Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Br:8][C:9]1[CH:10]=[C:11]([CH:15]=[C:16]([O:18][CH2:19][CH2:20][NH:21][C:22]2[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=2)[CH:17]=1)[C:12]([OH:14])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[CH3:69][NH:70][CH:71]1[CH2:76][CH2:75][CH2:74][CH2:73][CH2:72]1>CN(C=O)C>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Br:8][C:9]1[CH:10]=[C:11]([CH:15]=[C:16]([O:18][CH2:19][CH2:20][NH:21][C:22]2[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=2)[CH:17]=1)[C:12]([N:70]([CH:71]1[CH2:76][CH2:75][CH2:74][CH2:73][CH2:72]1)[CH3:69])=[O:14]
Reactant: O=C(O)c1cc(Br)cc(OCCNc2ccncc2)c1
Reactant: CNC1CCCCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: On1nnc2ccccc21
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(C(=O)c1cc(Br)cc(OCCNc2ccncc2)c1)C1CCCCC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of 3-bromo-5[-2-(pyridin-4-ylamino)-ethoxy]-benzoic acid trifluoroacetate salt (0.034 g), TBTU (0.048 g) and HOBt (0.014 g) in DMF (0.3 ml) was added DIPEA (0.026 ml) followed by N-methylcyclohexylamine (0.020 ml) after 15 min. The reaction mixture was stirred at room temperature for 18 h and then concentrated under reduced pressure. The residue was subjected to preparative hplc and the title compound (0.005 g) was obtained as a colourless gum by concentration of the required fraction under reduced pressure and drying by repetitive addition of acetonitrile and concentration under reduced pressure.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.[C:34]([N:41]1[CH2:45][CH2:44][CH:43](O)[CH2:42]1)([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35].[Br:47][C:48]1[CH:53]=[CH:52][N:51]=[C:50]([OH:54])[CH:49]=1>C1COCC1.O>[Br:47][C:48]1[CH:53]=[CH:52][N:51]([CH:43]2[CH2:44][CH2:45][N:41]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:42]2)[C:50](=[O:54])[CH:49]=1
Reactant: CC(C)(C)OC(=O)N1CCC(O)C1
Reactant: Oc1cc(Br)ccn1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(n2ccc(Br)cc2=O)C1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 109.9 %

Procedure:
To an ice cold solution of triphenylphosphine (0.17 g, 0.63 mmol) in THF (10.0 mL) was added DIAD (0.12 mL, 0.63 mmol) and the resulting solution was stirred at the same temperature for 15 min. after which a yellow precipitate was formed. 1-Boc-3-hydroxypyrrolidine (0.10 g, 0.53 mmol) was then added to the reaction mixture and allowed to stir for 20 min followed by addition of 4-bromo-2-hydroxypyridine (0.093 g, 0.53 mmol). The resulting reaction mixture was stirred for 16 h at room temperature. After completion of reaction (TLC monitoring), the reaction mixture was diluted with water and extracted with EtOAc (3×50 ml). The combined organics was dried (Na2SO4), filtered and concentrated. The residue was purified over silica gel (100-200 M, 0.5% MeOH-DCM) to obtain the desired product (0.20 g, quantitative yield). MS: 343.10 (M+H)+.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[OH:7][CH2:8][CH2:9][C:10]1[CH:11]=[C:12]([OH:16])[CH:13]=[CH:14][CH:15]=1.Br[CH2:18][CH:19]([O:23][CH2:24][CH3:25])[O:20][CH2:21][CH3:22].O>CN(C=O)C>[CH2:21]([O:20][CH:19]([O:23][CH2:24][CH3:25])[CH2:18][O:16][C:12]1[CH:11]=[C:10]([CH2:9][CH2:8][OH:7])[CH:15]=[CH:14][CH:13]=1)[CH3:22]
Reactant: OCCc1cccc(O)c1
Reactant: CCOC(CBr)OCC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(COc1cccc(CCO)c1)OCC
Temperature: 90 °C
Reaction time: 8 h

Procedure:
Caesium carbonate (8.84 g) was added to a solution of 3-(2-hydroxyethyl)phenol (2.5 g) and 2-bromo-1,1-diethoxyethane (3.74 g) in DMF (50 mL), and the resulting mixture was stirred at 90° C. overnight, then allowed to cool. The mixture was poured into water and extracted three times with ethyl acetate. The combined extracts were washed with water and brine, then dried over anhydrous sodium sulphate and purified by flash chromatography on silica eluted with a gradient of diethyl ether in isohexane to afford the subtitled compound as a pale yellow oil. Yield 3.0 g.
Reaction SMILES: [CH2:1]([OH:6])[C:2]([F:5])([F:4])[F:3].CC(C)([O-])C.[K+].F[C:14]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:15]=1[C:16]#[N:17].O>O1CCCC1.C(O)(C)(C)C>[F:22][C:20]1[CH:21]=[CH:14][C:15]([C:16]#[N:17])=[C:18]([O:6][CH2:1][C:2]([F:5])([F:4])[F:3])[CH:19]=1
Reactant: OCC(F)(F)F
Reactant: N#Cc1ccc(F)cc1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(C)(C)O
Product: N#Cc1ccc(F)cc1OCC(F)(F)F
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 81.4 %

Procedure:
To a solution of 359 mg of trifluoroethanol in 3 mL of anhydrous tetrahydrofuran at 5° C. was slowly added 3.6 mL of a molar solution of potassium tert-butoxide in tert-butanol. The resulting solution was stirred for 30 minutes at 5° C. and slowly added to a solution of 500 mg of 2,4-difluoro-benzonitrile in 3 mL of anhydrous tetrahydrofuran at 5° C. The resulting mixture was stirred for 1 h at 5° C., then poured into water and extracted with ethyl acetate. The organic extracts were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (gradient from heptane 100 to heptane 90/ethyl acetate 10) to give 640 mg of 4-fluoro-2-(2,2,2-trifluoro-ethoxy)-benzonitrile as a white solid.
Reaction SMILES: [CH:1]([C:3]1[N:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]2=[N:5][C:4]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[O:2].[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:20]=1[Mg]Br>C1COCC1.C([O-])(O)=O.[Na+]>[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:20]=1[CH:1]([OH:2])[C:3]1[N:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]2=[N:5][C:4]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)c1nc2ccccn2c1C=O
Reactant: COc1ccc(OC)c([Mg]Br)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1nc2ccccn2c1C(O)c1cc(OC)ccc1OC
Reaction time: 3 h
Yield: 56.1 %

Procedure:
A solution of 872 mg (4.0 mmol) of ethyl 3-formyl-imidazolo[1,2-a]pyridine-2-carboxylate in 40 mL THF is treated at −50° C. with 4 mL (4.0 mmol) 1M 2,5-dimethoxyphenylmagnesium bromide in THF. The temperature is allowed to reach −10° C. over 3 hr, diluted with 25 mL sat. NaHCO3 and extracted with 3×50 mL ethyl acetate. The combined organics are washed with 50 mL water and 50 mL brine. The resulting organic layer is dried over anhydrous MgSO4 and the solvent removed in vacuo. The residue is flash chromatographed with 1% methanol in dichloromethane to afford 800 mg (57%) ethyl 3-[(2,5-dimethoxyphenyl)hydroxymethyl]-imidazolo[1,2-a]pyridine-2-carboxylate.
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[CH:12]1([C:16]2([CH2:20][OH:21])[CH2:19][O:18][CH2:17]2)[CH2:15][CH2:14][CH2:13]1>ClCCl.C(OCC)C>[CH:12]1([C:16]2([CH:20]=[O:21])[CH2:19][O:18][CH2:17]2)[CH2:15][CH2:14][CH2:13]1
Reactant: OCC1(C2CCC2)COC1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOCC
Product: O=CC1(C2CCC2)COC1
Reaction time: 2 h
Yield: 75.8 %

Procedure:
To a stirred suspension of pyridinium chlorochromate (10 g, 45 mmol) in dry dichloromethane (100 ml) was added 3-cyclobutyl-3-hydroxymethyloxetane (5 g, 35 mmol). The mixture was stirred for 2 hours, diluted with diethylether and then purified on a florisil column with an ether rinse. Evaporation afforded 3-cyclobutyl-3-formyloxetane (3.72 g, 75%) as a liquid.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([N+:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[S:12][C:11]=1[CH3:19])[CH3:9].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[Cl:31][C:32]([C:35]1[N:40]=[C:39](C(Cl)(Cl)Cl)[N:38]=[C:37]([C:45]([Cl:48])([Cl:47])[Cl:46])[N:36]=1)([Cl:34])[Cl:33]>C1(C)C=CC=CC=1>[CH2:8]([N:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[S:12][C:11]1=[CH:19][C:39]1[N:40]=[C:35]([C:32]([Cl:31])([Cl:34])[Cl:33])[N:36]=[C:37]([C:45]([Cl:47])([Cl:48])[Cl:46])[N:38]=1)[CH3:9]
Reactant: CC[n+]1c(C)sc2ccccc21
Reactant: ClC(Cl)(Cl)c1nc(C(Cl)(Cl)Cl)nc(C(Cl)(Cl)Cl)n1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCN1C(=Cc2nc(C(Cl)(Cl)Cl)nc(C(Cl)(Cl)Cl)n2)Sc2ccccc21

Procedure:
Within a period of half an hour, 10 g (0.1 mol) of triethylamine was added dropwise to a suspension of 35 g (0.1 mol) of 3-ethyl-2-methyl-benzothiazolium-p-toluene-sulfonate and 43 g (0.1 mol) of tris-trichloromethyl-s-triazine in 300 ml of toluene. After completion of the addition the reaction mixture was stirred for half an hour, until the exothermic reaction ceased; the product which had precipitated was filtered off and dried. Compound 2 was obtained in nearly pure form in a quantity of 40 g. By evaporating the toluene in vacuo and treating the solid residue with ethanol, another 9 g of the product resulted. After recrystallization from 2-methoxy-ethanol 40 g (82%) of yellow needles of melting point 238° to 241° C. were obtained.
Reaction SMILES: C([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=2[F:22])[CH2:10][CH2:9]1)C1C=CC=CC=1>CO.[Pd]>[F:22][C:15]1[CH:16]=[C:17]([O:20][CH3:21])[CH:18]=[CH:19][C:14]=1[CH:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: COc1ccc(C2=CCN(Cc3ccccc3)CC2)c(F)c1
Agent: [Pd]
Solvent: CO
Product: COc1ccc(C2CCNCC2)c(F)c1
Reaction time: 48 h

Procedure:
A solution of 1-benzyl-4-(2-fluoro-4-methoxyphenyl)1,2,3,6-tetrahydropyridine (Step B; 117 mg; 0.393 mmol) in MeOH (10 mL) was treated with a catalytic amount of 10% Pd/C and the reaction was placed under an atmosphere of H2 (Parr Shaker; 45 PSI) for 48 h. The reaction was filtered through Celite and the filtrate was concentrated in vacuo. The residue was purified by flash silica gel chromatography (0-100% EtOAc/hexanes gradient) to afford 4-(2-fluoro-4-methoxyphenyl)piperidine as a tan solid. LCMS 210.1 (M+1)+. 1H NMR (CDCl3, 500 MHz) δ 7.16 (t, J=8.7 Hz, 1H), 6.68 (dd, J=8.7, 2.5 Hz, 1H), 6.60 (dd, J=12.3, 2.5 Hz, 1H), 3.78 (s, 3H), 3.63 (d, J=12.6 Hz, 2H), 3.09-2.98 (m, 2H), 2.18 (q, J=12.1 Hz, 2H), 2.02 (d, J=13.3 Hz, 2H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:12])[C@@H:7]1[CH2:11][CH2:10][CH2:9][NH:8]1)([CH3:4])([CH3:3])[CH3:2].OC1C2N=NNC=2C=CC=1.C1(N=C=NC2CCCCC2)CCCCC1.[C:38]([O:42][C:43]([NH:45][C@@H:46]([C:58](O)=[O:59])[CH2:47][S:48][CH2:49][C:50]1[CH:55]=[CH:54][C:53]([O:56][CH3:57])=[CH:52][CH:51]=1)=[O:44])([CH3:41])([CH3:40])[CH3:39]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:12])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:58](=[O:59])[C@@H:46]([CH2:47][S:48][CH2:49][C:50]1[CH:51]=[CH:52][C:53]([O:56][CH3:57])=[CH:54][CH:55]=1)[NH:45][C:43]([O:42][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:44])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(CSC[C@@H](NC(=O)OC(C)(C)C)C(=O)O)cc1
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Oc1cccc2[nH]nnc12
Solvent: ClCCl
Product: COc1ccc(CSC[C@@H](NC(=O)OC(C)(C)C)C(=O)N2CCC[C@H]2C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of L-proline tert-butyl ester (0.85 g) and hydroxybenzotriazole (0.67 g) in methylene chloride (10 ml) chilled in an ice bath, dicyclohexylcarbodiimide (1.03 g) and N-tert-butyloxycarbonyl-S-p-methoxybenzyl-D-cysteine (1.7 g) are added in that order. After fifteen minutes, the ice bath is removed and the mixture is stirred at room temperature overnight. The precipitate is filtered off and the filtrate is washed with 10% potassium bisulfate, water, saturated sodium bicarbonate, and water. The organic phase is dried and concentrated to dryness in vacuo to give N-tert-butyloxycarbonyl-S-p-methoxybenzyl-D-cysteinyl-L-proline tert-butyl ester as an oil. Rf =0.2 (silica gel, chloroform).
Reaction SMILES: [N:1]#[N:2].[CH3:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([CH:9]=[CH:10][C:11]([S:15]([NH:18][C@H:19]([C:27]([OH:29])=[O:28])[CH2:20][CH2:21][CH2:22][NH:23][C:24](=[NH:26])[NH2:25])(=[O:17])=[O:16])=[CH:12]2)=[CH:7][CH:6]=1.O.[C:31]1([CH3:41])[CH:36]=[CH:35][C:34]([S:37]([OH:40])(=[O:39])=[O:38])=[CH:33][CH:32]=1>C(O)C1C=CC=CC=1.C1C=CC=CC=1>[N:1]#[N:2].[C:31]1([CH3:41])[CH:32]=[CH:33][C:34]([S:37]([OH:40])(=[O:38])=[O:39])=[CH:35][CH:36]=1.[CH2:41]([O:28][C:27](=[O:29])[C@H:19]([CH2:20][CH2:21][CH2:22][NH:23][C:24](=[NH:25])[NH2:26])[NH:18][S:15]([C:11]1[CH:10]=[CH:9][C:8]2[C:13](=[CH:14][C:5]([O:4][CH3:3])=[CH:6][CH:7]=2)[CH:12]=1)(=[O:16])=[O:17])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: COc1ccc2ccc(S(=O)(=O)N[C@@H](CCCNC(=N)N)C(=O)O)cc2c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: N#N
Solvent: O
Solvent: c1ccccc1
Solvent: OCc1ccccc1
Product: COc1ccc2ccc(S(=O)(=O)N[C@@H](CCCNC(=N)N)C(=O)OCc3ccccc3)cc2c1
Yield: 94 %

Procedure:
A mixture of 1.0 gram of N2 -(7-methoxy-2-naphthalenesulfonyl)-L-arginine, 1.0 gram of p-toluenesulfonic acid monohydrate in 5 ml of benzyl alcohol and 30 ml of benzene was refluxed for 5 hours, removing water by azeotropic distillation. After the solvent was removed by distillation, 100 ml of ethyl ether was added to the residae, giving a crystalline mass of N2 -(7-methoxy-2-naphthalenesulfonyl)-L-arginine benzyl ester p-toluenesulfonate in 94% yield; mp. 115 - 117° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]2[C:24]([F:25])=[CH:23][C:15]([O:16][CH2:17][C:18](OCC)=[O:19])=[C:14]([N+:26]([O-])=O)[CH:13]=2)=[N:4][N:5]([CH3:11])[C:6]=1[C:7]([F:10])([F:9])[F:8]>C(O)(=O)C.[Fe]>[Cl:1][C:2]1[C:3]([C:12]2[C:24]([F:25])=[CH:23][C:15]3[O:16][CH2:17][C:18](=[O:19])[NH:26][C:14]=3[CH:13]=2)=[N:4][N:5]([CH3:11])[C:6]=1[C:7]([F:10])([F:9])[F:8]
Reactant: CCOC(=O)COc1cc(F)c(-c2nn(C)c(C(F)(F)F)c2Cl)cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Product: Cn1nc(-c2cc3c(cc2F)OCC(=O)N3)c(Cl)c1C(F)(F)F
Temperature: 80 °C
Reaction time: 3 h
Yield: 79.6 %

Procedure:
A solution of 4.5 g (0.0106 mole) (4-(4-chloro-1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-5-fluoro-2-nitrophenoxy)-acetic acid, ethyl ester in 75 mL acetic acid was heated to 80° C. under a nitrogen atmosphere. The heat and nitrogen were removed and 1.8 g (0.033 mole) iron powder was added in 3 portions over 5 min. The solution was stirred at 80° C. for an additional 3 hours. The solution was cooled and filtered through Celite®. The filtrate was diluted with 100 mL water and extracted three times with ethyl acetate. The ethyl acetate extracts were washed with a saturated NaHCO3 solution, dried over anhydrous MgSO4, and concentrated in vacuo. The residue was recrystallized from methylcyclohexane/ethyl acetate to give 2.95 g (80%) of 6-(4-chloro-1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-7-fluoro-2H-1,4-benzoxazin-3(4H)-one as a white solid, mp 207° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[NH:9][C:10]3[C:15]([CH:16]=2)=[C:14]([F:17])[CH:13]=[CH:12][CH:11]=3)[C:5]([OH:18])=[CH:4][CH:3]=1.[CH:19]1[CH:24]=[CH:23][C:22]([CH2:25]Br)=[CH:21][CH:20]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[CH2:25]([O:18][C:5]1[C:6]([C:8]2[NH:9][C:10]3[C:15]([CH:16]=2)=[C:14]([F:17])[CH:13]=[CH:12][CH:11]=3)=[N:7][C:2]([Cl:1])=[CH:3][CH:4]=1)[C:22]1[CH:23]=[CH:24][CH:19]=[CH:20][CH:21]=1
Reactant: Oc1ccc(Cl)nc1-c1cc2c(F)cccc2[nH]1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Fc1cccc2[nH]c(-c3nc(Cl)ccc3OCc3ccccc3)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.6 %

Procedure:
A mixture of 6-chloro-2-(4-fluoro-1H-indol-2-yl)pyridin-3-ol (100 mg, 0.38 mmol, prepared using similar method described in Example 1), BnBr (97 mg, 0.572 mmol) and K2CO3 (158 mg, 1.146 mmol) in DMF (1 mL) was stirred at room temperature overnight. The mixture was then concentrated in vacuo. The resulting resulting residue was diluted with water (15 mL) and extracted with ethyl acetate (10 mL×3). The organic layer was washed with brine (20 mL), dried over Na2SO4 and concentrated in vacuo. The resulting residue was purified using Prep-TLC (petroleum ether:EA=3:1) to provide 2-(3-(benzyloxy)-6-chloropyridin-2-yl)-4-fluoro-1H-indole (100 mg, yield: 74.6%). 1H-NMR (CDCl3, 400 MHz) δ 9.64 (s, 1H), 7.12˜7.48 (m, 10H), 6.76 (t, J=8.8 Hz, 1H), 5.33 (s, 2H). MS (M+H)+: 353/355.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)[S:4][C:3]=1[C:14]([O:16][CH3:17])=[O:15].CO[CH:20](OC)[N:21]([CH3:23])[CH3:22]>C(O)C>[Cl:13][C:10]1[CH:9]=[CH:8][C:7]([C:5]2[S:4][C:3]([C:14]([O:16][CH3:17])=[O:15])=[C:2](/[N:1]=[CH:20]/[N:21]([CH3:23])[CH3:22])[CH:6]=2)=[CH:12][CH:11]=1
Reactant: COC(OC)N(C)C
Reactant: COC(=O)c1sc(-c2ccc(Cl)cc2)cc1N
Solvent: CCO
Product: COC(=O)c1sc(-c2ccc(Cl)cc2)cc1/N=C/N(C)C
Yield: 98.8 %

Procedure:
A mixture of methyl 3-amino-5-(4-chlorophenyl)-2-thiophenecarboxylate (37.3 mmol, 10.0 g) and N,N-dimethylformamide dimethyl acetal (74.7 mmol, 8.9 g) in ethanol (350 mL) was heated at reflux for 3 hours. The solvent was removed by rotary evaporation. To the residue 15 mL of toluene was added and the solvent was removed by rotary evaporation. This was repeated three times. To the resulting sticky residue, 20 mL hexanes was added followed by the gradual addition of ethyl acetate at 0° C. until it solidified. The resulting solid was collected by filtration giving the product (11.9 g, 98.9%). 1H NMR (CDCl3): δ 3.08 (6H, d, J=6.5 Hz), 3.81 (3H, s),6.98 (1 H. s), 7.35 (2H, d, J=8.6 Hz), 7.53 (2H, d, J=8.5 Hz), 7.69 (1H, s). LCMS m/z=323 (m+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:11][CH:12]2[CH2:14][CH2:13]2)=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].C(N(CC)CC)C.Cl[C:23](Cl)([O:25]C(=O)OC(Cl)(Cl)Cl)Cl.CN(C1C=CC=CN=1)C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH:12]3[CH2:13][CH2:14]3)[C:23](=[O:25])[O:8][C:7](=[O:9])[C:6]=2[CH:10]=1
Reactant: O=C(O)c1cc(Cl)ccc1NC1CC1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: CN(C)c1ccccn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=c1oc(=O)n(C2CC2)c2ccc(Cl)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 270.3 %

Procedure:
A solution of 5-chloro-2-(cyclopropylamino)benzoic acid (4.70 g) and triethylamine (3.12 mL, 1 eq) in DCM (111 mL) was cooled to 0° C. and treated with triphosgene (2.31 g, 0.35 eq) in small portions. Dimethylaminopyridine (271 mg, 0.1 eq) was then added and the reaction was stirred at room temperature overnight. The crude was washed with cold 1 N HCl, and the organic portion was dried over sodium sulfate, and concentrated, then held under vacuum for 18 h delivering product (5.00 g, 95% yield). 1H-NMR (400 MHz, DMSO-d6) δ 7.88 (m, 2H), 7.68 (d, 1H), 2.90 (m, 1H), 1.16 (m, 2H), 0.80 (m, 2H). MS (ES+) m/z 260.0 (M+Na).
Reaction SMILES: [CH2:1]([C:4]1([S:7]([N:10]2[C:14]3=[CH:15][C:16]4[S:20][CH:19]=[N:18][C:17]=4[C:21]([F:22])=[C:13]3[N:12]([C:23]3[CH:28]=[CH:27][C:26]([I:29])=[CH:25][C:24]=3[F:30])C2=O)(=[O:9])=[O:8])[CH2:6][CH2:5]1)[CH:2]=[CH2:3].C[Si](C)(C)[O-].[K+]>C1COCC1>[CH2:1]([C:4]1([S:7]([NH:10][C:14]2[C:13]([NH:12][C:23]3[CH:28]=[CH:27][C:26]([I:29])=[CH:25][C:24]=3[F:30])=[C:21]([F:22])[C:17]3[N:18]=[CH:19][S:20][C:16]=3[CH:15]=2)(=[O:9])=[O:8])[CH2:6][CH2:5]1)[CH:2]=[CH2:3]
Reactant: C=CCC1(S(=O)(=O)n2c(=O)n(-c3ccc(I)cc3F)c3c(F)c4ncsc4cc32)CC1
Agent: C[Si](C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=CCC1(S(=O)(=O)Nc2cc3scnc3c(F)c2Nc2ccc(I)cc2F)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83 %

Procedure:
To a solution of 7-((1-allylcyclopropyl)sulfonyl)-4-fluoro-5-(2-fluoro-4-iodophenyl)-5H-imidazo[4′,5′:4,5]benzo[1,2-d]thiazol-6(7H)-one (60 mg, 0.11 mmol) in THF (5 mL) was added potassium trimethylsilanolate (14 mg, 0.11 mmol). The reaction was stirred at room temperature for 1 h and quenched with saturated NH4Cl (aq.). The aqueous layer was extracted with EA (10 mL×2). The combined organic phase was washed with brine (20 mL), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (petroleum ether/ethyl acetate, 5:1-3:1, v/v) to give the desired product (50 mg, 91.3% yield). 1H NMR (400 MHz, CDCl3): δ 8.67 (s, 1H), 7.97 (s, 1H), 7.92 (d, 1H), 7.78 (d, 1H), 7.46 (m, 1H), 6.82 (s, 1H), 6.64 (s, 1H), 5.75-5.58 (m, 1H), 5.05 (m, 2H), 2.90-2.80 (m, 1H), 2.10-2.00 (m, 1H), 1.95-1.86 (m, 2H), 1.25-1.10 (m, 2H).
Reaction SMILES: C1(=O)[N:5]([CH2:6][C:7]([N:9]([C:11]2[CH:16]=[CH:15][C:14]([NH:17]/[C:18](=[C:25]3\[C:26](=[O:37])[NH:27][C:28]4[C:33]\3=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][CH:29]=4)/[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:13][CH:12]=2)[CH3:10])=[O:8])C(=O)C2=CC=CC=C12.ClCCl.O.NN>C(O)C>[NH2:5][CH2:6][C:7]([N:9]([C:11]1[CH:16]=[CH:15][C:14]([NH:17]/[C:18](=[C:25]2\[C:26](=[O:37])[NH:27][C:28]3[C:33]\2=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][CH:29]=3)/[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[CH:13][CH:12]=1)[CH3:10])=[O:8]
Reactant: CN(C(=O)CN1C(=O)c2ccccc2C1=O)c1ccc(N/C(=C2\C(=O)Nc3ccc([N+](=O)[O-])cc32)c2ccccc2)cc1
Agent: NN
Solvent: CCO
Solvent: O
Solvent: ClCCl
Product: CN(C(=O)CN)c1ccc(N/C(=C2\C(=O)Nc3ccc([N+](=O)[O-])cc32)c2ccccc2)cc1
Temperature: 50 °C
Reaction time: 18 h

Procedure:
287 mg (0.5 mmol) of (Z)-3-{1-[4-(N-phthalimidomethylcarbonyl-N-methylamino)phenylamino]-1-phenyl-methylidene}-5-nitro-2-indolinone are suspended in 20 ml of ethanol and 20 ml of dichloromethane and after the addition of 0.3 ml of 80% hydrazine hydrate solution stirred for 18 hours at 50° C. The mixture is then cooled to ambient temperature, the insoluble matter is suction filtered and the mother liquor is concentrated by evaporation. The residue is chromatographed on silica gel (dichloromethane/methanol/ammonia=92:8:0.8) and the product is again triturated with methanol, suction filtered and dried.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[C:7]1[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].[C:25]1([S:31](Cl)(=[O:33])=[O:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[NH2:19][C:10]1[C:9]2[N:8]=[C:7]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][S:31]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)(=[O:33])=[O:32])[C:18]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CCCCCc1nc2c(N)nc3ccccc3c2n1CCCCN
Product: CCCCCc1nc2c(N)nc3ccccc3c2n1CCCCNS(=O)(=O)c1ccccc1
Yield: 24.2 %

Procedure:
Using the general method of Example 232, 1-(4-aminobutyl)-2-pentyl-1H-imidazo[4,5-c]quinolin-4-amine (1.00 g, 3.1 mmol) was reacted with benzenesulfonyl chloride (0.51 mL, 4.0 mmol) to provide 0.35 g of N-[4-(4-amino-2-pentyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]benzenesulfonamide as a yellow crystalline solid.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9]([CH2:14][CH2:15][CH3:16])[N:8]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]([O:32]C(C)(C)C)=[O:31])=[CH:20][CH:19]=1)[C:7]2=[O:37])([CH3:3])[CH3:2].FC(F)(F)C(O)=O.C1(OC)C=CC=CC=1>C(Cl)Cl>[CH:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9]([CH2:14][CH2:15][CH3:16])[N:8]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]([OH:32])=[O:31])=[CH:20][CH:19]=1)[C:7]2=[O:37])([CH3:2])[CH3:3]
Reactant: CCCc1nc2ccc(C(C)C)cc2c(=O)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: CCCc1nc2ccc(C(C)C)cc2c(=O)n1Cc1ccc(-c2ccccc2C(=O)O)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 6-isopropyl-2-n-propyl-3-[(2'-(t-butoxycarbonyl)biphen-4-yl)-methyl]-quinazolin-4(3H)-one (0.198 g, 0.44 mmol) in a mixture of methylene chloride (3 ml) and anhydrous trifluoro acetic acid (3 ml) containing anisole (0.05 ml) was stirred at room temperature for 4 hours. The solvent was then removed under reduced pressure and the residue was triturated with dry ether to give the solid product, which was then collected by filteration and dried in vacuo over NaOH and P2O5 to give the desired product as the mono trifluoroacetate salt. 1H-NMR(CDCl3): 0.91 (t, 3H, J=7.35 Hz), 1.32 (d, 6H, J=6.9 Hz), 1.47 (m, 2H), 1.72 (m, 2H), 3.12 (m, 3H), 5.48 (s, 2H), 7.14-7.96 (m, 11H), 8.16 (d, 1H, J=1.9 Hz). FAB-MS m/e 399 (M+H).