Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][N:5]([CH3:27])[C:6]2[C:7]=1[CH:8]=[N:9][C:10]1[N:19]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[CH2:18][CH:17]=[C:12]3[NH:13][C:14](=[O:16])[C:15]=2[C:11]=13.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl:61][C:62]1[CH:67]=[CH:66][C:65]([F:68])=[CH:64][C:63]=1[CH2:69][C:70](O)=[O:71]>CN(C)C(=O)C>[Cl:61][C:62]1[CH:67]=[CH:66][C:65]([F:68])=[CH:64][C:63]=1[CH2:69][C:70]([NH:1][C:2]1[CH:3]=[CH:4][N:5]([CH3:27])[C:6]2[C:7]=1[CH:8]=[N:9][C:10]1[N:19]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[CH2:18][CH:17]=[C:12]3[NH:13][C:14](=[O:16])[C:15]=2[C:11]=13)=[O:71]
Reactant: CN1C=CC(N)=c2cnc3c4c([nH]c(=O)c-4c21)=CCN3c1ccc(F)cc1
Reactant: O=C(O)Cc1cc(F)ccc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: CN1C=CC(NC(=O)Cc2cc(F)ccc2Cl)=c2cnc3c4c([nH]c(=O)c-4c21)=CCN3c1ccc(F)cc1
Yield: 30 %

Procedure:
A stock solution of Example 14e and N,N-diisopropylethylamine (0.11 M and 0.33 M in N,N-dimethylacetamide, respectively, 350 μL, 0.038 mmol Example 14e and 0.11 mmol N,N-diisopropylethylamine), 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (0.13 M in N,N-dimethylacetamide, 350 μL, 0.046 mmol), and 2-(2-chloro-5-fluorophenyl)acetic acid (0.40 M in N,N-dimethylacetamide, 113 μL, 0.050 mmol) were aspirated from their respective source vials, mixed through a perfluoroalkoxy mixing tube (0.2 mm inner diameter), and loaded into an injection loop. The reaction segment was injected into the flow reactor (Hastelloy coil, 0.75 mm inner diameter, 1.8 mL internal volume) set at 100° C., and passed through the reactor at 180 μL per minute (10 minute residence time). Upon exiting the reactor, the reaction mixture was loaded directly into an injection loop and purified by reverse phase HPLC(C8, acetonitrile/water (0.1% ammonium acetate), 5-100%) to give 0.0062 g (30%) of the title compound. 1H NMR (400 MHz, DMSO-d6/D2O) δ 8.54 (d, J=2.75 Hz, 1H), 8.44 (d, J=2.75 Hz, 1H), 7.76 (s, 1H), 7.53 (dd, J=8.85, 5.19 Hz, 1H), 7.37 (dd, J=9.46, 3.05 Hz, 1H), 7.21 (m, 1H), 7.07 (s, 1H), 6.87 (m, 2H), 6.58 (m, 2H), 4.62 (m, 2H), 4.05 (s, 3H), 3.94 (s, 2H). MS (APCI+) m/z 532.0 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:31])[CH2:7][CH2:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]3(O)[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[CH:11]=[CH:10][C:9]=2[NH:21][C:22]([C:24]2[NH:25][C:26]([C:29]#[N:30])=[CH:27][N:28]=2)=[O:23])=[CH:4][CH2:3]1.O=S(Cl)Cl.[CH3:36][O:37][CH2:38][CH2:39][NH2:40]>C(Cl)Cl.CCOC(C)=O>[CH3:31][C:2]1([CH3:1])[CH2:7][CH2:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]3([NH:40][CH2:39][CH2:38][O:37][CH3:36])[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[CH:11]=[CH:10][C:9]=2[NH:21][C:22]([C:24]2[NH:28][CH:27]=[C:26]([C:29]#[N:30])[N:25]=2)=[O:23])=[CH:4][CH2:3]1
Reactant: CC1(C)CC=C(c2cc(C3(O)CCOCC3)ccc2NC(=O)c2ncc(C#N)[nH]2)CC1
Reactant: COCCN
Solvent: O=S(Cl)Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COCCNC1(c2ccc(NC(=O)c3nc(C#N)c[nH]3)c(C3=CCC(C)(C)CC3)c2)CCOCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 64.2 %

Procedure:
To a suspension of 4-cyano-1H-imidazole-2-carboxylic acid [2-(4,4-dimethyl-cyclohex-1-enyl)-4-(4-hydroxy-tetrahydro-pyran-4-yl)-phenyl]-amide (as prepared in Example 1, step (h), 50.0 mg, 0.120 mmol) in 1.5 mL of DCM at 0° C. was added SOCl2 (26.0 μL, 0.360 mmol) under Ar. After stirring at RT for 2 h, the mixture was cooled to 0° C. To the reaction was then added 2-methoxyethylamine (104 μL, 1.20 mmol) and the resulting mixture was stirred at 0° C. for 2 h. The mixture was diluted with EtOAc (30 mL) and washed with H2O (2×10 mL) and brine (10 mL). After drying over Na2SO4 and concentrating in vacuo, the residue was purified by silica gel chromatography (1-4% MeOH/DCM) to afford the title compound (36.8 mg, 65%) as a white solid. 1H-NMR (1:5 CD3OD/CDCl3; 400 MHz): δ 8.31 (d, 1H, J=8.6 Hz), 7.70 (s, 1H), 7.30 (dd, 1H, J=8.6, 2.3 Hz), 7.20 (d, 1H, J=2.3 Hz), 5.77 (m, 1H), 3.94 (m, 2H), 3.69 (m, 2H), 3.41 (t, 2H, J=6.1 Hz), 3.28 (s, 3H), 2.38 (t, 2H, J=6.1 Hz), 2.28 (m, 2H), 2.07-2.20 (m, 4H), 1.88 (m, 2H), 1.59 (t, 2H, J=6.3 Hz), 1.10 (s, 6H). Mass spectrum (ESI, m/z): Calcd. for C27H35N5O3, 476.3 (M−H). found 476.3.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[CH3:9][C:10]([CH3:12])=O.O.O.O.C([O-])(=O)C.[Na+].C(=O)=O.CC(C)=O.[BH4-].[Na+].[OH-].[NH4+]>C(O)C.C(O)(=O)C>[F:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][CH2:9][CH2:10][CH3:12])=[CH:4][CH:3]=1
Reactant: Nc1ccc(F)cc1
Reactant: CC(C)=O
Agent: CC(=O)[O-]
Agent: O=C=O
Agent: [BH4-]
Solvent: O
Solvent: CC(=O)O
Solvent: CCO
Product: CCCNc1ccc(F)cc1
Temperature: 25 °C
Yield: 91.9 %

Procedure:
A 3 L three neck round bottom flask equipped with a nitrogen inlet, a thermometer, an overhead stirrer and a solid addition funnel was charged with 250 mL acetic acid, 50 mL absolute ethanol and 29.5 g (0.27 mol) of 4-fluoroaniline. To this mixture was added acetone (23 mL, 6.31 mol) in one portion followed by the portion-wise addition of sodium acetate trihydrate over 5 min. This vigorously stirred mixture was cooled to 0° C. (dry-ice/acetone) and 4.5 g of sodium borohydride (1.2 mol) was added portion-wise via a solid addition funnel over 50 min while keeping the internal temperature below 10° C. During this addition, acetic acid (100 mL) and absolute ethanol (50 mL) were added to facilitate stirring. After the addition, the mixture was allowed to warm to room temperature, and then stirred at ambient temperature for 12 h. Sufficient ammonium hydroxide (30% aqueous) was added to adjust the pH to ˜8 while maintaining the internal temperature below 30° C. using an ice/water bath. The mixture was extracted with ether (4×400 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered, then concentrated under reduced pressure to give the desired product as a black/brown oil (38 g).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][CH2:5][C:6]([C:8]1[C:16]([F:17])=[CH:15][C:11]2[S:12][CH:13]=[CH:14][C:10]=2[CH:9]=1)=[O:7].C1(C2(C3C=CC=CC=3)OB(C)N3CCC[C@H]23)C=CC=CC=1.B.O>O1CCCC1.C(OCC)(=O)C>[Cl:1][CH2:2][CH2:3][O:4][CH2:5][CH:6]([C:8]1[C:16]([F:17])=[CH:15][C:11]2[S:12][CH:13]=[CH:14][C:10]=2[CH:9]=1)[OH:7]
Reactant: O=C(COCCCl)c1cc2ccsc2cc1F
Agent: B
Agent: CB1OC(c2ccccc2)(c2ccccc2)[C@H]2CCCN12
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: OC(COCCCl)c1cc2ccsc2cc1F
Reaction time: 1.5 h
Yield: 99.3 %

Procedure:
To a solution of 4.5 g of 2-(2-chloroethoxy)-1-(6-fluorobenzo[b]thiophen-5-yl)ethanone in 45 ml of tetrahydrofuran is added 0.46 g of (R)-5,5-diphenyl-2-methyl-3,4-propano-1,3,2-oxazaborolidine at -10° C., and thereafter, 9.9 ml of 1 M borane solution of tetrahydrofuran is dropwise added thereto. The temperature of the resulting mixture is elevated to room temperature, and the mixture is stirred at the same temperature for 1.5 hours, after which 100 ml of water and 100 ml of ethyl acetate are added thereto. The resulting organic layer is separated, washed successively with water and a saturated saline solution and then dried over anhydrous magnesium sulfate. The solvent is then removed from the thus dried layer by distillation under reduced pressure. The residue obtained is purified by a column chromatography [eluent:toluene:ethyl acetate=10:1], to obtain 4.5 g of oily (+)-2-(2-chloroethoxy)-1-(6-fluoro-benzo[b]thiophen-5-yl)ethanol.
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:11][CH2:10][C@H:9]([NH2:12])[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H][H]>[Rh]>[CH:1]1([C@@H:7]2[CH2:11][CH2:10][C@H:9]([NH2:12])[CH2:8]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: N[C@H]1CC[C@@H](c2ccccc2)C1
Reactant: [H][H]
Agent: [Rh]
Product: N[C@H]1CC[C@@H](C2CCCCC2)C1
Yield: 70.1 %

Procedure:
A solution of (1S,3R)-3-phenylcyclopentanamine (second eluting diastereomer from Example 15B, 106 mg, 0.657 mmol) and 1,1,1-trifluoroethanol (20 mL) was added to 5% Rh/Al2O3 (42.4 mg) in a 50 mL pressure bottle. The reaction was heated for 16 hours under 30 psi hydrogen pressure and at 50° C. The mixture was filtered through a nylon membrane, washing with EtOH (50 mL). The solution was concentrated to provide the title compound (77 mg, 70%). MS (DCI) m/z 168 (M+H)+.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][C:4]([C:7]2([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)=[CH:3][CH2:2]1.[ClH:18]>C(O)C.[Pt]=O>[ClH:18].[O:1]1[CH2:6][CH2:5][CH:4]([C:7]2([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH2:3][CH2:2]1
Reactant: CCOC(=O)C1(C2=CCOCC2)CCNCC1
Agent: O=[Pt]
Agent: Cl
Solvent: CCO
Product: CCOC(=O)C1(C2CCOCC2)CCNCC1
Reaction time: 20 h

Procedure:
To a suspension of platinum oxide (0.24 gm; 0.87 mmol) in ethanol (40 mL) and conc HCl (10 mL) was added the compound from Step B (0.41 gm; 1.71 mmol). The reaction mixture was purged with hydrogen and then shaken under a hydrogen atmosphere (50 psi) for 20 hours. The mixture was purged with nitrogen and filtered through celite and washed with EtOH and concentrated to give the title compound (0.36 gm) as a white solid.
Reaction SMILES: [CH2:1](/[C:3](=[CH:9]\[CH3:10])/[CH:4]=[CH:5]/[C:6](O)=[O:7])[CH3:2].C([N:13](CC)CC)C.ClC(OC(C)C)=O.N>ClCCl>[CH2:1](/[C:3](=[CH:9]\[CH3:10])/[CH:4]=[CH:5]/[C:6]([NH2:13])=[O:7])[CH3:2]
Reactant: CCN(CC)CC
Reactant: C/C=C(/C=C/C(=O)O)CC
Agent: CC(C)OC(=O)Cl
Agent: N
Solvent: ClCCl
Product: C/C=C(/C=C/C(N)=O)CC
Reaction time: 1 h
Yield: 75 %

Procedure:
To a solution of 16.0 kg (114 mol) of (E,E)-4-ethyl-2,4-hexadienoic acid and 11.5 kg (114 mol) of triethylamine in 112 l of dichloromethane is added dropwise 14.0 kg (114 mol) of isopropyl chloroformate at -5°~-10° C. and the reaction is continued for 1 hour at same temperature. To this solution is introduced 7.4 kg (435 mol) of anhydrous ammonia gas and allowed to stand overnight at 20°-30° C. The solvent and excess ammonia gas is removed under reduced pressure. The residue is dissolved in 128 l of ethyl acetate and washed with 80 l of 5%-sodium chloride solution, 80 l of 5%-hydrochloric acid solution, 80 l of 5%-sodium chloride solution, 80l of 7%-sodium hydroxide solution and 80 l of 5%-sodium chloride solution respectively. The solvent is removed under reduced pressure to give 11.9 kg of (E,E)-4-ethyl-2,4 -hexadienamide as a yellow oil (Yield 74.7%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][OH:10])[CH:5]=[N:6][C:7]=1[Cl:8].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C([O-])(O)=O.[Na+].O.C(Cl)Cl>[Cl:1][C:2]1[C:7]([Cl:8])=[N:6][CH:5]=[C:4]([CH:3]=1)[CH:9]=[O:10]
Reactant: OCc1cnc(Cl)c(Cl)c1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: O=Cc1cnc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 5,6-dichloro-3-pyridinemethanol (2.9967 g, 16.8 mmol) in DCM (3.00 mL, 46.6 mmol) was treated with Dess-Martin periodinane (7.14 g, 16.8 mmol) at room temperature and the mixture was stirred at room temperature overnight. The resulting reaction mixture was diluted with NaHCO3 (aq) and water (5 mL each) and diluted with DCM (5 mL). The separated aqueous layer was extracted with DCM (2×10 mL) and the combined organic layers were washed with brine, dried over Na2SO4, and concentrated to give a pale-yellow solid which was used directly for the next step.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:24]#[N:25])[C:5](F)=[C:6]([C:8]([CH:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)=O)[CH:7]=1.O.[NH2:27][NH2:28]>C(O)C>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[C:4]([C:24]#[N:25])[CH:3]=1)[NH:28][N:27]=[C:8]2[CH:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]1
Reactant: NN
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)c2cc(Br)cc(C#N)c2F)CC1
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(c2n[nH]c3c(C#N)cc(Br)cc23)CC1
Yield: 58.3 %

Procedure:
A mixture of 1,1-dimethylethyl 4-[(5-bromo-3-cyano-2-fluorophenyl)carbonyl]-1-piperidinecarboxylate (1.35 g, 3.3 mmols) and hydrazine hydrate (0.21 ml, 6.9 mmols) in ethanol (30 mL) was heated at reflux overnight. After cooling, the solvent was evaporated and the residue was purified by flash chromatography eluting with pentane/ethyl acetate 4:1 v/v to give the title compound (0.78 g) as a yellow solid (59%).
Reaction SMILES: Br[C:2]1[S:6]/[C:5](=[N:7]\[C:8]([C:10]23[CH2:17][CH:16]4[CH2:18][CH:12]([CH2:13][CH:14]2[CH2:15]4)[CH2:11]3)=[O:9])/[N:4]([CH2:19][CH2:20][O:21][CH3:22])[CH:3]=1.[CH:23]1(B(O)O)[CH2:25][CH2:24]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O.C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH:23]1([C:2]2[S:6]/[C:5](=[N:7]\[C:8]([C:10]34[CH2:17][CH:16]5[CH2:18][CH:12]([CH2:13][CH:14]3[CH2:15]5)[CH2:11]4)=[O:9])/[N:4]([CH2:19][CH2:20][O:21][CH3:22])[CH:3]=2)[CH2:25][CH2:24]1
Reactant: OB(O)C1CC1
Reactant: COCCn1cc(Br)s/c1=N\C(=O)C12CC3CC(CC1C3)C2
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: COCCn1cc(C2CC2)s/c1=N\C(=O)C12CC3CC(CC1C3)C2
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A flask was charged with the product from Example 130B (150.0 mg, 0.39 mmol), cyclopropylboronic acid (Aldrich) (86 mg, 0.51 mmol), K3PO4 (212 mg, 1.36 mmol) and dichlorobis(trichlorohexylphosphine)palladium (II) (29 mg, 0.04 mmol) in 5 mL of H2O/toluene (1:1). The mixture was warmed to 100° C. and stirred overnight. After cooling to room temperature, the mixture was diluted with ethyl acetate and washed with water. The organic extract was dried (MgSO4), filtered and concentrated. The residue was purified by flash chromatography on SiO2 using a gradient of 0% to 100% ethyl acetate:hexane to afford the title compound. 1H NMR (300 MHz, dimethylsulfoxide-d6) δ 0.59-0.65 (m, 2H), 0.86-0.95 (m, 2H), 1.53-1.61 (m, 4H), 1.65-1.79 (m, 4H), 1.86-1.97 (m, 1H), 2.04-2.13 (m, 2H), 2.22-2.29 (m, 2H), 2.51-2.56 (m, 1H), 3.24 (s, 3H), 3.66 (t, J=5.3 Hz, 2H), 4.20 (t, J=5.4 Hz, 2H), 7.15 (d, J=1.0 Hz, 1H); MS (ESI+) m/z 347 (M+H)+.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]([NH:15][C:16]([C:18]1[N:19]=[C:20]([N:23]2[CH2:26][CH:25]([OH:27])[CH2:24]2)[S:21][CH:22]=1)=[O:17])[CH2:11][CH:12]([CH3:14])[CH3:13])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:28][S:29](Cl)(=[O:31])=[O:30].C(N(CC)CC)C>C(Cl)Cl>[Si:1]([O:8][CH2:9][C@@H:10]([NH:15][C:16]([C:18]1[N:19]=[C:20]([N:23]2[CH2:24][CH:25]([O:27][S:29]([CH3:28])(=[O:31])=[O:30])[CH2:26]2)[S:21][CH:22]=1)=[O:17])[CH2:11][CH:12]([CH3:14])[CH3:13])([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)C[C@@H](CO[Si](C)(C)C(C)(C)C)NC(=O)c1csc(N2CC(O)C2)n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)C[C@@H](CO[Si](C)(C)C(C)(C)C)NC(=O)c1csc(N2CC(OS(C)(=O)=O)C2)n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 97.8 %

Procedure:
To a solution of 1-{4-[(1S)-1-(t-butyldimethylsilyloxymethyl)-3-methylbutylcarbamoyl]-1,3-thiazol-2-yl}-3-hydroxyazetidine (730 mg, 1.76 mmol) (obtained as described in Reference Example 37(4)) in methylene chloride (37 ml) were added methanesulfonyl chloride (409 μl, 5.29 mmol) and triethylamine (741 μl, 5.29 mmol) in an ice bath. After stirring the mixture in the ice bath for 10 minutes, the mixture was stirred at room temperature for 1.5 hours. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using n-hexane:ethyl acetate (2:1→1:2) as the eluant to afford 1-{4-[(1S)-1-(t-butyldimethylsilyloxymethyl)-3-methylbutylcarbamoyl]-1,3-thiazol-2-yl}-3-methanesulfonyloxyazetidine (846 mg, yield 98%) as a pale yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[CH:11][C:12]([NH:15][C:16]([C:18]3[C:19](=[O:31])[N:20]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[N:21]([CH3:24])[C:22]=3[CH3:23])=[O:17])=[N:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.CCN(CC)CC.[CH:39]1([C:43](Cl)=[O:44])[CH2:42][CH2:41][CH2:40]1>C1COCC1.CCOC(C)=O>[CH:39]1([C:43]([NH:1][C:2]2[CH:7]=[C:6]([O:8][C:9]3[CH:10]=[CH:11][C:12]([NH:15][C:16]([C:18]4[C:19](=[O:31])[N:20]([C:25]5[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=5)[N:21]([CH3:24])[C:22]=4[CH3:23])=[O:17])=[N:13][CH:14]=3)[CH:5]=[CH:4][N:3]=2)=[O:44])[CH2:42][CH2:41][CH2:40]1
Reactant: Cc1c(C(=O)Nc2ccc(Oc3ccnc(N)c3)cn2)c(=O)n(-c2ccccc2)n1C
Reactant: O=C(Cl)C1CCC1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Cc1c(C(=O)Nc2ccc(Oc3ccnc(NC(=O)C4CCC4)c3)cn2)c(=O)n(-c2ccccc2)n1C
Temperature: 0 °C
Reaction time: 1.25 h
Yield: 41.8 %

Procedure:
To a suspension of N-(5-((2-aminopyridin-4-yl)oxy)pyridin-2-yl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (50 mg, 0.12 mmol) in THF (13 mL) was added Et3N (0.034 mL, 0.24 mmol). The suspension was cooled to 0° C., then a solution of cyclobutanecarbonyl chloride (28.5 mg, 0.24 mmol) in THF (3 mL) was added to the mixture slowly. The reaction was stirred at rt for 1.25 hours, then diluted with EtOAc (15 mL). The mixture was washed with water (15 mL×2), followed by washing with brine (15 mL), dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by a silica gel column chromatography (DCM/MeOH (v/v)=60/1) to give the title compound as a white solid (25 mg, 41%).
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]3[CH3:29])[C:16]3[CH2:22][CH2:21][NH:20][CH2:19][C:17]=3[N:18]=2)=[CH:9][CH:8]=1)=[O:5])[CH3:2].[Cl:30][C:31]1[CH:36]=[C:35](Cl)[N:34]=[CH:33][N:32]=1.CN(C)C=O>>[Cl:30][C:31]1[N:32]=[CH:33][N:34]=[C:35]([N:20]2[CH2:21][CH2:22][C:16]3[C:15]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]4[CH3:29])=[N:14][C:13]([C:10]4[CH:9]=[CH:8][C:7]([NH:6][C:4]([NH:3][CH2:1][CH3:2])=[O:5])=[CH:12][CH:11]=4)=[N:18][C:17]=3[CH2:19]2)[CH:36]=1
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCNC3)cc1
Reactant: Clc1cc(Cl)ncn1
Solvent: CN(C)C=O
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCN(c2cc(Cl)ncn2)C3)cc1

Procedure:
(S)-1-ethyl-3-(4-(4-(3-methylmorpholino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)urea (0.196 g, 0.376 mmol), 4,6-dichloropyrimidine (0.112 g, 0.752 mmol) N,N-Diisopropylethylamine (0.150 mL, 0.861 mmol) and dry N,N-Dimethylformamide (1.1 mL, 14 mmol) were combined, The reaction was microwaved on 200 watts, 120° C. for 20 minutes on a CEM microwave. The reaction mixture was concentrated and chromatographed through silica gel (40 g, 0-10% MeOH in dichloromethane), and purified by HPLC. 1H NMR (500 MHz, DMSO) δ 8.69 (s, 1H), 8.41 (s, 1H), 8.20 (d, J=8.7, 2H), 7.50 (d, J=8.7, 2H), 7.12 (s, 1H), 6.20 (t, J=5.6, 1H), 4.72 (s, 3H), 4.12 (s, 1H), 4.08-3.92 (m, 1H), 3.88 (d, J=9.4, 1H), 3.80 (s, 1H), 3.64 (dt, J=25.7, 10.3, 4H), 3.43 (t, J=12.6, 1H), 3.17-3.04 (m, 2H), 2.75 (s, 2H), 1.26 (d, J=6.7, 3H), 1.06 (t, J=7.2, 3H). LC/MS-m/z+509.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][CH:7]=1.Br[C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd].O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:12]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: OB(O)c1cccc(Cl)c1
Reactant: Brc1ccncc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Clc1cccc(-c2cccnc2)c1
Temperature: 80 °C
Yield: 50 %

Procedure:
This Example was carried out in the same manner as Example 1, except that 5.0 g (0.032 mol) of 3-chloro-phenyl boronic acid, 10.0 g (0.064 mol) of 4-bromopyridine, 150□ of tetrahydrofuran and 2M potassium carbonate solution (20□) were added and then 0.37 g (3 mol %) of palladium tetrakistriphenylphosphine [(pd(PPh3)4] was used as a catalyst. Finally, after the resulting solution was heated to reflux at 80° C. for 24 hours, the 3-(3-chloro-phenyl)pyridine was isolated. The yield was 50%.
Reaction SMILES: [Br:1]CC1C2C(C=CC=1)=CC1C3C=CC=CC=3OC=1C=2.[CH3:20][C:21]1[C:29]2[C:28]3[CH:30]=[C:31]4[C:36](=[CH:37][C:27]=3[O:26][C:25]=2[CH:24]=[CH:23][CH:22]=1)[CH:35]=[CH:34][CH:33]=[CH:32]4>>[Br:1][CH2:20][C:21]1[C:29]2[C:28]3[CH:30]=[C:31]4[C:36](=[CH:37][C:27]=3[O:26][C:25]=2[CH:24]=[CH:23][CH:22]=1)[CH:35]=[CH:34][CH:33]=[CH:32]4
Reactant: BrCc1cccc2cc3c(cc12)oc1ccccc13
Reactant: Cc1cccc2oc3cc4ccccc4cc3c12
Product: BrCc1cccc2oc3cc4ccccc4cc3c12
Yield: 72 %

Procedure:
Using the procedure outlined in 6A, 1-methylbenzo[b]naphtho[2,3-d]furan (Cambridge Chemicals, Inc.) gave 72% yield of crude 1-bromomethylbenzo[b]naphtho[2,3-d]furan which was used without further purification.
Reaction SMILES: C([O:3][P:4]([C:9]([C:11]1[S:12][C:13]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH3:25])=[CH:19][CH:18]=2)=[CH:14][CH:15]=1)=[O:10])(=[O:8])[O:5]CC)C.Br[Si](C)(C)C.CO>ClCCl>[CH2:24]([O:23][C:20]1[CH:21]=[CH:22][C:17]([CH2:16][C:13]2[S:12][C:11]([C:9]([P:4](=[O:3])([OH:8])[OH:5])=[O:10])=[CH:15][CH:14]=2)=[CH:18][CH:19]=1)[CH3:25]
Reactant: CCOc1ccc(Cc2ccc(C(=O)P(=O)(OCC)OCC)s2)cc1
Agent: C[Si](C)(C)Br
Solvent: CO
Solvent: ClCCl
Product: CCOc1ccc(Cc2ccc(C(=O)P(=O)(O)O)s2)cc1
Temperature: 25 °C
Reaction time: 22 h
Yield: 32.6 %

Procedure:
To a solution of [5-(4-ethoxybenzyl)thiophen-2-carbonyl]phosphonic acid diethylester (0.54 g) in dichloromethane (14.0 mL) was added bromotrimethylsilane (0.9 mL) at 0° C., and the reaction mixture was stirred for 22 hr at room temperature. Methanol (1.0 mL) was added to the reaction mixture, and the mixture was stirred for 10 min at room temperature. After evaporation, the residue was crystallized from ethyl acetate to give the title compound (0.15 g) as a colorless crystal.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[O:15][C:14]([O:20][CH3:21])([CH3:19])[CH2:13][CH2:12]2)C1C=CC=CC=1.[H][H]>[Pd].C(O)C>[OH:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[O:15][C:14]([O:20][CH3:21])([CH3:19])[CH2:13][CH2:12]2
Reactant: COC1(C)CCc2cc(OCc3ccccc3)ccc2O1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: COC1(C)CCc2cc(O)ccc2O1
Reaction time: 9 h

Procedure:
To a solution of the (±)-6-benzyloxy-2-methoxy-2-methylchroman prepared in Example 45 in 250 ml. of ethanol was added 2.5 g. of 10% palladium on carbon catalyst, and the resulting mixture was hydrogenated at atmospheric pressure and room temperature. After nine hours, the uptake of hydrogen (3100 ml.) had ceased. The catalyst was removed by filtration and the filtrates were stripped of solvent at reduced pressure. Crystallization of the solid residue from ether-30°-60° petroleum ether gave (±)-6-hydroxy-2-methoxy-2-methylchroman as white needles, m.p. 128°-130°.
Reaction SMILES: [NH2:1][N:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[C:3]1[S-:13].[K+].[CH3:15]I.O>CN(C)C=O>[NH2:1][N:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[C:3]1[S:13][CH3:15]
Reactant: CI
Reactant: Nn1c([S-])nc2ccccc2c1=O
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CSc1nc2ccccc2c(=O)n1N
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 86 %

Procedure:
To a solution 209 mg of potassium 3-amino-3H-quinazolin-4-one-2-thiolate in 5 ml of dimethylformamide, 141 mg of methyl iodide was added, and stirred for 20 minutes at room temperature. Water was added to the solution, followed by extraction with ethyl acetate and drying over anhydrous magnesium sulfate. Distilling the solvent off under reduced pressure, 161 mg (86%) of 3-amino-2-methylthio-3H-quinazolin-4-one was obtained.