Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COP([CH:7]([F:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])(OC)=O.[Mg+2].[Br-].[Br-].[Cl:17][C:18]1[C:19]([NH:26][C@@H:27]2[CH2:32][CH2:31][CH2:30][N:29]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:28]2)=[N:20][CH:21]=[C:22]([CH:24]=O)[CH:23]=1.Cl>C1COCC1.CCOC(C)=O.CCN(CC)CC>[Cl:17][C:18]1[C:19]([NH:26][C@@H:27]2[CH2:32][CH2:31][CH2:30][N:29]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:28]2)=[N:20][CH:21]=[C:22](/[CH:24]=[C:7](\[F:13])/[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:23]=1
Reactant: CCOC(=O)C(F)P(=O)(OC)OC
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](Nc2ncc(C=O)cc2Cl)C1
Agent: Cl
Agent: [Br-]
Agent: [Mg+2]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)/C(F)=C/c1cnc(N[C@@H]2CCCN(C(=O)OC(C)(C)C)C2)c(Cl)c1
Temperature: 4 °C
Reaction time: 1 h

Procedure:
The mixture of ethyl (dimethoxyphosphoryl)(fluoro)acetate (2.51 mL), MgBr2 (2.73 g), Et3N (1.89 mL) in THF (45 mL) was stirred at 3-5° C. for 1 hr and to the mixture was dropwise added a solution of tert-butyl (3R)-3-[(3-chloro-5-formyl-2-pyridinyl)amino]-1-piperidinecarboxylate (3.0 g) in THF (21 mL) at 3-5° C. The reaction mixture was stirred at same temperature for 2.5 hrs. The reaction mixture was poured into a mixture of AcOEt and ice-water and the mixture was adjusted to pH 3.5 with 1N-HCl. The separated organic layer was washed with water, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel using a mixture of AcOEt and hexane (1:2 v/v) as an eluant. The eluted fractions containing the desired product were collected and evaporated in vacuo to give tert-butyl (3R)-3-({3-chloro-5-[(1Z)-3-ethoxy-2-fluoro-3-oxo-1-propen-1-yl]-2-pyridinyl}amino)-1-piperidinecarboxylate (3.38 g).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]([CH3:23])[C:9]2[CH:22]=[CH:21][C:12]3[N:13]([CH3:20])[C:14]([NH:16][CH:17]([CH3:19])[CH3:18])=[N:15][C:11]=3[CH:10]=2)[CH:5]=[CH:4][N:3]=1.[CH3:24][S:25]([CH2:28][C:29]1[CH:30]=[C:31]([NH2:35])[CH:32]=[CH:33][CH:34]=1)(=[O:27])=[O:26]>>[ClH:1].[CH:17]([NH:16][C:14]1[N:13]([CH3:20])[C:12]2[CH:21]=[CH:22][C:9]([N:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:35][C:31]4[CH:32]=[CH:33][CH:34]=[C:29]([CH2:28][S:25]([CH3:24])(=[O:27])=[O:26])[CH:30]=4)[N:7]=3)[CH3:23])=[CH:10][C:11]=2[N:15]=1)([CH3:19])[CH3:18]
Reactant: CS(=O)(=O)Cc1cccc(N)c1
Reactant: CC(C)Nc1nc2cc(N(C)c3ccnc(Cl)n3)ccc2n1C
Product: CC(C)Nc1nc2cc(N(C)c3ccnc(Nc4cccc(CS(C)(=O)=O)c4)n3)ccc2n1C
Product: Cl

Procedure:
The title compound was prepared following the procedure of example 1 with N5-(2-chloropyrimidin-4-yl)-N2-isopropyl-N5,1-dimethyl-1H-benzimidazole-2,5-diamine (83 mg, 0.25 mmol) and 3-Methanesulfonylmethyl-phenylamine (46 mg, 0.25 mmol) as a white solid (69 mg, 53%). 1H NMR (300 MHz, d6-DMSO) δ 9.20 (s, 1H), 7.90 (s, 1H), 7.77 (d, J=6.0 Hz, 1H), 7.69 (d, J=8.1 Hz, 1H), 7.18-7.25 (m, 2H), 7.09 (d, J=1.8 Hz, 1H), 6.91 (d, J=7.5 Hz, 1H), 6.82 (dd, J=8.1 and 1.8 Hz, 1H), 6.49 (d, J=7.5 Hz, 1H), 5.64 (d, J=6.0 Hz, 1H), 4.34 (s, 2H), 4.03 (m, 1H), 3.51 (s, 3H), 3.43 (s, 3H), 2.89 (s, 3H), 1.24 (d, J=6.6 Hz, 6H) ppm. MS (ESI) m/z=480 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[CH2:7][C:8]([C:10]1[CH:15]=[CH:14][N:13]=[C:12]([N:16]2[CH:20]=[CH:19][N:18]=[CH:17]2)[CH:11]=1)=[O:9])(C)([CH3:3])[CH3:2].C(OC(C(F)(F)F)=O)(C(F)(F)F)=O>C(O)(C(F)(F)F)=O.CC(C)=O>[N:16]1([C:12]2[CH:11]=[C:10]([C:8]3[O:9][C:1]([CH3:3])([CH3:2])[O:5][C:6](=[O:21])[CH:7]=3)[CH:15]=[CH:14][N:13]=2)[CH:20]=[CH:19][N:18]=[CH:17]1
Reactant: CC(C)(C)OC(=O)CC(=O)c1ccnc(-n2ccnc2)c1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: CC(C)=O
Product: CC1(C)OC(=O)C=C(c2ccnc(-n3ccnc3)c2)O1

Procedure:
Prepared from 3-(2-imidazol-1-yl-pyridin-4-yl)-3-oxo-propionic acid tert.-butyl ester (Example H5) by stirring in TFA/acetone with TFAA according to general procedure J (method b). Obtained as a brown solid (10.8 g).
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][CH:13]=1)[C:6](=[NH:10])[O:7][CH2:8][CH3:9].C(N(CC)CC)C.[Cl:21][CH2:22][C:23](Cl)=[O:24]>ClCCl>[Cl:21][CH2:22][C:23](/[N:10]=[C:6](\[O:7][CH2:8][CH3:9])/[C:5]1[CH:11]=[CH:12][CH:13]=[C:3]([F:2])[CH:4]=1)=[O:24]
Reactant: CCOC(=N)c1cccc(F)c1
Reactant: O=C(Cl)CCl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCO/C(=N\C(=O)CCl)c1cccc(F)c1
Temperature: 2.5 °C
Reaction time: 2 h
Yield: 101 %

Procedure:
To a suspension of ethyl 3-fluorobenzimidate hydrochloride (400 mg, 1.96 mmol) in dichloromethane (15 mL) was added triethylamine (497 mg, 684 μL, 4.91 mmol) at RT. The reaction mixture was cooled to 0-5° C. and 2-chloroacetyl chloride (333 mg, 234 μL, 2.95 mmol) was added dropwise over a period of 5 min. After 20 min the ice bath was removed and the mixture was stirred at RT for 2 h. The reaction mixture was poured into KHSO4 (10% aqueous solution, 25 mL) and extracted with dichloromethane (3×50 mL). The combined organic layer was dried over MgSO4 and concentrated in vacuo to give the product as light brown oil (537 mg, 1.98 mmol, 101%) which was used without further purification for the next step.
Reaction SMILES: [Br:1]C1N=C(CC)C(N[C@@H]2C3C(=CC=CC=3)C[C@@H]2O)=NC=1CC.[CH2:23]([C:25]1[C:26]([NH:33][C@H:34]2[C@@H:38]([O:39][CH2:40][CH2:41][F:42])[CH2:37][N:36]([C:43]([O:45][CH3:46])=[O:44])[CH2:35]2)=[N:27][C:28]([CH2:31][CH3:32])=[CH:29][N:30]=1)[CH3:24]>>[Br:1][C:29]1[N:30]=[C:25]([CH2:23][CH3:24])[C:26]([NH:33][C@H:34]2[C@@H:38]([O:39][CH2:40][CH2:41][F:42])[CH2:37][N:36]([C:43]([O:45][CH3:46])=[O:44])[CH2:35]2)=[N:27][C:28]=1[CH2:31][CH3:32]
Reactant: CCc1cnc(CC)c(N[C@@H]2CN(C(=O)OC)C[C@@H]2OCCF)n1
Reactant: CCc1nc(N[C@@H]2c3ccccc3C[C@@H]2O)c(CC)nc1Br
Product: CCc1nc(N[C@@H]2CN(C(=O)OC)C[C@@H]2OCCF)c(CC)nc1Br

Procedure:
Following the procedure for the preparation of (1R,2S)-1-[(5-bromo-3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol but substituting methyl(3R,4S)-3-[(3,6-diethylpyrazin-2-yl)amino]-4-(2-fluoroethoxy)pyrrolidine-1-carboxylate and making non-critical variations provided the title compound as a oil: 1H NMR (400 MHz, DMSO-d6) δ) 6.12, 4.49, 4.37, 4.21, 3.69–3.39, 2.71–2.55, 1.20–1.12; IR (liq.) 2973 (s), 2957, 2068 (b), 1996, 1705 (s), 1561 (s), 1541 (s), 1481 (s), 1454 (s), 1392 (s), 1191 (s), 1175, 1140 (s), 1114 (s), 1048, cm−1; HRMS (FAB) calcd for C16H24BrFN4O3+H 419.1094, found 419.1112. Anal. Calcd for C16H24BrFN4O3: C, 45.83; H, 5.77; N, 13.36. Found: C, 45.49; H, 5.81; N, 13.03.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH2:13])(=[O:12])=[O:11])=[CH:6][CH:5]=1)(=O)C.O.[C:15]([OH:19])(=[O:18])[CH:16]=O.OS(O)(=O)=O.[O:25]1[CH2:30][CH2:29]OCC1>O>[NH2:13][S:10]([C:7]1[CH:8]=[CH:9][C:4]([CH2:1][C:30](=[O:25])[CH:29]=[CH:16][C:15]([OH:19])=[O:18])=[CH:5][CH:6]=1)(=[O:11])=[O:12]
Reactant: CC(=O)c1ccc(S(N)(=O)=O)cc1
Reactant: C1COCCO1
Reactant: O=CC(=O)O
Agent: O=S(=O)(O)O
Solvent: O
Product: NS(=O)(=O)c1ccc(CC(=O)C=CC(=O)O)cc1

Procedure:
A mixture of 37 g of p-acetylbenzenesulfonamide, 78.4 g of glyoxylic acid hydrate, 20 ml of 80% H2SO4 and 180 ml of dioxane is refluxed for 24 hours. An additional 10 g of glyoxylic acid hydrate is added and the mixture is refluxed for 24 hours. The reaction mixture is poured into 2 liters of water and extracted with ether. The organic layers are combined, dried, and evaporated to leave a solid which is crystallized from acetonitrile yielding 10.9 g of the title compound, melting point 180°-181° C.
Reaction SMILES: [H-].[Na+].Br[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]Br.[CH3:10][CH:11]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([O:21][CH3:22])[CH:19]=2)[CH2:14][CH2:13][C:12]1=[O:23].Cl>C1C=CC=CC=1>[CH3:10][C:11]12[C:12](=[O:23])[CH:13]([CH2:14][C:15]3[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][C:20]=31)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]2
Reactant: COc1ccc2c(c1)C(C)C(=O)CC2
Reactant: BrCCCCCBr
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Product: COc1ccc2c(c1)C1(C)CCCCCC(C2)C1=O
Reaction time: 12 h
Yield: 27 %

Procedure:
Oil-free sodium hydride (5.28 g.) in benzene (50 ml.) is added to a stirred mixture of 1,5-dibromopentane (184 g.) and 1-methyl-7-methoxy-2-tetralone (32 g.) in dry benzene (300 ml.). Stirring is continued for 12 hours at 25° and at reflux for an additional 15 hours. The mixture is cooled, sodium hydride (5.8 g.) in 50 ml. benzene added, stirring continued at 25° for 10 hours. and refluxed for 12 additional hours. After cooling excess base is neutralized with concentrated hydrochloric acid and the inorganic solids which precipitate are removed by filtration. Washing and filtrate with saline, drying over sodium sulfate, concentrating and vacuum distilling gives an oil (21 g.), b.p. 160°-190° C. (0.5 mm.) containing 6.5 g. (27%) of the title product by vapor phase chromatography (3% OVI, C200-225-250).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:14][C:11]([CH:12]=O)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[NH2:15][CH2:16][CH:17]([OH:19])[CH3:18].[BH4-].[Na+]>CO>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:14][C:11]([CH2:12][NH:15][CH2:16][CH:17]([OH:19])[CH3:18])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: CC(O)CN
Reactant: O=Cc1ccc(-c2ccc(Cl)cc2)o1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(O)CNCc1ccc(-c2ccc(Cl)cc2)o1
Product: Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.3 %

Procedure:
5-(4-Chlorophenyl)furfural (42 g, 0.20 mole) was added in portions to a solution of 15 g (0.20 mole) of 1-amino-2-propanol in 200 ml of methanol with stirring at room temperature. The mixture was stirred for 0.5 hr., heated under reflux for 1.5 hr., and allowed to stand overnight. To this solution 7.6 g (0.20 mole) of sodium borohydride was added in portions over 1 hr. at 15°-20°. The solution was stirred at ambient temperature for 1 hr. and heated under reflux for 0.5 hr. The solvent was removed on a rotary evaporator, and the residual solid was partitioned between chloroform and water. The layers were separated, and the aqueous layer was extracted once with chloroform. The combined chloroform layers were dried over MgSO4 and concentrated on a rotary evaporator. The residual solid was dissolved in 150 ml of absolute methanol with warming and was treated with 40 ml of methanolic HCl with cooling. Anhydrous ether (1 1.) was added, and the solid which was deposited was collected by filtration to give 30 g (50%) of 1-[5-(4-chlorophenyl)furfurylamino]-2-propanol hydrochloride. One recrystallization from CH3CN gave an analytical sample; m.p. 197°-202°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:31]=[CH:32][C:33]=1[Cl:34])[C:5]([NH:7][C:8]1[CH:30]=[CH:29][C:11]([CH2:12][C:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]([CH2:22][C:23]([O:25]CC)=[O:24])[C:14]=2[CH3:28])=[CH:10][CH:9]=1)=[O:6].O.[OH-].[Li+].O1CCCC1.CO>O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:31]=[CH:32][C:33]=1[Cl:34])[C:5]([NH:7][C:8]1[CH:30]=[CH:29][C:11]([CH2:12][C:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]([CH2:22][C:23]([OH:25])=[O:24])[C:14]=2[CH3:28])=[CH:10][CH:9]=1)=[O:6]
Reactant: CCOC(=O)Cn1c(C)c(Cc2ccc(NC(=O)c3ccc(Cl)c(Cl)c3)cc2)c2ccccc21
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1c(Cc2ccc(NC(=O)c3ccc(Cl)c(Cl)c3)cc2)c2ccccc2n1CC(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.8 %

Procedure:
Into a dry reaction vessel, ethyl 2-[3-[4-(3,4-dichlorobenzamido)benzyl]-2-methyl-1H-indol-1-yl]acetate (691 mg, 1.39 mmol), lithium hydroxide monohydrate (176 mg, 4.19 mmol), 10 mL tetrahydrofuran, 10 mL methanol, 10 mL water were weighed, and stirred at room temperature for 1 h. The reaction was monitored to be complete by TLC. The solvent was rotate evaporated. It was adjusted to pH=3-4 with 2 N HCl solution. It was filtered, and the filter cake was washed with 20 mL methanol to obtain the product as a white solid 551 mg, at a yield of 84.9%.
Reaction SMILES: O1CCCCC1[O:7][CH2:8][CH2:9][CH2:10][CH2:11][NH:12][S:13]([C:16]1[CH:28]=[CH:27][C:19]2OC(C(O)=O)C[O:23][C:18]=2[CH:17]=1)(=[O:15])=[O:14].C(N(CC)CC)C.Cl[C:37]([O:39][CH3:40])=O.[C:41](=O)([O-])[O-:42].[Na+].[Na+]>ClCCl>[OH:7][CH2:8][CH2:9][CH2:10][CH2:11][N:12]1[C:18](=[O:23])[C:17]23[O:42][CH2:41][CH2:40][O:39][CH:37]2[CH:19]=[CH:27][CH:28]=[C:16]3[S:13]1(=[O:14])=[O:15]
Reactant: COC(=O)Cl
Reactant: O=C([O-])[O-]
Reactant: O=C(O)C1COc2cc(S(=O)(=O)NCCCCOC3CCCCO3)ccc2O1
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1N(CCCCO)S(=O)(=O)C2=CC=CC3OCCOC123
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of 10 g of N-(4-(2-tetrahydropyranyloxy)butyl)-carboxy-1,4-benzodioxane-6-sulfonamide and 7 mL of triethylamine in 200 mL of dichloromethane cooled to 0° C. was added 2 mL of methyl chloroformate dropwise. After 3 h at 20° C., the mixture was shaken with 50 mL of saturated sodium carbonate, dried over MgSO4 and concentrated under reduced pressure. The residue was disolved in 200 mL of methanol containing 1 g of p-toluenesulfonic acid monohydrate, stirred overnight at ambient temperature, and concentrated to dryness under reduced pressure. The residue was dissolved in 200 mL of ethyl acetate, washed with 5 mL of saturated sodium carbonate, dried over MgSO4 and concentrated under reduced pressure. Trituration with ether gave 4 g of 2-(4-hydroxybutyl)-1,1-dioxido-5,6-dihydro-[1,4]dioxino[2,3-d]benzisothiazol-3(2H)-one as a white crystalline solid: mp °C.; 1H NMR (400 MHz, CDCl3): 7.4 (d, 1H), 7.25 (d, 1H), 4.5 (m, 2H), 4.4 (m, 2H), 3.8 (t, 2H), 3.7 (t, 2H), 1.95 (m, 2H), 1.7 (m, 2H), 1.55 (br s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9](Cl)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8].N1CC[CH:16]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:15]C1.C([N:29]([CH2:32][CH3:33])[CH2:30][CH3:31])C.CO>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([S:9]([N:29]2[CH2:30][CH2:31][CH:15]([CH2:16][NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:33][CH2:32]2)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(Cl)c1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: CCN(CC)CC
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)OC(=O)NCC1CCN(S(=O)(=O)c2ccc(Cl)c(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a solution of 3,4-dichlorobenzene-1-sulfonyl chloride (490 mg, 2.00 mmol) was added tert-butyl piperidin-4-ylcarbamate (400 mg, 2.00 mmol), followed by triethylamine (0.278 mL, 2.00 mmol). The reaction was stirred at rt overnight. The reaction mixture was diluted with DCM and the organic portion washed with 1N HCl, H2O, and brine, dried over Na2SO4 and decanted. The solvent was evaporated under reduced pressure and the crude residue was purified on a 24 g silica gel cartridge eluting with 0 to 100% EtOAc in hexane, then 0 to 20% MeOH in DCM to provide Intermediate 4A (810 mg, 2.0 mmol, 99% yield). HPLC/MS (Method D) RT=2.12 min, [M+1]+ 309.
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][C@H:10]([NH:13][C:14](=[O:25])[C@@H:15]([NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH3:16])[CH2:9]1)C1C=CC=CC=1.O.[H][H]>CO.[OH-].[OH-].[Pd+2]>[C:21]([O:20][C:18]([NH:17][C@@H:15]([CH3:16])[C:14]([NH:13][C@H:10]1[CH2:11][CH2:12][NH:8][CH2:9]1)=[O:25])=[O:19])([CH3:24])([CH3:22])[CH3:23]
Reactant: [H][H]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@H]1CCN(Cc2ccccc2)C1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@H]1CCNC1
Yield: 92.6 %

Procedure:
1 Benzyl-3-(S)-[2-(S)-(tert-butoxycarbonylamino)propionylamino]pyrrolidine (21.3 g) was dissolved in methanol (250 mL), and hydrogenated over 20% palladium hydroxide on charcoal, 50% water wet (5.0 g) at 50 psig and 25° to 40° C. until the uptake of hydrogen ceased. The reaction was then filtered through celite to remove the catalyst and the residue rinsed with methanol (100 mL) and the combined filtrates concentrated under vacuum to give 3-(S)-[2-(S)-(tert-butoxycarbonylamino)propionylamino]pyrrolidine (14.6 g) as a colorless oil which crystallized on standing: HPLC: 99% S,S isomer. A portion was recrystallized from methyl tert-butyl ether: mp 137°-138° C.
Reaction SMILES: [CH:1]([C:9]1[NH:13][C:12]2[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=2[N:10]=1)=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[C:19]1[S:20][CH:21]=[CH:22][N:23]=1.C(=O)([O-])[O-].[K+].[K+].[N+](C1C=CC=CC=1)([O-])=O>C(OCC)(=O)C.[Cu]>[CH:1](/[C:9]1[N:10]([C:19]2[S:20][CH:21]=[CH:22][N:23]=2)[C:11]2[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=2[N:13]=1)=[CH:2]\[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: Brc1nccs1
Reactant: C(=Cc1nc2ccccc2[nH]1)c1ccccc1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O=[N+]([O-])c1ccccc1
Product: C(=C/c1nc2ccccc2n1-c1nccs1)\c1ccccc1
Yield: 65.6 %

Procedure:
A stirred mixture of 2-styryl-1H-benzimidazole (220 mg, 1 mmol), 2-bromothiazole (328 mg, 2 mmol), potassium carbonate (138 mg, 1 mmol), copper bronze (20 mg) and nitrobenzene (10 ml) was heated to reflux under a nitrogen atmosphere for 7 h. The cooled reaction mixture was diluted with ethyl acetate (150 ml) and filtered through a pad of celite. The filtrate was washed consecutively with water (50 ml), and brine (50 ml), dried (magnesium sulfate) and concentrated to dryness. Column chromatography (silica gel, 100 g; n-hexane/ethyl acetate (9/1 to 3/1)) gave 199 mg of the titled compound as an orange oil, which was solidified on standing at room temperature. Recrystallization from isopropyl ether gave 117 mg (39%) of the titled compound as colorless crystals. MW: 303.39; mp: 99.0-99.5° C.; 1H-NMR (CDCl3) δ: 8.01 (1H. d, J=15.8 Hz), 7.91 (1H, d, J=3.7 Hz), 7.85-7.80 (1H, m), 7.69-7.64 (1H, m), 7.59-7.54 (2H, m), 7.51 (1H, d, J=3.7 Hz), 7.40 (1H, d, J=15.8 Hz), 7.42-7.29 (5H, m).
Reaction SMILES: [Cl-].[Cl:2][C:3]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5][Zn+].I[C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=1.[Cl-].[NH4+]>C1COCC1.O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1>[Cl:11][C:10]1[CH:9]=[CH:8][CH:7]=[C:4]([CH2:5][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=2)[C:3]=1[Cl:2]
Reactant: O=[N+]([O-])c1ccc(I)cc1
Reactant: Clc1cccc(C[Zn+])c1Cl
Agent: [Cl-]
Agent: [NH4+]
Agent: c1coc(P(c2ccco2)c2ccco2)c1
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(Cc2cccc(Cl)c2Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.9 %

Procedure:
Under an argon stream, bis(dibenzylidenacetone)palladium(0) (3.2 g, 5.6 mmol) and tri(2-furyl)phosphine (2.6 g, 11.2 mmol) were dissolved in THF (310 ml), the reaction mixture of 2,3-dichlorobenzylzinc chloride (421.7 mmol) in THF obtained in Reference Example 1 was added dropwise under ice-cooling through a cannula, and then a solution of 4-iodonitrobenzene (70.0 g, 281 mmol) in THF (700 ml) was added dropwise, after which the mixture was stirred at room temperature for 2 hr, saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was filtered through celite. The filtrate was concentrated under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the precipitated solid was collected by filtration on the way. The filtrate was again concentrated under reduced pressure, and the precipitated solid was collected by filtration on the way. The collected solids were combined washed with n-hexane and vacuum dried to give the object product (60.2 g, yield 76%) as a pale-brown solid.
Reaction SMILES: [C:1]([O:5][C:6]([CH:8]=[N:9][C:10]1[CH:11]=[C:12](C2N=C(N)N=C(N)C=2F)[CH:13]=[CH:14][CH:15]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].NC1C=C([C:32]2[N:37]=[C:36]([NH2:38])[N:35]=[C:34]([NH2:39])[C:33]=2[F:40])C=CC=1.BrCC(O[C:46]([CH3:49])([CH3:48])C)=O>>[NH2:9][C:10]1[CH:15]=[C:14]([NH:39][C:34]2[C:33]([F:40])=[CH:32][N:37]=[C:36]([NH:38][C:12]3[CH:13]=[CH:14][CH:15]=[C:10]([N:9]=[CH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH:11]=3)[N:35]=2)[CH:49]=[CH:46][CH:48]=1
Reactant: CC(C)(C)OC(=O)C=Nc1cccc(-c2nc(N)nc(N)c2F)c1
Reactant: Nc1cccc(-c2nc(N)nc(N)c2F)c1
Reactant: CC(C)(C)OC(=O)CBr
Product: CC(C)(C)OC(=O)C=Nc1cccc(Nc2ncc(F)c(Nc3cccc(N)c3)n2)c1

Procedure:
In like manner to the preparation of N2,N4-bis(3-tert-butoxycarbonylmethyleneaminophenyl-5-fluoro-2,4-pyrimidinediamine, N2,N4-bis(3-aminophenyl-5-fluoro-2,4-pyrimidinediamine and tert-butyl bromoacetate were reacted together to give N4-(3-aminophenyl)-N2-(3-tert-butoxycarbonylmethyleneaminophenyl)-5-fluoro-2,4-pyrimidinediamine. LCMS: ret. time: 18.33 min.; purity: 94.5%; MS (m/e): 369.09 (MH+).
Reaction SMILES: [CH3:1][N:2]([CH3:35])[C:3](=[O:34])[NH:4][C@@H:5]1[CH2:10][CH2:9][CH2:8][N:7]([C:11]2[N:12]=[C:13]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]4([CH3:33])[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]4)=[CH:23][CH:22]=3)[C:14]([C:17]([NH2:19])=[O:18])=[N:15][CH:16]=2)[CH2:6]1.CCN(C(C)C)C(C)C.[CH3:45][N:46]([CH3:50])[C:47]([Cl:49])=[O:48]>CN1C(=O)CCC1>[CH3:45][N:46]([CH3:50])[C:47]([N:30]1[CH2:29][CH2:28][C:27]([C:24]2[CH:25]=[CH:26][C:21]([NH:20][C:13]3[C:14]([C:17]([NH2:19])=[O:18])=[N:15][CH:16]=[C:11]([N:7]4[CH2:8][CH2:9][CH2:10][C@@H:5]([NH:4][C:3]([N:2]([CH3:1])[CH3:35])=[O:34])[CH2:6]4)[N:12]=3)=[CH:22][CH:23]=2)([CH3:33])[CH2:32][CH2:31]1)=[O:48].[ClH:49]
Reactant: CN(C)C(=O)Cl
Reactant: CN(C)C(=O)N[C@@H]1CCCN(c2cnc(C(N)=O)c(Nc3ccc(C4(C)CCNCC4)cc3)n2)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CN(C)C(=O)N[C@@H]1CCCN(c2cnc(C(N)=O)c(Nc3ccc(C4(C)CCN(C(=O)N(C)C)CC4)cc3)n2)C1
Product: Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 836.5 %

Procedure:
(R)-5-(3-(3,3-Dimethylureido)piperidin-1-yl)-3-(4-(4-methylpiperidin-4-yl)phenylamino)pyrazine-2-carboxamide (289) (90 mg, 0.2 mmol) was dissolved in 4 mL NMP. To it were added DIEA (350 μL, 2.0 mmol) and then dimethylcarbamoyl chloride (55 μL, 0.6 mmol). The mixture was stirred at RT for 30 min, quenched with 0.5 mL TFA, and directly subjected to reverse phase prep HPLC using 5 mM HCl (aq) and neat MeCN as mobile phases to isolate (R)-3-(4-(1-(dimethylcarbamoyl)-4-methylpiperidin-4-yl)phenylamino)-5-(3-(3,3-dimethylureido)piperidin-1-yl)pyrazine-2-carboxamide (291) as HCl salt (61 mg, 55%). MS found for C28H41N9O3 as (M+H)+ 552.4, (M−H)− 550.3. UV: λ=268, 277, 305, 336, 372 nm Proton NMR (CD3OD): δ 7.63 (1H, s), 7.61 (2H, d, J=8.5 Hz), 7.32 (2H, d, J=8.5 Hz), 4.37 (1H, m), 4.21 (1H, m), 3.77 (1H, m), 3.37-3.31 (2H, m), 3.21-3.15 (3H, m), 3.10 (1H, m), 2.88 (6H, s), 2.83 (6H, s), 2.15 (2H, m), 2.02 (1H, m), 1.87 (1H, m), 1.75-1.63 (4H, m), 1.26 (3H, s) ppm.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[OH:18])[N:6]=[C:5]2[N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.C(N(CC)CC)C.[OH:32][C@H:33]([CH2:37][C:38]([CH3:41])([CH3:40])[CH3:39])[C:34](O)=[O:35].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[OH:18])[N:6]=[C:5]2[N:19]1[CH2:20][CH2:21][N:22]([C:34](=[O:35])[C@H:33]([OH:32])[CH2:37][C:38]([CH3:41])([CH3:40])[CH3:39])[CH2:23][CH2:24]1
Reactant: CC(C)(C)C[C@@H](O)C(=O)O
Reactant: Oc1ccccc1-c1nc(N2CCNCC2)c2cc(F)ccc2n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)C[C@@H](O)C(=O)N1CCN(c2nc(-c3ccccc3O)nc3ccc(F)cc23)CC1
Reaction time: 3 h
Yield: 86.9 %

Procedure:
To a solution of 2-(6-fluoro-4-(piperazin-1-yl)quinazolin-2-yl)phenol (200 mg, 0.61 mmol) in CH2Cl2 (5 mL) was added triethylamine (170 μL, 1.22 mmol) followed by the addition of (R)-2-hydroxy-4,4-dimethylpentanoic acid (116 mg, 0.79 mmol), then HATU (301 mg, 0.79 mmol). An additional 3 mL of CH2Cl2 was added, and the reaction was stirred for 3 h. After quenching with water, the mixture was extracted twice with CH2Cl2. The organic phase was dried over MgSO4 and concentrated. Purification via silica gel chromatography using 0-10% EtOAc in 50:50 CH2Cl2:hexanes yielded (R)-1-(4-(6-fluoro-2-(2-hydroxyphenyl)quinazolin-4-yl)piperazin-1-yl)-2-hydroxy-4,4-dimethylpentan-1-one (240 mg, 86%). m/z: M+1 obs=453.5; tR=3.19 minutes; 1H NMR (400 MHz, DMSO-d6) d 8.46 (m, 1H), 8.01 (m, 1H), 7.84 (m, 2H), 7.40 (m, 1H), 6.96 (m, 2H), 4.89 (d, J=7.1 Hz, 1H), 4.45 (m, 1H), 3.97 (m, 4H), 3.76 (m, 4H), 1.56 (m, 1H), 1.42 (m, 1H), 0.97 (s, 9H) ppm.