Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][CH:27]=1)[CH2:5][CH2:6][O:7][CH2:8][CH2:9][C:10]([N:12]([CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)[CH2:13][CH:14](OC)[O:15]C)=[O:11].Cl>CC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][CH:27]=1)[CH2:5][CH2:6][O:7][CH2:8][CH2:9][C:10]([N:12]([CH:19]1[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]1)[CH2:13][CH:14]=[O:15])=[O:11]
Reactant: COC(CN(C(=O)CCOCCc1cccc(Br)c1)C1CCCCC1)OC
Agent: Cl
Solvent: CC(C)=O
Product: O=CCN(C(=O)CCOCCc1cccc(Br)c1)C1CCCCC1
Reaction time: 2 h
Yield: 111.6 %

Procedure:
To a stirred solution of 3-(3-bromophenethoxy)-N-cyclohexyl-N-(2,2-dimethoxyethyl)propanamide (1.5 g) in acetone (30 mL) was added 2M hydrochloric acid (15 mL). The mixture was stirred for 2 h before the solvent was removed under vacuum, followed by the addition of water. The aqueous phase was extracted three times with DCM and the pooled DCM was washed once with brine, dried over sodium sulphate, filtered and the solvent removed to afford the desired material (1.5 g). This material was used in the next step directly.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[CH:11]=[C:10]([CH3:24])[N:9]=2)[CH:5]=[N:6][CH:7]=1.[NH2:25][C:26]1[N:31]=[CH:30][C:29](B2OC(C)(C)C(C)(C)O2)=[CH:28][N:27]=1>>[CH3:24][C:10]1[N:9]=[C:8]([C:4]2[CH:5]=[N:6][CH:7]=[C:2]([C:29]3[CH:28]=[N:27][C:26]([NH2:25])=[N:31][CH:30]=3)[CH:3]=2)[CH:13]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:11]=1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cncc(Br)c2)n1
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cncc(-c3cnc(N)nc3)c2)n1

Procedure:
The title compound was prepared from 5′-bromo-6-methyl-4-(4-trifluoromethyl-phenyl)-[2,3′]bipyridinyl (example E.24) (0.15 g, 0.38 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (0.093 g, 0.42 mmol) according to the general procedure VI. Obtained as a white solid (0.035 g, 22%). MS (ISP) 408.3 [(M+H)+]; mp 248-252° C.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][C:5]([CH3:11])=[CH:4][N:3]=1.[C:12]1([NH:18][C:19](=O)[CH3:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH3:20][C:19]1[N:18]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:2]2=[N:3][CH:4]=[C:5]([CH3:11])[CH:6]=[C:7]2[N:8]=1
Reactant: CC(=O)Nc1ccccc1
Reactant: Cc1cnc(Cl)c([N+](=O)[O-])c1
Product: Cc1cnc2c(c1)nc(C)n2-c1ccccc1
Yield: 80.6 %

Procedure:
Method A applied to 2-chloro-5-methyl-3-nitropyridine (86 mg, 0.5 mmol) and N-phenylacetamide (81 mg, 0.6 mmol) afforded the title compound as brown solid (90 mg, 81%). mp 77-79° C. 1H NMR (DMSO) δ 2.44 (s, 3H), 2.54 (s, 3H), 7.56-7.63 (m, 5H), 7.95 (s, 1H), 8.20 (s, 1H); 13C NMR δ 13.1, 17.9, 124.4, 127.5, 129.5, 129.6, 129.8, 132.9, 145.1, 145.7, 153.2. HRMS (FAB): cal. for C14H14N3 [M+H+]: 224.1187; found: 224.1184.
Reaction SMILES: [N:1]1[C:9]([NH2:10])=[C:8]2[C:4]([N:5]=[CH:6][NH:7]2)=[N:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].[O:17]1[CH:19]([CH2:20][S:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH2:18]1.C(Cl)(Cl)Cl.CO>CN(C)C=O>[OH:17][CH:19]([CH2:20][S:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH2:18][N:5]1[CH:6]=[N:7][C:8]2[C:4]1=[N:3][CH:2]=[N:1][C:9]=2[NH2:10]
Reactant: CCCCCCCCCCCCCCCCCCSCC1CO1
Reactant: Nc1ncnc2nc[nH]c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCCCCCSCC(O)Cn1cnc2c(N)ncnc21
Reaction time: 20 h

Procedure:
A mixture of adenine (0.829 g, 6.10 mmol), anhydrous potassium carbonate (45 mg) and rac-1,2-epoxy-3-octadecylthiopropane (2.0 g, 5.83 mmol) in anhydrous dimethyl formamide (10 mL) is stirred at 70°-75° C. for 20 hours under a nitrogen atmosphere. The reaction mixture is filtered directly without cooling and the filtrate is concentrated under reduced pressure to afford a white residue. The residue is stirred with 95:5 (v/v) chloroform-methanol. The insoluble solid is filtered, purified by chromatography, and dried in vacuo to 9-[2'-hydroxy-3'-octadecylthiopropyl]-adenine.
Reaction SMILES: [SiH4].CCCCCCCCC([O:12][C@@H:13]1[CH2:26][C:25]2[C@@:16]([CH3:39])([C@@H:17]3[C@@H:22]([CH2:23][CH:24]=2)[C@@H:21]2[CH2:27][CH2:28][C@H:29]([C@@H:30]([CH2:32][CH2:33][CH2:34][CH:35]([CH3:37])[CH3:36])[CH3:31])[C@@:20]2([CH3:38])[CH2:19][CH2:18]3)[CH2:15][CH2:14]1)=O.COC(=O)C(C)=C>C(Cl)Cl>[CH3:37][CH:35]([CH2:34][CH2:33][CH2:32][C@H:30]([C@@H:29]1[C@:20]2([CH3:38])[C@H:21]([C@H:22]3[C@H:17]([CH2:18][CH2:19]2)[C@:16]2([CH3:39])[C:25]([CH2:26][C@H:13]([CH2:14][CH2:15]2)[OH:12])=[CH:24][CH2:23]3)[CH2:27][CH2:28]1)[CH3:31])[CH3:36]
Reactant: CCCCCCCCC(=O)O[C@H]1CC[C@@]2(C)C(=CC[C@H]3[C@@H]4CC[C@H]([C@H](C)CCCC(C)C)[C@@]4(C)CC[C@@H]32)C1
Agent: C=C(C)C(=O)OC
Agent: [SiH4]
Solvent: ClCCl
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C

Procedure:
The obtained silane copolymer 7.2 g, cholesteryl nonanoate 8 g and methylmethacrylate monomer 72 g were dissolved uniformly in 20 ml of methylene chloride under irradiation of ultrasonic wave. And then, the procedure described in Example 1 was followed, to give cholesterol liquid crystal polymer microcapsules 80 g as powders.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][C:5]([N:8]2[C@@H:15]3[C@@H:10]([CH2:11][CH2:12][NH:13][CH2:14]3)[CH2:9]2)=[N:6][CH:7]=1.CC1C=C(C)N=C(N2[C@@H]3[C@@H](CCNC3)C2)N=1.[F:32][C:33]1[CH:41]=[CH:40][CH:39]=[C:38]([N:42]2[N:46]=[CH:45][CH:44]=[N:43]2)[C:34]=1[C:35](O)=[O:36].S1C=CC=C1C1C=CC=CC=1C(O)=O>C(Cl)Cl>[F:32][C:33]1[CH:41]=[CH:40][CH:39]=[C:38]([N:42]2[N:46]=[CH:45][CH:44]=[N:43]2)[C:34]=1[C:35]([N:13]1[CH2:12][CH2:11][C@@H:10]2[C@@H:15]([N:8]([C:5]3[CH:4]=[N:3][C:2]([CH3:1])=[CH:7][N:6]=3)[CH2:9]2)[CH2:14]1)=[O:36]
Reactant: Cc1cnc(N2C[C@@H]3CCNC[C@@H]32)cn1
Reactant: O=C(O)c1c(F)cccc1-n1nccn1
Agent: Cc1cc(C)nc(N2C[C@@H]3CCNC[C@@H]32)n1
Agent: O=C(O)c1ccccc1-c1cccs1
Solvent: ClCCl
Product: Cc1cnc(N2C[C@@H]3CCN(C(=O)c4c(F)cccc4-n4nccn4)C[C@@H]32)cn1

Procedure:
The title compound was prepared in a manner analogous to Example 1, substituting (1R,6S)-8-(5-methylpyrazin-2-yl)-3,8-diazabicyclo[4.2.0]octane (Intermediate 29) for (1R,6S)8-(4,6-dimethyl-pyrimidin-2-yl)-3,8-diaza-bicyclo[4.2.0]octane and 2-fluoro-6-[1,2,3]triazol-2-yl-benzoic acid (Intermediate 15) for 2-thiophen-2-yl-benzoic acid. DCM was used in place of DMF. MS (ESI) mass calcd. For C20H20FN7O, 393.43; m/z found 394.1 [M+H]+. 1H NMR (CDCl3): 7.99-7.69 (m, 3H), 7.58-7.39 (m, 2H), 7.31 (s, 1H), 7.19-6.84 (m, 1H), 4.67-4.34 (m, 1H), 4.15-3.80 (m, 4H), 3.69-3.18 (m, 2H), 2.96 (br s, 1H), 2.45-2.05 (m, 5H).
Reaction SMILES: F[C:2](F)(F)[C:3]([OH:5])=O.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C@H:15]([N:17]2[C:21]3[CH:22]=[C:23]([N:26]4[CH2:31][CH2:30][NH:29][C@H:28]([CH3:32])[CH2:27]4)[CH:24]=[CH:25][C:20]=3[N:19]=[CH:18]2)[CH3:16])=[C:11]([C:33]([F:36])([F:35])[F:34])[CH:10]=1>ClCCl>[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C@H:15]([N:17]2[C:21]3[CH:22]=[C:23]([N:26]4[CH2:31][CH2:30][N:29]([C:3]([C@H:2]5[CH2:11][CH2:12][CH2:15][NH:17]5)=[O:5])[C@H:28]([CH3:32])[CH2:27]4)[CH:24]=[CH:25][C:20]=3[N:19]=[CH:18]2)[CH3:16])=[C:11]([C:33]([F:36])([F:34])[F:35])[CH:10]=1
Reactant: O=C(O)C(F)(F)F
Reactant: C[C@@H]1CN(c2ccc3ncn([C@H](C)c4ccc(Cl)cc4C(F)(F)F)c3c2)CCN1
Solvent: ClCCl
Product: C[C@@H]1CN(c2ccc3ncn([C@H](C)c4ccc(Cl)cc4C(F)(F)F)c3c2)CCN1C(=O)[C@H]1CCCN1
Temperature: 25 °C
Reaction time: 1 h
Yield: 52 %

Procedure:
Trifluoroacetic acid (0.5 mL) was added to a solution of the crude 1-((R)-1-(4-chloro-2-(trifluoromethyl)phenyl)ethyl)-6-((R)-3-methylpiperazin-1-yl)-1H-benzo[d]imidazole (0.060 g, 0.1 mmol) in dichloromethane (1.5 mL) and the resulting solution was stirred at room temperature for 1 h. Excess solvent was removed in vacuo, and the residue was diluted with dichloromethane (10 mL). The organic layer was neutralized with saturated aqueous sodium bicarbonate, and the aqueous layer was further extracted with dichloromethane (2×15 mL) The combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo. The crude product was purified by flash chromatography (SiO2, 0-20% methanol in dichloromethane) to give the title compound as a white solid (0.027 g, 0.052 mmol, 52%). 1H NMR (400 MHz, CDCl3) δ 8.17 (s, 1 H), 7.71 (d, J=2.8 Hz, 1 H), 7.65 (d, J=9.2 Hz, 1 H), 7.37 (d, J=8.8 Hz, 1 H), 6.95-6.90 (m, 2 H), 6.49 (d, J=2.0 Hz, 1 H), 5.84 (q, J=6.8 Hz, 1 H), 4.78-4.84 (m, 1 H), 4.53-4.50 (m, 1 H), 4.25-4.20 (m, 1 H), 3.99-3.84 (m, 1 H), 3.88-3.82 (m, 1 H), 3.71-3.68 (m, 1 H), 3.54-3.51 (m, 1 H), 3.35-3.11 (m, 3 H), 2.87-2.75 (m, 2 H), 2.64-2.58 (m, 2 H), 1.99 (d, J=7.2 Hz, 3 H), 1.44-1.31 (m, 3 H); MS: (ES) m/z calculated for C26H30ClFN5O [M+H]+ 520.2, found 520.4.
Reaction SMILES: C(O[C@H:5]1[O:27][C@@H:26]([CH2:28][O:29][C:30](=[O:37])[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C@H:16]([O:17][C:18](=[O:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C@@H:6]1[O:7][C:8](=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=O)C.[Br:38][C:39]1[C:40](=[O:46])[NH:41][C:42](=[O:45])[NH:43][CH:44]=1.C[Si](N[Si](C)(C)C)(C)C.C[Si](Cl)(C)C>CC#N>[C:8]([O:7][C@H:6]1[C@@H:16]([O:17][C:18](=[O:25])[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C@H:26]([CH2:28][O:29][C:30](=[O:37])[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[O:27][C@@H:5]1[N:43]1[CH:44]=[C:39]([Br:38])[C:40](=[O:46])[NH:41][C:42]1=[O:45])(=[O:15])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CC(=O)O[C@H]1O[C@@H](COC(=O)c2ccccc2)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1
Reactant: O=c1[nH]cc(Br)c(=O)[nH]1
Agent: C[Si](C)(C)Cl
Agent: C[Si](C)(C)N[Si](C)(C)C
Solvent: CC#N
Product: O=C(OC[C@@H]1O[C@H](n2cc(Br)c(=O)[nH]c2=O)[C@@H](OC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1)c1ccccc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 98.6 %

Procedure:
A solution of 1-O-acetyl-2,3,5-tri-O-benzoyl-β-L-ribofuranose (2.3 g, 4.55 mmol) in CH3CN (30 mL) was added to silylated 5-bromouracil [generated from 5-bromouracil (2.2 g, 14.3 mmol), HMDS (10 mL), and TMSCl (0.2 mL) by heating for 2 h at 80° C. followed by evaporation of the solvents], and the mixture cooled to 0° C. 1 M SnCl4 (13.6 mL) was added drop-wise, and the mixture stirred for 2 h at room temperature. The mixture was diluted with CHCl3 (100 mL) and quenched with cold saturated NaHCO3. The mixture was filtered over a Celite pad, and the organic phase separated, dried (MgSO4), and evaporated to give a white solid. The solid was washed with cold EtOAc and crystallized from EtOAc in hexanes to give the title compound (2.85 g, 98%) as a white crystals. 1H-NMR (CDCl3) δ 8.06 (1H, br s, NH), 8.06-7.29 (15H, m, Bz) 7.68 (1H, s, H-6), 6.29 (1H, d, H-1′, J=6 Hz), 5.81 (1H, m, H-3′), 5.65 (1H, t, H-2′, J=6 Hz), 4.77-4.62 (3H, m, H-4′, H-5′a, and 5′b).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.Br.Br.Br[CH2:24][C:25]1[C:26]([NH2:32])=[N:27][C:28]([NH2:31])=[N:29][CH:30]=1>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:24][C:25]3[C:26]([NH2:32])=[N:27][C:28]([NH2:31])=[N:29][CH:30]=3)[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: Nc1ncc(CBr)c(N)n1
Reactant: Clc1ccc(N2CCNCC2)cc1
Agent: Br
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Nc1ncc(CN2CCN(c3ccc(Cl)cc3)CC2)c(N)n1
Temperature: 25 °C
Reaction time: 60 h
Yield: 41.2 %

Procedure:
A solution of 0.97 g (0.00493 mol) of 1-(4-chloro-phenyl)-piperazine in 35 ml of dimethylformamide was treated with 1.37 ml (0.00986 mol) of triethylamine and 0.60 g (0.0016 mol) of 5-bromomethyl-pyrimidine-2,4-diamine dihydrobromide and the mixture was stirred at room temperature under argon for 60 hours. The mixture was completely freed from the solvents. The residue was chromatographed over silica gel with acetonitrile/methanol 1:1 as the eluent, digested in dichloromethane/water 1:1 and subsequently filtered off under suction. 0.21 g (40%) of 5-[4-(4-chloro-phenyl)-piperazin-1-ylmethyl]-pyrimidine-2,4-diamine was obtained as white crystals; m.p. 296°-298°.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH2:11][CH2:12][CH3:13])[CH:9]=2)[CH2:4][N:3]1[C:14]1[CH:19]=[CH:18][C:17]([CH:20]([CH3:28])[C:21]([O:23]C(C)(C)C)=[O:22])=[CH:16][CH:15]=1>C(O)=O>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH2:11][CH2:12][CH3:13])[CH:9]=2)[CH2:4][N:3]1[C:14]1[CH:19]=[CH:18][C:17]([CH:20]([CH3:28])[C:21]([OH:23])=[O:22])=[CH:16][CH:15]=1
Reactant: CCCc1ccc2c(c1)C(=O)N(c1ccc(C(C)C(=O)OC(C)(C)C)cc1)C2
Solvent: O=CO
Product: CCCc1ccc2c(c1)C(=O)N(c1ccc(C(C)C(=O)O)cc1)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.6 %

Procedure:
A mixture of tert-butyl 2-(4-(1-oxo-6-propylisoindolin-2-yl)phenyl)propanoate (0.084 g, 0.22 mmol) and formic acid (15 mL) was stirred overnight at room temperature. The mixture was then concentrated under reduced pressure, suspended in hexanes (5 mL), sonicated, and the solid collected by filtration to afford 2-(4-(1-oxo-6-propylisoindolin-2-yl)phenyl)propanoic acid (0.041 g, 57%) as a white solid: mp 175-177° C.; 1H NMR (300 MHz, CDCl3) δ 7.83 (d, J=8.6 Hz, 2H), 7.74 (s, 1H), 7.41-7.37 (m, 4H), 4.81 (s, 2H), 3.77 (q, J=7.1 Hz, 1H), 2.70 (t, J=7.4 Hz, 2H), 1.73-1.65 (m, 2H), 1.54 (d, J=7.2 Hz, 3H), 0.95 (t, J=7.3 Hz, 3H); ESI MS m/z 324 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][N:4]=[C:5]([C:10]1[N:15]=[C:14]([NH2:16])[CH:13]=[CH:12][N:11]=1)[C:6]([O:8]C)=[O:7])[CH3:2].C(ON=C(C1N=C(N)C=CN=1)C(OCC)=O)C>[OH-].[Na+]>[CH2:1]([O:3][N:4]=[C:5]([C:10]1[N:15]=[C:14]([NH2:16])[CH:13]=[CH:12][N:11]=1)[C:6]([OH:8])=[O:7])[CH3:2]
Reactant: CCON=C(C(=O)OC)c1nccc(N)n1
Agent: CCON=C(C(=O)OCC)c1nccc(N)n1
Agent: [Na+]
Agent: [OH-]
Product: CCON=C(C(=O)O)c1nccc(N)n1
Yield: 91.8 %

Procedure:
A mixture (930 mg) of methyl 2-ethoxyimino-2-(4-aminopyrimidin-2-yl)acetate (syn isomer) and ethyl 2-ethoxyimino-2-(4-aminopyrimidin-2-yl)acetate (syn isomer) in 1 N aqueous sodium hydroxide (4.95 ml) was stirred for 3.5 hours at ambient temperature. The solution was passed through an ion exchange resin [16 ml, Amberlite IRC-50 (trademark: Prepared by Rohm and Haas Co.)] and evaporated to dryness. The residue was triturated in a mixed solvent of acetone (20 ml) and water (2 ml) to give 2-ethoxyimino-2-(4-aminopyrimidin-2-yl)acetic acid (syn isomer) (0.8 g), mp. 180° to 182° C. (dec.).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:13]2[CH:17]=[CH:16][NH:15][N:14]=2)[N:3]=1.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1B(O)O>>[CH3:18][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:13]2[CH:17]=[CH:16][NH:15][N:14]=2)[N:3]=1
Reactant: Clc1nc(Nc2cc[nH]n2)cc2ccccc12
Reactant: COc1ccccc1B(O)O
Product: COc1ccccc1-c1nc(Nc2cc[nH]n2)cc2ccccc12

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-isoquinolin-3-yl)-(1H-pyrazol-3-yl)-amine and 2-methoxy-phenylboronic acid to give [1-(2-Methoxy-phenyl)-isoquinolin-3-yl]-(1H-pyrazol-3-yl)-amine. LC-MS m/e 317(MH+).
Reaction SMILES: [C:1]1([CH:7]([OH:9])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:10]([O:13]C=COCC)(=[O:12])[CH3:11]>CCCCCC>[C:1]1([CH:7]([OH:9])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:10]([O-:13])(=[O:12])[CH3:11]
Reactant: CCOC=COC(C)=O
Agent: CC(O)c1ccccc1
Solvent: CCCCCC
Product: CC(=O)[O-]
Reaction time: 3 h

Procedure:
1-Phenylethanol (100 mg) was dissolved in a 10% solution of ethoxyvinyl acetate in hexane (2 ml), followed by addition of lipase PS (10 mg). After about 3 hours at room temperature, 50% conversion was observed by TLC. The alcohol and acetate were isolated using flash chromatography on silica gel 60 using a 1:10 to 1:1 gradient of ethyl acetate in hexane. The isolated yield of the acetate was 40%, corresponding to 80% of the theoretical maximum at 50% conversion, and that of the alcohol 39%. The enantiomeric excess (ee) of the acetate was >95% (determined by 1H-NMR, chiral shift experiment with Eu(hfc)3, 10 mg of acetate, 40 mg of shift reagent); αD +103.5° (c=1, MeOH).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:7]=[C:8]([Cl:15])[C:9]=1[O:10][CH2:11][CH:12]1[CH2:14][CH2:13]1.Cl>CN(C=O)C.O>[Br:3][C:4]1[CH:5]=[C:6]([CH:16]([CH2:4][CH2:9][O:10][CH3:11])[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:7]=[C:8]([Cl:15])[C:9]=1[O:10][CH2:11][CH:12]1[CH2:13][CH2:14]1
Reactant: CCOC(=O)Cc1cc(Cl)c(OCC2CC2)c(Br)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(CCOC)c1cc(Cl)c(OCC2CC2)c(Br)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 48.4 %

Procedure:
To a stirred solution of NaH (0.3 g, 12.5 mmol) in DMF (10 mL) was added ethyl 2-(3-bromo-5-chloro-4-(cyclopropylmethoxy)phenyl)acetate (2.0 g, 5.70 mmol) at 0° C. The reaction mixture was stirred at 0° C. over a period of 30 min. To the reaction mixture was added 2-bromo ethyl methyl ether (0.87 g, 6.25 mmol) and stirred at 0° C. for 30 min. After completion of starting material (by TLC), the reaction mixture was diluted with water (20 mL), acidified with 1N HCl (pH=5) and extracted with EtOAc (3×50 mL). Combined organic layers were washed with water (3×25 mL), brine and dried over anhydrous Na2SO4. After filtration and concentration under reduced pressure, the crude material was purified by column chromatography to afford ethyl 2-(3-bromo-5-chloro-4-(cyclopropylmethoxy)-phenyl)-4-methoxybutanoate (560 mg) as an off white solid.
Reaction SMILES: [H-].[Na+].[C:3]([O:10][CH2:11][CH3:12])(=[O:9])[C:4]([O:6]CC)=O.[C:13]([C:16]1[O:17][CH:18]=[CH:19][CH:20]=1)(=[O:15])[CH3:14].Cl>O1CCCC1>[O:17]1[CH:18]=[CH:19][CH:20]=[C:16]1[C:13](=[O:15])[CH2:14][C:4](=[O:6])[C:3]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)C(=O)OCC
Reactant: CC(=O)c1ccco1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(=O)CC(=O)c1ccco1
Temperature: 70 °C
Reaction time: 1 h
Yield: 58.2 %

Procedure:
To a suspension of sodium hydride (5.4 g of 60% dispersion in mineral oil, 136 mmol, mineral oil was removed by washing twice with hexanes) in 100 mL of tetrahydrofuran at ambient temperature was added diethyl oxalate (12.3 mL, 91 mmol). To this mixture was added 2-acetylfuran (5.0 g, 45 mmol) as a solution in 25 mL of tetrahydrofuran. The resulting mixture was stirred at 70° C. for 1 h. The reaction was cooled to room temperature and then 10% HCl was added slowly until the solution was acidic. The tetrahydrofuran was removed in vacuo and the residue was taken up in ethyl acetate. The organics were washed with brine, dried (MgSO4) and concentrated to afford 5.5 g (58%) of the title compound which was used without purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=[O:19])N(OC)C)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br-].O.Cl>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14](=[O:19])[CH2:12][CH2:11][CH:10]=[CH2:9])[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CON(C)C(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Agent: [Br-]
Solvent: O
Solvent: C1CCOC1
Product: C=CCCC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 176.4 %

Procedure:
A solution of tert-butyl-4-[methoxy(methyl)-carbamoyl]-piperidine-1-carboxylate (5.04 g, 18.53 mmol), in tetrahydrofuran (50 mL) maintained under an atmosphere of nitrogen was cooled to 0° C. To this cold solution was added a THF solution of 4-butenylmagnesiun bromide (0.5 M in THF, 45 mL, 22.5 mmol) in a dropwise manner. The solution was stirred for 1 hour at 0° C. then allowed to warm to room temperature overnight. The resulting solution was poured into water, acidified to pH 3-4 with 1 N hydrochloric acid, and extracted with ethyl acetate (3×). The combined organic phase was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. Purification by flash column chromatography (silica gel, 0-25% ethyl acetate in heptane) gave tert-butyl-4-pent-4-enoylpiperidine-1-carboxylate as a colorless oil (4.37 g, 88%); 1H NMR (CDCl3, 300 MHz) δ 5.79 (m, 1H), 4.98 (m, 2H), 4.10 (m, 2H), 2.76 (t, J=11.5 Hz, 2H), 2.54 (m, 2H), 2.46 (tt, J1=11.5 Hz, J2=3.5 Hz, 1H), 2.32 (m, 2H), 1.78 (m, 2H), 1.48-1.58 (m, 2H) and 1.45 (s, 9H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])=[CH:12][CH:11]=2)[CH:5]=[CH:6][CH:7]=1.Br[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:23]([O:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[CH:11]=[CH:12][C:13]([CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])=[CH:14][CH:15]=2)[CH:5]=[CH:6][CH:7]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)CCc1ccc(C#Cc2cccc(O)c2)cc1
Product: COC(=O)CCc1ccc(C#Cc2cccc(OCc3ccccc3)c2)cc1

Procedure:
The title compound was prepared from methyl 3-(4-((3-hydroxyphenyl)ethynyl)phenyl)propanoate (98 mg, 0.45 mmol) and (bromomethyl)benzene (142 mg, 1.03 mmol) according to the general procedure IV to give 112 mg (68%) of a pure pale yellow solid. Rf=0.60 (EtOAc:PE, 1:1); 1H NMR (CDCl3): δ 7.46-7.32 (m, 7H), 7.46-7.22 (m, 1H), 7.17 (d, J=8.5 Hz, 2H), 7.14-7.12 (m, 2H), 6.95 (ddd, J=8.3 Hz, 2.8 Hz, 1.0 Hz, 1H), 5.07 (s, 2H), 3.66 (s, 3H), 2.95 (t, J=7.8 Hz, 2H), 2.63 (t, J=7.8 Hz, 2H); 13C NMR (CDCl3): δ 173.8, 158.6, 140.9, 136.7, 131.8, 129.4, 128.6, 128.3, 128.0, 127.5, 124.4, 124.4, 121.1, 117.3, 115.6, 89.2, 89.0, 70.0, 51.6, 35.4, 30.8; MALDI-MS m/z 393.4 (M+Na+).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[N:5][C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[C:8]([CH2:13][N:14]([CH3:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH:7]=2>C(Cl)(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH3:21][N:14]([CH2:13][C:8]1[CH:7]=[C:6]2[C:11]([CH:12]=[C:3]([CH:2]=[O:1])[CH:4]=[N:5]2)=[CH:10][CH:9]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CN(Cc1ccc2cc(CO)cnc2c1)c1ccccc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: CN(Cc1ccc2cc(C=O)cnc2c1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73 %

Procedure:
The above 3-hydroxymethyl-7-(methylphenylamino)methylquinoline (306 mg, 1.10 mmol.) was dissolved in dry chloroform (8 mL). To this was added manganese dioxide (0.95 g), and the mixture was stirred overnight at room temperature. The reaction mixture was filtered over Celite®, and the residue was washed with chloroform. The chloroform washings were combined with the filtrate. The solvent was distilled off under reduced pressure, to leave the desired compound as brown oil (222 mg, yield: 73%).
Reaction SMILES: [CH3:1][C:2]([CH3:15])([O:4][C:5]([NH:7][C@H:8]([C:12]([OH:14])=[O:13])[CH:9]([CH3:11])[CH3:10])=[O:6])[CH3:3].O[CH:17]([C:20]1[CH:36]=[C:35]2[N:23]([CH2:24][C:25]3[C:26]2=[N:27][C:28]2[C:33]([CH:34]=3)=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22](=[O:37])[C:21]=1[CH3:38])[CH2:18][CH3:19]>>[CH3:38][C:21]1[C:22](=[O:37])[N:23]2[C:35](=[CH:36][C:20]=1[CH:17]([O:13][C:12](=[O:14])[CH:8]([NH:7][C:5]([O:4][C:2]([CH3:3])([CH3:1])[CH3:15])=[O:6])[CH:9]([CH3:11])[CH3:10])[CH2:18][CH3:19])[C:26]1=[N:27][C:28]3[C:33]([CH:34]=[C:25]1[CH2:24]2)=[CH:32][CH:31]=[CH:30][CH:29]=3
Reactant: CCC(O)c1cc2n(c(=O)c1C)Cc1cc3ccccc3nc1-2
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Product: CCC(OC(=O)C(NC(=O)OC(C)(C)C)C(C)C)c1cc2n(c(=O)c1C)Cc1cc3ccccc3nc1-2

Procedure:
The title compound was prepared according to the procedure in Example 3A except using N-[(1,1-dimethylethoxy)carbonyl]-L-valine and (±)-7-(1-hydroxypropyl)-8-methylindolizino[1,2-b]quinolin-9(11H)-one. 1H NMR (CDCl3) d 8.34 (s, 1H), 8.22 (m, 1H), 7.91 (d, J=8.2 Hz, 1H), 7.80 (m, 1H), 7.62 (m, 1H), 7.34 (two s, 1H), 5.94 (m, 1H), 5.26 (s, 2H), 5.04 (two br d, J=9.3 Hz, 1H), 4.36 (two d, J=4.5 Hz, 1H), 2.36 (s, 3H), 2.4-2.2 (m, 1H), 2.1-1.8 (m, 2H), 1.44 and 1.38 (two s, 9H), 1.00 (overlapping t and d, 9H).