Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8](OC)=[O:9])[CH:3]=1.[BH4-].[Na+]>CO.C(Cl)Cl>[I:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][OH:9])[CH:3]=1
Reactant: COC(=O)c1cc(I)ccn1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: OCc1cc(I)ccn1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of methyl 4-iodopicolinate 5AN (2.83 g, 10.78 mmol) in MeOH (30 ml) was added NaBH4 (1.59 g, 43.12 mmol) portion wise at 0° C. Reaction mixture was allowed to warm up to r.t. After stirring for 3 days at r.t, it was quenched with, 14 ml of 1N NaOH. Reaction mixture was diluted with DCM (200 ml). The organic layer was washed with water (2×30 ml), dried over MgSO4, filtered and concentrated. The residue was purified on silica gel eluting with 3/1 EtOAc/Hexane to give the desired product (4-iodo-pyridin-2-yl)-methanol 6AN (2.27 g, 90%).
Reaction SMILES: [C:1](N1C=CC=CC1=O)(N1C=CC=CC1=O)=[S:2].[CH3:17][S:18][C:19]1[N:20]=[CH:21][C:22]([NH2:25])=[N:23][CH:24]=1>ClCCl>[N:25]([C:22]1[CH:21]=[N:20][C:19]([S:18][CH3:17])=[CH:24][N:23]=1)=[C:1]=[S:2]
Reactant: CSc1cnc(N)cn1
Reactant: O=c1ccccn1C(=S)n1ccccc1=O
Solvent: ClCCl
Product: CSc1cnc(N=C=S)cn1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 1,1′-thiocarbonyldipyridin-2(1H)-one (1.069 g, 4.60 mmol) in dichloromethane at room temperature was added 5-(methylthio)pyrazin-2-amine (0.50 g, 3.54 mmol). The reaction was stirred at room temperature for 18 hours. LC/MS showed the desired product peak as the major peak. The deep orange mixture was purified by silica gel chromatography (0-40% ethyl acetate-hexanes) to afford 2-isothiocyanato-5-(methylthio)pyrazine (0.545 g, 0.257 mmol, 84% yield) as an orange oil. LCMS R.T.=2.65; [M+H]+=184.02.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][CH3:15])[CH:7]=1)[CH:2]1[O:4][CH2:3]1.[NH2:16][CH2:17][CH2:18][NH:19][C:20]1[N:21]([CH3:30])[C:22](=[O:29])[N:23]([CH3:28])[C:24](=[O:27])[C:25]=1[CH3:26].CN(C)C=O.O>C(Cl)Cl>[CH3:15][O:14][C:8]1[CH:7]=[C:6]([CH:11]=[CH:10][C:9]=1[O:12][CH3:13])[O:5][CH2:1][CH:2]([OH:4])[CH2:3][NH:16][CH2:17][CH2:18][NH:19][C:20]1[N:21]([CH3:30])[C:22](=[O:29])[N:23]([CH3:28])[C:24](=[O:27])[C:25]=1[CH3:26]
Reactant: Cc1c(NCCN)n(C)c(=O)n(C)c1=O
Reactant: COc1ccc(OCC2CO2)cc1OC
Solvent: CN(C)C=O
Solvent: O
Solvent: ClCCl
Product: COc1ccc(OCC(O)CNCCNc2c(C)c(=O)n(C)c(=O)n2C)cc1OC
Reaction time: 48 h

Procedure:
4.2 g. 3,4-Dimethoxyphenyl glycidyl ether and 8.5 g. 4-(2-aminoethylamino)-1,3,5-trimethylpyrimidine-2,6(1H,3H)-dione in 5 ml. dimethylformamide are left to stand for 48 hours at ambient temperature. The reaction mixture is then dissolved in methylene chloride, shaken out five times with water and the organic phase is extracted with 1 N acetic acid. The aqueous phase is rendered alkaline by the addition of dilute aqueous sodium hydroxide solution and then extracted with methylene chloride. After drying the extract, the solution is chromatographed over silica gel using, as elution agent, methylene chloride-methanol-ammoniacal methanol (saturated) (20.1:1 v/v/v). After evaporating the pure fractions, the residue obtained is recrystallized from ethyl acetate. There are obtained 2.0 g. (24% of theory) of the desired product in the form of colorless crystals; m.p. 103°-104° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][CH2:12][CH:13]2[O:18][CH2:17][CH2:16][NH:15][CH2:14]2)=[O:10])=[CH:4][CH:3]=1.Br[CH:20]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:21]([O:23][CH2:24][CH3:25])=[O:22]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][CH2:12][CH:13]2[O:18][CH2:17][CH2:16][N:15]([CH:20]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:14]2)=[O:10])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(Br)c1ccccc1
Reactant: O=C(NCC1CNCCO1)Nc1ccc(Cl)cc1
Product: CCOC(=O)C(c1ccccc1)N1CCOC(CNC(=O)Nc2ccc(Cl)cc2)C1
Yield: 232.3 %

Procedure:
Example 44 was prepared in an analogous manner to Example 19 using a mixture of Intermediate 9 (0.01 g) and ethyl bromo(phenyl)acetate (0.029 g) to give the title compound (0.0372 g). LC-MS (System A): Rt 3.43 mins, Mass Spectrum m/z 432 [MH+].
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]2[S:9][C:10]([C:23]3[NH:27][CH:26]=[N:25][N:24]=3)=[C:11]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[Cl:22])[C:12]=2[C:13]#[N:14])[CH:5]=[CH:4][N:3]=1.N1C=CC=CC=1.[CH:34]1([C:37](Cl)=[O:38])[CH2:36][CH2:35]1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[C:13]([C:12]1[C:11]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[Cl:22])=[C:10]([C:23]2[NH:27][CH:26]=[N:25][N:24]=2)[S:9][C:8]=1[C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:1][C:37]([CH:34]2[CH2:36][CH2:35]2)=[O:38])[CH:7]=1)#[N:14]
Reactant: N#Cc1c(-c2ccnc(N)c2)sc(-c2nnc[nH]2)c1-c1ccc(Cl)cc1Cl
Reactant: O=C(Cl)C1CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: N#Cc1c(-c2ccnc(NC(=O)C3CC3)c2)sc(-c2nnc[nH]2)c1-c1ccc(Cl)cc1Cl
Temperature: 0 °C
Reaction time: 2 h
Yield: 35.5 %

Procedure:
To a mixture of 2-(2-aminopyridin-4-yl)-4-(2,4-dichlorophenyl)-5-(4H-1,2,4-triazol-3-yl)thiophene-3-carbonitrile (0.100 g, 0.24 mmol) in pyridine (0.39 mL, 4.8 mmol) and methylene chloride (10 mL) was added cyclopropanecarbonyl chloride 0.050 mL, 0.54 mmol) at 0° C. The mixture was stirred at 0° C. for 2 hours. Saturated sodium bicarbonate solution (5 mL) was added and the mixture was vigorously stirred for 15 min. The mixture was extracted with DCM, dried, filtered and evaporated and the residue was purified by column chromatography on silica gel (40 g) using DCM to 3% MeOH in DCM over 30 minutes to afford the product (0.041 g, 36%). LCMS: (FA) ES+, 481, 483. 1H NMR (400 MHz, d4-Methanol) 8.49-8.42 (m, 2H), 8.40 (s, 1H), 7.66 (dd, J=5.58, 1.76 Hz, 1H), 7.62 (t, J=1.16, 1.16 Hz, 1H), 7.46-7.44 (m, 2H), 1.99-1.87 (m, 1H), 1.11-1.03 (m, 2H), 1.00-0.94 (m, 2H)
Reaction SMILES: [F:1][C:2]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:3]=1[CH2:4][O:5][C:6]1[CH:11]=[C:10]([CH3:12])[N:9]([C:13]2[CH:14]=[C:15]([CH:20]=[CH:21][CH:22]=2)[C:16]([O:18][CH3:19])=[O:17])[C:8](=[O:23])[CH:7]=1.[Br:29]N1C(=O)CCC1=O>C(#N)C>[Br:29][C:7]1[C:8](=[O:23])[N:9]([C:13]2[CH:14]=[C:15]([CH:20]=[CH:21][CH:22]=2)[C:16]([O:18][CH3:19])=[O:17])[C:10]([CH3:12])=[CH:11][C:6]=1[O:5][CH2:4][C:3]1[CH:24]=[CH:25][C:26]([F:28])=[CH:27][C:2]=1[F:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1cccc(-n2c(C)cc(OCc3ccc(F)cc3F)cc2=O)c1
Solvent: CC#N
Product: COC(=O)c1cccc(-n2c(C)cc(OCc3ccc(F)cc3F)c(Br)c2=O)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 92.3 %

Procedure:
Methyl 3-[4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]benzoate (from step 2) (15.85 g, 41.130 mmol) suspended in acetonitrile (165 mL) was cooled in an ice-bath. N-bromosuccinimide (7.687 g, 43.186 mmol) was added and the ice-bath was removed. The reaction mixture was stirred for 1.5 hours at room temperature. Reaction was concentrated and subjected to chromatography (silica gel, ethyl acetate with 10% methanol/hexanes) afforded an off white solid (17.63 g, 92%). 1H NMR (400 MHz, CDCl3) δ 8.17 (dt, J=1.41, 7.85 Hz, 1H), 7.90 (t, J=1.81 Hz, 1H), 7.67-7.41 (m, 3H), 7.05-6.88 (m, 2H), 6.13 (s, 1H), 5.30 (s, 2H), 3.95 (s, 1H), 2.01 (s, 3H). ES-HRMS m/z 464.0286 (M+H C21H16BrF2NO4 requires 464.0304).
Reaction SMILES: C([O:3][C:4](=[O:29])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]3[CH:24]=[CH:23][C:22]([N+:25]([O-])=O)=[CH:21][CH:20]=3)[C:14]2=[O:28])=[CH:9][CH:8]=1)C.[NH2:30][C:31](N)=[O:32]>>[O:28]=[C:14]1[CH:15]([C:19]2[CH:24]=[CH:23][C:22]([NH:25][C:31]([NH:30][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=3[CH3:6])=[O:32])=[CH:21][CH:20]=2)[CH2:16][CH2:17][CH2:18][N:13]1[C:10]1[CH:11]=[CH:12][C:7]([CH2:6][CH2:5][C:4]([OH:3])=[O:29])=[CH:8][CH:9]=1
Reactant: CCOC(=O)CCc1ccc(-n2cccc(-c3ccc([N+](=O)[O-])cc3)c2=O)cc1
Reactant: NC(N)=O
Product: Cc1ccccc1NC(=O)Nc1ccc(C2CCCN(c3ccc(CCC(=O)O)cc3)C2=O)cc1

Procedure:
The title compound was prepared from 3-{4-[3-(4-nitrophenyl)-2-oxo-2H-pyridin-1-yl]phenyl}propionic acid ethyl ester which is prepared as described in Preparation 24 with subsequent hydrogenation, urea formation, and hydrolysis steps analogous to the procedures of Preparation 23, Preparation 9 and Example 1 respectively.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=O)[C:3]=1[N+:10]([O-:12])=[O:11].P(Cl)(Cl)([Cl:15])=O>>[Cl:15][C:4]1[C:3]([N+:10]([O-:12])=[O:11])=[C:2]([CH3:1])[CH:7]=[C:6]([CH3:8])[N:5]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cc(C)c([N+](=O)[O-])c(=O)[nH]1
Product: Cc1cc(C)c([N+](=O)[O-])c(Cl)n1
Temperature: 95 °C
Reaction time: 3 h
Yield: 180.4 %

Procedure:
A mixture of 4,6-dimethyl-3-nitro-2(1H)-pyridinone (step 1, 10.0 g, 29.7 mmol) in phosphorus oxychioride (35 mL, 187.3 mmol) was stirred at 95° C. for 3 h, then cooled to 45° C. The excess amount of phosphorus oxychloride was removed by distillation under reduced pressure at 45° C. The residue was cooled to room temperature, and diluted with dichloromethane (75 mL). The resulting solution was cooled to 0° C., and 2N hydrochloric acid (50 mL) was added dropwise into the solution. The organic layer was separated, and washed with 2N hydrochloric acid (4×25 mL), 2N aqueous NaOH (2×50 mL) and brine (50 mL). The organic phase was dried (MgSO4) and concentrated under reduced pressure to give 10.0 g (90%) of the title compound as white solids: 1H-NMR (CDCl3) δ 7.07 (1H, s), 2.56 (3H, s), 2.35 (3H, s).
Reaction SMILES: [C:1]([N:4]1[CH2:10][CH2:9][C:8]2[N:11]=[CH:12][C:13]([NH2:15])=[N:14][C:7]=2[CH2:6][CH2:5]1)(=O)[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].[ClH:22]>>[ClH:22].[NH2:15][C:13]1[CH:12]=[N:11][C:8]2[CH2:9][CH2:10][N:4]([CH2:1][CH3:2])[CH2:5][CH2:6][C:7]=2[N:14]=1
Reactant: CC(=O)N1CCc2ncc(N)nc2CC1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Product: CCN1CCc2ncc(N)nc2CC1

Procedure:
This compound was prepared analogous to Example 17 from 7-acetyl-2-amino-6,7,8,9-tetrahydro-5H-pyrazino[2,3-d]azepine by reduction with lithium aluminum hydride and subsequent precipitation of the monohydrochloride.
Reaction SMILES: [F:1][C:2]1[C:3]2[CH2:9][S:8][CH2:7][C:4]=2[S:5][CH:6]=1.C([Li])CCC.C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:25])(=O)=O)=CC=1>O1CCCC1.O=O>[F:25][C:6]1[S:5][C:4]2[CH2:7][S:8][CH2:9][C:3]=2[C:2]=1[F:1]
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Reactant: Fc1csc2c1CSC2
Agent: O=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Fc1sc2c(c1F)CSC2

Procedure:
In an alternate embodiment, a method is described of producing a monomer wherein the method begins by dissolving 3-fluoro-4,6 dihydrothieno[3,4-b]thiophene in tetrahydrofuran in a non-oxygen atmosphere to create a solution. An initiator of n-butyllithium is then added to the solution to produce an initiated solution. This is followed by adding N-fluorobenzenesulfonimide to the initiated solution to produce 2,3-difluoro-4,6-dihydrothieno[3,4-b]thiophene. 2,3-difluoro-4,6-dihydrothieno[3,4-b]thiophene is then oxidized with meta-chloroperoxybenzoic acid to produce 2,3-difluorothieno[3,4-b]thiophene. 2,3-difluorothieno[3,4-b]thiophene is then bromoated with N-bromosuccinimide to produce 4,6-dibromo-2,3-difluorothieno[2,3-c]thiophene. The final step involves debrominating 4,6-dibromo-2,3-difluorothieno[2,3-c]thiophene and adding an aryl group to produce the monomer
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[O:10])=[CH:7][CH:6]=1.[F:13][C:14]([Si](C)(C)C)([F:16])[F:15].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>O1CCCC1.C(OCC)(=O)C>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]([OH:10])[C:14]([F:16])([F:15])[F:13])=[CH:7][CH:6]=1
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: COCOc1ccc(C=O)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COCOc1ccc(C(O)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.7 %

Procedure:
4-Methoxymethoxybenzaldehyde (658 mg, 3.96 mmol) was dissolved in tetrahydrofuran (4.0 mL). To this, (trifluoromethyl)trimethylsilane (702 μL, 475 mmol) and tetrabutylammonium fluoride (a 1.0 mol/L solution in tetrahydrofuran, 396 μL, 0.396 mmol) were added under a nitrogen atmosphere at 0° C. and the mixture was stirred at room temperature for 1 hour. To the reaction mixture, tetrabutylammonium fluoride (a 1.0 mol/L solution in tetrahydrofuran, 4.00 mL, 4.00 mmol) was added and the mixture was further stirred for 10 minutes. After water was added to the reaction mixture, extraction with ethyl acetate was performed, followed by washing with brine and drying over anhydrous sodium sulfate. The solvent was evaporated off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=7/3) to give 1-methoxymethoxy-4-(2,2,2-trifluoro-1-hydroxyethyl)benzene (Compound CQ) (895 mg, yield: 96%).
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[C:10]1([CH3:19])[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=1.C(=O)([O-])[O-].[Na+].[Na+].C1C=C(S([O-])(=O)=O)C=C(P(C2C=CC=C(S([O-])(=O)=O)C=2)C2C=CC=C(S([O-])(=O)=O)C=2)C=1.[Na+].[Na+].[Na+].O>CC1C=CC(C)=CC=1.OCC(CO)O.O.CS(C)=O.[Pd](Cl)Cl.C([O-])(=O)C.[Na+]>[C:4]([C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[C:13]1[CH:14]=[CH:15][C:10]([CH3:19])=[CH:11][CH:12]=1)#[N:5]
Reactant: Cc1ccc(B(O)O)cc1
Reactant: N#Cc1ccccc1Cl
Agent: Cl[Pd]Cl
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: OCC(O)CO
Solvent: Cc1ccc(C)cc1
Product: Cc1ccc(-c2ccccc2C#N)cc1
Yield: 87 %

Procedure:
15 g of 2-chlorobenzonitrile, 14.8 g of p-tolueneboronic acid and 28.9 g of sodium carbonate in 50 ml of p-xylene, 40 ml of glycerol and 10 ml of water were heated to 120° C. At 80° C., a mixture of 19.3 mg of palladium chloride, 17.9 mg of sodium acetate and 0.55 ml of TPPTS/H2O solution (0.6 molar) in 2.5 ml of DMSO was added. After the reaction was complete, the phases were separated. The aqueous phase was washed with 50 ml of toluene. The combined organic phases were washed with 20 ml of water and subsequently dried over sodium sulfate. Crystallization from n-heptane gave 18.3 g of 2-cyano-4'-methylbiphenyl.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:9][NH:10][CH2:11][C:12]2[C:17]([CH:18]([CH3:20])[CH3:19])=[CH:16][CH:15]=[CH:14][N:13]=2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.[OH:21][N:22]1[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][CH2:29][CH:30]=O)[C:23]1=[O:32].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH3:1][C:2]1[C:3]([CH2:9][N:10]([CH2:11][C:12]2[C:17]([CH:18]([CH3:20])[CH3:19])=[CH:16][CH:15]=[CH:14][N:13]=2)[CH2:30][CH2:29][CH2:28][CH2:27][N:24]2[CH2:25][CH2:26][N:22]([OH:21])[C:23]2=[O:32])=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cnc(CNCc2ncccc2C(C)C)c(C)c1
Reactant: O=CCCCN1CCN(O)C1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cnc(CN(CCCCN2CCN(O)C2=O)Cc2ncccc2C(C)C)c(C)c1

Procedure:
Using General Procedure B: Reaction of (3,5-Dimethyl-pyridin-2-ylmethyl)-(3-isopropyl-pyridin-2-ylmethyl)-amine and 4-(3-Hydroxy-2-oxo-imidazolidin-1-yl)-butyraldehyde with NaBH(OAc)3 in CH2Cl2 gave COMPOUND 153 as a colorless oil. 1H NMR (CDCl3) δ 0.98 (d, 6H, J=6.9 Hz), 1.28-1.46 (m, 4H), 2.19 (s, 3H), 2.28 (s, 3H), 2.53 (dd, 2H, J=7.2, 7.2 Hz), 2.93 (septet, 1H, J=6.9 Hz), 3.05 (t, 2H, J=7.2 Hz), 3.14 (t, 2H, J=7.2 Hz), 3.41 (t, 2H, J=7.2 Hz), 3.72 (s, 4H), 7.14 (dd, 1H, J=7.5, 4.8 Hz), 7.25 (s, 1H), 7.51 (dd, 1H, J=7.5, 1.2 Hz), 8.10 (br s, 1H), 8.19 (s, 1H), 8.33 (dd, 1H, J=4.8, 1.2 Hz); 13C NMR (CDCl3) δ 18.29 (2 carbons), 23.52 (2 carbons), 24.17, 25.51, 27.48, 41.29, 44.36, 48.91, 54.31, 58.75, 59.38, 123.20, 132.28, 133.29, 133.85, 139.13, 144.34, 145.95, 146.48, 154.29, 156.08, 165.16; ES-MS m/z 426 (M+H). Anal. Calcd. For C24H35N5O2.1.2H2O: C, 64.46; H, 8.43; N, 15.66. Found: C, 64.57; H, 8.03; N, 15.28.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:11]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)(=[O:13])=[O:12])[CH:6]=[C:5]2[OH:22].C(=O)([O-])[O-].[K+].[K+].[CH3:29][O:30][C:31](=[O:34])[CH2:32]Br>C(#N)C>[CH3:29][O:30][C:31](=[O:34])[CH2:32][O:22][C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([Br:1])[CH:3]=2)[N:7]([S:11]([C:14]2[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=2)(=[O:13])=[O:12])[CH:6]=1
Reactant: COC(=O)CBr
Reactant: COc1ccc(S(=O)(=O)n2cc(O)c3cc(Br)ccc32)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)COc1cn(S(=O)(=O)c2ccc(OC)cc2)c2ccc(Br)cc12
Temperature: 80 °C
Yield: 46.6 %

Procedure:
To a stirring solution of 5-bromo-1-(4-methoxy-benzenesulfonyl)-1H-indol-3-ol (21, 130 mg, 0.340 mmol) in acetonitrile (3.5 mL) in a high pressure reaction vessel was added potassium carbonate (235 mg, 1.70 mmol) and bromoacetic acid methyl ester (38.6 μL, 0.408 mmol). The vessel was flushed with a nitrogen atmosphere, sealed with a Teflon stopcock and heated to 80° C. for overnight. After the reaction mixture was cooled to 25° C., ethyl acetate was added and washed with saturated sodium bicarbonate. The organic layer was dried over magnesium sulfate, filtered and concentrated at reduced pressure to obtain a light brown solid. Purification of the crude material was carried out using biotage chromatography (30% ethyl acetate in hexanes) which afforded the product as an off-white solid (22, 72.0 mg, 47% yield). MS(ESI) [M+H+]+=454.2; 456.2.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[C:23]1([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29][NH2:30])[CH:24]=1.C(N(CC)CC)C>CN(C)C=O.C(OCC)(=O)C>[C:23]1([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29][NH:30][C:6](=[O:8])[C:5]2[CH:9]=[CH:10][C:2]([Cl:1])=[N:3][CH:4]=2)[CH:24]=1
Reactant: O=C(O)c1ccc(Cl)nc1
Reactant: NCc1cccc(-c2ccccc2)c1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O=C(NCc1cccc(-c2ccccc2)c1)c1ccc(Cl)nc1
Temperature: 100 °C
Reaction time: 0.75 h
Yield: 80.8 %

Procedure:
6-Chloronicotinic acid (0.29 g) and 1,1′-carbonylbis(1H-imidazole) (0.34 g) were dissolved in N,N-dimethylformamide (5 mL), and the solution was heated with stirring at 100° C. for 45 minutes. The reaction solution was brought back to room temperature. 1-Biphenyl-3-ylmethanamine (0.37 g) and triethylamine (0.51 mL) were added thereto, and the mixture was stirred at 70° C. for 2 hours. Ethyl acetate was added thereto, and the organic layer was washed with water and dried over sodium sulfate. After concentration under reduced pressure, the obtained residue was purified by silica gel column chromatography (Moritex Corporation, elution solvent: hexane/ethyl acetate) to obtain the title compound (0.48 g) as a white solid (yield: 81%).
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[CH:4]=[C:5]([CH2:9][N:10]2[C:22]3[CH:21]=[CH:20][CH:19]=[C:18]([OH:23])[C:17]=3[C:16]3[C:11]2=[CH:12][CH:13]=[CH:14][C:15]=3[C:24](=[O:26])[NH2:25])[CH:6]=[CH:7][CH:8]=1.Br[CH2:30][C:31]([O:33][CH3:34])=[O:32]>CN(C=O)C.C(OCC)(=O)C>[F:28][C:2]([F:27])([F:1])[C:3]1[CH:4]=[C:5]([CH2:9][N:10]2[C:22]3[CH:21]=[CH:20][CH:19]=[C:18]([O:23][CH2:30][C:31]([O:33][CH3:34])=[O:32])[C:17]=3[C:16]3[C:11]2=[CH:12][CH:13]=[CH:14][C:15]=3[C:24](=[O:26])[NH2:25])[CH:6]=[CH:7][CH:8]=1
Reactant: COC(=O)CBr
Reactant: NC(=O)c1cccc2c1c1c(O)cccc1n2Cc1cccc(C(F)(F)F)c1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)COc1cccc2c1c1c(C(N)=O)cccc1n2Cc1cccc(C(F)(F)F)c1
Reaction time: 0.25 h
Yield: 87.9 %

Procedure:
40% Methanolic Triton B (0.18 mL, 0.4 mM) was added to a solution of the 9-[(3-trifluoromethylphenyl)methyl]-4-hydroxy-5-carbamoyl carbazole (115 mg, 0.3 mN) in 5 mL DMF at room temperature. After 15 minutes, methyl bromoacetate (95 mg, 0.6 mM) was added and the resultant mixture stirred at room temperature for 22 hours. The mixture was diluted with ethyl acetate, washed four times with H2O, 1 N HCl, H2O, sat. NaHCO3, and saturated brine, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel (elution with ethyl acetate) to afford 120 mg (88%) of the {9-[(3-trifluoromethylphenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid, methyl ester as a white solid. 1H NMR (CDCl3) δ7.5-7.2 (m, 7H), 7.1 (d, 1H, J=8 Hz), 7.0 (d, 1H, J=8 Hz), 6.6 (d, 1H, J=8 Hz), 6.4 (br s, 1H), 6.0 (br s, 1H), 5.55 (s, 2H), 4.9 (s, 2H), and 3.9 (s, 3H). IR (KBr, cm−1) 1763 and 1673. MS (ES) m/e 457.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:16]=[CH:15][C:6]([O:7][C:8]2[C:9]([NH2:14])=[N:10][CH:11]=[CH:12][CH:13]=2)=[CH:5][CH:4]=1.[Br:19]Br>C(Cl)(Cl)Cl>[Br:19][C:12]1[CH:13]=[C:8]([O:7][C:6]2[CH:15]=[CH:16][C:3]([C:2]([F:1])([F:17])[F:18])=[CH:4][CH:5]=2)[C:9]([NH2:14])=[N:10][CH:11]=1
Reactant: BrBr
Reactant: Nc1ncccc1Oc1ccc(C(F)(F)F)cc1
Solvent: ClC(Cl)Cl
Product: Nc1ncc(Br)cc1Oc1ccc(C(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 52.3 %

Procedure:
A 250 mL round-bottomed flask was charged with 3-(4-(trifluoromethyl)phenoxy)pyridin-2-amine (1.24 g, 4.88 mmol) and CHCl3 (150 mL), cooled to 0° C. and bromine (0.275 mL, 5.37 mmol) was added dropwise. The reaction was stirred for 60 minutes. The reaction was quenched into a saturated aqueous NaHCO3 solution and extracted with CH2Cl2 (2×150 mL). The combined organics were dried over sodium sulfate, filtered and concentrated. The residue was purified on silica gel eluting with 20% EtOAc/hexanes. The combined fractions of product were treated with charcoal, filtered through GFF paper and concentrated to afford the title compound (0.850 g, 52.3% yield) as a tan solid.
Reaction SMILES: Cl[C:2]1[N:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][C:3]=1[C:4]([NH:6][CH2:7][C:8]1([CH2:21][CH:22]2[CH2:24][CH2:23]2)[CH2:13][CH2:12][CH:11]([S:14]([CH2:17][CH:18]2[CH2:20][CH2:19]2)(=[O:16])=[O:15])[CH2:10][CH2:9]1)=[O:5].O1CCCC1.[CH3:38][NH:39][CH3:40]>>[CH:18]1([CH2:17][S:14]([CH:11]2[CH2:12][CH2:13][C:8]([CH2:7][NH:6][C:4](=[O:5])[C:3]3[CH:25]=[CH:26][C:27]([C:29]([F:32])([F:31])[F:30])=[N:28][C:2]=3[N:39]([CH3:40])[CH3:38])([CH2:21][CH:22]3[CH2:24][CH2:23]3)[CH2:9][CH2:10]2)(=[O:16])=[O:15])[CH2:20][CH2:19]1
Reactant: CNC
Reactant: O=C(NCC1(CC2CC2)CCC(S(=O)(=O)CC2CC2)CC1)c1ccc(C(F)(F)F)nc1Cl
Solvent: C1CCOC1
Product: CN(C)c1nc(C(F)(F)F)ccc1C(=O)NCC1(CC2CC2)CCC(S(=O)(=O)CC2CC2)CC1
Temperature: 70 °C
Yield: 96 %

Procedure:
2-Chloro-N-(4-cyclopropylmethanesulfonyl-1-cyclopropylmethylcyclohexylmethyl)-6-trifluoromethylnicotinamide (50 mg, 0.10 mmol) was dissolved in 2M dimethylamine in tetrahydrofuran (2 ml, 4 mmol) and heated in a sealed tube at 70° C. for 2 hours. The mixture was allowed to cool to ambient temperature then evaporated. The residue was purified by preparative plate chromatography eluting with 10% ethyl acetate in dichloromethane. Collecting the appropriate band, followed by trituration of the silica with ethyl acetate, filtration and evaporation gave a white foam (49 mg, 96%). 1H NMR δ (ppm) (CDCl3): 8.18 (1H, d, J=7.7 Hz), 7.65 (1H, s), 7.26 (1H, d, J=7.7 Hz), 3.63 (2H, d, J=6.2 Hz), 2.94-2.89 (9H, m), 2.07-1.81 (6H, m), 1.39-1.31 (2H, m), 1.28-1.14 (3H, m), 0.79-0.67 (3H, m), 0.55-0.49 (2H, m), 0.42 (2H, q, J=5.3 Hz), 0.06 (2H, t, J=4.2 Hz). MS (m/e)=503.