Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].Br[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[Br:14].[Cl:15][C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1>C1(C)C=CC=CC=1.O.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:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:19]1[CH:20]=[CH:21][C:16]([Cl:15])=[CH:17][CH:18]=1
Reactant: Brc1ccccc1Br
Reactant: OB(O)c1ccc(Cl)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: Clc1ccc(-c2ccccc2Br)cc1
Temperature: 25 °C
Yield: 70.5 %

Procedure:
Sodium carbonate (19.8 g, 186.81 mmol) and tetrakis(triphenylphosphine)palladium(0) (1.05 g, 0.90 mmol) were added to a solution of 1,2-dibromobenzene (12.8 ml, 105.98 mmol) and 4-chlorophenylboronic acid (14.1 g, 90.08 mmol) in toluene (170 ml) and water (80 ml). The mixture was purged with nitrogen and heated at reflux overnight. The reaction mixture was allowed to cool to room temperature, and partitioned between saturated aq. NH4Cl and ethyl acetate (500 ml). The organic layer was dried over MgSO4, filtered and the volatiles were evaporated under reduced pressure to give a residue. The residue was purified by column chromatography (ISCO, 330 g silica gel column, eluting with 100% hexanes) to give the title product (17.0 g, yield: 71%).
Reaction SMILES: [CH2:1]=[C:2]1[CH2:7][CH2:6][C@H:5]2[C@H:8]3[C@H:17]([CH2:18][CH2:19][C@:3]12[CH3:4])[C:16]1[CH:15]=[CH:14][C:13]([OH:20])=[CH:12][C:11]=1[CH2:10][CH2:9]3.N1C=CC=CC=1.[C:27](OC(=O)C)(=[O:29])[CH3:28]>C(OCC)(=O)C>[C:27]([O:20][C:13]1[CH:14]=[CH:15][C:16]2[C@@H:17]3[C@H:8]([C@H:5]4[C@@:3]([CH2:19][CH2:18]3)([CH3:4])[C:2](=[CH2:1])[CH2:7][CH2:6]4)[CH2:9][CH2:10][C:11]=2[CH:12]=1)(=[O:29])[CH3:28]
Reactant: C=C1CC[C@H]2[C@@H]3CCc4cc(O)ccc4[C@H]3CC[C@]12C
Reactant: CC(=O)OC(C)=O
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: C=C1CC[C@H]2[C@@H]3CCc4cc(OC(C)=O)ccc4[C@H]3CC[C@]12C

Procedure:
A solution of 17-methylenestra-1,3,5(10)-trien-3-ol (10, 5.84 g, 21.8 mmol) in anh. pyridine (32 mL, 0.40 mol) and acetic anhydride (9.7 mL, 0.10 mol) was stirred 24, after which ethyl acetate (250 mL) was added. See FIG. 17. The mixture was washed with three 100 mL portions of 1 N hydrochloric acid+100 mL of saturated sodium bicarbonate+100 mL of saturated copper sulfate+100 mL of brine, dried over magnesium sulfate, and filtered through diatomaceous earth. The residue was washed with 25 mL of ethyl acetate and the combined filtrates were concentrated under reduced pressure. Recrystallization from aqueous ethanol gave lustrous white platelets (5.84 g, 18.8 mmol), m.p. 77-79° C.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15](=[O:21])[CH2:16][O:17][C:18](=[O:20])[CH3:19])=[CH:5][CH:4]=1.[C:22]([O:26][C:27]([NH:29][C:30]([CH3:48])([CH3:47])[CH2:31][C:32]([NH:34][C@@H:35]1[CH2:41][CH2:40][C:39]2[CH:42]=[CH:43][CH:44]=[CH:45][C:38]=2[NH:37][C:36]1=[O:46])=[O:33])=[O:28])([CH3:25])([CH3:24])[CH3:23]>>[C:18]([O:17][CH2:16][C:15]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[C:6]1[CH:7]=[CH:8][C:3]([CH2:2][N:37]2[C:38]3[CH:45]=[CH:44][CH:43]=[CH:42][C:39]=3[CH2:40][CH2:41][C@@H:35]([NH:34][C:32](=[O:33])[CH2:31][C:30]([NH:29][C:27](=[O:28])[O:26][C:22]([CH3:24])([CH3:23])[CH3:25])([CH3:47])[CH3:48])[C:36]2=[O:46])=[CH:4][CH:5]=1)=[O:21])(=[O:20])[CH3:19]
Reactant: CC(C)(CC(=O)N[C@@H]1CCc2ccccc2NC1=O)NC(=O)OC(C)(C)C
Reactant: CC(=O)OCC(=O)c1ccccc1-c1ccc(CBr)cc1
Product: CC(=O)OCC(=O)c1ccccc1-c1ccc(CN2C(=O)[C@H](NC(=O)CC(C)(C)NC(=O)OC(C)(C)C)CCc3ccccc32)cc1

Procedure:
Prepared from 4'-bromomethyl-2-(acetoxyacetyl)-1,1'-biphenyl and 3-t-butoxycarbonylamino-3-methyl-N-[2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl]-butanamide (Example 57, Step A) by the procedure described in Example 69, Step D. 1H NMR (200 MHz,CDCl3): 1.33 (s,6H), 1.39 (s,9H), 1.87 (m,1H), 2.03 (s,3H), 2.35-2.70 (m,5H), 4.36 (s,2H), 4.51 (m,1H), 4.85 (d,15 Hz,1H), 5.28 (d,15 Hz,1H), 6.66 (m,1H), 7.1-7.6 (m,12H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14](=[O:18])OCC)=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH3:19])[CH:9]=2)[N:4]=1.[CH3:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[C:22]=1[N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([N:31]2[CH2:32][CH2:33][N:28]([C:22]3[C:23]([CH3:27])=[CH:24][CH:25]=[CH:26][C:21]=3[CH3:20])[CH2:29][CH2:30]2)=[O:18])=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH3:19])[CH:9]=2)[N:4]=1
Reactant: CCOC(=O)Nc1nc2cc(C)ccc2nc1OC
Reactant: Cc1cccc(C)c1N1CCNCC1
Product: COc1nc2ccc(C)cc2nc1NC(=O)N1CCN(c2c(C)cccc2C)CC1
Yield: 88 %

Procedure:
Ethyl N-(2-methoxy-6-methylquinoxalin-3-yl)carbamate and 1-(2,6-dimethylphenyl)piperazine were reacted by the same way with the example 43 to obtain the titled compound (yield, 88%). 1H NMR (300 MHz, CDCl3): δ 2.04-2.58 (m, 9H), 3.14-3.20 (m, 4H), 3.71-3.76 (m, 3H), 4.07-4.14 (m, 4H), 7.00-7.15 (m, 4H), 7.25-7.76 (m, 3H).
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[OH:19][NH:20][C:21]([CH:23]1[CH2:28][N:27]([C:29]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[O:30])[CH2:26][CH2:25][N:24]1[S:39]([N:42]1[CH2:47][CH2:46][CH:45]([C:48]2[C:56]3[C:51](=[CH:52][CH:53]=[C:54]([F:57])[CH:55]=3)[N:50](S(CC[Si](C)(C)C)(=O)=O)[CH:49]=2)[CH2:44][CH2:43]1)(=[O:41])=[O:40])=[O:22].C(O)(=O)C>O1CCCC1>[OH:19][NH:20][C:21]([CH:23]1[CH2:28][N:27]([C:29]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[O:30])[CH2:26][CH2:25][N:24]1[S:39]([N:42]1[CH2:47][CH2:46][CH:45]([C:48]2[C:56]3[C:51](=[CH:52][CH:53]=[C:54]([F:57])[CH:55]=3)[NH:50][CH:49]=2)[CH2:44][CH2:43]1)(=[O:41])=[O:40])=[O:22]
Reactant: C[Si](C)(C)CCS(=O)(=O)n1cc(C2CCN(S(=O)(=O)N3CCN(C(=O)OCc4ccccc4)CC3C(=O)NO)CC2)c2cc(F)ccc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: O=C(NO)C1CN(C(=O)OCc2ccccc2)CCN1S(=O)(=O)N1CCC(c2c[nH]c3ccc(F)cc23)CC1
Temperature: 45 °C
Yield: 71 %

Procedure:
Tetrabutylammonium fluoride (0.194 ml, 1M solution in tetrahydrofuran) was added to a solution of N-hydroxy-4-benzyloxycarbonyl-1-{4-[5-fluoro-1-(2-trimethylsilylethanesulfonyl)-indol-3-yl]-piperidine-1-sulfonyl}piperazine-2-(RS)-carboxamide (0.067 mg, 0.093 mmol), [prepared as described in Step 7 above] in tetrahydrofuran (1.6 ml). The reaction mixture was heated at 45° C. for approx. 20 min., and then quenched with glacial acetic acid (0.011 ml, 0.194 mmol). The reaction mixture was concentrated and the residue was chromatographed by preparatory TLC (10% methanol/methylene chloride) to give N-hydroxy-4-benzyloxycarbonyl-1-{4-[5-fluoroindol-3-yl]piperidine-1-sulfonyl}piperazine-2-(RS)-carboxamide (71%), mp 85.7-89.7° C.
Reaction SMILES: C(N(CC)CC)C.[O:8]=[C:9]1[N:15]([CH:16]2[CH2:21][CH2:20][N:19]([C:22]([O:24][C@@H:25]([C:39](O)=[O:40])[CH2:26][C:27]3[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[C:30]([NH2:37])=[C:29]([Cl:38])[CH:28]=3)=[O:23])[CH2:18][CH2:17]2)[CH2:14][CH2:13][C:12]2[CH:42]=[CH:43][CH:44]=[CH:45][C:11]=2[NH:10]1.[CH3:46][N:47]1[CH2:52][CH2:51][CH:50]([N:53]2[CH2:58][CH2:57][NH:56][CH2:55][C@H:54]2[C:59]([O:61][CH2:62][CH3:63])=[O:60])[CH2:49][CH2:48]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[NH2:37][C:30]1[C:31]([C:33]([F:36])([F:35])[F:34])=[CH:32][C:27]([CH2:26][C@@H:25]([O:24][C:22]([N:19]2[CH2:20][CH2:21][CH:16]([N:15]3[CH2:14][CH2:13][C:12]4[CH:42]=[CH:43][CH:44]=[CH:45][C:11]=4[NH:10][C:9]3=[O:8])[CH2:17][CH2:18]2)=[O:23])[C:39]([N:56]2[CH2:57][CH2:58][N:53]([CH:50]3[CH2:49][CH2:48][N:47]([CH3:46])[CH2:52][CH2:51]3)[C@H:54]([C:59]([O:61][CH2:62][CH3:63])=[O:60])[CH2:55]2)=[O:40])=[CH:28][C:29]=1[Cl:38]
Reactant: Nc1c(Cl)cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc1C(F)(F)F
Reactant: CCOC(=O)[C@@H]1CNCCN1C1CCN(C)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@@H]1CN(C(=O)[C@@H](Cc2cc(Cl)c(N)c(C(F)(F)F)c2)OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)CCN1C1CCN(C)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
0.25 mL (2.88 mmol) triethylamine were added to a mixture of 200 mg (0.36 mmol) (R)-2-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-1-carboxy-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate (Example 1f), 150 mg (0.58 mmol) ethyl(S)-1-(1-methyl-piperidin-4-yl)-piperazine-2-carboxylate (Example A10c) and 140 mg (0.44 mmol) TBTU in 2.0 mL DMF and the reaction mixture was stirred for 5 h at RT. This was purified by HPLC without any further working up; the fractions containing the product were combined and lyophilised.
Reaction SMILES: CS(O[CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)(=O)=O.[C:21]([O-:24])(=[S:23])[CH3:22].[K+].O>CS(C)=O>[C:21]([S:23][CH:6]1[CH2:7][CH2:8][N:9]([C:12]2[CH:13]=[CH:14][C:15]([N+:18]([O-:20])=[O:19])=[CH:16][CH:17]=2)[CH2:10][CH2:11]1)(=[O:24])[CH3:22]
Reactant: CS(=O)(=O)OC1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Reactant: CC([O-])=S
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CC(=O)SC1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Yield: 61.6 %

Procedure:
A solution of 4-[4-(methanesulfonyloxy)piperidin-1-yl]nitrobenzene (2.0 g), and potassium thioacetate (1.14 g) in dimethylsulfoxide (DMSO) (20 ml) was stirred at 100-110° C. for 3 hours. The reaction mixture was poured into water (100 ml) and extracted twice with ethyl acetate (100 ml). The extracts were collected, washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and evaporated in vacuo. The resulting precipitates were washed with IPE (50 ml), collected by filtration and dried in vacuo to give 4-(4-acetylthiopiperidin-1-yl)nitrobenzene (1.15 g).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][OH:5].[CH:6]([S:8]([CH:11]=[CH2:12])(=[O:10])=[O:9])=[CH2:7]>>[O:9]=[S:8]1(=[O:10])[CH2:11][CH2:12][N:1]([CH2:2][CH2:3][CH2:4][OH:5])[CH2:7][CH2:6]1
Reactant: C=CS(=O)(=O)C=C
Reactant: NCCCO
Product: O=S1(=O)CCN(CCCO)CC1
Temperature: 110 °C
Yield: 49.3 %

Procedure:
A mixture of 3-amino-1-propanol (650;1, 8.4 mmol) and vinyl sulphone (1 g, 8.4 mmol) was heated at 110° C. for 45 minutes. The mixture was allowed to cool and was purified by column chromatography eluting with methylene chloride/methanol (95/5) to give 3-(1,1-dioxothiomorpholino)-1-propanol (800 mg, 90%).
Reaction SMILES: C([O:3][C:4](=[O:34])[CH:5]=[C:6]([C:8]1[O:12][C:11]2[C:13]([C:17]3[CH:22]=[C:21]([CH:23]([CH3:25])[CH3:24])[CH:20]=[C:19]([CH:26]([CH3:28])[CH3:27])[C:18]=3[O:29][CH2:30][CH:31]([F:33])[F:32])=[CH:14][CH:15]=[CH:16][C:10]=2[CH:9]=1)[CH3:7])C.C1COCC1.[Li+].[OH-]>CO>[F:33][CH:31]([F:32])[CH2:30][O:29][C:18]1[C:19]([CH:26]([CH3:28])[CH3:27])=[CH:20][C:21]([CH:23]([CH3:25])[CH3:24])=[CH:22][C:17]=1[C:13]1[C:11]2[O:12][C:8]([C:6]([CH3:7])=[CH:5][C:4]([OH:34])=[O:3])=[CH:9][C:10]=2[CH:16]=[CH:15][CH:14]=1
Reactant: CCOC(=O)C=C(C)c1cc2cccc(-c3cc(C(C)C)cc(C(C)C)c3OCC(F)F)c2o1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(=CC(=O)O)c1cc2cccc(-c3cc(C(C)C)cc(C(C)C)c3OCC(F)F)c2o1
Temperature: 25 °C

Procedure:
A mixture of 0.450 mmol of 3-{7-[2-(2,2-difluoroethoxy)-3,5-diisopropylphenyl]-benzo[b]furan-2-yl}-but-2-enoic acid ethyl ester, 3 mL of THF, 3 mL of methanol and 1 mL of LiOH (2N aqueous) was refluxed for 2 hours. After cooling at room temperature, the mixture was acidified to pH=2 and extracted with ethyl acetate. The organic layer was dried over MgSO4 and after evaporation of the solvents, the crude acid was recrystallized from acetonitrile. 3-{7-[2-(2,2-Difluoroethoxy)-3,5-diisopropylphenyl]-benzo[b]furan-2-yl}-but-2-enoic acid was isolated as a white solid. 1H-NMR (400 MHz, CDCl3) δ 7.60 (d, J=7.1 Hz, 1H, Ar—H), 7.57 (d, J=7.4 Hz, 1H, Ar—H), 7.32 (d, J=2.3 Hz, 1H, Ar—H), 7.31 (t, J=7.6 Hz, 1H, Ar—H), 7.18 (d, J=2.2 Hz, 1H, Ar—H), 7.11 (s, 1H, furan-H), 6.58 (s, 1H, C═C—H), 5.54 (tt, J=55.3 Hz, J=4.2 Hz, 1H, O—CH2—CF2H), 3.54 (dt, J=13.6 Hz, J=4.2 Hz, 2H, O—CH2—CF2H), 3.42 (m, 1H, CH3—CH—CH3), 2.96 (m, 1H, CH3—CH—CH3), 2.57 (s, 3H, C═C—CH3), 1.32 (d, J=6.8 Hz, 6H, CH3—CH—CH3), 1.31 (d, J=6.8 Hz, 6H, CH3—CH—CH3).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][C:6]1[NH:7][C:8]([CH3:28])=[C:9]([C:24]([O:26][CH3:27])=[O:25])[CH:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:23])[C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13].C(N(CC)CC)C.Cl[CH2:37][CH2:38][N:39]=[C:40]=[S:41]>C(Cl)Cl>[Cl:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[CH:10]1[C:9]([C:24]([O:26][CH3:27])=[O:25])=[C:8]([CH3:28])[NH:7][C:6]([CH2:5][O:4][CH2:3][CH2:2][NH:1][C:40]2[S:41][CH2:37][CH2:38][N:39]=2)=[C:11]1[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: S=C=NCCCl
Reactant: CCOC(=O)C1=C(COCCN)NC(C)=C(C(=O)OC)C1c1ccccc1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C1=C(COCCNC2=NCCS2)NC(C)=C(C(=O)OC)C1c1ccccc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-[2-Aminoethoxymethyl]-3-ethoxycarbonyl-4-(2-chlorophenyl)-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine (0.5 g), triethylamine (0.3 ml) and 2-chloroethylisothiocyanate (0.16 ml) were dissolved in methylene chloride (5 ml) and the mixture was stirred at room temperature for 2 hours. The mixture was then washed with water (5 ml), dried, filtered and evaporated to give a gum. Chromatography of the gum on silica "Kieselgel 60H" (Trade Mark) eluting initially with toluene then with chloroform with a trace of methanol gave the title compound, which was recrystallised from ether, yield 0.102 g, m.p. 145°-147°.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:16])=[CH:4][C:5]([Cl:15])=[C:6]([S:8][C:9]2([C:12]([OH:14])=[O:13])[CH2:11][CH2:10]2)[CH:7]=1.[CH3:17]O>S(=O)(=O)(O)O>[CH3:17][O:13][C:12]([C:9]1([S:8][C:6]2[CH:7]=[C:2]([NH2:1])[C:3]([F:16])=[CH:4][C:5]=2[Cl:15])[CH2:11][CH2:10]1)=[O:14]
Reactant: Nc1cc(SC2(C(=O)O)CC2)c(Cl)cc1F
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)C1(Sc2cc(N)c(F)cc2Cl)CC1

Procedure:
A solution of 3.6 g of 1-(5-amino-2-chloro-4-fluorophenylthio)-cyclopropanecarboxylic acid and a few drops of sulfuric acid in 50 ml of methanol is heated under reflux until the starting material can no longer be detected. The methanol is then evaporated off, water and ethyl acetate are added to the residue and the organic phase is washed in succession with sodium hydrogen carbonate solution, water and saturated sodium chloride solution. Concentration and purification of the crude product by means of silica gel chromatography yield 5.7 g of 1-(5-amino-2-chloro-4-fluorophenylthio)-cyclopropanecarboxylic acid methyl ester having a melting point of from +119° to +121° C.
Reaction SMILES: Cl[C:2]1[C:3](=[O:15])[N:4]([C@H:9]([CH2:12][O:13][CH3:14])[CH2:10][CH3:11])[CH:5]=[C:6]([Cl:8])[N:7]=1.[Br:16][C:17]1[CH:18]=[C:19]2[C:23](=[C:24]([Cl:26])[CH:25]=1)[NH:22][CH2:21][CH2:20]2>>[Br:16][C:17]1[CH:18]=[C:19]2[C:23](=[C:24]([Cl:26])[CH:25]=1)[N:22]([C:2]1[C:3](=[O:15])[N:4]([C@H:9]([CH2:12][O:13][CH3:14])[CH2:10][CH3:11])[CH:5]=[C:6]([Cl:8])[N:7]=1)[CH2:21][CH2:20]2
Reactant: CC[C@@H](COC)n1cc(Cl)nc(Cl)c1=O
Reactant: Clc1cc(Br)cc2c1NCC2
Product: CC[C@@H](COC)n1cc(Cl)nc(N2CCc3cc(Br)cc(Cl)c32)c1=O

Procedure:
Prepared in a similar fashion as described for Example 413 using 3,5-dichloro-1-[(1S)-1-(methoxymethyl)propyl]-2(1H)-pyrazinone and 5-bromo-7-chloroindoline as the starting materials. mp 121–122° C.; 1H NMR (300 MHz, CDCl3): δ 7.24 (s, 1 H), 7.18 (s, 1 H), 6.99 (s, 1 H), 4.90–4.80 (m, 1 H), 4.26 (t, J=8.1 Hz, 2 H), 3.60 (dd, J=10.2, 5.5 Hz, 1 H), 3.49 (dd, J=10.6, 3.3 Hz, 1 H), 3.28 (s, 3 H), 3.06 (t, J=8.1 Hz, 2 H), 1.83–1.65 (m, 2 H), 0.86 (t, J=7.4 Hz, 3 H); HRMS (ESI) calcd for C17H19N3O2BrCl2 (M+H)+: 446.0038; Found m/z 446.0048.
Reaction SMILES: P(Br)(Br)[Br:2].[CH2:5]([O:7][C:8]([C:10]1[CH:11]=[N:12][C:13]2[C:18]([C:19]=1O)=[CH:17][C:16]([O:21][CH3:22])=[CH:15][CH:14]=2)=[O:9])[CH3:6]>CN(C=O)C>[CH2:5]([O:7][C:8]([C:10]1[CH:11]=[N:12][C:13]2[C:18]([C:19]=1[Br:2])=[CH:17][C:16]([O:21][CH3:22])=[CH:15][CH:14]=2)=[O:9])[CH3:6]
Reactant: CCOC(=O)c1cnc2ccc(OC)cc2c1O
Reactant: BrP(Br)Br
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnc2ccc(OC)cc2c1Br
Reaction time: 0.5 h
Yield: 55.3 %

Procedure:
PBr3 (64.5 g, 22.5 mL, 0.239 mole) was added dropwise to a stirred, ice cold suspension of 4-hydroxy-6-methoxy-quinoline-3-carboxylic acid ethyl ester (59 g, 0.239 mole) in DMF (750 mL); the temperature rose to 15-20° C. for 30 min and then dropped to ca. 5° C. (the starting material dissolved fairly quickly and a new solid precipitated out). After 3 hr the solid was collected, washed sequentially with cold DMF, hexane, and water, then was dried at 40° C. in vacuo overnight to give the title compound (41 g, 78%): LC/MS (ES) m/e 310/312 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:13]1([CH3:19])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[N:53]1([S:58]([NH:61][C:62]([C@@:64]2([NH:69][C:70]([C@@H:72]3[CH2:83][C@:75]4([C:80]([CH3:82])([CH3:81])[C:76]54[CH2:79][CH2:78][CH2:77]5)[CH2:74][N:73]3[C:84](=[O:94])[C@@H:85]([NH2:93])[C:86]3(C)[CH2:91][CH2:90][O:89][CH2:88][CH2:87]3)=[O:71])[CH2:66][C@H:65]2[CH:67]=[CH2:68])=[O:63])(=[O:60])=[O:59])[CH2:57][CH2:56][CH2:55][CH2:54]1>C(Cl)Cl>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]([C:10](=[O:12])[NH:93][C@@H:85]([CH:86]1[CH2:91][CH2:90][O:89][CH2:88][CH2:87]1)[C:84]([N:73]1[C@H:72]([C:70](=[O:71])[NH:69][C@:64]2([C:62]([NH:61][S:58]([N:53]3[CH2:57][CH2:56][CH2:55][CH2:54]3)(=[O:59])=[O:60])=[O:63])[CH2:66][C@H:65]2[CH:67]=[CH2:68])[CH2:83][C@:75]2([C:80]([CH3:82])([CH3:81])[C:76]32[CH2:79][CH2:78][CH2:77]3)[CH2:74]1)=[O:94])[C:13]1([CH3:19])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@]2(CN1C(=O)[C@@H](N)C1(C)CCOCC1)C(C)(C)C21CCC1)C(=O)NS(=O)(=O)N1CCCC1
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)O)C1(C)CCCCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@]2(CN1C(=O)[C@@H](NC(=O)[C@@H](NC(=O)OC(C)(C)C)C1(C)CCCCC1)C1CCOCC1)C(C)(C)C21CCC1)C(=O)NS(=O)(=O)N1CCCC1
Reaction time: 3 h

Procedure:
A solution of (S)-tert-Butoxycarbonylamino-(1-methyl-cyclohexyl)-acetic acid (0.15 g; 0.55 mmol) (prepared according to Tetrahedron Let. 2007, 48, 6343-6347) and HATU (0.31 g; 0.82 mmol) in DCM (15 mL) was stirred for 30 min at ambient temperature. After addition of DIPEA (0.56 mL; 3.27 mmol) and (5R,8S)-7-[(S)-2-Amino-2-(4-methyl-tetrahydro-pyran-4-yl)-acetyl]-10,10-dimethyl-7-aza-dispiro-[3.0.4.1]decane-8-carboxylic acid [(1R,2S)-1-(pyrrolidine-1-sulfonylaminocarbonyl)-2-vinyl-cyclopropyl]-amide (0.412 g; 0.55 mmol) in DCM (5 mL) the reaction mixture was stirred for 3 h, the solvent was removed in vacuo and the residue was purified by preparative HPLC (method L) to yield the title compound. LC-MS (method E): Rt=2.78 min; M/z=859 [M+], HPLC (method A3) Rt=6.81 min
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Si]([O:26][CH2:27][C@H:28]([O:30][CH2:31][C@H:32]([O:43][C:44]1[N:49]=[CH:48][N:47]=[C:46]2[N:50]([C:53]3[C:58]([Cl:59])=[CH:57][CH:56]=[CH:55][N:54]=3)[N:51]=[CH:52][C:45]=12)[C:33]([NH:35][C:36]1[CH:41]=[CH:40][C:39]([F:42])=[CH:38][N:37]=1)=[O:34])[CH3:29])(C(C)(C)C)(C)C>C1COCC1>[Cl:59][C:58]1[C:53]([N:50]2[C:46]3=[N:47][CH:48]=[N:49][C:44]([O:43][C@@H:32]([CH2:31][O:30][C@H:28]([CH3:29])[CH2:27][OH:26])[C:33]([NH:35][C:36]4[CH:41]=[CH:40][C:39]([F:42])=[CH:38][N:37]=4)=[O:34])=[C:45]3[CH:52]=[N:51]2)=[N:54][CH:55]=[CH:56][CH:57]=1
Reactant: C[C@H](CO[Si](C)(C)C(C)(C)C)OC[C@H](Oc1ncnc2c1cnn2-c1ncccc1Cl)C(=O)Nc1ccc(F)cn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C[C@H](CO)OC[C@H](Oc1ncnc2c1cnn2-c1ncccc1Cl)C(=O)Nc1ccc(F)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 45.9 %

Procedure:
Tetrabutylammonium fluoride (1M in THF) (604 μl, 0.60 mmol) was added to (2S)-3-((R)-1-(tert-butyldimethylsilyloxy)propan-2-yloxy)-2-(1-(3-chloropyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)-N-(5-fluoropyridin-2-yl)propanamide (Intermediate AN5) (303 mg, 0.50 mmol) in THF (5 mL) under nitrogen. The resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched with saturated NH4Cl (10 mL), extracted with Et2O (3×15 mL), the combined organic layers were back washed with water (10 mL), dried (MgSO4) and evaporated to afford crude product. The crude product was purified by preparative chiral-HPLC on a Merck 50 mm 20 μm Chiralpak AS column, eluting isocratically with 30% EtOH in isohexane (modified with Et3N) as eluent to afford the product (112 mg, 45.6%). 1H NMR (400 MHz, CDCl3) δ1.17 (d, 3H), 2.99-3.05 (m, 1H), 3.54-3.61 (m, 1H), 3.62-3.70 (m, 1H), 3.75-3.84 (m, 1H), 4.07-4.13 (m, 1H), 4.25-4.31 (m, 1H), 6.04-6.09 (m, 1H), 7.43-7.50 (m, 2H), 7.99-8.03 (m, 1H), 8.13 (d, 1H), 8.18-8.23 (m, 1H), 8.45 (s, 1H), 8.61-8.63 (m, 1H), 8.64 (s, 1H), 9.17 (s, 1H); m/z (ESI+) (M+H)+=488.42; HPLC tR=1.74 min
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.[CH2:13]([C:21]1[CH:22]=[N:23][C:24]([C:27]2[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=2)=[N:25][CH:26]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].[CH3:34][Si:35]([CH3:51])([CH2:45][CH2:46][Si:47]([CH3:50])([CH3:49])[CH3:48])[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[CH3:51][Si:35]([CH3:34])([CH2:45][CH2:46][Si:47]([CH3:48])([CH3:49])[CH3:50])[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][O:33][C:30]1[CH:31]=[CH:32][C:27]([C:24]2[N:23]=[CH:22][C:21]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:26][N:25]=2)=[CH:28][CH:29]=1
Reactant: C[Si](C)(C)CC[Si](C)(C)CCCCCCCCO
Reactant: CCCCCCCCc1cnc(-c2ccc(O)cc2)nc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCCCCCCc1cnc(-c2ccc(OCCCCCCCC[Si](C)(C)CC[Si](C)(C)C)cc2)nc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of diethylazodicarboxylate (0.065 g, 0.375 mmol) in THF (5.0 ml) was added dropwise to a stirred solution of 4-(5-octylpyrimidin-2-yl)-phenol (0.085g, 0.300 mmol), compound 17 (0.083 g, 0.300 mmol) and triphenylphosphine (0.098 g, 0.375 mmol) in THF (10 ml). The treaction mixture was stirred at room temperature for 24 h, the solvent removed in vacuo and the residues purified by column chromatography [silica gel eluted with hexane/ethyl acetate (9:1)] to yield a colorless solid that was recrystallized from acetonitrile.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][CH2:7][CH2:8][C:9]1[O:10][C:11]2[C:16]([C:17](=[O:27])[C:18]=1[C:19]1[CH:24]=[CH:23][C:22]([O:25]C)=[CH:21][CH:20]=1)=[C:15]([OH:28])[CH:14]=[C:13]([OH:29])[CH:12]=2)=[O:5])C.B(Br)(Br)Br.CO>C(Cl)Cl>[CH3:1][O:3][C:4]([CH2:6][CH2:7][CH2:8][C:9]1[O:10][C:11]2[C:16]([C:17](=[O:27])[C:18]=1[C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=1)=[C:15]([OH:28])[CH:14]=[C:13]([OH:29])[CH:12]=2)=[O:5]
Reactant: CCOC(=O)CCCc1oc2cc(O)cc(O)c2c(=O)c1-c1ccc(OC)cc1
Agent: BrB(Br)Br
Solvent: CO
Solvent: ClCCl
Product: COC(=O)CCCc1oc2cc(O)cc(O)c2c(=O)c1-c1ccc(O)cc1
Temperature: 25 °C
Yield: 74.8 %

Procedure:
To a solution of 2-[3-(ethoxycarbonyl)propyl]-7,5-dihydroxy-4′-methoxyisoflavone (104 mg, 0.26 mmol), prepared according to Pelter et al. (Pelter et al, 1998) in anhydrous DCM (2 ml) at −78° C. under nitrogen, 1.0 M BBr3 in DCM (2.1 ml, 2.1 mmol) was added slowly. The mixture was allowed to warm gradually to room temperature overnight. The mixture was then cooled in an ice bath and anhydrous MeOH (2 ml) was added slowly. The solvents were evaporated under reduced pressure leaving a brown solid that was purified by column chromatography on silica gel (gradient elution: DCM to DCM/acetone 8:2) yielding 2-[3-(methoxycarbonyl)propyl]-5,7,4′-trihydroxyisoflavone as a solid (72 mg, 75%).