Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:14][O:15][CH2:16][C@H:17]([CH2:27][C:28]1[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=1)[C@@H:18]([O:22][CH2:23][CH:24]([CH3:26])[CH3:25])[C@@H:19]([OH:21])[CH3:20])[C:10]([O:12]C)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].O[Li].O>C1COCC1.O>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:14][O:15][CH2:16][C@H:17]([CH2:27][C:28]1[CH:29]=[CH:30][C:31]([CH3:34])=[CH:32][CH:33]=1)[C@@H:18]([O:22][CH2:23][CH:24]([CH3:25])[CH3:26])[C@@H:19]([OH:21])[CH3:20])[C:10]([OH:12])=[O:11])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: COC(=O)[C@H](COC[C@H](Cc1ccc(C)cc1)[C@@H](OCC(C)C)[C@H](C)O)NC(=O)OC(C)(C)C
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(C[C@@H](COC[C@H](NC(=O)OC(C)(C)C)C(=O)O)[C@@H](OCC(C)C)[C@H](C)O)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 85.4 %

Procedure:
To a solution of (S)-methyl 2-((tert-butoxycarbonyl)amino)-3-(((2S,3R,4S)-4-hydroxy-3-isobutoxy-2-(4-methylbenzyl)pentyl)oxy)propanoate (2.06 g, 4.28 mmol) in aqueous THF (16 THF:5 H2O; 21 mL total volume) was added LiOH—H2O (0.54 g, 12.83 mmol) and the reaction was stirred for 4 h at room temperature. The reaction was diluted with H2O (50 mL) and the majority of the THF was removed on the rotovap. The aqueous residue was acidified with 2 N HCl and extracted with CH2Cl2 (6×50 mL) until the aqueous phase was nearly clear. The combined organic extracts were washed with brine (2×50 mL), dried over Na2SO4, filtered, and concentrated to a colorless oil (1.96 g). The oil was purified by RP flash chromatography (C18; 0→85% CH3CN/H2O) to give (S)-2-((tert-butoxycarbonyl)amino)-3-(((2S,3R,4S)-4-hydroxy-3-isobutoxy-2-(4-methyl-benzyl)pentyl)oxy)-propanoic acid (1.71 g, 85%) as a colorless oil: 1H NMR (400 MHz, CDCl3) δ 7.05 (m, 4H), 6.57 (s, 2H), 5.47 (d, J=8.1 Hz, 1H), 4.44 (m, 1H), 3.92 (m, 1H), 3.77 (m, 1H), 3.58 (m, 1H), 3.41 (d, J=7.2 Hz, 1H), 3.24 (m, 4H), 2.91 (dd, J=13.7, 4.0 Hz, 1H), 2.46 (dd, J=13.7, 10.8 Hz, 1H), 2.31 (s, 3H), 2.10 (dd, J=6.8, 3.3 Hz, 1H), 1.81 (dp, J=13.2, 6.6 Hz, 1H), 1.44 (s, 9H), 1.25 (d, J=6.2 Hz, 3H), 0.91 (dd, J=6.7, 2.7 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 171.72, 153.71, 135.81, 133.44, 127.15, 127.02, 81.61, 78.33, 76.81, 69.13, 68.31, 67.08, 51.93, 40.98, 31.48, 27.16, 26.42, 19.12, 17.65, 17.58, 17.38; ESIMS m/z 491 ([M+Na]+).
Reaction SMILES: [CH:1]1([C:4]2[CH:8]=[C:7]([NH:9][C:10](=[O:18])OC3C=CC=CC=3)[N:6]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:5]=2)[CH2:3][CH2:2]1.[CH3:25][O:26][C:27]1[CH:28]=[C:29]2[C:34](=[CH:35][C:36]=1[O:37][CH3:38])[N:33]=[CH:32][N:31]=[C:30]2[O:39][C:40]1[CH:41]=[C:42]([CH:44]=[CH:45][CH:46]=1)[NH2:43].O>CS(C)=O>[CH:1]1([C:4]2[CH:8]=[C:7]([NH:9][C:10]([NH:43][C:42]3[CH:44]=[CH:45][CH:46]=[C:40]([O:39][C:30]4[C:29]5[C:34](=[CH:35][C:36]([O:37][CH3:38])=[C:27]([O:26][CH3:25])[CH:28]=5)[N:33]=[CH:32][N:31]=4)[CH:41]=3)=[O:18])[N:6]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:5]=2)[CH2:2][CH2:3]1
Reactant: COc1cc2ncnc(Oc3cccc(N)c3)c2cc1OC
Reactant: O=C(Nc1cc(C2CC2)nn1-c1ccccc1)Oc1ccccc1
Solvent: CS(C)=O
Solvent: O
Product: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C5CC5)nn4-c4ccccc4)c3)c2cc1OC
Temperature: 70 °C
Yield: 32.6 %

Procedure:
A stirred mixture of phenyl 3-cyclopropyl-1-phenyl-1H-pyrazol-5-ylcarbamate (125 mg, 0.39 mmol) and 3-(6,7-dimethoxyquinazolin-4-yloxy)aniline (prepared as described in Example 113A) (100 mg, 0.34 mmol) in DMSO (1 mL) was heated to 70° C. for 18 h. After cooling to rt, water (20 mL) was added. The resulting suspension was filtered and the collected solid purified via preparative silica gel thin-layer chromatography (eluting with a mixture of 10:10:1 ethyl acetate: dichloromethane: methanol) to give a solid which was triturated with diethyl ether (50 mL) to afford 1-(3-cyclopropyl-1-phenyl-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)urea (58 mg, 33%) as a colorless solid. 1H NMR (400 MHz, DMSO-d6) δ9.21 (s, 1H), 8.55 (s, 1H), 8.49 (s, 1H), 7.51-7.55 (m, 6H), 7.34-7.39 (m, 3H), 7.17 (m, 1H), 6.91 (m, 1H), 6.14 (s, 1H), 3.99 (s, 3H), 3.98 (s, 3H), 1.86 (m, 1H), 0.86-0.88 (m, 2H), 0.65-0.67 (m, 2H); LC-MS (ESI) m/z 523 (M+H)+.
Reaction SMILES: [OH:1][CH:2]1[CH:7]2[CH2:8][CH2:9][N:4]([CH2:5][CH2:6]2)[CH2:3]1.[F:10][C:11]([F:27])([F:26])[C:12]1[CH:25]=[CH:24][C:15]([O:16][C:17]2[CH:22]=[CH:21][C:20](O)=[CH:19][CH:18]=2)=[CH:14][CH:13]=1>>[F:10][C:11]([F:26])([F:27])[C:12]1[CH:25]=[CH:24][C:15]([O:16][C:17]2[CH:22]=[CH:21][C:20]([O:1][CH:2]3[CH:7]4[CH2:8][CH2:9][N:4]([CH2:5][CH2:6]4)[CH2:3]3)=[CH:19][CH:18]=2)=[CH:14][CH:13]=1
Reactant: Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1
Reactant: OC1CN2CCC1CC2
Product: FC(F)(F)c1ccc(Oc2ccc(OC3CN4CCC3CC4)cc2)cc1

Procedure:
3-Hydroxy quinuclidine (Aldrich, 254 mg, 2 mmol) was treated with 4-(4-trifluoromethyl-phenoxy)-phenol (Aldrich, 255 mg, 1 mmol) according to the procedure of Example 1A. The title compound was purified by chromatography (SiO2, CH2Cl2:MeOH:NH3.H2O, 90:10:1, Rf. 0.50) as oil (180 mg, yield, 49%). H NMR (MeOH-d4, 300 MHz) δ 1.50–1.58 (m, 1H), 1.64–1.85 (m, 2H), 2.00–2.15 (m, 1H), 2.20–2.30 (m, 1H), 2.76–3.10 (m, 5H), 3.38–3.50 (m, 1H), 4.60 (m, 1H), 6.96–7.04 (m, 6H), 7.60 (d, J=8.5 Hz, 2H) ppm. MS (DCl/NH3) m/z 364 (M+H)+.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[NH:4][C:3](=[O:11])[CH2:2]1.[Cl:12][CH2:13][CH2:14][CH2:15]I.CCCCCCC>C(#N)C>[Cl:12][CH2:13][CH2:14][CH2:15][N:4]1[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[O:1][CH2:2][C:3]1=[O:11]
Reactant: ClCCCI
Reactant: O=C1COc2ccccc2N1
Solvent: CCCCCCC
Solvent: CC#N
Product: O=C1COc2ccccc2N1CCCCl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2H-1,4 benzoxazine-3(4H)one (1.0 g, 6.70 mmol) and Cs2CO3-(3.28 g, 10.1 mmol) were dissolved in dry acetonitrile (20 mL) under nitrogen atmosphere and stirred at rt for 30 min. 3-chloro-1-iodopropane (1.58 g, 7.38 mmol) dissolved in acetonitrile (4 mL) was added via a syringe. The reaction mixture was stirred at rt for 18 hours and concentrated in vacuo. Water (150 mL) was added and the reaction mixture was extracted with ethyl acetate (3×150 mL). The combined organic phases were dried (MgSO4) and concentrated in vacou to give 1.65 g of crude. The crude product was subjected to CC[eluent:Heptane:EtOAC(4:1)] to give the pure title compound as a colorless oil. Yield 1.36 g, 89.2%. Rf=0.24 [Heptane:EtOAC(4:1)], 1H NMR (CDCl3): δ 2.16 (m, 2H), 3.62 (t, 2H), 4.10 (t, 2H), 4.59 (s, 2H), 7.00 (m, 2H), 7.05 (m, 2H), 13C NMR (CDCl3): δ 30.16, 39.04, 42.45, 67.72, 114.80, 117.38, 123.07, 124.14, 128.49, 145.47, 164.58.
Reaction SMILES: [C:1]1([CH:11]=[CH:12][C:13]2[NH:22][C:21](=O)[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C(N(CC)C1C=CC=CC=1)C.P(Cl)(Cl)([Cl:37])=O>>[Cl:37][CH:21]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=[C:13]([CH:12]=[CH:11][C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)[NH:22]1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]c(C=Cc2cccc3ccccc23)nc2ccccc12
Solvent: CCN(CC)c1ccccc1
Product: ClC1NC(C=Cc2cccc3ccccc23)=Nc2ccccc21
Temperature: 25 °C

Procedure:
2-(2-Naphthalen-1-yl-vinyl)-3H-quinazolin-4-one (11 mmol), phosphorus oxychloride (20 ml) and N,N-diethylaniline (1.0 ml) is added to a round-bottomed flask. The mixture is heated at 110° for 12 h. After cooling to rt, the reaction is quenched with ice-water and the crude product is collected by suction filtration. The crude solid is dissolved in ethyl acetate. Customary working up afforded 4-chloro-2-(2-naphthalen-1-yl-vinyl)-3,4-dihydro-quinazoline.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.O[C@@H:10]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:11][N:12]1[CH2:17][CH2:16][CH:15]([C:18]2[CH:19]=[C:20]([NH:24][C:25](=[O:29])[CH:26]([CH3:28])[CH3:27])[CH:21]=[CH:22][CH:23]=2)[CH2:14][CH2:13]1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C@H:10]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:11][N:12]2[CH2:17][CH2:16][CH:15]([C:18]3[CH:19]=[C:20]([NH:24][C:25](=[O:29])[CH:26]([CH3:28])[CH3:27])[CH:21]=[CH:22][CH:23]=3)[CH2:14][CH2:13]2)=[CH:4][CH:3]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(C[C@@H](O)c3ccccc3)CC2)c1
Reactant: Oc1ccc(F)cc1
Product: CC(C)C(=O)Nc1cccc(C2CCN(C[C@H](Oc3ccc(F)cc3)c3ccccc3)CC2)c1

Procedure:
Prepared by Procedure B and Scheme B1 using 4-fluorophenol and N-(3-{1-[(2S)-2-hydroxy-2-phenylethyl]-4-piperidinyl}phenyl)-2-methylpropanamide: ESMS m/e: 461.2. (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9]([C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=3)=[O:20])[C:10]3[N:14]=[C:13]([O:15][CH2:16][CH3:17])[NH:12][C:11]=3[CH:18]=2)=[C:5]([CH3:27])[O:4][N:3]=1.[CH3:28][CH2:29][CH:30]([Mg]Br)[CH2:31][CH3:32]>C1COCC1>[CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9]([C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=3)([OH:20])[CH:30]([CH2:31][CH3:32])[CH2:29][CH3:28])[C:10]3[N:14]=[C:13]([O:15][CH2:16][CH3:17])[NH:12][C:11]=3[CH:18]=2)=[C:5]([CH3:27])[O:4][N:3]=1
Reactant: CCC(CC)[Mg]Br
Reactant: CCOc1nc2c(C(=O)c3ccccn3)cc(-c3c(C)noc3C)cc2[nH]1
Solvent: C1CCOC1
Product: CCOc1nc2c(C(O)(c3ccccn3)C(CC)CC)cc(-c3c(C)noc3C)cc2[nH]1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
(6-(3,5-dimethylisoxazol-4-yl)-2-ethoxy-1H-benzo[d]imidazol-4-yl)(pyridin-2-yl)methanone (50 mg, 0.14 mmol) was dissolved in dry THF (1.4 mL) and cooled to 0° C. Pentan-3-ylmagnesium bromide (2.0 M, 0.21 mL, 0.41 mmol) was added dropwise and the reaction was allowed to stir for 10 mins and then quenched with water. Reaction was extracted three times with EtOAc and combined organic layers were washed once with water, concentrated, and purified by reverse-phase HPLC to give 1-(6-(3,5-dimethylisoxazol-4-yl)-2-ethoxy-1H-benzo[d]imidazol-4-yl)-2-ethyl-1-(pyridin-2-yl)butan-1-ol intermediate. The intermediate was taken up in EtOH (1.5 mL) and 0.2 mL concentrated HCl and heated to 65° C. for 2 hours and concentrated to afford the desired product as a white powder.
Reaction SMILES: [Si](I)(C)(C)C.[CH3:6][O:7][C:8](=[O:46])[CH:9]([NH:38]C(OC(C)(C)C)=O)[CH2:10][S:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]3[C:30]4[O:31][C:32]5[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=5[C:29]=4[CH:28]=[CH:27][CH:26]=3)=[CH:21][CH:20]=2)=[CH:15][CH:14]=1.C(Cl)Cl.C(=O)(O)[O-].[Na+]>O>[CH3:6][O:7][C:8](=[O:46])[CH:9]([NH2:38])[CH2:10][S:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:20]=[CH:21][C:22]([C:25]3[C:30]4[O:31][C:32]5[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=5[C:29]=4[CH:28]=[CH:27][CH:26]=3)=[CH:23][CH:24]=2)=[CH:15][CH:14]=1
Reactant: COC(=O)C(CSCc1ccc(-c2ccc(-c3cccc4c3oc3ccccc34)cc2)cc1)NC(=O)OC(C)(C)C
Agent: C[Si](C)(C)I
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: COC(=O)C(N)CSCc1ccc(-c2ccc(-c3cccc4c3oc3ccccc34)cc2)cc1
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
TMS-I (290 mg, 0.21 mL, 1.45 mmol) was added dropwise to a stirred solution of methyl-2-tert-butoxycarbonylamino-3-(4′-dibenzofuran-4-yl-biphenyl-4-ylmethyl-sulfanyl)-propionate (748 mg, 1.32 mmol) in anhyd methylene chloride (20 mL). The reaction mixture was stirred at room temperature for 20-30 min (TLC control), and then diluted with water (20 mL). Sat'd aq sodium bicarbonate solution was added to adjust the solution to pH 8-9. The reaction mixture was extracted with diethyl ether (2×30 mL). The combined organic extracts were washed with water, sat'd aq NaCl, dried over anhydrous MgSO4, filtered and concentrated in vacuo. Purification by flash column chromatography (5% methanol in methylene chloride) afforded the title compound has a pale yellow solid (596 mg).
Reaction SMILES: Cl[C:2]([CH2:4][O:5][C:6](=[O:8])[CH3:7])=[O:3].[Br:9][C:10]1[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][C:11]=1[CH3:17].N1C=CC=CC=1>ClCCl>[Br:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:2]([CH2:4][O:5][C:6](=[O:8])[CH3:7])=[O:3])=[CH:12][C:11]=1[CH3:17]
Reactant: Cc1cc(N)ccc1Br
Reactant: CC(=O)OCC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)OCC(=O)Nc1ccc(Br)c(C)c1
Temperature: 40 °C
Reaction time: 2.5 h

Procedure:
Acetic acid chlorocarbonylmethyl ester (1.73 ml) was added to a solution of 4-bromo-3-methyl-phenylamine (2.0 g, 10.7 mmol) and pyridine (5.21 ml) in dichloromethane (20 ml), and the mixture was stirred at 40° C. for 2.5 hours. The mixture was cooled, and then quenched with water and extracted with dichloromethane. The organic layer was sequentially washed with water and saturated brine, and then dried over anhydrous sodium sulfate and concentrated under reduced pressure to give acetic acid (4-bromo-3-methyl-phenylcarbamoyl)-methyl ester (3.19 g).
Reaction SMILES: [OH-].[K+].[CH3:3][SH:4].O.Cl[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=2[CH:20]=[O:21])=[CH:9][CH:8]=1>C(O)C>[F:19][C:17]1[CH:16]=[CH:15][C:14]([CH:20]=[O:21])=[C:13]([C:10]2[CH:11]=[CH:12][C:7]([S:4][CH3:3])=[CH:8][CH:9]=2)[CH:18]=1
Reactant: CS
Reactant: O=Cc1ccc(F)cc1-c1ccc(Cl)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CSc1ccc(-c2cc(F)ccc2C=O)cc1
Temperature: 25 °C

Procedure:
85% potassium hydroxide solution (66 g) is dissolved in ethanol (700 ml) and cooled to room temperature. To this with stirring is added methyl mercaptan subsurface (50 g), water (2ml) and a solution of 4-chloro-5'-fluoro-2'-formylbiphenyl (234.5 g) in ethanol (300 ml). A slow stream of methyl mercaptan is continuously fed in while the reaction mixture is held at reflux for 3 hours. The reaction is poured into water (1 liter), and the solid is filtered off. The solid is recrystallized from benzene.
Reaction SMILES: FC(F)(F)C(O)=O.[N:8]1([C:14]2[N:19]3[N:20]=[C:21]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH:22]=[C:18]3[N:17]=[C:16]([NH:29][NH2:30])[CH:15]=2)[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.[C:31]([C:33]1[CH:40]=[CH:39][CH:38]=[CH:37][C:34]=1[CH:35]=O)#[N:32]>C(O)C>[C:31]([C:33]1[CH:40]=[CH:39][CH:38]=[CH:37][C:34]=1[CH:35]=[N:30][NH:29][C:16]1[CH:15]=[C:14]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:19]2[N:20]=[C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:22]=[C:18]2[N:17]=1)#[N:32]
Reactant: N#Cc1ccccc1C=O
Reactant: NNc1cc(N2CCOCC2)n2nc(-c3ccccc3)cc2n1
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccccc1C=NNc1cc(N2CCOCC2)n2nc(-c3ccccc3)cc2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 102.6 %

Procedure:
There was dissolved, in ethanol (2 mL), trifluoroacetic acid salt of (7-morpholin-4-yl-2-phenyl-pyrazolo[1,5-a]pyrimidin-5-yl)-hydrazine (30.0 mg, 0.0557 mM), then 2-cyano-benzaldehyde (6.7 mg, 0.061 mM) was added to the solution and the mixture was stirred at room temperature for one hour. This reaction liquid was filtered and the resulting solid was purified by the NH-silica gel column chromatography (methanol/methylene chloride=1/20) to thus give the title compound (22.2 mg, yield: 94%).
Reaction SMILES: [O-:1][C:2]#[N:3].[K+].[NH2:5][C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:7]=1[OH:13]>O.C(O)(=O)C>[Cl:12][C:10]1[CH:9]=[CH:8][C:7]([OH:13])=[C:6]([NH:5][C:2]([NH2:3])=[O:1])[CH:11]=1
Reactant: N#C[O-]
Reactant: Nc1cc(Cl)ccc1O
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: NC(=O)Nc1cc(Cl)ccc1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 50.4 %

Procedure:
A solution of potassium cyanate (6.14 g, 75.6 mmol) in water (50 mL) was added dropwise to a stirred suspension of 2-amino-4-chlorophenol (5.00 g, 34.8 mmol) in a mixture of acetic acid (350 mL) and water (250 mL) and the resulting solution was stirred at room temperature for 3 hours. The reaction mixture was extracted three times with ethyl ether. The ether extracts were combined and concentrated to a thick oil. A 10% solution of sodium hydrogen carbonate (250 mL) was added to the above oil. The solid product was filtered and washed several times with water and recrystallized (toluene containing a little methanol) to afford the subtitle compound (3.27 g, 50.4%)
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([SH:11])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([OH:19])[N:6]2[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:27][CH2:28][CH2:29][N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>CN(C)C=O>[NH2:1][C:2]1[N:10]=[C:9]([S:11][CH2:27][CH2:28][CH2:29][N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([OH:19])[N:6]2[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: ClCCCN1CCNCC1
Reactant: Nc1nc(S)nc2c1nc(O)n2Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1nc(SCCCN2CCNCC2)nc2c1nc(O)n2Cc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 5.1 %

Procedure:
Crude 6-amino-9-benzyl-8-hydroxy-2-mercaptopurine (134 mg, 0.49 mmol) was suspended in dimethylformamide (60 ml). To the suspension were added potassium carbonate (100 mg, 0.72 mmol) and 1-(3-chloropropyl)piperazine (179 mg, 0.73 mmol) in order. The mixture was stirred at room temperature for 2 hours. The solvent was removed in vacuo, and the residue was purified by silica gel chromatography (20% methanol/chloroform) to give the subject compound (10 mg, yield 5%).
Reaction SMILES: [OH:1][C:2]1[C:11]2[N:10]=[C:9]([CH3:12])[CH:8]=[CH:7][C:6]=2[C:5]([S:13]([OH:16])(=[O:15])=[O:14])=[CH:4][CH:3]=1.[OH-].[K+].[Cl:19][O-].[Na+]>O>[Cl:19][C:3]1[CH:4]=[C:5]([S:13]([OH:16])(=[O:15])=[O:14])[C:6]2[CH:7]=[CH:8][C:9]([CH3:12])=[N:10][C:11]=2[C:2]=1[OH:1]
Reactant: Cc1ccc2c(S(=O)(=O)O)ccc(O)c2n1
Reactant: [O-]Cl
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1ccc2c(S(=O)(=O)O)cc(Cl)c(O)c2n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 34 %

Procedure:
8-Hydroxy-2-methyl-quinoline-5-sulfonic acid (14.0 g, 58.52 mmol) was added to a solution of potassium hydroxide (9.20 g, 164 mmol, 2.8 equiv) in water (136 ml) to form a yellow solution. An aqueous solution of sodium hypochlorite (13%, 136 ml) was added. The mixture was stirred at room temperature for 90 minutes. Upon dilution with water (300 ml), the mixture was filtered through amberlite IR-120 (H+). After washing the column with water (2 liters), the eluent was concentrated (to ˜200 ml) and diluted with acetone (300 ml). The precipitate was filtered off and washed with acetone to afford the title compound (5.51 g, 34%). 1H NMR (400 MHz, d6-DMSO): δ=8.52 (d, J=8.3 Hz, 1H), 7.67 (d, J=8.3 Hz, 1H), 7.00 (s, 1H), 2.58 (s, 3H). MS (ES−): 274 (M−H)−.
Reaction SMILES: C([O:8][C:9](=[O:28])[C@@H:10]([NH2:27])[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][O:20][CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:13][CH:12]=1)C1C=CC=CC=1.[H][H]>CO.[Pd]>[NH2:27][C@@H:10]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][O:20][CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:13][CH:12]=1)[C:9]([OH:28])=[O:8]
Reactant: [H][H]
Reactant: N[C@H](C(=O)OCc1ccccc1)c1ccc(OCCOC2CCCCC2)cc1
Agent: [Pd]
Solvent: CO
Product: N[C@H](C(=O)O)c1ccc(OCCOC2CCCCC2)cc1
Yield: 68 %

Procedure:
A solution of (S)-alpha-amino-N-[[(1,1 -dimethyethyl)oxy]carbonyl]-4-[[2-(cyclohexyloxy) ethyl]oxy]benzeneacetic acid benzyl ester (2.15 g) in dichloromethane (15 mL) containing trifluoroacetic acid (15 mL) was stirred at room temperature for 1 hour. After the solvents were removed under reduced pressure, the residue was dissolved in ethyl acetate and the mixture was basified to ~pH 9.5 with concentrated ammonium hydroxide. The organic layer was washed in turn with ammonium bicarbonate solution and brine, then was dried over anhydrous potassium carbonate (K2CO3) and evaporated to give 1.3 g of (S)-alpha-amino-4-[[2-(cyclohexyloxy)ethyl]oxy]benzeneacetic acid benzyl ester. A solution of the crude ester (1.25 g) in methanol (50 mL) was hydrogenated over 10% Pd/C at ambient temperature and pressure until the uptake of hydrogen had ceased. The reaction was diluted with methanol (100 ml), heated to reflux for five minutes, then the catalyst was filtered off through a bed of Celite, and washed with hot methanol (3×30 mL). The combined filtrates were concentrated at reflux to ~50 mL, then were cooled and the solids collected by filtration to yield 0.65 g of (S)-alpha-amino-4-[[2(cyclohexyloxy)ethyl]oxy]benzeneacetic acid, mp 219°-220° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:13])=[C:4]([C:6]([C:9]([F:12])([F:11])[F:10])=[CH:7][CH:8]=1)[NH2:5].C([O-])([O-])=O.[K+].[K+].[Cl:20][CH2:21][C:22](Cl)=[O:23]>C1COCC1>[Cl:20][CH2:21][C:22]([NH:5][C:4]1[C:6]([C:9]([F:12])([F:11])[F:10])=[CH:7][CH:8]=[C:2]([Cl:1])[C:3]=1[F:13])=[O:23]
Reactant: O=C(Cl)CCl
Reactant: Nc1c(C(F)(F)F)ccc(Cl)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=C(CCl)Nc1c(C(F)(F)F)ccc(Cl)c1F
Temperature: 0 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
To a solution of 3-chloro-2-fluoro-6-(trifluoromethyl)aniline (250 mg, 1.136 mmol) in THF (2 mL) was added K2CO3 (235 mg, 1.703 mmol). The mixture was cooled to 0° C. and added 2-chloroacetyl chloride (0.099 mL, 1.249 mmol). The ice-water bath was removed and the reaction was allowed to warm to rt. After stirred at rt overnight, The reaction mixture was diluted with ether and water. The organic ether layer was separated and washed with brine, dried over MgSO4, filtered and concentrated to yield a crude white solid product, which was purified by silica gel chromatography to yield desired product (280 mg, 85%) as a white solid. 1H NMR (500 MHz, CDCl3) δ 8.06 (br. s., 1H), 7.55-7.49 (m, 1H), 7.48-7.42 (m, 1H), 4.27 (s, 2H). MS (ESI) m/z: 289.9 (M+H)+.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[F:12])=O.Cl.[NH:14]1[CH2:18][CH2:17][CH2:16][C:15]1=[NH:19].C([O-])([O-])=O.[Na+].[Na+].O>CN(C=O)C>[F:12][C:6]1[CH:7]=[C:8]([F:11])[CH:9]=[CH:10][C:5]=1[C:3]1[N:19]=[C:15]2[CH2:16][CH2:17][CH2:18][N:14]2[CH:2]=1
Reactant: O=C(CBr)c1ccc(F)cc1F
Reactant: N=C1CCCN1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Fc1ccc(-c2cn3c(n2)CCC3)c(F)c1
Temperature: 25 °C
Yield: 70 %

Procedure:
A mixture of 2-bromo-1-(2,4-difluorophenyl)ethanone (150 g, 640 mmol, Example #8, Step A), pyrrolidin-2-imine hydrochloride (108 g, 894 mmol) and Na2CO3 (134 mL, 3190 mmol) in DMF (650 mL) was stirred and heated at about 80° C. in a 3 L 3 necked flask for about 24 h. The mixture was cooled to ambient temperature and poured into water (about 5 L). The product was partitioned between EtOAc (800 mL) and the basic aqueous phase. The aqueous layer was extracted with additional EtOAc (3×800 mL). The combined organic extracts were washed with water (4×800 mL), dried over MgSO4 and filtered through a pad of Florisil® (2″ depth×3″ diameter). The pad was washed with EtOAc (4×250 mL) and the filtrate was concentrated to dryness under reduced pressure to yield the title compound as a solid (98.6 g, 70%): LC/MS (Table 1, Method a) Rt=2.72 min; MS m/z: 221.0 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10](I)[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[Cl-].[N:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[Zn+].O>C1COCC1.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>[Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][N:14]=2)[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: [Zn+]c1ccccn1
Reactant: COC(=O)c1cc(Br)cc(I)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1cc(Br)cc(-c2ccccn2)c1
Reaction time: 8 h

Procedure:
To an argon purged solution of methyl 3-bromo-5-iodobenzoate (834 mg, 2.45 mmol) and Pd(PPh3)4 (142 mg, 0.12 mmol) in THF (20 mL) was added 2-pyridylzinc chloride (0.5 M, 7.4 mL, 3.7 mmol). The mixture was stirred overnight and then poured into a large volume of water (100 mL). The resulting solution was extracted with EtOAc (3×20 mL) and the combined organics were successively washed with water (1×20 mL), brine (1×20 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude residue was purified via automated flash chromatography (silica gel; 0 to 25% EtOAc in hexanes) to afford methyl 3-bromo-5-(pyridin-2-yl)benzoate. MS m/z=292, 294 [M+1]+; Calc'd for C13H10BrNO2: 292.