Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6](Cl)[N:5]=[C:4]([CH3:9])[N:3]=1.[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1.O.[C:22](=[O:25])([O-])[O-].[K+].[K+]>O1CCOCC1.[Pd].C(O)C>[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C:2]2[CH:7]=[C:6]([C:12]3[CH:17]=[CH:16][C:15]([O:25][CH3:22])=[CH:14][CH:13]=3)[N:5]=[C:4]([CH3:9])[N:3]=2)=[CH:14][CH:13]=1
Reactant: Cc1nc(Cl)cc(Cl)n1
Reactant: COc1ccc(B(O)O)cc1
Reactant: O=C([O-])[O-]
Agent: [Pd]
Agent: [K+]
Solvent: CCO
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(-c2cc(-c3ccc(OC)cc3)nc(C)n2)cc1

Procedure:
The 4,6-dichloro-2-methylpyrimidine 22 (0.10 g, 0.6 mmol) is dissolved in dioxane (1 mL). 4-Methoxy-phenylboronic acid (0.32 g, 2.1 mmol) is added, followed by water (0.01 mL), ethanol (0.01 mL), potassium carbonate (0.40 g, 2.9 mmol), and tetrakistriphenyl-phosphino)palladium (0.13 g, 0.11 mmol). The mixture is stirred under nitrogen and subjected to microwave (170° C. for 5 min). The resulting orange suspension is filtered, the solids are washed with more dioxane, and the resulting solution is concentrated and purified by silica gel chromatography (5% to 25% ethyl acetate in hexanes) to yield the 4,6-bis-(4-methoxy-phenyl)-2-methyl-pyrimidine 23 as an oil. 1H-NMR (400 MHz, CDCl3) δ=8.03 (d, J=8.8 Hz, 2H), 7.70 (s, 1H), 6.95 (d, J=8.8 Hz, 2H), 3.82 (s, 6H), 2.77 (s, 3H). MS calculated for C19H19N2O2 (M+H+) 306.15, found 306.9.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([C:12]([N:14]2[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15]2)=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:23]3[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=3[CH:25]=O)[CH:8]=2)[N:3]=1.Cl.[F:32][C@H:33]1[CH2:37][CH2:36][NH:35][CH2:34]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>ClCCCl.O1CCCC1>[NH2:1][C:2]1[N:11]=[C:10]([C:12]([N:14]2[CH2:15][C:16]3[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:22]2)=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:23]3[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=3[CH2:25][N:35]3[CH2:36][CH2:37][C@H:33]([F:32])[CH2:34]3)[CH:8]=2)[N:3]=1
Reactant: F[C@H]1CCNC1
Reactant: Nc1nc(C(=O)N2Cc3ccccc3C2)c2cc(-c3ccccc3C=O)ccc2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: ClCCCl
Product: Nc1nc(C(=O)N2Cc3ccccc3C2)c2cc(-c3ccccc3CN3CC[C@H](F)C3)ccc2n1
Temperature: 40 °C
Reaction time: 6 h

Procedure:
200 mg of 2-[2-amino-4-(1,3-dihydroisoindole-2-carbonyl)quinazolin-6-yl]benzaldehyde are dissolved in 3 ml of 1,2-dichloroethane and 3 ml of tetrahydrofuran. 92 mg of (S)-(+)-3-fluoropyrrolidine hydrochloride are added, and the mixture is stirred at 40° C. for 6 h. After cooling to 25° C., 226 mg of sodium triacetoxyborohydride are added and stirred at 25° C. for a further 12 h. The mixture is poured into water, extracted three times with dichloromethane, and the combined organic phases are dried over sodium sulfate. After filtration, the filtrate is evaporated to dryness and purified by chromatography (reversed phase HPLC).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([OH:13])=O)=[CH:5][CH:4]=1.S(Cl)(Cl)=O.[OH-].[Na+].[CH2:20]([NH2:23])[CH2:21][CH3:22]>ClCCl>[CH2:20]([NH:23][C:11](=[O:13])[CH2:10][CH2:9][C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=1)[CH2:21][CH3:22]
Reactant: COc1ccc(CCC(=O)O)cc1
Reactant: CCCN
Agent: [Na+]
Agent: [OH-]
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CCCNC(=O)CCc1ccc(OC)cc1
Reaction time: 1 h

Procedure:
3-(4-methoxyphenyl)-propionic acid (8.8 g, 49 mmol) was refluxed in dichloromethane (200 mL) with thionylchloride (6,6 mL, 90 mmol) for 1 h. The volatiles were evaporated and the resulting oil was dissolved in dichloromethane (100 mL). This was added to a vigorously stirred mixture of 5% aqueous NaOH (200 mL), dichloromethane (100 mL) and n-propylamine (3.0 mL, 71 mmol). After stirring for 1 h the layers were separated and the aqueous layer was extracted with dichloromethane (3×50 mL). The combined organic layers were washed with water (50 mL) and brine (50 mL) and was dried over MgSO4. Evaporation of the solvent gave the amide in quantitative yield (10.7 g, 49 mmol, 100%). IR (neat) cm−1 3300, 2961; 1734, 1642; MS (EI) m/z 221 (M+). Analyses were in agreement with literature data.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([CH2:22][CH:23]2[CH2:27][CH2:26][CH2:25][C:24]2=O)[C:13]([NH:15][C:16]2[CH:21]=[N:20][CH:19]=[CH:18][N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].Cl.[CH3:30][O:31][NH2:32]>N1C=CC=CC=1.CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([CH2:22][CH:23]2[CH2:27][CH2:26][CH2:25][C:24]2=[N:32][O:31][CH3:30])[C:13]([NH:15][C:16]2[CH:21]=[N:20][CH:19]=[CH:18][N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9]
Reactant: CON
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2=O)C(=O)Nc2cnccn2)cc1Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: CO
Product: CON=C1CCCC1CC(C(=O)Nc1cnccn1)c1ccc(S(C)(=O)=O)c(Cl)c1
Temperature: 25 °C
Yield: 89.4 %

Procedure:
A solution of 2-(3-chloro-4-methanesulfonyl-phenyl)-3-(2-oxo-cyclopentyl)-N-pyrazin-2-yl-propionamide (prepared as in Example 32, 99.5 mg, 0.23 mmol) in pyridine (0.69 mL) and methanol (0.69 mL) at 25° C. was treated with methoxyamine hydrochloride (30 mg, 0.35 mmol). The reaction mixture was heated under reflux for 12 h. At this time, the reaction was cooled to 25° C. and was concentrated in vacuo. The resulting residue was dissolved in ethyl acetate (75 mL) and was washed with a 1N aqueous sodium hydroxide solution (1×50 mL) and a saturated aqueous sodium chloride solution (1×50 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 75/25 ethyl acetate/hexanes) afforded 2-(3-chloro-4-methanesulfonyl-phenyl)-3-(2-methoxyimino-cyclopentyl)-N-pyrazin-2-yl-propionamide (92.7 mg, 87.2%) as a white wax: mp 74-76° C.; FAB-HRMS m/e calcd for C20H23ClN4O4S (M+Na)+ 473.1021. found 473.1024.
Reaction SMILES: N[C:2]1[CH2:3][O:4][C:5]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:6]=2[S:7][C:8]=1[C:9]#[N:10].Cl.[Cl-].[NH4+].C([OH:22])C>>[CH3:16][O:15][C:12]1[CH:13]=[CH:14][C:5]2[O:4][CH2:3][C:2](=[O:22])[CH:8]([C:9]#[N:10])[S:7][C:6]=2[CH:11]=1
Reactant: COc1ccc2c(c1)SC(C#N)=C(N)CO2
Reactant: CCO
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Product: COc1ccc2c(c1)SC(C#N)C(=O)CO2
Temperature: 85 °C
Reaction time: 0.5 h

Procedure:
In 60 ml of ethanol is suspended 6.0 g of 3-amino-7-methoxy-2H-1,5-benzoxathiepin-4-carbonitrile, and 18 ml of concentrated hydrochloric acid is added to the suspension, followed by stirring at 80 to 90° C. for 30 minutes. After the reaction mixture is cooled, ammonium chloride, which separates out, is filtered off, and the filtrate is concentrated under reduced pressure. The residue is recrystallized from ethyl acetate-hexane to give colorless prisms of 7-methoxy-3-oxo-3,4-dihydro-2H-1,5-benzoxathiepin-4-carbonitrile. Yield of 5.1 g, m.p. of 132°-133° C.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([I:10])=[CH:6][C:3]=1[CH:4]=O.[NH:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1)[NH2:12].C(=O)([O-])[O-].[Cs+].[Cs+].CN1C(=O)CCC1>C(OC(=O)C)C.O>[I:10][C:7]1[CH:6]=[C:3]2[C:2](=[CH:9][CH:8]=1)[N:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1)[N:12]=[CH:4]2
Reactant: O=Cc1cc(I)ccc1F
Reactant: NNc1ccccn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN1CCCC1=O
Product: Ic1ccc2c(cnn2-c2ccccn2)c1
Temperature: 100 °C
Yield: 4.6 %

Procedure:
2-Fluoro-5-iodobenzaldehyde (527 mg, 2.11 mmol), 2-hydrazinopyridine (237 mg, 2.17 mmol), cesium carbonate (2.06 g, 6.32 mmol) and NMP (10 ml) werer charged in a 10 ml vial which was sealed and stirred (magnetic bar) over night at 100° C. Water and ethylacetate were added and the phases was separated. The organic layer was washed three times with brine and concentrated. Purification on silica with ethylacetate:heptane 5:95 to 10:90 over 15 min, 10 ml/min, followed by evaporation afforded 31 mg (5%) of 5-iodo-1-pyridin-2-yl-1H-indazole.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[C:11]([CH3:13])[N:10]([CH2:14][C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[C:9](=[O:21])[C:8]=1[Br:22])(=O)=O.CCN(C(C)C)C(C)C.[F:34][C:35]1[CH:40]=[CH:39][C:38]([C:41]#[CH:42])=[CH:37][CH:36]=1>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Br:22][C:8]1[C:9](=[O:21])[N:10]([CH2:14][C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[C:11]([CH3:13])=[CH:12][C:7]=1[C:42]#[C:41][C:38]1[CH:39]=[CH:40][C:35]([F:34])=[CH:36][CH:37]=1
Reactant: Cc1cc(OS(=O)(=O)C(F)(F)F)c(Br)c(=O)n1Cc1cccnc1
Reactant: C#Cc1ccc(F)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(C#Cc2ccc(F)cc2)c(Br)c(=O)n1Cc1cccnc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.7 %

Procedure:
To a degassed solution of 3-bromo-6-methyl-2-oxo-1-(pyridin-3-ylmethyl)-1,2-dihydropyridin-4-yl trifluoromethanesulfonate (0.6675 g, 1.56 mmol) in DMF (9 mL), DIEA (0.35 mL, 2.03 mmol), 4-fluorophenylacetylene (0.235 mL, 1.95 mmol) and PdCl2(PPh3)2 (0.11 g) were added. The reaction mixture stirred at room temperature under nitrogen for 1 hour and then heated in an oil bath (65° C.) under nitrogen overnight. The solvents were distilled in vacuo and the residue was purified by flash column chromatography (5% methanol in ethyl acetate). The extracts were concentrated to afford the desired compound (0.432 g, 69%) after drying. 1H-NMR (CD3OD, 400 MHz) δ 8.45 (s, 2H), 7.96 (s, 1H), 7.64 (m, 3H), 7.41 (dd, 1H, J=4.8 Hz, 4.8 Hz), 7.18 (t, 2H, J=8.8 Hz), 6.46 (s, 1H), 5.45 (s, 2H), 2.37 (s, 3H); ES-HRMS m/z 397.0361/399.0310 (M+H calculated for C20H15N2OFBr requires 397.0346/399.0328).
Reaction SMILES: [NH3:1].Cl[C:3]1[C:4]2[C:11]([I:12])=[CH:10][N:9]([CH:13]3[CH2:16][CH2:15][CH2:14]3)[C:5]=2[N:6]=[CH:7][N:8]=1.C(=O)=O.CC(C)=O>O1CCOCC1.CC(O)C>[CH:13]1([N:9]2[C:5]3[N:6]=[CH:7][N:8]=[C:3]([NH2:1])[C:4]=3[C:11]([I:12])=[CH:10]2)[CH2:16][CH2:15][CH2:14]1
Reactant: Clc1ncnc2c1c(I)cn2C1CCC1
Reactant: N
Agent: O=C=O
Solvent: CC(C)=O
Solvent: C1COCCO1
Solvent: CC(C)O
Product: Nc1ncnc2c1c(I)cn2C1CCC1
Temperature: 100 °C

Procedure:
Gaseous ammonia (from a lecture bottle) was condensed into a suspension of 4-chloro-7-cyclobutyl-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (70.7 mg, 0.8115 mmol) in dioxane (2 mL) and iPrOH (2 mL) in a sealable glass tube, cooled by dry ice/acetone, until the volume increased by ≈2 mL, then the tube was sealed and heated to 100° C. overnight. The solvents were evaporated, water was added, the mixture was extracted with CH2Cl2 (3×30 mL), and the combined CH2Cl2 extracts were washed with brine, dried over MgSO4, filtered and concentrated to give the title compound as a white solid. 1H NMR (CDCl3, 400 MHz): δ=1.83-1.95 (m, 2H), 2.34-2.47 (m, 2H), 2.48-2.58 (m, 2H), 5.22 (quint, J=8.7 Hz, 1H), 5.63 (brs, 2H), 7.26 (s, 1H), 8.26 (s, 1H). 13C NMR (CDCl3, 100.6 MHz, DEPT135): δ=14.92 (−), 31.05 (2C, −), 48.50 (+), 48.82 (Cquart), 104.11 (Cquart), 126.39 (+), 149.82 (Cquart), 152.00 (+), 156.94 (Cquart). MS (ES+): m/z 315.0 (100) [MH+]. HPLC: tR=2.4 min (OpenLynx, polar—5 min).
Reaction SMILES: Br[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5]([NH:12][C:13]2[N:17]=[C:16]([NH2:18])[NH:15][N:14]=2)=[CH:4][C:3]=1[Cl:19].[CH:20]([S:23]([C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1)(=[O:25])=[O:24])([CH3:22])[CH3:21].C([O-])([O-])=O.[K+].[K+]>COCCOC.O1CCOCC1.CO.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>[Cl:19][C:3]1[CH:4]=[C:5]([NH:12][C:13]2[N:17]=[C:16]([NH2:18])[NH:15][N:14]=2)[CH:6]=[C:7]([C:8]([F:11])([F:10])[F:9])[C:2]=1[C:29]1[CH:28]=[CH:27][C:26]([S:23]([CH:20]([CH3:22])[CH3:21])(=[O:25])=[O:24])=[CH:31][CH:30]=1
Reactant: CC(C)S(=O)(=O)c1ccc(B(O)O)cc1
Reactant: Nc1nc(Nc2cc(Cl)c(Br)c(C(F)(F)F)c2)n[nH]1
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: COCCOC
Solvent: C1COCCO1
Solvent: CO
Product: CC(C)S(=O)(=O)c1ccc(-c2c(Cl)cc(Nc3n[nH]c(N)n3)cc2C(F)(F)F)cc1
Temperature: 125 °C

Procedure:
A mixture of N3-(4-bromo-3-chloro-5-(trifluoromethyl)phenyl)-1H-1,2,4-triazole-3,5-diamine Intermediate 1 (150 mg, 421 μmol), 4-(isopropylsulfonyl)phenylboronic acid (240 mg, 1.05 mmol) and 3M K2CO3 (351 μl, 1.05 mmol) in DME (1 ml) and dioxane (1 ml) was degassed with argon and tetrakis(triphenylphosphine)palladium(0) (97.2 mg, 84.1 μmol) was added. The reaction mixture was heated in microwave at 125° C. for 3 hours, diluted with MeOH, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, 24 g, 3% to 7% MeOH in DCM). Further purification by super fluid chromatography afforded a white foam (32 mg, 16% yield) as desired product. MS +m/z: 460 (M+H)+
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[CH2:7][C:8]1[CH:9]=[C:10]([N+:14]([O-:16])=[O:15])[CH:11]=[CH:12][CH:13]=1.[CH3:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](Cl)=[O:23])=[CH:20][CH:19]=1.C(N(CC)CC)C>>[CH3:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([C:6]2[N:2]([CH3:1])[C:3]([CH2:7][C:8]3[CH:9]=[C:10]([N+:14]([O-:16])=[O:15])[CH:11]=[CH:12][CH:13]=3)=[CH:4][CH:5]=2)=[O:23])=[CH:20][CH:19]=1
Reactant: Cn1cccc1Cc1cccc([N+](=O)[O-])c1
Reactant: Cc1ccc(C(=O)Cl)cc1
Solvent: CCN(CC)CC
Product: Cc1ccc(C(=O)c2ccc(Cc3cccc([N+](=O)[O-])c3)n2C)cc1
Yield: 28 %

Procedure:
3-(1-Methylpyrrol-2-ylmethyl)nitrobenzene (2.0 g, 9.2 mmol) [prepared as in Example 8, Step (b)], 4-methylbenzoyl chloride (2.84 g, 18.4 mmol), and triethylamine (2.0 ml, 14.3 mmol) were dissolved in xylenes (80 ml) and the reaction mixture was refluxed for 36 h. Purification on a Florisil column (hexane-ethyl acetate, 95:5) gave 3-{5-(4-methyl-benzoyl)-1-methyl-1H-pyrrol-2-ylmethyl}nitrobenzene (0.86 g, 28%) as a solid. ##STR45##
Reaction SMILES: [O:1]=[C:2]1[CH:10]([CH2:11][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][N:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.Br[CH2:25][CH2:26][CH2:27][CH2:28][C:29]#[N:30]>>[O:1]=[C:2]1[C:10]([CH2:11][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][N:13]=2)([CH2:25][CH2:26][CH2:27][CH2:28][C:29]#[N:30])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=C1C(Cc2ccncn2)c2ccccc2N1c1ccccc1
Reactant: N#CCCCCBr
Product: N#CCCCCC1(Cc2ccncn2)C(=O)N(c2ccccc2)c2ccccc21
Yield: 68 %

Procedure:
By substituting 2,3-Dihydro-2-oxo-1-phenyl-3-(4-pyrimidinylmethyl)-1H-indole and 5-bromopentanenitrile in Example 1, the desired product was obtained in 68% yield as an oil; NMR(CDCl3TMS): δ1.21 (m, 1H); 1.35 (m, 1H); 1.60 (m, 1H); 1.65 (m, 1H); 2.00 (m, 1H); 2.20 (m, 1H); 2.26 (m, 2H); 3.25 (d, 1H, J=14 Hz); 3.55 (d, 1H, J=14 Hz); 6.65 (d, 1H, J=8 Hz); 6.98 (m, 1H); 7.09 (m, 2H); 7.21 (m, 1H); 7.27 (m, 2H); 7.42 (m, 1H); 7.51 (t, 2H, J=7 Hz); 8.44 (d, 1H, J=5 Hz); 8.90 (s, 1H); IR(KBr): 1718, 1612, 1583, 1549, 1500, 1481, 1465, 1454, 1376, 1326, 1221, 758, 733, 700 cm-1 ; mass spec m/e 383 (M+1). HRMS: m/e calcd 383.187187, m/e found 383.185396 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:58]=[CH:57][C:6]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([O:17][C:18]4[CH:23]=[CH:22][C:21]([NH:24][C:25]([C:27]5[C:32](=[O:33])[N:31]([C:34]6[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=6)[N:30]=[CH:29][CH:28]=5)=[O:26])=[CH:20][C:19]=4[F:41])=[C:11]3[C:10]([N:42]3[CH2:46][CH:45]4[CH2:47][N:48](C(OC(C)(C)C)=O)[CH2:49][CH:44]4[CH2:43]3)=[N:9]2)=[CH:5][CH:4]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[F:41][C:19]1[CH:20]=[C:21]([NH:24][C:25]([C:27]2[C:32](=[O:33])[N:31]([C:34]3[CH:35]=[CH:36][C:37]([F:40])=[CH:38][CH:39]=3)[N:30]=[CH:29][CH:28]=2)=[O:26])[CH:22]=[CH:23][C:18]=1[O:17][C:16]1[CH:15]=[CH:14][N:13]=[C:12]2[N:8]([CH2:7][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:58][CH:57]=3)[N:9]=[C:10]([N:42]3[CH2:46][CH:45]4[CH:44]([CH2:49][NH:48][CH2:47]4)[CH2:43]3)[C:11]=12
Reactant: COc1ccc(Cn2nc(N3CC4CN(C(=O)OC(C)(C)C)CC4C3)c3c(Oc4ccc(NC(=O)c5ccnn(-c6ccc(F)cc6)c5=O)cc4F)ccnc32)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(Cn2nc(N3CC4CNCC4C3)c3c(Oc4ccc(NC(=O)c5ccnn(-c6ccc(F)cc6)c5=O)cc4F)ccnc32)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 37.2 %

Procedure:
A round-bottomed flask was charged with tert-butyl 5-(1-(4-methoxybenzyl)-4-(2-fluoro-4-(1-(4-fluorophenyl)-6-oxo-1,6-dihydropyridazine-5-carboxamido)phenoxy)-1H-pyrazolo[3,4-b]pyridin-3-yl)-hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (42.5 mg, 0.0537 mmol), 2,2,2-trifluoroacetic acid (123 mg, 1.07 mmol) and CH2Cl2 (10 mL). The reaction mixture was stirred at ambient temperature for 4 hours. The solvent was removed and the residue was purified by silica gel chromatography (DCM/7 M NH3 in MeOH from 50/1 to 10/1, v/v) to give product (13.8 mg, 37.2%). LRMS (APCI neg): m/e 690 (M).
Reaction SMILES: O=[C:2]([CH2:20][CH3:21])[CH:3]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=1)[C:4]([O:6]CC)=O.[Br:22][C:23]1[CH:29]=[CH:28][C:26]([NH2:27])=[CH:25][CH:24]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(OC2C=CC=CC=2)C=CC=CC=1>CCOCC.C1(C)C=CC=CC=1>[Br:22][C:23]1[CH:24]=[C:25]2[C:26](=[CH:28][CH:29]=1)[N:27]=[C:2]([CH2:20][CH3:21])[C:3]([CH2:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]([F:17])([F:18])[F:19])=[CH:14][CH:15]=1)=[C:4]2[OH:6]
Reactant: Nc1ccc(Br)cc1
Reactant: CCOC(=O)C(Cc1ccc(C(F)(F)F)cc1)C(=O)CC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: CCOCC
Product: CCc1nc2ccc(Br)cc2c(O)c1Cc1ccc(C(F)(F)F)cc1
Temperature: 125 °C
Reaction time: 18 h

Procedure:
A round-bottomed flask equipped with a Dean-Stark apparatus was charged with ethyl 3-oxo-2-(4-(trifluoromethyl)benzyl)pentanoate (8.84 g, 29.2 mmol, Intermediate 5: step a), 4-bromoaniline (5.00 g, 29.2 mmol), para-toluenesulfonic acid (0.503 g, 2.9 mmol), and toluene (146 mL). The mixture was heated to 125° C. After 18 hours, the flask was cooled to room temperature. The toluene was removed by rotary evaporation to provide an amber colored solid. A mixture of the solid and diphenyl ether (29.1 mL) was heated to 220° C. After 70 minutes, the mixture was cooled to room temperature. Ether (100 mL) and hexanes (50 mL) were added. The mixture was allowed to stir for 30 minutes during which time a white solid crashed out of solution. The suspension was filtered through filter paper, rinsing with ether. The gummy solids were collected. Acetonitrile (20 mL) was added and the mixture was sonicated for 5 minutes. The slurry was filtered through filter paper and the solids were rinsed with acetonitrile. The off-white solids were collected, dried, and then used in the next step without further purification.
Reaction SMILES: [CH3:1][N:2]([CH3:34])[CH2:3][C@H:4]([NH:16][S:17]([C:20]1[S:21][C:22]([C:25]#[C:26][C:27]2[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=2)=[CH:23][CH:24]=1)(=[O:19])=[O:18])[CH2:5][C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7].[CH3:35][I:36]>>[I-:36].[CH2:9]([O:8][C:6](=[O:7])[CH2:5][C@@H:4]([NH:16][S:17]([C:20]1[S:21][C:22]([C:25]#[C:26][C:27]2[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=2)=[CH:23][CH:24]=1)(=[O:18])=[O:19])[CH2:3][N+:2]([CH3:35])([CH3:1])[CH3:34])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: CI
Reactant: Cc1ccc(C#Cc2ccc(S(=O)(=O)N[C@H](CC(=O)OCc3ccccc3)CN(C)C)s2)cc1
Product: Cc1ccc(C#Cc2ccc(S(=O)(=O)N[C@H](CC(=O)OCc3ccccc3)C[N+](C)(C)C)s2)cc1
Product: [I-]

Procedure:
According to the method described in example S76b, (R)-benzyl 4-(dimethylamino)-3-(5-(p-tolylethynyl)thiophene-2-sulfonamido)butanoate was reacted with methyl iodide to give the title compound as a yellow solid (quantitative). MS ESI 511.2 [M+H]+, calcd for [C27H30N2O4S2+H]+ 511.17.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:28][C:29]([O:37][CH2:38][CH2:39]O)([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH3:30]>C(Cl)Cl.[Al]>[Br:1][CH2:39][CH2:38][O:37][C:29]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)([CH3:30])[CH3:28]
Reactant: CC(C)(OCCO)c1ccccc1
Reactant: O=C1CCC(=O)N1Br
Agent: [Al]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(OCCBr)c1ccccc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 42 %

Procedure:
N-bromosuccinimide (119 mg, 0.666 mmol) was added to resin-bound triphenylphosphine (222 mg, 0.666 mequiv, Fluka) and 2-[(1-methyl-1-phenylethyl)oxy]ethanol (60 mg, 0.333 mmol) in DCM (4 mL). The reaction vial was sealed with a Teflon-lined cap, wrapped in aluminum foil, and shaken at rt for 17 h. The reaction was filtered through a SPE cartridge (5 g silica) eluting with the following 10 mL fractions: DCM (fraction 1), 30% EtOAc/hexanes (fraction 2), and 50% EtOAc/hexanes (fraction 3) to give the title compound (34 mg, 42%). The product was characterized by 1H NMR (400 MHz) in CDCl3.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH2:11][C:12](Cl)=[O:13])=[CH:8][CH:7]=[CH:6][CH:5]=2.[F:15][C:16]1[CH:21]=[CH:20][C:19]([CH:22]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)[N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[CH:18][CH:17]=1.N1C=CC=CC=1.C(=O)(O)[O-].[Na+]>O1CCCC1.C(OCC)(=O)C>[CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH2:11][C:12]([N:26]1[CH2:25][CH2:24][N:23]([CH:22]([C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)[C:19]3[CH:18]=[CH:17][C:16]([F:15])=[CH:21][CH:20]=3)[CH2:28][CH2:27]1)=[O:13])=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: Cc1[nH]c2ccccc2c1CC(=O)Cl
Reactant: Fc1ccc(C(c2ccc(F)cc2)N2CCNCC2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: Cc1[nH]c2ccccc2c1CC(=O)N1CCN(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 53.6 %

Procedure:
Under a nitrogen atmosphere a 15 mL solution of 2-methylindol-3-ylacetyl chloride (0.013 mole) in tetrahydrofuran was added to a stirred solution of 3.9 grams (0.014 mole) of N-[bis(4-fluorophenyl)methyl]piperazine and 1.1 mL (0.013 mole) of pyridine in 50 mL of dried tetrahydrofuran. Upon completion of the addition the reaction mixture was stirred at ambient temperature for about 18 hours, after which the reaction mixture was poured into a mixture of 200 mL of ethyl acetate and 100 mL of aqueous saturated sodium bicarbonate solution. The organic layer was separated and washed with one portion of a saturated sodium chloride solution, dried with sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to a solid, which was taken up in hexane. This solution was concentrated under reduced pressure, yielding 3.2 grams of N-(2-methylindol-3-ylacetyl)-N′-[bis(4-fluorophenyl)methyl]piperazine, mp 93-103° C. The NMR spectrum was consistent with the proposed structure.