Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH2:5][C:6]1[N:7]=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2O)[S:9][CH:10]=1)[CH3:2].[OH:19]C1C=C(C(=S)N)C=CC=1.ClCC(=O)CC(OCC)=O>C1COCC1>[CH2:1]([O:3][C:4](=[O:18])[CH2:5][C:6]1[N:7]=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([OH:19])[CH:12]=2)[S:9][CH:10]=1)[CH3:2]
Reactant: NC(=S)c1cccc(O)c1
Reactant: CCOC(=O)Cc1csc(-c2ccccc2O)n1
Agent: CCOC(=O)CC(=O)CCl
Solvent: C1CCOC1
Product: CCOC(=O)Cc1csc(-c2cccc(O)c2)n1
Yield: 78 %

Procedure:
The procedure used for the preparation of 4a was repeated with 3-hydroxybenzenecarbothioamide 3d (1.53 g, 10.0 mmol ) and ethyl 4 -chloroacetoacetate (1.65 g, 10.0 mmol) in dry THF (20 mL) to give 4d (2.04 g, 78%) as a white solid after chromatographic purification on silica gel (gradient EtOAc/hexane: 30-40%) and recrystallization from EtOAc/hexane. mp 95.5°-97.2° C.; IR (KBr) 3112, 1727, 1278 cm-1 ; 1H NMR (DMSO-d6) δ1.15 (3H, t, J=7.0 Hz, CH3), 3.81 (2H, s, CH2), 4.07 (2H, g, J=7.0 Hz, CH2), 6.81 (1H, d, J=7.3 Hz, Ar), 7.22-7.30 (3H, m, Ar), 7.46 (1H, s), 9.68 (1H, s, OH); FDMS m/z 263 (M+); Anal. Calcd for C13H13NO3S: C, 59.30; H, 4.98; N, 5.32. Found: C, 59.41; H, 4.91; N, 5.30.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][CH:24]=[CH:23][C:3]=1[CH2:4][C:5]1[O:6][C:7]2[C:13]([CH2:14][CH2:15][CH2:16][O:17]S(C)(=O)=O)=[CH:12][C:11]([Cl:22])=[CH:10][C:8]=2[N:9]=1.[CH3:27][O-].[Na+].CO.[Na]>O>[Cl:1][C:2]1[CH:26]=[CH:25][CH:24]=[CH:23][C:3]=1[CH2:4][C:5]1[O:6][C:7]2[C:13]([CH2:14][CH2:15][CH2:16][O:17][CH3:27])=[CH:12][C:11]([Cl:22])=[CH:10][C:8]=2[N:9]=1
Reactant: C[O-]
Reactant: CS(=O)(=O)OCCCc1cc(Cl)cc2nc(Cc3ccccc3Cl)oc12
Agent: [Na+]
Agent: [Na]
Solvent: CO
Solvent: O
Product: COCCCc1cc(Cl)cc2nc(Cc3ccccc3Cl)oc12

Procedure:
2-(2-Chlorobenzyl)-5-chloro-7-(3-methanesulfonyloxy-1-propyl)-benzoxazole was stirred overnight with a solution of sodium methoxide prepared from methanol (100 ml) and sodium (2.7 g, 0.118 mol). The reaction mixture was diluted with water and extracted with dichloromethane. The dichloromethane solution was washed with water and evaporated to give the crude product (10 g). The crude product was purified over flash chromatography silica gel and eluted with 30% dichloromethane/hexane. The effluent was collected in 200 ml fractions. Fractions 1-7 contained an impurity (7.1 g); fractions 8-11 were collected (1.8 g) and recrystallized three times from hexane to give the title compound (0.4 g), mp 49-51°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:14]([O-])=O)[C:5]([O:12][CH3:13])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[Cl-].[NH4+].O>CO.[Fe]>[NH2:14][C:4]1[C:5]([O:12][CH3:13])=[C:6]([CH:11]=[C:2]([Cl:1])[CH:3]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cc(Cl)cc([N+](=O)[O-])c1OC
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Product: COC(=O)c1cc(Cl)cc(N)c1OC
Temperature: 70 °C
Yield: 83.9 %

Procedure:
To a solution of methyl 5-chloro-2-methoxy-3-nitrobenzoate (1.21 g, 4.93 mmol) in methanol (50 ml) at room temperature was added ammonium chloride (2.59 g, 49.2 mmol) followed by deionized water (25 ml). The mixture was heated to 70° C. before the addition of iron (1.65 g, 29.6 mmol). The reaction turned to a dark color over the 2 hours it was stirred at 70° C. This mixture was allowed to cool to room temperature and was filtered through Kieselgel. The filter pad was washed with MeOH (50 ml) and the filtrate concentrated under reduced pressure. The residue was dissolved in deionized water (25 ml) and EtOAc (25 ml). The phases were separated and the aqueous phase was extracted with EtOAc (2×25 ml). The combined organic extracts were washed with brine (25 ml), dried over MgSO4, filtered and concentrated under reduced pressure to give 892 mg (67%) of the title compound as a viscous brown oil. This material was used without further purification. LC-MS 89%, 1.75 min (3 minute LC-MS method), m/z=216.3/218.0, 1H NMR (500 MHz, Chloroform-d) δ ppm 7.16 (1H, d, J=2.52 Hz), 6.87 (1H, d, J=2.52 Hz), 4.03 (2H, br. s.), 3.89-3.94 (3H, m), 3.84 (3H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[N+:17]([O-:19])=[O:18])[CH2:5]P(=O)(OCC)OCC.O=[C:21]1[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]1.O1CCCC1.[H-].[Na+]>O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[N+:17]([O-:19])=[O:18])[CH:5]=[C:21]1[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: CCOP(=O)(Cc1ccc([N+](=O)[O-])c(Cl)c1)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(=Cc2ccc([N+](=O)[O-])c(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
Diethyl 3-chloro-4-nitrobenzylphosphonate (2.80 mmol, 0.86 g), tert-butyl 4-oxopiperidine-1-carboxylate (2.80 mmol, 0.557 g) and tetrahydrofuran (4.89 mL) were stirred and sodium hydride (4.19 mmol, 0.168 g) was added. The reaction was stirred overnight at room temperature. Water was added and the reaction extracted with dichloromethane. The organic phase was dried over sodium sulfate and concentrated under vacuum to afford the intermediate tert-butyl 4-(3-chloro-4-nitrobenzylidene)-piperidine-1-carboxylate (0.85 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:12][O:11][C:10]3[CH:13]=[CH:14][C:15]([Cl:17])=[CH:16][C:9]=3[NH:8][CH2:7][C:6]=2[CH:18]=1.[C:19](OC(=O)C)(=[O:21])[CH3:20].N1C=CC=CC=1>CN(C1C=CN=CC=1)C.C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:12][O:11][C:10]3[CH:13]=[CH:14][C:15]([Cl:17])=[CH:16][C:9]=3[N:8]([C:19](=[O:21])[CH3:20])[CH2:7][C:6]=2[CH:18]=1
Reactant: CC(=O)OC(C)=O
Reactant: Clc1ccc2c(c1)NCc1cc(Br)ccc1CO2
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CC(=O)N1Cc2cc(Br)ccc2COc2ccc(Cl)cc21
Temperature: 70 °C
Yield: 96 %

Procedure:
To a stirred solution of 9-Bromo-2-chloro-11,12-dihydro-6H-5-oxa-12-aza-dibenzo[a,e]cyclooctene Example 347E (3.8 mg, 11.7 umol) and DMAP (cat. amount) in toluene (0.3 mL) was added acetic anhydride (0.10 mL, 1.05 mmol) and pyridine (0.05 mL, 46.9 umol). This reaction mixture was heated at 70° C. for 30 minutes, cooled to room temperature and concentrated in vacuo. This was purified by a ISCO auto CombiFlash with a RediSep 4 g column, eluted with Hexane-CH2Cl2, detected at 220 nM to give 4.1 mg of 1-(9-Bromo-2-chloro-6,11-dihydro-5-oxa-12-aza-dibenzo[a,e]cycloocten-12-yl)-ethanone Example 347E in 96% yield. HPLC Rt=3.56 min (YMC S5 ODS column 4.6×50 mm, 10-90% aqueous methanol over 4 minutes containing 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm) LC/MS: M+H=366.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]([CH:14]=[O:15])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[B:18](OC)([O:21]C)[O:19]C.CC1C=C(C2C=CC(C(F)(F)F)=CC=2)SC=1C=O>>[CH:14]([C:12]1[S:13][C:9]([C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:16])([F:1])[F:17])=[CH:8][CH:7]=2)=[CH:10][C:11]=1[B:18]([OH:21])[OH:19])=[O:15]
Reactant: O=Cc1ccc(-c2ccc(C(F)(F)F)cc2)s1
Reactant: COB(OC)OC
Agent: Cc1cc(-c2ccc(C(F)(F)F)cc2)sc1C=O
Product: O=Cc1sc(-c2ccc(C(F)(F)F)cc2)cc1B(O)O

Procedure:
The titled compound is prepared from 5-(4-Trifluoromethyl-phenyl)-thiophene-2-carbaldehyde (2.70 g, 10 mmole) and trimethyl borate (5.68 g, 50.0 mmole) in a similar manner to 3-Methyl-5-(4-trifluoromethyl-phenyl)-thiophene-2-carbaldehyde.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[CH:13]=[N:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1.C(=O)([O-])[O-].[K+].[K+].[N+:20]([C:23]1[CH:33]=[CH:32][C:26]([O:27][CH2:28][CH2:29][CH2:30]I)=[CH:25][CH:24]=1)([O-:22])=[O:21]>C(#N)C.C(O)C>[N+:20]([C:23]1[CH:33]=[CH:32][C:26]([O:27][CH2:28][CH2:29][CH2:30][N:2]([CH2:3][C:4]2[CH:13]=[N:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=2)[CH3:1])=[CH:25][CH:24]=1)([O-:22])=[O:21]
Reactant: O=[N+]([O-])c1ccc(OCCCI)cc1
Reactant: CNCc1cnc2ccccc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: CC#N
Product: CN(CCCOc1ccc([N+](=O)[O-])cc1)Cc1cnc2ccccc2n1
Temperature: 85 °C
Yield: 83.1 %

Procedure:
To a stirred suspension of 2-(methylaminomethyl)quinoxaline (1.10 g, 6.35 mmol) and potassium carbonate (0.88 g, 6.35 mmol) in 2:1 acetonitrile/ethanol (40 mL) was added 1-(4-nitrophenoxy)-3-iodopropane (1.95 g, 6.35 mmol). The resulting mixture was heated at 85° C. overnight, concentrated, and partitioned between ethyl acetate and 10% aqueous potassium carbonate. The organic phase was dried (MgSO4), decolorized (charcoal), and concentrated to afford 1.86 g (83%) of product as a yellow semi-solid which was of sufficient purity to use in the next step.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[O:9][CH3:10].C([Li])CCC.[CH2:16]1[O:18][CH2:17]1>O1CCCC1.CCCCCC>[OH:18][CH2:17][CH2:16][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[C:4]=1[O:9][CH3:10]
Reactant: C1CO1
Reactant: COc1ccccc1OC
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1cccc(CCO)c1OC
Reaction time: 17 h
Yield: 18.9 %

Procedure:
To 20 g (0.145 mol) of 1,2-dimethoxybenzene in 300 mL of anhydrous tetrahydrofuran stirred at room temperature under argon was added 90 mL (0.145 mol) of 1.6M butyl lithium in hexane over 30 minutes. The reaction mixture was stirred and heated at 40° for 4 hours and then cooled in an ice bath. Ethylene oxide (14 mL, 0.29 mol) was allowed to distill into the ice cooled reaction mixture over 45 minutes. The reaction mixture was stirred with ice bath cooling for 1.5 hours and then at room temperature for 17 hours. Most of the solvent was removed under reduced pressure and water was added to the residue. The product was extracted with ether and the dried extract was concentrated under reduced pressure to an oil. The remaining 1,2-dimethoxybenzene (7.5 g) was removed by distillation (bp 45°-60°/0.2 mm) and the residue was purified by HPLC using 20% ethylacetate-toluene to give 5 g (19% yield) of 1-(2-hydroxyethyl)-2,3-dimethoxybenzene. This intermediate (5 g, 0.028 mol) was dissolved in 100 mL of anhydrous methylene chloride and the solution was cooled in an ice bath. Triethylamine (7.7 mL, 0.056 mol) was added and followed by 2.6 mL (0.033 mol) of methane sulfonyl chloride added dropwise. The reaction mixture was stirred with ice bath cooling for two hours and then was washed with water, with sodium bicarbonate solution, dried and concentrated under reduced pressure to give (7.2 g) of 1-[(2-methanesulfonyloxy)ethyl]-2,3-dimethoxybenzene as an oil which was used without purification.
Reaction SMILES: [C:1]1([NH:7][C:8]2[S:9][CH:10]=[C:11]([CH2:13][CH2:14][NH2:15])[N:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:16](O)(=O)C.C=O>CO>[C:1]1([NH:7][C:8]2[S:9][C:10]3[CH2:16][NH:15][CH2:14][CH2:13][C:11]=3[N:12]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(=O)O
Reactant: NCCc1csc(Nc2ccccc2)n1
Agent: C=O
Solvent: CO
Product: c1ccc(Nc2nc3c(s2)CNCC3)cc1
Reaction time: 0.33 h
Yield: 382.9 %

Procedure:
A solution of 2-phenylamino-4-(2-aminoethyl)-thiazole (0.30 g, 1.37 mmol) in methanol (15 ml) was treated with acetic acid (0.02 ml, 0.35 mmol) and formaldehyde (0.11 ml of a 37% aqueous solution, 1.37 mmol). After 20 minutes, the reaction mixture was concentrated in vacuo and the residue dissolved in ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate, water, and saturated aqueous sodium chloride, dried over sodium sulfate, and concentrated in vacuo to provide a glassy solid (0.31 g, 1.34 mmol, 98% yield) which was used without further purification.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[CH:6]=1)=O.[NH2:12][C:13]([CH:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1)=[S:14].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[F:11][C:7]1[CH:6]=[C:5]([C:3]2[N:12]=[C:13]([CH:15]3[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]3)[S:14][CH:2]=2)[CH:10]=[CH:9][CH:8]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(N)=S)CC1
Reactant: O=C(CBr)c1cccc(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(c2nc(-c3cccc(F)c3)cs2)CC1
Yield: 97.5 %

Procedure:
A solution of 2-bromo-1-(3-fluorophenyl)ethanone (1.95 g, 8.98 mmol), tert-butyl 4-(aminocarbonothioyl)piperidine-1-carboxylate (2.00 g, 8.18 mmol) and potassium carbonate (2.26 g, 16.4 mmol) in dimethylformamide (60 ml) was stirred at 110° C. for 1.5 hours. Water was poured into the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to give the desired product (2.89 g, 97.0%) as an oil.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:5]=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=1)=[O:3].[CH3:11][O:12][C:13]1[CH:20]=[C:19]([OH:21])[C:18]([C:22]([CH3:26])([CH3:25])[CH:23]=[CH2:24])=[CH:17][C:14]=1[CH:15]=O.Cl.O>C(O)C>[CH3:26][C:22]([C:18]1[CH:17]=[C:14](/[CH:15]=[CH:1]/[C:2]([C:4]2[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=2)=[O:3])[C:13]([O:12][CH3:11])=[CH:20][C:19]=1[OH:21])([CH:23]=[CH2:24])[CH3:25]
Reactant: CC(=O)c1ccc(O)cc1
Reactant: C=CC(C)(C)c1cc(C=O)c(OC)cc1O
Agent: Cl
Solvent: O
Solvent: CCO
Product: C=CC(C)(C)c1cc(/C=C/C(=O)c2ccc(O)cc2)c(OC)cc1O
Reaction time: 2 h
Yield: 35.2 %

Procedure:
A solution of 150 mg (1.1 mmol) of 4-hydroxyacetophenone and 220 mg (1.0 mmol) of 2-methoxy-4-hydroxy-5-(1,1-dimethylprop-2-enyl)benzaldehyde in 3 ml of ethanol was left on an ice bath, and 1.1 ml of ethanol saturated with dry hydrogen chloride was added. The solution was left for 2 hours and poured into 10 ml of water. The mixture was concentrated in vacuo and extracted with two 10 ml portions of ethyl acetate, and the extract was dried and concentrated in vacuo to give 281 mg of an oil from which 119 mg of licochalcone A was isolated by column chromatography over silica gel 60 (Merck 0.063-0.200 mm, 23 g) using petroleum ether-ethyl acetate (1:1, 1000 ml) as an eluent.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[Br:7][C:8]1[C:14]([O:15][CH2:16][CH3:17])=[CH:13][C:11]([NH2:12])=[C:10]([F:18])[CH:9]=1.N1C=CC=CC=1>C(Cl)Cl>[Br:7][C:8]1[C:14]([O:15][CH2:16][CH3:17])=[CH:13][C:11]([NH:12][C:2](=[O:3])[O:4][CH2:5][CH3:6])=[C:10]([F:18])[CH:9]=1
Reactant: CCOC(=O)Cl
Reactant: CCOc1cc(N)c(F)cc1Br
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)Nc1cc(OCC)c(Br)cc1F
Temperature: 10 °C
Reaction time: 3 h
Yield: 96.3 %

Procedure:
Ethyl chloroformate (2.15 g) was added dropwise to a solution of 4-bromo-5-ethoxy-2-fluoroaniline (4.21 g) and pyridine (2.84 g) in methylene chloride (36 ml) at 0° C., and the mixture was stirred at 10° C. for 3 hours. After the reaction, this was extracted with methylene chloride, then washed with diluted hydrochloric acid and an aqueous sodium hydrogencarbonate solution, and dried over anhydrous magnesium sulfate. Then, methylene chloride was distilled off, and the resulting crude crystals were crystallized from a mixed solvent of ethyl acetate and n-hexane (1:5 v/v) to obtain the objective ethyl N-(4-bromo-5-ethoxy-2-fluorophenyl)carbamate (5.30 g).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3](=O)[CH2:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)=O.[NH2:16][C:17]1[NH:21][N:20]=[C:19]([C:22]([OH:24])=[O:23])[CH:18]=1>C(O)(=O)C>[N:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[C:5]1[CH:4]=[C:3]([C:2]([F:15])([F:14])[F:1])[N:21]2[N:20]=[C:19]([C:22]([OH:24])=[O:23])[CH:18]=[C:17]2[N:16]=1
Reactant: Nc1cc(C(=O)O)n[nH]1
Reactant: O=C(CC(=O)C(F)(F)F)c1ccccn1
Solvent: CC(=O)O
Product: O=C(O)c1cc2nc(-c3ccccn3)cc(C(F)(F)F)n2n1
Yield: 71.5 %

Procedure:
4,4,4-Trifluoro-1-pyridin-2-yl-butane-1,3-dione (3.00g, 13.8 mmol) and 5-amino-1H-pyrazole-3-carboxylic acid (1.76 g, 13.8 mmol) in acetic acid (100 ml) was heated at reflux overnight. The reaction mixture was concentrated under reduced pressure and the crude product was purified by column chromatography on silica gel to give 5-pyridin-2-yl-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid (3.04 g, 71%).
Reaction SMILES: [CH:1]([N:4]([CH:9]([CH3:11])[CH3:10])[C:5](=[O:8])[O:6][CH3:7])([CH3:3])[CH3:2].CN(CCN(C)C)C.[Li]C(CC)C.[CH:25](=[O:29])[CH:26]([CH3:28])[CH3:27].Cl>C1COCC1.CCOCC>[CH:9]([N:4]([CH:1]([CH3:3])[CH3:2])[C:5](=[O:8])[O:6][CH2:7][CH:25]([OH:29])[CH:26]([CH3:28])[CH3:27])([CH3:11])[CH3:10]
Reactant: COC(=O)N(C(C)C)C(C)C
Reactant: CC(C)C=O
Agent: CN(C)CCN(C)C
Agent: Cl
Agent: [Li]C(C)CC
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)C(O)COC(=O)N(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
478 mg (3 mmol) of methyl N,N-diisopropylcarbamate are lithiated with 392 mg (3.3 mmol) of TMEDA in 4 ml of THF at -78° C. using 3.3 mmol of sec-BuLi. After 1 h, the reaction mixture is treated with 144 mg (2 mmol) of isobutyraldehyde and stirred for 21 h. The reaction mixture is then treated at -78° C. with 10 ml of 2N hydrochloric acid and 10 ml of ether and the mixture is warmed to room temperature. The phases are separated, the aqueous phase is extracted twice with ether and the combined organic phases are neutralized with saturated NaHCO3 solution. After drying over magnesium sulphate, the solvent is stripped off and the crude product of 500 mg weight is purified by chromatography on silica gel using ether/petroleum ether (1:3). 299 mg (64.6% of theory) of the title compound are obtained as a colorless liquid.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][N:13]=2)=[CH:7][CH:6]=1)=[O:3].[N:22]1[CH:27]=[CH:26][N:25]=[CH:24][C:23]=1[N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1.[K+].[Br-]>>[F:19][C:18]([F:21])([F:20])[C:15]1[CH:16]=[CH:17][C:12]([O:11][C:8]2[CH:9]=[CH:10][C:5]([O:4][C:2]([N:31]3[CH2:32][CH2:33][N:28]([C:23]4[CH:24]=[N:25][CH:26]=[CH:27][N:22]=4)[CH2:29][CH2:30]3)=[O:3])=[CH:6][CH:7]=2)=[N:13][CH:14]=1
Reactant: c1cnc(N2CCNCC2)cn1
Reactant: O=C(Cl)Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Agent: [Br-]
Agent: [K+]
Product: O=C(Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1)N1CCN(c2cnccn2)CC1

Procedure:
The title compound was prepared from 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl chloroformate and 1-(pyrazin-2-yl)-piperazine White crystals, m.p. 160-161° C.; HPLC-MS: m/z=446 (M+1) at Rt=4.0 min.; 1H NMR (DMSO-d6): δ 8.60-8.57 (m, 1H), 8.39-8.36 (m, 1H), 8.27-8.22 (dd-like, 1H), 8.14-8.11 (m, 1H) 7.91-7.87 (d-like, 1H), 7.29-7.21 (m, 5H), 3.80-3.64 (br, 6H), 3.64-3.50 (br, 2H); IR (KBr): ν 1737, 1714 (C═O) cm−1.
Reaction SMILES: Br[CH2:2][C:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[S:5][C:4]=1[C:18](OC)=[O:19].[CH3:22][C:23]1[CH:28]=[CH:27][C:26]([CH3:29])=[C:25]([CH3:30])[C:24]=1[OH:31]>>[F:17][C:14]([F:15])([F:16])[C:11]1[CH:10]=[CH:9][C:8]([C:6]2[S:5][C:4]([CH2:18][OH:19])=[C:3]([CH2:2][O:31][C:24]3[C:23]([CH3:22])=[CH:28][CH:27]=[C:26]([CH3:29])[C:25]=3[CH3:30])[CH:7]=2)=[CH:13][CH:12]=1
Reactant: COC(=O)c1sc(-c2ccc(C(F)(F)F)cc2)cc1CBr
Reactant: Cc1ccc(C)c(O)c1C
Product: Cc1ccc(C)c(OCc2cc(-c3ccc(C(F)(F)F)cc3)sc2CO)c1C

Procedure:
The title compound was prepared using methyl 3-(bromomethyl)-5-[4-(trifluoromethyl)phenyl]thiophene-2-carboxylate (intermediate 132) and 2,5,6-trimethylphenol.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[C:6]([N+:11]([O-:13])=[O:12])[C:5]=1[CH3:14].[Br:16]N1C(=O)CCC1=O.C1(=O)NC(=O)CC1>C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[C:6]([N+:11]([O-:13])=[O:12])[C:5]=1[CH2:14][Br:16]
Reactant: COC(=O)c1cc(F)cc([N+](=O)[O-])c1C
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: O=C1CCC(=O)N1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1cc(F)cc([N+](=O)[O-])c1CBr
Yield: 76.1 %

Procedure:
2.37 g (11.12 mmol) of 5-fluoro-2-methyl-3-nitrobenzoic acid methyl ester is added into 35 ml of carbon tetrachloride, and mixed with 2.24 g (12.24 mmol) of N-bromosuccinimide and 5.4 mg of benzoyl peroxide. After four days of refluxing, and after cooling, the succinimide is suctioned off (glass-fiber filter), and then the filtrate is spun in to the dry state. Chromatography on a Flashmaster yields 2.47 g (75.9%) of the desired compound.
Reaction SMILES: O1CCCC1.[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[S:22])[CH2:15][CH2:16][CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])=[CH:9][CH:8]=1.II.C1(C2CCCCCCCCCC=2)CCCCCCCCNN=1>O>[Cl:6][C:7]1[CH:8]=[CH:9][C:10]([N:13]=[C:14]2[CH2:15][CH2:16][CH2:17][C:18](=[C:19]([CH3:20])[CH3:21])[S:22]2)=[CH:11][CH:12]=1
Reactant: CC(C)=CCCCC(=S)Nc1ccc(Cl)cc1
Agent: C1=C(C2=NNCCCCCCCC2)CCCCCCCCC1
Agent: II
Solvent: C1CCOC1
Solvent: O
Product: CC(C)=C1CCCC(=Nc2ccc(Cl)cc2)S1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.4 %

Procedure:
In a tetrahydrofuran (40 ml) solution of 6-methyl-5-heptenethioic acid (4-chloro-phenyl)-amide (2.0 g), a tetrahydrofuran (15 ml) solution of iodine (2.3 g) was added dropwise at 0° C. The temperature was raised to room temperature, followed by stirring overnight. After cooling to 0° C., a tetrahydrofuran (5 ml) solution of diazabicycloundecene (2.9 g) was added dropwise. After raising the temperature to room temperature and further stirring for 1 hour, water was added and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with a saturated saline solution, dried over anhydrous magnesium sulfate, filtered and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 1.1 g of the target compound.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]3[CH2:18][O:17][CH2:16][C@H:15]([CH3:19])[N:14]3[C:10]=2[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([OH:20])[CH:8]=2)[N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:27](Br)[C:28]#[CH:29].O>CN(C=O)C>[CH3:19][C@@H:15]1[N:14]2[C:10]3[C:9]4[C:4](=[CH:5][CH:6]=[C:7]([O:20][CH2:29][C:28]#[CH:27])[CH:8]=4)[N:3]=[C:2]([NH2:1])[C:11]=3[N:12]=[C:13]2[CH2:18][O:17][CH2:16]1
Reactant: C#CCBr
Reactant: C[C@H]1COCc2nc3c(N)nc4ccc(O)cc4c3n21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: C#CCOc1ccc2nc(N)c3nc4n(c3c2c1)[C@@H](C)COC4
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.7 %

Procedure:
A solution of (11S)-6-amino-11-methyl-10,11-dihydro-8H-[1,4]oxazino[4′,3′:1,2]imidazo[4,5-c]quinolin-2-ol (100 mg, 0.370 mmol) dissolved in 15 mL of DMF was treated with cesium carbonate (241 mg, 0.740 mmol) and propargyl bromide (49 mg, 0.410 mmol) and stirred overnight at ambient temperature. The dark brown mixture was then poured into 150 mL of H2O and stirred for 30 minutes. The mixture was filtered to give a dark brown solid. Chromatography (SiO2, 0-30% CMA/CHCl3) followed by crystallization from ethyl acetate gave 51 mg of the title compound as an off-white solid, mp 184-186° C.