Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([CH:19]3[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]3)=[CH:15][C:14]=2[O:32][CH3:33])[N:3]=1.[C:34]([C:36]1[CH:37]=[C:38]([CH:42]=[CH:43][CH:44]=1)[C:39]([NH2:41])=[O:40])#[CH:35].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>CN(C=O)C.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.[Cu]I>[C:39]([C:38]1[CH:37]=[C:36]([C:34]#[C:35][C:2]2[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]3[CH:18]=[CH:17][C:16]([CH:19]4[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]4)=[CH:15][C:14]=3[O:32][CH3:33])[N:3]=2)[CH:44]=[CH:43][CH:42]=1)(=[O:40])[NH2:41]
Reactant: COc1cc(C2CCN(C(=O)OC(C)(C)C)CC2)ccc1Nc1ncc(C(F)(F)F)c(Cl)n1
Reactant: C#Cc1cccc(C(N)=O)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc(C2CCN(C(=O)OC(C)(C)C)CC2)ccc1Nc1ncc(C(F)(F)F)c(C#Cc2cccc(C(N)=O)c2)n1
Temperature: 120 °C
Reaction time: 8 h
Yield: 61.3 %

Procedure:
To a mixture of tert-butyl 4-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidine-1-carboxylate (I34) (0.098 g, 0.20 mmol), 3-ethynylbenzamide (I31) (0.038 g, 0.26 mmol), PdCl2(PPh3)2 (9 mg, 0.01 mmol), triphenylphosphine (0.010 g, 0.04 mmol) and copper(I) iodide (0.009 g, 0.05 mmol) in DMF (2 mL), that had been degassed with nitrogen for 10 minutes, was added triethylamine (0.090 mL, 0.65 mmol). The mixture was degassed with nitrogen then heated to 120° C. for 25 minutes under microwave irradiation. On cooling to room temperature the resulting mixture was left overnight, then an additional portion of 3-ethynylbenzamide (I26) (0.047 g, 0.32 mmol) was added. After degassing with nitrogen the reaction was heated at 120° C. for 25 minutes under microwave irradiation. The volatiles were evaporated under reduced pressure and the residue purified using silica gel column chromatography (20-70% EtOAc/petroleum benzine 40-60° C.) to give the title compound (I35) (0.073 g, 61%) as a yellow solid; 1H NMR (400 MHz, CDCl3) δ 8.66 (s, 1H), 8.35 (d, J=8.3 Hz, 1H), 8.04 (dd, J=1.4, 1.4 Hz, 1H), 8.02 (s, 1H), 7.93 (ddd, J=7.9, 1.8, 1.2 Hz, 1H), 7.80 (m, 1H), 7.53 (m, 1H), 6.88 (dd, J=8.3, 1.6 Hz, 1H), 6.76 (d, J=1.8 Hz, 1H), 4.27 (m, 2H), 3.91 (s, 3H), 2.81 (m, J=12.2 Hz, 2H), 2.64 (tt, J=12.2, 3.4 Hz, 1H), 1.84 (m, 2H), 1.65 (m, 2H), 1.49 (s, 9H). LCMS Method C: rt 6.59 min; m/z 496.1 [(M-Boc)+H]+, 540.0 [(M-t-Bu)+H]+.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH:3]=[CH:2]1.[CH:8]1[CH2:13][CH2:12][CH:11]=[CH:10][CH:9]=1>C1(C)C=CC=CC=1>[C:8]12[CH2:13][CH2:12][CH:11]([CH2:10][CH2:9]1)[CH:2]1[C:1]([O:6][C:4](=[O:5])[C:3]=21)=[O:7]
Reactant: O=C1C=CC(=O)O1
Reactant: C1=CCCC=C1
Solvent: Cc1ccccc1
Product: O=C1OC(=O)C2C1=C1CCC2CC1
Temperature: 25 °C

Procedure:
To a solution of maleic anhydride (10.30 g) in toluene (100 ml) was added 1,3-cyclohexadiene (8.41 g). The mixture was refluxed for 3 hours. After cooling to 25° C., the solvent was evaporated at reduced pressure. The solid was recrystallized from EtOAC/hexane to yield bicyclo[2.2.2]oct-en-2,3-dicarboxylic anhydride as colorless crystals.
Reaction SMILES: [CH2:1]1[CH:16]2[N:4]([CH2:5][CH2:6][C:7]3[C:15]4[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=4)[NH:9][C:8]=32)[CH2:3][CH2:2]1.[H-].[Na+].[CH3:19]I>CN(C)C=O>[CH3:19][N:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:7]2[CH2:6][CH2:5][N:4]3[CH:16]([C:8]1=2)[CH2:1][CH2:2][CH2:3]3
Reactant: CI
Reactant: c1ccc2c3c([nH]c2c1)C1CCCN1CC3
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c2c(c3ccccc31)CCN1CCCC21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2,3,5,6,11,11b-Hexahydro-1H-indolizino[8,7-b]-indole (8.49 g.) is stirred for 1 hour at 25°C. in dimethylformamide (200 ml.) containing sodium hydride (2.11 g. of a 50% mineral oil dispersion). Methyl iodide (6.25 g.) in dimethylformamide (25 ml.) is added and the mixture is stirred at 25°C. for 16 hours. The dimethylformamide is distilled off, and the residue is dissolved in chloroform and washed with aqueous potassium bicarbonate and water, and dried. The product is chromatographed on neutral alumina to give 2,3,5,6,11,11b-hexahydro-11-methyl-1H-indolizino[8,7-b]indole as a clear oil (5.88 g.).
Reaction SMILES: S=[C:2]1[CH2:6][S:5][C:4](=[O:7])[NH:3]1.C(O)C.[CH2:11]([NH2:13])[CH3:12]>C(O)C>[CH2:11]([NH:13][C:2]1[CH2:6][S:5][C:4](=[O:7])[N:3]=1)[CH3:12]
Reactant: O=C1NC(=S)CS1
Reactant: CCN
Solvent: CCO
Product: CCNC1=NC(=O)SC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 46.2 %

Procedure:
To a solution of 4-thioxo-1,3-thiazolidin-2-one (640 mg) in ethanol (6 mL) was added 30% ethanamine ethanol solution (722 mg), and the mixture was stirred at room temperature for 3 hr. The reaction mixture was concentrated under reduced pressure, and the residue was washed with 2-propanol to give the title compound (320 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11](/[CH:14]=[C:15]3/[C:16](=[O:22])[N:17]=[C:18](SC)[S:19]/3)[CH:12]=2)[N:7]=[CH:6][C:5]=1[C:23]#[N:24])[CH3:2].[CH3:25][O:26][CH2:27][CH2:28][O:29][CH2:30][CH2:31][NH2:32].CCN(C(C)C)C(C)C>>[CH3:25][O:26][CH2:27][CH2:28][O:29][CH2:30][CH2:31][NH:32][C:18]1[S:19]/[C:15](=[CH:14]\[C:11]2[CH:12]=[C:13]3[C:8](=[CH:9][CH:10]=2)[N:7]=[CH:6][C:5]([C:23]#[N:24])=[C:4]3[O:3][CH2:1][CH3:2])/[C:16](=[O:22])[N:17]=1
Reactant: CCOc1c(C#N)cnc2ccc(/C=C3\SC(SC)=NC3=O)cc12
Reactant: COCCOCCN
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1c(C#N)cnc2ccc(/C=C3\SC(NCCOCCOC)=NC3=O)cc12

Procedure:
Similar procedure as described in example 14h was used, starting from 4-ethoxy-6-[2-methylsulfanyl-4-oxo-4H-thiazol-(5Z)-ylidenemethyl]-quinoline-3-carbonitrile (example 14g), 2-(2-methoxy-ethoxy)-ethylamine and DIEA to give 6-[2-[2-(2-methoxy-ethoxy)-ethylamino]-4-oxo-4H-thiazol-(5Z)-ylidenemethyl]-4-ethoxy-quinoline-3-carbonitrile. LC-MS m/e 427 (MH+).
Reaction SMILES: [CH2:1]([OH:4])[CH:2]=[CH2:3].[H-].[Na+].[NH2:7][C:8]1[CH:13]=[N:12][CH:11]=[C:10](Cl)[N:9]=1>O1CCOCC1>[CH2:1]([O:4][C:10]1[N:9]=[C:8]([NH2:7])[CH:13]=[N:12][CH:11]=1)[CH:2]=[CH2:3]
Reactant: Nc1cncc(Cl)n1
Reactant: C=CCO
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: C=CCOc1cncc(N)n1
Temperature: 140 °C
Reaction time: 0.5 h
Yield: 57.1 %

Procedure:
A mixture of allyl alcohol (0.21 mL, 3.08 mmol) in dioxane (4 mL) was treated with NaH (60%, 3.08 mmol), stirred for 30 minutes, treated with 2-amino-6-chloropyrazine (200 mg, 1.54 mmol), heated to 140° C. in a Smith Synthesizer for 2200 seconds, and filtered. The filtrate was concentrated and purified by flash column chromatography eluting with hexanes/ethyl acetate (2:1) to provide the desired product (133 mg, 57%). MS (DCI/NH3) m/z 152.0 (M+H)+; 1H NMR (500 MHz, CD2Cl2) δ 4.75 (m, 2H), 5.24 (m, 1H), 5.37 (m, 1H), 6.05 (m, 1H), 7.50 (s, 1H), 7.53 (s, 1H).
Reaction SMILES: C([O:4][C:5]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:6]=1[O:7][CH2:8][C@H:9]1[CH2:11][O:10]1)C=C.C(=O)(O)[O-].[Na+].[C:22]1(C)[CH:27]=C(C)C=C(C)[CH:23]=1>>[CH2:27]([C:15]1[C:5]2[O:4][C@@H:9]([CH2:11][OH:10])[CH2:8][O:7][C:6]=2[CH:12]=[C:13]([Cl:16])[CH:14]=1)[CH:22]=[CH2:23]
Reactant: Cc1cc(C)cc(C)c1
Reactant: C=CCOc1ccc(Cl)cc1OC[C@H]1CO1
Agent: O=C([O-])O
Agent: [Na+]
Product: C=CCc1cc(Cl)cc2c1O[C@@H](CO)CO2
Temperature: 25 °C
Reaction time: 24 h

Procedure:
(R)-2-(2-Allyloxy-5-chlorophenoxymethyl)-oxirane (9.2 g, 38 mmole) was dissolved in 500 ml of mesitylene and refluxed under nitrogen for 48 hours. The solvent was then removed in vacuum and replaced with 500 ml of ethanol. Sodium bicarbonate (50 g, 0.60 mole) was added and the mixture stirred at room temperature under nitrogen for 24 hours. The mixture was then filtered and concentrated in vacuum. The solvent was replaced with 500 ml of methylene chloride and the solution was washed with water and with saturated brine, dried over sodium sulfate, filtered and evaporated in vacuum. The residue was column chromatographed on silica gel using chloroform as eluant to give 8.9 g of the title compound as a colorless oil. 1H (CDCl3) singlet, 6.80 δ (1 H); singlet, 6.73 δ (1 H); multiplet, 5.95 δ (1 H); doublet, 5.10 δ (1 H); doublet, 5.05 δ (1 H); multiplet, 4.25 δ (2 H); multiplet, 4.10 δ (1 H); multiplet, 3.85 δ (2 H); multiplet, 3.30 δ (2 H); broad singlet, 2.00 δ (1 H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][N:3]=1.[NH2:11][CH:12]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13]1>>[NH2:8][C:5]1[CH:6]=[CH:7][C:2]([NH:11][CH:12]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13]2)=[N:3][CH:4]=1
Reactant: CC(C)(C)OC(=O)N1CCC(N)C1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Product: CC(C)(C)OC(=O)N1CCC(Nc2ccc(N)cn2)C1
Yield: 47.2 %

Procedure:
Following General procedure H, 2-chloro-5-nitropyridine (500 mg, 3.1 mmol) was reacted with tert-butyl 3-aminopyrrolidine-1-carboxylate (632 mg, 3.5 mmol) followed by reduction to afford the desired product (407 mg, 47%) as a purple solid: ESI MS m/z 279 [C14H22N4O2+H]+.
Reaction SMILES: [NH3:1].Cl[C:3]1[C:4]2[C:11]([I:12])=[CH:10][N:9]([CH2:13][CH2:14][C@@H:15]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH:16]=[CH2:17])[C:5]=2[N:6]=[CH:7][N:8]=1.O>COCCOC>[NH2:1][C:3]1[C:4]2[C:11]([I:12])=[CH:10][N:9]([CH2:13][CH2:14][C@@H:15]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH:16]=[CH2:17])[C:5]=2[N:6]=[CH:7][N:8]=1
Reactant: C=C[C@@H](CCn1cc(I)c2c(Cl)ncnc21)NC(=O)OC(C)(C)C
Reactant: N
Solvent: COCCOC
Solvent: O
Product: C=C[C@@H](CCn1cc(I)c2c(N)ncnc21)NC(=O)OC(C)(C)C
Temperature: 105 °C
Reaction time: 8 h

Procedure:
28% aqueous ammonia (17.5 ml) was added to a solution of (R)-tert-butyl (5-(4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine-7-yl)pent-1-en-3-yl)carbamate (3.49 g) obtained in Step 4 in DME (17.5 ml), and the mixture was stirred in an autoclave at an internal temperature of 105° C. for 8 hours. After cooling the reaction mixture, water (70 ml) was added thereto, and the mixture was stirred at room temperature for 4 hours. The resulting precipitate was collected by filtration, washed with water, and dried to obtain the title compound as a light-yellow solid (3.20 g).
Reaction SMILES: [C:1]1(B(O)O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:21]1[C:29]([CH3:30])=[CH:28][CH:27]=[C:26]2[C:22]=1[CH:23]=[CH:24][CH2:25]2>C(COC)OC.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>[C:1]1([C:21]2[C:29]([CH3:30])=[CH:28][CH:27]=[C:26]3[C:22]=2[CH:23]=[CH:24][CH2:25]3)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: OB(O)c1cccc2ccccc12
Reactant: Cc1ccc2c(c1Br)C=CC2
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: [Cs+]
Solvent: COCCOC
Product: Cc1ccc2c(c1-c1cccc3ccccc13)C=CC2
Yield: 86 %

Procedure:
1-Naphthylboronic acid (10 g, 58.1 mmol) was dissolved in dimethoxyethane (150 mL), and aqueous solution (100 mL) of cesium carbonate (25.3 g, 78 mmol), 4-bromo-5-methylindene (8.1 g, 39 mmol), tetrakis(triphenylphosphine)palladium (1.8 g) were sequentially added. Solution was reacted for 21 hours while heating under reflux, then, reaction solution was poured into 1N hydrochloric acid-ice water, and after stirring, reaction solution was extracted with diethyl ether. Organic layer was washed with magnesium sulfate, then, solvent was distilled off under reduced pressure to obtain the crude product. This was purified by silica-gel column chromatography to obtain the desired 4-(1-naphthyl)-5-methylindene (8.6 g, yield: 87%).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@H:9]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])[C@@H:8](/[CH:20]=[CH:21]/[C:22](=[O:30])[C:23]([F:29])([F:28])[CH2:24][CH2:25][CH2:26][CH3:27])[C@H:7]([O:31][CH:32]2[CH2:37][CH2:36][CH2:35][CH2:34][O:33]2)[CH2:6]1)(=[O:3])[CH3:2]>C(OCC)(=O)C.[Pd]>[C:1]([O:4][C@@H:5]1[C@H:9]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])[C@@H:8]([CH2:20][CH2:21][C:22](=[O:30])[C:23]([F:28])([F:29])[CH2:24][CH2:25][CH2:26][CH3:27])[C@H:7]([O:31][CH:32]2[CH2:37][CH2:36][CH2:35][CH2:34][O:33]2)[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CCCCC(F)(F)C(=O)/C=C/[C@@H]1[C@@H](CCCCCCC(=O)OC)[C@@H](OC(C)=O)C[C@H]1OC1CCCCO1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCCC(F)(F)C(=O)CC[C@@H]1[C@@H](CCCCCCC(=O)OC)[C@@H](OC(C)=O)C[C@H]1OC1CCCCO1
Yield: 99.8 %

Procedure:
To a solution of methyl 7-[(1R,2R,3R,5S)-5-acetoxy-2-((E)-4,4-difluoro-3-oxo-1-octenyl)-3-(2-tetrahydropyranyloxy)cyclopentyl]heptanate (3) (70.90 g, 133.6 mmol) in ethyl acetate (357 ml), 5%-palladium on carbon (7.12 g) was added and the solution was hydrogenated at room temperature and the ambient pressure. The reaction mixture was filtered, the filtrate was concentrated under reduced pressure to give methyl 7-[(1R,2R,3R,5S)-5-acetoxy-2-(4,4-difluoro-3-oxooctyl)-3-(2-tetrahydropyranyloxy)cyclopentyl]heptanate (15) (71.02 g; 133.3 mmol; yield: 99.8%) as a colorless oil.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([N:9]=[C:10]=[O:11])[CH3:8].[Cl:12][C:13]1[C:14]([O:23][C:24]2[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[NH:26][N:25]=2)=[N:15][CH:16]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:18]=1.Cl>C(OCC)(=O)C>[CH2:7]([NH:9][C:10]([N:26]1[C:27]([C:29]([F:32])([F:31])[F:30])=[CH:28][C:24]([O:23][C:14]2[C:13]([Cl:12])=[CH:18][C:17]([C:19]([F:22])([F:21])[F:20])=[CH:16][N:15]=2)=[N:25]1)=[O:11])[CH3:8]
Reactant: FC(F)(F)c1cnc(Oc2cc(C(F)(F)F)[nH]n2)c(Cl)c1
Reactant: CCN=C=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: CCNC(=O)n1nc(Oc2ncc(C(F)(F)F)cc2Cl)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 41.2 %

Procedure:
Potassium carbonate (0.69 g, 5.0 mmol) and ethyl isocyanate (0.28 g, 5.0 mmol) were added to a solution of 3-(3-chloro-5-trifluoromethylpyridin-2-yloxy)-5-trifluoromethylpyrazole (1.66 g, 5.0 mmol) in ethyl acetate (20 ml), and the mixture was stirred at room temperature for 3 hours. After completion of the reaction, the reaction mixture was poured into 2N hydrochloric acid and extracted with ethyl acetate (20 ml×3). An organic layer was washed with water, dried over anhydrous magnesium sulfate and filtered to remove a desiccant, and the solvent was distilled off from the filtrate under reduced pressure. The resultant crude product was purified with a silica gel column (ethyl acetate/hexane=1/5→1/1), to give a white solid of N-ethyl-3-(3-chloro-5-trifluoromethylpyridin-2-yloxy)-5-trifluoromethylpyrazole-1-carboxamide (0.83 g, yield: 51.6%). mp: 52-54° C./1H-NMR (CDCl3, TMS, ppm): δ 1.34 (t, J=7.1 Hz, 3H), 3.75-4.30 (m, 2H), 5.66 (s, 1H), 7.98 (d, J=1.5 Hz, 1H), 8.64 (m, 1H), 10.20-10.40 (m, 1H).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH:6]=[O:7].I[CH2:9][CH3:10].[H-].[Na+]>CN(C=O)C>[CH2:9]([N:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH:6]=[O:7])[CH3:10]
Reactant: O=Cc1ncc[nH]1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCn1ccnc1C=O
Temperature: 25 °C
Reaction time: 120 h

Procedure:
In DMF (15 ml), 2-imidazole carboxaldehyde (500 mg) was dissolved. Then, the solution was added with iodoethane (1.25 ml) and sodium hydride (208 mg), followed by stirring at room temperature for 5 days. After completion of the reaction, the solvent was distilled off and the residue was then added with chloroform, followed by washing with water and saturated saline solution. The resultant was dried with anhydrous sodium sulfate, and the solvent was then distilled off. The residue was purified through silica gel column chromatography (chloroform/methanol), thereby obtaining the subject compound (280 mg) as a yellow oily substance.
Reaction SMILES: Br[CH2:2][C:3]([OH:5])=[O:4].[CH3:6][O:7][C:8]1[C:9]([N+:17]([O-:19])=[O:18])=[C:10]([NH2:16])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15]>>[CH3:6][O:7][C:8]1[C:9]([N+:17]([O-:19])=[O:18])=[C:10]([NH:16][CH2:2][C:3]([OH:5])=[O:4])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15]
Reactant: O=C(O)CBr
Reactant: COc1ccc(N)c([N+](=O)[O-])c1OC
Product: COc1ccc(NCC(=O)O)c([N+](=O)[O-])c1OC
Temperature: 58 °C
Reaction time: 16 h
Yield: 68 %

Procedure:
Bromoacetic acid (0.876 g, 6.31 mmol, 0.5 eq) is added portionwise to 3,4-dimethoxy-2-nitro-phenylamine (2.5 g, 12.61 mmol, 1.0 eq) and the mixture is stirred at 58° C. for 16 hours. The reaction is then quenched by 25% ammonia in water and diluted with water. The solid is filtered off and washed with 10% ammonia in water. The combined solutions are acidified by concentrated hydrochloric acid and the resulting precipitate is collected by filtration, washed with water and dried under vacuum to afford (3,4-dimethoxy-2-nitro-phenylamino)-acetic acid as a red solid (1.1 g, 34% yield).
Reaction SMILES: [F:1][CH:2]([F:24])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]#[CH:13])=[C:7]2[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:4]=1.Br[C:26]1[CH:27]=[CH:28][C:29]([CH3:39])=[C:30]([S:32]([NH:35][CH2:36][CH2:37][OH:38])(=[O:34])=[O:33])[CH:31]=1>>[F:24][CH:2]([F:1])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]#[C:13][C:26]3[CH:27]=[CH:28][C:29]([CH3:39])=[C:30]([S:32]([NH:35][CH2:36][CH2:37][OH:38])(=[O:34])=[O:33])[CH:31]=3)=[C:7]2[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:4]=1
Reactant: Cc1ccc(Br)cc1S(=O)(=O)NCCO
Reactant: C#Cc1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: Cc1ccc(C#Cc2cnn3c(C(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)cc1S(=O)(=O)NCCO

Procedure:
The title compound was prepared from 7-Difluoromethyl-3-ethynyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.2) (340 mg, 1.0 mmol) and 5-bromo-N-(2-hydroxy-ethyl)-2-methyl-benzenesulfonamide (example B.17) (267 mg, 1.0 mmol) according to general procedure II. Obtained as a yellow solid (230 mg, 41%). MS (ISP) 551.3[(M+H)+]; mp 184–186° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=[CH:5][C:4]=1/[CH:13]=[CH:14]/[C:15](=[O:17])[CH3:16].O.[C:19]([OH:23])(=[O:22])[CH:20]=O>C(O)(=O)C.O>[O:17]=[C:15](/[CH:14]=[CH:13]/[C:4]1[CH:5]=[CH:6][C:7]([O:11][CH3:12])=[C:8]([O:9][CH3:10])[C:3]=1[O:2][CH3:1])/[CH:16]=[CH:20]/[C:19]([OH:23])=[O:22]
Reactant: COc1ccc(/C=C/C(C)=O)c(OC)c1OC
Reactant: O=CC(=O)O
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc(/C=C/C(=O)/C=C/C(=O)O)c(OC)c1OC

Procedure:
A solution of 18 g (76 mmol) of (E)-4-(2,3,4-trimethoxyphenyl)but-3-en-2-one and 7 g (76 mmol) of glyoxylic acid monohydrate in 19 ml of acetic acid was heated at reflux for 20 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was extracted twice with 3N sodium hydroxide solution. The combined aqueous phases were treated with 3N hydrochloric acid to produce a strongly acidic reaction and extracted twice with ethyl acetate. The combined organic phases were dried over magnesium sulphate and concentrated. Crystallization of the residue from ether/methylene chloride yielded (E,E)-4-oxo-6-(2,3,4-trimethoxyphenyl)-2,5-hexadienoic acid of melting point 125°-127°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](/[CH:11]=[CH:12]/[C:13]([NH:15][C:16]2[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=2[C:18]([OH:20])=[O:19])=O)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]>C(OC(=O)C)(=O)C.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][C:8]=1[O:9][CH3:10])/[CH:11]=[CH:12]/[C:13]1[O:19][C:18](=[O:20])[C:17]2[CH:21]=[CH:22][CH:23]=[CH:24][C:16]=2[N:15]=1
Reactant: COc1ccc(/C=C/C(=O)Nc2ccccc2C(=O)O)cc1OC
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: COc1ccc(/C=C/c2nc3ccccc3c(=O)o2)cc1OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 88.4 %

Procedure:
A solution of (E)-2-[[3-(3,4-dimethoxyphenyl)-1-oxo-2-propenyl]amino]benzoic acid (0.5 g, 1.5 mmol) in acetic anhydride (3 mL) was heated to reflux and stirred for 3 h. The reaction was cooled to rt and the resulting suspension was diluted with water. The suspension was stirred at rt for 1 h and the precipitate was collected by filtration, providing (E)-2-(3,4-dimethoxystyryl)-4H-benzo[d][1,3]oxazin-4-one (0.41 g, 88%) as a yellow crystalline solid; mp 175-179° C.; δH (500 MHz, DMSO-d6) 3.82 (s, 3H, OCH3), 3.85 (s, 3H, OCH3), 6.94 (d, J=16.0 Hz, 1H, CH═CHCO), 7.02 (d, J5′,6′=8.0 Hz, 1H, H5′), 7.35 (dd, J5′,6=8.0, J2′,6′=1.5 Hz, 1H, H6′), 7.47 (d, J2,6′=1.5 Hz, 1H, H2′), 7.58 (t, J3,4=J4,5=8.0 Hz, 1H, H4), 7.61 (d, J3,4=8.0 Hz, 1H, H3), 7.73 (d, J=16.0 Hz, 1H, CH═CHCO), 7.92 (t, J4,5=J5,6=8.0 Hz, 1H, H5), 8.12 (d, J5,6=8.0 Hz, 1H, H6); δC (125 MHz, DMSO-d6) 55.5, 55.6, 110.3, 111.6, 116.6, 122.9, 126.5, 127.4, 128.0, 128.0, 128.1, 136.8, 141.4, 146.8, 149.0, 150.9, 157.3, 158.8; HRMS (ESI) calculated for C18H15NO4 [M+H]+310.1074; found 310.1073; νmax 1020, 1254, 1515, 1634, 1755, 2835, 2940 cm−1.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([NH:18][C:19]3[C:24](=[O:25])[N:23]([CH3:26])[CH:22]=[C:21]([C:27]4[CH:32]=[C:31]([F:33])[CH:30]=[C:29]([N:34]5[CH2:46][CH2:45][N:37]6[C:38]7[CH2:39][CH2:40][CH2:41][CH2:42][C:43]=7[CH:44]=[C:36]6[C:35]5=[O:47])[C:28]=4[CH2:48][O:49][C:50](=[O:52])[CH3:51])[N:20]=3)[CH:14]=2)[CH2:9]1)=O)(C)(C)C.Cl>C(Cl)Cl.O1CCOCC1>[C:50]([O:49][CH2:48][C:28]1[C:29]([N:34]2[CH2:46][CH2:45][N:37]3[C:38]4[CH2:39][CH2:40][CH2:41][CH2:42][C:43]=4[CH:44]=[C:36]3[C:35]2=[O:47])=[CH:30][C:31]([F:33])=[CH:32][C:27]=1[C:21]1[N:20]=[C:19]([NH:18][C:13]2[CH:14]=[C:15]3[C:10](=[CH:11][CH:12]=2)[CH2:9][NH:8][CH2:17][CH2:16]3)[C:24](=[O:25])[N:23]([CH3:26])[CH:22]=1)(=[O:52])[CH3:51]
Reactant: CC(=O)OCc1c(-c2cn(C)c(=O)c(Nc3ccc4c(c3)CCN(C(=O)OC(C)(C)C)C4)n2)cc(F)cc1N1CCn2c(cc3c2CCCC3)C1=O
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC(=O)OCc1c(-c2cn(C)c(=O)c(Nc3ccc4c(c3)CCNC4)n2)cc(F)cc1N1CCn2c(cc3c2CCCC3)C1=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 99.5 %

Procedure:
To the solution of 129a (360 mg 0.51 mmol) in DCM (30 mL) was added 3M HCl in dioxane (8 mL) at room temperature. The mixture was stirred at room temperature for 5 h. After the reaction was completed, the solvent was removed at reduced pressure to afford 129b as a yellow solid (310 mg, 99%).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[F:9].O[CH2:11][CH:12]([CH2:14]O)O.[N+](C1C=CC=CC=1)([O-])=O.S(=O)(=O)(O)O>>[Br:1][C:2]1[CH:8]=[C:7]2[C:5](=[CH:4][C:3]=1[F:9])[N:6]=[CH:14][CH:12]=[CH:11]2
Reactant: Nc1ccc(Br)c(F)c1
Reactant: OCC(O)CO
Agent: O=S(=O)(O)O
Solvent: O=[N+]([O-])c1ccccc1
Product: Fc1cc2ncccc2cc1Br
Reaction time: 7 h
Yield: 42.5 %

Procedure:
A mixture of 4-bromo-3-fluoroaniline (2.85 g, 15 mmol), ferric sulfate (0.95 g, 6.25 mmol), glycerol (5.66 g, 61 mmol), nitrobenzene (0.93 mL, 9.1 mmol), and concentrated sulfuric acid (2.61 ml) was heated gently. After the first vigorous reaction, the mixture was boiled for 7 h. Nitrobenzene was then evaporated in vacuo. The aqueous solution was acidified with glacial acetic acid, and a dark brown precipitate separated, which was collected and purified by flash chromatography (silica gel, petroleum/ethyl acetate=8/1) to give 1.44 g of 6-bromo-7-fluoro-quinoline as white crystals (42.5% yield).