Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:8]1([OH:28])[C:21]2[O:22][C@@H:18]3[C@@:19]45[CH2:23][CH2:24][N:25]([CH3:26])[C@@H:13]([C@@H:14]4[CH:15]=[CH:16][C@@H:17]3[OH:27])[CH2:12][C:11]([C:20]5=2)=[CH:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:36](OC(=O)C)(=[O:38])[CH3:37]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[C:36]([C@:17]1([OH:27])[CH:16]=[CH:15][C@@H:14]2[C@@:19]34[CH2:23][CH2:24][N:25]([CH3:26])[C@@H:13]2[CH2:12][C:11]2[C:20]3=[C:21]([O:22][C@@H:18]14)[C:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)([OH:28])[CH2:9][CH:10]=2)(=[O:38])[CH3:37]
Reactant: CN1CC[C@]23C4=C5O[C@H]2[C@@H](O)C=C[C@H]3[C@H]1CC4=CCC5(O)Cc1ccccc1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)[C@]1(O)C=C[C@H]2[C@H]3CC4=CCC(O)(Cc5ccccc5)C5=C4[C@@]2(CCN3C)[C@H]1O5
Temperature: 0 °C
Yield: 97.5 %

Procedure:
To a solution of 3-benzylmorphine (12.7 g, 33.9 mmol) in CH2Cl2 (300 ml), was added triethylamine (10 ml, 99%, 71.2 mmol), acetic anhydride (7.5 ml, 99%, 78.6 mmol), and 4-dimethylaminopyridine (0.3 g). The reaction mixture was heated under reflux for 2 hr, cooled with an ice--H2O bath, then transferred to a separatory funnel, and washed with cold 10% aqueous NaHCO3 solution (3×100 ml). The organic layer was separated and dried over anhydrous Na2SO4. Removal of solvent gave 6-acetyl-3-benzylmorphine (13.87 g, 96% yield). IR (KBr)(ν, cm-1): 2900 (m, sharp), 1727 (s, sharp, AcO); NMR (δH)(CDCl3): 7.47-7.20 (5, m, --C6H5), 6.68 (1, d, J, 8.1, 2-H), 6.48 (1, d, J, 8.2, 1-H), 5.63 (1, dm, J, 10.1, 7-H), 5.43 (1, dt, J, 10.1 & 2.3, 8-H), 5.25-5.15 (1, m, 6-H), 5.14 (2, s, --OCH2Ph), 5.10 (1, dd, J, 6.7 & 1.1, 5-H), 3.34 (1, dd, J, 6.0 & 3.3, 9-H), 3.01 (1, d, J, 18.6, 10-Hβ), 2.79-2.70 (1, m, 14-H), 2.59 (1, dd, J, 12.1 & 3.4, 16-He), 2.43 (3, s, N--CH3), 2.37 (1, td, J, 11.8 & 3.6, 16-Ha), 2.27 (1, dd, J, 18.8 & 6.6, 10-Hα), 2.10 (3, s, AcO), 2.04 (1, td, J, 11.9 & 5.1, 15-Ha), 1.86 (1, dm, J, 12.5, 15-He).
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:4]=[C:5]([C:9]2[CH:13]=[C:12]([C:14]3[CH:23]=[CH:22][CH:21]=[CH:20][C:15]=3[C:16]([O:18]C)=[O:17])[O:11][N:10]=2)[CH:6]=[CH:7][CH:8]=1.C(O)(=O)C.Cl>O>[F:25][C:2]([F:1])([F:24])[C:3]1[CH:4]=[C:5]([C:9]2[CH:13]=[C:12]([C:14]3[CH:23]=[CH:22][CH:21]=[CH:20][C:15]=3[C:16]([OH:18])=[O:17])[O:11][N:10]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: COC(=O)c1ccccc1-c1cc(-c2cccc(C(F)(F)F)c2)no1
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)c1ccccc1-c1cc(-c2cccc(C(F)(F)F)c2)no1
Yield: 65 %

Procedure:
A solution of 6.20 g of methyl 2-[3-(3-trifluoromethylphenyl)-5-isoxazolyl]benzoate, 75 ml. of acetic acid, and 50 ml. of concentrated HCl was held at reflux for 4 hours, cooled, and poured into 450 ml. of cold water. The resultant solid was recrystallized from CH3CN to give 3.87 g of solid, mp 176°-177° C.
Reaction SMILES: [N:1]1([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][CH2:14][CH2:13][C@H:2]1[C:3]([O:5]N1C(=O)CCC1=O)=O.[NH2:23][C@@H:24]([C:32]([OH:34])=[O:33])[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[N:1]1([C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])[CH2:15][CH2:14][CH2:13][C@H:2]1[C:3]([NH:23][C@@H:24]([C:32]([OH:34])=[O:33])[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:5]
Reactant: N[C@H](Cc1ccccc1)C(=O)O
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)ON1C(=O)CCC1=O
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)N[C@H](Cc1ccccc1)C(=O)O
Yield: 67 %

Procedure:
Condesation of BocProOH (6.46 g.) and N-hydroxysuccinimide (3.5 g.) using dicyclohexylcarbodiimide gave BocProOSu in 75% yield. Condensation of BocProOSu (5.0 g.) and HDPheOH (2.75 g.) by the salt coupling method gave BocPro-DPheOH in 67% yield. Condensation of BocPro-DPheOH (3.98 g.) and HPheOMe hydrochloride salt (2.4 g.) using dicyclohexylcarbodiimide and N-hydroxysuccinimide gave BocPro-DPhe-PheOMe in 74% yield. Hydrazinolysis of Boc-Pro-DPhe-PheOMe (3.14 g.) gave BocPro-DPhe-PheNHNH2 in 79% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([CH3:14])=[N:12][NH:11][C:10](=O)[C:9]=2[C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=2[F:23])=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:26])=O>>[Cl:26][C:10]1[N:11]=[N:12][C:13]([CH3:14])=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:9]=1[C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=1[F:23]
Reactant: Cc1n[nH]c(=O)c(-c2ccc(F)cc2F)c1-c1ccc(Cl)cc1
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1nnc(Cl)c(-c2ccc(F)cc2F)c1-c1ccc(Cl)cc1
Temperature: 110 °C
Reaction time: 1 h
Yield: 96.3 %

Procedure:
1.20 g of 5-(4-chlorophenyl)-4-(2,4-difluorophenyl)-6-methyl-2H-pyridazin-3-one and 10 g of phosphorus oxychloride were mixed and stirred at 110° C. for 1 hour. The reaction mixture was allowed to cool down to room temperature and concentrated under reduced pressure. To the residue was added ethyl acetate and ice water, and was separated to two layer. The organic layer was washed sequentially with water and saturated brine, and dried over anhydrous sodium sulfate, then, concentrated under reduced pressure, to obtain 1.22 g of 3-chloro-5-(4-chlorophenyl)-4-(2,4-difluorophenyl)-6-methyl pyridazine (hereinafter, referred to as compound (xv) of the present invention).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[N:10][NH:11][N:12]=2)[CH:5]=[CH:6][CH:7]=1.[C:13]([O:17][C:18](=[O:29])[CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27]Br)=[CH:23][CH:22]=1)([CH3:16])([CH3:15])[CH3:14]>>[C:13]([O:17][C:18](=[O:29])[CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][N:10]2[N:11]=[N:12][C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=3)=[N:9]2)=[CH:23][CH:22]=1)([CH3:16])([CH3:15])[CH3:14]
Reactant: Brc1cccc(-c2nn[nH]n2)c1
Reactant: CC(C)(C)OC(=O)COc1ccc(CBr)cc1
Product: CC(C)(C)OC(=O)COc1ccc(Cn2nnc(-c3cccc(Br)c3)n2)cc1
Yield: 84.6 %

Procedure:
This reaction was carried out as described in Example D2, Step (a) using 5-(3-bromophenyl)-2H-tetrazole (0.87 g, 2.89 mmol) and (4-bromomethylphenoxy) acetic acid tert-butyl ester (0.50 g, 2.22 mmol) in place of (4-bromo-methylbenzyl) phosphonic acid dimethyl ester. This afforded 0.85 g of light oil (84.6% yield) NMR (CDCl3); 8.28 (s, 1H), 8.07–8.05 (d, 1H), 7.58–7.55 (d, 1H), 7.38–7.31 (m, 3H), 6.90–6.88 (d, 2H), 5.72 (s, 2H), 4.50 (s, 2H), 1.48 (s, 9H)
Reaction SMILES: [CH:1]([N:14]1[CH2:19][CH2:18][N:17]([C:20](=[O:36])[CH2:21][C:22]2[C:31]([CH:32]3[CH2:34][CH2:33]3)=[CH:30][C:25]([C:26]([O:28]C)=[O:27])=[C:24]([F:35])[CH:23]=2)[CH2:16][CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>C1COCC1.CO.[OH-].[Li+]>[CH:1]([N:14]1[CH2:19][CH2:18][N:17]([C:20](=[O:36])[CH2:21][C:22]2[C:31]([CH:32]3[CH2:34][CH2:33]3)=[CH:30][C:25]([C:26]([OH:28])=[O:27])=[C:24]([F:35])[CH:23]=2)[CH2:16][CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1cc(C2CC2)c(CC(=O)N2CCN(C(c3ccccc3)c3ccccc3)CC2)cc1F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1cc(C2CC2)c(CC(=O)N2CCN(C(c3ccccc3)c3ccccc3)CC2)cc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 52.9 %

Procedure:
To a solution of methyl 4-(2-(4-benzhydrylpiperazin-1-yl)-2-oxoethyl)-5-cyclopropyl-2-fluorobenzoate (70 mg, 0.14 mmol) in THF (2 mL) and methanol (2 mL), lithium hydroxide (2M, 2 mL) was added. After stirring at room temperature for 16 h, the mixture pH was adjusted to 2-3 with HCl (2 M) and extracted by ethyl acetate (10 mL×3). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by Combiflash (30%-40% CH3CN in 0.1% HCOOH) to afford target compound (35 mg, 53%) as a white solid. LCMS (ESI): m/z: 473.2 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:5]=[CH:6][CH:7]=1.C.[O:14]=[C:15](Cl)OC(Cl)(Cl)Cl>C1(C)C=CC=CC=1>[N:1]([C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:5]=[CH:6][CH:7]=1)=[C:15]=[O:14]
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: COC(=O)Cc1cccc(N)c1
Solvent: Cc1ccccc1
Product: COC(=O)Cc1cccc(N=C=O)c1
Temperature: -20 °C

Procedure:
Methyl 3-isocyanatophenylacetate is prepared as follows: at a temperature in the vicinity of -20° C. and under argon, 8.25 g of methyl 3-aminophenylacetate in solution in 100 cm3 of toluene are added to a suspension of 1 g of charcoal and 6 cm3 of diphosgene in 70 cm3 of toluene. The reaction mixture is stirred and maintained at -20° C. for 15 minutes, then, after returning to a temperature in the vicinity of 20° C., heated under reflux for 2 hours and 30 minutes. The mixture is then degassed by bubbling through argon for 30 minutes, filtered on Celite, rinsed with 50 cm3 of dichloromethane and concentrated under reduced pressure at a temperature in the vicinity of 50° C. 9.30 g of methyl 3-isocyanatophenylacetate are thus obtained in the form of a yellow liquid stored under argon and used as it is in subsequent syntheses.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([N+:9]([O-:11])=[O:10])[C:3]=1[OH:12].CI.[C:15](=O)([O-])[O-].[K+].[K+]>>[N+:9]([C:4]1[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[C:3]=1[O:12][CH3:15])([O-:11])=[O:10]
Reactant: O=C([O-])[O-]
Reactant: O=[N+]([O-])c1cc(Cl)cc(Cl)c1O
Agent: [K+]
Solvent: CI
Product: COc1c(Cl)cc(Cl)cc1[N+](=O)[O-]
Yield: 90.1 %

Procedure:
2-Nitro-4,6-dichloroanisole was prepared by the same procedure as described for Step 2 of Preparation 2a except using 2,4-dichloro-6-nitrophenol (52 g), methyl iodide (71 g), and potassium carbonate (41.4 g). Workup gave crude 2-nitro-4,6-dichloroanisole (50 g, 90%) which was used in the next step without purification.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6](Cl)[C:3]=1[CH:4]=[O:5].[CH3:11][S-:12].[Na+].O>CN(C)C=O>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([S:12][CH3:11])[C:3]=1[CH:4]=[O:5]
Reactant: C[S-]
Reactant: O=Cc1c(Cl)cccc1Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CSc1cccc(Cl)c1C=O
Temperature: 25 °C

Procedure:
To a solution of 2,6-dichlorobenzaldehyde (20 g, 114.28 mmol) in N,N-dimethylformamide (200 ml), sodium thiomethoxide (8.81 g, 125.7 mmol) was added at 0° C. The reaction mixture was allowed to warm to room temperature overnight, then poured into water. A yellow precipitate was collected by vacuum filtration and dried to afford 2-chloro-6-(methylthio)benzaldehyde (11. g), as a light yellow solid. (This method is general for other 2-haloaldehydes). 1H NMR (300 MHz, CDCl3): 10.6 (s, 1H), 7.4 (t, 1H), 7.2 (dd, 2H), 2.4 ppm (s, 3H). MW=187 confirmed by LC-MS, tr=13.18 min (Method Y) MH+=188.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:23][O:24][C:25]([C:27]1[CH:28]=[N:29][CH:30]=[C:31](Br)[CH:32]=1)=[O:26]>C(COC)OC.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>[CH3:23][O:24][C:25](=[O:26])[C:27]1[CH:32]=[C:31]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[CH:30]=[N:29][CH:28]=1
Reactant: COC(=O)c1cncc(Br)c1
Reactant: CC1(C)OB(c2cccc(Cl)c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Product: COC(=O)c1cncc(-c2cccc(Cl)c2)c1
Temperature: 25 °C
Yield: 80.5 %

Procedure:
104 mg (0.09 mmol)Pd(PPh3)4, 1.5 g (6.29 mmol) of 3-chlorophenylboronic acid pinacol ester 2.86 ml (8.58 mmol) and 3M cesium carbonate solution were added under argon at room temperature to a solution of 1.24 g (5.72 mmol) methyl-5-bromo-pyridine-3-carboxylate in 45 ml dimethoxyethane and the mixture was heated to reflux for 30 min. The reaction mixture was cooled to room temperature and evaporated. The residue was taken up with ethyl acetate, washed with water, dried over sodium sulphate and evaporated. Chromatography on silica (eluent: ethyl acetate/n-heptane 1:3) gave 1.14 g (72%) of 5-(3-Chloro-phenyl)-nicotinic acid methyl ester
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:49][CH3:50])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:28]=[C:27]([CH3:29])[CH:26]=[C:25]([C:30]([NH:32][CH2:33][C:34]4[CH:35]=[C:36]([C:41]5[CH:46]=[CH:45][CH:44]=[C:43]([CH:47]=O)[CH:42]=5)[C:37]([F:40])=[CH:38][CH:39]=4)=[O:31])[CH:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[CH3:51][C@H:52]1[CH2:57][NH:56][CH2:55][CH2:54][N:53]1C(OC(C)(C)C)=O.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C>CS(C)=O>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:49][CH3:50])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:28]=[C:27]([CH3:29])[CH:26]=[C:25]([C:30]([NH:32][CH2:33][C:34]4[CH:35]=[C:36]([C:41]5[CH:46]=[CH:45][CH:44]=[C:43]([CH2:47][N:56]6[CH2:55][CH2:54][NH:53][C@@H:52]([CH3:51])[CH2:57]6)[CH:42]=5)[C:37]([F:40])=[CH:38][CH:39]=4)=[O:31])[CH:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: C[C@H]1CNCCN1C(=O)OC(C)(C)C
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cc(C)cc(C(=O)NCc2ccc(F)c(-c3cccc(C=O)c3)c2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Solvent: CC(=O)O
Solvent: CS(C)=O
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cc(C)cc(C(=O)NCc2ccc(F)c(-c3cccc(CN4CCN[C@@H](C)C4)c3)c2)c1
Temperature: 60 °C
Reaction time: 8 h
Yield: 60.2 %

Procedure:
N-{[1,6-Diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N′-[(6-fluoro-3′-formyl-3-biphenylyl)methyl]-5-methyl-1,3-benzenedicarboxamide (30 mg, 0.044 mmol), 1,1-dimethylethyl (2S)-2-methyl-1-piperazinecarboxylate (89 mg, 0.44 mmol, 10 eq) and acetic acid (2.54 μL, 0.044 mmol, 1 eq) were dissolved in DMSO (1.5 mL). The mixture was stirred in VX-2500 Multi-Tube Vortexer for overnight at room temperature. MP-triacetoxyborohydride (133 mg, 0.310 mmol, 7 eq) was then added and the mixture was stirred again in VX-2500 Multi-Tube Vortexer for overnight at room temperature. The reaction mixture was filtered through a polypropylene cartridge (10 mL tube) on Bohdan Miniblock in a reaction tube and concentrated in a Glas-Col evaporator. Methanol (2 mL) then hydrochloric acid (5 μL) were added for the deprotection of 1,1-dimethylethyl (2S)-4-[(5′-{[({3-[({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]-5-methylphenyl}carbonyl)amino]methyl}-2′-fluoro-3-biphenylyl)methyl]-2-methyl-1-piperazinecarboxylate. The vial containing the reaction mixture was closed and stirred in a Glas-Col evaporator for overnight at 60° C. The reaction mixture was then concentrated and purified using a Gilson HPLC with a water-acetonitrile with 0.1% TFA buffer. The desired product fractions were combined, filtered through amine cartouche (500 mg) on Bohdan Miniblock and concentrated in a Glas-Col evaporator, giving 20.16 mg (53.8%) of the title compound. LC-MS m/z 761 (M+H)+, 1.31 min (ret time).
Reaction SMILES: [CH2:1]([O:4][C:5]1([CH3:45])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[N:17]=[C:18]([CH2:20][N:21]4[CH:25]=[C:24]([C:26]5[CH:31]=[CH:30][CH:29]=[C:28]([OH:32])[CH:27]=5)[N:23]=[N:22]4)[CH:19]=[C:15]3[N:14]=[C:13]([CH3:33])[C:12]=2[C@H:34]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])[C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH2:7][CH2:6]1)[CH:2]=[CH2:3].C([O-])([O-])=O.[K+].[K+].[CH2:52](Br)[CH:53]=[CH2:54]>CN(C=O)C>[CH2:1]([O:4][C:5]1([CH3:45])[CH2:6][CH2:7][N:8]([C:11]2[N:16]3[N:17]=[C:18]([CH2:20][N:21]4[CH:25]=[C:24]([C:26]5[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH2:54][CH:53]=[CH2:52])[CH:27]=5)[N:23]=[N:22]4)[CH:19]=[C:15]3[N:14]=[C:13]([CH3:33])[C:12]=2[C@H:34]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])[C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH2:9][CH2:10]1)[CH:2]=[CH2:3]
Reactant: C=CCBr
Reactant: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OCC)c(C)nc3cc(Cn4cc(-c5cccc(O)c5)nn4)nn23)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCOc1cccc(-c2cn(Cc3cc4nc(C)c([C@H](OC(C)(C)C)C(=O)OCC)c(N5CCC(C)(OCC=C)CC5)n4n3)nn2)c1
Temperature: 60 °C
Yield: 32.9 %

Procedure:
A mixture of (S)-ethyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-((4-(3-hydroxyphenyl)-1H-1,2,3-triazol-1-yl)methyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (0.0525 g, 0.085 mmol), K2CO3 (0.047 g, 0.340 mmol) and allyl bromide (0.074 ml, 0.850 mmol) in DMF (3 mL) was heated at 60° C. for 24 h. Then, cooled and purified prep-HPLC to afford (S)-ethyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-((4-(3-(allyloxy)phenyl)-1H-1,2,3-triazol-1-yl)methyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (0.0184 g, 0.028 mmol, 32.9% yield) as colorless paste. 1H NMR (500 MHz, CDCl3) δ 7.90 (s, 1H), 7.46 (dd, J=1.5, 2.4 Hz, 1H), 7.35-7.38 (m, 1H), 7.29-7.34 (m, 1H), 6.90 (ddd, J=1.0, 2.6, 8.1 Hz, 1H), 6.51 (s, 1H), 5.98-6.14 (m, 2H), 5.88 (br. s., 1H), 5.79 (s, 2H), 5.45 (qd, J=1.6, 17.2 Hz, 2H), 5.31 (qd, J=1.4, 10.4 Hz, 1H), 5.20 (qd, J=1.6, 10.4 Hz, 1H), 4.62 (td, J=1.5, 5.3 Hz, 2H), 4.14-4.28 (m, 2H), 4.00 (d, J=5.0 Hz, 2H), 2.70-3.90 (m, 3H), 2.61 (s, 3H), 1.85-2.03 (m, 3H), 1.64-1.74 (m, 2H), 1.31 (s, 3H), 1.25 (t, J=7.1 Hz, 3H), 1.24 (s, 9H). LCMS (M+H)=658.6.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:16][C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19]>C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:16][C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:4][CH:3]=1
Reactant: Sc1ccc(Cl)cc1
Reactant: CC(C)(C)C(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)C(=O)CSc1ccc(Cl)cc1

Procedure:
A 14.45 g quantity of p-chlorothiophenol and 13.8 g of anhydrous potassium carbonate were added to 200 ml of acetonitrile, and 13.45 of 1-chloro-3,3-dimethyl-2-butanone was added in small portions to the mixture while stirring the mixture. After stirring the mixture at 70° to 75° C. for 6 hours, the solid separating out was filtered off. The filtrate was concentrated to obtain a residue, which was subjected to extraction with benzene. To the extract was added 200 ml of 10% sodium hydroxide solution, followed by stirring at room temperature for 1 hour. The benzene layer was separated off, washed with water, then dried over anhydrous magnesium sulfate and distilled in a vacuum to remove the solvent, giving 20.2 g of the above-identified desired compound in the form of a pale yellow oil.
Reaction SMILES: Br[C:2]1[N:6]([S:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]#[N:17])(=[O:9])=[O:8])[CH:5]=[C:4]([CH2:18][N:19]([CH3:27])[C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH:3]=1.[N:28]1[CH:33]=[CH:32][CH:31]=[C:30](B(O)O)[CH:29]=1.C(=O)([O-])[O-].[Na+].[Na+]>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>[C:16]([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[S:7]([N:6]1[C:2]([C:30]2[CH:29]=[N:28][CH:33]=[CH:32][CH:31]=2)=[CH:3][C:4]([CH2:18][N:19]([CH3:27])[C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:5]1)(=[O:9])=[O:8])#[N:17]
Reactant: CN(Cc1cc(Br)n(S(=O)(=O)c2ccccc2C#N)c1)C(=O)OC(C)(C)C
Reactant: OB(O)c1cccnc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CN(Cc1cc(-c2cccnc2)n(S(=O)(=O)c2ccccc2C#N)c1)C(=O)OC(C)(C)C
Yield: 63.4 %

Procedure:
Using tert-butyl {[5-bromo-1-(2-cyanophenyl)sulfonyl-1H-pyrrol-3-yl]methyl}methylcarbamate (296 mg), 3-pyridineboronic acid (162 mg), sodium carbonate (208 mg) and tetrakis(triphenylphosphine)palladium (38.2 mg), a procedure as in Reference Example 267 was performed to give the title compound as a white solid (yield 187 mg, 63%).
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:13](O)(=[O:15])[CH3:14]>>[C:13]([NH:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:15])[CH3:14]
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Reactant: CC(=O)O
Product: CC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Temperature: 150 °C
Reaction time: 1 h
Yield: 78.4 %

Procedure:
Phenylalanine (1 g, 6.05 mmol) and acetic acid (20 mL) were mixed together and heated at 150° C. in a microwave for one hour. The excess acetic acid was removed using a rotary evaporator. The residue was taken up in toluene and the solvent was removed using a rotary evaporator. The residue was stirred in methyl t-butyl ether (MTBE) at ambient temperature for one hour. The mixture was filtered and the solid was washed with MTBE. The solid was dried in a vacuum oven at 60° C. The product was obtained as a white solid (983 mg, 78.4%). 1H NMR (500 MHz, DMSO-d6) δ ppm 1.79 (s, 3H), 2.84 (dd, 1H), 3.05 (dd, 1H), 4.41 (td, 1H), 7.09-7.33 (m, 6H), 8.20 (d, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:7](=[O:22])[N:8]3[CH2:21][CH2:20][CH2:19][CH:9]3[N:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:11]=2[CH:12]=1.Br[CH2:24]CCCC(Cl)=O>>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7](=[O:22])[N:8]3[CH2:21][CH2:20][CH2:19][CH2:24][CH:9]3[N:10]2[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc2c(c1)N(c1ccccc1)C1CCCN1C2=O
Reactant: O=C(Cl)CCCCBr
Product: COc1ccc2c(c1)N(c1ccccc1)C1CCCCN1C2=O

Procedure:
Following the procedure for 6-methoxy-4-phenyl-2,3,3a,4-tetrahydropyrrolo[2,1-b]quinazolin-9(1H)-one, using 5-bromovaleroyl chloride in place of 4-bromobutyryl chloride, the titled compound was obtained.
Reaction SMILES: [N:1]1([CH2:7][C:8]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]3[O:20][C:19]([C:21]4[CH:22]=[C:23]5[C:27](=[CH:28][CH:29]=4)[C:26](=[N:30][OH:31])[CH2:25][CH2:24]5)=[C:18]([C:32]4[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=4)[CH:17]=3)[CH2:12][CH2:11]2)=[O:9])[CH2:6][CH2:5]O[CH2:3][CH2:2]1.N1CCCC[CH2:39]1>>[N:1]1([CH2:7][C:8]([N:10]2[CH2:11][CH2:12][CH:13]([C:16]3[O:20][C:19]([C:21]4[CH:22]=[C:23]5[C:27](=[CH:28][CH:29]=4)[C:26](=[N:30][OH:31])[CH2:25][CH2:24]5)=[C:18]([C:32]4[CH:33]=[CH:34][N:35]=[CH:36][CH:37]=4)[CH:17]=3)[CH2:14][CH2:15]2)=[O:9])[CH2:6][CH2:5][CH2:39][CH2:3][CH2:2]1
Reactant: O=C(CN1CCOCC1)N1CCC(c2cc(-c3ccncc3)c(-c3ccc4c(c3)CCC4=NO)o2)CC1
Reactant: C1CCNCC1
Product: O=C(CN1CCCCC1)N1CCC(c2cc(-c3ccncc3)c(-c3ccc4c(c3)CCC4=NO)o2)CC1
Yield: 18 %

Procedure:
The title compound (0.03 g, 18%) was prepared from the product of Example 47 Step 1 and piperidine using the method of Example 47 Step 2; MS(ES+) m/e 484 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2[C:15]2[CH:20]=[CH:19][N:18]3[N:21]=[CH:22][C:23]([C:24]([OH:26])=O)=[C:17]3[N:16]=2)[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:60][CH2:61][CH2:62][OH:63]>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([C@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2[C:15]2[CH:20]=[CH:19][N:18]3[N:21]=[CH:22][C:23]([C:24]([NH:60][CH2:61][CH2:62][OH:63])=[O:26])=[C:17]3[N:16]=2)[C:5]([O:8][CH3:9])=[N:6][CH:7]=1
Reactant: COc1ncc(F)cc1[C@H]1CCCN1c1ccn2ncc(C(=O)O)c2n1
Reactant: NCCO
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ncc(F)cc1[C@H]1CCCN1c1ccn2ncc(C(=O)NCCO)c2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84.7 %

Procedure:
To a DMF (1 mL) suspension of (R)-5-(2-(5-fluoro-2-methoxy pyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (Preparation B, 100 mg, 0.28 mmol) and HATU (128 mg, 0.336 mmol) was added DIEA (0.146 mL, 0.840 mmol) at ambient temperature, followed by a solution of 2-aminoethanol (20.5 mg, 0.336 mmol) in minimal amount of DMF dropwise at 0° C. The reaction was warmed up to ambient temperature and stirred for 30 minutes, then directly purified by reverse-phase column chromatography (0 to 70% acetonitrile/water) to yield the product as white solid (95 mg, 85% yield). MS (apci pos) m/z=401.1 (M+H).