals. The yield was 1.25 g (63%). Spectrum data of 1H-NMR (400 MHz, CDCl3) is shown for the obtained compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:12]2[NH:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=3[C:11]=2[CH2:10][CH2:9][NH:8][CH:7]=1)=[O:5])[CH3:2].[CH3:20][C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][C:22]=1[N+:31]([O-:33])=[O:32]>>[CH2:1]([O:3][C:4]([C:6]1[C:12]2[NH:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=3[C:11]=2[CH2:10][CH2:9][N:8]([S:27]([C:24]2[CH:25]=[CH:26][C:21]([CH3:20])=[C:22]([N+:31]([O-:33])=[O:32])[CH:23]=2)(=[O:28])=[O:29])[CH:7]=1)=[O:5])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1[N+](=O)[O-]
Reactant: CCOC(=O)C1=CNCCc2c1[nH]c1ccccc21
Product: CCOC(=O)C1=CN(S(=O)(=O)c2ccc(C)c([N+](=O)[O-])c2)CCc2c1[nH]c1ccccc21

Procedure:
The title compound was prepared in a manner similar to that described in Example 70 by using ethyl-1,2,3,6-tetrahydroazepino[4,5-b]indole-5-carboxylate and 4-methyl-3-nitrobenzenesulfonyl chloride (˜3.4 mg); MS (ES): 456 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Br:10])[CH:9]=1)[C:5]#[N:6].[ClH:11].C(N(CC)CC)C.[N-:19]=[N+:20]=[N-:21].[Na+]>C1(C)C=CC=CC=1.C(Cl)Cl.CO>[ClH:11].[Br:10][C:8]1[CH:9]=[C:2]([NH2:1])[CH:3]=[C:4]([C:5]2[NH:21][N:20]=[N:19][N:6]=2)[CH:7]=1
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1cc(N)cc(Br)c1
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: Nc1cc(Br)cc(-c2nnn[nH]2)c1
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-amino-5-bromo-benzonitrile (200 mg, 1.02 mmol) in toluene (2 mL) was added 6N HCl (0.220 mL, 1.32 mmol), triethylamine (0.184 mL, 1.32 mmol) and sodium azide (86.0 mg, 1.32 mmol). The reaction mixture was stirred at 100° C. for 30 min in a microwave apparatus (Personal Chemistry, Biotage), and after cooling to RT was then diluted with CH2Cl2/MeOH (4:1) and washed with 10 mL of water. The organic phase was discarded, and the water phase was acidified to pH=1 by adding 12N HCl. The aqueous layer was freeze-dried overnight to afford the title compound as a yellowish solid. MS (LC/MS): 239.3 [M+H]+; tR (HPLC conditions c): 3.23 min.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Br:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][N:15]=1.[C:21]12([CH2:31][N:32]=[C:33]=[O:34])[CH2:30][CH:25]3[CH2:26][CH:27]([CH2:29][CH:23]([CH2:24]3)[CH2:22]1)[CH2:28]2.Cl>O1CCCC1.CCCCCC>[C:21]12([CH2:31][NH:32][C:33](=[O:34])[C:18]3[C:17]([Cl:20])=[CH:16][N:15]=[C:14]([Br:13])[CH:19]=3)[CH2:30][CH:25]3[CH2:26][CH:27]([CH2:29][CH:23]([CH2:24]3)[CH2:22]1)[CH2:28]2
Reactant: O=C=NCC12CC3CC(CC(C3)C1)C2
Reactant: Clc1ccc(Br)nc1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(Br)ncc1Cl
Temperature: -70 °C
Reaction time: 0.17 h
Yield: 70.5 %

Procedure:
To a stirred solution of di-isopropylamine (2.1 ml) in anhydrous tetrahydrofuran (15 ml) at is −5° C. was added, dropwise a solution of n-butyl lithium in hexane (2.5 molar, 4.8 ml) and the resulting solution was stirred for 30 minutes and was then cooled to −70° C. To the cooled solution was added a solution of 2-bromo-5-chloropyridine (2.39 g) in anhydrous tetrahydrofuran (10 ml) maintaining the internal temperature of the reaction below −65° C. The reaction was maintained at −70° C. for 15 minutes and then a solution of 1-adamantylmethyl isocyanate (1.91 g) in anhydrous tetrahydrofuran (5 ml) was dropwise added (care exotherm). The mixture was stirred for 10 minutes and was then poured into a solution of 1M aqueous hydrochloric acid solution (50 ml) and the mixture extracted into ethyl acetate (3×25 ml). The combined extracts were dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by chromatography on silica gel eluting with ethyl acetate:iso-hexane (1:9 to 1:4 to 1:1) to afford the sub-titled compound (2.70 g) as a white solid.
Reaction SMILES: [C:1]([C:5]1[CH2:6][N:7]([NH:12]C(=O)C)[C:8](=[O:11])[NH:9][N:10]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[OH-].[Na+]>CO>[NH2:12][N:7]1[CH2:6][C:5]([C:1]([CH3:3])([CH3:2])[CH3:4])=[N:10][NH:9][C:8]1=[O:11]
Reactant: CC(=O)NN1CC(C(C)(C)C)=NNC1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)C1=NNC(=O)N(N)C1
Temperature: 0 °C
Yield: 86.7 %

Procedure:
To a slurry of N-(6-tert-butyl-3-oxo-2,5-dihydro-3H-1,2,4-triazin-4-yl)-acetamide (0.51 g, 2.40 mmol) in MeOH (5 mL) is added concentrated HCl (0.33 mL, 3.84 mmol). The mixture is heated to reflux for 3 h. The mixture is then chilled to 0° C. and basified with 1 M aqueous NaOH (2.9 mL) to pH 12, and concentrated in vacuo. EtOH is added to the residue with stirring and the mixture is filtered. The filtrate is concentrated in vacuo. CH3CN is added to the residue with stirring and the mixture is filtered. The filtrate is concentrated in vacuo to afford 4-amino-6-tert-butyl-4,5-dihydro-2H-1,2,4-triazin-3-one (0.354 g, 84%) as a solid. MS: 171 (M+H); 1H NMR (300 MHz, DMSO-d6) δ 7.49 (br s, 1H), 4.22 (br s, 2H), 4.06 (s, 2H), 1.15 (s, 9H).