Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8](F)[CH:7]=[CH:6][C:5]=1[C:11]([F:14])([F:13])[F:12].Cl.[CH3:17][NH:18][CH3:19].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([N:18]([CH3:19])[CH3:17])[CH:7]=[CH:6][C:5]=1[C:11]([F:14])([F:13])[F:12]
Reactant: CNC
Reactant: COC(=O)c1cc(F)ccc1C(F)(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COC(=O)c1cc(N(C)C)ccc1C(F)(F)F
Temperature: 60 °C
Reaction time: 8 h
Yield: 72 %

Procedure:
To a stirred solution of 4.48 g (22.5 mmol) 5-Fluoro-2-trifluoromethyl-benzoic acid methyl ester (Rarechem) and 60.0 ml dimethylsulphoxid were added 2.23 g (27.0 mmol) dimethylamine hydrochloride and 6.54 g (47.3 mmol) potassium carbonate. The reaction mixture was stirred for 8 h at 60° C. in an autoclave and was reduced with high vacuum rotation evaporator at 65° C. The residue was diluted with dichloromethane, washed twice with water. The combined water phases were extracted with dichloromethane. The combined dichloromethane phases were washed with diluted sodium hydrogen carbonate solution, dried with sodium sulphate and concentrated. The oily crude was purified by column chromatography and the desired product 15a was obtained in 72% yield (4.00 g, 16.2 mmol).
Reaction SMILES: [O-:1][C:2]#[N:3].[K+].[CH2:5]([NH:9][CH2:10][C:11]([O:13]CC)=O)[CH2:6][CH2:7][CH3:8]>Cl>[CH2:5]([N:9]1[CH2:10][C:11](=[O:13])[NH:3][C:2]1=[O:1])[CH2:6][CH2:7][CH3:8]
Reactant: CCCCNCC(=O)OCC
Reactant: N#C[O-]
Agent: Cl
Agent: [K+]
Product: CCCCN1CC(=O)NC1=O
Temperature: 50 °C
Reaction time: 0.17 h
Yield: 68 %

Procedure:
A quantity of 24.4 g (0.30 mole) of potassium cyanate is added portionwise, at room temperature, to a stirred solution of 31.80 g (0.20 mole) of ethyl N-butylglycinate in 220 mL (0.22 mole) of 1 N hydrochloric acid. The solution is warmed to ca. 90° C. (at ca. 50° C. an oil separates). After 10 minutes at 90° C., concentrated hydrochloric acid (250 mL) is cautiously added over 2 minutes and the resulting solution is heated at 90°100° C. for 1/2 hour. The solution is concentrated at reduced pressure to dryness. The last amounts of water are chased by addition and removal of 3×100 mL of absolute ethanol. The residue is extracted with 400 mL 50% ethanol-methylene chloride. The inorganics are filtered and the filtrate is concentrated to dryness. Trituration of the residue with 100 mL of water and filtration gives pure 1-butylhydantoin in 68% yield; mp 90°92° C.; MS (EI) 156.1 (M+).
Reaction SMILES: [C:1]([NH:8][CH:9]1[CH2:13][CH2:12][NH:11][CH2:10]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(=O)(O)[O-].[Na+].[C:19](Cl)(=[O:30])[O:20][CH2:21][C:22]1[CH:27]=[C:26]([Cl:28])[CH:25]=[C:24]([Cl:29])[CH:23]=1>C(Cl)Cl>[C:4]([O:3][C:1]([NH:8][CH:9]1[CH2:13][CH2:12][N:11]([C:19]([O:20][CH2:21][C:22]2[CH:23]=[C:24]([Cl:29])[CH:25]=[C:26]([Cl:28])[CH:27]=2)=[O:30])[CH2:10]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: O=C(Cl)OCc1cc(Cl)cc(Cl)c1
Reactant: CC(C)(C)OC(=O)NC1CCNC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1CCN(C(=O)OCc2cc(Cl)cc(Cl)c2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture comprising of 3-(boc-amino)pyrrolidine (1 g, 5.37 mmol) and saturated sodium bicarbonate (9 mL, 5.37 mmol) in DCM (17.90 mL) was stirred at room temperature for 5 minutes. The resulting mixture was treated with 3,5-dichlorobenzyl carbonochloridate (1.286 g, 5.37 mmol) and stirred at room temperature for one hour. The reaction mixture was concentrated under reduced pressure, diluted with water and extracted with DCM. The organic portion was separated and dried over MgSO4, filtered and concentrated under reduced pressure to afford the title compound;
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][N:13]3[CH2:18][CH2:17][NH:16][CH:15]([CH2:19][CH3:20])[C:14]3=[O:21])=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.[Cl:22][C:23]1[S:27][C:26]([CH2:28][CH2:29][CH:30]=O)=[CH:25][CH:24]=1>>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][N:13]3[CH2:18][CH2:17][N:16]([CH:29]([CH2:28][C:26]4[S:27][C:23]([Cl:22])=[CH:24][CH:25]=4)[CH3:30])[C@@H:15]([CH2:19][CH3:20])[C:14]3=[O:21])=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: O=CCCc1ccc(Cl)s1
Reactant: CCC1NCCN(Cc2ccc3c(N)ncnc3c2)C1=O
Product: CC[C@H]1C(=O)N(Cc2ccc3c(N)ncnc3c2)CCN1C(C)Cc1ccc(Cl)s1

Procedure:
The title compound is prepared as described in EXAMPLE 278 using 1-(4-aminoquinazoline-7-ylmethyl)-3-ethyl-piperazine-2-one, EXAMPLE 77 and 3-(5-chloro-thiophen-2-yl)-propionaldehyde, EXAMPLE 28. 1H NMR (d6-DMSO+1 drop TFA, 300 MHz) δ9.80 (bs, 2H), 8.79 (s, 1H), 8.32 (d, 1H), 7.58 (m, 2H), 6.88 (d, 1H), 6.70 (d, 1H), 4.72 (AB, 2H), 4.00 (m, 1H), 3.72 (m, 1H), 3.48 (m, 2H), 3.23 (m, 3H), 2.72 (m, 2H), 1.96 (m, 4H), 0.98 (m, 3H). MS (ion spray), m/z, (M+H)=444, 446 (Cl pattern).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)O)=[CH:4][CH:3]=1.[Cl-].[In+3].[Cl-].[Cl-].ClC1C=C(Cl)C=CC=1C([C:33]1[C:41]2[C:36](=[C:37]([CH2:43][S:44][CH3:45])[CH:38]=[C:39](F)[CH:40]=2)[NH:35][CH:34]=1)CCO.O>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[C:33]2[C:41]3[C:36](=[C:37]([CH2:43][S:44][CH3:45])[CH:38]=[CH:39][CH:40]=3)[NH:35][CH:34]=2)=[CH:4][CH:3]=1
Reactant: CSCc1cc(F)cc2c(C(CCO)c3ccc(Cl)cc3Cl)c[nH]c12
Reactant: OC(c1ccc(F)cc1)c1ccc(Cl)cc1
Agent: [Cl-]
Agent: [In+3]
Solvent: CCOC(C)=O
Solvent: O
Solvent: Cc1ccccc1
Product: CSCc1cccc2c(C(c3ccc(F)cc3)c3ccc(Cl)cc3)c[nH]c12
Temperature: 80 °C
Reaction time: 3 h

Procedure:
2.94 g (12.41 mmol) of the compound from Example 81A and 2.50 g (11.28 mmol) of indium(III) chloride were added to 2.00 g (11.28 mmol) of the compound from Example 8 in 100 ml of toluene. The reaction mixture was stirred at 80° C. for 3 h. After cooling to RT, the reaction solution was mixed with water and ethyl acetate and the solid was filtered off. The phases of the filtrate were separated, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and concentrated. Purification of the crude product by preparative HPLC (mobile phase: acetonitrile/water gradient) resulted in 0.83 g (19% of theory) of the title compound.
Reaction SMILES: [N+](C1C=CC([O:10][C:11](=O)/[CH:12]=[CH:13]/[CH:14]=[C:15]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH3:31])[CH:25]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=2)=CC=1)([O-])=O.[CH3:33][C:34]([CH3:45])([NH2:44])[CH2:35][CH2:36][CH2:37][C:38]1[CH:39]=[N:40][CH:41]=[CH:42][CH:43]=1>O1CCCC1>[CH3:23][O:22][C:18]1[CH:17]=[C:16]([C:15]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH3:31])[CH:25]=2)=[CH:14]/[CH:13]=[CH:12]/[C:11]([NH:44][C:34]([CH3:45])([CH3:33])[CH2:35][CH2:36][CH2:37][C:38]2[CH:39]=[N:40][CH:41]=[CH:42][CH:43]=2)=[O:10])[CH:21]=[CH:20][CH:19]=1
Reactant: CC(C)(N)CCCc1cccnc1
Reactant: COc1cccc(C(=C/C=C/C(=O)Oc2ccc([N+](=O)[O-])cc2)c2cccc(OC)c2)c1
Solvent: C1CCOC1
Product: COc1cccc(C(=C/C=C/C(=O)NC(C)(C)CCCc2cccnc2)c2cccc(OC)c2)c1

Procedure:
As in Example 134, a solution of (E)-5,5-bis(3-methoxyphenyl)-2,4-pentadienoic acid 4-nitrophenyl ester 1.73 and alpha,alpha-dimethyl-3-pyridinebutanamine (0.9 mL) in tetrahydrofuran (20 mL) was stirred for 30 hours at reflux and, after the usual work up, the product was crystallized from ethyl acetate-hexane to afford 1.6 g of (E)-5,5-bis(3-methoxyphenyl)-N-[1,1-dimethyl-4-(3-pyridinyl)butyl]-2,4-pentadienamide mp 120°-121° C.
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[O:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1.[B:17](OC)([O:20]C)[O:18]C.C(=O)([O-])[O-].[K+].[K+]>C1COCC1.O>[F:9][C:7]1[CH:6]=[CH:5][C:4]([O:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)=[C:3]([B:17]([OH:20])[OH:18])[CH:8]=1
Reactant: COB(OC)OC
Reactant: Fc1ccc(OC2CCCCO2)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Mg]
Solvent: C1CCOC1
Solvent: O
Product: OB(O)c1cc(F)ccc1OC1CCCCO1
Temperature: 25 °C

Procedure:
48.6 g (2.00 mol) of magnesium and 510 g (1.85 mol) of 2-bromo-4-fluoro-1-(tetrahydropyran-2-yloxy)benzene in 1250 ml of THF were used to prepare a Grignard reagent. This Grignard reagent was slowly added dropwise at −78° C. to a mixture of 241.6 ml (2.00 mol) of trimethyl borate in 500 ml of THF. On completion of addition, the reaction mixture was allowed to warm to room temperature and was hydrolyzed by addition of 100 ml of saturated potassium carbonate solution and 1000 ml of water. The organic phase was washed with saturated sodium chloride, solution. (1×500 ml) and subsequently concentrated to dryness. The yield was 428.2 g (1.78 mol), and the product was obtained as a waxy solid which contained varying proportions of boronic anhydride and borinic acids and was used in the following stage without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[C:5]#[C:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)[CH3:2].[N:14]([CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])=[N+:15]=[N-:16]>C1C=CC=CC=1>[CH2:1]([O:3][C:4]([C:5]1[N:14]([CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[N:15]=[N:16][C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)=[O:13])[CH3:2]
Reactant: C[Si](C)(C)CN=[N+]=[N-]
Reactant: CCOC(=O)C#Cc1ccccn1
Solvent: c1ccccc1
Product: CCOC(=O)c1c(-c2ccccn2)nnn1C[Si](C)(C)C
Yield: 21.9 %

Procedure:
To a solution of pyridin-2-yl-propynoic acid ethyl ester (1.25 g, 7.14 mmol) in benzene (22 mL) was added azidomethyl-trimethyl-silane (1.11 g, 8.56 mmol) and the reaction mixture was refluxed under nitrogen for 72 h. The mixture was then evaporated and purification by chromatography [silica, 0 to 50% ethyl acetate in heptane then HPLC (Chiralpak AD, ethanol in heptane)] afforded the title compound (477 mg, 23%) as a yellow oil. MS: m/e=305.2 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:19])[NH:7][C:8]([C:12](=[O:18])[C:13]([CH3:17])([CH3:16])[CH2:14][CH3:15])=[N:9]2)=[CH:4][CH:3]=1.O[CH2:21][CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C(Cl)Cl>[CH3:15][CH2:14][C:13]([CH3:16])([CH3:17])[C:12]([C:8]1[NH:7][C:6](=[O:19])[C:5]2[C:10](=[CH:11][C:2]([O:1][CH2:21][CH2:22][CH2:23][N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)=[CH:3][CH:4]=2)[N:9]=1)=[O:18]
Reactant: OCCCN1CCOCC1
Reactant: CCC(C)(C)C(=O)c1nc2cc(O)ccc2c(=O)[nH]1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCC(C)(C)C(=O)c1nc2cc(OCCCN3CCOCC3)ccc2c(=O)[nH]1
Temperature: 5 °C
Reaction time: 0.08 h
Yield: 71.2 %

Procedure:
7-hydroxy-3-methylpivaloyl-3,4-dihydroquinazolin-4-one (750mg, 2.7 mmol) was suspended in methylene chloride (40 ml) and 4-(3-hydroxypropyl)morpholine (490 mg, 3.4 mmol) and triphenylphosphine (890 mg, 3.4 mmol) were added at 5° C. The mixture was stirred for 5 minutes at 5° C. and diethyl azodicarboxylate (590 mg, 3.4 mmol) was added over 5 minutes. The reaction mixture was stirred at 5° C. for 30 minutes then at ambient temperature for 1 hour. The reaction mixture was purified directly by column chromatography eluting with methylene chloride, then ethyl acetate, then acetonitrile/ethyl acetate (1/5), and finally acetonitrile/ethyl acetate/aqueous ammonia (50/50/0.5). The purified product was triturated with ether/isohexane and collected by filtration to give 3-methylpivaloyl-7-(3-morpholinopropoxy)-3,4-dihydroquinazolin-4-one (745 mg, 68%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]=[C:4]([C:9]2[S:10][CH:11]=[CH:12][N:13]=2)[CH:3]=1.CC1(C)C(C)(C)OB([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)O1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C1COCC1>CO.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].CCOC(C)=O.O>[Cl:1][C:2]1[CH:7]=[C:6]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)[N:5]=[C:4]([C:9]2[S:10][CH:11]=[CH:12][N:13]=2)[CH:3]=1
Reactant: Clc1cc(Cl)nc(-c2nccs2)c1
Reactant: CC1(C)OB(c2ccc(C(F)(F)F)cc2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: FC(F)(F)c1ccc(-c2cc(Cl)cc(-c3nccs3)n2)cc1
Reaction time: 16 h
Yield: 61.4 %

Procedure:
To a 2 dram vial equipped with a stir bar was added 2-(4,6-dichloropyridin-2-yl)thiazole (50 mg, 0.22 mmol), 4,4,5,5-tetramethyl-2-(4-(trifluoromethyl)phenyl)-1,3,2-dioxaborolane (59 mg, 0.22 mmol), Pd(dppf)Cl2 (8 mg, 11 μmol) and K3PO4 (344 mg, 1.62 mmol). The vial was capped with a septum screwcap and then placed under N2 atmosphere. To the vial was added THF (1 mL) and water (0.5 mL). The mixture was placed in a 60° C. heating block with stirring for 16 h. The reaction mixture was cooled to room temperatured; diluted with MeOH and then concentrated in vacuo. The resulting residue was dissolved/suspended in CH2Cl2 and then filtered through Celite. The filtrate was concentrated to afford a solid orange residue. This material was subjected to silica gel chromatography (hexanes:EtOAc, 100:0 to 95:5) to afford 2-(4-chloro-6-(4-(trifluoromethyl)phenyl)pyridin-2-yl)thiazole as a white solid (46 mg, 62%). 1H-NMR (400 MHz, CDCl3) 8.23 (d, J=1.8 Hz, 2H), 8.21 (s, 1H), 7.98 (d, J=3.3 Hz, 1H), 7.80 (d, J=1.5 Hz, 2H), 7.78 (s, 1H), 7.53 (d, J=3.3 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N+:16]([O-])=O)=[CH:4][C:5]2[C:6](=[O:15])[C:7]3[N:8]([CH2:11][CH2:12][CH2:13][N:14]=3)[C:9]=2[CH:10]=1.O.O.Cl[Sn]Cl.CN(C=O)C>CCOC(C)=O>[NH2:16][C:3]1[C:2]([Cl:1])=[CH:10][C:9]2[N:8]3[CH2:11][CH2:12][CH2:13][N:14]=[C:7]3[C:6](=[O:15])[C:5]=2[CH:4]=1
Reactant: O=C1C2=NCCCN2c2cc(Cl)c([N+](=O)[O-])cc21
Agent: Cl[Sn]Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: Nc1cc2c(cc1Cl)N1CCCN=C1C2=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 16.3 %

Procedure:
To a suspension of finely ground 7-chloro-8-nitro-3,4-dihydropyrimido[1,2-a]indol-10(2H)-one (0.200 g, 0.753 mmol ) in EtOAc (10 mL) was added SnCl2.2H2O and the mixture was heated at reflux for 1.75 hr after which DMF (2 mL) was added and the reaction proceeded quickly. The reaction was cooled to room temperature and quenched with sat. aq. NaHCO3 (25 mL ). EtOAc (25 mL ) was added and the mixture was stirred for 0.5 hr then filtered. The biphasic layers were separated and the aqueous layer was extracted with EtOAc. The combined organic extracts were dried over Na2SO4, filtered, and concentrated. The crude product was purified on Biotage KP silica gel eluting with CH2Cl2/CH3OH/NH4OH (94/4/2) to give the title compound as a black solid (0.029 g, 16% yield). Anal. Calc'd for C11H10ClN3O: C, 56.06% , H, 4.28% ; N, 17.83% . Found: C, 55.81% ; H, 4.17% ; N, 17.54% . NMR (300 Mz, DMSO-d6): consistent. MS: (ES−) 238 [M−H]. m.p.>270° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1([C:12]2[NH:13][C:14]([C:22]3[CH:31]=[CH:30][CH:29]=[C:28]4[C:23]=3[N:24]=[C:25](F)[C:26]([CH3:32])=[N:27]4)=[CH:15][C:16]=2[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:34]1([NH2:37])[CH2:36][CH2:35]1.CCN(C(C)C)C(C)C>CS(C)=O.CCOC(C)=O>[C:1]([O:5][C:6]([NH:8][C:9]1([C:12]2[NH:13][C:14]([C:22]3[CH:31]=[CH:30][CH:29]=[C:28]4[C:23]=3[N:24]=[C:25]([NH:37][CH:34]3[CH2:36][CH2:35]3)[C:26]([CH3:32])=[N:27]4)=[CH:15][C:16]=2[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1cc(-c2cccc3nc(C)c(F)nc23)[nH]c1C1(NC(=O)OC(C)(C)C)CC1
Reactant: NC1CC1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc(-c2cccc3nc(C)c(NC4CC4)nc23)[nH]c1C1(NC(=O)OC(C)(C)C)CC1
Yield: 56.4 %

Procedure:
A solution of ethyl 2-(1-((tert-butoxycarbonyl)amino)cyclopropyl)-5-(3-fluoro-2-methylquinoxalin-5-yl)-1H-pyrrole-3-carboxylate (325b) (218 mg, 0.480 mmol), cyclopropanamine (82 mg, 1.44 mmol) and DIEA (0.17 mL, 0.96 mmol) in 3 mL of DMSO was heated in an oil bath at 80° C. for 5 h. It was diluted with 50 mL of EtOAc, washed with 5 mL of water. The organic solution was concentrated and the residue was stirred in 5 mL of ether. The insoluble yellow solid was filtered, rinsed with 2×2 mL of ether to give 133 mg of ethyl 2-(1-((tert-butoxycarbonyl)amino)cyclopropyl)-5-(3-(cyclopropylamino)-2-methylquinoxalin-5-yl)-1H-pyrrole-3-carboxylate, as a yellow crystalline solid. The filtrate was concentrated and the residue was purified on a silica gel column (25-70% EtOAc in Hexanes) to give 67 mg ethyl 2-(1-((tert-butoxycarbonyl)amino)cyclopropyl)-5-(3-(cyclopropylamino)-2-methylquinoxalin-5-yl)-1H-pyrrole-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.31 (1H, br.), 8.05 (1H, m), 7.61 (1H, dd, J=8.0, 1.2 Hz), 7.42 (1H, d, J=3.5 Hz), 7.35 (1H, t, J=7.8 Hz), 7.26 (1H, br.), 7.02 (2H, br.), 4.28 (2H, q, J=7.0 Hz), 2.56 (3H, s), 1.35 (4H, m), 1.32 (9H, s), 1.03-1.19 (5H, m), 0.63-0.78 (2H, m). m/z (ESI, +ve) 492.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][C:3]=1[NH2:4].[CH3:24][O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[N:32]=[C:33]=[O:34].CO>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][C:3]=1[NH:4][C:33]([NH:32][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[O:25][CH3:24])=[O:34]
Reactant: COc1cc2nccc(Oc3ccc(N)c(Cl)c3)c2cc1OC
Reactant: COc1ccccc1N=C=O
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COc1ccccc1NC(=O)Nc1ccc(Oc2ccnc3cc(OC)c(OC)cc23)cc1Cl
Temperature: 600 °C
Reaction time: 8 h
Yield: 76.5 %

Procedure:
2-Chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline (100 mg) was dissolved in chloroform(10 ml), and 2-methoxyphenyl isocyanate (54 mg) was added to the solution. The mixture was stirred at 600° C. overnight. Methanol was added to the reaction solution, and the solvent was removed by distillation under the reduced pressure. The residue was purified by chromatography on silica gel by development with chloroform/acetone (6/4) to give 111 mg (yield 77%) of the title compound.
Reaction SMILES: [C:1](Cl)(=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[N+:12]([C:15]1[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[CH:17][C:16]=1[OH:24])([O-:14])=[O:13].N1C=CC=CC=1>CC(C)=O>[C:1]([O:24][C:16]1[CH:17]=[CH:18][C:19]([N+:21]([O-:23])=[O:22])=[CH:20][C:15]=1[N+:12]([O-:14])=[O:13])(=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=C(Cl)C=Cc1ccccc1
Reactant: O=[N+]([O-])c1ccc(O)c([N+](=O)[O-])c1
Solvent: CC(C)=O
Solvent: c1ccncc1
Product: O=C(C=Cc1ccccc1)Oc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 20 h
Yield: 71.6 %

Procedure:
66.64 g (0.4 mole) of cinnamoyl chloride and 300 g of methyl ketone (hereinafter referred to as MEK) were placed in a reaction vessel to be stirred by heating at 60° C. under a nitrogen current. 73.64 g (0.4 mole) of 2,4-dinitrophenol, 50 g of pyridine, and 500 g of MEK were added dropwise to the above reaction vessel using a dropping funnel. After that, reflux stirring was conducted for approximately 20 hours under a nitrogen current. After the completion of the reaction, the precipitate was separated by filtration. The filtrate was concentrated until crystals separated out and poured into methanol. 90 g of light yellow colored needle-like crystals (2,4-dinitrophenyl cinnamate) were yielded.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl[C:17]1[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][N:18]=1>COCCOCCOC>[CH3:23][C:21]1[CH:20]=[CH:19][N:18]=[C:17]([N:13]2[CH2:14][CH2:15][N:10]([C:7]3[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=3)[CH2:11][CH2:12]2)[CH:22]=1
Reactant: Cc1ccnc(Cl)c1
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)cc1
Solvent: COCCOCCOC
Product: Cc1ccnc(N2CCN(c3ccc([N+](=O)[O-])cc3)CC2)c1

Procedure:
From 1-(4-nitro-phenyl)-piperazine and 2-chloro-4-methylpyridine, by heating in diglyme to give 1-(4-methyl-pyridin-2-yl)-4-(4-nitro-phenyl)-piperazine then catalytic hydrogenation over Raney nickel in methanol.
Reaction SMILES: [OH:1][C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5](=[O:13])(=[O:12])[N:4]([CH3:14])[C:3]=1[C:15]([O:17]C)=O.[NH2:19][C:20]1[C:21](=[O:28])[CH:22]=[CH:23][C:24]([OH:27])=[CH:25][CH:26]=1>C1(C)C(C)=CC=CC=1>[OH:1][C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5](=[O:12])(=[O:13])[N:4]([CH3:14])[C:3]=1[C:15]([NH:19][C:20]1[C:21](=[O:28])[CH:22]=[CH:23][C:24]([OH:27])=[CH:25][CH:26]=1)=[O:17]
Reactant: Nc1ccc(O)ccc1=O
Reactant: COC(=O)C1=C(O)c2ccccc2S(=O)(=O)N1C
Solvent: Cc1ccccc1C
Product: CN1C(C(=O)Nc2ccc(O)ccc2=O)=C(O)c2ccccc2S1(=O)=O
Temperature: 25 °C
Yield: 44.3 %

Procedure:
A mixture of methyl 4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxylate 1,1-dioxide (0.65 g) and 2-amino-5-hydroxy-2,4,6-cycloheptatrien-1-one (0.40 g) in xylene (12 ml) was refluxed for 48 hours. The reaction mixture was cooled to room temperature. The crystals were collected by filtration and washed successively with methanol, water and methanol to give 4-hydroxy-N-(5-hydroxy-1-oxo-2,4,6-cycloheptatrien-2-yl)-2-methyl-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide (0.4 g).
Reaction SMILES: [CH3:1][C:2]([O:4][C@H:5]1[C:14]2[C@@:15]3([CH3:30])[C@@H:26]([CH2:27][O:28][CH3:29])[O:25][C:23](=[O:24])[C:17]4=[CH:18][O:19][C:20]([C:21](=[O:22])[C:13]=2[C@@H:8]2[CH2:9][CH2:10][C@H:11]([OH:12])[C@@:7]2([CH3:31])[CH2:6]1)=[C:16]34)=[O:3].[CH2:32]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH2:35][CH2:34][NH:33]1>C(Cl)Cl>[C:2]([O:4][C@H:5]1[C:14]2[C@:15]3([CH3:30])[C:16](/[C:17](=[CH:18]\[N:33]4[CH2:34][CH2:35][C:36]5[C:41](=[CH:40][CH:39]=[CH:38][CH:37]=5)[CH2:32]4)/[C:23](=[O:24])[O:25][C@@H:26]3[CH2:27][O:28][CH3:29])=[C:20]([OH:19])[C:21](=[O:22])[C:13]=2[CH:8]2[C@@:7]([CH3:31])([C@@H:11]([OH:12])[CH2:10][CH2:9]2)[CH2:6]1)(=[O:3])[CH3:1]
Reactant: c1ccc2c(c1)CCNC2
Reactant: COC[C@H]1OC(=O)c2coc3c2[C@@]1(C)C1=C(C3=O)[C@@H]2CC[C@H](O)[C@@]2(C)C[C@H]1OC(C)=O
Solvent: ClCCl
Product: COC[C@H]1OC(=O)/C(=C/N2CCc3ccccc3C2)C2=C(O)C(=O)C3=C([C@H](OC(C)=O)C[C@@]4(C)C3CC[C@@H]4O)[C@]21C
Temperature: 25 °C
Reaction time: 8 h
Yield: 13.3 %

Procedure:
To a solution of 50 mg (0.12 mmol) 17-hydroxywortmannin in 0.5 mL CH2Cl2 is added 32 mg (0.24 mmol) 1,2,3,4-tetrahydroisoquinoline. The reaction mixture is stirred at room temperature overnight. CH2Cl2 is removed in vacuo. The residue is triturated with Et2O to give 9 mg (13.3%) product as an orange powder. MS (ESI) m/z 564.25 (M+1).
Reaction SMILES: [C:1](O)(=[O:5])/[CH:2]=[CH:3]/[CH3:4].[S:7]1[CH:11]=[CH:10][CH:9]=[CH:8]1.ClCC(OC(=O)CCl)=O>C1(C)C=CC=CC=1>[C:1]([C:8]1[S:7][CH:11]=[CH:10][CH:9]=1)(=[O:5])/[CH:2]=[CH:3]/[CH3:4]
Reactant: c1ccsc1
Reactant: C/C=C/C(=O)O
Agent: O=C(CCl)OC(=O)CCl
Solvent: Cc1ccccc1
Product: C/C=C/C(=O)c1cccs1
Temperature: 50 °C
Reaction time: 6.5 h
Yield: 56 %

Procedure:
In 50 ml of toluene were dissolved 4.31 g (0.05 mole) of crotonic acid, 5.47 g (0.065 mole) of thiophene and 10.26 g (0.06 mole) of monochloroacetic anhydride. To the resulting solution was added 0.71 g of boron trifluoride-diethyl ether complex and the resulting mixture was stirred at 50° C. for 6.5 hours. After completion of the reaction, the reaction solution was cooled and washed with 5% aqueous sodium carbonate solution and water in this order. The organic layer was concentrated under reduced pressure to obtain 4.26 g of 2-crotonylthiophene.