Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:3]C(O)=O)#[N:2].[N+:7]([C:10]1[CH:17]=[CH:16][C:13]([CH:14]=O)=[CH:12][CH:11]=1)([O-:9])=[O:8].C([O-])(=O)C.[NH4+].C1(C)C=CC=CC=1>N1C=CC=CC=1>[N+:7]([C:10]1[CH:17]=[CH:16][C:13]([CH:14]=[CH:3][C:1]#[N:2])=[CH:12][CH:11]=1)([O-:9])=[O:8]
Reactant: N#CCC(=O)O
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: N#CC=Cc1ccc([N+](=O)[O-])cc1

Procedure:
A mixture of cyanoacetic acid (12.76 g, 150.0 mmol), 4-nitrobenzaldehyde (24.60 g, 162.8 mmol), ammonium acetate (500 mg), toluene (140 mL), and pyridine (75 mL) is refluxed for 64 hours in a flask fitted with a Dean-Stark trap and condenser. After evaporation of the solvents, a solution of the residue in CHCl3 is filtered and washed with H2O. The dried (Na2SO4) organic layer is evaporated, and the bright yellow-orange solid is recrystallized from benzene. The yellow solid 3-(4-nitrophenyl)-acrylonitrile, obtained as a mixture of cis-trans isomers, is suitable for use as an intermediate without further purification.
Reaction SMILES: C(OC(N1[CH2:12][CH2:11][CH:10]([NH:13][C:14]([C:16]2[S:17][CH:18]=[CH:19][C:20]=2[NH:21][C:22]2[CH:27]=[CH:26][N:25]=[C:24]3[NH:28][CH:29]=[CH:30][C:23]=23)=[O:15])C1)=O)(C)(C)C.[C:31](N1CCC(N)C1)([O:33][C:34](C)([CH3:36])[CH3:35])=O>>[CH3:31][O:33][C:34]1[CH:35]=[C:10]([NH:13][C:14]([C:16]2[S:17][CH:18]=[CH:19][C:20]=2[NH:21][C:22]2[CH:27]=[CH:26][N:25]=[C:24]3[NH:28][CH:29]=[CH:30][C:23]=23)=[O:15])[CH:11]=[CH:12][CH:36]=1
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)c2sccc2Nc2ccnc3[nH]ccc23)C1
Reactant: CC(C)(C)OC(=O)N1CCC(N)C1
Product: COc1cccc(NC(=O)c2sccc2Nc2ccnc3[nH]ccc23)c1

Procedure:
This compound was prepared in an analogous manner as 3-{[3-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-2-carbonyl]-amino}-pyrrolidine-1-carboxylic acid tert-butyl ester using 3-methoxaniline instead of 1-BOC-3-aminopyrrolidine. LCMS (ESI) 365 (M+H) 1H NMR (400 MHz, DMSO-d6) δ ppm 11.55 (1H, br. s.) 10.06 (1H, s) 9.83 (1H, s) 8.03 (1H, d, J=5.42 Hz) 7.90 (1H, d, J=5.42 Hz) 7.49 (1H, d, J=5.42 Hz) 7.32 (1H, dd, J=3.51, 2.44 Hz) 7.20-7.30 (3H, m) 6.81 (1H, d, J=5.42 Hz) 6.68 (1H, dt, J=7.42, 2.12 Hz) 6.47 (1H, dd, J=3.56, 1.90 Hz) 3.74 (3H, s)
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:11][CH2:12][C:13]([F:16])([F:15])[F:14])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].S(=O)(=O)(O)O.[CH3:22]O>>[Cl:1][C:2]1[C:3]([O:11][CH2:12][C:13]([F:15])([F:16])[F:14])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([O:9][CH3:22])=[O:8]
Reactant: O=C(O)c1cnc(OCC(F)(F)F)c(Cl)c1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1cnc(OCC(F)(F)F)c(Cl)c1
Reaction time: 48 h
Yield: 56 %

Procedure:
A mixture of 5-chloro-6-(2,2,2-trifluoroethoxy)nicotinic acid (5.6 g, 21.9 mmol, Step-1 of Amine-5) and sulfuric acid (0.12 mL, 2.25 mmol) in methanol (40 mL) is refluxed with stirring for 2 days. After removal of the solvent, the residue is poured into 2M sodium hydroxide (100 mL) and extracted with ethyl acetate and dried over sodium sulfate and concentrated in vacuo to give 3.28 g (56% yield) of the title compound as a white solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[CH3:11][NH:12][CH2:13][CH2:14][C:15]#[N:16].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CCOC(C)=O>[CH3:11][N:12]([C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1)[CH2:13][CH2:14][C:15]#[N:16]
Reactant: CNCCC#N
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN(CCC#N)c1ccc([N+](=O)[O-])cn1

Procedure:
2-Chloro-5-nitropyridine (158 mg, 1 mmol), 3-methylamino-propionitrile (84 mg, 1 mmol), and finely ground potassium carbonate (414 mg, 3 mmol) were heated to 80° C. in 10 mL anhydrous DMF for 3.5 hrs. The mixture was diluted with EtOAc, extracted with H2O and dried over MgSO4. The EtOAc layer was filtered, evaporated to dryness. ES-MS calcd for C9H10N4O2 (m/e) 206.21, obsd 207.1 (M+H).
Reaction SMILES: [NH2:1][CH2:2][C:3]([CH2:22][O:23][C:24]([C:33]([F:36])([F:35])[F:34])([C:29]([F:32])([F:31])[F:30])[C:25]([F:28])([F:27])[F:26])([CH2:7][O:8][C:9]([C:18]([F:21])([F:20])[F:19])([C:14]([F:17])([F:16])[F:15])[C:10]([F:13])([F:12])[F:11])[C:4]([OH:6])=[O:5].C(=O)([O-])[O-].[Na+].[Na+].Cl[C:44]([O:46][CH2:47][CH:48]1[C:60]2[CH:59]=[CH:58][CH:57]=[CH:56][C:55]=2[C:54]2[C:49]1=[CH:50][CH:51]=[CH:52][CH:53]=2)=[O:45]>O1CCCC1.O>[CH:59]1[C:60]2[CH:48]([CH2:47][O:46][C:44]([NH:1][CH2:2][C:3]([CH2:7][O:8][C:9]([C:10]([F:13])([F:12])[F:11])([C:14]([F:17])([F:16])[F:15])[C:18]([F:19])([F:21])[F:20])([CH2:22][O:23][C:24]([C:29]([F:30])([F:31])[F:32])([C:25]([F:26])([F:27])[F:28])[C:33]([F:34])([F:35])[F:36])[C:4]([OH:6])=[O:5])=[O:45])[C:49]3[C:54](=[CH:53][CH:52]=[CH:51][CH:50]=3)[C:55]=2[CH:56]=[CH:57][CH:58]=1
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Reactant: NCC(COC(C(F)(F)F)(C(F)(F)F)C(F)(F)F)(COC(C(F)(F)F)(C(F)(F)F)C(F)(F)F)C(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(NCC(COC(C(F)(F)F)(C(F)(F)F)C(F)(F)F)(COC(C(F)(F)F)(C(F)(F)F)C(F)(F)F)C(=O)O)OCC1c2ccccc2-c2ccccc21
Temperature: 0 °C
Reaction time: 8 h
Yield: 95.8 %

Procedure:
To a stirred solution of amino acid 1 (10.1 g, 17.2 mmol) in tetrahydrofuran (100 mL) and water (100 mL) was added sodium carbonate (4.6 g, 42.9 mmol). After all the sodium carbonate was dissolved, the resulting mixture was cooled to 0° C. and 9-fluorenylmethyl chloroformate (6.7 g, 25.9 mol) was added in three portions. The resulted reaction mixture was stirred at room temperature overnight. The solvent was removed under vacuo and the residue was purified by flash column chromatography on silica gel (n-hexane/ethyl acetate=5/1) to give the acid 2 as a white solid (13.3 g, 96%). mp. 104-105° C.; 1H NMR (400 MHz, CD3OD) δ 3.45 (s, 2H), 4.16 (m), 4.27 (m, 4H), 4.46 (d, J=8.8 Hz, 2H) 7.26 (t, J=7.2 Hz, 2H), 7.35 (t, J=7.2 Hz, 2H), 7.60 (d, J=7.6 Hz, 2H), 7.74 (d, J=7.2 Hz, 2H); 19F NMR (376 MHz, CD3OD) δ −71.00 (s); 13C NMR (100.7 MHz, CD3OD) δ 36.9, 42.8, 53.7, 68.2, 69.0, 80.9 (m), 120.9, 121.7 (q, J=292.6 Hz), 126.2, 128.1, 128.8, 142.6, 145.2, 158.8, 174.4; MS (CI) m/z 808 (M++1, 100); HRMS (CI) Calcd for C28H20F18NO6: 808.1003, Found: 808.1010.
Reaction SMILES: C(O[C:9]([NH:11][C:12]1[CH:13]=[CH:14][C:15]([N:19]2[CH:23]=[CH:22][N:21]=[C:20]2[CH3:24])=[C:16]([F:18])[CH:17]=1)=O)C1C=CC=CC=1.C([Li])CCC.[CH2:30]([O:34][C:35](=[O:39])CCC)[C@@H:31]1[O:33]C1.C(=O)(O)[O-].[Na+]>O1CCCC1.CN1CCCN(C)C1=O>[F:18][C:16]1[CH:17]=[C:12]([N:11]2[CH2:9][C@H:30]([CH2:31][OH:33])[O:34][C:35]2=[O:39])[CH:13]=[CH:14][C:15]=1[N:19]1[CH:23]=[CH:22][N:21]=[C:20]1[CH3:24]
Reactant: Cc1nccn1-c1ccc(NC(=O)OCc2ccccc2)cc1F
Reactant: CCCC(=O)OC[C@H]1CO1
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN1CCCN(C)C1=O
Product: Cc1nccn1-c1ccc(N2C[C@H](CO)OC2=O)cc1F
Reaction time: 0.5 h
Yield: 44.5 %

Procedure:
5-Benzyloxycarbonylamino-2-(2-methylimidazol-1-yl)fluorobenzene (54 g, 0.166 M) was dissolved in a mixture of dry tetrahydrofuran (600 ml) and 1,3-dimethyl-2,4,5,6-tetrahydro-2(1H)-pyrimidinone (100 ml) under nitrogen, cooled to −70°, and treated with a solution of n-butyllithium (1.6 M in isohexane, 114 ml), over 30 minutes. After stirring for 30 minutes at −70°, a solution of (R)-glycidylbutyrate (26.35 g, 0.183 M) in dry tetrahydrofuran (50 ml) was added over 15 minutes. Stirring was continued for 16 hours allowing the temperature to rise to ambient. The mixture was treated with aqueous sodium bicarbonate.(5%, 500 ml) and ethyl acetate (800 ml), the organic layer separated, and the aqueous extracted with further ethyl acetate (3×750 ml). The combined extracts were dried (magnesium sulfate) and evaporated, and the resulting oil triturated with diethyl ether. The resulting solid was recrystallised from isopropanol to give the title compound (21.5 g). NMR (DMSO-d6) δ: 2.16 (s, 3H); 3.56 (dt, 1H); 3.69 (dt, 1H); 3.88 (dd, 1H); 4.15 (t, 1H); 4.74 (m, 1H); 5.24 (t, 1H); 6.92 (s, 1H); 7.20 (s, 1H); 7.48 (dd, 1H); 7.53 (t, 1H); 7.74 (dd, 1H). MS (ESP): 292 (MH+) for C14H14FN3O3
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])C.[CH3:8][O:9][C:10]([C:12]1[S:13][C:14](C)=[C:15]([CH3:18])[C:16]=1[NH2:17])=[O:11]>C(O)=O>[CH3:8][O:9][C:10]([C:12]1[S:13][CH:14]=[C:15]([CH3:18])[C:16]=1[NH:17][CH:1]=[O:3])=[O:11]
Reactant: COC(=O)c1sc(C)c(C)c1N
Reactant: CC(=O)OC(C)=O
Solvent: O=CO
Product: COC(=O)c1scc(C)c1NC=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 95 %

Procedure:
Formic acid (53 mL) was added to acetic anhydride (53 mL) while cooling in an ice bath. Solid methyl 3-amino-4-methyl-2-thiophenecarboxylic acid methyl ester (1, 18.2 g, 0.11 mol) was added to the cold solution in small portions. The cooling bath was removed and the resulting suspension was stirred at room temperature for 4 hours. The reaction mixture was diluted with water (100 mL) and the solid product collected by vacuum filtration to yield 3-(formylamino)-4-methyl-2-thiophenecarboxylic acid methyl ester (20.2 g, 95% yield) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[C:13]([N+:21]([O-:23])=[O:22])[CH:12]=1.[OH-].[Na+].Cl>>[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([S:17]([NH:6][C:5]2[CH:7]=[CH:8][C:2]([Cl:1])=[CH:3][CH:4]=2)(=[O:18])=[O:19])=[C:13]([N+:21]([O-:23])=[O:22])[CH:12]=1
Reactant: COc1ccc(S(=O)(=O)Cl)c([N+](=O)[O-])c1
Reactant: Nc1ccc(Cl)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: COc1ccc(S(=O)(=O)Nc2ccc(Cl)cc2)c([N+](=O)[O-])c1
Reaction time: 0.5 h
Yield: 95.8 %

Procedure:
To a mixture of 4-chloroaniline (14.51 g) and 4-methoxy-2-nitrobenzenesulfonyl chloride (28.54 g) was added dropwise aqueous sodium hydroxide solution (0.7 N, 162 ml) over a period of 30 minutes at 70° C. After addition, the mixture was stirred for 30 minutes at the same temperature. The colled mixture was diluted with aqueous IN-hydrochloric acid. The separated oil was extracted with ethyl acetate. The extract was dried over magnesium sulfate and concentrated under reduced pressure. The yellow solid was triturated with n-hexame and collected by filtration to yield 4-methoxy-2-nitro-N-(4-chlorophenyl) benzenesulfonamide (37,23 g).
Reaction SMILES: [CH3:1][N:2]([S:17]([C:20]1[N:21]([CH3:25])[CH:22]=[CH:23][N:24]=1)(=[O:19])=[O:18])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]([O:14]CC)=[O:13])=[CH:8]2.[OH-].[K+]>O1CCCC1.CO>[CH3:1][N:2]([S:17]([C:20]1[N:21]([CH3:25])[CH:22]=[CH:23][N:24]=1)(=[O:19])=[O:18])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]([OH:14])=[O:13])=[CH:8]2
Reactant: CCOC(=O)c1cc2cccc(N(C)S(=O)(=O)c3nccn3C)c2[nH]1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CN(c1cccc2cc(C(=O)O)[nH]c12)S(=O)(=O)c1nccn1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 100.1 %

Procedure:
Ethyl 7-{methyl[(1-methyl-1H-imidazol-2-yl)sulfonyl]amino}-1H-indole-2-carboxylate (2.87 g) was dissolved in a mixed solvent of tetrahydrofuran (30 mL)-methanol (20 mL). Aqueous potassium hydroxide solution (prepared by dissolving potassium hydroxide (2.0 g) in water (20 mL)) was added to this solution, and the mixture was stirred at room temperature for 16 hr, and concentrated under reduced pressure to evaporate methanol. The obtained residue was acidified with aqueous citric acid solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (2.65 g, yield: 100%) as colorless crystals. MS: 335(MH+). melting point: 241-242° C.
Reaction SMILES: C(N(CC)C(C)C)(C)C.[CH3:10][O:11][CH2:12]Cl.Cl.[C:15]([N:18]1[C:22]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:21]=2[S:20][CH:19]1[C:28]1[CH:33]=[C:32]([O:34][CH3:35])[CH:31]=[CH:30][C:29]=1[O:36][CH2:37][CH2:38][CH2:39][N:40]([CH2:44][CH2:45][OH:46])[CH:41]([CH3:43])[CH3:42])(=[O:17])[CH3:16].C(=O)([O-])O.[Na+]>C(Cl)Cl>[C:15]([N:18]1[C:22]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:21]=2[S:20][CH:19]1[C:28]1[CH:33]=[C:32]([O:34][CH3:35])[CH:31]=[CH:30][C:29]=1[O:36][CH2:37][CH2:38][CH2:39][N:40]([CH:41]([CH3:43])[CH3:42])[CH2:44][CH2:45][O:46][CH2:12][O:11][CH3:10])(=[O:17])[CH3:16]
Reactant: COc1ccc(OCCCN(CCO)C(C)C)c(C2Sc3cc(Cl)ccc3N2C(C)=O)c1
Reactant: COCCl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCOCCN(CCCOc1ccc(OC)cc1C1Sc2cc(Cl)ccc2N1C(C)=O)C(C)C
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 51.5 %

Procedure:
N,N-Diisopropylethylamine (0.18 ml, 1.01 mmol) and chlorodimethyl ether (0.05 ml, 0.55 mmol) were added to a solution of 3-acetyl-6-chloro-2-[2-(3-(N-(2-hydroxyethyl)-N-isopropylamino)-propoxy)-5-methoxyphenyl]benzothiazoline hydrochloride (235 mg, 0.46 mmol) in methylene chloride (2.0 ml) under ice-cooling. The mixture was stirred at room temperature for 3.5 hours, then a saturated aqueous sodium hydrogencarbonate solution (50 ml) was added to the reaction mixture, and the whole was extracted with ethyl acetate (50 ml). The ethyl acetate layer was washed with saturated brine (50 ml) and dehydrated with anhydrous magnesium sulfate, and ethyl acetate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (mobile phase: chloroform/methanol=20/1) to give 124 mg (52%) of the target compound.
Reaction SMILES: [CH2:1]([N:4]1[C:8]([C:9]([F:12])([F:11])[F:10])=[N:7][N:6]=[C:5]1[SH:13])[CH:2]=[CH2:3].[Cl:14][C:15](Cl)=[C:16]([Cl:19])[C:17]#[N:18].C(N(CC)CC)C>C(Cl)Cl>[CH2:1]([N:4]1[C:8]([C:9]([F:11])([F:12])[F:10])=[N:7][N:6]=[C:5]1[S:13][C:15]([Cl:14])=[C:16]([Cl:19])[C:17]#[N:18])[CH:2]=[CH2:3]
Reactant: C=CCn1c(S)nnc1C(F)(F)F
Reactant: N#CC(Cl)=C(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CCn1c(SC(Cl)=C(Cl)C#N)nnc1C(F)(F)F
Temperature: 25 °C
Yield: 57.6 %

Procedure:
A mixture of 4.0 g (0.019 mole) 4-allyl-5-trifluoromethyl-3-mercapto-1,2,4-triazole (the product of Example 2), 3.0 g (0.019 mole) trichloroacrylonitrile (the product of Example 3A), and 2.65 ml (0.019 mole) triethylamine in 100 ml methylene chloride was stirred at room temperature for several days. The reaction mixture washed with water, dried over magnesium sulfate, and stripped to give a yellow oil. Further purification by chromatography gave 3.6 g of the product as an oil which later crystallized, melting point 45°-48° C.
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][C@@H:12]2[O:25][C:16]3=[C:17]4[C:21](=[CH:22][CH:23]=[C:15]3[O:14][CH2:13]2)[NH:20][C:19](=[O:24])[CH2:18]4)(=O)=O)=CC=1.[CH:27]1([CH2:33][NH2:34])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1.C(O)(=O)/C=C/C(O)=O>CS(C)=O.C(O)(C)C>[CH:27]1([CH2:33][NH:34][CH2:11][CH:12]2[O:25][C:16]3=[C:17]4[C:21](=[CH:22][CH:23]=[C:15]3[O:14][CH2:13]2)[NH:20][C:19](=[O:24])[CH2:18]4)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc4c(c3O2)CC(=O)N4)cc1
Reactant: NCC1CCCCC1
Agent: O=C(O)/C=C/C(=O)O
Solvent: CS(C)=O
Solvent: CC(C)O
Product: O=C1Cc2c(ccc3c2OC(CNCC2CCCCC2)CO3)N1
Temperature: 80 °C

Procedure:
(R)-2-(Toluene-4-sulfonyloxymethyl)-2,3,8,9-tetrahydro-7H-1,4-dioxino[2,3-e]indol-8-one (0.80 g, 2.13 mmole), and cyclohexylmethylamine (1.33 g, 11.7 mmole) were combined in 15 ml of dry DMSO and heated to 80° C. for 6 hours under a nitrogen atmosphere. The reaction was allowed to cool and was partitioned between 100 ml of ethyl acetate and 150 ml of deionized water. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated to yield a black oil. This oil was column chromatographed on silica gel using 0.75% methanol/CH2Cl2 to remove impurities. A concentration of 2% methanol/CH2Cl2 eluted the desired product, which was as an oil (0.38 g, 56%) upon concentration in vacuum. This oil was crystallized from isopropanol with the addition of a solution of fumaric acid (0.15 g, 1.3 mmole) in hot isopropanol to give 0.39 g of the (S) enantiomer of the title compound as an off-white solid monofumarate, half hydrate, m.p. 187°-188° C.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([CH3:9])[C:6]([N+:10]([O-:12])=[O:11])=[CH:5][C:3]=1N.N([O-])=O.[Na+].[BrH:17]>O.CCOC(C)=O>[Br:17][C:3]1[CH:5]=[C:6]([N+:10]([O-:12])=[O:11])[C:7]([CH3:9])=[CH:8][C:2]=1[F:1]
Reactant: Cc1cc(F)c(N)cc1[N+](=O)[O-]
Reactant: Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1cc(F)c(Br)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 91 %

Procedure:
2-Fluoro-4-methyl-5-nitro-aniline (1.85 g, 10.90 mmol) was suspended in concentrated hydrobromic acid (22 mL) and cooled to 0° C. Solution of sodium nitrite (0.83 g, 12.00 mmol) in water (3.6 mL) was added dropwise while maintaining the temperature at 0˜5° C. After stirring for 15 min, the mixture was filtered through a cotton pad and slowly poured into a solution of cuprous oxide (2.60 g, 17.5 mmol) and concentrated hydrobromic acid (20 mL) at 0° C. After stirring overnight, the reaction mixture was diluted with EtOAc, washed with 10% aq NaOH and 5% aq Na2S2O5 successively, dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography (ethyl acetate:hexane; 2:98) to afford 1-Bromo-2-fluoro-4-methyl-5-nitro-benzene as a colorless oil (2.30 g, 91%). 1H NMR (CDCl3, 400 MHz,): 2.59 (s, 3H), 7.11 (d, J=8.4 Hz, 1H), 8.24 (d, J=6.3 Hz, 1H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([N+:12]([O-:14])=[O:13])=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.[C:15]([C:17]1[CH:18]=[C:19]([NH2:23])[CH:20]=[CH:21][CH:22]=1)#[CH:16]>C(O)(C)C>[C:15]([C:17]1[CH:18]=[C:19]([NH:23][C:2]2[C:11]3[C:6](=[CH:7][C:8]([N+:12]([O-:14])=[O:13])=[CH:9][CH:10]=3)[N:5]=[CH:4][N:3]=2)[CH:20]=[CH:21][CH:22]=1)#[CH:16]
Reactant: O=[N+]([O-])c1ccc2c(Cl)ncnc2c1
Reactant: C#Cc1cccc(N)c1
Solvent: CC(C)O
Product: C#Cc1cccc(Nc2ncnc3cc([N+](=O)[O-])ccc23)c1
Temperature: 25 °C
Yield: 93.9 %

Procedure:
A mixture of 4-chloro-7-nitroquinazoline (2.0 g, 9.54 mmol), isopropanol (30 mL), and 3-ethynylbenzenamine (1.2 g, 10.00 mmol) was refluxed for 5 h. The reaction mixture was cooled to room temperature and refrigerated. The solid was filtered, washed with cold isopropanol several times, and dried in vacuo to give 2.6 g (94%) of N-(3-ethynylphenyl)-7-nitroquinazolin-4-amine as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][CH:5]=1.[Br:12][C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[CH:15]=O>CO>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7](/[N:10]=[CH:15]/[C:14]2[CH:17]=[CH:18][CH:19]=[CH:20][C:13]=2[Br:12])=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(N)cc1
Reactant: O=Cc1ccccc1Br
Solvent: CO
Product: COC(=O)c1ccc(/N=C/c2ccccc2Br)cc1
Reaction time: 8 h

Procedure:
4-aminobenzoic acid methyl ester (1.51 g, 10 mmol) and 2-bromobenzaldehyde (1.45 mL, 12.5 mmol) were dissolved in 15 mL of methanol. The mixture was let stand overnight. A white precipitate formed and the crystals were filtered off, washed with cold methanol (2×) and dried.
Reaction SMILES: Br[C:2]1([CH2:10][C:11]([O:13][Si:14]([C:27]([CH3:30])([CH3:29])[CH3:28])([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[C:6](=[O:7])[O:5][C:4]([CH3:9])([CH3:8])[O:3]1.N12CCCN=C1CCCCC2>O1CCCC1>[CH3:8][C:4]1([CH3:9])[O:5][C:6](=[O:7])/[C:2](=[CH:10]/[C:11]([O:13][Si:14]([C:27]([CH3:30])([CH3:29])[CH3:28])([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])/[O:3]1
Reactant: CC1(C)OC(=O)C(Br)(CC(=O)O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)O1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: CC1(C)OC(=O)/C(=C/C(=O)O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)O1
Temperature: 5 °C
Reaction time: 1.5 h

Procedure:
A solution of 4-bromo-2,2-dimethyl-5-oxo-1,3-dioxolane-4-acetic acid, tert-butyldiphenylsilyl ester (˜26 g, 52.4 mmol) in dry tetrahydrofuran (160 ml) was cooled to 0° C. and treated dropwise over 5 minutes with 1,8-diazabicyclo[5,4,0]undec-7-ene (12.7 g, 78.8 mmol) and the resulting mixture was stirred at 5° C. for 1.5 hour. The solid formed was filtered and washed with a small amount of tetrahydrofuran. The filtrate was used as such for the next step.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([Cl:20])[C:5]([CH2:8][N:9]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]2=[O:19])=[N:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].[C:27]1(C)C=CC=C[CH:28]=1>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>[Cl:20][C:4]1[C:5]([CH2:8][N:9]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]2=[O:19])=[N:6][CH:7]=[C:2]([CH:27]=[CH2:28])[CH:3]=1
Reactant: O=C1c2ccccc2C(=O)N1Cc1ncc(Br)cc1Cl
Reactant: Cc1ccccc1
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: [K+]
Product: C=Cc1cnc(CN2C(=O)c3ccccc3C2=O)c(Cl)c1
Yield: 65 %

Procedure:
To a stirred solution of 2-((5-bromo-3-chloropyridin-2-yl)methyl)isoindoline-1,3-dione (0.23 g, 0.65 mmol) in toluene (10 mL) were added Pd(PPh3)4 (3.7 mg, 0.003 mmol), K2CO3 (0.269 g, 1.95 mmol) and vinyl boronic anhydride pyridine complex (0.78 g, 3.28 mmol), and the reaction mixture was heated at reflux for 16 h. The reaction mixture was filtered, and the filtrate was washed with H2O and brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. Purification by flash column chromatography (20-30% EtOAc in hexane) afforded the title compound as an off-white solid (0.2 g, 65%): 1H NMR (400 MHz, CDCl3) δ 8.30 (s, 1H), 7.91 (m, 2H), 7.77 (m, 3H), 7.72 (m, 1H), 6.63 (m, 1H), 5.79 (d, J=16.0 Hz, 1H), 5.39 (d, J=16.0 Hz, 1H), 5.12 (s, 2H); ESIMS m/z 299.20 ([M+H]+).
Reaction SMILES: [H-].[Na+].[C:3]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11](=[O:16])[CH2:10][C:9]2([CH3:18])[CH3:17])(=[O:5])[CH3:4].I[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>CN(C=O)C>[CH2:20]([N:12]1[C:13]2[C:8](=[CH:7][C:6]([C:3](=[O:5])[CH3:4])=[CH:15][CH:14]=2)[C:9]([CH3:18])([CH3:17])[CH2:10][C:11]1=[O:16])[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CC(=O)c1ccc2c(c1)C(C)(C)CC(=O)N2
Reactant: CCCCCCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCN1C(=O)CC(C)(C)c2cc(C(C)=O)ccc21
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 0.3 %

Procedure:
Sodium hydride (21 mg, 90 mmol) was slowly added into a solution of 6-acetyl-4,4-dimethyl-3,4-dihydro-1H-quinolin-2-one (Intermediate 5, 98 mg, 45 mmol) in 3 mL of DMF at 0° C. After stirring at 0° C. for 10 min, 1-iodo-n-hexane (29 mg, 135 mmol) was added to the reaction mixture and the ice-bath was removed. The reaction was allowed to stir for 2 h before quenching with ice water. The resulting solution was then extracted with ether (3×10 mL), washed with brine (1×10 mL), dried (MgSO4) and concentrated at reduced pressure. Purification by flash chromatography (75:25 hexane/ethyl acetate) yielded the title compound as a colorless oil (41.8 mg, 31% yield).