Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[C:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:16]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:15]=[C:14]1[C:30]1[CH:35]=[CH:34][C:33]([O:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])=[CH:32][CH:31]=1)=[O:5])C.[OH-].[Na+]>>[C:4]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[C:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:16]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:15]=[C:14]1[C:30]1[CH:31]=[CH:32][C:33]([O:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])=[CH:34][CH:35]=1)([OH:5])=[O:3]
Reactant: CCCCCCCCOc1ccc(-c2nc(-c3ccccc3)c(-c3ccccc3)n2CCCCCCCC(=O)OCC)cc1
Agent: [Na+]
Agent: [OH-]
Product: CCCCCCCCOc1ccc(-c2nc(-c3ccccc3)c(-c3ccccc3)n2CCCCCCCC(=O)O)cc1
Yield: 55.8 %

Procedure:
1-(7-Ethoxycarbonylheptyl)-2-[4-octyloxyphenyl]-4,5-diphenylimidazole (3.2 g) was reacted with 2N sodium hydroxide in a method similar to Example 9. Column chromatography on silica gel eluted with a dichloro-methane:methanol gradient and recrystallisation from acetonitrile gave 1-(7-carboxyheptyl)-2-[4-octyloxy-phenyl]-4,5-diphenylimidazole (1.7 g, 58.6%) as a white solid, m.p. 114°-115°. Found: C, 78.61; H, 8.23; N, 4.96%; C37H46N2O3 requires: C, 78.41; H, 8.18; N, 4.94%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][NH:10][C:11]([CH3:16])([CH3:15])[CH2:12][O:13][CH3:14].[OH:17]O.[Na+].[Cl-]>CO>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]=[N+:10]([C:11]([CH3:16])([CH3:15])[CH2:12][O:13][CH3:14])[O-:17]
Reactant: OO
Reactant: COCC(C)(C)NCc1ccc(F)cc1F
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Product: COCC(C)(C)[N+]([O-])=Cc1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 15 h
Yield: 51 %

Procedure:
A solution of N-(2,4-difluorophenylmethyl)-N-[dimethyl(methoxymethyl)methyl]amine obtained in Example 14 (378.8 mg, 1.65 mmol) and Na2WO4 2H2O (84.3 mg, 0.256 mmol) in methanol (5 ml) was cooled to 0° C. in ice-water bath. To the mixture was added dropwise 31% H2O2 aqueous solution (439.3 mg, 4.00 mmol). After addition the mixture was gradually warmed to room temperature and stirred for 15 hours. The mixture was added to sat. NaCl aqueous solution and extracted three times with ethyl acetate and dried over MgSO4. The mixture was concentrated and purified by silica gel chromatography (toluene/ethyl acetate=5/1) to give the title compound (204.8 mg; 51%).
Reaction SMILES: [F:1][CH:2]([F:21])[O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[C:12]3[CH2:20][CH2:19][NH:18][CH2:17][C:13]=3[N:14]=[CH:15][N:16]=2)=[CH:6][CH:5]=1.Cl[C:23]1[C:28]([Cl:29])=[CH:27][CH:26]=[CH:25][N:24]=1.C(N(CC)C(C)C)(C)C>>[Cl:29][C:28]1[C:23]([N:18]2[CH2:19][CH2:20][C:12]3[C:11]([NH:10][C:7]4[CH:8]=[CH:9][C:4]([O:3][CH:2]([F:1])[F:21])=[CH:5][CH:6]=4)=[N:16][CH:15]=[N:14][C:13]=3[CH2:17]2)=[N:24][CH:25]=[CH:26][CH:27]=1
Reactant: Clc1cccnc1Cl
Reactant: FC(F)Oc1ccc(Nc2ncnc3c2CCNC3)cc1
Solvent: CCN(C(C)C)C(C)C
Product: FC(F)Oc1ccc(Nc2ncnc3c2CCN(c2ncccc2Cl)C3)cc1
Temperature: 170 °C

Procedure:
The title compound was prepared according to the procedure given for Example 9 using N-(4-(difluoromethoxy)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-amine (0.091 g, 0.31 mmol), 2,3-dichloropyridine (0.092 g, 0.62 mmol) and N,N-diisopropylethylamine (0.081 mL, 0.47 mmol) and heating the reaction mixture for 10 h at 170° C. to obtain 0.038 g of a light yellow solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[O:16][C:13]([CH:14]=O)=[CH:12][CH:11]=2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=1[O:28][CH3:29])[CH2:22][C:23]#[N:24]>>[CH3:17][O:18][C:19]1[CH:20]=[C:21](/[C:22](=[CH:14]/[C:13]2[O:16][C:10]([C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=3)=[CH:11][CH:12]=2)/[C:23]#[N:24])[CH:25]=[CH:26][C:27]=1[O:28][CH3:29]
Reactant: O=Cc1ccc(-c2cccc([N+](=O)[O-])c2)o1
Reactant: COc1ccc(CC#N)cc1OC
Product: COc1ccc(/C(C#N)=C/c2ccc(-c3cccc([N+](=O)[O-])c3)o2)cc1OC
Yield: 98 %

Procedure:
5-(3-Nitrophenyl)furfural (1.09 g) was condensed with 3,4-dimethoxybenzyl cyanide (889 mg) through Method A (production step 2), to thereby yield the target product (yield: 1.85 g, 98%).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[N:7][C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([CH:21]=O)=[CH:10][CH:9]=2)(=[O:4])=[O:3].[S:23]1[CH2:29][C:27](=[O:28])[NH:26][C:24]1=[S:25].C([O-])(=O)C.[Na+]>C(O)(=O)C>[CH3:1][S:2]([C:5]1[CH:6]=[N:7][C:8]2[C:13]([C:14]=1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[CH:12][C:11]([CH:21]=[C:29]1[S:23][C:24](=[S:25])[NH:26][C:27]1=[O:28])=[CH:10][CH:9]=2)(=[O:4])=[O:3]
Reactant: O=C1CSC(=S)N1
Reactant: CS(=O)(=O)c1cnc2ccc(C=O)cc2c1-c1ccccc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CS(=O)(=O)c1cnc2ccc(C=C3SC(=S)NC3=O)cc2c1-c1ccccc1
Yield: 76.9 %

Procedure:
A mixture of 3-methanesulfonyl-4-phenyl-quinoline-6-carbaldehyde (example 611,78 mg, 0.25 mmol), rhodanine (67 mg, 0.50 mmol), sodium acetate (82 mg, 1.0 mmol), and acetic acid (2.5 mL) was heated under the microwave irradiation at 160 degrees for 40 min. After cooling to about room temperature, the reaction mixture was filtered, and the solid was collected, washed with water, dried to give 5-(3-methanesulfonyl-4-phenyl-quinolin-6-ylmethylene)-2-thioxo-thiazolidin-4-one (82 mg, 76%) with a yellow color. LC-MS m/e 427 (MH+).
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=2[C:18]([F:21])([F:20])[F:19])[C:4]([CH3:10])=[CH:5][C:6]=1[C:7](Cl)=[O:8].[S:22]([NH2:32])(=[O:31])([C:24]1[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][CH:25]=1)=[O:23].C(N(C(C)C)CC)(C)C>C1COCC1>[S:22]([C:24]1[CH:25]=[CH:26][C:27]([NH:30][C:7]([C:6]2[CH:5]=[C:4]([CH3:10])[N:3]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=3[C:18]([F:21])([F:20])[F:19])[C:2]=2[CH3:1])=[O:8])=[CH:28][CH:29]=1)(=[O:23])(=[O:31])[NH2:32]
Reactant: Cc1cc(C(=O)Cl)c(C)n1-c1ccc(F)cc1C(F)(F)F
Reactant: Nc1ccc(S(N)(=O)=O)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1cc(C(=O)Nc2ccc(S(N)(=O)=O)cc2)c(C)n1-c1ccc(F)cc1C(F)(F)F
Temperature: 80 °C
Yield: 65.5 %

Procedure:
Into an oven-dried 1 dram vial was added 2,5-dimethyl-1-[4-fluoro-2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxylic acid chloride (106 mg, 332 μmol), sulfanilamide (62.0 mg, 360 μmol), anhyd THF (2.0 mL) and diisopropylethylamine (50 μL). The vial was sealed and heated at 80° C. overnight. The resulting residue was purified by flash chromatography (SiO2), eluting with EtOAc/Hex (30:70 to 60:40) to afford the title compound as an off-white solid (99 mg, 66%); 1H NMR (CDCl3): δ 8.85 (s, 1H), 7.88 (d, J=7 Hz, 2H), 7.84 (d, J=7 Hz, 2H), 7.58 (dd, J=8, 3 Hz, 1H), 7.46 (m, 1H), 7.31 (dd, J=5, 8 Hz, 1H), 6.46 (s, 1H), 6.19 (s, 2H), 2.25 (s, 3H), 1.94 (s, 3H); MS (ESI) m/z 456 [M+H]+. D. In a manner similar to that described in Examples 1A-1C, but replacing 4-fluoro-2-(trifluoromethyl)aniline with 2-(trifluoromethyl)aniline, the following compound was prepared:
Reaction SMILES: O=[C:2]([CH2:9][CH3:10])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[NH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1.O>C1C=CC=CC=1>[N:11]1([C:2]([CH2:9][CH3:10])=[CH:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: C1CCNC1
Reactant: CCOC(=O)CC(=O)CC
Solvent: O
Solvent: c1ccccc1
Product: CCOC(=O)C=C(CC)N1CCCC1
Temperature: 25 °C
Yield: 100.8 %

Procedure:
Ethyl 3-oxopentanoate (2.5 mL, 17.6 mmole) and pyrrolidine (1.4 mL, 17.1 mmole) were dissolved in benzene and added to a 100 mL flask fitted with a Dean-Stark water separator. The reaction was stirred at reflux for 3 hours. After cooling to room temperature, the solvent was evaporated under reduced pressure and the product was dried in vacuo, affording ethyl 3-(pyrrolidin-1-yl)pent-2-enoate (3.4 g, 98% yield). The product was used without further purification.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[C:11]([O:15][C:16](=[O:24])[NH:17][C:18]([CH3:23])([CH3:22])[CH2:19][CH2:20][OH:21])([CH3:14])([CH3:13])[CH3:12].C(N(CC)CC)C>ClCCl>[C:11]([O:15][C:16]([NH:17][C:18]([CH3:23])([CH3:22])[CH2:19][CH:20]=[O:21])=[O:24])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(CCO)NC(=O)OC(C)(C)C
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(CC=O)NC(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 63.6 %

Procedure:
DMSO (1.22 mL, 17.2 mmol) was added to a solution of oxalyl chloride (1.1 mL, 12.9 mmol) at -78° C. in dichloromethane (15 mL). The mixture was stirred for 15 min at -78° C. A solution of 3-hydroxy-1,1-dimethylpropylcarbamic acid tert-butyl ester (1.75 g, 8.6 mmol) in dichloromethane (10 mL) was added dropwise over a period of 15 min. The solution was stirred at -78° C. for another 15 min. Triethylamine (6.0 mL, 43 mmol) was added. The solution was stirred at -78° C. for 5 min and then warmed to room temperature. The solution was diluted with dichloromethane (100 mL) and extracted with 1N hydrochloric acid (100 mL). The aqueous phase was extracted with dichloromethane (50 mL). The combined organic layers were washed with saturated sodium hydrogen carbonate solution (100 mL) and dried over magnesium sulfate. The solvent was removed in vacuo. The crude product was purified by column chromatography on silica (140 g) with ethyl acetate/heptane (1:3) to give 1.10 g of 3-(tert-butoxycarbonylamino)-3-methylbutanal.
Reaction SMILES: NC1C([N+]([O-])=O)=C(N)C([N+]([O-])=O)=C(N)C=1[N+]([O-])=O.[Cl:19][C:20]1[C:21]([N+:35]([O-:37])=[O:36])=[C:22](OC)[C:23]([N+:30]([O-:32])=[O:31])=[C:24]([Cl:29])[C:25]=1[N+:26]([O-:28])=[O:27].S(Cl)([Cl:40])=O>CN(C)C=O>[Cl:19][C:20]1[C:21]([N+:35]([O-:37])=[O:36])=[C:22]([Cl:40])[C:23]([N+:30]([O-:32])=[O:31])=[C:24]([Cl:29])[C:25]=1[N+:26]([O-:28])=[O:27]
Reactant: COc1c([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c(Cl)c1[N+](=O)[O-]
Reactant: O=S(Cl)Cl
Agent: Nc1c([N+](=O)[O-])c(N)c([N+](=O)[O-])c(N)c1[N+](=O)[O-]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1c(Cl)c([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c1Cl

Procedure:
Preparation of 1,3,5-triamino-2,4,6-trinitrobenzene (TATB) from 3,5-dichloroanisole. Nitration of 3,5-dichloroanisole under relatively mild conditions gave 3,5-dichloro-2,4,6-trinitroanisole in high yield and purity. Ammonolysis of this latter compound gave the desired TATB. Another route to TATB was through the treatment of the 3,5-dichloro-2,4,6-trinitroanisole with thionyl chloride and dimethylformamide to yield 1,3,5-trichloro-2,4,6-trinitrobenzene. Ammonolysis of this product produced TATB.
Reaction SMILES: [O:1]=[C:2]1[C:6]2[CH:7]=[CH:8][C:9]3[C:14]([C:5]=2[S:4](=[O:16])(=[O:15])[NH:3]1)=[CH:13][CH:12]=[CH:11][CH:10]=3.[Na].Cl[CH2:19][C:20]([O:22][CH3:23])=[O:21]>CO>[CH3:23][O:22][C:20](=[O:21])[CH2:19][N:3]1[C:2](=[O:1])[C:6]2[CH:7]=[CH:8][C:9]3[C:14]([C:5]=2[S:4]1(=[O:16])=[O:15])=[CH:13][CH:12]=[CH:11][CH:10]=3
Reactant: COC(=O)CCl
Reactant: O=C1NS(=O)(=O)c2c1ccc1ccccc21
Agent: [Na]
Solvent: CO
Product: COC(=O)CN1C(=O)c2ccc3ccccc3c2S1(=O)=O
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 98.3 %

Procedure:
70.0 gm (0.30 mol) of 3-oxo-naphth[2,1-d]isothiazoline-1,1-dioxide were added to a solution of 7.82 gm (0.34 gm-atom) of sodium in 300 ml of absolute methanol. The majority of the alcohol was subsequently distilled off, and the residual sodium salt of 3-oxo-naphth[2,1-d]isothiazoline-1,1-dioxide was dissolved in 100 ml of absolute dimethylsulfoxide. At a temperature of 50° C, 43.41 gm (0.40 mol) of methyl chloroacetate were added dropwise to this solution. The resulting mixture was stirred at room temperature for half an hour, then slowly heated to 130° C and finally kept at this temperature for 2.5 hours. Then, the dimethylsulfoxide was distilled off in vacuo, andthe residue was stirred into a solution of 40 gm of sodium acetate in 400 ml of water, filtered off and washed with water and ice-cold methanol, yielding 90.0 gm (98% of theory) of 3-oxo-naphth[2,1-d]isothiazoline-2-acetic acid methyl ester-1,1-dioxide, m.p. 188° C (methanol/ethylene chloride).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=1[NH:24][C:25](=[O:42])[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[CH:36]=[N:37][C:38]([CH3:41])=[CH:39][CH:40]=2)[CH:30]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:41][C:38]1[N:37]=[CH:36][C:35]([C:31]2[CH:30]=[C:29]([C:27]3[CH2:26][C:25](=[O:42])[NH:24][C:9]4[CH:10]=[C:11]([C:20]([F:22])([F:23])[F:21])[C:12]([O:14][CH2:15][C:16]([F:17])([F:18])[F:19])=[CH:13][C:8]=4[N:7]=3)[CH:34]=[CH:33][CH:32]=2)=[CH:40][CH:39]=1
Reactant: Cc1ccc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)c(OCC(F)(F)F)cc3NC(=O)OC(C)(C)C)c2)cn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(-c2cccc(C3=Nc4cc(OCC(F)(F)F)c(C(F)(F)F)cc4NC(=O)C3)c2)cn1

Procedure:
The title compound was prepared from [2-{3-[3-(6-methyl-pyridin-3-yl)-phenyl]-3-oxo-propionylamino}-5-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example M219) (191 mg, 0.31 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (95 mg, 62%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:15][CH2:16][CH3:17])=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:18]#[N:19].[Br:20][C:21]1[CH:22]=[C:23]([CH:25]=[CH:26][CH:27]=1)[NH2:24].C(=O)(O)[O-].[Na+]>C(O)C>[Br:20][C:21]1[CH:22]=[C:23]([NH:24][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:15][CH2:16][CH3:17])=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:18]#[N:19])[CH:25]=[CH:26][CH:27]=1
Reactant: CCOc1cc2ncc(C#N)c(Cl)c2cc1[N+](=O)[O-]
Reactant: Nc1cccc(Br)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCOc1cc2ncc(C#N)c(Nc3cccc(Br)c3)c2cc1[N+](=O)[O-]
Yield: 82.8 %

Procedure:
A mixture of 2.1 g (7.6 mmol) of 4-chloro-7-ethoxy-6-nitro-3-quinolinecarbonitrile and 0.91 ml (8.3 mmol) of 3-bromo aniline in 100 ml ethanol was refluxed under nitrogen for 4.5 hours. The reaction mixture was poured into diluted sodium bicarbonate solution. Ethanol was removed under vacuum. The mixture was diluted with ethyl acetate and the organic layer was separated and dried over sodium sulfate. The solution was concentrated and solid was collected and then washed with hexane. Upon drying, 2.6 g of yellow solid obtained: mass spectrum (electrospray, m/e) M+H 412.8 and 414.9.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5](I)=[CH:4][N:3]=1.[CH3:10][O:11][C:12]1[CH:17]=[C:16]([CH:18]([O:21][CH3:22])[C:19]#[CH:20])[CH:15]=[C:14]([O:23][CH3:24])[C:13]=1[O:25][CH3:26]>>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([C:20]#[C:19][CH:18]([O:21][CH3:22])[C:16]2[CH:15]=[C:14]([O:23][CH3:24])[C:13]([O:25][CH3:26])=[C:12]([O:11][CH3:10])[CH:17]=2)=[CH:4][N:3]=1
Reactant: Nc1ncc(I)c(N)n1
Reactant: C#CC(OC)c1cc(OC)c(OC)c(OC)c1
Product: COc1cc(C(C#Cc2cnc(N)nc2N)OC)cc(OC)c1OC
Yield: 90 %

Procedure:
2,4-Diamino-5-iodopyrimidine (236 mg) was allowed to react with 1,2,3-Trimethoxy-5-(1-methoxyprop-2-ynyl)benzene (473 mg) as per the general procedure to afford 2,4-Diamino-5-(3-methoxy-3-(3,4,5-trimethoxyphenyl)prop-1-ynyl)pyrimidine as an orange powder (310 mg, 90%): Rf=0.31 (9:1, CHCl3:MeOH); mp=184-186° C.; 1H NMR (DMSO-d6) δ 7.91 (s, 1H), 6.82 (s, 2H), 6.40 (s, 2H), 5.30 (s, 1H), 3.79 (s, 6H), 3.66 (s, 3H), 3.35 (s, 3H); 13C NMR (DMSO-d6) δ 163.8, 162.3, 159.7, 152.8, 137.2, 134.8, 104.6, 92.6, 89.1, 81.9, 73.0, 60.0, 55.9, 55.4; Anal. (C17H20N4O4) C, H, N.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH:15]([CH3:20])[C:16]([F:19])([F:18])[F:17])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:5][CH:4]=1>CN1CCCC1=O.[Cu]I>[F:17][C:16]([F:19])([F:18])[CH:15]([CH3:20])[CH:9]([C:6]1[CH:7]=[CH:8][C:3]([CH2:2][C:16]([F:19])([F:18])[F:17])=[CH:4][CH:5]=1)[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)C(c1ccc(CBr)cc1)C(C)C(F)(F)F
Agent: [Cu]I
Solvent: CN1CCCC1=O
Product: CCOC(=O)C(c1ccc(CC(F)(F)F)cc1)C(C)C(F)(F)F
Temperature: 80 °C
Reaction time: 8 h

Procedure:
529 mg (2.78 mmol) of copper(I) iodide and 4 g (20.82 mmol) of methyl 2,2-difluoro-2-(fluorosulphonyl) acetate were added to 3.77 g (10.67 mmol) of ethyl 2-[4-(bromomethyl)phenyl]-4,4,4-trifluoro-3-methylbutanoate in 40 ml of 1-methylpyrrolidin-2-one, and the mixture was stirred at 80° C. overnight. After the reaction had gone to completion, the reaction solution was slowly poured onto 100 ml of ice-water. The mixture obtained was then extracted three times with diethyl ether. The combined organic phases were dried over magnesium sulphate. After filtration, the solvent was removed under reduced pressure. The crude product obtained was purified chromatographically on silica gel (mobile phase cyclohexane/dichloromethane 4:1). This gave 1.48 g (4.32 mmol, 41% of theory) of the title compound as a yellowish oil.
Reaction SMILES: N[C:2]1C(=O)C2[C:9]([C:10](=[O:13])[C:11]=1N)=[CH:8][CH:7]=[CH:6][CH:5]=2.[C:15]1([C:21](=O)[C:22](=[O:24])[CH3:23])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(O)(=O)C.O>[CH3:2][C:11]1[C:10](=[O:13])[C:9]2[C:23]([C:22](=[O:24])[C:21]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:5][CH:6]=[CH:7][CH:8]=2
Reactant: CC(=O)C(=O)c1ccccc1
Reactant: NC1=C(N)C(=O)c2ccccc2C1=O
Solvent: O
Solvent: CC(=O)O
Product: CC1=C(c2ccccc2)C(=O)c2ccccc2C1=O
Reaction time: 0.08 h
Yield: 94.5 %

Procedure:
In a 200 ml Erlenmeyer flask were placed 5.0 g (26.5 mmols) of 2,3-diaminonaphthoquinone and 75 ml of acetic acid/water (1/1), then a solution composed of 5.9 g (39.8 mmols) of 1-phenyl-1,2-propanedione and 25 ml of acetic acid/water (1/1) was added dropwise to the mixture under ice-cooling over a period of about 10 minutes, and after stirring the mixture for 5 minutes, yellow precipitates formed were collected by filtration and washed with water. The precipitates were dissolved in methylene chloride; and, after purifying the solution by silica gel short column (eluted by methylene chloride), the product obtained was recrystallized from methylene chloride-methanol to provide 6.22 g (yield 78%) of 2-methyl-3-phenylnaphthoquinone as a yellow powder. Melting point 235°-236° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]1[N:6]=[C:7]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=2[F:30])[C:8]2[CH:14]=[CH:13][C:12](=[O:15])[N:11]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[F:22])[C:9]=2[N:10]=1.[CH:31]1[CH:36]=[CH:35][C:34]([O:37][C:38](OC2C=CC=CC=2)=[N:39][C:40]#[N:41])=[CH:33][CH:32]=1>C(O)(C)C>[C:40]([NH:39][C:38](=[N:1][CH2:2][CH2:3][NH:4][C:5]1[N:6]=[C:7]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=2[F:30])[C:8]2[CH:14]=[CH:13][C:12](=[O:15])[N:11]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[F:22])[C:9]=2[N:10]=1)[O:37][C:34]1[CH:35]=[CH:36][CH:31]=[CH:32][CH:33]=1)#[N:41]
Reactant: NCCNc1nc(-c2ccc(F)cc2F)c2ccc(=O)n(-c3ccccc3F)c2n1
Reactant: N#CN=C(Oc1ccccc1)Oc1ccccc1
Solvent: CC(C)O
Product: N#CNC(=NCCNc1nc(-c2ccc(F)cc2F)c2ccc(=O)n(-c3ccccc3F)c2n1)Oc1ccccc1
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-[(2-aminoethyl)amino]-4-(2,4-difluorophenyl)-8-(2-fluorophenyl)pyrido[2,3-d]pyrimidin-7(8H)-one (28 mg, 0.070 mmol) in isopropanol (2 mL) was added diphenyl cyanocarbonimidate (17 mg, 0.070 mmol). The mixture was stirred for about 30 min at about 20° C. LC/MS showed a new peak corresponding to the desired product and no starting material in the solution. LC-MS m/z 556 (M+H)+, 3.24 min (ret time).
Reaction SMILES: C([N:4]1[C:9]2=[CH:10][C:11]3[C:12](=[N:14][O:15][N:16]=3)[CH:13]=[C:8]2[O:7][C:6]([CH3:18])([CH3:17])[CH2:5]1)(=O)C.CO.C(=O)([O-])[O-].[K+].[K+]>O>[CH3:17][C:6]1([CH3:18])[CH2:5][NH:4][C:9]2=[CH:10][C:11]3[C:12](=[N:14][O:15][N:16]=3)[CH:13]=[C:8]2[O:7]1
Reactant: CC(=O)N1CC(C)(C)Oc2cc3nonc3cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CC1(C)CNc2cc3nonc3cc2O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.7 %

Procedure:
A mixture of 1.22 g 8-acetyl-7,8dihydro-6,6-dimethyl-6H-[1,2,5]oxadiazolo[3,4-g][1,4]benzoxazine, 40 ml methanol, 4 ml water and 1.37 g potassium carbonate was stirred at room temperature for one hour, the reaction mixture was poured into 300 ml ice water, and the resulting mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, the solvents were distilled off from the dried solution, and the residue was subjected to column chromatography on silica gel. Elution was conducted by the use of a 2:1 mixture of hexane and ethyl acetate, giving 1.02 g of 7,8-dihydro-6,6-dimethyl-6H-[1,2,5]oxadiazolo[3,4-g][1,4]benzoxazine.
Reaction SMILES: [Br:1]C1SC(Br)=CC=1Br.COC1C=C(B(O)O)C=CC=1OC.[CH3:22][O:23][C:24]1[CH:25]=[C:26]([C:32]2[S:33][C:34]([C:37]3[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[C:39]([O:45][CH3:46])[CH:38]=3)=[CH:35][CH:36]=2)[CH:27]=[CH:28][C:29]=1[O:30][CH3:31]>>[Br:1][C:36]1[CH:35]=[C:34]([C:37]2[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[C:39]([O:45][CH3:46])[CH:38]=2)[S:33][C:32]=1[C:26]1[CH:27]=[CH:28][C:29]([O:30][CH3:31])=[C:24]([O:23][CH3:22])[CH:25]=1
Reactant: Brc1cc(Br)c(Br)s1
Reactant: COc1ccc(-c2ccc(-c3ccc(OC)c(OC)c3)s2)cc1OC
Agent: COc1ccc(B(O)O)cc1OC
Product: COc1ccc(-c2cc(Br)c(-c3ccc(OC)c(OC)c3)s2)cc1OC
Yield: 77 %

Procedure:
3-bromo-2,5-bis(3′,4′-dimethoxyphenyl)thiophene (18) was prepared by the reaction of 2,3,5-tribromothiophene (17) (321 mg, 1 mmol) and (3,4-dimethoxyphenyl)boronic acid (15) (419 mg, 2.3 mmol) according to the similar procedure for compound 16. The reaction mixture was purified by column chromatography (10%-30% EtOAc in hexanes) and afforded 18 (337 mg, 77% yield) as a yellow solid. SA-60 was also isolated (97 mg, 20% yield) from the reaction above as a dark yellow solid.
Reaction SMILES: O1CCCCC1[O:7][NH:8][C:9](=[O:43])/[CH:10]=[CH:11]/[C:12]1[CH:16]=[CH:15][N:14]([S:17]([C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[CH:30][C:29]([NH:32][S:33]([C:36]4[CH:41]=[CH:40][C:39]([CH3:42])=[CH:38][CH:37]=4)(=[O:35])=[O:34])=[CH:28][CH:27]=3)=[CH:22][CH:21]=2)(=[O:19])=[O:18])[CH:13]=1>CO>[OH:7][NH:8][C:9](=[O:43])/[CH:10]=[CH:11]/[C:12]1[CH:16]=[CH:15][N:14]([S:17]([C:20]2[CH:21]=[CH:22][C:23]([C:26]3[CH:31]=[CH:30][C:29]([NH:32][S:33]([C:36]4[CH:37]=[CH:38][C:39]([CH3:42])=[CH:40][CH:41]=4)(=[O:35])=[O:34])=[CH:28][CH:27]=3)=[CH:24][CH:25]=2)(=[O:18])=[O:19])[CH:13]=1
Reactant: Cc1ccc(S(=O)(=O)Nc2ccc(-c3ccc(S(=O)(=O)n4ccc(/C=C/C(=O)NOC5CCCCO5)c4)cc3)cc2)cc1
Solvent: CO
Product: Cc1ccc(S(=O)(=O)Nc2ccc(-c3ccc(S(=O)(=O)n4ccc(/C=C/C(=O)NO)c4)cc3)cc2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 53.7 %

Procedure:
A mixture of 0.278 g (E)-N-(tetrahydro-pyran-2-yloxy)-3-{1-[4′-(toluene-4-sulfonylamino)-biphenyl-4-sulfonyl]-1H-pyrrol-3-yl}-acrylamide with 6.0 ml methanol and 13.0 ml 1M aqueous HCL is stirred at ambient temperature for 2 days. In case of incomplete deprotection the suspension is treated again with 1M aqueous HCL until the reaction is at completion. The mixture is evaporated and the resulting solid is washed with water and diisopropylether. The crude product is isolated by PLC plates chromatography. By this method 0.129 g of a red solid are obtained. Melting point: 119-126° C., sinter is beginning from 97° C.