Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][C:9](=O)[CH:8](Br)[CH2:7]1)=[O:5])[CH3:2].[C:14]([NH2:24])(=[O:23])/[CH:15]=[CH:16]/[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][C:9]2[N:24]=[C:14](/[CH:15]=[CH:16]/[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[O:23][C:8]=2[CH2:7]1)=[O:5])[CH3:2]
Reactant: NC(=O)/C=C/c1ccccc1
Reactant: CCOC(=O)N1CCC(=O)C(Br)C1
Product: CCOC(=O)N1CCc2nc(/C=C/c3ccccc3)oc2C1
Temperature: 125 °C
Reaction time: 60 h
Yield: 26.7 %

Procedure:
A mixture of 3-bromo-4-oxo-1-piperidinecarboxylic acid ethyl ester (13.5 g, 26.99 mmol) and trans-cinnamamide (3.0 g, 20.7 mmol) was supported in silica gel (48 g) and mechanically stirred at 125° C. for 60 hours. The product was eluted from the silica gel with a 7M solution of ammonia in MeOH (3×140 mL). The filtrate was evaporated in vacuo and the crude product was basified with a saturated solution of NaHCO3 and extracted with DCM. The organic layer was separated, dried (Na2SO4), filtered and the solvent evaporated in vacuo. The crude product was purified by flash column chromatography (silica; AcOEt in DCM 0/100 to 20/80). The desired fractions were collected and the solvents evaporated in vacuo to yield 6,7-dihydro-2-[(E)-2-phenylethenyl]-oxazolo[5,4-c]pyridine-5(4H)-carboxylic acid ethyl ester (1.65 g, 27% yield) as an orange oil. C17H18N2O3 LCMS: Rt 2.91, m/z 299 [M+H]+ (using method, LC-MS Method 6)
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])=[N:6][CH:7]=1.[CH2:15](N(CC)CC)[CH3:16].C([B-](F)(F)F)=C.[K+]>C(O)C.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C(Cl)Cl.Cl[Pd]Cl.[Fe]>[CH3:11][C:10]([CH3:13])([CH3:12])[C:9]([NH:8][C:5]1[CH:4]=[N:3][C:2]([CH:15]=[CH2:16])=[CH:7][N:6]=1)=[O:14]
Reactant: CCN(CC)CC
Reactant: CC(C)(C)C(=O)Nc1cnc(Br)cn1
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: C=C[B-](F)(F)F
Solvent: CCO
Solvent: ClCCl
Product: C=Cc1cnc(NC(=O)C(C)(C)C)cn1
Temperature: 100 °C
Yield: 91.7 %

Procedure:
A mixture of N-(5-bromo-pyrazin-2-yl)-2,2-dimethyl-propionamide (29.67 g, 114.9421 mmol), dichloro[1,1′-bis(diphenylphosphino)ferro-cene]palladium(II) dichloromethane adduct (0.95 g, 1.1633 mmol), triethylamine (17.6 mL, 126.2733 mmol), and potassium vinyltrifluoroborate (19.25 g, 143.7103 mmol) in ethanol (245 mL) was heated at 100° C. for 90 min. At this time, the reaction mixture was allowed to cool to 25° C. and then was concentrated in vacuo. The resulting orange slurry was diluted with methylene chloride (200 mL). The organic layer was washed with a 1N aqueous hydrochloric acid solution (2×200 mL), a saturated aqueous sodium bicarbonate solution (1×200 mL), and a saturated aqueous sodium chloride solution (1×200 mL). The combined aqueous layers were back-extrated with methylene chloride (1×200 mL). The combined organic layers were dried over magnesium chloride and decolorizing carbon, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 75S, Silica, 100% hexanes to 10% ethyl acetate/hexanes) afforded 2,2-dimethyl-N-(5-vinyl-pyrazin-2-yl)-propionamide (21.64 g, 92%) as an off-white solid: mp 80.4–81.8° C.; EI-HRMS m/e calcd for C11H15N3O (M+) 205.1215, found 205.1214.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[C:4]([O:10][C:11]([F:14])([F:13])[F:12])[CH:3]=1.[H][H]>C(O)C.C(O)(=O)C.[Pd]>[CH3:6][C:5]1[CH:8]=[CH:9][C:2]([OH:1])=[CH:3][C:4]=1[O:10][C:11]([F:12])([F:13])[F:14]
Reactant: [H][H]
Reactant: O=Cc1ccc(O)cc1OC(F)(F)F
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: Cc1ccc(O)cc1OC(F)(F)F
Reaction time: 22 h

Procedure:
A solution of 4-hydroxy-2-(trifluoromethoxy)benzaldehyde (210 g, 1 equiv) in ethanol: acetic acid 3:1 (1050 Lt) was treated with Pd/C 5% catalyst-50% wet (21 g) and stirred at 800 rpm under 5 bar of hydrogen for 2.5 hrs. A second aliquot of Pd/C 5% catalyst-50% wet (33.6 g) was then added and the mixture subjected to the same hydrogenation conditions until reaching 22 hrs in total. The reaction mixture was filtered on a charcoal cartridge and washed with ethanol (525 mL). The resulting clear solution was concentrated to ca. 420 mL and the residue diluted with ethyl acetate (1050 Lt) and an aqueous 10% solution of ammonium chloride (525 mL). The phases were allowed separating and the organic one washed with water (2×525 mL), dried over sodium sulfate, filtered and concentrated to dryness. The title compound was obtained as colorless oil (196 g).
Reaction SMILES: [CH3:1][O:2][C:3](=O)[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([F:14])([F:13])[F:12])[CH:6]=1.CCO.[NH2:19][NH2:20]>>[F:12][C:11]([F:14])([F:13])[C:7]1[CH:6]=[C:5]([CH:10]=[CH:9][CH:8]=1)[CH2:4][C:3]1[O:2][CH:1]=[N:19][N:20]=1
Reactant: COC(=O)Cc1cccc(C(F)(F)F)c1
Reactant: NN
Solvent: CCO
Product: FC(F)(F)c1cccc(Cc2nnco2)c1
Temperature: 135 °C

Procedure:
(3-Trifluoromethyl-phenyl)-acetic acid methyl ester (0.720 g, 3.30 mmol) was dissolved in hydrazine (7 mL) and EtOH (15 mL) and heated to 90° C. overnight. Analytical LCMS indicated complete reaction so the mixture was concentrated and azeotroped twice with toluene. The crude material was dissolved in triethylorthoformate and heated to 135° C. for 20 hours then allowed to cool. The reaction mixture was concentrated to afford the title compound.
Reaction SMILES: Cl.[F:2][CH2:3][C:4]([C:8]1[CH:9]=[C:10]([NH:20][C:21]([NH:23][C:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:27]([O:34][CH:35]3[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]3)=[N:26][CH:25]=2)=[O:22])[N:11]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[N:12]=1)([CH2:6][F:7])[CH3:5].[F:41][C:42]1[CH:50]=[CH:49][CH:48]=[C:47]([F:51])[C:43]=1[C:44](Cl)=[O:45].C(N(CC)CC)C.O>ClCCl>[F:41][C:42]1[CH:50]=[CH:49][CH:48]=[C:47]([F:51])[C:43]=1[C:44]([N:38]1[CH2:39][CH2:40][CH:35]([O:34][C:27]2[C:28]3[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:24]([NH:23][C:21]([NH:20][C:10]3[N:11]([C:13]4[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=4)[N:12]=[C:8]([C:4]([CH2:6][F:7])([CH3:5])[CH2:3][F:2])[CH:9]=3)=[O:22])=[CH:25][N:26]=2)[CH2:36][CH2:37]1)=[O:45]
Reactant: Cc1ccc(-n2nc(C(C)(CF)CF)cc2NC(=O)Nc2cnc(OC3CCNCC3)c3ccccc23)cc1
Reactant: O=C(Cl)c1c(F)cccc1F
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: Cc1ccc(-n2nc(C(C)(CF)CF)cc2NC(=O)Nc2cnc(OC3CCN(C(=O)c4c(F)cccc4F)CC3)c3ccccc23)cc1

Procedure:
Stir 1-[5-(2-fluoro-1-fluoromethyl-1-methyl-ethyl)-2-p-tolyl-2H-pyrazol-3-yl]-3-[1-(piperidin-4-yloxy)-isoquinolin-4-yl]-urea hydrochloride (Preparation 37, 0.6 mmol, 0.3 g), 2,6-difluorobenzoyl chloride (0.6 mmol, 0.07 mL) and triethylamine (1.7 mmol, 0.2 mL) in 5 mL of dichloromethane at room temperature overnight. Add some water and extract in dichloromethane. Wash organic layer with saturated aq. sodium chloride. Dry over anhydrous sodium sulfate and concentrate under reduced pressure. Subject residue to silica gel chromatography eluting with hexanes/ethyl acetate as eluent (30%-70%). LCMS ES+(m/z) 675 [M+H].
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:10]([I:11])=[CH:9][N:8]([CH:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:18][N:19]1[CH2:24][CH2:23][C:22](=O)[CH2:21][CH2:20]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>ClC(Cl)C.O>[Cl:1][C:2]1[C:3]2[C:10]([I:11])=[CH:9][N:8]([CH:12]3[CH2:17][CH2:16][N:15]([CH:22]4[CH2:23][CH2:24][N:19]([CH3:18])[CH2:20][CH2:21]4)[CH2:14][CH2:13]3)[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: CN1CCC(=O)CC1
Reactant: Clc1ncnc2c1c(I)cn2C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Solvent: O
Product: CN1CCC(N2CCC(n3cc(I)c4c(Cl)ncnc43)CC2)CC1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 60.8 %

Procedure:
A mixture of 4-chloro-5-iodo-7-(4-piperidinyl)-7H-pyrrolo[2,3-d]pyrimidine (0.52 g, 1.43 mmol), 1-methyl-4-piperidone (0.178 g, 1.57 mmol), and glacial acetic acid (0.094 g, 1.57 mmol) in dichloroethane was stirred at 0° C. for 20 minutes. Sodium 15 triacetoxy borohydride (0.455 g, 2.15 mmol) was added and stirred for 15 minutes at 0° C., after which the ice bath was removed, allowed to warm to room temperature and stirred over night. Additional 1-methyl-4-piperidone (0.178 g, 1.57 mmol), glacial acetic acid (0.094 g, 1.57 mmol), and sodium triacetoxy borohydride (0.455 g, 2.15 mmol) were added and stirred at room temperature. To the reaction solution was added sodium bicarbonate (0.721 g, 8.58 mmol) in water (10 mL) and stirred for 1 hour. The organic layer was evaporated under reduced pressure. Ethyl acetate was added, the layers were partitioned, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with water and brine, dried over magnesium sulfate, filtered and evaporated under reduced pressure. The compound was purified by flash chromatography on silica using dichloromethane/ethyl acetate (1:1), 10% methanol in dichloromethane, and then 20% methanol in dichloromethane to give 400 mg (61%) of 4-chloro-5-iodo-7-[1-(1-methyl-4-piperidinyl)-4-piperidinyl]-7H-pyrrolo[2,3-d]pyrimidine
Reaction SMILES: [CH2:1]([OH:13])[C:2]#[C:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[CH:14]#[C:15]CCCCCCCCCCC.[Li]CCCC.C=O>CCOCC>[CH2:1]([OH:13])[C:2]#[C:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:14][CH3:15]
Reactant: CCCCCCCCCC#CCO
Reactant: C#CCCCCCCCCCCC
Agent: C=O
Agent: [Li]CCCC
Solvent: CCOCC
Product: CCCCCCCCCCCC#CCO

Procedure:
2-Tetradecyn-1-ol was prepared as described above for 2-dodecyn-1-ol except that 5.0 g (27 mmole) of 1-tridecyne in 200 ml of ether, 11.6 ml (29 mmole) of n-BuLi, and 874 mg (29 mmole) of paraformaldehyde was used. The reaction afforded a white solid after workup which was crystallized from petroleum ether to yield 4.78 g of white crystals, mp 44-6° C. 1H NMR δ 4.25 (m, 2), 2.20 (m, 2), 1.6-1.2 (m, 20), 0.88 (t, 3, J=7 Hz).
Reaction SMILES: [NH2:1][CH:2]1[CH2:6][CH2:5][N:4]([C:7]2[N:12]=[C:11]([NH:13][C@H:14]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[CH3:15])[N:10]=[C:9]([NH:23][C:24]3[CH:29]=[N:28][CH:27]=[CH:26][N:25]=3)[CH:8]=2)[CH2:3]1.C(N(CC)C(C)C)(C)C.[CH3:39][S:40](Cl)(=[O:42])=[O:41].O>O1CCCC1>[F:22][C:19]1[CH:20]=[CH:21][C:16]([C@@H:14]([NH:13][C:11]2[N:12]=[C:7]([N:4]3[CH2:5][CH2:6][CH:2]([NH:1][S:40]([CH3:39])(=[O:42])=[O:41])[CH2:3]3)[CH:8]=[C:9]([NH:23][C:24]3[CH:29]=[N:28][CH:27]=[CH:26][N:25]=3)[N:10]=2)[CH3:15])=[CH:17][CH:18]=1
Reactant: C[C@H](Nc1nc(Nc2cnccn2)cc(N2CCC(N)C2)n1)c1ccc(F)cc1
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1nc(Nc2cnccn2)cc(N2CCC(NS(C)(=O)=O)C2)n1)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
110 mg of 6-(3-aminopyrrolidin-1-yl)-N2—[(S)-1-(4-fluorophenyl)ethyl]-N4-(pyrazin-2-yl)pyrimidine-2,4-diamine (Example 59) was dissolved in 3 ml of tetrahydrofuran, and 91 μl of N,N-diisopropylethylamine and 21 μl of methanesulfonyl chloride were added at 0° C., and the mixture was stirred at 0° C. for 1 hour. Water was added to the reaction solution, and then the reaction solution was subjected to extraction with ethyl acetate, and the organic layer was washed with water and brine in turn, and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography to obtain 92 mg of N-(1-{2-[(S)-1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-yl amino)pyrimidin-4-yl}pyrrolidin-3-yl)methanesulfonamide as a pale yellow amorphous solid. The obtained compound was subjected to hydrochlorination using a conventional method to obtain 70 mg of the objective compound as pale yellow powder.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[C:8]([CH2:10][C:11]3[N:15]4[N:16]=[C:17](NCCO)[CH:18]=[CH:19][C:14]4=[N:13][CH:12]=3)[CH:7]=[CH:6][C:5]=12.[CH3:24][N:25]([CH3:31])[C@@H:26]1[CH2:30][CH2:29][NH:28][CH2:27]1>>[N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[C:8]([CH2:10][C:11]3[N:15]4[N:16]=[C:17]([N:28]5[CH2:29][CH2:30][C@@H:26]([N:25]([CH3:31])[CH3:24])[CH2:27]5)[CH:18]=[CH:19][C:14]4=[N:13][CH:12]=3)[CH:7]=[CH:6][C:5]=12
Reactant: OCCNc1ccc2ncc(Cc3ccc4nccn4c3)n2n1
Reactant: CN(C)[C@@H]1CCNC1
Product: CN(C)[C@@H]1CCN(c2ccc3ncc(Cc4ccc5nccn5c4)n3n2)C1

Procedure:
The title compound was prepared in analogy to the compound of Example 75 using dimethyl(R)-pyrrolidin-3-yl-amine as starting material (tR 0.93 min (conditions 7), MH+=362.1, 1H-NMR in DMSO-d6: 8.48 (s, 1H); 7.86 (s, 1H); 7.76 (d, 1H); 7.52 (s, 1H); 7.46 (d, 1H); 7.37 (s, 1H); 7.19 (d, 1H); 6.78 (d, 1H); 4.17 (s, 2H); 3.63 (m, 2H); 3.35 (m, 1H); 3.16 (m, 1H); 2.78 (m, 1H); 2.18 (m, 7H); 1.81 (m, 1H)).
Reaction SMILES: N1C=CC=CC=1.[C:7]1([N:17]2[C:21](=[S:22])[N:20]=[N:19][NH:18]2)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1.Br[CH2:24][C:25]([O:27]C)=[O:26]>CS(C)=O.CCOC(C)=O>[C:7]1([N:17]2[C:21]([S:22][CH2:24][C:25]([OH:27])=[O:26])=[N:20][N:19]=[N:18]2)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1
Reactant: COC(=O)CBr
Reactant: S=c1nn[nH]n1-c1cccc2ccccc12
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: c1ccncc1
Product: O=C(O)CSc1nnnn1-c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.3 %

Procedure:
Pyridine (0.83 mL, 10.3 mmol) and 1,2-dihydro-1-(1-naphthalenyl)-5H-tetrazole-5-thione (2.14 g, 9.38 mmol) were added to a solution of methyl 2-bromoacetate (977 μL, 10.3 mmol) in DMSO (50 mL). The resulting light yellow solution was stirred at room temperature for 2 h. The reaction mixture was then diluted with EtOAc (300 ml) and was successively washed with water (2×250 ml) and brine (100 ml), dried (MgSO4), filtered and concentrated under reduced pressure. The crude ester was dissolved in THF and aqueous 1 N NaOH solution was added. The solution was stirred at room temperature for 30 min. The THF was evaporated under reduced pressure and the residue was dissolved in aqueous 1 N NaOH solution. The solution was slowly acidified to pH 2 at 0° C. with aqueous 1 N HCl solution. The suspension was filtered and the resulting solid was rinsed with water and dried under reduced pressure to give the title compound (2.48 g, 92% yield) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH2:7][C:8]([OH:10])=O)=[C:4]([O:13][CH3:14])[CH:3]=1.[Cl:15][C:16]1[CH:17]=[C:18]([NH2:30])[CH:19]=[CH:20][C:21]=1[O:22][CH2:23][CH2:24][N:25]([CH2:28][CH3:29])[CH2:26][CH3:27]>>[Br:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH2:7][C:8]([NH:30][C:18]2[CH:19]=[CH:20][C:21]([O:22][CH2:23][CH2:24][N:25]([CH2:28][CH3:29])[CH2:26][CH3:27])=[C:16]([Cl:15])[CH:17]=2)=[O:10])=[C:4]([O:13][CH3:14])[CH:3]=1
Reactant: COc1cc(Br)ccc1OCC(=O)O
Reactant: CCN(CC)CCOc1ccc(N)cc1Cl
Product: CCN(CC)CCOc1ccc(NC(=O)COc2ccc(Br)cc2OC)cc1Cl

Procedure:
The product was prepared according to general working method I from 2-(4-bromo-2-methoxy-phenoxy)-acetic acid (1 32b) and 3-chloro-4-(2-diethylamino-ethoxy)-phenylamine (Z1b).
Reaction SMILES: [C:1]1([C:7]2[N:11]3[N:12]=[C:13]([C:16]([F:19])([F:18])[F:17])[CH:14]=[CH:15][C:10]3=[N:9][C:8]=2[C:20]2[CH:25]=[CH:24][C:23]([C:26]3([NH:30]C(=O)OC(C)(C)C)[CH2:29][CH2:28][CH2:27]3)=[CH:22][CH:21]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.O1CCOCC1.[OH-].[Na+]>C(Cl)Cl.CO>[C:1]1([C:7]2[N:11]3[N:12]=[C:13]([C:16]([F:19])([F:17])[F:18])[CH:14]=[CH:15][C:10]3=[N:9][C:8]=2[C:20]2[CH:21]=[CH:22][C:23]([C:26]3([NH2:30])[CH2:29][CH2:28][CH2:27]3)=[CH:24][CH:25]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4ccc(C(F)(F)F)nn4c3-c3ccccc3)cc2)CCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: CO
Product: NC1(c2ccc(-c3nc4ccc(C(F)(F)F)nn4c3-c3ccccc3)cc2)CCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92 %

Procedure:
To a mixture of tert-butyl (1-{4-[3-phenyl-6-(trifluoromethyl)imidazo[1,2-b]pyridazin-2-yl]phenyl}cyclobutyl)carbamate that was prepared in a manner analgous to that described for Intermediate Example Int-3 (680 mg, 1.177 mmol, 1.0 eq) in DCM (7.6 mL) and methanol (4.8 mL) was added a solution of 4 M hydrogen chloride in dioxane (5.9 mL, 23.5 mmol, 20.0 eq) and the mixture was stirred for overnight at rt. The mixture was poured onto ice, made alkaline with aqueous sodium hydroxide (2 N) and extracted with EtOAc (3×). The combined organic phases were washed with brine, dried and concentrated in vacuo. Purification was achieved by crystallization from diisopropyl ether. The resulting solid was filtered and dried under high vacuum overnight to give 440 mg (92% yield) of the title compound.
Reaction SMILES: [CH:1]1([N:4]2[C:8]3[C:9]([O:22][C@@H:23]([C@H:25]4[CH2:29][NH:28][C:27](=[O:30])[CH2:26]4)[CH3:24])=[CH:10][C:11](B4OC(C)(C)C(C)(C)O4)=[CH:12][C:7]=3[N:6]=[CH:5]2)[CH2:3][CH2:2]1.I[C:32]1[N:36](C(OC(C)(C)C)=O)[C:35]([CH3:44])=[N:34][CH:33]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].N#N>CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.Cl[Pd]Cl.C(Cl)Cl.O.O1CCOCC1>[CH:1]1([N:4]2[C:8]3[C:9]([O:22][C@@H:23]([C@H:25]4[CH2:29][NH:28][C:27](=[O:30])[CH2:26]4)[CH3:24])=[CH:10][C:11]([C:32]4[NH:36][C:35]([CH3:44])=[N:34][CH:33]=4)=[CH:12][C:7]=3[N:6]=[CH:5]2)[CH2:3][CH2:2]1
Reactant: Cc1ncc(I)n1C(=O)OC(C)(C)C
Reactant: C[C@@H](Oc1cc(B2OC(C)(C)C(C)(C)O2)cc2ncn(C3CC3)c12)[C@H]1CNC(=O)C1
Agent: Cl[Pd]Cl
Agent: CN(C)c1ccc(P(C(C)(C)C)C(C)(C)C)cc1
Agent: N#N
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O
Product: Cc1ncc(-c2cc(O[C@H](C)[C@H]3CNC(=O)C3)c3c(c2)ncn3C2CC2)[nH]1
Temperature: 100 °C
Yield: 0.6 %

Procedure:
To a microwave tube equipped with a stirring bar, (R)-4-((R)-1-((1-cyclopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazol-7-yl)oxy)ethyl)pyrrolidin-2-one: (200 mg, 0.486 mmol), tert-butyl 5-iodo-2-methyl-1H-imidazole-1-carboxylate (299.7 mg, 0.973 mmol), 1,4-dioxane (1.1 mL), water (0.82 mL), K3PO4 (355 mg, 1.673 mmol) were added, the mixture was bubbled N2 for 5 minutes before bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (27.5 mg, 0.039 mmol) was added. The tube was sealed and heated in an oil bath at 100° C. overnight. DCM (200 mL) was added and the resulting mixture was washed with saturated NaHCO3 aqueous solution (20 mL×4), brine (20 mL×1), dried over anhydrous Na2SO4, filtered, removed solvents in vacuo. The resulting residue was passed a ISCO silica gel column (MeOH:DCM=5:95) to give light brown solids, 1.1 mg (yield 0.6%). 1H NMR (300 MHz, DMSO-d6) δ 11.71 (broad s, 1H), 8.00 (s, 1H), 7.59 (s, 1H), 7.49 (s, 1H), 7.44 (s, 1H), 7.24 (s, 1H), 4.81-4.70 (m, 1H), 3.66 (m, 1H), 3.47-3.33 (m, 1H), 3.19 (m, 1H), 2.81 (m, 1H), 2.31 (s, 3H), 2.42-2.20 (m, 2H), 1.31 (d, J=6.0 Hz, 3H), 1.13-1.04 (m, 2H), 1.04-0.93 (m, 2H) ppm; MS (ESI+) m/z 366.54 (M+H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([I:12])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[O:13]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[NH:16][CH2:15][CH2:14]1.C(N(CC)CC)C.N1C2C(=CC=CC=2)C=NC=1>O1CCOCC1>[I:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[CH:4][N:3]=[C:2]2[N:16]1[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[O:13][CH2:14][CH2:15]1
Reactant: c1ccc2c(c1)NCCO2
Reactant: Clc1ncnc2ccc(I)cc12
Agent: c1ccc2ncncc2c1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: Ic1ccc2ncnc(N3CCOc4ccccc43)c2c1
Yield: 34.8 %

Procedure:
0.75 g of 4-chloro-6-iodoquinazoline, 0.39 g of 3,4-dihydro-2H-benzo-1,4-oxazine and 0.50 ml of triethylamine in 5 ml of dioxane are heated at 80° C. in a flask until the quinazoline has reacted completely (HPLC check, about 24 hours). The cooled reaction solution is evaporated to dryness. The residue is washed by stirring with EA and filtered off with suction, giving 0.35 g of 4-(6-iodoquinazolin-4-yl)-3,4-dihydro-2H-benzo-1,4-oxazine as yellowish solid (yield 40%, content 96%); MS-FAB (M+H+)=390.0; Rf (polar method): 2.36 min.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[Br:10][C:11]1[CH:16]=[C:15](Br)[CH:14]=[CH:13][N:12]=1>CN(C)C=O>[Br:10][C:11]1[CH:16]=[CH:15][C:14]([O:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:13][N:12]=1
Reactant: Oc1ccccc1
Reactant: Brc1ccnc(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Brc1ccc(Oc2ccccc2)cn1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of phenol (1.99 g, 0.021 mol) in N,N-dimethylformamide (60 mL) was cooled to 0° C. and a 60% suspension of sodium hydride in parafine (0.89 g, 0.022 mol) was added at once. The mixture was stirred at this temperature for 10 min and 2,4-dibromopyridine was added at once. The mixture was allowed to warm up to ambient temperature while stirring under nitrogen for 72 hours and heated at 70° C. for 24 hours. The solvent was removed under reduced pressure; the residue was dissolved in ethyl acetate (150 mL) and washed with saturated aqueous sodium bicarbonate solution (100 mL), brine (80 mL), dried with magnesium sulfate and evaporated. The residue was purified by preparative RP-LC/MS (Gilson-Micromass C18, 5 m, 130 A, 21 cm, 0%-100% acetonitrile-0.1M ammonium acetate over 9 min, 25 mL/min) to give 2-bromo-5-phenoxypyridine as a yellow oil (1.40 g, 0.0056 mol): 1H NMR (DMSO-d6, 400 MHz) 8.28 (s, 1H), 8.07 (d, 1H), 7.45 (t, 2H), 7.25 (t, 1H), 7.16 (d, 2H), 7.04 (d, 1H); MS: MH+ 250.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[O:9][N:8]=[C:7]([C:11]3[CH:16]=[N:15][CH:14]=[CH:13][N:12]=3)[C:6]=2[CH:5]=[C:4]([CH:17]=O)[C:3]=1[N:19]1[CH2:24][C@H:23]([CH3:25])[O:22][C@H:21]([CH3:26])[CH2:20]1.[NH:27]1[C:32](=[O:33])[CH2:31][C:30](=[O:34])[NH:29][C:28]1=[O:35]>C(O)(C)C>[Cl:1][C:2]1[C:10]2[O:9][N:8]=[C:7]([C:11]3[CH:16]=[N:15][CH:14]=[CH:13][N:12]=3)[C:6]=2[CH:5]=[C:4]2[C:3]=1[N:19]1[CH2:24][C@@H:23]([CH3:25])[O:22][C@@H:21]([CH3:26])[C@@H:20]1[C:31]1([C:30](=[O:34])[NH:29][C:28](=[O:35])[NH:27][C:32]1=[O:33])[CH2:17]2
Reactant: C[C@@H]1CN(c2c(C=O)cc3c(-c4cnccn4)noc3c2Cl)C[C@H](C)O1
Reactant: O=C1CC(=O)NC(=O)N1
Solvent: CC(C)O
Product: C[C@@H]1CN2c3c(cc4c(-c5cnccn5)noc4c3Cl)CC3(C(=O)NC(=O)NC3=O)[C@H]2[C@H](C)O1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
Isopropanol (10 ml) was added to 7-chloro-6-((2R,6S)-2,6-dimethylmorpholino)-3-(pyrazin-2-yl)benzo[d]isoxazole-5-carbaldehyde (Intermediate 472, 198 mg, 0.53 mmol) to give a yellow slurry. The pyrimidine-2,4,6(1H,3H,5H)-trione (barbituric acid) (68.0 mg, 0.53 mmol) was added and the yellow mixture was heated to 80° C. The resulting solution was stirred overnight. The resulting off-white suspension cooled to room temperature, then filtered. The filtercake was washed with MeOH/hexanes to give a white solid, 171 mg (67%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Br:13])[C:11]=1[OH:12])[NH:8][C:7](=[O:14])[CH2:6][CH2:5]2.[OH-].[Na+].Br[CH2:18][CH2:19][CH2:20][Cl:21]>C(O)(C)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Br:13])[C:11]=1[O:12][CH2:18][CH2:19][CH2:20][Cl:21])[NH:8][C:7](=[O:14])[CH2:6][CH2:5]2
Reactant: O=C1CCc2cc(Cl)c(O)c(Br)c2N1
Reactant: ClCCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Product: O=C1CCc2cc(Cl)c(OCCCCl)c(Br)c2N1
Reaction time: 1 h

Procedure:
5 grams of 6-chloro-8-bromo-7-hydroxy-3,4-dihydrocarbostyril and 3 g of sodium hydroxide are mixed with 120 ml of isopropanol and stirred at 50°-60° C. for 1 hour. Then 10 ml of 3-bromo-1-chloropropane are added thereto and stirred at 70°-80° C. for 6 hours. The reaction mixture is concentrated under reduced pressure to dryness and the residue thus obtained is extracted with chloroform. The chloroform layer is washed with water and dried. Then chloroform is removed by distillation and the residue thus formed is recrystallized from ethanol to obtain 6.2 g of 6-chloro-8-bromo-7-(3-chloropropoxy)-3,4-dihydrocarbostyril in the form of colorless needle-like crystals with a melting point of 87°-88° C.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11]([OH:23])([CH2:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:10][CH2:9]1)C1C=CC=CC=1>CO.[OH-].[OH-].[Pd+2]>[OH:23][C:11]1([CH2:14][CH2:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: OC1(CCCc2ccccc2)CCN(Cc2ccccc2)CC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: OC1(CCCc2ccccc2)CCNCC1
Reaction time: 24 h

Procedure:
A mixture of 3.3 g (10.7 mmol) of 1-benzyl-4-hydroxy-4-(3-phenylpropyl)piperidine and 0.5 g of Pd(OH)2 (Pearlman's catalyst) in 80 mL of MeOH was hydrogenated at 50 psi for 24 h. The reaction mixture was filtered through a thin pad of celite and concentrated to give the title compound.