Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]12[O:10][B:9]([C@@H:11]([NH:28][C:29]([C:31]3[CH:32]=[C:33]4[C:37](=[CH:38][CH:39]=3)[CH2:36][NH:35][CH2:34]4)=[O:30])[CH2:12][C:13]3[C:14]([O:26][CH3:27])=[C:15]([CH:23]=[CH:24][CH:25]=3)[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[O:8][CH:7]1[CH2:6][CH:5]1[CH2:40][CH:3]2[C:4]1([CH3:42])[CH3:41].[CH:43](=O)[C:44]1[CH:49]=[CH:48][CH:47]=[N:46][CH:45]=1.O>ClCCCl>[CH3:27][O:26][C:14]1[C:13]([CH2:12][C@H:11]([NH:28][C:29]([C:31]2[CH:32]=[C:33]3[C:37](=[CH:38][CH:39]=2)[CH2:36][N:35]([CH2:43][C:44]2[CH:45]=[N:46][CH:47]=[CH:48][CH:49]=2)[CH2:34]3)=[O:30])[B:9]2[O:8][CH:7]3[C:2]([CH3:1])([CH:3]4[CH2:40][CH:5]([CH2:6]3)[C:4]4([CH3:42])[CH3:41])[O:10]2)=[CH:25][CH:24]=[CH:23][C:15]=1[C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17]
Reactant: O=Cc1cccnc1
Reactant: COc1c(C[C@H](NC(=O)c2ccc3c(c2)CNC3)B2OC3CC4CC(C4(C)C)C3(C)O2)cccc1C(=O)OC(C)(C)C
Solvent: ClCCCl
Solvent: O
Product: COc1c(C[C@H](NC(=O)c2ccc3c(c2)CN(Cc2cccnc2)C3)B2OC3CC4CC(C4(C)C)C3(C)O2)cccc1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To tert-butyl 3-((2R)-2-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-yl)-2-(isoindoline-5-carboxamido)ethyl)-2-methoxybenzoate from Example 9 step 2 (240 mg, 0.42 mmol) in 1,2-dichloroethane (5 mL) was added nicotinaldehyde (90 mg, 0.84 mmol) and Na(OAc)3BH4 (211 mg, 1 mmol). The reaction mixture was stirred at room temperature for 6 hr. Water (10 mL) was added at 0° C. and the aqueous phase was extracted with EtOAc. The organic phase was washed brine, dried over Na2SO4 and concentrated in vacuo. The crude product was carried to the next step without further purification. ESI-MS m/z 666.1 (MH)+.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][C@H:7]([C:12]([NH:14][C@H:15]([CH2:19][N:20]3[CH2:25][CH2:24][C@:23]([C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([OH:33])[CH:28]=4)([CH3:26])[C@@H:22]([CH3:34])[CH2:21]3)[CH:16]([CH3:18])[CH3:17])=[O:13])[NH:8][CH2:9]2)=[CH:4][CH:3]=1.[CH3:35][N:36]([CH3:41])[CH2:37][C:38](O)=[O:39]>>[CH3:35][N:36]([CH3:41])[CH2:37][C:38]([N:8]1[C@@H:7]([C:12]([NH:14][C@H:15]([CH2:19][N:20]2[CH2:25][CH2:24][C@:23]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([OH:33])[CH:28]=3)([CH3:26])[C@@H:22]([CH3:34])[CH2:21]2)[CH:16]([CH3:18])[CH3:17])=[O:13])[CH2:6][C:5]2[C:10](=[CH:11][C:2]([OH:1])=[CH:3][CH:4]=2)[CH2:9]1)=[O:39]
Reactant: CN(C)CC(=O)O
Reactant: CC(C)[C@@H](CN1CC[C@@](C)(c2cccc(O)c2)[C@@H](C)C1)NC(=O)[C@H]1Cc2ccc(O)cc2CN1
Product: CC(C)[C@@H](CN1CC[C@@](C)(c2cccc(O)c2)[C@@H](C)C1)NC(=O)[C@H]1Cc2ccc(O)cc2CN1C(=O)CN(C)C
Yield: 86 %

Procedure:
(3R)-7-Hydroxy-N-((1S)-1-{[(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl]methyl}-2-methylpropyl)-1,2,3,4-tetrahydro-3-isoquinolinecarboxamide (14, 0.100 g, 0.285 mmol) was coupled to N,N-dimethylglycine as described above to yield crude product which was purified by flash chromatography (50% (CHCl3:MeOH:NH4OH, 80:18:2) in CHCl3) to afford (3R)-2-(N,N-dimethylglycyl)-7-hydroxy-N-((1S)-1-{[(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl]methyl}-2-methylpropyl)-1,2,3,4-tetrahydro-3-isoquinolinecarboxamide (17, 0.101 g, 86%) as a white foam. LRMS (ES) m/z 551.4 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](Cl)=[O:6].[Cl-].[Al+3].[Cl-].[Cl-].[CH3:15][N:16]1[CH:20]=[CH:19][CH:18]=[C:17]1[C:21]([O:23][CH3:24])=[O:22]>ClCCCl>[CH3:15][N:16]1[CH:20]=[C:19]([C:5](=[O:6])[C:4]2[CH:8]=[CH:9][CH:10]=[C:2]([Cl:1])[CH:3]=2)[CH:18]=[C:17]1[C:21]([O:23][CH3:24])=[O:22]
Reactant: O=C(Cl)c1cccc(Cl)c1
Reactant: COC(=O)c1cccn1C
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: COC(=O)c1cc(C(=O)c2cccc(Cl)c2)cn1C
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 94.5 %

Procedure:
To 100 ml 1,2-dichloroethane are added 5 g 3-chloro-benzoyl chloride followed by 8.4 g aluminium chloride. The mixture is cooled to 5° C. and 4 g methyl 1-methylpyrrole-2-carboxylate dissolved in 15 ml 1,2-dichloroethane are added thereto. The resulting mixture is stirred 0.5 hour at said temperature and then 1 hour at room temperature, after which the solution is hydrolyzed over ice, the organic phase is decanted and the solvent is evaporated off. Recrystallization of the solid residue from methanol give 7.5 g methyl 1-methyl-4-(3-chlorobenzoyl)pyrrole-2-carboxylate, m.p.=126° C.
Reaction SMILES: [Br:1][C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[O:4][CH:5]([CH2:11][CH2:12][CH3:13])[C:6]([O:8]CC)=[O:7].CO.[OH-].[Na+]>O>[Br:1][C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[O:4][CH:5]([CH2:11][CH2:12][CH3:13])[C:6]([OH:8])=[O:7]
Reactant: CCCC(Oc1ccccc1Br)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCC(Oc1ccccc1Br)C(=O)O
Temperature: 25 °C
Yield: 46.4 %

Procedure:
26.5 g (188 mmol) of ethyl 2-(2-bromophenoxy)pentanoate, 50 ml of methanol, 21.1 g (528 mmol) of sodium hydroxide pellets and 3 ml of water are placed in 250 ml three-necked flask equipped with a reflux condenser. The mixture is heated at reflux for 3 hours and then cooled to room temperature and concentrated. 200 ml of water are added and extraction is carried out with 150 ml of petroleum ether. The aqueous phase is subsequently acidified by the addition of a hydrochloric acid solution and then extracted with 3×200 ml of chloroform. The combined organic phases are dried over magnesium sulphate, filtered and concentrated under vacuum to give 23.8 g (99% yield) of 2-(2-bromophenoxy)pentanoic acid--M.p.=63° C.
Reaction SMILES: [F:1][C:2]1[CH:28]=[CH:27][C:5]([O:6][CH2:7][C@H:8]2[CH2:26][N:12]3[CH2:13][CH2:14][N:15]([C:17]4[CH:22]=[CH:21][C:20]([N+:23]([O-])=O)=[CH:19][CH:18]=4)[CH2:16][C@@H:11]3[CH2:10][CH2:9]2)=[CH:4][CH:3]=1>C1COCC1.[Pd]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][C@H:8]2[CH2:26][N:12]3[CH2:13][CH2:14][N:15]([C:17]4[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=4)[CH2:16][C@@H:11]3[CH2:10][CH2:9]2)=[CH:27][CH:28]=1
Reactant: O=[N+]([O-])c1ccc(N2CCN3C[C@H](COc4ccc(F)cc4)CC[C@H]3C2)cc1
Agent: [Pd]
Solvent: C1CCOC1
Product: Nc1ccc(N2CCN3C[C@H](COc4ccc(F)cc4)CC[C@H]3C2)cc1
Reaction time: 4 h
Yield: 81.2 %

Procedure:
A mixture of 0.600 g (1.56 mmol) of (7R,9aS)-7-(4-fluorophenoxy)methyl-2-(4-nitrophenyl)-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine and 90 mg of 10% Pd/C in 25 mL of THF was placed in a Parr hydrogenator at 30 psi for 4 h. The catalyst was removed by filtration through Celite and the filtrate was evaporated to give 0.45 g (82%) of (7R,9aS)-7-(4-fluorophenoxy)methyl-2-(4-aminophenyl)-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine.
Reaction SMILES: C1(OC2C=CC=CC=2)C=CC=CC=1.[C:14]([N:17]1[CH2:22][CH2:21][N:20]([C:23]2[N:28]=[C:27]([NH:29][CH:30]=[C:31]([C:37]([O:39]CC)=O)[C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:26]=[CH:25][N:24]=2)[CH2:19][CH2:18]1)(=[O:16])[CH3:15]>CCCCCC>[C:14]([N:17]1[CH2:18][CH2:19][N:20]([C:23]2[N:24]=[CH:25][C:26]3[C:37](=[O:39])[C:31]([C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:30][NH:29][C:27]=3[N:28]=2)[CH2:21][CH2:22]1)(=[O:16])[CH3:15]
Reactant: CCOC(=O)C(=CNc1ccnc(N2CCN(C(C)=O)CC2)n1)C(=O)OCC
Solvent: CCCCCC
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCOC(=O)c1c[nH]c2nc(N3CCN(C(C)=O)CC3)ncc2c1=O
Temperature: 25 °C
Yield: 86.1 %

Procedure:
To diphenyl ether (16 ml) kept at 250°-255° C. was added with stirring diethyl N-[2-(4-acetyl-1-piperazinyl)-4-pyrimidinyl]-aminomethylenemalonate (2.0 g). The mixture was gently refluxed for 10 minutes, and then allowed to cool to room temperature. To the mixture was added n-hexane (12 ml). The resulting precipitate was collected, washed with ethanol, and recrystallized from ethanol to yield ethyl 2-(4-acetyl-1-piperazinyl)-5,8-dihydro-5-oxopyrido[2,3-d]pyrimidine-6-carboxylate (1.52 g), m.p. 300°-302° C. (decomp.).
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[K].[I-].[Na+].Cl[CH2:16][CH2:17][CH2:18][CH2:19][C:20]1[N:21]([CH2:34][CH2:35][CH3:36])[N:22]=[C:23]2[C:32]=1[C:31]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[N:25]=[C:24]2[NH2:33]>CN(C=O)C>[NH2:33][C:24]1[C:23]2=[N:22][N:21]([CH2:34][CH2:35][CH3:36])[C:20]([CH2:19][CH2:18][CH2:17][CH2:16][N:5]3[C:1](=[O:11])[C:2]4[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=4)[C:4]3=[O:6])=[C:32]2[C:31]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[N:25]=1
Reactant: CCCn1nc2c(N)nc3ccccc3c2c1CCCCCl
Reactant: O=C1NC(=O)c2ccccc21
Agent: [I-]
Agent: [K]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCn1nc2c(N)nc3ccccc3c2c1CCCCN1C(=O)c2ccccc2C1=O
Temperature: 90 °C
Reaction time: 0.17 h
Yield: 93.8 %

Procedure:
A mixture of potassium phthalimide (6.61 g, 35.7 mmol), sodium iodide (0.669 g, 4.46 mmol) and 1-(4-chlorobutyl)-2-propyl-2H-pyrazolo[3,4-c]quinolin-4-amine (prepared as described in Example 46, 5.65 g, 17.8 mmol) in DMF (30 mL) was heated at 90° C. for 3 hours. The reaction mixture was allowed to cool to room temperature overnight, then was diluted with ice water (300 mL) and stirred for 10 minutes. A solid formed that was collected by filtration and dried to yield 7.14 g of 2-[4-(4-amino-2-propyl-2H-pyrazolo[3,4-c]quinolin-1-yl)butyl]-1H-isoindole-1,3(2H)-dione as a tan solid, mp 204-206° C. 1H-NMR (300 MHz, CDCl3) δ 7.86-7.70 (m, 5H), 7.69-7.64 (m, 1H), 7.43-7.36 (m, 1H), 7.29-7.22 (m, 1H), 5.37 (br s, 2H), 4.30 (t, J=7.3 Hz, 2H), 3.77 (t, J=6.8 Hz, 2H), 3.31-3.21 (m, 2H), 2.05-1.75 (m, 6H), 0.98 (t, J=7.4 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@H:17]3[CH2:18][CH2:19][N:20](C(OCC4C=CC=CC=4)=O)[C@H:16]3[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[NH:9]2)=[CH:4][CH:3]=1.[ClH:31]>[Pd].C(O)C.CO>[ClH:1].[ClH:31].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@H:17]3[CH2:18][CH2:19][NH:20][C@H:16]3[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[NH:9]2)=[CH:4][CH:3]=1
Reactant: O=C(OCc1ccccc1)N1CC[C@@H]2[C@H](c3ccc(Cl)cc3)Nc3ccccc3[C@@H]21
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: CO
Product: Clc1ccc([C@@H]2Nc3ccccc3[C@@H]3NCC[C@H]23)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of benzyl (3aR*,4R*,9bR*)-4-(4-chlorophenyl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-carboxylate (730 mg, 1.75 mmol) and 10% palladium on carbon (50% aqueous, 0.3 g) in ethanol (10 ml) was added a hydrogen chloride in methanol solution (1 ml) and the mixture was stirred at room temperature under hydrogen atmosphere for 3 hrs. The reaction mixture was filtered, washed with aqueous methanol, and the filtrate was concentrated. The residue was dried under reduced pressure to give the crude title compound as an oil. (350 mg, ca. 100%)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[N:17]2[C:12]([CH:13]=[N:14][C:15](O)=[N:16]2)=[CH:11][CH:10]=1.[NH2:19][C:20]1[CH:25]=[CH:24][C:23]([CH:26]2[N:31]([CH3:32])[CH2:30][CH2:29][N:28]([CH3:33])[C:27]2=[O:34])=[CH:22][CH:21]=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[N:17]2[C:12]([CH:13]=[N:14][C:15]([NH:19][C:20]3[CH:21]=[CH:22][C:23]([CH:26]4[N:31]([CH3:32])[CH2:30][CH2:29][N:28]([CH3:33])[C:27]4=[O:34])=[CH:24][CH:25]=3)=[N:16]2)=[CH:11][CH:10]=1
Reactant: CN1CCN(C)C(c2ccc(N)cc2)C1=O
Reactant: COc1ccccc1-c1ccc2cnc(O)nn12
Product: COc1ccccc1-c1ccc2cnc(Nc3ccc(C4C(=O)N(C)CCN4C)cc3)nn12

Procedure:
3-{4-[7-(2-Methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino]-phenyl}-1,4-dimethyl-piperazin-2-one was prepared from 7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-ol and 3-(4-amino-phenyl)-1,4-dimethyl-piperazin-2-one in an analogous manner to Example 1052a. Product isolated as a yellow solid (55 mg, 42%). m.p.=249-251° C.; LCMS (m/e) 443 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 8.68 (s, 1H), 7.95 (d, 1H, J=7.6 Hz), 7.55 (d, 2H, J=8.4 Hz), 7.46-7.38 (m, 1H), 7.24 (d, 2H, J=8.4 Hz), 7.17-7.09 (m, 1H), 7.06 (d, 1H, J=8.3 Hz), 7.01 (d, 1H, J=4.6 Hz), 6.84 (d, 1H, J=4.6 Hz), 6.79 (bs, 1H), 3.84 (s, 3H), 3.77-3.68 (m, 1H), 3.66 (s, 1H), 3.24-3.17 (m, 1H), 3.05-2.97 (m, 1H), 2.98 (s, 3H), 2.71-2.61 (m, 1H), 2.17 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[O:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1.[CH2:16]1[O:19][CH:17]1[CH3:18].C(N(CC)CC)C>C(OCC)C>[F:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[O:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:16][CH:17]([OH:19])[CH3:18])=[CH:8][CH:7]=1
Reactant: Oc1ccc(Oc2cccc(F)c2)cc1
Reactant: CC1CO1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CC(O)COc1ccc(Oc2cccc(F)c2)cc1
Temperature: 90 °C
Reaction time: 18 h

Procedure:
A mixture of 6.13 g of p-(m-fluorophenoxy)phenol, 2.79 g of propylene oxide and 0.12 g of triethylamine is stirred at 90° C. for 18 hours. The cooled mixture is subsequently diluted with 100 ml of diethyl ether and washed successively twice with 50 ml of 2N hydrochloric acid each time, three times with 50 ml of 2N sodium hydroxide each time, with 50 ml of water and with 50 ml of saturated sodium chloride solution. After drying over anhydrous sodium sulfate and evaporation there is obtained 1-[p-(m-fluorophenoxy)phenoxy]-2-propanol of melting point 37°-39° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[CH:3]=1.C([Li])CCC.CCCCCC.Cl[Si:21](Cl)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[CH:35]1[C:43]2[C:42]3[CH:44]=[CH:45][CH:46]=[CH:47][C:41]=3[O:40][C:39]=2[C:38]([Li])=[CH:37][CH:36]=1>CCOCC>[Br:8][C:4]1[CH:3]=[C:2]([Si:21]([C:47]2[C:41]3[O:40][C:39]4[CH:38]=[CH:37][CH:36]=[CH:35][C:43]=4[C:42]=3[CH:44]=[CH:45][CH:46]=2)([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: Brc1cccc(Br)c1
Reactant: Cl[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: [Li]c1cccc2c1oc1ccccc12
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: Brc1cccc([Si](c2ccccc2)(c2ccccc2)c2cccc3c2oc2ccccc23)c1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 52 %

Procedure:
Into a solution of dibenzo[b,d]furan (4.98 g, 29.6 mmol) in ether (50 mL) at −78° C. was added n-butyllithium solution in hexane (2.5 M, 9.48 mL, 23.70 mmol) dropwise and the solution was allowed to warm to room temperature and stirred for 20 h to yield a dibenzo[b,d]furan-4-yl lithium solution. Into a solution of 1,3-dibromobenzene (2.56 mL, 21.20 mmol) in ether (50 mL) was added n-butyllithium solution in hexane (2.5 M, 9.48 mL, 23.70 mmol) dropwise at −78° C. The reaction solution was stirred at this temperature for 3.5 h before adding into a solution of dichlorodiphenylsilane (4.88 mL, 23.70 mmol) in ether (50.0 mL) at −78° C. The resultant reaction solution was stirred at this temperature for 2 h before the dibenzo[b,d]furan-4-yl lithium solution prepared above was introduced dropwise. The reaction mixture was allowed to slowly warm to room temperature overnight at which time it was quenched with water, extracted with ether, and dried over Na2SO4. Upon filtration and evaporation of the solvent, the residue was purified by column chromatography on silica gel with hexane/DCM (9/1, v/v) as eluent to yield (3-bromophenyl)(dibenzo[b,d]furan-4-yl)diphenylsilane (6.2 g, 52%) as a white powder.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3([C:17]4[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=4)[CH2:16][CH2:15]3)=[O:13])[CH2:8]2)[CH:2]=1.C(Cl)Cl.[C:27]1(B(O)O)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(N(CC)CC)C>C([O-])(=O)C.C([O-])(=O)C.[Cu+2]>[O:23]([C:20]1[CH:19]=[CH:18][C:17]([C:14]2([C:12]([N:9]3[CH2:10][CH2:11][CH:7]([C:3]4[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=4)[CH2:8]3)=[O:13])[CH2:16][CH2:15]2)=[CH:22][CH:21]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: OB(O)c1ccccc1
Reactant: O=C(N1CCC(c2cccnc2)C1)C1(c2ccc(O)cc2)CC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(N1CCC(c2cccnc2)C1)C1(c2ccc(Oc3ccccc3)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-{1-[(3-pyridin-3-ylpyrrolidin-1-yl)carbonyl]cyclopropyl}phenol (40.0 mg, 0.000130 mol) in methylene chloride (1 mL, 0.02 mol) were added phenylboronic acid (15.8 mg, 0.000130 mol), copper(II) diacetate (0.0236 g, 0.000130 mol) and molecular sieves at rt. Triethylamine (0.0904 mL, 0.000648 mol) was then added and the reaction mixture was stirred at rt overnight. The reaction mixture was filtered and the filtrate was concentrated. The desired product from the residue was isolated and purified by prep-HPLC. LCMS: m/z 385.1 (M+H)+
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:9]([C:11]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[C:15]([OH:20])[CH:14]=2)=O)=O)[CH:5]=[CH:6][C:7]=1[OH:8].C1C(O)=CC=CC=1C.S(O)(O)(=O)=O.[NH2:34][C:35]1[C:36]([OH:43])=[N:37][C:38]([OH:42])=[N:39][C:40]=1[NH2:41].S(O)(O)(=O)=O>>[OH:1][C:2]1[CH:3]=[C:4]([C:9]2[N:34]=[C:35]3[C:40](=[N:41][C:11]=2[C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[C:15]([OH:20])[CH:14]=2)[N:39]=[C:38]([OH:42])[N:37]=[C:36]3[OH:43])[CH:5]=[CH:6][C:7]=1[OH:8]
Reactant: Nc1nc(O)nc(O)c1N
Reactant: O=C(C(=O)c1ccc(O)c(O)c1)c1ccc(O)c(O)c1
Agent: O=S(=O)(O)O
Solvent: Cc1cccc(O)c1
Product: Oc1nc(O)c2nc(-c3ccc(O)c(O)c3)c(-c3ccc(O)c(O)c3)nc2n1
Temperature: 50 °C

Procedure:
A 5-mL reaction vial with a stirring vane and a teflon cap was charged with 3,3′,4,4′-tetrahydroxybenzil (137 mg; 0.500 mmol) and 1.00 mL of m-cresol (Acros) which gives a yellow-brown slurry warming to ca. 50° C. The suspension is treated with sulfate 5,6-diamino-2,4-dihydroxypyrimidine sulfate (120 mg; 0.500 mmol; 1.00 equiv) which is insoluble in the reaction solution at room temperature and goes into solution on heating to ca. 200° C. to give homogeneous dark solution. Heating between 200° C. and 220° C. for an additional 2 h, followed by cooling to room temperature, and precipitation by pouring into 40 mL of anhydrous diethyl ether resulted in a light yellow precipitate. The solid was centrifuged, the supernatant decanted, the solid precipitate was washed with 4×40 mL of diethyl ether and dried in a vacuum dessicator to yield a yellow solid. MS (M+H+: calcd 381; found 381).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[C@H:4]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[C:29]([O:30][CH3:31])=[CH:28][CH:27]=[CH:26][C:25]=2[O:32][CH3:33])=[CH:20][CH:19]=1)[NH:5][C:6](=[O:16])[C:7]1[C:12]([Cl:13])=[CH:11][C:10](Br)=[CH:9][C:8]=1[Cl:15].[C:35]([O:39][C:40]([N:42]1[CH:46]=[CH:45][CH:44]=[C:43]1B(O)O)=[O:41])([CH3:38])([CH3:37])[CH3:36]>C1COCC1>[CH3:1][O:2][C:3](=[O:34])[C@H:4]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[C:29]([O:30][CH3:31])=[CH:28][CH:27]=[CH:26][C:25]=2[O:32][CH3:33])=[CH:20][CH:19]=1)[NH:5][C:6](=[O:16])[C:7]1[C:12]([Cl:13])=[CH:11][C:10]([C:43]2[N:42]([C:40]([O:39][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:41])[CH:46]=[CH:45][CH:44]=2)=[CH:9][C:8]=1[Cl:15]
Reactant: CC(C)(C)OC(=O)n1cccc1B(O)O
Reactant: COC(=O)[C@H](Cc1ccc(-c2c(OC)cccc2OC)cc1)NC(=O)c1c(Cl)cc(Br)cc1Cl
Solvent: C1CCOC1
Product: COC(=O)[C@H](Cc1ccc(-c2c(OC)cccc2OC)cc1)NC(=O)c1c(Cl)cc(-c2cccn2C(=O)OC(C)(C)C)cc1Cl
Yield: 92.1 %

Procedure:
N-(4-Bromo-2,6-dichlorobenzoyl)-4-(2,6-dimethoxyphenyl)-L-phenylalanine methyl ester (0.410 g) was coupled with 1-tert-butoxycarbonyl-2-pyrroleboronic acid (0.930 g) in THF (10 mL) as described in Example 7-2) to give 0.435 g of N-[4-(1-tert-butoxycarbonyl-2-pyrrolyl)-2,6-dichlorobenzoyl]-4-(2,6-dimethoxyphenyl)-L-phenylalanine methyl ester. ESMS: m/z 653 (MH+).
Reaction SMILES: [C:1]([O:5][C:6]([CH:8]1C=[C:12]2[CH2:14][CH:9]1[CH2:10][CH2:11]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].ClC1C=C(C=CC=1)C(OO)=[O:20]>C(Cl)Cl>[C:1]([O:5][C:6]([CH:8]1[O:20][CH:12]2[CH2:14][CH:9]1[CH2:10][CH2:11]2)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C)(C)OC(=O)C1C=C2CCC1C2
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C1OC2CCC1C2
Reaction time: 24 h

Procedure:
Bicyclo[2.2.1]heptan-3-ene-2-carboxylic acid tert-butyl ester (1.94 g) is dissolved in CH2Cl2 (20 mL). m-Chloroperoxybenzoic acid (2.7 g, 70%) was added and the mixture was stirred 24 hrs. When bicyclo[2.2.1]heptan-3-ene-2-carboxylic acid tert-butyl ester disappeared, Na2CO3(sat.) (20 mL) was added then stirred for an additional 2 hrs. The reaction mixture was extracted with ethyl acetate (20 mL×3). The combined organic layers were washed till the pH=7 then evaporated to dryness to obtain the 3-oxa-bicyclo[2.2.1]heptan-2-carboxylic acid tert-butyl ester.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:10]1[N:15]=[CH:14][C:13]([F:16])=[CH:12][N:11]=1)[CH3:9])(C)(C)C.[ClH:18]>C(Cl)Cl.O1CCOCC1>[ClH:18].[F:16][C:13]1[CH:12]=[N:11][C:10]([C@@H:8]([NH2:7])[CH3:9])=[N:15][CH:14]=1
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1ncc(F)cn1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: C[C@H](N)c1ncc(F)cn1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of tert-butyl[(1S)-1-(5-fluoropyrimidin-2-yl)ethyl]carbamate (Intermediate 14, 0.21 g, 0.87 mmol) in DCM (5 ml) was added HCl (1.3 ml, 5.2 mmol) in dioxane. The reaction was stirred at room temperature for 3 hours. The solvent was removed give the title compound as white solid (quantitative). MS: Calculated: 141. Found: [M+H]+ 142.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11](O)[CH2:12][C:13]3[CH:18]=[CH:17][C:16]([CH2:19][CH3:20])=[CH:15][N:14]=3)=[N:7][NH:8]2)=[CH:4][CH:3]=1.S(Cl)(C)(=O)=O.C1CCN2C(=NCCC2)CC1>C(Cl)Cl>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]=[CH:12][C:13]3[CH:18]=[CH:17][C:16]([CH2:19][CH3:20])=[CH:15][N:14]=3)=[N:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: CCc1ccc(CC(O)c2n[nH]c3cc(Cl)ccc23)nc1
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: CCc1ccc(C=Cc2n[nH]c3cc(Cl)ccc23)nc1
Reaction time: 0.5 h
Yield: 79.3 %

Procedure:
To a stirred solution of 1-(6-Chloro-1H-indazol-3-yl)-2-(5-ethyl-pyridin-2-yl)-ethanol (232 mg, 0.60 mmol) in CH2Cl2 was added TEA (0.25 mL, 1.81 mmol) and mesyl chloride (0.070 mL, 0.90 mmol). The reaction was stirred for 30 minutes, and then DBU (2 mL) was added. The reaction was refluxed for 18 hours and then quenched with 40 mL of 1 N citric acid. The layers were separated, and the aqueous was extracted with 20 mL CH2Cl2. The combined organics were dried over Na2SO4, filtered, and concentrated by rotary evaporation. Purification by chromatography (12 g silica gel, 50–70% EtOAc/hexanes) yielded the desired compound (135 mg, 71%).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C@H:13]([NH:18][C:19]([C@@H:21](/[CH:35]=[CH:36]/[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][S:43]([CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH3:52])(=[O:45])=[O:44])[C@@:22]([OH:34])([CH2:30][CH2:31][O:32][CH3:33])[C:23]([O:25]C(C)(C)C)=[O:24])=[O:20])[C:14]([O:16][CH3:17])=[O:15])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4].FC(F)(F)C(O)=O>ClCCl>[CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C@H:13]([NH:18][C:19]([C@@H:21](/[CH:35]=[CH:36]/[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][S:43]([CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH3:52])(=[O:44])=[O:45])[C@@:22]([OH:34])([CH2:30][CH2:31][O:32][CH3:33])[C:23]([OH:25])=[O:24])=[O:20])[C:14]([O:16][CH3:17])=[O:15])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4]
Reactant: CC#CCOc1ccc(C[C@H](NC(=O)[C@@H](/C=C/CCCCCCS(=O)(=O)CCCCCCC)[C@@](O)(CCOC)C(=O)OC(C)(C)C)C(=O)OC)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC#CCOc1ccc(C[C@H](NC(=O)[C@@H](/C=C/CCCCCCS(=O)(=O)CCCCCCC)[C@@](O)(CCOC)C(=O)O)C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 74 %

Procedure:
tert-Butyl (E)-(2S,3S)-3-[(S)-2-(4-but-2-ynyloxy-phenyl)-1-methoxycarbonyl-ethylcarbamoyl]-11-(heptane-1-sulfonyl)-2-hydroxy-2-(2-methoxy-ethyl)-undec-4-enoate (No. 6804464; 56.1 mg, 0.0748 mmol) was dissolved in dichloromethane (3.0 mL), and trifluoroacetic acid (1.0 mL) was added. The mixture was stirred at room temperature for 15 hours. The solvent was distilled off under reduced pressure. To the residue was added dichloromethane, and the solvent was again distilled off under reduced pressure. This operation was repeated twice. The residue was then purified by HPLC (water with 0.05% TFA-acetonitrile with 0.05% TFA) to obtain (E)-(2S,3S)-3-[(S)-2-(4-but-2-ynyloxy-phenyl)-1-methoxycarbonyl-ethylcarbamoyl]-11-(heptane-1-sulfonyl)-2-hydroxy-2-(2-methoxy-ethyl)-undec-4-enoic acid (No. 5513214; 36.2 mg, 74% yield, white powder).