Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][C@H:3]1[CH2:7][CH2:6][N:5]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:9])[CH2:4]1.[C:16]([N:23]1[CH2:26][CH2:25][C:24]1=O)([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>ClCCCl.C(O)(=O)C>[C:19]([O:18][C:16]([N:23]1[CH2:26][CH:25]([N:2]([C@H:3]2[CH2:7][CH2:6][N:5]([C:8](=[O:9])[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH2:4]2)[CH3:1])[CH2:24]1)=[O:17])([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)OC(=O)N1CCC1=O
Reactant: CN[C@H]1CCN(C(=O)c2ccccc2)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CN(C1CN(C(=O)OC(C)(C)C)C1)[C@H]1CCN(C(=O)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 78.5 %

Procedure:
To a solution of compound 4d (TFA salt, 124 mg, 0.39 mmol) and compound 1e (94 mg, 0.55 mmol) in 1,2-DCE (2 mL) was added acetic acid (0.1 mL). To this mixture was added Na(OAc)3BH (132 mg, 0.624 mmol). The reaction was stirred at room temperature for 4 h. To the reaction mixture was added aq. NaHCO3, and the resultant mixture was extracted with CH2Cl2. The organic layer was dried over Na2SO4 and concentrated. Purification by flash column chromatography (silica gel, 5% MeOH/EtOAc+0.5% TEA) gave compound 4e (0.11 g). MS m/z (M+H+) 360.5.
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]#[C:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1)(=O)=O.[CH3:16][NH2:17]>>[CH3:16][NH:17][CH2:6][CH2:7][C:8]#[C:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1
Reactant: CN
Reactant: CS(=O)(=O)OCCC#Cc1ccccn1
Product: CNCCC#Cc1ccccn1
Temperature: 45 °C
Reaction time: 3 h
Yield: 39 %

Procedure:
4-(Pyridin-2-yl)but-3-ynyl methanesulfonate (2.90 g, 12.87 mmol) was dissolved in methylamine 40% in aqueous solution (20 mL) and stirred for 3 hours under nitrogen at 45° C. The reaction mixture was cooled with ice, quenched with water and extracted with DCM. The organic phases were washed with brine, dried over MgSO4 and concentrated. The crude residue was purified over silicagel chromatography (prepacked 70 g silicagel column, DCM/MeOH: from 90/10 to 90/10 with 1% of TEA as eluent) to afford 817 mg N-methyl-4-(pyridin-2-yl)but-3-yn-1-amine (Yield: 39%) as a brown oil
Reaction SMILES: [CH2:1]([C:3]1[C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[C:6]([CH2:20][OH:21])=[C:5]([CH2:22][CH3:23])[N:4]=1)[CH3:2].[O:24]1[CH:29]=[CH:28][CH2:27][CH2:26][CH2:25]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>ClCCl>[CH2:1]([C:3]1[C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]([C:13]2[CH:14]=[CH:15][C:16]([F:19])=[CH:17][CH:18]=2)[C:6]([CH2:20][O:21][CH:25]2[CH2:26][CH2:27][CH2:28][CH2:29][O:24]2)=[C:5]([CH2:22][CH3:23])[N:4]=1)[CH3:2]
Reactant: CCc1nc(CC)c(C(=O)OC)c(-c2ccc(F)cc2)c1CO
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: CCc1nc(CC)c(C(=O)OC)c(-c2ccc(F)cc2)c1COC1CCCCO1
Yield: 87.8 %

Procedure:
A solution of 2,6-diethyl-4-(4-fluorophenyl)-5-(hydroxymethyl)-3-pyridinecarboxylic acid, methyl ester (10.0 g, 0.0315 mol), dihydropyran (4.3 ml, 0.0473 mol) and 6.17 g of p-toluene sulfonic acid was stirred (25° C.) for 24 hours, taken up in dichloromethane (400 ml), washed with saturated NaHCO3 (1×170 ml), washed with brine (1×170 ml), dried (MgSO4), and chromatographed on silica (85:15 hexane:ethyl acetate) to yield 11.1 g of the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.Br[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[CH:22]=1.[H-].[Na+]>O1CCCC1>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[CH:22]=2)(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)NCc2ccccn2)cc1
Reactant: CCCCCCCCCCCCCCOc1cccc(CBr)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCOc1cccc(CN(Cc2ccccn2)S(=O)(=O)c2ccc(C)cc2)c1
Temperature: 25 °C
Reaction time: 68 h
Yield: 45.7 %

Procedure:
The title compound is prepared by the procedure of Example 27, using 1.23 g of product from Example 79, 1.71 g of product from Example 25, 0.321 g of washed 50% sodium hydride and 70 ml of tetrahydrofuran. The reaction is stirred at room temperature for 68 hours. The residue is purified by column chromatography (silica gel: 25% ethyl acetate/hexane) to give 1.15 g of the desired product as a colorless oil, which crystallized on standing.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:25]=[CH:26][C:27]=1[O:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:38])([F:37])[F:36])[CH:30]=1)[CH2:6][O:7][C:8]1[CH:9]=[C:10]2[N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15][N:11]2[C:12](=[O:14])[N:13]=1)#[N:2]>C(O)(C(F)(F)F)=O>[O:14]=[C:12]1[N:11]2[CH2:15][CH2:16][NH:17][C:10]2=[CH:9][C:8]([O:7][CH2:6][C:5]2[CH:25]=[CH:26][C:27]([O:28][C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:37])([F:38])[F:36])[CH:30]=3)=[C:3]([CH:4]=2)[C:1]#[N:2])=[N:13]1
Reactant: CC(C)(C)OC(=O)N1CCn2c1cc(OCc1ccc(Oc3cccc(C(F)(F)F)c3)c(C#N)c1)nc2=O
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cc(COc2cc3n(c(=O)n2)CCN3)ccc1Oc1cccc(C(F)(F)F)c1

Procedure:
Prepared in a manner similar to that described for E60 using tert-butyl 7-((3-cyano-4-(3-(trifluoromethyl)phenoxy)benzyl)oxy)-5-oxo-2,3-dihydroimidazo[1,2-c]pyrimidine-1(5H)-carboxylate (30 mg, 0.057 mmol) in TFA (5 mL).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([NH:5][C:6](=[O:21])[CH2:7][NH:8][C:9](=[O:20])[C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)[CH2:2]1.[OH:22][C:23]1([C:30]2[S:34][CH:33]=[N:32][CH:31]=2)[CH2:28][CH2:27][C:26](=O)[CH2:25][CH2:24]1>CC1CCCO1.[Pt]>[OH:22][C:23]1([C:30]2[S:34][CH:33]=[N:32][CH:31]=2)[CH2:24][CH2:25][CH:26]([N:1]2[CH2:4][CH:3]([NH:5][C:6](=[O:21])[CH2:7][NH:8][C:9](=[O:20])[C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:18])([F:19])[F:17])[CH:11]=3)[CH2:2]2)[CH2:27][CH2:28]1
Reactant: O=C1CCC(O)(c2cncs2)CC1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Agent: [Pt]
Solvent: CC1CCCO1
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CN(C2CCC(O)(c3cncs3)CC2)C1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
N-[2-(3-azetidinylamino)-2-oxoethyl]-3-(trifluoromethyl)benzamide (3.44 kg, 4.8 w/w % in 2-MeTHF, 0.548 mol) in 2-methyl tetrahydrofuran (2-MeTHF, 3.3 kg) was added to an inertisized reactor. 4-hydroxy-4-(1,3-thiazol-5-yl)cyclohexanone (108.1 g, 0.537 mol) was added. Pt/C 5% wet (213.8 g) was added. The reactor was rinsed three times with N2, then rinsed three times with H2 and stirred vigorous for 12 hours at 25° C. and 1 bar H2. The catalyst was filtered and the mother liquor cooled to 15° C. 1N HCl (866 ml) was added to the mother liquor. Water (510 ml) was added and the mixture stirred for 30 minutes at 25° C. The layers were allowed to separate during 30 minutes and the organic layer was removed. 607 ml of isopropyl acetate (iPrOAc) was added to the water layer and stirred for 10 minutes. The layers were allowed to separate and the organic layer was removed. iPrOAc (607 ml) was added to the water layer and stirred for 10 minutes; the layers were allowed to separate and the organic layer was removed. 790 ml of iPrOAc was added to the water layer. Then, NaOH 50% (75.10 g) was added. The mixture was heated to 55° C., stirred for 30 minutes at 55° C., cooled to 25° C. over 2 hours and stirred for 3 hours at 25° C. The precipitate was filtered, washed with 152 ml iPrOAc and then washed three times with 152 ml water. The precipitate was dried for 20 hours at 40° C. under vacuum and N2 atmosphere to afford the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:16][C:17]([CH3:23])=[C:18]([CH2:20][CH2:21][OH:22])[N:19]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:31]([Si:35](Cl)([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)([CH3:34])([CH3:33])[CH3:32]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:16][C:17]([CH3:23])=[C:18]([CH2:20][CH2:21][O:22][Si:35]([C:31]([CH3:34])([CH3:33])[CH3:32])([C:42]3[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=3)[C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[N:19]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: Cc1oc(-c2ccc(OCc3ccccc3)cc2)nc1CCO
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1oc(-c2ccc(OCc3ccccc3)cc2)nc1CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 6 h
Yield: 99.6 %

Procedure:
To a mixture of 2-[2-(4-Benzyloxy-phenyl)-5-methyl-oxazol-4-yl]-ethanol [CAS 403611-91-6] (4.04 g, 13.0 mmol), triethylamine (3.6 mL, 25 mmol, and DMAP (0.16 g, 1.3 mmol) in CH2Cl2 (80 mL) at 0° C. is added a solution of tert-butylchlorodiphenylsilane (3.95 g, 14.4 mmol) in CH2Cl2 (10 mL) drop wise. The mixture is warmed to room temperature and stirred for 6 h. The mixture is washed with 0.5 N HCl (80 mL), and the organic phase is dried (MgSO4). After the solvent is removed in vacuo, the residue is purified by flash chromatography (elute 2:1 hexanes:EtOAc) to yield 7.09 g of the title compound as a white solid. MS (ES+) 548
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.C(=O)([O-])[O-].[Ca+2]>CN(C)C=O>[O:15]1[CH2:16][CH2:17][N:12]([C:2]2[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=2[N+:8]([O-:10])=[O:9])[CH2:13][CH2:14]1
Reactant: C1COCCN1
Reactant: O=[N+]([O-])c1ccc(O)cc1F
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(O)cc1N1CCOCC1
Temperature: 130 °C
Yield: 94 %

Procedure:
3-Fluoro4-nitrophenol (300 mg), morpholine (800 μl), and calcium carbonate (50 mg) were added to dimethylformamide (3 ml), and the mixture was heated at 130° C. for 12 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give 3-morpholino-4-nitrophenol (400 mg, yield 94%). The resultant 3-morpholino-4-nitrophenol (400 mg) was added to dimethylformamide (3 ml). Palladium hydroxid-carbon (110 mg) and hydrogen were added thereto, and the mixture was stirred at room temperature for 4 hr. The reaction solution was filtered through Celite, and the filtrate was concentrated. The residue was then purified by chromatography on silica gel using chloroform/acetone for development to give 4-amino-3-morpholinophenol (296 mg, yield 85%). The resultant 4-amino-3-morpholinophenol (296 mg), 4-chloro-6,7-dimethoxyquinazoline (479 mg), and n-tetraethylammonium bromide (244 mg) were dissolved in ethyl methyl ketone (10 ml) to prepare a solution. A solution (10 ml) of sodium hydroxide (479 mg) in water was added to the solution, and the mixture was sitrred at 80° C. for 4 hr. Water was added to the reaction solution, and the organic layer was extracted and was concentrated. The residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (396 mg, yield 68%).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[C:3]=1[OH:9].[Br:10]Br>C(Cl)(Cl)(Cl)Cl.C(Cl)(Cl)Cl>[Br:10][C:8]1[C:2]([F:1])=[C:3]([OH:9])[C:4](=[CH:6][CH:7]=1)[OH:5]
Reactant: Oc1cccc(F)c1O
Reactant: BrBr
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: Oc1ccc(Br)c(F)c1O
Temperature: -10 °C
Reaction time: 1 h

Procedure:
3-Fluorocatechol (7.2 g) in 50 ml of carbon tetrachloride and 40 ml of chloroform are treated at -10° C. within 10 minutes with a solution of 2.88 ml of bromine in 30 ml of carbon tetrachloride. After stirring at -10° C. for 1 hour the reaction mixture is filtered. The residual solid is washed with a small amount of cold carbon tetrachloride and dried. There are obtained 6.30 g of 4-bromo-3-fluorocatechol as a white powder. This is treated with 6.0 ml of diphenylchloromethane and heated to 130° C. within 1 hour. Subsequently, the product is distilled at 135° C./0.05 Torr and recrystallized from ethanol. There are obtained 6.40 g of 5-bromo-4-fluoro-2,2-diphenyl-1,3-benzodioxol as a white crystalline powder of m.p. 61.5°-63° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[N:14]([CH:15]=2)[CH:13]=[CH:12][O:11]3)=[CH:4][CH:3]=1.[C:16](OC(=O)C)(=[O:18])[CH3:17]>S(=O)(=O)(O)O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]3[N:14]([C:15]=2[C:16](=[O:18])[CH3:17])[CH:13]=[CH:12][O:11]3)=[CH:6][CH:7]=1
Reactant: CC(=O)OC(C)=O
Reactant: Fc1ccc(-c2cn3ccoc3n2)cc1
Agent: O=S(=O)(O)O
Product: CC(=O)c1c(-c2ccc(F)cc2)nc2occn12
Temperature: 135 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
To a mixture of 6-(4-fluorophenyl)-imidazo[2,1-b]oxazole (2675 g, 13.23 mol) and acetic anhydride (6.35 l) is added 160 ml of concentrated sulfuric acid. The reaction mixture is heated at 135° C. for 1.5 hours, then cooled to 80° C. with an ice bath. The reaction mixture is slowly quenched with 12.5 l of water. The solids are stirred overnight, filtered and air-dried. The solids are again suspended in water (15 l), stirred overnight, filtered, and washed with water (4 l) and then with toluene (4 l). The solid is dried under vacuum at 60° C., to give 2771 g (86%) of a dark brown solid; M.p.=173° C.; 300 MHz 1H NMR (DMSO-d6) δ 8.25-8.19 (m, 2H), 7.75-7.68 (m, 2H), 7.35-7.25 (m, 2H), 2.15 (s, 3H). LCMS: 245 [M+H].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9]O)=[CH:7][CH:8]=1.S(Cl)([Cl:13])=O>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][Cl:13])=[CH:7][CH:8]=1
Reactant: COc1ccc(CO)cc1
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: COc1ccc(CCl)cc1

Procedure:
To 138.0 g of p-methoxybenzyl alcohol in 500 ml of dry chloroform is added, dropwise, 119 g of thionyl chloride. Subsequently, the mixture is stirred and heated under reflux for 2 hours, concentrated from the steam bath and the residue fractionated to give p-methoxybenzyl chloride.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12]C(C(F)(F)F)=[CH:10][C:9]=1[NH:18][C:19](=[O:38])[CH2:20][C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]2[CH:30]=[N:31][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:34]=2)[CH:24]=1)=O)(C)(C)C.[C:40](O)([C:42]([F:45])([F:44])[F:43])=O>C(Cl)Cl>[CH:35]([C:32]1[N:31]=[CH:30][C:29]([C:25]2[CH:24]=[C:23]([C:21]3[CH2:20][C:19](=[O:38])[NH:18][C:9]4[CH:10]=[C:40]([C:42]([F:45])([F:44])[F:43])[CH:12]=[CH:13][C:8]=4[N:7]=3)[CH:28]=[CH:27][CH:26]=2)=[CH:34][CH:33]=1)([CH3:37])[CH3:36]
Reactant: CC(C)c1ccc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)ccc3NC(=O)OC(C)(C)C)c2)cn1
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)c1ccc(-c2cccc(C3=Nc4ccc(C(F)(F)F)cc4NC(=O)C3)c2)cn1

Procedure:
The title compound was prepared from (2-{3-[3-(6-isopropyl-pyridin-3-yl)-phenyl]-3-oxo-propionylamino}-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example M159) (260 mg, 0.506 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as an off-white solid (94 mg, 53%).
Reaction SMILES: Br[C:2]1[C:11]([C@H:12]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:13][O:14][C:15](=[O:20])[C:16]([CH3:19])([CH3:18])[CH3:17])=[C:10]([CH3:26])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:28])=[N+:7]2[O-:27].C(OC[C@@H](OC(C)(C)C)C1C([C:50]2[CH:55]=[CH:54][C:53]([Cl:56])=[CH:52][CH:51]=2)=C2C(=CC=1C)N=C(C)C=C2)(=O)C(C)(C)C>>[C:22]([O:21][C@@H:12]([C:11]1[C:2]([C:50]2[CH:55]=[CH:54][C:53]([Cl:56])=[CH:52][CH:51]=2)=[C:3]2[C:8](=[CH:9][C:10]=1[CH3:26])[N+:7]([O-:27])=[C:6]([CH3:28])[CH:5]=[CH:4]2)[CH2:13][O:14][C:15](=[O:20])[C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:25])([CH3:24])[CH3:23]
Reactant: Cc1ccc2c(-c3ccc(Cl)cc3)c([C@@H](COC(=O)C(C)(C)C)OC(C)(C)C)c(C)cc2n1
Reactant: Cc1cc2c(ccc(C)[n+]2[O-])c(Br)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Product: Cc1cc2c(ccc(C)[n+]2[O-])c(-c2ccc(Cl)cc2)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C

Procedure:
Following the procedure used to prepare compound (S)-5-bromo-6-(1-tert-butoxy-2-(pivaloyloxy)ethyl)-2,7-dimethylquinoline 1-oxide of Example 9, except that (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-2,7-dimethylquinolin-6-yl)ethyl pivalate was used instead of (S)-2-(5-bromo-2,7-dimethylquinolin-6-yl)-2-tert-butoxyethyl pivalate. LCMS-ESI+ (m/z): 484.3, 486.3 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][NH:13][S:14]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH:23]2[C:32]3[C:27](=[C:28]([Cl:34])[CH:29]=[C:30]([Cl:33])[CH:31]=3)[CH2:26][N:25]([CH3:35])[CH2:24]2)[CH:18]=1)(=[O:16])=[O:15].C(O[N:44]1[C:48](=[O:49])[CH2:47][CH2:46][C:45]1=[O:50])(=O)CCC([O-])=O>>[Cl:33][C:30]1[CH:31]=[C:32]2[C:27](=[C:28]([Cl:34])[CH:29]=1)[CH2:26][N:25]([CH3:35])[CH2:24][CH:23]2[C:19]1[CH:18]=[C:17]([S:14]([NH:13][CH2:12][CH2:11][O:10][CH2:9][CH2:8][O:7][CH2:6][CH2:5][O:4][CH2:3][CH2:2][NH:1][C:45](=[O:50])[CH2:46][CH2:47][C:48]([NH:44][CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][NH:13][S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH:23]3[C:32]4[C:27](=[C:28]([Cl:34])[CH:29]=[C:30]([Cl:33])[CH:31]=4)[CH2:26][N:25]([CH3:35])[CH2:24]3)[CH:18]=2)(=[O:16])=[O:15])=[O:49])(=[O:16])=[O:15])[CH:22]=[CH:21][CH:20]=1
Reactant: O=C([O-])CCC(=O)ON1C(=O)CCC1=O
Reactant: CN1Cc2c(Cl)cc(Cl)cc2C(c2cccc(S(=O)(=O)NCCOCCOCCOCCN)c2)C1
Product: CN1Cc2c(Cl)cc(Cl)cc2C(c2cccc(S(=O)(=O)NCCOCCOCCOCCNC(=O)CCC(=O)NCCOCCOCCOCCNS(=O)(=O)c3cccc(C4CN(C)Cc5c(Cl)cc(Cl)cc54)c3)c2)C1
Reaction time: 0.32 h

Procedure:
Compound 181 was prepared from compound 28 and (2,5-dioxopyrrolidin-1-yl) succinate following the procedure outlined in example 175. The crude product (200 mg) was purified by Flash-Prep-HPLC with the following conditions: Column, C18 silica gel; mobile phase, CH3CN/H2O/CF3COOH=0.05/100/0.05 increasing to CH3CN/H2O/CF3COOH=90/100/0.05 within 19 min; Detector, UV 254 nm. This resulted in 201 mg (78%) of a TFA salt of N1,N4-bis(2-(2-(2-(2-(3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylsulfonamido)ethoxy)ethoxy)ethoxy)ethyl)succinamide as a white solid. 1H-NMR (300 MHz, DMSO+DCl, ppm): δ 7.76 (d, J=7.5 Hz, 2H), 7.68 (s, 2H), 7.63-7.52 (m, 6H), 6.64 (s, 1H), 4.88-4.82 (m, 2H), 4.62-4.42 (m, 4H), 3.76-3.60 (m, 4H), 3.43-3.30 (m, 25H), 3.14-3.10 (m, 4H), 2.97 (s, 6H), 2.86-2.82 (m, 4H), 2.27 (s, 4H). MS (m/z): 589 [M/2+1]+.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[N:12]=[N:13][N:14]([CH2:16][C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[CH:15]=3)[CH:9]=2)[N:4](C(OC(C)(C)C)=O)[N:3]=1.C(N(C(C)C)CC)(C)C.Br[CH2:40][CH2:41][CH2:42][C:43](Cl)=[O:44]>O1CCCC1>[CH2:16]([N:14]1[CH:15]=[C:11]([C:8]2[CH:9]=[C:10]3[C:5](=[CH:6][CH:7]=2)[NH:4][N:3]=[C:2]3[N:1]2[CH2:40][CH2:41][CH2:42][C:43]2=[O:44])[N:12]=[N:13]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC(C)(C)OC(=O)n1nc(N)c2cc(-c3cn(Cc4ccccc4)nn3)ccc21
Reactant: O=C(Cl)CCCBr
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C1CCCN1c1n[nH]c2ccc(-c3cn(Cc4ccccc4)nn3)cc12
Temperature: 60 °C
Reaction time: 16 h

Procedure:
A suspension of Example 64A (200 mg, 0.51 mmol) and diisopropylethylamine (0.089 mL, 0.51 mmol) in tetrahydrofuran (5 mL) was stirred for about 15 minutes at ambient temperature then 4-bromobutanoyl chloride (0.059 mL, 0.51 mmol) was added. The reaction mixture was stirred for about 16 hours. The precipitate was removed by filtration and the filtrate concentrated under reduced pressure. The residue was taken up in acetonitrile (5 mL) and treated with diisopropylethylamine (0.089 mL, 0.51 mmol) and heated at about 60° C. for about 16 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was treated with hydrochloric acid (4 N in dioxane, 5 mL) and the reaction mixture stirred at room temperature for about 2 hours. The reaction mixture was concentrated under reduced pressure and the crude material was purified by reverse-phase HPLC using acetonitrile/water (0.05 M ammonium acetate) gradient elution method to afford the title compound as the acetate salt. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.84 (s, 1H), 8.56 (s, 1H), 8.49 (s, 1H), 7.84 (d, J=8.6 Hz, 1H), 7.51 (d, J=8.7 Hz, 1H), 7.29-7.46 (m, 5H), 5.64 (s, 2H), 3.96 (t, J=6.9 Hz, 2H), 2.56 (t, J=7.9 Hz, 2H), 2.25-2.12 (m, 2H). MS (ESI+) m/z 359 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([O:13][CH3:14])[CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2O.P(Cl)(Cl)([Cl:18])=O.CN(C)C=O>O>[Cl:18][C:6]1[C:5]2[C:10](=[C:11]([O:13][CH3:14])[CH:12]=[C:3]([O:2][CH3:1])[CH:4]=2)[N:9]=[CH:8][CH:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1cc(OC)c2nccc(O)c2c1
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(OC)c2nccc(Cl)c2c1

Procedure:
A solution of 6.5 g (31.6 mmol) of 6,8-dimethoxyquinolin-4-ol, 29 mL (316 mmol) of phosphorous oxychloride and 2.6 mL of N,N-dimethylformamide was stirred at room temperature for seven hours. The reaction solution was poured into a stirred mixture of ice and water. The aqueous mixture was washed three times with 300 mL portions of ethyl acetate, and then adjusted to pH 6 by the addition of solid sodium carbonate. 4-Chloro-6,8-dimethoxyquinoline was thus obtained as a colorless solid: yield 5.73 g (81%). The product was recrystallized from hot water for analysis: m.p. 115°-116° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:47]=[CH:46][CH:45]=[CH:44][C:4]=1[CH2:5][O:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH:18]2[O:30][CH2:31][CH2:32]OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:13][CH:12]=1.[F:48][C:49]1[CH:50]=[CH:51][C:52]([OH:61])=[C:53]([CH2:55][CH2:56][NH:57][C:58](=[O:60])[CH3:59])[CH:54]=1>>[C:58]([NH:57][CH2:56][CH2:55][C:53]1[CH:54]=[C:49]([F:48])[CH:50]=[CH:51][C:52]=1[O:61][CH2:32][CH2:31][O:30][CH:18]1[CH:17]([C:14]2[CH:13]=[CH:12][C:11]([O:10][CH2:9][CH2:8][CH2:7][O:6][CH2:5][C:4]3[CH:44]=[CH:45][CH:46]=[CH:47][C:3]=3[O:2][CH3:1])=[CH:16][CH:15]=2)[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:27])([CH3:29])[CH3:28])=[O:24])[CH2:19]1)(=[O:60])[CH3:59]
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCCOS(=O)(=O)c2ccc(C)cc2)cc1
Reactant: CC(=O)NCCc1cc(F)ccc1O
Product: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCCOc2ccc(F)cc2CCNC(C)=O)cc1

Procedure:
Analogously to Method G, 0.45 g of tert-butyl 4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}-3-[2-(toluene-4-sulphonyloxy)ethoxy]piperidine-1-carboxylate (Example 14b) and 0.27 g of N-[2-(5-fluoro-2-hydroxyphenyl)ethyl]acetamide are reacted. The title compound is obtained as a yellow oil. Rf=0.50 (EtOAc); Rt=5.59.
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[S:3].Br[CH:6]([C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=1)[C:7]([C:9]1[CH:10]=[C:11]([C:27]([NH:29][CH3:30])=[O:28])[C:12](=[O:26])[N:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=2)[C:14]=1[CH3:15])=O>C(#N)C>[NH2:1][C:2]1[S:3][C:6]([C:31]2[CH:32]=[CH:33][C:34]([Cl:37])=[CH:35][CH:36]=2)=[C:7]([C:9]2[CH:10]=[C:11]([C:27]([NH:29][CH3:30])=[O:28])[C:12](=[O:26])[N:13]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:24])([F:23])[F:25])[CH:17]=3)[C:14]=2[CH3:15])[N:4]=1
Reactant: CNC(=O)c1cc(C(=O)C(Br)c2ccc(Cl)cc2)c(C)n(-c2cccc(C(F)(F)F)c2)c1=O
Reactant: NC(N)=S
Solvent: CC#N
Product: CNC(=O)c1cc(-c2nc(N)sc2-c2ccc(Cl)cc2)c(C)n(-c2cccc(C(F)(F)F)c2)c1=O
Temperature: 120 °C
Yield: 17.5 %

Procedure:
Thiourea (8.5 mg, 0.11 mmol) was added to 5-[bromo(4-chlorophenyl)acetyl]-N,6-dimethyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide (SM4, mg, 55 mmol) in acetonitrile (1 ml) and the mixture was heated in a microwave oven to 120° C. for 10 min. The crude product was purified on an Xterra C8 column using a gradient of acetonitrile/water. Freeze drying of the mixture afforded the title compound (10 mg, 35%).
Reaction SMILES: [CH:1]1[C:2]([C:10]#[N:11])=[CH:3][C:4](Br)=[C:5](O)[C:6]=1Br.C1C(C#N)=CC(I)=C([OH:19])C=1I>>[OH:19][C:3]1[CH:4]=[CH:5][CH:6]=[CH:1][C:2]=1[C:10]#[N:11]
Reactant: N#Cc1cc(Br)c(O)c(Br)c1
Reactant: N#Cc1cc(I)c(O)c(I)c1
Product: N#Cc1ccccc1O

Procedure:
Bromoxynil and ioxynil.