Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]3[N:28]([C:29]([C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[N:27]=[N:26][N:25]=3)=[CH:14][CH:13]=2)[C:7](=[O:10])[NH:8][N:9]=1)[CH2:2][CH2:3][CH3:4].Br[CH:49]([C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)[C:50]([O:52][CH3:53])=[O:51]>>[CH2:1]([C:5]1[N:6]([CH2:11][C:12]2[CH:13]=[CH:14][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]3[N:28]([C:29]([C:36]4[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=4)([C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=4)[C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)[N:27]=[N:26][N:25]=3)=[CH:16][CH:17]=2)[C:7](=[O:10])[N:8]([CH:49]([C:50]([O:52][CH3:53])=[O:51])[C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1n[nH]c(=O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: COC(=O)C(Br)c1ccccc1
Product: CCCCc1nn(C(C(=O)OC)c2ccccc2)c(=O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Yield: 57 %

Procedure:
The alkylation of 5-n-butyl-2,4-dihydro-4-[[2'-(N-trityltetrazol-5-yl)biphenyl-4-yl]methyl]-3H-1,2,4-triazol-3-one (from Example 2, Step D) with methyl α-bromophenyl-acetate was carried out as described in Example 3, Step A, except 3 equivalents of the alkylating agent was used. After work-up, flash chromatography of the crude product over silica gel (50 mL for 0.24 mmole, elution with 0.5% MeOH/CH2Cl2) gave the title compound in 57% yield as an oil, homogeneous by TLC in 2% MeOH/CH2Cl2, mass spectrum (FAB) m/e 766 (M+1)+.
Reaction SMILES: [N+:1]([O-:4])([O-:3])=[O:2].[N+]([O-])(O)=O.[C:9]([O:12][CH2:13][CH3:14])(=[O:11])C.CCOCC>C(OCC)(=O)C>[N+:1]([O-:4])([OH:3])=[O:2].[O:11]1[CH2:14][CH2:13][O:12][CH2:9]1
Reactant: CCOC(C)=O
Reactant: O=[N+]([O-])[O-]
Solvent: CCOCC
Solvent: O=[N+]([O-])O
Product: C1COCO1

Procedure:
analysis: C28H23Cl2N3O4 (MW 536.43) calc. C 62.69, H 4.32, N 7.83; found C 62.4, H 4.4, N 7.6. Nitrate formation: 1.93 g (3.6 mmol) of base were dissolved in 15 ml of ethyl acetate, and 3.6 ml of 1M HNO3 /ethyl acetate were added with stirring. Ether was subsequently added until no further precipitate was produced, and the precipitate was filtered off under suction. 2.05 g (yield of nitrate, 95.3% of theory) of cis-2-(2,4-dichlorophenyl)-2-(imidazol-1-ylmethyl)-4-[4-(benzoxazol-2-yl)benzyl)oxymethyl]-1,3-dioxolane nitrate were obtained; melting point 121°-2° C.,
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[N+:13]([O-])=O)[C:6]([O:8][CH3:9])=[O:7]>CO.[Ni]>[NH2:13][C:12]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: COC(=O)c1ccc([N+](=O)[O-])c(OC)c1
Agent: [Ni]
Solvent: CO
Product: COC(=O)c1ccc(N)c(OC)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 86.7 %

Procedure:
To a solution of methyl 3-methoxy-4-nitrobenzoate (172 g, 0.815 mol) in methanol (2 L) was added Raney Ni (60 g) in one portion. The resulting mixture was stirred at ambient temperature under H2 for 24 h. TLC (EtOAc: Petroleum ether 1:3) indicated the reaction was complete. The reaction mixture was filtered through a pad of Celite and the filter cake was washed with methanol (100 mL×5). The filtrate was concentrated in vacuum to afford the desired amine (128 g, 86.7%) as a yellow solid. 1H NMR (400 MHz, CDCl3): δ 7.383-7.349 (dd, 1H), 7.268 (d, 1H), 6.633-6.605 (d, 1H), 5.617 (s, 2H), 3.782 (s, 3H), 3.740 (s, 3H).
Reaction SMILES: FC(F)(F)C(O)=O.[Br:8][C:9]1[C:14]([CH2:15][CH2:16][CH:17]2[CH2:21][CH2:20][CH2:19][N:18]2C(OC(C)(C)C)=O)=[C:13]([C:29]([O:31][CH3:32])=[O:30])[C:12]([NH:33][C:34](=[O:39])[C:35]([CH3:38])([CH3:37])[CH3:36])=[CH:11][CH:10]=1>C(Cl)Cl>[Br:8][C:9]1[C:14]([CH2:15][CH2:16][CH:17]2[CH2:21][CH2:20][CH2:19][NH:18]2)=[C:13]([C:12]([NH:33][C:34](=[O:39])[C:35]([CH3:37])([CH3:38])[CH3:36])=[CH:11][CH:10]=1)[C:29]([O:31][CH3:32])=[O:30]
Reactant: COC(=O)c1c(NC(=O)C(C)(C)C)ccc(Br)c1CCC1CCCN1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1c(NC(=O)C(C)(C)C)ccc(Br)c1CCC1CCCN1
Reaction time: 0.5 h
Yield: 100.4 %

Procedure:
Trifluoroacetic acid (15 mL) was added to a solution of tert-butyl 2-{2-[6-bromo-3-(2,2-dimethylpropionylamino)-2-methoxycarbonylphenyl]-ethyl}-pyrrolidine-1-carboxylate (Intermediate 36, 2.54 g) in DCM (15 mL) and the mixture was left to stand at room temperature for 30 minutes. The resultant solution was concentrated in vacuo and the residue was partitioned between ethyl acetate and potassium carbonate solution. The organic layer was dried (Na2SO4) and filtered and the filtrate was concentrated in vacuo to give methyl 3-bromo-6-(2,2-dimethylpropionylamino)-2-(2-pyrrolidin-2-yl-ethyl)benzoate (2.05 g) as a white foam.
Reaction SMILES: Cl.[CH3:2][N:3]1[CH2:7][CH2:6][CH2:5][C:4]1=[NH:8].O.[OH-].[Na+].[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=1[N:20]=[C:21]=[O:22]>C1C=CC=CC=1>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=1[NH:20][C:21]([N:8]=[C:4]1[CH2:5][CH2:6][CH2:7][N:3]1[CH3:2])=[O:22]
Reactant: CN1CCCC1=N
Reactant: O=C=Nc1cc(Cl)ccc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Solvent: O
Product: CN1CCCC1=NC(=O)Nc1cc(Cl)ccc1Cl

Procedure:
To 6.73 g. (0.05 mole) of 1-methyl-2-iminopyrrolidine HCl is added 1 ml. of water and 50 ml. of benzene. After solution is complete (magnetic stirring), 10 ml. of aqueous sodium hydroxide (50%) is added in one portion. After stirring for about 1 min., the benzene layer is decanted onto anhydrous potassium carbonate. The extraction is repeated twice. After drying (occasional swirling) the combined benzene extracts are filtered (dicalite) from drying agent and 9.4 g. (0.05 mole) of 2,5-dichlorophenylisocyanate is added to the filtrate in one portion with swirling. After stirring for 3 hours, the solvent is removed in vacuo affording a colorless solid 1-(2,5-dichlorophenyl)-3-(1-methyl-2-pyrrolidylidene)urea. Recrystallization from acetone (twice) yields the pure product, m.p. = 148.5°-150.5° C.
Reaction SMILES: C([O:8][C:9]([C:11]1([C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24]3[CH:29]=[CH:28][N:27]=[C:26]([NH:30][C:31]([N:33]([CH3:41])[CH:34]4[CH2:39][CH2:38][N:37]([CH3:40])[CH2:36][CH2:35]4)=[O:32])[CH:25]=3)=[CH:19][C:18]=2[F:42])=[O:15])[CH2:13][CH2:12]1)=[O:10])C1C=CC=CC=1.CO>O1CCCC1.[OH-].[OH-].[Pd+2]>[F:42][C:18]1[CH:19]=[C:20]([O:23][C:24]2[CH:29]=[CH:28][N:27]=[C:26]([NH:30][C:31]([N:33]([CH3:41])[CH:34]3[CH2:39][CH2:38][N:37]([CH3:40])[CH2:36][CH2:35]3)=[O:32])[CH:25]=2)[CH:21]=[CH:22][C:17]=1[NH:16][C:14]([C:11]1([C:9]([OH:10])=[O:8])[CH2:13][CH2:12]1)=[O:15]
Reactant: CN1CCC(N(C)C(=O)Nc2cc(Oc3ccc(NC(=O)C4(C(=O)OCc5ccccc5)CC4)c(F)c3)ccn2)CC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CN1CCC(N(C)C(=O)Nc2cc(Oc3ccc(NC(=O)C4(C(=O)O)CC4)c(F)c3)ccn2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 83.4 %

Procedure:
To a solution of 1-(benzyloxycarbonyl)-N-(2-fluoro-4-{2-[3-methyl-3-(1-methylpiperidin-4-yl)ureido]pyridin-4-yloxy}phenyl)cyclopropanecarboxamide (510 mg) in tetrahydrofuran (20 ml)-methanol (20 ml) was added 20% palladium hydroxide on carbon (377 mg), followed by stirring under a hydrogen atmosphere at room temperature for 24 hr. The catalyst was removed by filtration, and washed with tetrahydrofuran-methanol (1:1). The filtrate was concentrated under reduced pressure, and the residue was dried under reduced pressure to provide the titled compound as white crystals (358.7 mg, 83%).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][NH:2]1.[CH2:10]([O:12][C:13]([CH:15]([C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[N:25]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[C:24](=[O:36])[C:23]2=[O:37])[CH2:16][CH2:17][CH2:18][CH3:19])=[O:14])[CH3:11]>O1CCCC1>[C:32]([O:31][C:29]([NH:25][C:26]1[CH:27]=[CH:28][C:20]([CH:15]([CH2:16][CH2:17][CH2:18][CH3:19])[C:13]([O:12][CH2:10][CH3:11])=[O:14])=[CH:21][C:22]=1[C:23](=[O:37])[C:24]([N:2]1[CH2:3][C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:1]1)=[O:36])=[O:30])([CH3:35])([CH3:34])[CH3:33]
Reactant: CCCCC(C(=O)OCC)c1ccc2c(c1)C(=O)C(=O)N2C(=O)OC(C)(C)C
Reactant: c1ccc2c(c1)CNC2
Solvent: C1CCOC1
Product: CCCCC(C(=O)OCC)c1ccc(NC(=O)OC(C)(C)C)c(C(=O)C(=O)N2Cc3ccccc3C2)c1
Temperature: 23 °C
Reaction time: 1 h
Yield: 45.7 %

Procedure:
1.95 g of isoindoline are added to 6.4 g of 5-(1-ethoxycarbonylpentyl)-1-tertbutoxycarbonyl-2,3-dioxoindoline in 100 ml of tetrahydrofuran, and the mixture is subsequently stirred at 23° C. for 1 h. The mixture is evaporated to dryness in vacuo and purified by column chromatography, giving 3.8 g (46%) of ethyl 2-[4-(tert-butoxycarbonylamino)-3-(2-isoindolin-2-yl-2-oxoacetyl)phenyl]hexanoate; LC-MS retention time: 2.89 min (“nonpolar” gradient).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:15][C:14]3[C:13]4[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=4[S:11][CH2:10][CH2:9][C:8]=3[C:7]=2[CH:20]=1.Cl.Cl[CH2:23][C:24]1[CH:38]=[CH:37][C:27]([O:28][CH2:29][CH2:30][NH:31][CH:32]2C[CH2:35][CH2:34][CH2:33]2)=[CH:26][CH:25]=1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:15]([CH2:23][C:24]3[CH:25]=[CH:26][C:27]([O:28][CH2:29][CH2:30][N:31]4[CH2:32][CH2:33][CH2:34][CH2:35]4)=[CH:37][CH:38]=3)[C:14]3[C:13]4[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=4[S:11][CH2:10][CH2:9][C:8]=3[C:7]=2[CH:20]=1
Reactant: ClCc1ccc(OCCNC2CCCC2)cc1
Reactant: COc1ccc2[nH]c3c(c2c1)CCSc1ccccc1-3
Agent: Cl
Product: COc1ccc2c(c1)c1c(n2Cc2ccc(OCCN3CCCC3)cc2)-c2ccccc2SCC1

Procedure:
Following the same procedure in Example 102, using 9-methoxy-6,7-dihydro-12H-5-thia-12-aza-dibenzo[a,e]azulene (562 mg) and [2-(4-chloromethyl-phenoxy)-ethyl]-cyclopentyl-amine hydrochloride salt as the starting material, the title compound was prepared as a brown solid.
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[OH:25][CH2:26][C:27]1[N:28]=[C:29]([C:33]2[CH:41]=[CH:40][C:36]([C:37]([OH:39])=O)=[CH:35][CH:34]=2)[O:30][C:31]=1[CH3:32].C(N(C(C)C)CC)(C)C.[N:51]1[CH:56]=[CH:55][CH:54]=[C:53]([CH2:57][NH2:58])[CH:52]=1>CN(C=O)C.C(Cl)Cl>[OH:25][CH2:26][C:27]1[N:28]=[C:29]([C:33]2[CH:34]=[CH:35][C:36]([C:37]([NH:58][CH2:57][C:53]3[CH:52]=[N:51][CH:56]=[CH:55][CH:54]=3)=[O:39])=[CH:40][CH:41]=2)[O:30][C:31]=1[CH3:32]
Reactant: NCc1cccnc1
Reactant: Cc1oc(-c2ccc(C(=O)O)cc2)nc1CO
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1oc(-c2ccc(C(=O)NCc3cccnc3)cc2)nc1CO
Temperature: 20 °C
Reaction time: 0.17 h
Yield: 59.1 %

Procedure:
HBTU (170 mg, 0.45 mmol) was added to a solution of acid 55 (80 mg, 0.34 mmol) and diisopropylethylamine (0.13 mL, 0.69 mmol) in anhydrous DMF (7 mL). The solution was stirred at 20° C. for 10 min. 3-Pyridinylmethanamine (0.14 mL, 1.4 mmol) was then added and the reaction mixture was stirred at 20° C. for 1 h. It was the diluted with DCM (300 mL) and washed with H2O (3×50 mL) and then washed with brine (50 mL). The combined organic phase was dried, filtered and the solvent evaporated. The residue was purified by column chromatography, eluting with 10% MeOH/DCM, to give amide 56 (65 mg, 59%) as a cream powder: mp (MeOH/DCM) 182-184° C.; 1H NMR δ 9.19 (t, J=5.7Hz, 1 H, NH), 8.57 (br s, 1 H, H-2′), 8.46 (br d, J=4.6Hz, 1 H, H-6′), 8.00 (s, 4 H, H-2, H-3, H-5, H-6), 7.74 (br d, J=7.8Hz, 1 H, H-4′), 7.36 (dd, J=7.8, 4.8Hz, 1 H, H-5′), 5.06 (t, J=5.6Hz, 1 H, OH), 4.51 (d, J=5.8Hz, 2 H, CH2N), 4.39 (d, J=5.6Hz, 2 H, CH2O), 2.41 (s, 3 H, CH3); MS m/z 324.8 (MH+, 100%); Anal. calcd for C18H17N3O3.¼H2O: C, 65.94; H, 5.38; N, 12.82. Found: C, 66.06; H, 5.20; N, 12.85.
Reaction SMILES: [C:1]([CH:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[C:7]([C:18]([CH3:21])([CH3:20])[CH3:19])[CH:6]=1)[OH:4])#[CH:2].O[C:23]1[CH:32]=[C:31](I)[CH:30]=[CH:29][C:24]=1[C:25]([O:27][CH3:28])=[O:26]>>[OH:4][CH:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[C:7]([C:18]([CH3:20])([CH3:19])[CH3:21])[CH:6]=1)[C:1]#[C:2][C:31]1[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][CH:32]=1
Reactant: COC(=O)c1ccc(I)cc1O
Reactant: C#CC(O)c1ccc(OCCCCCC)c(C(C)(C)C)c1
Product: CCCCCCOc1ccc(C(O)C#Cc2ccc(C(=O)OC)cc2)cc1C(C)(C)C
Yield: 71.7 %

Procedure:
Following the basic procedure of Example 11(d), by reacting 3.8 g (13.2 mmol) of α-ethynyl-3-tert-butyl-4-(hexyloxy)benzenemethanol with 3.7 g (13.7 mmol) of methyl 2-hydroxy-4-iodobenzoate, 4 g (69%) of methyl 4-[3-hydroxy-3-(3-tert-butyl-4-hexyloxyphenyl)-1-propynyl]benzoate were obtained in the form of a dark brown oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[F:10].[Li]CCCC.[O:16]=[C:17]1[CH2:20][CH:19]([C:21]([O:23][CH3:24])=[O:22])[CH2:18]1.[NH4+].[Cl-]>C1COCC1.CCOCC>[F:10][C:3]1[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=1[C:17]1([OH:16])[CH2:20][CH:19]([C:21]([O:23][CH3:24])=[O:22])[CH2:18]1
Reactant: COC(=O)C1CC(=O)C1
Reactant: COc1ccc(Br)c(F)c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COC(=O)C1CC(O)(c2ccc(OC)cc2F)C1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 45.4 %

Procedure:
To a dry and N2 flashed flask was added 4-bromo-3-fluoroanisole (1.04 g, 5.07 mmol) in THF (6 mL) under N2. This was cooled to −78° C., and n-BuLi (1.72 mL, 4.29 mmol) was added. The reaction was stirred at −78° C. for 30 min. The mixture above was added via cannula to a stirred solution of methyl 3-oxocyclobutane carboxylate (500 mg, 3.90 mmol) in dry Et2O (35 mL) at −78° C. under N2. The reaction mixture was allowed to warm to room temperature and was stirred for 1 h. Satd aq. NH4Cl was added and the mixture was stirred until a clear solution resulted. This mixture was extracted with Et2O (3×). The combined extracts were dried (MgSO4) and concentrated in vacuo to give the crude product, which was purified by flash chromatography (Biotage Horizon, 40M, Si, ˜30 mL/min, 100% hexanes for 260 mL, gradient to 40% EtOAc in hexanes over 5184 mL) to afford methyl 3-(2-fluoro-4-methoxyphenyl)-3-hydroxycyclobutanecarboxylate (450 mg, 45%). 1H NMR (500 MHz, CDCl3): δ 7.32 (t, J=8.9 Hz, 1H); 6.69-6.63 (m, 2H); 3.80 (s, 3H); 3.74 (s, 3H); 3.40 (s, 1H); 3.03-2.93 (m, 2H); 2.90-2.82 (m, 1H); 2.67-2.61 (m, 2H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Br:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[C:10]([Cl:15])[CH:9]=1.[CH3:16][O:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Br)=[CH:20][CH:19]=1>CC(C)=O>[Br:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:22][C:21]2[CH:24]=[CH:25][C:18]([O:17][CH3:16])=[CH:19][CH:20]=2)=[C:10]([Cl:15])[CH:9]=1
Reactant: COc1ccc(CBr)cc1
Reactant: Oc1ccc(Br)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccc(COc2ccc(Br)cc2Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.8 %

Procedure:
Potassium carbonate (0.98 g, 7.086 mmol) was added to a solution of 4-bromo-2-chlorophenol (0.7 g, 3.374 mmol) and 4-methoxybenzylbromide (0.51 mL, 3.543 mmol) in acetone (20 mL) and the mixture was stirred at room temperature overnight. The solid phase was removed by filtration and the filtrate was evaporated to dryness under reduced pressure. The residue was partitioned between EtOAc and aqueous NaOH (2 M). The organic layer was washed with water and brine; dried over Na2SO4, filtered, and evaporated under reduced pressure. The residue was purified via flash chromatography (hexane/EtOAc, 99/1) to give 0.937 g (85% yield) of 4-bromo-2-chloro-1-(4-methoxy-benzyloxy)-benzene as yellow solid.
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+].[CH2:26]([O:33][CH2:34]Cl)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CN(C)C=O>[NH2:1][C:2]1[N:10]=[C:9]([S:11][CH2:34][O:33][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=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: Nc1nc(S)nc2c1nc(O)n2Cc1ccccc1
Reactant: ClCOCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1nc(SCOCc2ccccc2)nc2c1nc(O)n2Cc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 46.7 %

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 benzyloxymethyl chloride (0.1 ml, 0.7 mmol) in order. The mixture was stirred at room temperature for 4 hours. The solvent was removed in vacuo, and the residue was purified by silica gel chromatography (3% methanol/chloroform) to give the subject compound (90 mg, yield 47%).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([S:16][CH2:17][CH2:18][OH:19])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.[C:26]([C:30]1[CH:31]=[C:32]([CH:36]=[C:37]([C:40]([CH3:43])([CH3:42])[CH3:41])[C:38]=1[OH:39])[C:33](Cl)=[O:34])([CH3:29])([CH3:28])[CH3:27]>C1(C)C=CC=CC=1>[C:40]([C:37]1[CH:36]=[C:32]([CH:31]=[C:30]([C:26]([CH3:29])([CH3:28])[CH3:27])[C:38]=1[OH:39])[C:33]([O:19][CH2:18][CH2:17][S:16][C:7]1[CH:6]=[C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])[C:10]([OH:11])=[C:9]([C:12]([CH3:13])([CH3:15])[CH3:14])[CH:8]=1)=[O:34])([CH3:43])([CH3:42])[CH3:41]
Reactant: CC(C)(C)c1cc(SCCO)cc(C(C)(C)C)c1O
Reactant: CC(C)(C)c1cc(C(=O)Cl)cc(C(C)(C)C)c1O
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CC(C)(C)c1cc(SCCOC(=O)c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)cc(C(C)(C)C)c1O
Temperature: 25 °C
Reaction time: 15 h
Yield: 84 %

Procedure:
A solution of 9.8 g of 2-(3,5-di-tert-butyl-4-hydroxyphenylthio) ethanol and 3.1 g of pyridine in 40 ml of toluene was added at 15°-20° C. over five minutes to a solution of 9.4 g of 3,5-di-tert-butyl-4-hydroxybenzoyl chloride in 50 ml of toluene. The reaction mixture was stirred at room temperature for 15 hours and then the resultant precipitate of triethylamine hydrochloride was removed by filtration. The solvent was removed in vacuo and the residue was recrystalized from n-heptane to give 15 g (84%) of a white solid, mp 136°-139° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([CH:12]=[C:13]([C:15]([OH:17])=O)[N:14]=2)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:20]=1[S:27]([NH2:30])(=[O:29])=[O:28]>CN(C)C1C=CN=CC=1.C(O)(C)(C)C.ClCCl>[Cl:1][C:2]1[C:3]2[N:4]([CH:12]=[C:13]([C:15]([NH:30][S:27]([C:20]3[CH:21]=[C:22]([O:25][CH3:26])[CH:23]=[CH:24][C:19]=3[Cl:18])(=[O:29])=[O:28])=[O:17])[N:14]=2)[CH:5]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:7]=1
Reactant: O=C(O)c1cn2cc(C(F)(F)F)cc(Cl)c2n1
Reactant: COc1ccc(Cl)c(S(N)(=O)=O)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CC(C)(C)O
Product: COc1ccc(Cl)c(S(=O)(=O)NC(=O)c2cn3cc(C(F)(F)F)cc(Cl)c3n2)c1
Reaction time: 0.25 h
Yield: 59.6 %

Procedure:
To the carboxylic acid from Step C (243 mg, 0.92 mmol) was added a solution of 4-(dimethylamino)pyridine (340 mg, 2.76 mmol) and 1-(3-dimethyl-aminopropyl)-3-ethylcarbodiimide hydrochloride (232 mg, 2.3 mmol) in t-butanol (5 mL) and dichloromethane (5 mL). The reaction mixture was stirred for 15 min, 2-chloro-5-methoxybenzenesulfonamide (190 mg, 0.86 mmol) was added, and the reaction mixture was stirred at room temperature overnight. Dichloromethane (200 mL) was then added, the mixture was extracted with 1 N hydrochloric acid (3×100 mL), and the separated organic phase was dried over magnesium sulfate and concentrated under reduced pressure to afford a solid. The solid was rinsed with diethyl ether to afford 240 mg of the title compound, a compound of the present invention, as a white solid, m.p. 211-212° C. 1H NMR (CDCl3) δ 10.10 (br s, 1H), 8.46 (s, 1H), 8.27 (s, 1H), 7.86 (d, 1H), 7.54 (s, 1H), 7.38 (d, 1H), 7.09 (dd, 1H) 3.91 (s, 3H).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[CH2:11][C:12]([O:14]CC)=[O:13]>[OH-].[Na+]>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[CH2:11][C:12]([OH:14])=[O:13]
Reactant: CCOC(=O)Cc1cc2ccccc2n1C
Agent: [Na+]
Agent: [OH-]
Product: Cn1c(CC(=O)O)cc2ccccc21
Yield: 48.2 %

Procedure:
A mixture of ethyl 1-methyl-1H-indole-2-acetate (5.0 g) and 2N sodium hydroxide (50 ml) was heated to reflux for 4 h. After cooling, the reaction mixture was extracted with ethyl acetate (2x50 ml) and theresulting aqueous solution was made acidic (pH 1) by addition of 2N hydrochloric acid. The resulting solid was filtered off, washed with ether (100 ml) and dried in vacuo to give the title compound (2.1 g), m.p. 146-148°.
Reaction SMILES: C([Li])CCC.CCCCCC.C(NC(C)C)(C)C.[CH3:19][CH:20]([CH3:32])[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C:29]([OH:31])=[O:30])=[CH:24][CH:23]=1.[CH3:33][Si:34]([CH3:37])([CH3:36])Cl>O1CCCC1>[CH3:19][CH:20]([CH3:32])[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([CH:28]=[C:29]([O:31][Si:34]([CH3:37])([CH3:36])[CH3:33])[O:30][Si:34]([CH3:37])([CH3:36])[CH3:33])=[CH:24][CH:23]=1
Reactant: CC(C)Cc1ccc(CC(=O)O)cc1
Reactant: C[Si](C)(C)Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC(C)Cc1ccc(C=C(O[Si](C)(C)C)O[Si](C)(C)C)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 70.2 %

Procedure:
Butyllithium in hexane (175 ml of 1.6 M solution, 0.28 mol) was added to a solution of 30 g (0.3 mol) of diisopropylamine in 200 ml of tetrahydrofuran at 25° C. The reaction mixture was cooled to 0° C. and a solution of 26.0 g (0.135 mol) of 4-(2-methylpropyl)benzeneacetic acid in 200 ml of tetrahydrofuran was added dropwise near 0° C. The mixture was stirred for 1 hour at 0° C. and then 70 ml (0.55 mol) of trimethylchlorosilane were added. The reaction mixture was warmed to room temperature and stirred for 2 hours. The solid that formed was filtered off; the filtrate was concentrated under reduced pressure and then mixed with 100 ml of diethyl ether. The resultant mixture was filtered and the filtrate was concentrated. Distillation of the residue gave 31.92 g (70% yield) of 4-(2-methylpropyl)-β,β-bis(trimethylsiloxy)styrene as a colorless liquid: bp 128° -130° C. (0.4 mm); ir (liquid) 6.07μ (C=C). Anal. Calcd. for C18H32O2Si2 : C, 64.22; H, 9.58; Found: C, 64.34; H, 9.95.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][P:20]3(=[O:26])[O:25][CH2:24][CH2:23][CH2:22][O:21]3)=[CH:15][CH:14]=2)[N:3]=1.[NH2:27][C:28]1[CH:29]=[CH:30][C:31]([CH:39]2[CH2:44][CH2:43][CH:42]([OH:45])[CH2:41][CH2:40]2)=[C:32]2[C:36]=1[C:35](=[O:37])[N:34]([CH3:38])[CH2:33]2>>[OH:45][C@H:42]1[CH2:41][CH2:40][C@H:39]([C:31]2[CH:30]=[CH:29][C:28]([NH:27][C:2]3[C:7]([C:8]([F:9])([F:11])[F:10])=[CH:6][N:5]=[C:4]([NH:12][C:13]4[CH:18]=[CH:17][C:16]([CH2:19][P:20]5(=[O:26])[O:25][CH2:24][CH2:23][CH2:22][O:21]5)=[CH:15][CH:14]=4)[N:3]=3)=[C:36]3[C:32]=2[CH2:33][N:34]([CH3:38])[C:35]3=[O:37])[CH2:44][CH2:43]1
Reactant: CN1Cc2c(C3CCC(O)CC3)ccc(N)c2C1=O
Reactant: O=P1(Cc2ccc(Nc3ncc(C(F)(F)F)c(Cl)n3)cc2)OCCCO1
Product: CN1Cc2c(c(Nc3nc(Nc4ccc(CP5(=O)OCCCO5)cc4)ncc3C(F)(F)F)ccc2[C@H]2CC[C@H](O)CC2)C1=O

Procedure:
The title compounds were prepared according to the procedure for compound 102 using 4-chloro-N-{4-[(2-oxido-1,3,2-dioxaphosphinan-2-yl)methyl]phenyl}-5-(trifluoromethyl)pyrimidin-2-amine (Compound 230A, 22.8 mg, 0.0559 mmol) and 7-amino-4-(4-hydroxycyclohexyl)-2-methyl-2,3-dihydro-1H-isoindol-1-one (22.0 mg, 0.0845 mmol). The crude material was purified using a Teledyne/ISCO Combiflash system, eluting with 0-15% 7N NH3(MeOH):EtOAc. The collected material was a mixture of regioisomers and was purified again by Supercritical Fluid Chromatography (SFC).