Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]([O:14]CC)=[O:13])[CH:6]=[N:5]2.[OH-].[Na+].C(O)C>C(O)(=O)C>[I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]([OH:14])=[O:13])[CH:6]=[N:5]2
Reactant: CCOC(=O)c1cnc2cc(I)ccc2n1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCO
Product: O=C(O)c1cnc2cc(I)ccc2n1
Temperature: 25 °C
Yield: 83.1 %

Procedure:
A solution of compound 9 (1.30 g, 3.96 mmol) in a 2.0 N sodium hydroxide/ethanol solution (1/1, v/v, 6 mL) was refluxed for 30 min. After cooling to room temperature, the reaction mixture was acidified (pH=4-5) with acetic acid and cooled to 0° C. The resulting precipitate was removed by filtration and dried in a vacuum oven to afford acid 23 (1.08 g, 3.29 mmol) as a white solid. Yield 91%; mp 242-244° C.; 1H NMR (200 MHz, DMSO-d6) δ 7.97 (d, 1H, J=8 Hz), 8.15 (d, 1H, J=8 Hz), 8.52 (s, 1H), 9.36 (s, 1H); ESI-MS m/z 298.6 [M−H]−.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Br:13])[N:8]=1.N1C=CC=CC=1>ClCCl>[Br:13][C:9]1[N:8]=[C:7]([NH:6][S:2]([CH3:1])(=[O:4])=[O:3])[CH:12]=[CH:11][CH:10]=1
Reactant: CS(=O)(=O)Cl
Reactant: Nc1cccc(Br)n1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=O)Nc1cccc(Br)n1
Reaction time: 4 h
Yield: 75.2 %

Procedure:
Methanesulphonyl chloride (0.74 g) in dichloromethane (5 ml) was added over 2 min to a stirred solution of 2-amino-6-bromopyridine (1.1 g) and pyridine (0.57 g) in dichloromethane (5 ml). After 4 h, the solvent was evaporated in vacuo to give an oil which was purified by FCC eluting with System A (95:5:1) to give the title compound as a white solid (1.2 g), m.p. 90°-94° C.
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH:16][C:17]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=2[F:27])=[O:18])[CH:11]=[CH:12][C:13]=1[O:14]C.[Cl-].[Al+3].[Cl-].[Cl-].C(OCC)(=O)C>ClCCCl>[Cl:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH:16][C:17]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=2[F:27])=[O:18])[CH:11]=[CH:12][C:13]=1[OH:14]
Reactant: COc1ccc(NC(=O)Nc2ccc(F)cc2F)cc1-c1c(Cl)cnn1C
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: Cn1ncc(Cl)c1-c1cc(NC(=O)Nc2ccc(F)cc2F)ccc1O
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 75 %

Procedure:
A mixture of 1-[3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)urea (Compound 77, example 1.61) (0.270 g, 0.69 mmol) in anhydrous 1,2-dichloroethane (10 mL) was cooled to 0° C. on an ice bath and stirred for 10 minutes. Anhydrous aluminium chloride (0.368 g, 2.76 mmol) was added and the reaction mixture stirred at 0° C. for 20 minutes, then moved to an oil bath and stirred at 80° C. for 1 hour. Ethyl acetate was added and washed with potassium sodium tartrate (10%) twice. Organic layer was separated, dried over anhydrous Na2SO4, filtered and concentrated to give the crude product that was further purified via HPLC. The corresponding fractions were collected and lyophilized to afford Compound 120 as a white solid in 75.0% yield. LCMS m/z (%)=379 (M+H35Cl, 100), 381 (M+H37Cl, 40). 1H NMR (400 MHz. DMSO-d6) δ: 9.81 (s, 1H), 8.92 (s, 1H), 8.45 (s, 1H), 8.12-8.06 (m, 1H), 7.63 (s, 1H), 7.40-7.31 (m, 3H), 7.09-7.04 (m, 1H), 6.99 (d, J1=8.72 Hz, 1H), 3.69 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:13][CH2:12][C@H:11](O)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OC(N=NC(OC(C)(C)C)=O)=O)(C)(C)C.C1(P([N:64]=[N+:65]=[N-:66])(C2C=CC=CC=2)=O)C=CC=CC=1>O1CCCC1.C(OCC)C>[N:64]([C@@H:11]1[CH2:12][CH2:13][C@H:8]([C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=2)[CH2:9][CH2:10]1)=[N+:65]=[N-:66]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: O[C@H]1CC[C@H](c2ccc(Br)cc2)CC1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: [N-]=[N+]=N[C@H]1CC[C@@H](c2ccc(Br)cc2)CC1
Temperature: -5 °C
Reaction time: 0.08 h

Procedure:
(trans)-4-(4-Bromophenyl)cyclohexanol (500 mg) is dissolved under argon in tetrahydrofurane (8 mL) and cooled to −5° C. Triphenylphosphine (770 mg) and di-tert-butyl-azodicarboxylate (550 mg) are added and the mixture is stirred for 5 minutes. A solution of diphenylphosphorylazide (650 μL) in tetrahydrofurane (8 mL) is added dropwise during 2 hours and the mixture is stirred at 0° C. for 48 hours. Then the mixture is diluted with diethylether, washed with saturated aqueous NaHCO3 solution and the organic phase is dried (MgSO4) and concentrated. The residue is chromatographed on silica gel (petrole ether/ethyl acetate 99:1→70:30) to give the title compound. LC (method 4): tR=0.97 min.
Reaction SMILES: [CH:1]([CH:3]1[C:12]2[C:7](=[CH:8][C:9]([C:13]#[N:14])=[CH:10][CH:11]=2)[O:6][CH2:5][CH2:4]1)=O.[N:15]1([CH2:21][CH2:22][C:23]2[CH:32]=[CH:31][C:26]3[C:27](=[O:30])[O:28][CH2:29][C:25]=3[CH:24]=2)[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[O:30]=[C:27]1[C:26]2[CH:31]=[CH:32][C:23]([CH2:22][CH2:21][N:15]3[CH2:20][CH2:19][N:18]([CH2:1][CH:3]4[C:12]5[C:7](=[CH:8][C:9]([C:13]#[N:14])=[CH:10][CH:11]=5)[O:6][CH2:5][CH2:4]4)[CH2:17][CH2:16]3)=[CH:24][C:25]=2[CH2:29][O:28]1
Reactant: N#Cc1ccc2c(c1)OCCC2C=O
Reactant: O=C1OCc2cc(CCN3CCNCC3)ccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: N#Cc1ccc2c(c1)OCCC2CN1CCN(CCc2ccc3c(c2)COC3=O)CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a 12 mL reaction vial was added 4-formyl-3,4-dihydro-2H-chromene-7-carbonitrile (50 mg, 0.27 mmol), 5-[2-(piperazin-1-yl)ethyl]-2-benzofuran-1(3H)-one (66 mg, 0.27 mmol) and dichloromethane (3 mL). The solution was stirred at RT under N2 for 10 min. To above solution was added sodium tris(acetoxy) borohydride (224 mg, 1.1 mmol). The reaction was stirred at RT for 18 hours under N2, extracted with DCM, washed with brine and water. The organic phase was dried over MgSO4, filtered and purified by flash column chromatography. LC-MS (IE, m/z): 418.1 [M+1]+. 1H NMR (500 MHz, CDCl3, δ in ppm): 7.84 (1H, d, J=7.8 Hz), 7.38 (1H, d, J=7.8 Hz), 7.32 (2H, m), 7.11 (1H, dxd, J=8.0 Hz, J=1.6 Hz), 7.08 (1H, d, J=1.6 Hz), 5.60 (2H, s), 4.4 (2H, m), 3.0 (4H, m), 2.4-2.8 (10H, m), 2.0 (2H, m). (0.092 μM)
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1.[S-:14][C:15]#[N:16].[K+].[CH2:18]([O:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[CH:36]=[C:35]([NH2:37])[NH:34][N:33]=2)=[C:28]([F:38])[CH:27]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(#N)C>[CH2:18]([O:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[CH:36]=[C:35]([NH:37][C:15]([NH:16][C:7](=[O:8])[C:6]3[CH:10]=[CH:11][C:3]([C:2]([F:13])([F:12])[F:1])=[CH:4][CH:5]=3)=[S:14])[NH:34][N:33]=2)=[C:28]([F:38])[CH:27]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: Nc1cc(-c2ccc(OCc3ccccc3)cc2F)n[nH]1
Reactant: N#C[S-]
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Agent: [K+]
Solvent: CC#N
Product: O=C(NC(=S)Nc1cc(-c2ccc(OCc3ccccc3)cc2F)n[nH]1)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81 %

Procedure:
4-Trifluoromethylbenzoyl chloride (590 mg, 2.83 mmol) was dissolved in acetonitrile (˜30 mL) and potassium thiocyanate (302 mg, 3.22 mmol) was added to provide a reaction mixture. The reaction mixture was stirred at room temperature for 30 minutes, and then 3-(4-benzyloxy-2-fluoro-phenyl)-1H-pyrazol-5-amine (801 mg, 2.83 mmol) was added to the reaction mixture. Next, the reaction mixture was stirred at room temperature overnight, then concentrated in vacuo, slurried with water, and collected by filtration. The wet solid was held under heated vacuum for 24 hours to provide the title compound in 81% yield.
Reaction SMILES: [CH:1]1([NH:7][C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([OH:16])=O)[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[C:20]([CH3:25])[C:19]=1[CH3:26]>ClCCl>[CH:1]1([NH:7][C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([OH:24])=[C:20]([CH3:25])[C:19]=3[CH3:26])=[O:16])[CH:9]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Cc1c(N)ccc(O)c1C
Reactant: O=C(O)c1cc(NC2CCCCC2)ncn1
Solvent: ClCCl
Product: Cc1c(O)ccc(NC(=O)c2cc(NC3CCCCC3)ncn2)c1C

Procedure:
Following the general method as outlined in Example 1, starting from 6-(cyclohexylamino)pyrimidine-4-carboxylic acid (Intermediate 4) and 4-amino-2,3-xylenol (TCI), the title compound was obtained as a white solid after trituration in dichloromethane. 1H NMR (300MHz, DMSO-d6) δ [ppm] 9.91 (1H, s), 9.20 (1H, s), 8.50 (1H, s), 7.73 (1H, d, J=8.0 Hz), 7.18 (1H, d, J=8.5 Hz), 7.12 (1H, s), 6.65 (1H, d, J=8.5 Hz), 3.87 (1H, m), 2.07 (3H, s), 2.06 (3H, s), 1.91-1.61 (5H, m), 1.56-1.15 (5H, m). MS (ESI): 341.1. HPLC (Condition A): Rt 3.02 min (HPLC purity 77.8%).
Reaction SMILES: [Na].[NH2:2][C:3]1[N:8]([NH2:9])[C:7](=[O:10])[CH:6]=[C:5]([CH3:11])[N:4]=1.[F:12][C:13]([F:21])([CH2:19][CH3:20])[C:14](OCC)=O.Cl>O1CCOCC1.C(O)C>[F:12][C:13]([C:14]1[N:2]=[C:3]2[N:4]=[C:5]([CH3:11])[CH:6]=[C:7]([OH:10])[N:8]2[N:9]=1)([F:21])[CH2:19][CH3:20]
Reactant: Cc1cc(=O)n(N)c(N)n1
Reactant: CCOC(=O)C(F)(F)CC
Agent: Cl
Agent: [Na]
Solvent: C1COCCO1
Solvent: CCO
Product: CCC(F)(F)c1nc2nc(C)cc(O)n2n1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
To a solution of NaEtO prepared from sodium (FLUKA, 0.152 g, 6.62 mmol) and ethanol (25 mL), Intermediate 1 (0.773 g, 5.52 mmol) was added, and the mixture was heated at 80° C. for 30 min. Then, the reaction was cooled down to room temperature and ethyl 2,2-difluorobutanoate (FLUOROCHEM, 1007 mg, 6.62 mmol) was added and the reaction mixture was stirred at 80° C. for 3 h. A solution of HCl (1.655 mL, 6.62 mmol) in dioxane was added and a white solid was formed. The residue was purified (silica gel column, eluting with DCM:MeOH mixtures from 100:0 to 90:10%) to obtain Intermediate 6 as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:10]2[CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][CH2:11]2)[CH:5]=[C:6]([CH:8]=O)[CH:7]=1.[NH2:23][C:24]1[CH:32]=[C:31]([O:33][CH3:34])[CH:30]=[C:29]([O:35][CH3:36])[C:25]=1[C:26]([NH2:28])=[O:27].CC1C=CC(S(O)(=O)=O)=CC=1.OS([O-])=O.[Na+].FC(F)(F)C(O)=O>CC(N(C)C)=O>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[NH:28][C:26](=[O:27])[C:25]3[C:24](=[CH:32][C:31]([O:33][CH3:34])=[CH:30][C:29]=3[O:35][CH3:36])[N:23]=2)[CH:5]=[C:4]([N:10]2[CH2:11][CH2:12][NH:13][CH2:14][CH2:15]2)[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc(Cl)cc(C=O)c2)CC1
Reactant: COc1cc(N)c(C(N)=O)c(OC)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(OC)c2c(=O)[nH]c(-c3cc(Cl)cc(N4CCNCC4)c3)nc2c1
Temperature: 110 °C
Yield: 29.3 %

Procedure:
A solution of tert-butyl 4-(3-chloro-5-formylphenyl)piperazine-1-carboxylate (3, 0.300 g, 0.918 mmol) and 2-amino-4,6-dimethoxybenzamide (4, 0.120 g, 0.612 mmol) in DMA (4 mL) was treated with p-TsOH (0.424 g, 1.46 mmol) and NaHSO3 (0.290 g, 1.84 mmol) and then heated at 110° C. for 16 h. The reaction mixture was cooled to room temperature, trifluoroacetic acid (5 mL) was added and the mixture was heated at 70° C. for 1 h. The reaction mixture was cooled to room temperature and concentrated. The residue was purified by silica gel chromatography eluting with 0-100% 92:7:1 CHCl3/MeOH/concentrated NH4OH in CH2Cl2. This material was further purified by reverse phase HPLC eluting with 10% to 90% CH3CN in H2O with 0.1% TFA. The product fractions were concentrated and the residue was dissolved in acetonitrile and water. The mixture was basified with concentrated NH4OH and the precipitate filtered, washed with water, and dried under vacuum to afford the title compound (0.072 g, 29%) as an off-white solid: 1H NMR (500 MHz, DMSO-d6) δ 7.60-7.70 (m, 2H), 7.08-7.12 (m, 1H), 6.78 (d, J=2.3 Hz, 1H), 6.55 (d, J=2.3 Hz, 1H), 3.89 (s, 3H), 3.85 (s, 3H), 3.24 (t, J=5.2 Hz, 4H), 3.28 (t, J=5.2 Hz, 4H); ESI MS m/z 401 [M+H]+.
Reaction SMILES: C[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][N:8]=2)[N:3]=1.C1C(=O)N(Cl)C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.CCOC(C)=O.[C:44]([Cl:48])(Cl)(Cl)[Cl:45]>>[Cl:45][CH:44]([Cl:48])[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][N:8]=2)[N:3]=1
Reactant: Cc1ccc2ncccc2n1
Reactant: ClC(Cl)(Cl)Cl
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: O=C1CCC(=O)N1Cl
Solvent: CCOC(C)=O
Product: ClC(Cl)c1ccc2ncccc2n1

Procedure:
A mixture of 2-methyl-1,5-naphthyridine (CAS#7675-32-3, Synchem-OHG #CDP146FP1, 998 mg, 6.92 mmol), NCS (1109 mg, 8.31 mmol), and benzoyl peroxide (84 mg, 0.347 mmol) in CCl4 (34 mL) was stirred at reflux for 17 h. The reaction mixture was checked by TLC (100% EtOAc). Volatiles were removed under reduced pressure and the residue was partitioned between EtOAc and saturated aqueous sodium bicarbonate. The organic layer was washed with brine, dried (MgSO4), and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography on an Analogix IF-280 (Agilent SF15-24 g, 7:3 to 3:7 hexane/EtOAc). Fractions #7-8 were combined and concentrated under reduced pressure to give the undesired byproduct, 2-(dichloromethyl)-1,5-naphthyridine, as an off-white solid (113 mg, 7.7% yield). Fractions #12-18 were combined and concentrated under reduced pressure to give the desired 2-(chloromethyl)-1,5-naphthyridine as an off-white solid (472 mg, 38.2%). 1H NMR (300 MHz, CDCl3) δ 8.99 (dd, J=4.2, 1.6, 1H), 8.45 (d, J=8.8, 1H), 8.38 (ddd, J=8.5, 1.5, 0.8, 1H), 7.85 (d, J=8.7, 1H), 7.66 (dd, J=8.6, 4.2, 1H), 4.86 (s, 2H). MS (DCI—NH3) m/z=179 (M+H)+, m/z=196 (M+NH4)+, m/z=213 (M+NH4+NH3)+.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.C([Li])CCC.[N:11]1[O:12][CH2:13][CH:14]2[CH2:18][N:17]([C:19]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[O:20])[CH2:16][C:15]=12>O1CCCC1>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:15]12[CH2:16][N:17]([C:19]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[O:20])[CH2:18][CH:14]1[CH2:13][O:12][NH:11]2
Reactant: O=C(OCc1ccccc1)N1CC2=NOCC2C1
Reactant: c1ccsc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)N1CC2CONC2(c2cccs2)C1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 65.9 %

Procedure:
A −78° C. solution of thiophene (17 g, 203 mmol) in tetrahydrofuran (250 mL) under nitrogen is treated drop wise with a solution of n-butyl lithium (81 mL, 203 mmol, 1.6 M in hexanes) and the reaction is stirred at −78° C. for 10 minutes. In a separate flask, a −78° C. solution of benzyl 3,3a,4,6-tetrahydropyrrolo[3,4-c]isoxazole-5-carboxylate (25 g, 101 mmol) in tetrahydrofuran (500 mL) under nitrogen is treated with boron trifluoride ether complex (19 mL, 152 mmol) and the mixture is stirred for 10 minutes. The solution is added by cannula to the organolithium solution generated above at −78° C. and the resulting mixture is stirred for 1 hour at −78° C. The reaction is quenched with saturated ammonium chloride and warmed to room temperature. The aqueous layer is separated, the organic layer is dried over magnesium sulfate and the solvent is removed under vacuum. The crude product is purified over silica gel using a 5 to 50% gradient of ethyl acetate/hexanes gradient to give the title compound (22 g, 65%). ES/MS (m/e): 331 (M+H).
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][CH2:9][N:8](C(OC(C)(C)C)=O)[CH2:7]2)[CH:5]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:4][N:3]1[CH2:25][C:26]([F:29])([F:28])[F:27].[ClH:30].O1CCOCC1>C(Cl)Cl>[ClH:30].[C:19]1([CH:5]2[C:6]3([CH2:11][CH2:10][CH2:9][NH:8][CH2:7]3)[C:2](=[O:1])[N:3]([CH2:25][C:26]([F:28])([F:29])[F:27])[CH2:4]2)[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CC(C)(C)OC(=O)N1CCCC2(C1)C(=O)N(CC(F)(F)F)CC2c1ccccc1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: O=C1N(CC(F)(F)F)CC(c2ccccc2)C12CCCNC2
Temperature: 25 °C
Reaction time: 9 h

Procedure:
Tert-butyl 1-oxo-4-phenyl-2-(2,2,2-trifluoroethyl)-2,7-diazaspiro[4.5]decane-7-carboxylate (0.874 g, 2.119 mmol) in DCM (10 ml) was treated with 4M HCl in 1,4-dioxane (4.5 ml, 0.018 mmol). The reaction mixture was stirred at room temperature for 9 hours. The solvent was removed in vacuo to give the title compound.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([C:17]1[N:18]=[C:19]([CH3:48])[N:20]([CH2:39][C:40]2[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][CH:41]=2)[C:21](=[O:38])[C:22]=1[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[C:31]([C:36]#[N:37])=[CH:32][CH:33]=[CH:34][CH:35]=2)=[CH:26][CH:25]=1)[CH2:14][CH2:15][CH3:16]>C(OCC)(=O)C>[CH2:13]([C:17]1[N:18]=[C:19]([CH3:48])[N:20]([CH2:39][C:40]2[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][CH:41]=2)[C:21](=[O:38])[C:22]=1[CH2:23][C:24]1[CH:25]=[CH:26][C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:36]2[NH:3][C:4](=[O:7])[O:5][N:37]=2)=[CH:28][CH:29]=1)[CH2:14][CH2:15][CH3:16]
Reactant: [NH3+]O
Reactant: CCCCc1nc(C)n(Cc2ccc(OC)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCCCc1nc(C)n(Cc2ccc(OC)cc2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 54.7 %

Procedure:
A mixture of hydroxylammonium chloride (1.81 g), sodium hydrogen carbonate (2.92 g) and dimethyl sulfoxide (15 mL) was stirred at 40° C. for 30 min, 4′-{[4-butyl-1-(4-methoxybenzyl)-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (0.83 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (20 mL), N,N′-carbonyldiimidazole (0.34 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.29 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.51 g, 54%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([B:9]2[O:13][C:12]([CH3:15])([CH3:14])[C:11]([CH3:17])([CH3:16])[O:10]2)[CH:6]=[CH:5][C:4]=1[NH:18]C(=O)OC(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([B:9]2[O:13][C:12]([CH3:15])([CH3:14])[C:11]([CH3:17])([CH3:16])[O:10]2)[CH:6]=[CH:5][C:4]=1[NH2:18]
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1N
Temperature: 5 °C
Reaction time: 2 h
Yield: 67.5 %

Procedure:
A mixture of tert-butyl N-[2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]carbamate (45.0 g, 0.129 mol) was dissolved in dichloromethane (270 mL) then the solution was cooled to 5° C. in and ice bath. A mixture of 20% trifluoroacetic acid in dichloromethane was added dropwise over the course of one hour while maintaining the temperature of the mixture at <5° C. The reaction mixture was warmed to ambient temperature and stirred for 2 hours. The solvents were removed under reduced pressure then the resulting oil was dissolved in dichloromethane (250 mL) and cautiously extracted with 2.5 N aqueous sodium hydroxide (300 mL) then brine (100 mL). The organic solution was dried over magnesium sulfate, filtered and the fitrate concentrated under reduced pressure to give 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (21.7 g, 67.5%) as a light brown solid bismaleate: 1H NMR (DMSO-d6, 400 MHz) δ 7.06 (d, 1H), 6.98 (s, 1H), 8.09 (d, 1H), 6.59 (d, 1H), 5.13 (bs, 2H), 3.76 (s, 3H), 1.26 (s, 12H); RP-HPLC (Hypersil HS C18 Hypersil HS C18, 5 μm, 100A, 250×4.6 mm; 25%-100% acetonitrile-0.05 M ammonium acetate over 10 min, 1 mL/min) tr 10.85 min.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]([NH:12][C@H:13]1[C@@H:19]([OH:20])[C@H:18]([OH:21])[C@@H:17]([CH2:22][OH:23])[O:16][CH:14]1[OH:15])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O[C:28](=[O:30])[CH3:29])(=O)C>N1C=CC=CC=1.CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:1]([O:15][CH:14]1[O:16][C@H:17]([CH2:22][O:23][C:28](=[O:30])[CH3:29])[C@@H:18]([O:21][C:14](=[O:15])[CH3:13])[C@H:19]([O:20][C:10](=[O:11])[CH3:9])[C@@H:13]1[NH:12][C:10](=[O:11])[CH2:9][O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:8])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(COCc1ccccc1)N[C@@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)OC[C@H]1OC(OC(C)=O)[C@@H](NC(=O)COCc2ccccc2)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 192.8 %

Procedure:
A solution of 31 (512 mg, 1.56 mmol) in pyridine (5 mL) was cooled to 0° C. To this solution was added acetic anhydride (2.5 mL, 27 mmol) and a catalytic amount of DMAP. The reaction mixture was stirred overnight and allowed to warm to rt. The resulting light yellow solution was diluted with CH2Cl2 (100 mL) and washed with 1 N HCl (3×50 mL), sat. NaHCO3 (2×50 mL), water (2×50 mL) and sat. NaCl (1×50 mL). The combined aqueous layers were back extracted with 50 mL of CH2Cl2. The combined organic layers were dried over Na2SO4 and concentrated. The crude product was purified by silica gel chromatography eluting with a gradient of 1:4 to 1:1 EtOAc/hexanes to afford 745 mg (96%) of a light yellow oil. IR (thin film): 3409, 2959, 2357, 1750, 1692, 1520 cm−1. 1H NMR (300 MHz, CDCl3): δ 1.90 (s, 6H), 1.99 (s, 6H), 2.06 (s, 6H), 2.18 (s, 6H), 3.79-3.84 (m, 1H), 3.91-3.99 (m, 1H), 4.02 (d, 2H, J=2.8), 4.04-4.07 (m, 2H), 4.14 (dd, 2H, J=2.7, 17.8), 4.20 (dd, 1H, J=3.9, 9.1), 4.55 (app t, 1H, J=6.3), 4.60-4.65 (m, 4H), 4.66-4.68 (m, 1H), 4.79 (ddd, 1H, J=1.6, 3.8, 13.2), 5.07 (dd, 1H, J=3.9, 9.8), 5.19 (app t, 1H, J=4.7), 5.24 (app t, 1H, J=9.8), 5.35 (dd, 1H, J=4.2, 10.2), 5.90 (d, 1H, J=1.6), 6.03 (d, 1H, J=1.6), 6.89 (d, 1H, J=9.6), 7.03 (d, 1H, J=9.3), 7.32-7.39 (m, 10H). 13C NMR (125 MHz, CDCl3): δ 20.3, 20.4, 20.6, 20.7, 20.8, 48.6, 61.7, 65.1, 65.2, 68.9, 69.1, 69.3, 70.2, 71.3, 73.3, 73.5, 73.6, 77.8, 97.1, 127.8, 127.9, 128.2, 128.3, 128.4, 128.6, 128.7, 136.4, 136.6, 169.4, 169.7, 170.1, 170.5. MS (FAB) m/z 496 (MH+). Anal. Calcd for C23H29NO11: C, 55.75; H, 5.90; N, 2.83. Found: C, 55.54; H, 5.93; N, 2.68.
Reaction SMILES: C[O:2][C:3](=[O:32])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][NH:9][C:10]1[C:11]2[C:18]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)=[C:17]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[O:16][C:12]=2[N:13]=[CH:14][N:15]=1.[OH-].[Na+].Cl>CO.C1COCC1.O>[CH3:25][C:22]1[CH:21]=[CH:20][C:19]([C:18]2[C:11]3[C:10]([NH:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]([OH:32])=[O:2])=[N:15][CH:14]=[N:13][C:12]=3[O:16][C:17]=2[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[CH:24][CH:23]=1
Reactant: COC(=O)CCCCCNc1ncnc2oc(-c3ccccc3)c(-c3ccc(C)cc3)c12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(-c2c(-c3ccccc3)oc3ncnc(NCCCCCC(=O)O)c23)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Dissolve 30 mg (0.07 mmol) 6-{[5-(4-methylphenyl)-6-phenylfuro[2,3-d]pyrimidin-4-yl]amino}-hexanoic acid methyl ester in 0.1 ml methanol, 0.05 ml THF and one drop of water, and add 0.1 ml of 2.5 M sodium hydroxide solution. Stir the mixture for 1 h at RT and then lightly acidify with 1 N hydrochloric acid. Filter off the precipitate with suction, wash several times with water, and dry at high vacuum. 28 mg (96.5% of theor.) of the target compound is obtained.