Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][OH:7].C(N(CC)CC)C.[CH3:15][S:16](Cl)(=[O:18])=[O:17]>ClCCl>[S:16]([O:7][CH2:6][CH2:5][O:4][CH2:3][CH2:2][Cl:1])(=[O:18])(=[O:17])[CH3:15]
Reactant: CS(=O)(=O)Cl
Reactant: OCCOCCCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCOCCCl
Reaction time: 8 h
Yield: 100.3 %

Procedure:
To a solution of 2-(2-chloroethoxy)ethanol (3.9 g, 31 mmol) in dichloromethane (15 ml) kept at 0° C. was added triethylamine (6.2 g, 61 mmol). A solution of methanesulfonyl chloride (3.6 g, 31 mmol) in dichloromethane (15 ml) was carefully added keeping the temperature below 0° C. When addition was complete the reaction mixture was left overnight at room temperature and then diluted with dichloromethane (150 ml). The organic phase was washed with a 2 N hydrochloric acid solution (75 ml) and water (75 ml) and dried over magnesium sulphate. The solvent was evaporated in vacuo to give 6.3 g of crude 2-(2-chloroethoxy)ethyl mesylate as an oil. A suspension of 5,6,11,12-tetrahydrodibenz[b,f]azocine (5.0 g, 20 mmol) in dry THF (75 ml) placed under an atmosphere of nitrogen was cooled to -68° C. A solution of n-butyl lithium in hexanes (19 ml, 49 mmol, 2.5 M) was added dropwise keeping the temperature below -60° C. When addition was complete stirring was continued at this temperature for 30 minutes and then the reaction mixture was left overnight at room temperature. The mesylate prepared above was dissolved in dry THF (50 ml) and added dropwise to the reaction mixture. When addition was complete the mixture was stirred at room temperature for 168 h. Ice was added (80 g) and the phases were separated. The aqueous phase was extracted with diethyl ether (2×50 ml). The combined organic phases were washed with water (2×50 ml) and dried over magnesium sulphate. The solvent was evaporated in vacuo to give a residue which was submitted to column chromatography on silica gel using a mixture of ethyl acetate and n-heptane (2:3) as eluent. This afforded 2.5 g of 2-(2-(5,6,11,12-tetrahydrodibenz[b,f]azocin-12-yl)ethoxy)ethylchloride as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][N:3]=1.Cl[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]#[N:17])[N:11]=1.C(=O)([O-])[O-].[K+].[K+].CCCCCC.C(OCC)(=O)C>CN(C)C=O.O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:10]2[N:11]=[C:12]([C:16]#[N:17])[CH:13]=[CH:14][CH:15]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Oc1ccnc(Cl)c1
Reactant: N#Cc1cccc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N#Cc1cccc(Oc2ccnc(Cl)c2)n1
Yield: 81.3 %

Procedure:
A mixture of 2-chloro-4-hydroxypyridine (38.9 g, 0.3 mol), 2-chloro-6-cyanopyridine (45.7 g, 0.3 mol), and potassium carbonate (45.6 g, 0.3 mol) in N,N-dimethylformamide is refluxed for three hours, cooled and diluted with water and ethyl acetate. The resultant mixture is filtered through a layer of silica gel using ethyl acetate as eluent. The phases are separated and the aqueous phase is extracted with ethyl acetate. The organic extract is combined with the organic phase and the resultant solution is washed with brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo to obtain a residue. Flash column chromatography of the residue using silica gel and a 7:3 hexane/ethyl acetate solution gives the title product as light brown crystals (56.5 g, 81.3%, mp 114° C.).
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:23])[C:6]2[CH:11]=[C:10](B3OC(C)(C)C(C)(C)O3)[C:9]([CH3:21])=[C:8]([F:22])[CH:7]=2)[CH2:3][CH2:2]1.Br[C:25]1[C:26](=[O:43])[N:27]([CH3:42])[C:28]2[N:33]([C:34]3[C:39]([F:40])=[CH:38][CH:37]=[CH:36][C:35]=3[F:41])[N:32]=[CH:31][C:29]=2[N:30]=1>O1CCOCC1.C([O-])([O-])=O.[Na+].[Na+].CCOC(C)=O>[CH:1]1([NH:4][C:5](=[O:23])[C:6]2[CH:7]=[C:8]([F:22])[C:9]([CH3:21])=[C:10]([C:25]3[C:26](=[O:43])[N:27]([CH3:42])[C:28]4[N:33]([C:34]5[C:39]([F:40])=[CH:38][CH:37]=[CH:36][C:35]=5[F:41])[N:32]=[CH:31][C:29]=4[N:30]=3)[CH:11]=2)[CH2:2][CH2:3]1
Reactant: Cn1c(=O)c(Br)nc2cnn(-c3c(F)cccc3F)c21
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1B1OC(C)(C)C(C)(C)O1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1nc2cnn(-c3c(F)cccc3F)c2n(C)c1=O
Temperature: 125 °C

Procedure:
A mixture of N-cyclopropyl-3-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (520 mg, 1.63 mmol), 5-bromo-1-(2,6-difluorophenyl)-7-methyl-1H-pyrazolo[4,3-b]pyrazin-6(7H)-one (505 mg, 1.48 mmol) in 3.5 mL of dioxane and 1.5 mL of 2 N Na2CO3 was heated in a microwave at 125° C. for 25 min. It was diluted with EtOAc and washed with 1 N NaOH. The EtOAc layer was separated, dried and concentrated. Purification of the crude material on an ISCO 40 g column (with 30-75% EtOAc in Hexanes) provided N-cyclopropyl-3-(1-(2,6-difluorophenyl)-7-methyl-6-oxo-6,7-dihydro-1H-pyrazolo[4,3-b]pyrazin-5-yl)-5-fluoro-4-methylb enzamide as an off white amorphous solid. MS (ES+): 454.1 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10](=[O:19])[NH:11][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:13][N:14]=1.[C:20](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10]([O:19][CH3:20])=[N:11][C:12]([C:15]([F:16])([F:18])[F:17])=[CH:13][N:14]=1
Reactant: O=c1[nH]c(C(F)(F)F)cnc1-c1ccc(F)cc1F
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COc1nc(C(F)(F)F)cnc1-c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 15 h
Yield: 65.8 %

Procedure:
First, 23.3 g of 3-(2,4-difluorophenyl)-6-trifluoromethyl-2-oxo-1,2-dihydropyrazine (compound 1-1004) was dissolved in 150 ml of acetone, to which 17.5 g of potassium carbonate and 14.3 g of methyl iodide were added, and the mixture was stirred at room temperature for 15 hours. After completion of the reaction, most of the acetone was distilled out under reduced pressure, and the residue was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography (eluent, hexane/ethyl acetate=19:1), which afforded 16.1 g of 3-(2,4-difluorophenyl)-2-methoxy-6-trifluoromethylpyrazine (m.p., 55.3° C.) as the earlier eluted O-methylated compound and 7.13 g (yield, 29%) of 3-(2,4-difluorophenyl)-1-methyl-6-trifluoromethyl-2-oxo-1,2-dihydropyrazine (present compound 1-10; m.p., 73.0° C.) as the later eluted desired compound.
Reaction SMILES: [CH2:1]([CH:3]([NH:6][C:7]1[C:8]([N+:20]([O-:22])=[O:21])=[CH:9][C:10]([CH2:17][C:18]#[N:19])=[C:11]([CH3:16])[C:12]=1[N+:13]([O-:15])=[O:14])[CH2:4][CH3:5])[CH3:2].[OH-:23].[K+]>C(O)(C)(C)C>[CH2:1]([CH:3]([NH:6][C:7]1[C:8]([N+:20]([O-:22])=[O:21])=[CH:9][C:10]([CH2:17][C:18]([NH2:19])=[O:23])=[C:11]([CH3:16])[C:12]=1[N+:13]([O-:15])=[O:14])[CH2:4][CH3:5])[CH3:2]
Reactant: CCC(CC)Nc1c([N+](=O)[O-])cc(CC#N)c(C)c1[N+](=O)[O-]
Reactant: [OH-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: CCC(CC)Nc1c([N+](=O)[O-])cc(CC(N)=O)c(C)c1[N+](=O)[O-]
Yield: 55.1 %

Procedure:
A sample of {5-[(1-ethylpropyl)amino]-4,6-dinitro-o-tolyl}acetonitrile (4.25 g; 0.014 mol) is added to warm t-butanol (40°-45° C.; 50 ml) followed by finely powdered potassium hydroxide (9.0 g; 0.16 mol). Additional t-butanol (20 ml) is added, and the reaction mixture heated at the reflux overnight. The reaction mixture is then cooled, diluted with 200 ml salt solution, and filtered to give 2.5 g (55%) of an orange solid, melting point 192°-194° C. A sample is recrystallized from methanol for analysis, melting point 194°-196° C.
Reaction SMILES: [NH:1]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C@@H:2]([C:13]([OH:15])=O)[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[NH2:23][C@H:24]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:25][CH2:26][CH2:27][CH2:28][NH:29][C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31].Cl.OC1C2N=NNC=2C=CC=1.Cl.CNC(N=C=NCC)CCNC>CN(C)C1C=CN=CC=1.C(Cl)Cl>[NH:1]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C@@H:2]([C:13]([NH:23][C@H:24]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:25][CH2:26][CH2:27][CH2:28][NH:29][C:30]([O:32][CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)=[O:31])=[O:15])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)[C@@H](N)CCCCNC(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1c[nH]c2ccccc12)C(=O)O
Agent: CCN=C=NC(CCNC)NC
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H](Cc1c[nH]c2ccccc12)C(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Yield: 94.7 %

Procedure:
To a solution of 1.52 gm of BOC-D-Trp (5 mmol), 1.89 gm of Lys(Z)-OtBu HCl (5 mmol), 1.01 gm of hydroxybenzotriazole (7.5 mmol) and 1.83 gm of 4-dimethylaminopyridine (15 mmol) in 450 mL of methylene chloride was added 2.22 gm (11.6 mmol) of 1,3-dimethylaminopropyl-3-ethylcarbodiimide hydrochloride. After stirring for 15 hours 300 mL more methylene chloride was added to the reaction, and it was washed four times with 100 mL portions of 50% saturated aqueous citric acid solution, once with 100 mL of 50% saturated sodium bicarbonate solution, once with 100 mL of saturated brine (NaCl), dried over anhydrous magnesium sulfate, filtered, and the solvent removed under reduced pressure to yield 2.95 gm (94%) of BOC-D-Trp-Lys(CBZ)-OtBu. (see Scheme 1A, for reaction of reactants 5 and 4→3).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[C:7]([C:9]2[O:10][CH2:11][C:12](=[O:21])[N:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:14]=2)[CH:6]=[CH:5][N:4]=1.C([O-])(=O)C.[Na+]>CO.[Pd]>[ClH:2].[N:4]1[CH:5]=[CH:6][C:7]([C:9]2[O:10][CH2:11][C:12](=[O:21])[N:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:14]=2)=[CH:8][CH:3]=1
Reactant: O=C1COC(c2ccnc(Cl)c2)=NN1c1ccccc1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: CO
Product: O=C1COC(c2ccncc2)=NN1c1ccccc1
Yield: 33.1 %

Procedure:
2-(2-Chloro-4-pyridyl)-4-phenyl-4H-1,3,4-oxadiazine-5(6H)-one hydrochloride (780 mg, 2.4 mmol) obtained in Example 12 was hydrogenated in a usual manner in methanol in the presence of sodium acetate and 10% palladium/carbon catalyst, to give the title compound (230 mg, yield 33%).
Reaction SMILES: [CH:1]1([N:4]2[C:8]([C:9]([F:12])([F:11])[F:10])=[C:7]([C:13]([OH:15])=O)[CH:6]=[N:5]2)[CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.[B-](F)(F)(F)F.CN(C(ON1C(=O)CCC1=O)=[N+](C)C)C.Cl.[NH2:46][CH:47]1[CH:54]2[CH2:55][CH:50]3[CH2:51][CH:52]([CH2:56][CH:48]1[CH2:49]3)[CH2:53]2>ClCCl.CN(C=O)C.O>[CH:48]12[CH2:56][CH:52]3[CH2:51][CH:50]([CH2:55][CH:54]([CH2:53]3)[CH:47]1[NH:46][C:13]([C:7]1[CH:6]=[N:5][N:4]([CH:1]3[CH2:2][CH2:3]3)[C:8]=1[C:9]([F:10])([F:11])[F:12])=[O:15])[CH2:49]2
Reactant: O=C(O)c1cnn(C2CC2)c1C(F)(F)F
Reactant: NC1C2CC3CC(C2)CC1C3
Agent: CN(C)C(ON1C(=O)CCC1=O)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(NC1C2CC3CC(C2)CC1C3)c1cnn(C2CC2)c1C(F)(F)F
Reaction time: 1 h
Yield: 56.6 %

Procedure:
1-Cyclopropyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid (Intermediate 6, 20 mg, 0.09 mmol) was dissolved in a mixture of dry dichloromethane (1.6 mL) and dry DMF (0.2 mL). DIPEA (0.1 mL, 0.57 mmol) and TSTU (33 mg, 0.11 mmol) were added to the above mixture. After the mixture was stirred for 1 h, the appearance of active ester was detected by LC-MS. Then 2-aminoadamantane hydrochloride (17 mg, 0.09 mmol) was added. After another 2 hours water was added and the organic layer was separated. The aqueous layer was extracted twice with dichloromethane. The combined organic layers were dried under vacuum and purified by silica chromatography eluting with a gradient of 0-40% ethyl acetate/hexanes, then 40% ethyl acetate/hexanes to give 1-cyclopropyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid adamantan-2-ylamide (18 mg, 56%). Mass spectrum: m/z: 354.2 (M+1).
Reaction SMILES: Br[C:2]1[C:3](=[O:14])[N:4]([CH:9]([CH2:12][CH3:13])[CH2:10][CH3:11])[CH:5]=[C:6]([Br:8])[N:7]=1.Cl.[CH3:16][O:17][C:18]1[CH:19]=[C:20]2[C:24](=[C:25]([CH3:27])[CH:26]=1)[NH:23][CH2:22][CH2:21]2>>[Br:8][C:6]1[N:7]=[C:2]([N:23]2[C:24]3[C:20](=[CH:19][C:18]([O:17][CH3:16])=[CH:26][C:25]=3[CH3:27])[CH2:21][CH2:22]2)[C:3](=[O:14])[N:4]([CH:9]([CH2:12][CH3:13])[CH2:10][CH3:11])[CH:5]=1
Reactant: COc1cc(C)c2c(c1)CCN2
Reactant: CCC(CC)n1cc(Br)nc(Br)c1=O
Agent: Cl
Product: CCC(CC)n1cc(Br)nc(N2CCc3cc(OC)cc(C)c32)c1=O

Procedure:
Prepared in a similar fashion as described for Example 413 using 3,5-dibromo-1-(1-ethylpropyl)-2(1H)-pyrazinone and 5-methoxy-7-methylindoline hydrochloride as the starting materials. mp 152–154° C.; 1H NMR (300 MHz, CDCl3): δ 6.73 (s, 1 H), 6.67 (s, 1 H), 6.59 (d, J=1.9 Hz, 1 H), 4.84–4.76 (m, 1 H), 4.38 (t, J=7.7 Hz, 2 H), 3.78 (s, 3 H), 3.05 (t, J=7.7 Hz, 2 H), 2.06 (s, 3 H), 1.87–1.73 (m, 2 H), 1.70–1.59 (m, 2 H), 0.89 (t, J=7.3 Hz, 6 H); HRMS (ESI) calcd for C19H25N3O2Br (M+H)+: 406.1130; found m/z 406.1125.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[C:12]1([CH2:18][CH2:19][CH2:20][CH2:21]O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1.C(OCC)C>[C:12]1([CH2:18][CH2:19][CH2:20][CH2:21][O:1][C:2]2[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: OCCCCc1ccccc1
Reactant: COC(=O)c1ccc(O)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OCCCCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 36 h
Yield: 68.8 %

Procedure:
A mixture of methyl 4-hydroxybenzoate (3 g, 19.7 mmol), 4-phenylbutanol (3.04 ml, 19.7 mmol) and triphenylphosphine (7.74 g, 29.6 mmol) in anhydrous tetrahydrofuran (110 ml) was added with diethyl azodicarboxylate (4.65 ml, 29.6 mmol). The resulting mixture was left under stirring at room temperature for 36 h, then was added with ethyl ether (500 ml) and left to crystallize for 24 hours at 0° C. After that the solid was filtered and the filtrate was washed successively with 0.2M hydrochloric acid, 5% sodium bicarbonate and a sodium chloride saturated solution. After drying and removing the solvent under reduced pressure, a residue was obtained which was purified by chromatography through a silica gel column, eluting with petroleum ether:chloroform mixtures of increasing polarity, thereby recovering 3.856 g of the title compound (70% yield).
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[F:23][C:24]1[CH:39]=[CH:38][C:27]([C:28]([N:30]([C@@H:32]([CH:35]([CH3:37])[CH3:36])[CH2:33][OH:34])[CH3:31])=[O:29])=[CH:26][C:25]=1[CH3:40].C([O-])(O)=O.[Na+].S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+]>C(Cl)Cl>[F:23][C:24]1[CH:39]=[CH:38][C:27]([C:28]([N:30]([CH3:31])[C@@H:32]([CH:35]([CH3:36])[CH3:37])[CH:33]=[O:34])=[O:29])=[CH:26][C:25]=1[CH3:40]
Reactant: Cc1cc(C(=O)N(C)[C@H](CO)C(C)C)ccc1F
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])S(=O)(=O)[O-]
Solvent: ClCCl
Product: Cc1cc(C(=O)N(C)[C@H](C=O)C(C)C)ccc1F
Yield: 94.9 %

Procedure:
Dess-Martin periodinane (0.25 g, 0.59 mmol) was added to (S)-4-fluoro-N-(1-hydroxy-3-methylbutan-2-yl)-N,3-dimethylbenzamide (Compound Z) (0.1 g, 0.39 mmol) in DCM (3 mL) at rt. The resultant mixture was stirred at rt for 2 h. An aqueous NaHCO3 (8 wt %) solution containing sodium pyrosulphite (0.059 mL, 0.43 mmol) was added and the resultant mixture was stirred vigorously for 15 min. The organic phases was washed with Na2CO3 (8 wt %), filtered through a phase separator and dried using Na2SO4. The solvent was removed under reduced pressure to give the title compound (93 mg, 94%). The obtained crude product was used without further purification. LCMS (M+H)+: 252.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([C:14]2[S:15][CH:16]=[CH:17][CH:18]=2)=[NH:13])=[CH:7][CH:6]=1)(=[O:4])=[O:3].C(=O)(O)[O-].[Na+].Br[CH2:25][C:26](=[O:31])[C:27]([F:30])([F:29])[F:28]>C(O)(C)C>[OH:31][C:26]1([C:27]([F:30])([F:29])[F:28])[CH2:25][N:11]([C:8]2[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:10][CH:9]=2)[C:12]([C:14]2[S:15][CH:16]=[CH:17][CH:18]=2)=[N:13]1
Reactant: O=C(CBr)C(F)(F)F
Reactant: CS(=O)(=O)c1ccc(NC(=N)c2cccs2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: CS(=O)(=O)c1ccc(N2CC(O)(C(F)(F)F)N=C2c2cccs2)cc1
Yield: 39.7 %

Procedure:
To a mixture of the amidine of step 1 (2.0 g, 7.1 mmol) and sodium bicarbonate (1.2 g, 14.3 mmol) in isopropanol (200 ml), 3-bromo-1,1,1-trifluoroacetone (1.1 ml, 10.7 mmol) was added. After heating at 80°-85° C. for 16 hours, the reaction mixture was cooled and filtered. The residue was washed with methylene chloride and the combined organic fractions were dried over sodium sulfate, filtered and concentrated. The crude mixture (25.7 g) was chromatographed (silica gel, ethyl acetate/hexane 55/45) to give the 4,5-dihydroimidazole (1.1 g, 38%) as a white solid: mp (DSC) 214° C. Anal. Calc'd. for C15H13N2S2O3F3 : C, 46.15, H, 3.36, N, 7.18, S, 16.43 Found C, 46.09, H, 3.26, N, 7.07, S, 16.71.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].Cl[C:10]1[N:15]=[C:14]([NH:16][C:17]2[C:18]([O:25][CH3:26])=[N:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=2)[C:13]([F:27])=[CH:12][N:11]=1>>[CH3:26][O:25][C:18]1[C:17]([NH:16][C:14]2[C:13]([F:27])=[CH:12][N:11]=[C:10]([NH:5][C:4]3[CH:6]=[CH:7][CH:8]=[C:2]([OH:1])[CH:3]=3)[N:15]=2)=[CH:22][CH:21]=[C:20]([O:23][CH3:24])[N:19]=1
Reactant: Nc1cccc(O)c1
Reactant: COc1ccc(Nc2nc(Cl)ncc2F)c(OC)n1
Product: COc1ccc(Nc2nc(Nc3cccc(O)c3)ncc2F)c(OC)n1

Procedure:
In like manner to the preparation of N4-(3-chloro-4-trifluoromethoxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidineamine, the reaction of 3-hydroxyaniline with 2-chloro-N4-(2,6-dimethoxypyridin-3-yl)-5-fluoro-4-pyrimidineamine gave N4-(2,6-dimethoxypyridin-3-yl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine. 1H NMR (DMSO-d6): δ 9.98 (bs, 2H), 8.20 (d, 1H, J=5.4 Hz), 7.72 9 m, 1H), 6.90 (t, 1H, J=7.8 Hz), 6.81 (m, 2H), 6.42 (m, 2H), 3.88 (s, 3H), 3.86 (s, 3H); LCMS: purity: 94%; MS (m/e): 358 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:17]=[CH:16][C:7](/[CH:8]=[C:9]2/[C:10](=[O:15])[NH:11][C:12](=[O:14])[S:13]/2)=[CH:6][CH:5]=1)[CH3:2].[N:18]1[CH:23]=[CH:22][C:21]([CH2:24]Cl)=[CH:20][CH:19]=1.Cl.[I-].[Na+].C(=O)([O-])[O-].[K+].[K+].C(OC1C=CC(/C=C2/C(=O)N(CCC)C(=O)S/2)=CC=1)C>>[CH2:1]([O:3][C:4]1[CH:17]=[CH:16][C:7](/[CH:8]=[C:9]2/[C:10](=[O:15])[N:11]([CH2:24][C:21]3[CH:22]=[CH:23][N:18]=[CH:19][CH:20]=3)[C:12](=[O:14])[S:13]/2)=[CH:6][CH:5]=1)[CH3:2]
Reactant: ClCc1ccncc1
Reactant: CCOc1ccc(/C=C2\SC(=O)NC2=O)cc1
Agent: CCCN1C(=O)S/C(=C\c2ccc(OCC)cc2)C1=O
Agent: Cl
Agent: O=C([O-])[O-]
Product: CCOc1ccc(/C=C2\SC(=O)N(Cc3ccncc3)C2=O)cc1

Procedure:
The title compound 28l was prepared from compound 2 (75 mg, 0.30 mmol), 4-picolyl chloride.HCl (54 mg, 0.33 mmol), sodium iodide (45 mg, 0.30 mmol) and potassium carbonate (124 mg, 0.90 mmol) in a manner similar to that described for 28d in 96.1% (98 mg) yield as a white solid.
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1)=O.[CH2:13]([OH:16])[CH2:14][OH:15].C1(C)C(C)=CC=CC=1>[Cl-].[Cl-].[Zn+2].O>[O:15]1[CH2:14][CH2:13][O:16][CH:1]1[C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1
Reactant: COC(=O)c1ccc(C=O)cc1
Reactant: OCCO
Agent: [Cl-]
Agent: [Zn+2]
Solvent: O
Solvent: Cc1ccccc1C
Product: COC(=O)c1ccc(C2OCCO2)cc1

Procedure:
8.2 g (0.05 mol) of methyl 4-formylbenzoate, 25 ml of ethylene glycol, 3.5 g of ZnCl2 and 200 ml of xylene are introduced into a round-bottomed flask. The mixture is heated to reflux and the water formed is separated after settling has taken place, the organic phase is evaporated to dryness, the reaction medium is poured into water, the mixture is extracted with ethyl ether and the organic phase is separated after settling has taken place, dried over magnesium sulphate and evaporated. 10.4 g (100%) of the expected product are collected in the form of a colorless oil.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].C([Li])(C)(C)C.[CH3:15][O:16][C:17](=[O:25])[C:18]1[CH:23]=[CH:22][C:21](I)=[CH:20][CH:19]=1.[OH-].[NH4+]>C1COCC1.CCCCC.[Cl-].[Zn+2].[Cl-].[Ni].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:15][O:16][C:17](=[O:25])[C:18]1[CH:23]=[CH:22][C:21]([C:2]2[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=2[C:4]#[N:5])=[CH:20][CH:19]=1
Reactant: N#Cc1ccccc1Br
Reactant: COC(=O)c1ccc(I)cc1
Agent: [Ni]
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCCCC
Product: COC(=O)c1ccc(-c2ccccc2C#N)cc1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a solution of 2-bromobenzonitrile (1.00 g, 5.494 mmol), in THF (16.5 mL) at -100° C. was added t-butyl lithium (6.46 mL, of a 1.7M solution in pentane, 10.98 mmol. After 5 minutes zinc chloride(5.494 mL, of a 1M solution in THF, 5.494 mmol) was added. The reaction was stirred for 10 minutes at -78° C. and then allowed to warm to 0° C. and stirred for 1 hour. This solution was added via cannula to a solution of methyl-4-iodobenzoate (1.44 g, 5.494 mmol) and bis(triphenylphosphine) Nickel II chloride (0.359 g, 0.549 mmol) in THF (12 mL). The reaction stirred for 1 hour at 0° C. and then at ambient temperature for a further 16 hours. Saturated ammonium hydroxide solution (5 mL) was added and the mixture stirred until homogenous, extracted with EtOAc and the organic extracts washed with saturated brine, dried (MgSO4) and evaporated in vacuo. The residue was chromatographed (Silica gel, 50% CH2Cl2 to 50%) EtOAc in hexanes) to afford the title compound.
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][CH:8]([N:11]([CH2:22][C:23]2[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][CH:24]=2)[C:12]2[N:16]([CH3:17])[C:15]3[CH:18]=[CH:19][CH:20]=[CH:21][C:14]=3[N:13]=2)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[CH3:32][O:33][C:34](=[O:39])[CH:35]([OH:38])[CH2:36][NH2:37].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.CCN(C(C)C)C(C)C>CN(C=O)C>[C:1]([CH:5]1[CH2:6][CH2:7][CH:8]([N:11]([CH2:22][C:23]2[CH:24]=[CH:25][C:26]([C:27]([NH:37][CH2:36][C@@H:35]([OH:38])[C:34]([O:33][CH3:32])=[O:39])=[O:28])=[CH:30][CH:31]=2)[C:12]2[N:16]([CH3:17])[C:15]3[CH:18]=[CH:19][CH:20]=[CH:21][C:14]=3[N:13]=2)[CH2:9][CH2:10]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)C(O)CN
Reactant: Cn1c(N(Cc2ccc(C(=O)O)cc2)C2CCC(C(C)(C)C)CC2)nc2ccccc21
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: COC(=O)[C@H](O)CNC(=O)c1ccc(CN(c2nc3ccccc3n2C)C2CCC(C(C)(C)C)CC2)cc1

Procedure:
To a solution of the title compound of Example 5 Step A (0.32 mmol, 145 mg), the hydrochloride salt of 2-hydroxy β-alanine methyl ester (0.48 mmol, 74 mg), HOBt (0.8 mmol, 121 mg) and EDC (0.96 mmol, 183 mg) in 2 mL of DMF was added DIEA (1.6 mmol, 0.28 mL). After 3 h the reaction was partitioned into EtOAc/brine. The organic phase was dried with MgSO4 and concentrated under reduced pressure. The product was purified by flash chromatography on silica eluting with 1:25:74 MeOH/EtOAc/DCM, affording the title compound as a foamy solid. 1HNMR (500 MHz, DMSO-d6): δ 8.47 (t, 1H), 7.75 (d, 2H), 7.60 (m, 1H), 7.48 (m, 1H), 7.45 (d, 2H), 7.30-7.37 (overlapping m, 2H), 4.80 (s, 2H), 3.76 (s, 3H), 3.70 (m, 1H), 3.60 (s, 3H), 3.50 (m, 1H), 3.39 (m, 1H), 2.02 (m, 2H), 1.82 (m, 2H), 1.71 (m, 2H), 1.18 (m, 2H), 1.03 (m, 1H), 0.85 (s, 9H). MS (ESI): m/z 521 (M+H). HPLC A: 1.94 min.