Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:54])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12][CH2:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][CH2:30][S:31][C:32]4[CH:37]=[CH:36][C:35]([O:38][CH2:39][C:40]([O:42]C)=[O:41])=[C:34]([CH3:44])[CH:33]=4)=[CH:24][C:23]=3[C:45]([F:48])([F:47])[F:46])=[C:18]([C:49]([F:52])([F:51])[F:50])[CH:17]=2)=[CH:8][C:7]=1[CH3:53].[OH-].[Na+].O.Cl>C(O)C>[C:40]([CH2:39][O:38][C:35]1[CH:36]=[CH:37][C:32]([S:31][CH2:30][CH2:29][CH2:28][C:25]2[CH:26]=[CH:27][C:22]([C:19]3[CH:20]=[CH:21][C:16]([CH2:15][CH2:14][CH2:13][S:12][C:9]4[CH:10]=[CH:11][C:6]([O:5][CH2:4][C:3]([OH:54])=[O:2])=[C:7]([CH3:53])[CH:8]=4)=[CH:17][C:18]=3[C:49]([F:50])([F:51])[F:52])=[C:23]([C:45]([F:48])([F:47])[F:46])[CH:24]=2)=[CH:33][C:34]=1[CH3:44])([OH:42])=[O:41]
Reactant: COC(=O)COc1ccc(SCCCc2ccc(-c3ccc(CCCSc4ccc(OCC(=O)OC)c(C)c4)cc3C(F)(F)F)c(C(F)(F)F)c2)cc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1cc(SCCCc2ccc(-c3ccc(CCCSc4ccc(OCC(=O)O)c(C)c4)cc3C(F)(F)F)c(C(F)(F)F)c2)ccc1OCC(=O)O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of [4-(3-{4′-[3-(4-methoxycarbonylmethoxy-3-methyl-phenylsulfanyl)-propyl]-2,2′-bis-trifluoromethyl-biphenyl-4-yl}-propylsulfanyl)-2-methyl-phenoxy]-acetic acid methyl ester (example 25) (102 mg, 0.12 mmol) in ethanol (5 ml) was added aqueous 1N NaOH (0.5 ml). The reaction mixture was stirred for 3 hours at room temperature and the evaporated. Water (10 ml) and 1 N HCl (0.6 ml) was added to the residue and the mixture was extracted with methylene chloride (2×30 ml). The combined organic phases were dried (MgSO4), filtered and evaporated to give the title compound in 96 mg (98%) yield.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]([OH:9])([CH3:8])[CH3:7].C([O-])(O)=O.[Na+].[Br:15]Br.CO>C(Cl)(Cl)Cl.[O-]S([O-])(=S)=O.[Na+].[Na+]>[Br:15][C:5]1[S:1][C:2]([C:6]([OH:9])([CH3:8])[CH3:7])=[N:3][CH:4]=1
Reactant: BrBr
Reactant: CC(C)(O)c1nccs1
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CC(C)(O)c1ncc(Br)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.5 %

Procedure:
The product of Step 1 (8.97 g, 62.6 mmol) was dissolved in CHCl3 (125 mL), and NaHCO3 (5.79 g, 68.9 mmol) was added. Bromine (15.01 g, 94 mmol) was then added dropwise. After stirring for 2 h at room temperature, LC/MS showed a mixture of starting material and product (50% conversion). Additional NaHCO3 (2.89 g, 34.5 mmol), bromine (7.51 g, 47.0 mmol), and methanol (15 mL) were added, and the reaction was stirred for another 2 h at room temperature. The reaction was diluted with 10% Na2S2O3, neutralized with saturated NaHCO3, and extracted with dichloromethane (2×). The combined organic layers were dried (MgSO4), filtered and evaporated. Flash chromatography (0-15% ethyl acetate in toluene) afforded 9.38 g (67%) of 2-(5-bromo-1,3-thiazol-2-yl)propan-2-ol as a white solid. ESI: [M+H]+m/z 221.9/223.9.
Reaction SMILES: CN(C=O)C.[OH:6][C:7]1[CH:12]=[CH:11][C:10](C(=O)C)=[CH:9][CH:8]=1.Br[CH2:17][C:18]([NH:20]C1C=CC(Br)=CC=1)=[O:19].C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C>[O:6]([CH2:17][C:18]([NH2:20])=[O:19])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: O=C(CBr)Nc1ccc(Br)cc1
Reactant: CC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: NC(=O)COc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 223.1 %

Procedure:
DMF (20 ml) was added to 1-(4-hydroxyphenyl)ethanone (1.81 g, 13.3 mmol), 2-bromo-N-(4-bromophenyl)acetamide (3.00 g, 10.2 mmol), and potassium carbonate (4.25 g, 30.7 mmol), and the mixture was stirred at room temperature for 16 hrs. The reaction mixture was diluted with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by alumina column chromatography (developing solvent; ethyl acetate), and powderized with ethyl acetate-diisopropyl ether (1:5) to give a phenoxyacetamide derivative (3.44 g). The title compound was obtained by similar operations as in Reference Example 20, Reference Example 21, Example 10 and Example 6 and using this compound.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([S:12]([N:15](CC3C=CC(OC)=CC=3)[C:16]3[S:17][CH:18]=[CH:19][N:20]=3)(=[O:14])=[O:13])=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1.[OH:42][C:43]([C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=1B(O)O)([CH3:45])[CH3:44]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[OH:42][C:43]([C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=1[C:2]1[C:11]2[C:6](=[CH:7][C:8]([S:12]([NH:15][C:16]3[S:17][CH:18]=[CH:19][N:20]=3)(=[O:13])=[O:14])=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1)([CH3:45])[CH3:44]
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(Cl)nccc3c2)cc1
Reactant: CC(C)(O)c1ccccc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(O)c1ccccc1-c1nccc2cc(S(=O)(=O)Nc3nccs3)ccc12
Yield: 40 %

Procedure:
To a microwave vial charged with 1-chloro-N-(4-methoxybenzyl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide (Intermediate JJJ; 50 mg, 0.112 mmol), potassium carbonate (77 mg, 0.561 mmol) and Pd(Ph3P)4 (12.96 mg, 0.011 mmol) was added dioxane (561 μl), (2-(2-hydroxypropan-2-yl)phenyl)boronic acid (20.18 mg, 0.112 mmol) and Water (187 μl) and irradiated at 100° C. for 30 min affording conversion to desired product (˜40%) with starting material remaining. To the mixture was added additional boronate (50 ul) and Pd(Ph3P)4 (12.96 mg, 0.011 mmol) and irradiated another 30 min at 100° C. affording consumption of starting material and product as the primary species. The organic layer was decanted and the aqueous rinsed once with EtOAc and the organics combined and dried under reduced pressure. To the resulting oil was added DCM (2 ml) and TFA (0.6 ml) and the resulting solution stirred at room temperature. The mixture was dried under reduced pressure and purified with a 25 g HP spherical silica gel (15 μm spherical, Interchim) ramping DCM:MeOH (90:10) in DCM (0-100%) affording product as a yellow film which was lyophilized from MeOH/H2O affording a fluffy yellow solid 1-(2-(2-hydroxypropan-2-yl)phenyl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide 2,2,2-trifluoroacetate (39 mg, 0.072 mmol, 64.5% yield). 1H NMR (400 MHz, DMSO-d6) δ=12.92 (br. s., 1H), 8.67-8.55 (m, 2H), 8.27 (br. s., 1H), 7.94 (d, J=8.3 Hz, 1H), 7.77-7.65 (m, 2H), 7.56 (t, J=7.1 Hz, 1H), 7.38 (t, J=7.4 Hz, 1H), 7.29 (d, J=4.6 Hz, 1H), 7.21 (d, J=7.3 Hz, 1H), 6.89 (d, J=4.6 Hz, 1H), 1.37 (s, 3H), 1.24 (s, 4H). m/z (ESI) 426.0 (M+H)+
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[F:12][C:13]([F:26])([F:25])[C:14]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][C:15]=1[NH2:16]>>[F:12][C:13]([F:25])([F:26])[C:14]1[CH:20]=[CH:19][C:18]([C:21]([F:23])([F:24])[F:22])=[CH:17][C:15]=1[NH:16][C:7](=[O:9])[C:6]1[CH:10]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=1[OH:11]
Reactant: Nc1cc(C(F)(F)F)ccc1C(F)(F)F
Reactant: O=C(O)c1cc(Br)ccc1O
Product: O=C(Nc1cc(C(F)(F)F)ccc1C(F)(F)F)c1cc(Br)ccc1O
Yield: 24 %

Procedure:
Using 5-bromosalicylic acid and 2,5-bis(trifluoromethyl)aniline as the raw materials, the same operation as the example 16 gave the title compound.
Reaction SMILES: [C:1]([O-])(=O)[CH:2]=[CH2:3].C1CC=CC=1.[C:11]1([CH3:17])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH2:2]1[CH:1]2[CH:14]3[CH:13]=[CH:12][CH:16]([CH:11]2[CH:17]=[CH:3]1)[CH2:15]3
Reactant: Cc1ccccc1
Reactant: C=CC(=O)[O-]
Agent: C1=CCC=C1
Product: C1=CC2C3C=CC(C3)C2C1

Procedure:
The derivative was synthesized as follows. 20 grams of the derivative of acrylate obtained as the third example was dissolved in 20 milliliters of toluene. 7 grams of cyclopentadiene was dropped into the solution cooled with ice, and was agitated through all night. Dicyclopentadiene was produced as by-product, and was eliminated in vacuum. Then, 24.9 grams of the derivative of norbornene was obtained. The derivative of norbornene was viscous liquid, and the yield was 95%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10])[NH2:5].[Br:12]Br.C([O-])([O-])=O.[Na+].[Na+]>C(O)(=O)C>[Br:12][C:6]1[CH:7]=[C:8]([N+:9]([O-:11])=[O:10])[C:2]([F:1])=[CH:3][C:4]=1[NH2:5]
Reactant: BrBr
Reactant: Nc1ccc([N+](=O)[O-])c(F)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: Nc1cc(F)c([N+](=O)[O-])cc1Br
Temperature: 2.5 °C
Reaction time: 1 h
Yield: 53.9 %

Procedure:
To a solution of 3-fluoro-4-nitroaniline (56 g, 0.36 mol) in acetic acid (500 mL) was added drop-wise bromine (17.7 mL, 0.36 mol) over 1 hour. The reaction mixture was stirred for 1 hour at 0-5° C. in an ice bath. The reaction mixture was basified with saturated Na2CO3 and extracted with ethyl acetate (200 mL×3). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to yield a residue that was purified by column chromatography on silica gel (petroleum ether/ethyl acetate 10:1) to give the 2-bromo-5-fluoro-4-nitroaniline (45.6 g, 84%) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 8.29 (d, J=7.6 Hz, 1H), 653 (d, J=12.4 Hz, 1H), 4.94 (br s, 2H).
Reaction SMILES: [C:1]1([C:7]2([CH2:13][NH:14][C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[O:23][CH3:24])=[O:16])[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.[C:31](OC(=O)C)(=[O:33])[CH3:32]>C(OCC)(=O)C>[C:31]([N:10]1[CH2:9][CH2:8][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([CH2:13][NH:14][C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[O:23][CH3:24])=[O:16])[CH2:12][CH2:11]1)(=[O:33])[CH3:32]
Reactant: COc1ccccc1C(=O)NCC1(c2ccccc2)CCNCC1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: COc1ccccc1C(=O)NCC1(c2ccccc2)CCN(C(C)=O)CC1

Procedure:
A solution of 0.1 g (0.31 mmol) of 4-phenyl-4-(3-(2-methoxyphenyl)-3-oxo-2-azaprop-1-yl)piperidine (Example 2), 0.025 mL of pyridine (0.31 mmole) in 2 mL of acetic anhydride was mixed for 18 hr. The reaction was diluted with ethyl acetate and washed with saturated NaHCO3. The organic fraction was dried over MgSO4 and the filtrate was concentrated. The residue was purified by chromatography (silica, ethyl acetate) to give the title compound.
Reaction SMILES: [C:1]1([C:15]([O-])=[C:11]([N+]([O-])=O)[CH:10]=[C:6]([N+]([O-])=O)[CH:5]=1)[N+]([O-])=O.[C:17]1([C:31]([OH:32])=[C:27]([N+:28]([O-:30])=[O:29])[CH:26]=[C:22]([N+:23]([O-:25])=[O:24])[CH:21]=1)[N+:18]([O-:20])=[O:19].[CH2:33](O)C>>[CH2:33]1[C:15]2[C:1](=[CH:5][CH:6]=[CH:10][CH:11]=2)[CH:26]=[CH:27][NH:28]1.[C:27]1([C:31]([O-:32])=[C:17]([N+:18]([O-:20])=[O:19])[CH:21]=[C:22]([N+:23]([O-:25])=[O:24])[CH:26]=1)[N+:28]([O-:30])=[O:29]
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])c(O)c([N+](=O)[O-])c1
Reactant: CCO
Agent: O=[N+]([O-])c1cc([N+](=O)[O-])c([O-])c([N+](=O)[O-])c1
Product: C1=Cc2ccccc2CN1

Procedure:
A solution of N-3,4-dimethoxybenzoyl-2-phenylethylamine (A1) (9.3 g, 0.033 mol) in 550 ml of tetrachloroethane was distilled to remove 75 ml of the solvent. The resulting solution was added in one portion to a cooled solution of P2O5 (44.5 g, 0.31 mol) in hexamethyldisiloxane which had been heated to reflux for 1 h under nitrogen to dissolve the P2O5. The reaction mixture was boiled with stirring under nitrogen for 2.5 h after which an additional 4.5 g (0.031 mol) of P2O5 was added. After 2 h further heating another portion of P2O5 (12 g, 0.085 mol) was added. Continued boiling for 30 min completed the reaction as indicated by tlc. The reaction was cooled in an ice bath and water (770 ml) was added with stirring. The layers were separated and the organic layer was washed with 500 ml of water. The combined aqueous extract was brought to pH 8 and extracted three times with 300 ml portions of ether. Removal of the ether afforded the crude dihydroisoquinoline A2 which was converted to the picrate by treatment with picric acid (8.7 g, 0.038 mol) in ethanol (105 ml). The crude picrate was crystallized from chloroform-ethanol to give A2 picrate (10.5 g, 66%) mp 148-151° dec. A2 picrate in methylene chloride was extracted three times with saturated NaHCO3 and eluted from a short column of basic alumina to give the title compound (6.0 g) which was dissolved in ethanol and treated with 2 ml. of concentrated hydrochloric acid. Evaporation of the ethanol solution gave the crude hydrochloride which was recrystallized from acetone to give pure 1-(3,4-dimethoxyphenyl)-3,4-dihydroisoquinoline hydrochloride (4.5 g 45%) mp 200-201°.
Reaction SMILES: C([C@@H]([C@H](C(O)=O)O)O)(O)=O.[CH:11]1([C@@H:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][CH2:19][NH:18]2)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.C(=O)(O)[O-].[Na+].[Cl:32][CH2:33][C:34](Cl)=[O:35]>CCOC(C)=O>[Cl:32][CH2:33][C:34]([N:18]1[CH2:19][CH2:20][C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[C@H:17]1[CH:11]1[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]1)=[O:35]
Reactant: c1ccc2c(c1)CCN[C@@H]2C1CCCCC1
Reactant: O=C(Cl)CCl
Agent: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: O=C(CCl)N1CCc2ccccc2[C@H]1C1CCCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(1R)-1-cyclohexyl-1,2,3,4-tetrahydroisoquinoline (L)-tartrate (520 mg) was dissolved in EtOAc (10 mL) and saturated aqueous sodium bicarbonate (10 mL) was added thereto. Under ice-cooling, a solution of chloroacetyl chloride (0.14 mL) in EtOAc (5 mL) was added dropwise to the reaction liquid over 5 minutes, followed by stirring at room temperature for 1 hour. The reaction liquid was extracted with EtOAc and dried over magnesium sulfate to obtain (1R)-2-(chloroacetyl)-1-cyclohexyl-1,2,3,4-tetrahydroisoquinoline (415 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[OH:9].[CH3:10]C1C=CC(S(O)(=O)=O)=CC=1.CC(OO)=O>C1COCC1>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]2[O:9][CH:10]=[N:1][C:2]=2[CH:7]=1
Reactant: Nc1cc(Cl)ccc1O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: CC(=O)OO
Solvent: C1CCOC1
Product: Clc1ccc2ocnc2c1
Temperature: 60 °C

Procedure:
To a 250 mL 3-neck round bottom flask equipped with a distillation head, glass stopper, septum, thermocouple and magnetic stir bar was charged 2-amino-4-chlorophenol (20.00 g, 0.139 mol). The solid was dissolved in THF (60 mL) and p-TsOH (0.265 g, 1.39 mmol) was added. The brown solution was warmed to 60° C. over 10 min and aged for 90 min. HPLC assay of the reaction mixture showed 1 LCAP unreacted starting material. The temperature was increased from 60° C. to 74° C., and at 63° C. solvent distillation began. A total of 58 mL was collected during the first distillation. The mixture was diluted with THF (60 mL) and a total of 67 mL of solvent was removed between 71 and 84° C. The mixture was again diluted with THF (60 mL) and 61 mL of solvent was removed between 74 and 114° C. The dark brown solution was cooled to room temperature. The final mass of the solution was 27.96 g. Analysis of the crude stream by 1H NMR showed 0.1 wt % MeOH present in the sample. 1H NMR (500 MHz, CDCl3): δ=8.10 (s, 1H), 7.76 (d, J=1.5 Hz, 1H), 7.50 (d, J=8.7 Hz, 1H), 7.36 ppm (dd, J=8.7, 1.7 Hz, 1H).
Reaction SMILES: [C:1]1(=[O:8])[O:7][C:5](=[O:6])[CH2:4][O:3][CH2:2]1.[CH3:9][N:10]1[C:14]([C:15]([NH2:17])=[O:16])=[C:13]([NH2:18])[C:12]([CH2:19][CH2:20][CH3:21])=[N:11]1>ClCCl>[NH2:17][C:15]([C:14]1[N:10]([CH3:9])[N:11]=[C:12]([CH2:19][CH2:20][CH3:21])[C:13]=1[NH:18][C:5]([CH2:4][O:3][CH2:2][C:1]([OH:7])=[O:8])=[O:6])=[O:16]
Reactant: O=C1COCC(=O)O1
Reactant: CCCc1nn(C)c(C(N)=O)c1N
Solvent: ClCCl
Product: CCCc1nn(C)c(C(N)=O)c1NC(=O)COCC(=O)O
Reaction time: 1 h

Procedure:
1.1 13.5 g of diglycolic anhydride are added at 15° to a solution of 20.5 g of 1-methyl-3-propyl4-amino-5-aminocarbonyl-1H-pyrazole (“Z6”) in 400 ml of dichloromethane, and the mixture is stirred for a further 1 hour. The mixture is subjected to conventional work-up, giving 32.5 g of [(5-aminocarbonyl-1-methyl-3-propyl-1H-pyrazol4-ylcarbamoyl)methoxy]-acetic acid (“Z7”).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:35]=[CH:36][CH:37]=1)[CH2:6][N:7]([C@@H:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:28][CH2:27][CH2:26]1)[C:8]([C:10]1[CH:15]=[C:14]([C:16]([OH:18])=[O:17])[C:13]([C:19]([OH:21])=[O:20])=[CH:12][C:11]=1[C:22]([OH:24])=[O:23])=[O:9])=O.[C:38]([O:42][NH2:43])([CH3:41])([CH3:40])[CH3:39]>>[C:38]([O:42]/[N:43]=[CH:1]/[C:3]1[CH:4]=[C:5]([CH:35]=[CH:36][CH:37]=1)[CH2:6][N:7]([C@@H:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:28][CH2:27][CH2:26]1)[C:8]([C:10]1[CH:15]=[C:14]([C:16]([OH:18])=[O:17])[C:13]([C:19]([OH:21])=[O:20])=[CH:12][C:11]=1[C:22]([OH:24])=[O:23])=[O:9])([CH3:41])([CH3:40])[CH3:39]
Reactant: CC(C)(C)ON
Reactant: O=Cc1cccc(CN(C(=O)c2cc(C(=O)O)c(C(=O)O)cc2C(=O)O)[C@H]2CCCc3ccccc32)c1
Product: CC(C)(C)O/N=C/c1cccc(CN(C(=O)c2cc(C(=O)O)c(C(=O)O)cc2C(=O)O)[C@H]2CCCc3ccccc32)c1

Procedure:
The product from Example 76E and O-(tert-butyl)hydroxylamine were processed as described in Example 76F to provide the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([OH:16])=O)=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[NH2:21][C@H:22]1[CH2:27][CH2:26][C@H:25]([OH:28])[CH2:24][CH2:23]1>>[Cl:20][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:21][CH:22]2[CH2:27][CH2:26][CH:25]([OH:28])[CH2:24][CH2:23]2)=[O:16])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: N[C@H]1CC[C@H](O)CC1
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Product: O=C(NC1CCC(O)CC1)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1

Procedure:
Prepared according to the procedure described for example 70 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carboxylic acid (150 mg, 0.43 mmol) and trans-4-aminocyclohexanol (59 mg, 0.51 mmol). The title compound was obtained as a solid (45 mg, 23% yield). 1H NMR (400 MHz, d6-DMSO) δ: 8.98 (2H, m), 8.58 (1H, m), 8.47 (1H, s), 4.56 (1H, d), 3.55 (1H, m), 3.37 (1H, m), 1.78 (4H, m), 1.20 (6H, m). MS m/z: 446.19, 448.18 [M+H]+.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[N:12]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[C:13]4[C:18]([C:19]=3[CH:20]=2)=[CH:17][CH:16]=[CH:15][CH:14]=4)=[CH:4][CH:3]=1.[CH3:27][C:28]1([CH3:42])[C:40]2[CH:39]=[C:38]([NH2:41])[CH:37]=[CH:36][C:35]=2[C:34]2[C:29]1=[CH:30][CH:31]=[CH:32][CH:33]=2>C1(C)C=CC=CC=1>[CH3:27][C:28]1([CH3:42])[C:40]2[CH:39]=[C:38]([NH:41][C:2]3[CH:3]=[CH:4][C:5]([C:8]4[CH:9]=[CH:10][C:11]5[N:12]([C:21]6[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=6)[C:13]6[C:18]([C:19]=5[CH:20]=4)=[CH:17][CH:16]=[CH:15][CH:14]=6)=[CH:6][CH:7]=3)[CH:37]=[CH:36][C:35]=2[C:34]2[C:29]1=[CH:30][CH:31]=[CH:32][CH:33]=2
Reactant: CC1(C)c2ccccc2-c2ccc(N)cc21
Reactant: Ic1ccc(-c2ccc3c(c2)c2ccccc2n3-c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CC1(C)c2ccccc2-c2ccc(Nc3ccc(-c4ccc5c(c4)c4ccccc4n5-c4ccccc4)cc3)cc21
Temperature: 25 °C
Yield: 96.4 %

Procedure:
50 g (112 mmol) 3-(4-Iodo-phenyl)-9-phenyl-9H-carbazole and 23.5 g (112 mmol) 9,9-Dimethyl-9H-fluoren-2-ylamine are dissolved in 500 ml toluene and 21.5 g sodium-tert-butylat is added. The reaction mixture is carefully degassed and 80 mg bis(diphenylphosphino)ferrocendichloro-Pd(II) (Pd(dppf)) complex is added. The solution is refluxed for 6 h. The reaction mixture is then cooled to room temperature and 250 ml water are added. The layers are separated. The water phase is extracted three times with toluene, and then the organic layers is washed twice with water dried over magnesium sulphate, filtrated and the solvent is removed under vacuum. The residue is recrystallized from butanole, to yield 57 g (108 mmol) (96%) of a white solid with a purity of 99.5%.
Reaction SMILES: [SH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[CH3:11][C:12]1[C:17]([Cl:18])=[C:16](I)[CH:15]=[CH:14][C:13]=1[NH:20][C:21](=[O:29])[C@:22]([OH:28])([CH3:27])[C:23]([F:26])([F:25])[F:24].CCOC(C)=O>CN(C=O)C.[Cu-]=O>[CH3:11][C:12]1[C:17]([Cl:18])=[C:16]([S:1][C:2]2[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=2)[CH:15]=[CH:14][C:13]=1[NH:20][C:21](=[O:29])[C@:22]([OH:28])([CH3:27])[C:23]([F:26])([F:24])[F:25]
Reactant: Cc1c(NC(=O)[C@@](C)(O)C(F)(F)F)ccc(I)c1Cl
Reactant: O=C(O)c1ccc(S)cc1
Agent: O=[Cu-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1c(NC(=O)[C@@](C)(O)C(F)(F)F)ccc(Sc2ccc(C(=O)O)cc2)c1Cl
Temperature: 150 °C
Yield: 89.3 %

Procedure:
4-Mercaptobenzoic acid (308 mg) was added to a suspension of Copper(I) oxide (93 mg) and (R)-N-(2-methyl-3-chloro-4-iodo-phenyl)-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide (Method 46) (530 mg) in DMF (5 ml). The mixture was heated under Argon to 150° C. for 4.5 hours. The mixture was allowed to cool to ambient temperature and EtOAc (100 ml) was added and the resulting suspension was filtered through diatomaceous earth, and volatile material was removed by evaporation. The residue was purified by chromatography, eluting with 5-10% MeOH in DCM to give the title compound (504 mg). NMR: 1.58 (s, 3H), 2.26 (s, 3H), 7.34 (m, 4H), 7.51 (brs, 1H), 7.92 (brs, 2H), 9.94 (s, 1H), 13.00 (brs, 1H); m/z 432.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[CH2:5][N:6]1[C:10]2[N:11]=[C:12]([NH2:20])[N:13]=[C:14]([C:15]3[O:16][CH:17]=[CH:18][CH:19]=3)[C:9]=2[N:8]=[N:7]1.[F:24][C:25]1[CH:32]=[CH:31][C:28]([CH:29]=O)=[CH:27][CH:26]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>C1COCC1>[F:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][NH:1][C:2]2[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=2)[CH2:5][N:6]2[C:10]3[N:11]=[C:12]([NH2:20])[N:13]=[C:14]([C:15]4[O:16][CH:17]=[CH:18][CH:19]=4)[C:9]=3[N:8]=[N:7]2)=[CH:27][CH:26]=1
Reactant: Nc1cccc(Cn2nnc3c(-c4ccco4)nc(N)nc32)c1
Reactant: O=Cc1ccc(F)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: Nc1nc(-c2ccco2)c2nnn(Cc3cccc(NCc4ccc(F)cc4)c3)c2n1
Temperature: 40 °C
Reaction time: 0.25 h
Yield: 39 %

Procedure:
A suspension of 3-(3-aminobenzyl)-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine (200 mg, 0.65 mmol) and 4A molecular sieves in THF (10 mL) was treated with 4-fluorobenzaldehyde (0.04 mL, 0.37 mmol), heated to 40° C. for 3 h, cooled to room temperature, treated sodium triacetoxyborohydride (400 mg, 1.89 mmol) and acetic acid (0.1 mL) and stirred for 15 minutes. The reaction was quenched by addition of sat. NaHCO3 (5 mL), extracted with EtOAc (2×5 mL) and the combined organic phase dried (MgSO4), concentrated in vacuo and purified by chromatography [(SiO2; EtOAc:Heptane (1:2)] to give the title compound (60 mg, 44%) as a white solid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[CH3:15][C:16]([CH3:26])([CH2:19][C:20]1([CH3:25])[O:24][CH2:23][CH2:22][O:21]1)[CH2:17][NH2:18].C(N(CC)CC)C>ClCCl>[CH3:15][C:16]([CH3:26])([CH2:19][C:20]1([CH3:25])[O:21][CH2:22][CH2:23][O:24]1)[CH2:17][NH:18][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13]
Reactant: CC(C)(CN)CC1(C)OCCO1
Reactant: O=[N+]([O-])c1cnc2ccccc2c1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(CNc1c([N+](=O)[O-])cnc2ccccc12)CC1(C)OCCO1
Yield: 99.9 %

Procedure:
The general method described in Step 1 of Example 1 was used to react 4-chloro-3-nitroquinoline (21.8 g, 104 mmol), 2,2-dimethyl-3-(2-methyl-[1,3]dioxolan-2-yl)propylamine (19.8 g, 114 mmol) and triethylamine (15.2 g, 150 mmol) in dichloromethane for 75 hours to provide [2,2-dimethyl-3-(2-methyl-[1,3]dioxolan-2-yl)propyl]-(3-nitroquinolin-4-yl)amine (35.9 g) as a yellow solid that was used directly in the next step without further purification.