Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCN(C(C)C)C(C)C.[Cl:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([OH:17])=O)=[CH:13][CH:12]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH3:42][NH:43][C@@H:44]([CH3:51])[CH2:45][N:46]1[CH2:49][CH:48]([OH:50])[CH2:47]1>C(Cl)Cl.C1COCC1>[Cl:10][C:11]1[CH:12]=[CH:13][C:14]([C:15]([N:43]([C@@H:44]([CH3:51])[CH2:45][N:46]2[CH2:49][CH:48]([OH:50])[CH2:47]2)[CH3:42])=[O:17])=[CH:18][CH:19]=1
Reactant: CN[C@@H](C)CN1CC(O)C1
Reactant: O=C(O)c1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: ClCCl
Product: C[C@@H](CN1CC(O)C1)N(C)C(=O)c1ccc(Cl)cc1
Reaction time: 0.08 h
Yield: 15.8 %

Procedure:
DIPEA (0.200 mL, 1.15 mmol) was added to a stirred suspension of 4-chlorobenzoic acid (0.06 g, 0.38 mmol) and TBTU (0.123 g, 0.38 mmol) in DCM (2 mL) at rt. The suspension was stirred for 5 min before it was cooled on an ice-bath. A solution of (S)-1-(2-(methylamino)propyl)azetidin-3-ol (Compound M11) (0.06 g, 0.42 mmol) in THF (1.5 mL) was added over 10 min. The ice-bath was removed and the reaction was stirred at rt over night. DCM (3 mL) was added and the mixture was washed with NaHCO3 (8% aq., 3 mL), filtered through a phase separator and concentrated under reduced pressure. The residue was dissolved in MeOH (2 mL) and NaOH (aq., 2M) was added. The resulting mixture was stirred at rt for 3 h, then concentrated under reduced pressure. DCM (5 mL) and NaHCO3, (aq., 8%, 5 mL) was added. The organic phase was collected and the solvents were removed under reduced pressure. The residue was purified by preparative HPLC to give the title compound (17 mg, 16%). Mixture of rotamers: 1H NMR (600 MHz, DMSO-d6) δ 0.99-1.12, 2.18-2.23, 2.33-2.79, 3.15-3.56, 4.03-4.18, 4.44-4.54, 5.16-5.28, 7.32-7.55. Some signals overlap with solvent. HRMS (M+H)+: calculated 283.1213. found 283.1219.
Reaction SMILES: [CH3:1][N:2]([CH3:13])[C:3]1[N:8]=[C:7]([Cl:9])[C:6]([S:10][CH3:11])=[C:5](Cl)[N:4]=1.C1C=CC=CC=1.[CH2:20]([N:22]([CH2:26][CH3:27])[CH2:23][CH2:24][NH2:25])[CH3:21]>C(N(CC)CC)C>[CH3:21][CH2:20][N:22]([CH2:23][CH2:24][NH:25][C:5]1[N:4]=[C:3]([N:2]([CH3:1])[CH3:13])[N:8]=[C:7]([Cl:9])[C:6]=1[S:10][CH3:11])[CH2:26][CH3:27]
Reactant: CSc1c(Cl)nc(N(C)C)nc1Cl
Reactant: CCN(CC)CCN
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CCN(CC)CCNc1nc(N(C)C)nc(Cl)c1SC

Procedure:
23.8 parts of 2-dimethylamino-4,6-dichloro-5-methylthio-pyrimidine are placed in 300 parts by volume of benzene and a solution of 12.2 parts of N,N-diethylethylenediamine and 16 parts of triethylamine is added. The mixture is heated under reflux for three hours. After filtering off the triethylamine hydrochloride, the mixture is concentrated, extracted with ether/water, and the organic phase is concentrated and recrystallised from ethyl alcohol. 2-dimethylamino-4-(2'-diethylamine)ethylamino-5-methylthio-6-chloropyrimidine having a melting point of 56°C. is obtained.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](=[O:23])[C:10]([CH3:22])([CH3:21])[O:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)C.[Cl:35][C:36]1[CH:37]=[CH:38][C:39]2[N:40]([CH:42]=[C:43]([CH2:45]Cl)[N:44]=2)[N:41]=1>O>[Cl:35][C:36]1[CH:37]=[CH:38][C:39]2[N:40]([CH:42]=[C:43]([CH2:45][O:1][C:2]3[CH:3]=[CH:4][C:5]([C:8]4[C:9](=[O:23])[C:10]([CH3:21])([CH3:22])[O:11][C:12]=4[C:13]4[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=4)=[CH:6][CH:7]=3)[N:44]=2)[N:41]=1
Reactant: ClCc1cn2nc(Cl)ccc2n1
Reactant: COc1ccc(C2=C(c3ccc(O)cc3)C(=O)C(C)(C)O2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(C2=C(c3ccc(OCc4cn5nc(Cl)ccc5n4)cc3)C(=O)C(C)(C)O2)cc1
Temperature: 80 °C
Yield: 59.1 %

Procedure:
4-(4-Hydroxyphenyl)-5-(4-methoxyphenyl)-2,2-dimethylfuran-3(2H)-one (200 mg, 0.64 mmol) was added to a mixture of cesium carbonate (838 mg, 2.5 mmol) and DMF (5 mL) at RT under an atmosphere of nitrogen. The reaction mixture was stirred at RT for 30 min upon which 6-chloro-2-(chloromethyl) imidazo[1,2-b]pyridazine (196 mg, 9.6 mmol) was added. The mixture was heated at 80° C. for 4 h (the reaction was monitored by TLC). The reaction mixture was diluted with water and extracted with EtOAc; the combined organics were dried over sodium sulfate, filtered and concentrated under reduced pressure. The organic residue was purified by flash column chromatography using 30% ethyl acetate in n-hexane and silica gel (230-400 mesh) to afford 4-(4-((6-chloroimidazo[1,2-b]pyridazin-2-yl)methoxy)phenyl)-5-(4-methoxyphenyl)-2,2-dimethylfuran-3(2H)-one (180 mg, 63.0%) as an off-white solid. 1H NMR, 500 MHz, DMSO-d6: δ 8.45 (s, 1H), 8.2 (d, 1H), 7.55 (d, 2H), 7.4 (d, 1H), 7.15 (d, 2H), 7.1 (d, 2H), 7.0 (d, 2H), 5.25 (s, 2H), 3.8 (s, 3H), 1.25 (s, 6H). MS: [M+H]+: m/z=476.7. HPLC: (96.7%, Condition-A).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[N:8]=[CH:9][NH:10][CH:11]=2)[CH:2]=1.C(O)C.[CH:15](=[O:19])/[CH:16]=[CH:17]/[CH3:18]>C1COCC1>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[N:8]=[CH:9][N:10]([CH:17]([CH3:18])[CH2:16][CH:15]=[O:19])[CH:11]=2)[CH:2]=1
Reactant: c1cncc(-c2c[nH]cn2)c1
Reactant: C/C=C/C=O
Solvent: C1CCOC1
Solvent: CCO
Product: CC(CC=O)n1cnc(-c2cccnc2)c1

Procedure:
To a solution 4pyridin-3-yl-imidazole (10 g, 68.88 mmol) in THF (300 ml) were added ethanol (4.04 ml, 68.88 mmol) and crotonaldehyde (22.83 ml, 275.52 mmol). The resulting mixture was heated under reflux for 18 hours. At this point of time, an additional 2 equiv of crotonaldehyde was added and contiuned to reflux for another 20 hours. TLC analysis indicated the reaction was complete. Solvent was removed in vacuo and the crude aldehyde of formula 18, wherein R7 is methyl and R3 is pyridin-3-yl, which was used without purification.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1Cl)[C:7](=[O:12])[N:6]([CH2:13][C:14]([O:16][CH3:17])=[O:15])[C:5]2=[O:18].[N:19]([O-:21])=[O:20].[K+].Cl.CN(C=[O:28])C>>[OH:28][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[N+:19]([O-:21])=[O:20])[C:7](=[O:12])[N:6]([CH2:13][C:14]([O:16][CH3:17])=[O:15])[C:5]2=[O:18]
Reactant: O=N[O-]
Reactant: COC(=O)CN1C(=O)c2cc(Cl)c(Cl)cc2C1=O
Reactant: CN(C)C=O
Agent: Cl
Agent: [K+]
Product: COC(=O)CN1C(=O)c2cc(O)c([N+](=O)[O-])cc2C1=O
Temperature: 25 °C

Procedure:
A mixture of methyl 2-(5,6-dichloro-1,3-dioxoisoindolin-2-yl)acetate (1.420 g, 4.927 mmol) and potassium nitrite (1.678 g, 19.72 mmol) in dry DMF (23 ml) was heated to reflux for 5 hours. The reaction was cooled to room temperature, poured into 0.5N HCl (100 ml) and extracted twice with diethyl ether (2×100 ml). The combined organic layers were washed with 0.5N HCl (120 ml), with brine (100 ml) and dried over sodium sulfate. The solvent was removed, and the crude was purified by chromatography on silica gel cartridge (petroleum ether:ethyl acetate from 90:10 to 100% ethyl acetate). Two different impure fractions of desired compound were isolated. The first fraction was purified by trituration with MeOH affording 0.250 g of title compound. The second fraction was purified by flash chromatography on silica gel cartridge (petroleum ether:ethyl acetate:TFA from 80:20:0.2 to ethyl acetate:TFA=100:0.2) to obtain 0.160 g of title compound. The two clean portions of desired compound were mixed affording methyl 2-(5-hydroxy-6-nitro-1,3-dioxoisoindolin-2-yl)acetate (0.410 g, 1.463 mmol, 30% yield). MS/ESI+ 281.1 [MH]+.
Reaction SMILES: [CH:1]1([C:4](=[O:21])[C:5]2[CH:10]=[CH:9][C:8]([C:11]([CH3:20])([CH3:19])[C:12]3[O:13]CC(C)(C)N=3)=[CH:7][CH:6]=2)[CH2:3][CH2:2]1.[ClH:22].[O:23]1CCOCC1>>[Cl:22][CH2:2][CH2:3][CH2:1][C:4]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([CH3:20])([CH3:19])[C:12]([OH:23])=[O:13])=[CH:7][CH:6]=1)=[O:21]
Reactant: CC1(C)COC(C(C)(C)c2ccc(C(=O)C3CC3)cc2)=N1
Reactant: Cl
Reactant: C1COCCO1
Product: CC(C)(C(=O)O)c1ccc(C(=O)CCCCl)cc1
Yield: 68 %

Procedure:
A mixture of 4-(cyclopropyl-oxo-methyl)-α,α-dimethyl-α-(4,4-dimethyloxazolin-2-yl)toluene, prepared according to Example 3, (42 g, 0.15 mole), 150 mL concentrated hydrochloric acid, and 150 mL 1,4-dioxane was brought to reflux for 18 hours. The mixture was extracted three times with ethyl acetate. The organics were washed with saturated NaCl solution, dried over MgSO4, and concentrated. Crude product was purified by column chromatography using 240 g silica gel, and eluting with 81:14:5 hexanes/ethyl acetate/acetic acid. Cleaner fractions were combined and recrystallized from methylene chloride/hexanes to afford 27 g of 4-(4-chloro-1-oxobutyl)-α,α-dimethylphenylacetic acid as a white solid (68%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5](B2OC(C)(C)C(C)(C)O2)=[C:6]2[C:10]=1[C@H:9]([O:11][C:12]1[CH:25]=[CH:24][C:15]3[C@H:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:17][O:18][C:14]=3[CH:13]=1)[CH2:8][CH2:7]2.Br[C:36]1[C:48]([CH3:49])=[CH:47][C:39]([O:40][CH2:41][C:42]([CH3:46])([CH3:45])[CH2:43][OH:44])=[CH:38][C:37]=1[CH3:50].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:36]2[C:48]([CH3:49])=[CH:47][C:39]([O:40][CH2:41][C:42]([CH3:45])([CH3:46])[CH2:43][OH:44])=[CH:38][C:37]=2[CH3:50])=[C:6]2[C:10]=1[C@H:9]([O:11][C:12]1[CH:25]=[CH:24][C:15]3[C@H:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:17][O:18][C:14]=3[CH:13]=1)[CH2:8][CH2:7]2
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(B5OC(C)(C)C(C)(C)O5)ccc(F)c43)ccc21
Reactant: Cc1cc(OCC(C)(C)CO)cc(C)c1Br
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(OCC(C)(C)CO)cc5C)ccc(F)c43)ccc21
Temperature: 100 °C
Reaction time: 12 h

Procedure:
In a microwave vial methyl 2-((S)-6-((R)-7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-yloxy)-2,3-dihydrobenzofuran-3-yl)acetate (250 mg), 3-(4-bromo-3,5-dimethylphenoxy)-2,2-dimethylpropan-1-ol (226 mg), K3PO4 (230 mg) are suspended in toluene (2 mL) and water (200 μL) and purged for 10 minutes with argon. Palladium-(II)-acetate (12 mg) and dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine (S-Phos) (44 mg) are added, the vial is sealed and the mixture is stirred at 100° C. for 12 hours. After cooling to room temperature the mixture is partitioned between ethyl acetate and water. The organic phase is washed with brine, dried (MgSO4) and concentrated. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate 99:1→60:40) to give the title compound. Yield: 99 mg; LC (method 8): tR=0.87 min; Mass spectrum (ESI+): m/z=549 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([CH2:21][CH3:22])=[C:12]([C:14](=[O:20])[C:15]([O:17]CC)=[O:16])[CH:13]=2)=[CH:4][CH:3]=1.CO.[OH-].[K+].CCCCCC>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[CH:10][C:11]([CH2:21][CH3:22])=[C:12]([C:14](=[O:20])[C:15]([OH:17])=[O:16])[CH:13]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(=O)c1cc(-c2ccc(Cl)cc2)ccc1CC
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: CCCCCC
Product: CCc1ccc(-c2ccc(Cl)cc2)cc1C(=O)C(=O)O
Yield: 82.9 %

Procedure:
To a 50 ml volume three-necked flask, ethyl 2-[5-(4-chlorophenyl)-2-ethylphenyl]-2-oxoacetate (9-c) (1.43 g), methanol (1.9 ml), and potassium hydroxide (600 mg) dissolved in water (3 ml) were added at room temperature, then added methanol (7.6 ml) and water (3 ml), and stirred at 40° C. for 2 hours. To the mixture was added hexane and 2N aqueous potassium hydroxide solution (3 ml), and then the layers were separated. The aqueous layer was washed with hexane again. The organic layers were combined, and extracted with 2N potassium hydroxide. To the resulting aqueous layer, 10 w/w % of hydrochloric acid was added to adjust pH to less than 1, and extracted with ethyl acetate 3 times. The organic layers were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give 1.081 g of 2-[5-(4-chlorophenyl)-2-ethylphenyl]-2-oxoacetic acid (8-c).
Reaction SMILES: CO[C:3]1[CH2:4][CH2:5][CH2:6][CH:7]([CH2:9][CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:8]=1.[Cl-:18].[NH4+:19]>>[ClH:18].[C:12]1([CH2:11][CH2:10][CH2:9][CH:7]2[NH:8][C:3](=[NH:19])[CH2:4][CH2:5][CH2:6]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: [Cl-]
Reactant: [NH4+]
Reactant: COC1=NC(CCCc2ccccc2)CCC1
Product: Cl
Product: N=C1CCCC(CCCc2ccccc2)N1

Procedure:
The product of Example 100 is reacted with ammonium chloride by the method of Example 5 to generate the title compound.
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][N:12]=2)[CH2:7][CH2:6]1)=[O:4].[OH-].[Na+]>C1COCC1.CO>[Cl:17][C:16]1[C:11]([N:8]2[CH2:9][CH2:10][CH:5]([C:3]([OH:4])=[O:2])[CH2:6][CH2:7]2)=[N:12][CH:13]=[CH:14][CH:15]=1
Reactant: COC(=O)C1CCN(c2ncccc2Cl)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)C1CCN(c2ncccc2Cl)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of the ester from step (a) above (1.77 g, 6.9 mmol) and 5N NaOH (4 mL) in THF/MeOH (20 mL/30 mL) mixture was stirred at room temperature for 16 h. The organic solvent was removed in vacuo, the aqueous solution was acidified with 10% HCl to pH˜2 and then lyophilized to give the title compound, which was used in the next step without additional purification. MS (ESI, pos. ion) m/z: 241 (M+1).
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([NH:6][CH3:7])=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:18]2[CH:19]=[CH:20][C:21]3[S:25][CH:24]=[N:23][C:22]=3[CH:26]=2)O1>>[S:25]1[C:21]2[CH:20]=[CH:19][C:18]([C:2]3[CH:9]=[CH:8][C:5]([NH:6][CH3:7])=[CH:4][CH:3]=3)=[CH:26][C:22]=2[N:23]=[CH:24]1
Reactant: CNc1ccc(Br)cc1
Reactant: CC1(C)OB(c2ccc3scnc3c2)OC1(C)C
Product: CNc1ccc(-c2ccc3scnc3c2)cc1

Procedure:
Compound 4-(benzo[d]thiazol-5-yl)-N-methylaniline (W189) was prepared using the general procedure for Suzuki coupling reaction between 4-bromo-N-methylaniline (56 mg, 0.3 mmol) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazole (78 mg, 0.3 mmol), as a white solid (20 mg, 28%). 1H NMR (400 MHz, acetone-d6) δ 9.22 (s, 1 H), 8.22 (d, J=1.6 Hz, 1 H), 8.08 (d, J=8.4 Hz, 1 H), 7.71 (dd, J=8.4, 1.6 Hz, 1 H), 7.56 (m, 2 H), 6.72 (m, 2 H), 5.14 (brs, 1 H), 2.83 (s, 0.5 H), 2.82 (s, 0.5 H); MS (ESI) m/z 241 (M+H+).
Reaction SMILES: C([NH:8][CH2:9][CH2:10][S:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(OC(C)(C)C)=O.[C:19]([OH:25])([C:21]([F:24])([F:23])[F:22])=[O:20]>C(Cl)Cl>[F:22][C:21]([F:24])([F:23])[C:19]([O-:25])=[O:20].[CH2:12]([S:11][CH2:10][CH2:9][NH3+:8])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC(C)(C)OC(=O)NCCSCc1ccccc1
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C([O-])C(F)(F)F
Product: [NH3+]CCSCc1ccccc1

Procedure:
N-Boc-2-Benzylsulfanyl-ethylamine (56 mg, 0.21 mmol) in 1 mL dry CH2Cl2 was treated with 0.5 mL of TFA at 0° C. After reaction completion (checked by TLC), the reaction mixture was concentrated in vacuo. The residue was dissolved in toluene and concentrated. This procedure was repeated two more times and the residue was dried under high vacuum and used directly in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:4][NH:5][CH:6]=1.C1C(=O)N([Br:19])C(=O)C1>C1COCC1>[Br:19][C:6]1[NH:5][CH:4]=[C:3]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:2]=1[CH3:1]
Reactant: CCOC(=O)c1c[nH]cc1C
Reactant: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Product: CCOC(=O)c1c[nH]c(Br)c1C
Temperature: -30 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
To a solution of ethyl 4-methyl-3-pyrrolecarboxylate (1.57 g, 10 mmol) in anhyd THF (30 mL) cooled to −78° C. was added NBS (1.9 g, 10 mmol). After stirring 1 h at −30° C., the reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography, eluting with EtOAc-Hex (0:100 to 30:70), to yield ethyl 5-bromo-4-methyl-1H-pyrrole-3-carboxylate (2.0, 86%) as a white solid. 1H-NMR (CDCl3): δ 8.54 (1H, brs), 7.38 (1H, d), 4.27 (2H, q), 2.24 (3H, s), 1.33 (3H, t).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:23]C(=O)C)[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[N:10]=1.Cl.CO>CCOC(C)=O>[NH2:23][C:4]1[CH:5]=[CH:6][C:7]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]3[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=3)[N:10]=2)=[C:2]([F:1])[CH:3]=1
Reactant: CC(=O)Nc1ccc(Oc2ccnc(Nc3ccc(F)cc3)n2)c(F)c1
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: Nc1ccc(Oc2ccnc(Nc3ccc(F)cc3)n2)c(F)c1
Yield: 53 %

Procedure:
A mixture of N-(3-fluoro-4-(2-(4-fluorophenylamino)pyrimidin-4-yloxy)phenyl)acetamide (32 mg, 0.09 mmol), 6 M HCl (0.2 mL) and MeOH (2 mL) was heated at reflux for 2 h. The mixture was cooled, diluted with EtOAc (20 mL), washed with saturated NaHCO3 solution and brine, dried (MgSO4), and concentrated in vacuo. Flash chromatography on SiO2 using 30-40% EtOAc in hexanes containing 1% Et3N gave the title compound (15 mg, 46%) as a white solid. 1H NMR (DMSO-d6) δ 9.55 (s, 1H), 8.25 (d, 1H, J=5.5 Hz), 7.43 (br s, 2H), 6.92-6.85 (m, 3H), 6.45 (dd, 1H, J=13.5, 2.1 Hz), 6.38-6.35 (m, 2H), 5.35 (br s, 2H). MS(ESI+) m/z 315.17 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[C:14]2[C:13]3[C:8](=[CH:9][C:10]([CH2:15]O)=[CH:11][CH:12]=3)[NH:7][C:6]=2[C:5]([C:17]([NH2:19])=[O:18])=[CH:4][CH:3]=1.ClN1C(=O)CCC1=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:47][S-:48].[Na+]>C(Cl)Cl.CCOC(C)=O.CS(C)=O>[Br:1][C:2]1[C:14]2[C:13]3[C:8](=[CH:9][C:10]([CH2:15][S:48][CH3:47])=[CH:11][CH:12]=3)[NH:7][C:6]=2[C:5]([C:17]([NH2:19])=[O:18])=[CH:4][CH:3]=1
Reactant: C[S-]
Reactant: NC(=O)c1ccc(Br)c2c1[nH]c1cc(CO)ccc12
Agent: O=C1CCC(=O)N1Cl
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CSCc1ccc2c(c1)[nH]c1c(C(N)=O)ccc(Br)c12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 38.1 %

Procedure:
Step 1 A mixture of 4-bromo-7-(hydroxymethyl)-9H-carbazole-1-carboxamide (Example 30-2, 403 mg, 1.263 mmol), N-chlorosuccinimide (219 mg, 1.642 mmol) and triphenylphosphine (431 mg, 1.642 mmol) in DCM (50 mL) was heated at reflux for 1 h. The mixture was cooled to rt, washed with brine, and the aqueous layer was extracted with DCM. The aqueous layer was filtered and the collected precipitate was washed with water. The organic layers and the collected precipitate were combined and the mixture was concentrated under vacuum. The residue was dissolved in THF (20 mL) and DMSO (5 mL) and the solution was treated with sodium thiomethoxide (115 mg, 1.642 mmol). The mixture was stirred at rt for 30 min, diluted with EtOAc, washed twice with water, and the aqueous phase was extracted with EtOAc. The combined organic phases were dried and concentrated. The residue was purified by column chromatography (eluting with EtOAc-hexane) to provide 4-bromo-7-(methylthiomethyl)-9H-carbazole-1-carboxamide as a white solid (168 mg, 38%) used without further purification. 1H NMR (400 MHz, chloroform-d) δ 8.67 (1H, d, J=8.1 Hz), 7.46-7.52 (2H, m), 7.36-7.41 (1H, m), 7.26-7.29 (1H, m), 3.87 (2H, s), 2.03 (3H, s). Mass spectrum m/z 349, 351 (M+H)+.
Reaction SMILES: [CH:1]([N:4]1[CH2:11][CH:10]2[CH2:12][CH:6]([CH2:7][NH:8][CH2:9]2)[CH2:5]1)([CH3:3])[CH3:2].[OH-].[Na+].[N+:15]([C:18]1[CH:23]=[CH:22][C:21]([CH2:24][C:25](Cl)=[O:26])=[CH:20][CH:19]=1)([O-:17])=[O:16]>C(Cl)Cl>[N+:15]([C:18]1[CH:19]=[CH:20][C:21]([CH2:24][C:25]([N:8]2[CH2:9][CH:10]3[CH2:12][CH:6]([CH2:5][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:11]3)[CH2:7]2)=[O:26])=[CH:22][CH:23]=1)([O-:17])=[O:16]
Reactant: O=C(Cl)Cc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)N1CC2CNCC(C2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CC(C)N1CC2CC(CN(C(=O)Cc3ccc([N+](=O)[O-])cc3)C2)C1
Reaction time: 3 h
Yield: 69.2 %

Procedure:
A standard setup was used with a N2 inlet. Initially, the amine 105 (2.42 g, 14.38 mmol) in H2CCl2 (35 ml) was added followed by NaOH (10%, 14.42 g, 35.95 mmol) which resulted in a heterogenous mixture. To this mixture was added 4-nitrophenylacetyl chloride (3,16 g, 15.82 mmol) dropwise over a 15-min period. Stirring was continued for an additional 3 h upon which the brown mixture was transferred to a separatory funnel, and the layers were separated. The aqueous layer was extracted (H2CCl2, 3×25 ml), and the organic layers were combined. After drying (Na2SO4, 2 h), the organic solution was filtered and concentrated to give 94 as a light brown solid (3.3 g, 69.2 %); mp 93°-94° C. IR (KBr) 3090 (Ar-H), 2960, 2920, 2800, 2740 (C-H), 1625 (NC=O) cm-1 ; 1H NMR (DCCl3) d 0.94 (dd, 6 H, CH3 isopropyl), 1.69 [q, 2 H, H(9)], 1.92 ]bs, 2 H, H(1,5)], 2.46 [m, 3 H, ring protons, C-H isopropyl), 2.79 (d, 1 H, ring proton), 2.93 (td, 2 H, ring protons), 3.39 (d, 1 H, ring proton), 3.79(s, 2 H, CH2 -Ar), 3.84 (d, 1 H, ring proton), 4.57 (d, 1 H, ring proton), 7.44 (d, 2 H,-Ar-H), 8.15 (d, 2 H, Ar-H); 13C NMR (DCCl3) ppm 16.83, 18.44 (CH3 isopropyl), 28.76, 29.42 [C(1,5)], 31.57 [C(9)], 40.62 (CH2 -Ar), 46.76 (C-H isopropyl), 50.60, 52.78, 54.03, 54.42 [C(2,4,6,8)], 123.37, 130.02, 143.58, 146.56 (Ar-C), 167.93 (NC=O). Amide 94 was used without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5]([CH3:10])=[N:6][CH:7]=[CH:8][CH:9]=1)[CH3:2].[N+:11]([O-])([OH:13])=[O:12]>S(=O)(=O)(O)O>[CH2:1]([O:3][C:4]1[C:5]([CH3:10])=[N:6][C:7]([N+:11]([O-:13])=[O:12])=[CH:8][CH:9]=1)[CH3:2]
Reactant: O=[N+]([O-])O
Reactant: CCOc1cccnc1C
Agent: O=S(=O)(O)O
Product: CCOc1ccc([N+](=O)[O-])nc1C
Temperature: 0 °C

Procedure:
To a solution of 70 g of 3-ethoxy-2-methylpyridine (Compound II where R2 =C2H5) dissolved in 280 ml of sulfuric acid under ice-cooling, a mixed solution of 42 ml of fuming nitric acid and 50 ml of concentrated sulfuric acid was added dropwise while stirring and keeping the internal temperature at 0° to 3° C. After stirring for additional 30 minutes at the same temperature, the reaction mixture was poured into ice water and extracted with chloroform. The extract was washed with water, dried over anhydrous sodium sulfate and concentrated to give 85 g of 3-ethoxy-2-methyl-6-nitropyridine (Compound III where R2 =C2H5), m.p. 90°-92° C.
Reaction SMILES: [F:1][C:2]1[C:7]2[N:8]([CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][O:12]3)[CH:9]=[N:10][C:6]=2[CH:5]=[C:4]([CH2:17][NH2:18])[CH:3]=1.Cl[C:20]1[N:25]=[C:24]([NH:26][C:27]2[NH:31][N:30]=[C:29]([CH:32]3[CH2:34][CH2:33]3)[CH:28]=2)[CH:23]=[CH:22][N:21]=1.CCN(C(C)C)C(C)C>CC(O)C>[CH:32]1([C:29]2[NH:30][N:31]=[C:27]([NH:26][C:24]3[CH:23]=[CH:22][N:21]=[C:20]([NH:18][CH2:17][C:4]4[CH:3]=[C:2]([F:1])[C:7]5[N:8]([CH:11]6[CH2:16][CH2:15][CH2:14][CH2:13][O:12]6)[CH:9]=[N:10][C:6]=5[CH:5]=4)[N:25]=3)[CH:28]=2)[CH2:34][CH2:33]1
Reactant: Clc1nccc(Nc2cc(C3CC3)n[nH]2)n1
Reactant: NCc1cc(F)c2c(c1)ncn2C1CCCCO1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: Fc1cc(CNc2nccc(Nc3cc(C4CC4)[nH]n3)n2)cc2ncn(C3CCCCO3)c12
Temperature: 120 °C
Yield: 62.6 %

Procedure:
A tube was charged with 270 (260 mg, 1.04 mmol), 53 (100 mg, 0.57 mmol), DIPEA (0.5 ml) in IPA (3 mL), degassed, sealed and heated at 120° C. overnight. The solvent was evaporated under reduced pressure to afford 160 mg (34%) N4-(5-cyclopropyl-1H-pyrazol-3-yl)-N2-((7-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[d]imidazol-5-yl)methyl)pyrimidine-2,4-diamine (272) as yellow solid: MS (ESI) m/z=449.2 [M+1]+.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:10])[C@H:5]([CH:7]([CH3:9])[CH3:8])[NH2:6].[Br:11][C:12]1[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1.C(N(CC)CC)C>ClCCl>[Br:11][C:12]1[CH:17]=[CH:16][C:15]([S:18]([NH:6][C@H:5]([C:4]([O:3][CH3:2])=[O:10])[CH:7]([CH3:9])[CH3:8])(=[O:20])=[O:19])=[CH:14][CH:13]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: COC(=O)[C@@H](N)C(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@@H](NS(=O)(=O)c1ccc(Br)cc1)C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 101.1 %

Procedure:
To 0.838 g of L-valine methyl ester hydrochloride in 15 mL of dichloromethane, cooled in an ice bath, 1.34 g of 4-bromobenzenesulfonyl chloride was added followed by 2.79 mL of triethylamine. The mixture was stirred at room temperature overnight and then diluted with dichloromethane. The dichloromethane was washed with water and brine, dried over Na2SO4, filtered, and concentrated in vacuo to provide 1.77 g of methyl N-[(4-bromophenyl)sulfonyl]-L-valinate as a colorless solid. Yield ˜100%. m.p. 88-90° C.; MS: 348.2 (M−H)−.