Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:3]2[C:11]([I:12])=[CH:10][N:9]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[C:4]=2[N:5]=[C:6]([CH3:8])[N:7]=1.C[C@@H:22]1[O:27][CH2:26][CH2:25][N:24](C2C3C(C4C=C(C=CC=4)C#N)=CNC=3N=CN=2)[CH2:23]1>>[I:12][C:11]1[C:3]2[C:2]([N:24]3[CH2:25][CH2:26][O:27][CH2:22][CH2:23]3)=[N:7][C:6]([CH3:8])=[N:5][C:4]=2[N:9]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[CH:10]=1
Reactant: Cc1nc(Cl)c2c(I)cn(COCC[Si](C)(C)C)c2n1
Reactant: C[C@H]1CN(c2ncnc3[nH]cc(-c4cccc(C#N)c4)c23)CCO1
Product: Cc1nc(N2CCOCC2)c2c(I)cn(COCC[Si](C)(C)C)c2n1

Procedure:
The product was prepared from 4-chloro-5-iodo-2-methyl-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine (C23) according to the method described for synthesis of 3-{4-[(2S)-2-methylmorpholin-4-yl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}benzonitrile (6) in Example 6. In this case, purification was carried out via silica gel chromatography (Gradient: 0% to 50% ethyl acetate in petroleum ether) to provide the product as a yellow oil. Yield: 300 mg, 0.63 mmol, 67%. LCMS m/z 475.2 [M+H+].
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[C:9]([CH3:10])=[C:8]([CH3:11])[S:7][C:6]1=[NH:12].CCN(CC)CC.[F:20][C:21]1([F:33])[O:25][C:24]2[CH:26]=[CH:27][CH:28]=[C:29]([C:30](Cl)=[O:31])[C:23]=2[O:22]1>C1COCC1.CCOC(C)=O>[F:33][C:21]1([F:20])[O:25][C:24]2[CH:26]=[CH:27][CH:28]=[C:29]([C:30](/[N:12]=[C:6]3\[S:7][C:8]([CH3:11])=[C:9]([CH3:10])[N:5]\3[CH2:4][CH2:3][O:2][CH3:1])=[O:31])[C:23]=2[O:22]1
Reactant: COCCn1c(C)c(C)sc1=N
Reactant: O=C(Cl)c1cccc2c1OC(F)(F)O2
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COCCn1c(C)c(C)s/c1=N\C(=O)c1cccc2c1OC(F)(F)O2
Temperature: 25 °C
Reaction time: 17 h
Yield: 53.6 %

Procedure:
To the product of Example 126A (0.20 g, 1.1 mmol) in 30 mL THF was added Et3N (0.37 mL, 2.7 mmol) followed by 2,2-difluoro-1,3-benzodioxole-4-carbonyl chloride (Lancaster, 0.29 g, 1.3 mmol). This mixture was stirred at ambient temperature for 17 hours then was warmed to reflux and allowed to stir for an additional 4 hours. The mixture was then cooled to ambient temperature and additional 2,2-difluoro-1,3-benzodioxole-4-carbonyl chloride (73 mg, 0.33 mmol) and Et3N (0.37 mL, 2.7 mmol) were added. This mixture was warmed to reflux at which temperature it stirred for 2 hours. The mixture was then cooled to ambient temperature, diluted with 10 mL EtOAc and washed with 5 mL saturated, aqueous NH4Cl. The layers were separated and the aqueous layer was extracted 2×5 mL EtOAc. The combined organics were dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure and purified via flash column chromatography (SiO2, 50% hexanes:EtOAc) to afford the title compound (0.22 g, 0.59 mmol, 55% yield). 1H NMR (300 MHz, CDCl3) δ ppm 2.26 (s, 3H), 2.28 (s, 3H), 3.32 (s, 3H), 3.83 (t, J=5.1 Hz, 2H), 4.44 (t, J=5.1 Hz, 2H), 7.12 (d, J=4.4 Hz, 1H), 7.14 (s, 1H), 7.89 (dd, J=6.6, 2.9 Hz, 1H); MS (DCI/NH3) m/z 371 (M+H)+; Anal. calculated for C16H16F2N2O4S: C, 51.89; H, 4.35; N, 7.56. Found: C, 52.27; H, 4.24; N, 7.53.
Reaction SMILES: [OH:1][Si:2]1([CH2:8][CH2:9][CH2:10][CH2:11][C:12]([O:14]CC2C=CC=CC=2)=[O:13])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1>C(O)C.[Pd]>[OH:1][Si:2]1([CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: O=C(CCCC[Si]1(O)CCCCC1)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: O=C(O)CCCC[Si]1(O)CCCCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 96.7 %

Procedure:
To benzyl 5-(1-hydroxysilinan-1-yl)pentanoate (205 mg, 0.669 mmol) in ethanol (6 mL), palladium on activated carbon (10%, wet, 41 mg) was added. The reaction was stirred under hydrogen (1 atm) at room temperature for 16 hours. After this time, the reaction was filtered through Celite® and the filter cake washed with methanol. The filtrate was concentrated under reduced pressure to afford 5-(1-hydroxysilinan-1-yl)pentanoic acid (140 mg, 97%) as a colorless oil. 1H NMR (500 MHz, CDCl3) δ Exchangeable protons not observed (2H), 2.38-2.32 (m, 2H), 1.78-1.61 (m, 6H), 1.48-1.31 (m, 4H), 0.80-0.54 (m, 6H); ESI MS m/z=215 [M−H]−.
Reaction SMILES: C(OC(COC(=O)C)C[NH:7][C:8]([C:10]1[C:15]([I:16])=[C:14](N2[C@H](CO)COC2=O)[C:13]([I:25])=[C:12]([C:26]([NH:28]CC(OC(=O)C)COC(=O)C)=[O:27])[C:11]=1[I:40])=[O:9])(=O)C.C[O-].[Na+]>CO.O>[I:40][C:11]1[C:12]([C:26]([NH2:28])=[O:27])=[C:13]([I:25])[CH:14]=[C:15]([I:16])[C:10]=1[C:8]([NH2:7])=[O:9]
Reactant: CC(=O)OCC(CNC(=O)c1c(I)c(C(=O)NCC(COC(C)=O)OC(C)=O)c(I)c(N2C(=O)OC[C@H]2CO)c1I)OC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: NC(=O)c1c(I)cc(I)c(C(N)=O)c1I
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.6 %

Procedure:
To a solution of N,N'-Bis[2,3-bis(acetyloxy)propyl]-5-(4)-(R)-(hydroxymethyl)-2-oxo-3-oxazolidinyl]-2,4,6-triiodo-1,3-benzenedicarboxamide of Example 2b (0.410 g, 0.51 mmol) in anhydrous methanol (7 ml) was added a methanolic solution of sodium methoxide (1.18 ml, 1M solution) and the mixture was stirred at room temperature for 1 h. The methanol was then removed on the rotary evaporator and water (8 ml) was added to redissolve the white residue. Dowex-50 (H+) was added to this solution portionwise to bring the pH down to approximately 7.0. The Dowex 50 resin was filtered off, water was removed on the rotary evaporator, and the white solid dried in vacuo at 60° over P2O5. The solid thus obtained (0.350 g) was redissolved in water (0.5 ml), seeded with a tiny crystal of the racemate and left overnight. The crystallized product was filtered, washed with cold water and dried overnight over P2O5 to obtain N,N'-Bis[2,3-bis(acetyloxy)propyl]-5-(4)-(R)-(hydroxymethyl)-2-oxo-3-oxazolidinyl]-2,4,6-triiodo-1,3-benzenedicarboxamide as white crystalline needles (0.22 g, 84%).
Reaction SMILES: [CH2:1]([O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][OH:16])[CH:2]=[CH2:3].[H-].[Na+].[Si:19]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][C:31]([CH2:34]I)=[CH:30][CH:29]=1)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]>C1COCC1>[Si:19]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][C:31]([CH2:34][O:16][CH2:15][CH2:14][O:13][CH2:12][CH2:11][O:10][CH2:9][CH2:8][O:7][CH2:6][CH2:5][O:4][CH2:1][CH:2]=[CH2:3])=[CH:30][CH:29]=1)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]
Reactant: CC(C)(C)[Si](C)(C)OCc1ccc(CI)cc1
Reactant: C=CCOCCOCCOCCOCCO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCOCCOCCOCCOCCOCc1ccc(CO[Si](C)(C)C(C)(C)C)cc1
Reaction time: 0.5 h
Yield: 50.7 %

Procedure:
To a solution of 11-allyloxy-3,6,9-trioxaundecanol (83, 2.33 g, 9.94 mmol) in dry THF (40 mL), sodium hydride (0.95 g, 39.8 mmol) is added in several portions under an argon atmosphere. The mixture is stirred for 30 min. A solution of the iodo derivative 45 (3.0 g, 8.28 mmol) in dry THF (10 mL) is added dropwise, and the mixture stirred for 15 h. The reaction is quenched by adding 2 mL of water, and 70% of the amount of THF is evaporated in vacuo. To dilute the mixture, 70 mL of water are added, and the solution extracted with 5 times 50 mL ethyl acetate. The combined organic extracts are dried over MgSO4 and concentrated in vacuo. The yellow oil obtained is purified by flash column chromatography (gradient petrol ether/ethyl acetate 10:1 to 5:1) to give the title product 84 as a pale yellow oil (1.96 g, 4.2 mmol, 51%).
Reaction SMILES: [CH2:1]([C:4]1[C:5]([CH3:16])=[N:6][O:7][C:8]=1[C:9]1[CH:14]=[CH:13][C:12](Br)=[CH:11][CH:10]=1)[CH:2]=[CH2:3].[CH2:17]([O:19][C:20]([C:22]1([C:25]2[CH:30]=[CH:29][C:28](B3OC(C)(C)C(C)(C)O3)=[CH:27][CH:26]=2)[CH2:24][CH2:23]1)=[O:21])[CH3:18]>>[CH2:17]([O:19][C:20]([C:22]1([C:25]2[CH:30]=[CH:29][C:28]([C:12]3[CH:13]=[CH:14][C:9]([C:8]4[O:7][N:6]=[C:5]([CH3:16])[C:4]=4[CH2:1][CH:2]=[CH2:3])=[CH:10][CH:11]=3)=[CH:27][CH:26]=2)[CH2:23][CH2:24]1)=[O:21])[CH3:18]
Reactant: C=CCc1c(C)noc1-c1ccc(Br)cc1
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Product: C=CCc1c(C)noc1-c1ccc(-c2ccc(C3(C(=O)OCC)CC3)cc2)cc1

Procedure:
Prepared according to the procedure described in Example 110, Step 3, using 4-allyl-5-(4-bromo-phenyl)-3-methyl-isoxazole and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Cl:20])[C:9]=1[C:10]1[N:14]2[CH:15]=[C:16]([F:19])[CH:17]=[CH:18][C:13]2=[N:12][N:11]=1)[CH:5]=O.[CH3:21][N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(=O)(O)[O-].[Na+]>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:5][N:25]2[CH2:26][CH2:27][N:22]([CH3:21])[CH2:23][CH2:24]2)[CH:7]=[C:8]([Cl:20])[C:9]=1[C:10]1[N:14]2[CH:15]=[C:16]([F:19])[CH:17]=[CH:18][C:13]2=[N:12][N:11]=1
Reactant: CN1CCNCC1
Reactant: O=Cc1cc(Cl)c(-c2nnc3ccc(F)cn23)c(Cl)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: CN1CCN(Cc2cc(Cl)c(-c3nnc4ccc(F)cn34)c(Cl)c2)CC1
Reaction time: 5 h
Yield: 57.8 %

Procedure:
A cloudy solution of Intermediate 13c (0.66 g, 1.80 mmol) in DCE (18 mL) was treated with 1-methylpiperazine (0.22 mL, 2.00 mmol) then sodium triacetoxyborohydride (0.58 g, 2.70 mmol), and the solution was stirred at ambient temperature overnight. The mixture was treated with another portion of 1-methylpiperazine (0.22 mL, 2.00 mmol) and sodium triacetoxyborohydride (0.58 g, 2.70 mmol), and stirred for 5 h. The mixture was cautiously diluted with a saturated aqueous sodium bicarbonate solution and the layers were separated. The aqueous layer was then extracted with DCM (2×). The combined organic layers were washed with a saturated aqueous sodium bicarbonate solution and brine, dried (Na2SO4), filtered and evaporated in vacuo. The residue was dissolved in DCM and purified by FCC, using 0-8% [2M NH3 in MeOH] in DCM, to give the title compound (0.41 g, 57%). LCMS (Method 3): Rt 2.11 min, m/z 394, 396 [MH+].
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([NH:9][C:10]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[C:18]([O:22]C)=[N:17][N:16]=[C:15]3[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=2)=[O:11])[CH:6]=[CH:7][CH:8]=1.Br>O1CCOCC1>[F:30][C:2]([F:1])([F:31])[C:3]1[CH:4]=[C:5]([NH:9][C:10]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[C:18]([OH:22])=[N:17][N:16]=[C:15]3[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=2)=[O:11])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1nnc(-c2ccccn2)c2cc(C(=O)Nc3cccc(C(F)(F)F)c3)ccc12
Agent: Br
Solvent: C1COCCO1
Product: O=C(Nc1cccc(C(F)(F)F)c1)c1ccc2c(O)nnc(-c3ccccn3)c2c1
Temperature: 40 °C
Reaction time: 1.5 h
Yield: 101.8 %

Procedure:
A mixture of 1-methoxy-4-pyridin-2-yl-phthalazine-6-carboxylic acid (3-trifluoromethyl-phenyl)-amide (57 mg, 0.134 mmol), dioxane (3 mL) and 48% HBr (4 mL) was stirred at 40° C. for 1.5 hours. Concentration followed by chromatography (Hex/EtOAc) afforded 1-hydroxy-4-pyridin-2-yl-phthalazine-6-carboxylic acid (3-trifluoromethyl-phenyl)-amide (56 mg) as a white solid, 1H NMR (400 MHz, 4:1 CDCl3:d6-DMSO) δ: 7.27 (d, 1H), 7.36-7.44 (m, 2H), 7.90-7.95 (m, 2H), 8.05 (s, 1H), 8.21 (s, 1H), 8.33 (dd, 1H), 8.47 (d, 1H), 8.65 (dd, 1H), 8.81 (d, 1H), 10.50 (s, 1H), 12.80 (s, 1H) ppm. m/z 410.96.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Br:23])[C:10]=1[O:11][C:12]1[CH:17]=[CH:16][C:15]([O:18]C)=[C:14]([CH:20]([CH3:22])[CH3:21])[CH:13]=1)[C:5](O)=[O:6].[NH2:24][C:25]1[CH:30]=[CH:29][C:28]([S:31]([NH2:34])(=[O:33])=[O:32])=[CH:27][CH:26]=1>>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Br:23])[C:10]=1[O:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([CH:20]([CH3:21])[CH3:22])[CH:13]=1)[C:5]([C:29]1[CH:30]=[C:25]([NH2:24])[CH:26]=[CH:27][C:28]=1[S:31]([NH2:34])(=[O:33])=[O:32])=[O:6]
Reactant: COc1ccc(Oc2c(Br)cc(C(=O)O)cc2Br)cc1C(C)C
Reactant: Nc1ccc(S(N)(=O)=O)cc1
Product: CC(C)c1cc(Oc2c(Br)cc(C(=O)c3cc(N)ccc3S(N)(=O)=O)cc2Br)ccc1O
Yield: 34.2 %

Procedure:
3,5-Dibromo-4-(4-methoxy-3-isopropylphenoxy)benzoic acid (0.035 mmol) was coupled with 4-aminobenzenesulphonamide (0.175 mmol) using the method described in Example 58. Purification on HPLC of the residue gave 7 mg (34%) of the title compound.
Reaction SMILES: [NH2:1][C@@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=2)[C:4]([CH3:15])([CH3:14])[C@H:3]1[OH:16].[C:17]1([N:23]=[C:24]=[O:25])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(O)C>[OH:16][C@@H:3]1[C:4]([CH3:14])([CH3:15])[C:5]2[C:10](=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=2)[C@H:2]1[NH:1][C:24]([NH:23][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:25]
Reactant: O=C=Nc1ccccc1
Reactant: CC1(C)c2ccc([N+](=O)[O-])cc2[C@@H](N)[C@@H]1O
Solvent: CCO
Product: CC1(C)c2ccc([N+](=O)[O-])cc2[C@@H](NC(=O)Nc2ccccc2)[C@@H]1O
Temperature: 25 °C
Yield: 71.3 %

Procedure:
To a solution of trans-3-amino-1,1-dimethyl-2-hydroxy-5-nitro indane (0.75 g, 3.37 mmoles, as prepared in part H of Example 1) in refluxing ethanol (6 ml) was added phenyl isocyanate (0.40 g, 3.37 mmoles). The reaction mixture was heated at reflux for 3 hours and cooled to room temperature. The product, which had precipitated from solution, was collected via suction filtration and washed with isopropyl ether. In this manner 0.82 g of the title compound was obtained as a white solid, m.p. 194°-195° C. 1H NMR (DMSO-d6) δ 8.66 (s, 1H), 8.16 (d, J=8.79 Hz, 1H), 7.94 (s, 1H), 7.51 (m, 3H), 7.28 (m, 2H), 6.95 (m, 1H), 6.73 (d, J=7.62 Hz, 1H), 5.67 (d, J=5.28 Hz, 1H), 5.00 (t, J=8.21 Hz, 1H), 3.86 (dd, J=5.86 and 8.79 Hz, 1H), 1.36 (s, 3H), 1.09 (s, 3H). 13C NMR (DMSO-d6) δ 156.53, 155.75, 146.91, 142.36, 140.26, 128.74, 123.96, 123.47, 121.37, 118.63, 117.91, 84.71, 57.70, 44.11, 25.07, 22.42.
Reaction SMILES: C([O:8][C:9]1[CH:28]=[CH:27][C:12]([O:13][CH2:14][C:15]2[N:16]=[C:17]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[O:18][C:19]=2[CH3:20])=[CH:11][CH:10]=1)C1C=CC=CC=1>[C].[Pd].O1CCCC1>[CH3:20][C:19]1[O:18][C:17]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[N:16][C:15]=1[CH2:14][O:13][C:12]1[CH:11]=[CH:10][C:9]([OH:8])=[CH:28][CH:27]=1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(OCc2ccccc2)cc1
Agent: [Pd]
Solvent: C1CCOC1
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(O)cc1
Yield: 95.2 %

Procedure:
A mixture of 4-chloromethyl-5-methyl-2-phenyloxazole (20.18 g), 4-benzyloxyphenol (17.70 g), anhydrous potassium carbonate (12.22 g) and N,N-dimethylformamide (200 mL) was stirred at 90° C. for 15 hrs. The reaction mixture was poured into water, and the precipitated solid was collected by filtration, and dried with air to give crystals (29.03 g, 88%) of 4-[(4-benzyloxyphenoxy)methyl]-5-methyl-2-phenyloxazole. Recrystallization from ethyl acetate-hexane gave colorless leaflet crystals. melting point: 126-127° C. A mixture of the obtained 4-[(4-benzyloxyphenoxy)methyl]-5-methyl-2-phenyloxazole (22.6 g), 5% palladium carbon (10.0 g) and tetrahydrofuran (300 mL) was subjected to catalytic hydrogenation at room temperature and 1 atm. After filtering off the catalyst, the solvent was evaporated under reduced pressure to give crystals (16.3 g, 95%) of 4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]phenol. Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 168-169° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5]([C:9]#[C:10][C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[N:17]=[CH:16][N:15]=[C:14]3OC2C=CC=CC=2)([OH:8])[CH2:4][CH2:3]1.[NH2:28][C:29]1[CH:30]=[C:31]2[C:35](=[CH:36][CH:37]=1)[N:34]([CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[CH:33]=[CH:32]2.Cl.[NH+]1C=CC=CC=1.C1(O)C=CC=CC=1>CCOC(C)=O>[CH2:38]([N:34]1[C:35]2[C:31](=[CH:30][C:29]([NH:28][C:14]3[C:13]4[C:18](=[CH:19][CH:20]=[C:11]([C:10]#[C:9][C:5]5([OH:8])[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]5)[CH:12]=4)[N:17]=[CH:16][N:15]=3)=[CH:37][CH:36]=2)[CH:32]=[CH:33]1)[C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1
Reactant: Nc1ccc2c(ccn2Cc2ccccc2)c1
Reactant: CN1CCC(O)(C#Cc2ccc3ncnc(Oc4ccccc4)c3c2)CC1
Agent: Cl
Agent: c1cc[nH+]cc1
Solvent: CCOC(C)=O
Solvent: Oc1ccccc1
Product: CN1CCC(O)(C#Cc2ccc3ncnc(Nc4ccc5c(ccn5Cc5ccccc5)c4)c3c2)CC1
Temperature: 100 °C
Yield: 60.6 %

Procedure:
In a 1 mL Wheaton vial quinazoline 22 (80 mg, 0.22 mmol) was combined with 5-amino-1-benzylindole (54 mg, 0.24 mmol), pyridinium hydrochloride (5 mg, 0.04 mmol) and phenol (104 mg, 1.11 mmol). The vial was capped and heated at 100° C. for 16 hours. After cooling the contents of the Wheaton vial were solvated in a minimal amount of EtOAc and placed atop a silica gel (5 g) column. Elution of the column with 1:1:0.1 Hexanes:EtOAc/NEt3 removed high Rf impurities. The desired product 23 (Rf 0.05, 10:1 CH2Cl2:MeOH) was eluted off with 10:1 CH2Cl2:MeOH and gave a yellow solid (65 mg, 60%). 1H NMR (DMSO d6; 400 MHz): δ: 9.88 (s, 1H, NH), 8.67 (s, 1H), 8.45 (s, 1H), 7.92 (d, 1.7 Hz), 7.76 (d, 1H, J=8.5 Hz), 7.67 (d, 1H, J=8.5 Hz), 7.50 (d, 1H, J=3.1 Hz), 7.42 (d, 1H, J=8.9 Hz), 7.35 (dd, 1H, J=8.9 Hz, 1.9 Hz), 7.31-7.18 (m, 6H), 6.48 (dd, 1H, J+3.1 Hz, 0.8 Hz), 5.41 (s, 2H), 2.97 (br, 2H), 2.67 (br, 2H), 2.47 (s, 3H), 1.92 (br, 2H), 1.82 (br, 2H). LRMS: 488.2 (MH+), 126.1.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH2:7][CH2:6][C:5]2=O.Cl.[O:14]([NH2:16])[CH3:15]>N1C=CC=CC=1>[CH3:15][O:14][N:16]=[C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([CH3:1])[CH:3]=2)[O:8][CH2:7][CH2:6]1
Reactant: Cc1ccc2c(c1)C(=O)CCO2
Reactant: CON
Agent: Cl
Solvent: c1ccncc1
Product: CON=C1CCOc2ccc(C)cc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
6-Methylchroman-4-one (Aldrich, 3.24 g, 20 mmol) was dissolved in pyridine (15 mL). Methoxyl amine hydrochloride (1.84 g, 22 mmol) was added and the mixture stirred for 16 hours at ambient temperature. The pyridine was removed under reduced pressure, and the residue was added to water and diethyl ether. The aqueous layer was extracted with diethyl ether, and the combined organic layers washed with 1N sodium hydroxide and 1N hydrochloric acid and then dried with magnesium sulfate and filtered. The solvent was removed under reduced pressure to afford the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 2.28 (s, 3H), 2.88 (t, J=6.27 Hz, 2H), 3.98 (s, 3H), 4.17 (t, J=6.27 Hz, 2H), 6.78 (d, J=8.48 Hz, 1H), 7.05 (dd, J=8.48, 2.03 Hz, 1H), 7.70 (d, J=2.03 Hz, 1H). MS (DCI) m/z 192.02 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([C@H:16]3[CH2:21][CH2:20][CH2:19][CH2:18][C@H:17]3[C:22]([O:24]C)=[O:23])=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.Cl[C:27]1[S:28][C:29]2[CH:35]=[C:34]([Cl:36])[CH:33]=[CH:32][C:30]=2[N:31]=1.[OH-].[Na+]>C(O)CCC>[Cl:36][C:34]1[CH:33]=[CH:32][C:30]2[N:31]=[C:27]([NH:1][C:2]3[CH:3]=[CH:4][C:5]([C:8]4[CH:13]=[CH:12][C:11]([C:14]([C@@H:16]5[CH2:21][CH2:20][CH2:19][CH2:18][C@H:17]5[C:22]([OH:24])=[O:23])=[O:15])=[CH:10][CH:9]=4)=[CH:6][CH:7]=3)[S:28][C:29]=2[CH:35]=1
Reactant: COC(=O)[C@@H]1CCCC[C@@H]1C(=O)c1ccc(-c2ccc(N)cc2)cc1
Reactant: Clc1ccc2nc(Cl)sc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCO
Product: O=C(O)[C@@H]1CCCC[C@H]1C(=O)c1ccc(-c2ccc(Nc3nc4ccc(Cl)cc4s3)cc2)cc1
Temperature: 90 °C
Reaction time: 8 h
Yield: 15.5 %

Procedure:
To a solution of cis-methyl 2-[(4′-amino-1,1′-biphenyl-4-yl)carbonyl]cyclohexanecarboxylate (200 mg, 0.59 mmol) in n-butanol (8 mL) was added 2,6-dichloro-1,3-benzothiazole (241 mg, 1.19 mmol), and the resulting reaction mixture was heated at 90° C. overnight. The mixture was evaporated to dryness and the residue was combined with MeOH. Then 1 N NaOH (6.0 mL, 6.0 mmol) was added to the suspension, and the reaction mixture was stirred at 50° C. overnight. The reaction mixture was concentrated under reduced pressure, and the residue was suspended in water. Concentrated aqueous HCl was added to adjust the acidity to pH 1, and the precipitate was collected by filtration, washed with water and MeOH, and dried in a vacuum oven to give trans-2-({4′-[(6-chloro-1,3-benzothiazol-2-yl)amino]-1,1′-biphenyl-4-yl}carbonyl)cyclohexanecarboxylic acid (45 mg, 15%). LC-MS m/z 491.1 (MH+), ret. time 3.90 min; 1H NMR (400 MHz, DMSO-d6) δ 1.13 (m, 1H), 1.28˜1.51 (m, 3H), 1.78 (m, 1H), 1.93 (m, 1H), 2.09 (m, 1H), 2.68 (m, 1H), 3.63 (m, 1H), 7.35 (m, 1H), 7.60 (m, 1H), 7.80 (m, 4H), 7.90 (d, 1H), 7.96 (m, 1H), 8.05 (d, 2H), 10.75 (s, 1H).
Reaction SMILES: [C:1]1(=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(O)C.[OH-].[Na+]>Cl.C(OCC)(=O)C>[C:1]1([C:12]2[CH:13]=[CH:14][C:9]([NH2:8])=[CH:10][CH:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[NH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C1CCCCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Nc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCO
Product: Nc1ccc(C2=CCCCC2)cc1
Temperature: 110 °C

Procedure:
A mixture of cyclohexanone (50 g, 0.325 mol), and aniline (95 g, 1 mol) in 12 M HCl (100 mL), and ethanol (15 mL) was refluxed at 110° C. for four days. The solution was cooled and diluted with ethyl acetate. The aqueous layer was basified with 6 M NaOH. The organic layer was separate and washed with brine (3×), dried over MgSO4, and concentrated to give a brown oil. Approximately half of the crude product was introduced into a silica gel column and eluted with 5% ethyl acetate/hexane to obtain the desired product along with aniline. The combined organic fractions were extracted with 1 N HCl and separated. Addition of brine to the aqueous layer precipitated the 4-cyclohex-1-enylaniline as a cream colored solid (9 g).
Reaction SMILES: Br[C:2]1[N:3]([CH3:17])[C:4](=[O:16])[C:5]2[N:6]([CH:11]3[CH2:15][CH2:14][CH2:13][CH2:12]3)[CH:7]=[N:8][C:9]=2[N:10]=1.ClC1N(C)C(=O)C2N(C3CCCC3)C=NC=2N=1.[NH2:35][C@@H:36]1[CH2:40][CH2:39][CH2:38][C@H:37]1[OH:41].C(N(CC)CC)C>CC#N>[OH:41][C@@H:37]1[CH2:38][CH2:39][CH2:40][C@H:36]1[NH:35][C:2]1[N:3]([CH3:17])[C:4](=[O:16])[C:5]2[N:6]([CH:11]3[CH2:15][CH2:14][CH2:13][CH2:12]3)[CH:7]=[N:8][C:9]=2[N:10]=1
Reactant: Cn1c(Br)nc2ncn(C3CCCC3)c2c1=O
Reactant: N[C@@H]1CCC[C@H]1O
Agent: Cn1c(Cl)nc2ncn(C3CCCC3)c2c1=O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cn1c(N[C@@H]2CCC[C@H]2O)nc2ncn(C3CCCC3)c2c1=O

Procedure:
A mixture of 2-bromo-1-methyl-7-cyclopentylpurin-6-one and 2-chloro-1-methyl-7-cyclopentylpurin-6-one (11.4 g), (±) trans-2-aminocyclopentanol (1.2 g, 11 mmol), and triethylamine (1.2 ml) in CH3CN (20 ml) is heated to reflux for 12 hr. The resultant mixture is cooled, concentrated in vacuo, and partitioned between EtOAc/THF 1:1 and brine. The organic layers are concentrated in vacuo and the residue is purified by flash chromatography using 6% EtOH in CH2Cl2 to give 2-(trans-2-hydroxycyclopentylamino)-1-methyl-7-cyclopentylpurin-6-one, a colorless solid (1.4 gm, MS FAB: M+H=318). A mixture of 2-(trans-2-hydroxycyclopentylamino)-1-methyl-7-cyclopentylpurin-6-one (1.3 gm, 4.1 mm) and triphenylphosphine dibromide (prepared from triphenylphosphine (1.2 g) and 0.2 ml bromine) in DMF (20 ml) is stirred at room temperature for 18 hr and heated to 70° C. for 6 hr. Dilute NaOH is added to the cooled reaction mixture to adjust the pH to 10, and the resultant solution is extracted with EtOAC/THF (1:1). The organic layer is concentrated in vacuo and purified by flash chromatography using 15% EtOH in CH2Cl2 and recrystallized from CH2Cl2 /hexane to give the title compound, a solid, mp 133°-134° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]2[N:7]=[C:8]([SH:10])[O:9][C:5]=2[CH:4]=1.CS(O[CH2:18][CH2:19][CH2:20][C:21]([Br:24])([F:23])[F:22])(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]2[N:7]=[C:8]([S:10][CH2:18][CH2:19][CH2:20][C:21]([Br:24])([F:23])[F:22])[O:9][C:5]=2[CH:4]=1
Reactant: CS(=O)(=O)OCCCC(F)(F)Br
Reactant: COc1ccc2nc(S)oc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccc2nc(SCCCC(F)(F)Br)oc2c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 6-methoxy-2-mercaptobenzoxazole (1.77 g, 9.8 mmoles), 4-bromo-4,4-difluorobutyl methanesulphonate (2.4 g, 9 mmoles), potassium carbonate (5 g, 36.2 mmoles) and acetone (60 cm3) was stirred at the ambient temperature for 18 hours. The precipitate which formed was removed by filtration and the filtrate evaporated under reduced pressure to give a brown oil which was purified by chromatography on silica gel, eluted with a 1:4 mixture of ethyl acetate and hexane, to give the title intermediate product as a light yellow oil. 1H NMR (CDCl3): δ7.48(d,1H); 7.00(d,1H); 6.90(dd,1H); 3.85(s,3H); 3.38(t,2H); 2.50-2.68(m,2H).