Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)(C(F)(F)F)=O.C(O[C:11](=[O:22])[C:12]([N:17]1[CH:21]=[CH:20][N:19]=[N:18]1)=[CH:13][N:14](C)C)C.[Cl:23][C:24]1[CH:29]=[C:28]([NH:30]N)[N:27]=[CH:26][N:25]=1>C(O)C>[ClH:23].[Cl:23][C:24]1[N:25]=[CH:26][N:27]=[C:28]([N:30]2[C:11](=[O:22])[C:12]([N:17]3[CH:21]=[CH:20][N:19]=[N:18]3)=[CH:13][NH:14]2)[CH:29]=1
Reactant: NNc1cc(Cl)ncn1
Reactant: CCOC(=O)C(=CN(C)C)n1ccnn1
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Product: Cl
Product: O=c1c(-n2ccnn2)c[nH]n1-c1cc(Cl)ncn1
Temperature: 100 °C
Reaction time: 20 h

Procedure:
1.1 ml (1.6 g, 13.8 mmol) TFA are added to a mixture of 7.3 g (34.6 mmol) of the compound from Example 3A and 6.0 g (41.5 mmol) of the compound from Example 7A in 70 ml ethanol and the mixture is stirred at 100° C. for 20 h. The solid which has precipitated out is filtered off and the filtrate is concentrated in vacuo. The residue is suspended in 100 ml ethanol, 30 ml of a 30% strength sodium methanolate solution in methanol are added and the mixture is stirred at RT for 1.5 h. After addition of 42 ml of a 4 N solution of hydrogen chloride in dioxane (pH=5-6) and after stirring for 30 min, the solid is filtered off, washed first with ethanol and then with diethyl ether and dried in vacuo. Further purification is carried out by stirring in ethanol and acetonitrile several times. 10 ml of a 4 N solution of hydrogen chloride in dioxane are then added and the mixture is stirred at RT for 16 h. The product is filtered off, washed first with acetonitrile and then with diethyl ether and dried in vacuo.
Reaction SMILES: C[O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[N:8][C:9]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([S:20]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)(=[O:22])=[O:21])=[CH:16][CH:15]=3)=[N:10]2)=[CH:5][CH:4]=1.C[S-].[Na+].Cl>CN1C(=O)CCC1.O>[O:26]1[CH2:27][CH2:28][N:23]([S:20]([C:17]2[CH:18]=[CH:19][C:14]([NH:13][C:9]3[N:8]=[CH:7][C:6]4[C:11](=[CH:12][C:3]([OH:2])=[CH:4][CH:5]=4)[N:10]=3)=[CH:15][CH:16]=2)(=[O:21])=[O:22])[CH2:24][CH2:25]1
Reactant: COc1ccc2cnc(Nc3ccc(S(=O)(=O)N4CCOCC4)cc3)nc2c1
Agent: C[S-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: O=S(=O)(c1ccc(Nc2ncc3ccc(O)cc3n2)cc1)N1CCOCC1
Temperature: 80 °C
Yield: 99 %

Procedure:
A mixture of 7-methoxy-N-(4-(morpholinosulfonyl)phenyl)quinazolin-2-amine (1 eq) and sodium thiomethoxide (4 eq) in NMP was heated at 80° C. for 4 h. Reaction mixture was diluted with water and acidified with 1N HCl. Compound was extracted with ethyl acetate. The organic layer was washed with satd. NaHCO3, brine and dried over sodium sulfate. Filtration, evaporation and drying under vacuum provide 2-(4-(morpholinosulfonyl)phenylamino) quinazolin-7-ol as a light yellow viscous liquid in 99% yield. ES/MS m/z 387.0 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([F:23])[CH:17]=1.[F:24][C:25]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=1[N:32]=[C:33]=[O:34]>C(Cl)(Cl)Cl>[F:24][C:25]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=1[NH:32][C:33]([NH:20][C:19]1[CH:21]=[CH:22][C:16]([O:15][C:6]2[C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[N:9]=[CH:8][N:7]=2)=[CH:17][C:18]=1[F:23])=[O:34]
Reactant: O=C=Nc1ccc(F)cc1F
Reactant: COc1cc2ncnc(Oc3ccc(N)c(F)c3)c2cc1OC
Solvent: ClC(Cl)Cl
Product: COc1cc2ncnc(Oc3ccc(NC(=O)Nc4ccc(F)cc4F)c(F)c3)c2cc1OC
Temperature: 60 °C
Reaction time: 8 h
Yield: 67 %

Procedure:
4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]-2-fluoro-aniline (50 mg) was dissolved in chloroform (3 ml), and 2,4-difluorophenyl isocyanate (29 μl) was then added to the solution. The mixture was stirred at 60° C. overnight. The precipitated crystal was collected by filtration and was washed to give. 50 mg (yield 67%) of the title compound.
Reaction SMILES: [NH3:1].Br[C:3]1[N:8]=[CH:7][C:6]([CH2:9][N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH3:17])[CH2:12][CH2:11]2)=[CH:5][CH:4]=1>CO>[CH2:16]([N:13]1[CH2:14][CH2:15][N:10]([CH2:9][C:6]2[CH:5]=[CH:4][C:3]([NH2:1])=[N:8][CH:7]=2)[CH2:11][CH2:12]1)[CH3:17]
Reactant: CCN1CCN(Cc2ccc(Br)nc2)CC1
Reactant: N
Solvent: CO
Product: CCN1CCN(Cc2ccc(N)nc2)CC1
Temperature: 70 °C
Yield: 54.5 %

Procedure:
Add liquid ammonia (50.0 kg) to a degassed mixture of 1-(6-bromo-pyridin-3-ylmethyl)-4-ethyl-piperazine (14.2 kg), cuprous oxide (200 g), and MeOH (57 kg) at T≦40° C. Heat the mixture at 65-75° C. overnight. Cool to 20-30° C. and filter over a Celite® pad. Concentrate the filtrate and add DCM (113 kg) and adjust the pH to 12-14 with sodium hydroxide 2N (23 kg) separate the phases and wash the organic phase with DCM (58×2 kg) and combine the organic layers. Filter the mixture through Celite® and concentrate. Dissolve the residue in toluene (9.7 kg) and crystallize by the addition of MtBE (8.3 kg) to give 6.0 kg of the title compound. Obtain further purification through a toluene recrystallization. MS (ES+): m/z=221 (M+H)+.
Reaction SMILES: C(OC([O:8][C:9]1[CH:47]=[CH:46][C:45]([N:48]([CH2:53][CH:54]2[CH2:56][CH2:55]2)[S:49]([CH3:52])(=[O:51])=[O:50])=[CH:44][C:10]=1[C:11]([O:13][CH2:14][C:15]([O:17][C@H:18]([C:29]1[CH:34]=[CH:33][C:32]([O:35][CH:36]([F:38])[F:37])=[C:31]([O:39][CH2:40][CH:41]2[CH2:43][CH2:42]2)[CH:30]=1)[CH2:19][C:20]1[C:25]([Cl:26])=[CH:24][N+:23]([O-:27])=[CH:22][C:21]=1[Cl:28])=[O:16])=[O:12])=O)(C)(C)C.O1CCOCC1>C(Cl)Cl.Cl>[Cl:28][C:21]1[CH:22]=[N+:23]([O-:27])[CH:24]=[C:25]([Cl:26])[C:20]=1[CH2:19][C@@H:18]([C:29]1[CH:34]=[CH:33][C:32]([O:35][CH:36]([F:37])[F:38])=[C:31]([O:39][CH2:40][CH:41]2[CH2:43][CH2:42]2)[CH:30]=1)[O:17][C:15](=[O:16])[CH2:14][O:13][C:11](=[O:12])[C:10]1[CH:44]=[C:45]([N:48]([CH2:53][CH:54]2[CH2:55][CH2:56]2)[S:49]([CH3:52])(=[O:51])=[O:50])[CH:46]=[CH:47][C:9]=1[OH:8]
Reactant: CC(C)(C)OC(=O)Oc1ccc(N(CC2CC2)S(C)(=O)=O)cc1C(=O)OCC(=O)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CS(=O)(=O)N(CC1CC1)c1ccc(O)c(C(=O)OCC(=O)O[C@@H](Cc2c(Cl)c[n+]([O-])cc2Cl)c2ccc(OC(F)F)c(OCC3CC3)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.7 %

Procedure:
To a solution of (S)-4-(2-(2-(2-(tert-butoxycarbonyloxy)-5-(N-(cyclopropyl-methyl)methylsulfonamido)benzoyloxy)acetoxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)ethyl)-3,5-dichloropyridine 1-oxide (0.326 g, 0.385 mmol) in DCM (15 ml), HCl 4M in dioxane (1 ml, 4.00 mmol) was added, and the mixture was stirred at RT overnight. Additional HCl 4M in dioxane (1 ml, 4.00 mmol) was added, and the mixture was stirred at the same temperature for 3 days. The solvent was removed and the crude was triturated with MeOH. The solid was collected by filtration and washed with ethyl ether. A further trituration with EtOAc was required to afford (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-(5-(N-(cyclopropylmethyl)-methylsulfonamido)-2-hydroxybenzoyloxy)acetoxy)ethyl)pyridine 1-oxide as a white solid (0.160 g, 0.215 mmol, 55.7% yield, MS/ESI+ 745.19 [MH]+, [αD]=−36.29, c=0.49, DCM).
Reaction SMILES: [C:1]([N:20]1[C:24]([C:25](OC)=[O:26])=[C:23]([C:29](OC)=[O:30])[C:22]([C:33](OC)=[O:34])=[N:21]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1.CCOCC>[C:1]([N:20]1[C:24]([CH2:25][OH:26])=[C:23]([CH2:29][OH:30])[C:22]([CH2:33][OH:34])=[N:21]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: COC(=O)c1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(C(=O)OC)c1C(=O)OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: OCc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(CO)c1CO
Temperature: 22.5 °C
Reaction time: 16 h
Yield: 73 %

Procedure:
To a solution of trimethyl 1-trityl-3,4,5-pyrazoletricarboxylate (3.034 g, 6.26 mmol) in dry THF (60 mL) were added 50 mL of 1.0 M LiAlH4 in Et2O. The resulting solution was stirred for about 16 h at room temperature (20-25° C.). After this time, the reaction was quenched by the slow addition of 1.5 mL of distilled water, followed by addition of 1.5 mL of 10% NaOH and 3.5 mL of water. The solids formed were removed by filtration, and 80 mL of dichloromethane was added to the filtrate. The organic phase was separated, washed with distilled water (70 mL) and, after separation from the aqueous phase, was dried over MgSO4. After separation of the organic phase, the solvent was evaporated under vacuum yielding a yellowish solid. Yield: 73% (1.823 g, 4.54 mmol).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[CH:11][CH:10]=[C:9]2[C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.[Xe](F)[F:24].C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C>[F:24][C:12]1[N:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[C:9]([C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=2)=[CH:10][CH:11]=1
Reactant: F[Xe]F
Reactant: CS(=O)(=O)c1ccc(-c2cccn2-c2ccc(F)cc2)cc1
Agent: *CC*
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: CS(=O)(=O)c1ccc(-c2ccc(F)n2-c2ccc(F)cc2)cc1
Yield: 35.6 %

Procedure:
0.90 g (2.7 mmol) of 1-(4-fluorophenyl)-2-(4-methylsulfonylphenyl)pyrrole (prepared as described in Example 33) was dissolved in 10 ml of acetonitrile in a reaction vessel made of polyethylene, and 0.46 g (2.7 mmol) of xenon difluoride was added to the resulting solution at 0° C., whilst stirring. The temperature of the reaction mixture was then allowed to return to room temperature, and the mixture was stirred at room temperature for 20 hours. At the end of this time, 20 ml of a saturated aqueous solution of sodium carbonate was added to the mixture, which was then extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium carbonate and then with water, after which it was dried over anhydrous magnesium sulfate. The solvent was then removed by distillation under reduced pressure. The resulting residue was applied to a silica gel chromatography column and eluted with a 3:1 by volume mixture of hexane and ethyl acetate, to give 0.32 g of the title compound as white prismatic crystals (yield 34%), melting at 140-141° C.
Reaction SMILES: [CH:1]([Mg]Cl)([CH3:3])[CH3:2].[Br:6][C:7]1[CH:8]=[C:9]2[C:14](=[C:15]([Cl:20])[C:16]=1[O:17][CH2:18][CH3:19])[O:13][C:12]([CH3:22])([CH3:21])[CH2:11][C:10]2=O.CN1CCCN(C)C1=O>C1COCC1>[Br:6][C:7]1[CH:8]=[C:9]2[C:14](=[C:15]([Cl:20])[C:16]=1[O:17][CH2:18][CH3:19])[O:13][C:12]([CH3:22])([CH3:21])[CH:11]=[C:10]2[CH:1]([CH3:3])[CH3:2]
Reactant: CCOc1c(Br)cc2c(c1Cl)OC(C)(C)CC2=O
Reactant: CC(C)[Mg]Cl
Solvent: C1CCOC1
Solvent: CN1CCCN(C)C1=O
Product: CCOc1c(Br)cc2c(c1Cl)OC(C)(C)C=C2C(C)C
Reaction time: 12 h

Procedure:
Following General Procedure C, isopropylmagnesium chloride (2.0 M in THF, 111 mL, 22 mmol), 6-bromo-8-chloro-7-ethoxy-2,2-dimethyl-chroman-4-one (Compound 10, 1.5 g, 4.5 mmol), and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)pyrimidinone (DMPU, 2.6 mL) in THF was reacted then quenched with 10% HCl, and stored at room temperature for 12 h.
Reaction SMILES: C([O:3][C:4](=[O:33])[CH2:5][C:6]1[N:7]=[C:8]([NH:12][C:13]([C:15]2[N:16]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=3[F:32])[CH:17]=[C:18]([CH2:20][CH:21]([CH3:23])[CH3:22])[CH:19]=2)=[O:14])[S:9][C:10]=1[Cl:11])C.CO.O.[OH-].[Li+]>C1COCC1.O>[Cl:11][C:10]1[S:9][C:8]([NH:12][C:13]([C:15]2[N:16]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=3[F:32])[CH:17]=[C:18]([CH2:20][CH:21]([CH3:22])[CH3:23])[CH:19]=2)=[O:14])=[N:7][C:6]=1[CH2:5][C:4]([OH:33])=[O:3]
Reactant: CCOC(=O)Cc1nc(NC(=O)c2cc(CC(C)C)cn2Cc2ccc(F)cc2F)sc1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)Cc1cc(C(=O)Nc2nc(CC(=O)O)c(Cl)s2)n(Cc2ccc(F)cc2F)c1
Reaction time: 17 h

Procedure:
(5-Chloro-2-{[1-(2,4-difluoro-benzyl)-4-isobutyl-1H-pyrrole-2-carbonyl]-amino}-thiazol-4-yl)-acetic acid ethyl ester was taken in THF and methanol and to it lithium hydroxide monohydrate in water was added and stirred for 16-18 hrs. at room temperature. After completion of the reaction, the solvent was evaporated; the residue was diluted with water and was washed with diethyl ether. The aqueous layer was acidified with 1N HCl and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and evaporated the solvent to get the title compound (5-Chloro-2-{[1-(2,4-difluoro-benzyl)-4-isobutyl-1H-pyrrole-2-carbonyl]amino}-thiazol-4-yl)-acetic acid (E1).
Reaction SMILES: OC(C(F)(F)F)=O.[S:8](=[N:11][CH2:12][C:13]([OH:15])=O)(=[O:10])=[O:9].ON1[C:21]2[N:22]=[CH:23][CH:24]=C[C:20]=2N=N1.Cl.CN(C)CCCN=C=NCC>CN(C=O)C.C(N(C(C)C)CC)(C)C>[CH2:21]([N:22]1[CH2:23][CH2:24][S:8](=[O:10])(=[O:9])[NH:11][CH2:12][C:13]1=[O:15])[CH3:20]
Reactant: O=C(O)CN=S(=O)=O
Reactant: On1nnc2cccnc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: CCN1CCS(=O)(=O)NCC1=O

Procedure:
To a mixture of the above N-sulfonylglycine TFA salt (0.32 g, 0.98 mmol), 1-hydroxy-7-azabenzotriazole (36 mg, 0.26 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.22 g, 1.13 mmol) in DMF (50 mL), diisopropyl-ethylamine was added dropwise to adjust the pH to 5-6, and the resultant mixture was stirred at room temp overnight. The reaction mixture was concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluted with chloroform. Collection and concentration of appropriate fractions provided 5-ethyl-1,2,5-thiadiazepan-4-one 1,1-dioxide as white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:6]([C:16]([F:19])([F:18])[F:17])[CH:5]=1)([O-])=O.[H][H]>C(O)C.[Ni]>[C:10]1([C:7]2[CH:8]=[CH:9][C:4]([NH2:1])=[CH:5][C:6]=2[C:16]([F:17])([F:18])[F:19])[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: O=[N+]([O-])c1ccc(-c2ccccc2)c(C(F)(F)F)c1
Reactant: [H][H]
Agent: [Ni]
Solvent: CCO
Product: Nc1ccc(-c2ccccc2)c(C(F)(F)F)c1

Procedure:
Phenyl boronic acid (Aldrich, Buchs, Switzerland; 2.7 g, 22 mmol), Palladium II acetate (0.225 g, 1 mmol), tri-o-tolylphosphine (0.608 g, 2 mmol) and aqueous potassium carbonate solution (50 mL of 1 M) is added to a stirred solution of 2-bromo-5-nitrobenzotrifuoride (Lancaster Synthesis, GmbH; 5.4 g, 20 mmol) in dimethylformamide (200 mL) and heated at 120° C. under an argon atmosphere for 1 h. The mixture is then evaporated to dryness under reduced pressure and the residue is treated with water (100 mL) and extracted with ethyl acetate (3×80 mL). The combined extracts are washed (brine), dried (MgSO4), filltered and the solvent is evorated off under reduced pressure to afford 4′-nitro-2′-(trifluoromethyl)-[1,1′-Biphenyl]. The biphenyl is dissolved in ethanol (200 mL) and hydrogenated at atmospheric pressure over Raney nickel (2 g) at 22° C. The calculated amount of hydrogen is taken up in 11 hours. The mixture is then filtered and the solvent is evaporated off under reduced pressure to yield the crude product which is purified by chromatograghy (silica gel; eluent ethyl acetate) to give the title compound as a brown oil. 1H-NMR (400 MHz, DMSO-d6): 5.62 (br.s, 2H), 6.80 (dd, 1H), 6.96 (d, 1H), 6.99 (d, 1H), 7.19–7.23 (m, 2H), and 7.29–7.39 (m, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:10]([C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)=[CH:9][C:6]([CH:7]=O)=[C:5]([O:16][CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[CH:4]=1.[C:25]([C:28]1[CH:36]=[CH:35][C:31]([C:32]([OH:34])=[O:33])=[CH:30][CH:29]=1)(=[O:27])[CH3:26].C[O-].[Li+].[ClH:40]>CN(C)C=O.CO.O>[ClH:40].[CH3:1][O:2][C:3]1[C:10]([C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)=[CH:9][C:6](/[CH:7]=[CH:26]/[C:25]([C:28]2[CH:36]=[CH:35][C:31]([C:32]([OH:34])=[O:33])=[CH:30][CH:29]=2)=[O:27])=[C:5]([O:16][CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[CH:4]=1
Reactant: COc1cc(OCCN2CCOCC2)c(C=O)cc1-c1cccs1
Reactant: CC(=O)c1ccc(C(=O)O)cc1
Agent: C[O-]
Agent: Cl
Agent: [Li+]
Solvent: O
Solvent: CO
Solvent: CN(C)C=O
Product: COc1cc(OCCN2CCOCC2)c(/C=C/C(=O)c2ccc(C(=O)O)cc2)cc1-c1cccs1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98 %

Procedure:
4-Methoxy-2-(2-morpholin-4-yl-ethoxy)-5-thiophen-2-yl-benzaldehyde (Ex-60A, 0.15 g, 0.43 mmol) and 4-acetylbenzoic acid (0.071 g, 0.43 mmol) were dissolved in a dimethylformamide-methanol solution (3.0 mL, 7:3). After complete dissolution, lithium methoxide (0.065 g, 1.7 mmol) was added and the resulting bright orange slurry was stirred in the dark at room temperature for 2 h. Upon completion, as determined by HPLC, the mixture was diluted with water (10 mL), acidified with a 1 N hydrochloric acid solution, and extracted with an ethyl acetate:tetrahydrofuran mixture (1:1, 6×20 mL). The combined organic extracts were dried over sodium sulfate and evaporated to dryness. The crude solid was slurried in ethyl alcohol (5 mL) to remove residual impurities and the resulting solid was collected on filter paper and dried in vacuo to yield 0.21 g (98%) of the title compound as a dark yellow solid, mp: 255° C. (dec). 1H-NMR (300 MHz, DMSO-d6) δ 8.34 (s, 1H), 8.26 (d, 2H, J=8.7 Hz), 8.11 (d, 2H, J=8.7 Hz), 8.08 (s, 1H), 7.95 (d, 1H, J=15.9 Hz), 7.71 (d, 1H, J=3.3 Hz), 7.55 (d, 1H, J=4.5 Hz), 7.15 (dd, 1H, J=4.5, 3.3 Hz), 6.94 (s, 1H), 4.68 (brs, 2H), 4.04 (s, 3H), 3.98 (brs, 2H), 3.81–3.88 (brm, 2H), 3.70 (brs, 2H), 3.54–3.58 (brm, 2H), 3.29 (brs, 2H). MS (ESI) m/z=494 ([M+H]+, 100%). Anal. Calcd. for C27H28ClNO6S: C, 61.18; H, 5.32; Cl, 6.69; N, 2.64; S, 6.05. Found: C, 61.18; H, 5.41; Cl, 6.16; N, 2.73; S, 5.87.
Reaction SMILES: COC(C1C=C(OC2C=CC(S(C)(=O)=O)=CC=2)C=C2OC(C)CC=12)=O.[C:26]([O:30][C:31]([C:33]1[CH:44]=[C:43]([OH:45])[C:36]2[CH2:37][C:38]([CH2:41][OH:42])([CH3:40])[O:39][C:35]=2[CH:34]=1)=[O:32])([CH3:29])([CH3:28])[CH3:27].[CH:46]1([S:49]([C:52]2[CH:57]=[CH:56][C:55](F)=[CH:54][CH:53]=2)(=[O:51])=[O:50])[CH2:48][CH2:47]1>>[C:26]([O:30][C:31]([C:33]1[CH:44]=[C:43]([O:45][C:55]2[CH:56]=[CH:57][C:52]([S:49]([CH:46]3[CH2:48][CH2:47]3)(=[O:50])=[O:51])=[CH:53][CH:54]=2)[C:36]2[CH2:37][C:38]([CH2:41][OH:42])([CH3:40])[O:39][C:35]=2[CH:34]=1)=[O:32])([CH3:27])([CH3:28])[CH3:29]
Reactant: CC(C)(C)OC(=O)c1cc(O)c2c(c1)OC(C)(CO)C2
Reactant: O=S(=O)(c1ccc(F)cc1)C1CC1
Agent: COC(=O)c1cc(Oc2ccc(S(C)(=O)=O)cc2)cc2c1CC(C)O2
Product: CC(C)(C)OC(=O)c1cc(Oc2ccc(S(=O)(=O)C3CC3)cc2)c2c(c1)OC(C)(CO)C2

Procedure:
The title compound was prepared in a similar manner as described for Intermediate 1f, from 4-hydroxy-2-hydroxymethyl-2-methyl-2,3-dihydro-benzofuran-6-carboxylic acid tert-butyl ester (227c) and 1-cyclopropanesulfonyl-4-fluoro-benzene. 1H NMR (400 MHz, CDCl3) δ 7.86 (d, J=8.59 Hz, 2 H) 7.23 (s, 1 H) 7.07 (d, J=8.59 Hz, 2 H) 3.73 (dd, J=11.87, 5.81 Hz, 1 H) 3.62 (d, J=7.58 Hz, 1 H) 3.16 (d, J=116.67 Hz, 1 H) 2.78 (d, J=16.67 Hz, 1 H) 2.48 (td, J=8.02, 4.67 Hz, 1 H) 1.55-1.58 (m, 12 H) 1.45 (s, 2 H) 1.36 (dd, J=4.67, 1.89 Hz, 2 H) 0.97-1.13 (m, 2 H); LCMS for C24H27O7S m/z 460.80 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([C:8]([C:13]3[CH2:14][CH2:15][NH:16][CH2:17][CH:18]=3)=[CH:9][NH:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl[CH2:20][CH2:21][CH2:22][O:23][C:24]1[C:25]2[CH:26]=[CH:27][NH:28][C:29]=2[CH:30]=[CH:31][CH:32]=1.C(=O)([O-])[O-].[K+].[K+]>>[N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([C:8]([C:13]3[CH2:14][CH2:15][N:16]([CH2:20][CH2:21][CH2:22][O:23][C:24]4[CH:32]=[CH:31][CH:30]=[C:29]5[C:25]=4[CH:26]=[CH:27][NH:28]5)[CH2:17][CH:18]=3)=[CH:9][NH:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc2c(C3=CCNCC3)c[nH]c2c1
Reactant: ClCCCOc1cccc2[nH]ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=[N+]([O-])c1ccc2c(C3=CCN(CCCOc4cccc5[nH]ccc45)CC3)c[nH]c2c1

Procedure:
The title compound was prepared in a fashion similar to that described in Example 192 from 6-nitro-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole (0.50 g, 2.1 mmol), 1-chloro-3-(1H-indole-4-oxy)propane (0.43 g, 2.1 mmol) and potassium carbonate (0.32 g, 2.3 mmol). The product was isolated as an orange granular solid. Yield 0.49 g (56%). mp 215-225° C. FDMS m/e=416 (M+ of free base).
Reaction SMILES: [CH2:1]=[O:2].C(N(CC)CC)C.C(O[CH:14]([C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[CH:22][CH:21]=1)[CH2:15][CH2:16][N+:17]([O-:19])=[O:18])(=O)C.O.[O:35]1CCOC[CH2:36]1>>[N+:17]([C:16]([CH2:15][CH2:14][C:20]1[CH:21]=[CH:22][C:23]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[CH:24][CH:25]=1)([CH2:1][OH:2])[CH2:36][OH:35])([O-:19])=[O:18]
Reactant: C=O
Reactant: CCCCCCCCc1ccc(C(CC[N+](=O)[O-])OC(C)=O)cc1
Reactant: C1COCCO1
Solvent: CCN(CC)CC
Solvent: O
Product: CCCCCCCCc1ccc(CCC(CO)(CO)[N+](=O)[O-])cc1
Temperature: 25 °C

Procedure:
To a mixture of paraformaldehyde (0.13 mol, 9 eq), 4 ml (1.5 eq) of triethylamine in 40 ml of 1,4-dioxane, 3-nitro-1-(4-octylphenyl)propyl acetate (13) (5 g, 0.015 mol) in 50 ml of 1,4-dioxane was added dropwise with stirring at RT, the mixture was slowly heated to 70° C., and stirred for 24 h at this temperature, under TLC control. To the reaction mixture was added water and the mixture, pH adjusted to ˜9-10 and stirred 16 h at 40° C. for deprotection (TLC and HPLC monitoring). After reaction completion (˜2-3 h) the mixture was extracted with ethyl acetate and washed successively with 1 N HCl, sodium bicarbonate solution and brine. The ethyl acetate solution was dried over sodium sulfate and concentrated. The residue was pure enough for transformation to the next step or can be purified by crystallization or silica gel column chromatography using hexane-ethyl acetate as eluent to afford a white solid with mp. 80-82° C., ESIMS 376.2 [M+Na]+
Reaction SMILES: C([O:3][C:4]([C:6]1[C:11]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][C:14]=2[F:20])=[C:10]([CH3:21])[C:9](=[O:22])[N:8]([CH3:23])[C:7]=1[CH2:24]Br)=O)C.[NH3:26]>CO>[F:20][C:14]1[CH:15]=[C:16]([CH3:19])[CH:17]=[CH:18][C:13]=1[NH:12][C:11]1[C:6]2[C:4](=[O:3])[NH:26][CH2:24][C:7]=2[N:8]([CH3:23])[C:9](=[O:22])[C:10]=1[CH3:21]
Reactant: N
Reactant: CCOC(=O)c1c(Nc2ccc(C)cc2F)c(C)c(=O)n(C)c1CBr
Solvent: CO
Product: Cc1ccc(Nc2c3c(n(C)c(=O)c2C)CNC3=O)c(F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 41.5 %

Procedure:
To a solution of 2-bromomethyl-4-(2-fluoro-4-methylphenylamino)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid ethyl ester (0.016 g, 0.040 mmol) in MeOH (0.50 mL) was added ammonia (0.006 mL, 0.040 mmol, 7 M solution in MeOH). After stirring for 2 hours at room temperature, the reaction mixture was heated to 40° C. for 8 hours. The resulting white precipitate was filtered to yield clean desired product (0.005 g, 46%). MS ESI (+) m/z 303 (M+1) detected; 1H NMR (400 MHz, DMSO) δ 8.16 (br s, 1H), 8.04 (br s, 1H), 6.81-6.94 (m, 3H), 4.33 (s, 2H), 3.45 (s, 3H), 2.33 (s, 3H), 1.63 (s, 3H). 19F (376 MHz, DMSO)−127.1 (s, 1F).