Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5](=[O:8])[NH:6][CH:7]=1.Br[CH2:10][C:11]([C:13]1[S:17][CH:16]=[N:15][C:14]=1[CH3:18])=[O:12].C(N(CC)CC)C.N1C=CC=NC1=O>ClCCl.CCO>[Cl:1][C:2]1[CH:3]=[N:4][C:5](=[O:8])[N:6]([CH2:10][C:11]([C:13]2[S:17][CH:16]=[N:15][C:14]=2[CH3:18])=[O:12])[CH:7]=1
Reactant: O=c1ncc(Cl)c[nH]1
Reactant: Cc1ncsc1C(=O)CBr
Agent: O=c1nccc[nH]1
Solvent: CCO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ncsc1C(=O)Cn1cc(Cl)cnc1=O
Temperature: 25 °C

Procedure:
A suspension of 5-chloropyrimidin-2-one (392 mg) and 5-bromoacetyl-4-methylthiazole (660 mg) in dry dichloromethane was treated with triethylamine (0.42 ml) and the resulting pale yellow solution was stirred at room temperature. After 1.25 h a precipitate had formed and the mixture was cooled in an ice-bath. The solid was collected, washed with cold dichloromethane and dried (346 mg). A second crop was obtained by concentration of the mother liquors (255 mg). The combined solids were recrystallised from acetone and then dichloromethane to give white crystals, the title pyrimidinone (186 mg) m.p. 212°-215° C. λmax (EtOH) 250.5 nm (E1cm1% 403), 266.5 nm (E1cm1% 401), 334 nm (E1cm1% 65). High performance liquid chromatography (reverse phase column, acetonitrilewater, 1:3) showed only one major component. N.M.R. (DMSO d6): 0.68 (2'-H), 1.28, 1.54 (two doublets, J 4 Hz) (4,6-H), 4.69 (--CH2 --), 7.21 τ (4' -CH3).
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:22]=[C:21]2[C:12]([N:13]3[C:18]([CH2:19][O:20]2)=[N:17][NH:16][C:15](=[O:23])[C@H:14]3[CH3:24])=[CH:11][C:10]=1[C@@H:25]1[CH2:30][CH2:29][NH:28][CH2:27][C@@H:26]1[CH3:31].C=O.[B-][C:35]#N.[Na+]>CO.CC(O)=O>[CH3:35][N:28]1[CH2:29][CH2:30][C@@H:25]([C:10]2[CH:11]=[C:12]3[C:21](=[CH:22][C:9]=2[C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[F:2])[O:20][CH2:19][C:18]2[N:13]3[C@H:14]([CH3:24])[C:15](=[O:23])[NH:16][N:17]=2)[C@@H:26]([CH3:31])[CH2:27]1
Reactant: C[C@@H]1C(=O)NN=C2COc3cc(-c4ccccc4F)c([C@@H]4CCNC[C@@H]4C)cc3N21
Reactant: [B-]C#N
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: C[C@@H]1C(=O)NN=C2COc3cc(-c4ccccc4F)c([C@@H]4CCN(C)C[C@@H]4C)cc3N21
Temperature: 80 °C
Reaction time: 16 h
Yield: 39.6 %

Procedure:
A mixture of (R)-7-(2-fluoro-phenyl)-4-methyl-6-((3R,4R)-3-methyl-piperidin-4-yl)-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one hydrochloride acid (3.05 g, 6.88 mmol) and paraformaldehyde (2.066 g, 68.8 mmol) in MeOH (60 mL) and AcOH (6 mL) was stirred at 80° C. for 16 h. Then, sodium cyanotrihydroborate (0.865 g, 13.76 mmol) was added and the reaction mixture was stirred at ambient temperature for 0.5 h. The reaction mixture was concentrated in vacuo and the residue was purified by column chromatography on basified silica gel (eluting with 10% MeOH in DCM) to give (R)-6-((3R,4R)-1,3-dimethyl-piperidin-4-yl)-7-(2-fluoro-phenyl)-4-methyl-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one (1.15 g, 40%) as a white solid. The white solid was stirred in HCl/EtOAc (4 M, 50 mL) for 30 min and the reaction mixture was concentrated in vacuo to give (R)-6-((3R,4R)-1,3-dimethyl-piperidin-4-yl)-7-(2-fluoro-phenyl)-4-methyl-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one hydrochloride acid (1.215 g, 39%) as a white solid. 1H NMR (400 MHz, MeOD) δ 7.44 (m, 1H), 7.32-7.16 (m, 3H), 6.90 (m, 1H), 6.84 (s, 1H), 4.68-4.57 (d, J=13.2 Hz, 2H), 3.57 (m, 1H), 3.25 (m, 1H), 3.05 (m, 2H), 2.86 (m, 1H), 2.79 (s, 3H), 2.50 (m, 1H), 1.91 (m, 2H), 1.48 (d, J=6.8 Hz, 3H), 0.91 (m, 3H). LC/MS (Table 1, Method 5) Rt=2.275 min.; MS m/z: 423 [M+H]+. SFC (Table 1, Method 47), Rt=1.145 min.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[NH:11][N:10]=[CH:9][C:8]=2[C:12]2[CH:29]=[CH:28][C:15]([O:16][CH2:17][C:18]3[CH:27]=[CH:26][C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[N:19]=3)=[CH:14][CH:13]=2)=[CH:3][CH:2]=1.[CH3:30][NH:31][NH2:32]>>[CH3:30][N:11]1[C:7]([C:4]2[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=2)=[C:8]([C:12]2[CH:13]=[CH:14][C:15]([O:16][CH2:17][C:18]3[CH:27]=[CH:26][C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[N:19]=3)=[CH:28][CH:29]=2)[CH:9]=[N:10]1.[CH3:30][N:31]1[CH:9]=[C:8]([C:12]2[CH:29]=[CH:28][C:15]([O:16][CH2:17][C:18]3[CH:27]=[CH:26][C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[N:19]=3)=[CH:14][CH:13]=2)[C:7]([C:4]2[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=2)=[N:32]1
Reactant: CNN
Reactant: c1ccc2nc(COc3ccc(-c4cn[nH]c4-c4ccncc4)cc3)ccc2c1
Product: Cn1cc(-c2ccc(OCc3ccc4ccccc4n3)cc2)c(-c2ccncc2)n1
Product: Cn1ncc(-c2ccc(OCc3ccc4ccccc4n3)cc2)c1-c1ccncc1

Procedure:
Following the procedure for the preparation of 2-[4-(5-Pyridin-4-yl-1H-pyrazol-4-yl)-phenoxymethyl]-quinoline but substituting methyl hydrazine provided the title compound and 2-[4-(1-Methyl-3-pyridin-4-yl-1H-pyrazol-4-yl)-phenoxymethyl]-quinoline. 1H NMR (400 MHz, CDCl3) δ 8.66 (bs, 2H), 8.17 (d, J=8.7 Hz, 1H), 8.05 (d, J=7.9 Hz, 1H), 7.81 (d, J=8.3 Hz, 1H), 7.70 (m, 1H), 7.63 (m, 2H), 7.53 (t, J=7.1 Hz, 1H), 7.21 (m, 2H), 7.03 (d, J=9.1 Hz, 2H), 6.89 (d, J=8.7 Hz, 2H), 5.32 (s, 2H), 3.80 (s, 3H); MS: (M+H m/z=393.2).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1)=[CH2:2].[CH3:9][C:10]1[NH:11][CH:12]=[CH:13][N:14]=1.C(O)(=O)C.C>C(Cl)Cl>[CH3:9][C:10]1[N:11]([CH2:2][CH2:1][C:3]2[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=2)[CH:12]=[CH:13][N:14]=1
Reactant: Cc1ncc[nH]1
Reactant: C=Cc1ccncc1
Solvent: CC(=O)O
Solvent: ClCCl
Product: Cc1nccn1CCc1ccncc1
Temperature: 130 °C
Reaction time: 8 h

Procedure:
A stirred solution containing 52.5 g (0.50 mol) of 4-vinylpyridine, 36.9 g (0.45 mol) of 2-methylimidazole and 1.1 g of glacial acetic acid was heated to an internal temperature of 130° C. under a nitrogen atmosphere, maintained at this temperature for 5 hours, and then allowed to stand overnight at room temperature. The resultant solidified mass was dissolved in 150 ml of methylene dichloride, treated with charcoal, filtered through Celite and then concentrated in vacuo. The crude residue was crystallized from a mixture of methylene chloride and pentane in a ratio of 1:2.5 as the eluent to yield a solid.
Reaction SMILES: F[C:2]1[CH:8]=[C:7]([F:9])[C:6]([N+:10]([O-:12])=[O:11])=[CH:5][C:3]=1[NH2:4].C(=O)([O-])[O-].[K+].[K+].[SH:19][CH2:20][CH2:21][OH:22]>CN(C=O)C.C(OCC)(=O)C>[NH2:4][C:3]1[CH:5]=[C:6]([N+:10]([O-:12])=[O:11])[C:7]([F:9])=[CH:8][C:2]=1[S:19][CH2:20][CH2:21][OH:22]
Reactant: Nc1cc([N+](=O)[O-])c(F)cc1F
Reactant: OCCS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Nc1cc([N+](=O)[O-])c(F)cc1SCCO
Temperature: 25 °C
Reaction time: 2 h
Yield: 84 %

Procedure:
To a stirred suspension of 2,4-difluoro-5-nitroaniline (100 mg, 0.574 mmol) and potassium carbonate (159 mg, 1.149 mmol) in DMF (1 mL) was added 2-mercaptoethanol (0.081 mL, 1.149 mmol). The resulting mixture was stirred at room temperature for 2 hours. The mixture was then diluted with ethyl acetate and washed with saturated sodium carbonate (3×). The organic phase was dried, filtered, concentrated, and then chromatographed (1:1 EtOAc:hexanes) to give the major product. Ethyl acetate was then used as the eluent to give a minor product. The major product was determined to be the desired product (112 mg, 84%). 1H NMR (DMSO-d6) δ 7.32 (d, J=3.5 Hz, 1H), 7.27 (d, J=10.7 Hz, 1H), 4.39 (s, 2H), 3.85-3.76 (m, 2H), 3.16-3.08 (m, 2H), 2.13-2.05 (m, 1H); ESI-MS (m/z, %): 233 (MH+, 100), 215 (14), 187 (100), 129 (65).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[NH:10][CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:18][CH:19]([CH3:21])[CH3:20]>CN(C)C=O.O>[Cl:1][C:2]1[C:3]2[N:10]([CH2:18][CH:19]([CH3:21])[CH3:20])[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Clc1ncnc2cc[nH]c12
Reactant: CC(C)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)Cn1ccc2ncnc(Cl)c21
Temperature: 25 °C
Yield: 102.5 %

Procedure:
To a suspension of 4-chloro-5H-pyrrolo[3,2-d]pyrimidine (150 mg) in N,N-dimethylformamide (1.6 mL) was added cesium carbonate (478 mg) under ice-cooling, and the mixture was stirred while warming to room temperature for 15 min. To the reaction mixture was added 1-bromo-2-methylpropane (336 mg), and the mixture was stirred at room temperature for 19 hrs. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (30 mL×3). The organic layer was washed with saturated brine (30 mL×3) and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (silica gel, eluent:hexane/ethyl acetate=90/10→20/80). The object fraction was concentrated under reduced pressure and dried to give the title compound (210 mg) as a white solid.
Reaction SMILES: C[O:2][C:3](=[O:18])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][C:11]2[N:12]=[N:13][C:14]([Cl:17])=[CH:15][CH:16]=2)[CH:5]=1.[OH-].[Na+]>CO.C1COCC1.O>[Cl:17][C:14]1[N:13]=[N:12][C:11]([O:10][C:6]2[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=2)[C:3]([OH:18])=[O:2])=[CH:16][CH:15]=1
Reactant: COC(=O)c1cccc(Oc2ccc(Cl)nn2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(O)c1cccc(Oc2ccc(Cl)nn2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.3 %

Procedure:
A mixture of 3-(6-chloro-pyridazin-3-yloxy)-benzoic acid methyl ester (950 g, 3.6 mmol) and NaOH (700 mg, 16 mmol) in methanol:THF:water (1:1:1, 6 mL) was stirred at room temperature for 8 h, solvents were evaporated. Crude mass was taken in water (40 mL), acidified to pH 4.0 and extracted with ethyl acetate. Evaporation of ethyl acetate furnished 3-(6-chloro-pyridazin-3-yloxy)-benzoic acid (580 mg).
Reaction SMILES: [Cl:1][C:2]1[C:3]([S:11][CH3:12])=[N:4][CH:5]=[C:6]([CH:8]([OH:10])C)[CH:7]=1.[H-].[Na+].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.CN(C=[O:27])C>O>[C:15]([O:10][CH2:8][C:6]1[CH:7]=[C:2]([Cl:1])[C:3]([S:11][CH3:12])=[N:4][CH:5]=1)(=[O:27])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: BrCc1ccccc1
Reactant: CN(C)C=O
Reactant: CSc1ncc(C(C)O)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CSc1ncc(COC(=O)c2ccccc2)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79 %

Procedure:
3-Chloro-5-(1-hydroxyethyl)-2-methylthiopyridine (21.9 g, 0.108 mol) was dissolved with stirring in anhydrous DMF (250 mL) and 60% sodium hydride (5 g, 0.125 mol) added in portions. The mixture was stirred at room temperature for 30 minutes and benzyl bromide (17.6 g, 0.103 mol) added dropwise. The mixture was then stirred at room temperature for four hours, diluted with water (400 mL) and extracted three times with ethyl acetate (100 mL). The combined organic extracts were washed twice with water (200 mL) and saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulphate, and evaporated to dryness. Purification of the residue by chromatography over silica (0-5% ethyl acetate:hexane) gave the desired product (25.0 g, 79%) as a pale yellow oil.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11].[C:20]1(B(O)O)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.O>[OH:8][C:6]1[CH:5]=[CH:4][C:3]([CH2:9][C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])=[C:2]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:7]=1
Reactant: O=C(Cc1ccc(O)cc1Br)OCc1ccccc1
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: O=C(Cc1ccc(O)cc1-c1ccccc1)OCc1ccccc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 86.8 %

Procedure:
To a solution of benzyl (2-bromo-4-hydroxyphenyl)acetate (400 mg) in dimethoxyethane (4.00 mL) and water (1.20 mL) were added phenyl boronic acid (182 mg), sodium carbonate (396 mg), and 1,1′-bis(diphenylphosphino) ferrocene palladium (II) dichloride dichloromethane complex (50.9 mg), followed by stirring at 80° C. overnight. To the reaction mixture was added water, followed by extraction with ethyl acetate. The organic layer was washed with water and a saturated aqueous sodium chloride solution in this order, then dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain benzyl (5-hydroxybiphenyl-2-yl)acetate (344 mg).
Reaction SMILES: [C:1]1([S:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:15]1([O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O.[F:41][C:42]([F:48])([F:47])[S:43]([OH:46])(=[O:45])=[O:44]>ClCCl>[F:41][C:42]([F:48])([F:47])[S:43]([O-:46])(=[O:45])=[O:44].[C:9]1([S+:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:25]2[CH:24]=[CH:23][C:22]([O:21][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:27][CH:26]=2)[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: O=S(c1ccccc1)c1ccccc1
Reactant: O=S(=O)(O)C(F)(F)F
Reactant: c1ccc(Oc2ccccc2)cc1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: O=S(=O)([O-])C(F)(F)F
Product: c1ccc(Oc2ccc([S+](c3ccccc3)c3ccccc3)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 38 %

Procedure:
In 100 ml of dichloromethane were dissolved 10.1 g (0.05 mol) of diphenylsulfoxide and 8.51 g (0.05 mol) of diphenyl ether, and 12.6 g (0.06 mol) of trifluoroacetic anhydride was added thereto at 0° C. Then 7.5 g (0.05 mol) of trifluoromethanesulfonic acid was added dropwise thereto at 0 to 5° C., followed by gradually warming to room temperature and reacting for 2 hours with stirring. After completion of the reaction, the reaction solution was washed with 100 ml of water five times and concentrated under reduced pressure, followed by purifying the resulting crude product by a column chromatography to obtain 9.59 g (Yield: 38%) of diphenyl-4-phenoxyphenylsulfonium trifluoromethanesulfonate as a yellow oily substance.
Reaction SMILES: C([O:4][C@H:5]1[C@@H:18]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C@@H:17]([CH2:27][O:28]CC=C)[O:16][C@@H:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C@@H:6]1[O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)C=C.O.II>O1CCCC1.C(OCC)(=O)C.[Ir]>[CH2:33]([O:32][C@@H:6]1[C@@H:5]([OH:4])[C@@H:18]([O:19][CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C@@H:17]([CH2:27][OH:28])[O:16][C@H:7]1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: C=CCOC[C@H]1O[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@@H](OCC=C)[C@H]1OCc1ccccc1
Agent: [Ir]
Agent: II
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: OC[C@H]1O[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@@H](O)[C@H]1OCc1ccccc1
Reaction time: 7 h
Yield: 98.4 %

Procedure:
Under hydrogen gas atmosphere, a solution of Compound 12 (8.9 g, 16.7 mmol) in tetrahydrofuran (80 ml) was added to a solution of activated iridium complex (Ir(CoD)(PMePh2)2PF6, 287 mg, 0.34 mmol) in tetrahydrofuran (60 ml) at room temperature, and the mixture was stirred for 7 hours. Subsequently, water (100 ml) and iodine (8.5 g, 67.1 mmol) were added to the reaction mixture, and it was stirred for 15 hours. The reaction mixture was diluted with ethyl acetate, washed successively with saturated sodium thiosulfate solution, saturated aqueous sodium hydrogencarbonate, and saturated brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was recrystallized (ethanol/dichloromethane/diethyl ether) to obtain Compound 13 (7.4 g, 97%).
Reaction SMILES: [CH:1]1([NH2:8])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[C:10](OC1C=CC([N+]([O-])=O)=CC=1)=[O:11].C(N(C(C)C)CC)(C)C.[Cl:31][C:32]1[CH:41]=[C:40]2[C:35]([C:36]([N:42]3[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]3)=[CH:37][CH:38]=[N:39]2)=[CH:34][CH:33]=1>C(Cl)Cl.CO>[Cl:31][C:32]1[CH:41]=[C:40]2[C:35]([C:36]([N:42]3[CH2:47][CH2:46][N:45]([C:10]([NH:8][CH:1]4[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]4)=[O:11])[CH2:44][CH2:43]3)=[CH:37][CH:38]=[N:39]2)=[CH:34][CH:33]=1
Reactant: NC1CCCCCC1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: Clc1ccc2c(N3CCNCC3)ccnc2c1
Solvent: CO
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NC1CCCCCC1)N1CCN(c2ccnc3cc(Cl)ccc23)CC1

Procedure:
As described for example 78, cycloheptylamine (206 mg, 1.82 mmol), 4-nitrophenyl chloroformate (366 mg, 1.82 mmol), diisopropyl(ethyl)amine (554 mg, 4.3 mmol), and 7-chloro-4-(piperazin-1-yl)quinoline (300 mg, 1.21 mmol) are reacted affording the title product after flash chromatography with CH2Cl2-MeOH.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[C:9]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:10]=[CH:11][C:12]=2[OH:13])=[CH:5][CH:4]=[N:3]1.C(=O)([O-])[O-].[K+].[K+].[F:26][C:27]1[CH:28]=[C:29]([N+:34]([O-:36])=[O:35])[CH:30]=[CH:31][C:32]=1F>CN(C)C=O.C(OCC)(=O)C>[F:26][C:27]1[CH:28]=[C:29]([N+:34]([O-:36])=[O:35])[CH:30]=[CH:31][C:32]=1[O:13][C:12]1[CH:11]=[CH:10][C:9]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:8][C:7]=1[C:6]1[N:2]([CH3:1])[N:3]=[CH:4][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Reactant: Cn1nccc1-c1cc(-c2ccccc2)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cn1nccc1-c1cc(-c2ccccc2)ccc1Oc1ccc([N+](=O)[O-])cc1F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 112.3 %

Procedure:
To a stirred solution of 3-(1-Methyl-1H-pyrazol-5-yl)biphenyl-4-ol (Preparation 28, 600 mg, 2.39 mmol) in N,N-dimethylformamide (6 mL) at 0° C. was added potassium carbonate (332 mg, 2.39 mmol). The mixture was stirred for 30 minutes at 0° C. 3,4-Difluoronitrobenzene (318 mg, 1.99 mmol) was added drop wise to the reaction mixture and allowed to stir at room temperature for 16 hours. The reaction mixture was diluted with ethyl acetate (20 mL). The organic layer was washed sequentially with water (3×10 mL) and brine (1×10 ml), then dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford the title compound (870 mg, quantitative). This material was used without purification in the next step.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([NH:21][C@@H:22]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH2:24][C@H:23]3[NH2:31])=[N:6][C:7]([CH:18]3[CH2:20][CH2:19]3)=[C:8]([C:10]3[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=3[Cl:17])[N:9]=2)[CH2:3][CH2:2]1.Cl[C:33](Cl)(Cl)[C:34](=[O:36])C>C(Cl)(Cl)Cl>[CH:1]1([C:4]2[C:5]([NH:21][C@@H:22]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH2:24][C@H:23]3[NH:31][C:34](=[O:36])[CH3:33])=[N:6][C:7]([CH:18]3[CH2:19][CH2:20]3)=[C:8]([C:10]3[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=3[Cl:17])[N:9]=2)[CH2:2][CH2:3]1
Reactant: N[C@@H]1Cc2ccccc2[C@H]1Nc1nc(C2CC2)c(-c2ccc(Cl)cc2Cl)nc1C1CC1
Reactant: CC(=O)C(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CC(=O)N[C@@H]1Cc2ccccc2[C@H]1Nc1nc(C2CC2)c(-c2ccc(Cl)cc2Cl)nc1C1CC1
Temperature: 25 °C
Yield: 101.3 %

Procedure:
To a solution of (1R,2R)-N1-[3,6-dicyclopropyl-5-(2,4-dichlorophenyl)pyrazin-2-yl]-2,3-dihydro-1H-indene-1,2-diamine (0.10 g, 0.22 mmol) in CHCl3 (1 mL) at 0°C. under N2 was added trichloroacetone (30 μL, 0.26 mmol). The mixture was allowed to slowly warm to rt for 1.5 hr. The reaction was then heated at 60° C. for 1.5 h. Cool to rt, add additional trichloroacetone (10 μL) and continue heating at 60° C. for 2 hr. The reaction was concentrated and purified by biotage MPLC (90 g column, 80% ethyl acetate/hexanes) to afford 0.11 g (55%) of N-((1R,2R)-1-{[3,6-dicyclopropyl-5-(2,4-dichlorophenyl)pyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-yl)acetamide as a solid: 1H NMR (CDCl3) δ 0.84–1.01, 1.61–1.81, 2.04, 2.80–2.86, 3.58–3.64, 4.07–4.13, 4.46, 5.56, 6.56, 7.28–7.51; MS (ESI+) for C27H26Cl2N4O m/z 493 (M+H)+.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8](Br)[S:9][CH:10]=1)=[O:5])C.CO[C:14]1(B(O)O)[C:19]([F:20])=[CH:18][CH:17]=[CH:16][CH2:15]1.[C:24](=[O:27])([O-])[O-].[Na+].[Na+]>COCCOC.CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:20][C:19]1[CH:14]=[CH:15][CH:16]=[C:17]([O:27][CH3:24])[C:18]=1[C:8]1[S:9][CH:10]=[C:6]([C:4]([OH:3])=[O:5])[N:7]=1
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)c1csc(Br)n1
Reactant: COC1(B(O)O)CC=CC=C1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: COCCOC
Product: COc1cccc(F)c1-c1nc(C(=O)O)cs1
Temperature: 25 °C

Procedure:
Tetrakis(triphenylphosphine)palladium (0.54 g, 0.48 mmol, 2.2% mol eq) was added to a degassed (nitrogen) mixture of 2-bromo-thiazole-4-carboxylic acid ethyl ester (Combi-Blocks, Inc., San Diego, Calif.; 5 g, 21.2 mmol), 1-methoxy-6-flurophenylboronic acid (4.68 g, 27.56 mmol), and sodium carbonate(23 mL, 2 M solution in water) in DME (100 mL) and DMF (100 mL). The reaction mixture was refluxed under inert atmosphere overnight. After cooling to room temperature, the reaction mixture was filtered through celite, and water and EtOAc were added. The aqueous layer was separated, acidified with conc. HCl to pH 2 and then was extracted three times with EtOAc. The combined EtOAc layers were dried under vacuum. The residue was chromatographed on silica, eluting with EtOAc/Hexane (0-30% gradient) to give 2-(2-fluoro-6-methoxy-phenyl)-thiazole-4-carboxylic acid (4.5 g) which was used directly in the next step.
Reaction SMILES: [C:1]([C:4]1[N:5]=[C:6]2[N:11]=[C:10]([CH3:12])[C:9]([CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[C:8]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=3[Cl:29])[N:7]2[CH:30]=1)(=O)[NH2:2].N1C=CC=CC=1.C(OC(C(F)(F)F)=O)(C(F)(F)F)=O>O1CCOCC1>[C:1]([C:4]1[N:5]=[C:6]2[N:11]=[C:10]([CH3:12])[C:9]([CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[C:8]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=3[Cl:29])[N:7]2[CH:30]=1)#[N:2]
Reactant: Cc1nc2nc(C(N)=O)cn2c(-c2ccc(Cl)cc2Cl)c1CNC(=O)OC(C)(C)C
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Solvent: C1COCCO1
Product: Cc1nc2nc(C#N)cn2c(-c2ccc(Cl)cc2Cl)c1CNC(=O)OC(C)(C)C
Reaction time: 5 h
Yield: 66.1 %

Procedure:
To a stirred solution of tert-butyl (2-carbamoyl-5-(2,4-dichlorophenyl)-7-methylimidazo[1,2-a]pyrimidin-6-yl)methylcarbamate (Example 58, Step 2, 30 mg, 0.07 mmol) in dioxane (1.5 mL) was added pyridine (10.5 mg, 0.13 mmol) and TFAA (15.4 mg, 0.07 mmol). The reaction was kept at room temperature for 16 and additional pyridine (10.5 mg, 0.13 mmol) and TFAA (15.4 mg, 0.07 mmol) were added. After 5 h, the reaction was quenched by H2O and diluted with EtOAc. The organic layer was washed with satd aq NH4Cl and brine prior to drying over MgSO4. Filtration, concentration under reduced pressure and purification by silica gel chromatography afforded tert-butyl (2-cyano-5-(2,4-dichlorophenyl)-7-methylimidazo[1,2-a]pyrimidin-6-yl)methylcarbamate (20 mg, 69% yield).
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([O:9][C:10](=[O:22])[NH:11][C:12]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17](Br)[CH:16]=1)([CH3:14])[CH3:13])[CH2:2]2.[C:23]1(B(O)O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([O:9][C:10](=[O:22])[NH:11][C:12]([C:15]1[CH:16]=[C:17]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:18]=[CH:19][CH:20]=1)([CH3:14])[CH3:13])[CH2:2]2
Reactant: CC(C)(NC(=O)OC1CN2CCC1CC2)c1cccc(Br)c1
Reactant: OB(O)c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Product: CC(C)(NC(=O)OC1CN2CCC1CC2)c1cccc(-c2ccccc2)c1
Yield: 63.8 %

Procedure:
Using general procedure E, 1-azabicyclo[2.2.2]oct-3-yl[2-(3-bromophenyl)propan-2-yl]carbamate (600 mg, 1.63 mmol), phenylboronic acid (398 mg, 3.27 mmol) and palladium (II) acetate gave the title compound as a white solid (379 mg, 64%). 1H NMR (400 MHz, CDCl3) δ 7.61 (s, 1H), 7.56 (d, J=7.4 Hz, 2H), 7.50-7.38 (m, 4H), 7.34 (m, 2H), 5.16 (s, 1H), 4.63 (s, 1H), 3.39-2.09 (m, 6H), 1.72 (s, 6H), 2.02-0.73 (m, 5H) ppm. 13C NMR (100 MHz, CDCl3) δ 154.8, 147.8, 141.6, 129.0, 129.0, 128.6, 127.5, 125.8, 125.0, 124.0, 71.6, 71.3, 55.9, 55.5, 47.6, 46.8, 31.5, 30.2, 30.0, 29.5, 25.6, 24.8, 19.8 ppm. Purity: 99% UPLCMS (210 nm); retention time 0.84 min; (M+1) 365.0. Anal. Calcd. for C23H28N2O2.0.29 (CHC3): C, 70.02; H, 7.14; N, 7.01. Found: C, 70.02; H, 7.37; N, 6.84.