Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:3]=1[CH2:4][O:5][C:6]1[C:7]2[N:8]([C:12]([C:16](O)=[O:17])=[C:13]([CH3:15])[N:14]=2)[CH:9]=[CH:10][CH:11]=1.F[B-](F)(F)F.N1(O[C+](N(C)C)N(C)C)C2C=CC=CC=2N=N1.CN1CCOCC1.[NH:53]1[C:62]2[C:57](=[CH:58][CH:59]=[CH:60][CH:61]=2)[CH2:56][CH:55]([NH2:63])[CH2:54]1>ClCCl.O>[F:23][C:19]1[CH:20]=[CH:21][CH:22]=[C:2]([F:1])[C:3]=1[CH2:4][O:5][C:6]1[C:7]2[N:8]([C:12]([C:16]([NH:63][CH:55]3[CH2:56][C:57]4[C:62](=[CH:61][CH:60]=[CH:59][CH:58]=4)[NH:53][CH2:54]3)=[O:17])=[C:13]([CH3:15])[N:14]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: NC1CNc2ccccc2C1
Reactant: Cc1nc2c(OCc3c(F)cccc3F)cccn2c1C(=O)O
Agent: CN(C)[C+](On1nnc2ccccc21)N(C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CN1CCOCC1
Solvent: O
Product: Cc1nc2c(OCc3c(F)cccc3F)cccn2c1C(=O)NC1CNc2ccccc2C1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
70 mg of 8-[(2,6-difluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridine-3-carboxylic acid (0.22 mmol), 54 mg of (benzotriazol-1-yloxy)bisdimethylaminomethylium fluoroborate (TBTU, 0.26 mmol) and 133 mg of 4-methylmorpholine (1.32 mmol) were initially charged in 1.5 ml of dichloromethane. After 10 min at RT, 53 mg of 1,2,3,4-tetrahydroquinoline-3-amine (0.24 mmol) were added, and the mixture was stirred at RT overnight. About 5 ml of water were added, the reaction solution was stirred for another 30 min and the resulting precipitate was filtered off, washed thoroughly with water and dried under high vacuum. The crude product was purified by preparative thin-layer chromatography (dichloromethane/methanol 20:1). This gave 52 mg of the title compound (52% of theory).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]#[N:9])=[CH:4][N:3]=1.CS(C)=O.[CH:14]([N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)([CH3:16])[CH3:15]>O>[CH:14]([N:17]1[CH2:22][CH2:21][N:20]([C:2]2[CH:7]=[CH:6][C:5]([C:8]#[N:9])=[CH:4][N:3]=2)[CH2:19][CH2:18]1)([CH3:16])[CH3:15]
Reactant: N#Cc1ccc(Cl)nc1
Reactant: CC(C)N1CCNCC1
Solvent: CS(C)=O
Solvent: O
Product: CC(C)N1CCN(c2ccc(C#N)cn2)CC1
Temperature: 100 °C
Yield: 81.8 %

Procedure:
A mixture of 2-chloropyridine-5-carbonitrile (5.0 g, 36.1 mmol), DMSO (10 mL) and 1-isopropylpiperazine (10.7 mL, 75.8 mmol) was stirred under an atmosphere of nitrogen and heated on a 100° C. oil-bath for 3 h. The reaction mixture was allowed to cool, and then poured into cold water (500 mL). The solid was isolated by filtration, washed with water and dried to give 6.8 g (82%) of 6-(4-isopropylpiperazin-1-yl)nicotinonitrile.
Reaction SMILES: CC[Mg+].[Br-].[Br:5][C:6]1[N:7]=[C:8]([CH2:20][O:21][CH2:22][CH2:23][O:24][Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26])[N:9]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:10]=1Br.CN([CH:35]=[O:36])C>C(OCC)C.C1COCC1>[Br:5][C:6]1[N:7]=[C:8]([CH2:20][O:21][CH2:22][CH2:23][O:24][Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26])[N:9]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:10]=1[CH:35]=[O:36]
Reactant: CC(C)(C)[Si](C)(C)OCCOCc1nc(Br)c(Br)n1COCC[Si](C)(C)C
Reactant: CN(C)C=O
Agent: CC[Mg+]
Agent: [Br-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCCOCc1nc(Br)c(C=O)n1COCC[Si](C)(C)C
Reaction time: 3 h
Yield: 69 %

Procedure:
3N EtMgBr (0.086 mL of a 3N solution in diethyl ether, 0.26 mmol) was added to a solution of 4,5-dibromo-2-{[(2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}ethyl)oxy]methyl}-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole (0.12 g, 0.21 mmol) in THF (2 mL). The reaction mixture was stirred for 3 h, DMF was added (0.5 mL, 4.9 mmol), and stirring was continued overnight. The solution was quenched by addition of sat'd NH4Cl and extracted with EtOAc and CH2Cl2. The organic phase was dried (Na2SO4), filtered, and purified by silica gel chromatography (0-30% EtOAc/hex) to afford the title compound (0.073 g, 69%) as a clear oil. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 9.77 (s, 1H), 5.84 (s, 2H), 5.27-5.47 (m, 1H), 4.60-4.77 (m, 1H), 3.74 (ddd, J=9.16, 4.85, 4.67 Hz, 2H), 3.47-3.62 (m, 4H), 0.83-0.95 (m, 11H), 0.04 (s, 6H), −0.06-0.01 (m, 9H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]1[CH2:12][CH2:11][NH:10][C:9]1=[O:13].Br[C:15]1[CH:16]=[N:17][N:18]([C:20]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:19]=1.N[C@@H]1CCCC[C@H]1N.C(=O)([O-])[O-].[K+].[K+]>[Cu](I)I.O1CCOCC1>[CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]1[CH2:12][CH2:11][N:10]([C:15]2[CH:16]=[N:17][N:18]([C:20]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH:19]=2)[C:9]1=[O:13]
Reactant: Cc1ccncc1N1CCNC1=O
Reactant: Brc1cnn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Agent: I[Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: Cc1ccncc1N1CCN(c2cnn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c2)C1=O
Yield: 60.8 %

Procedure:
Using the same reaction conditions as in Example 14, 1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b: 150 mg, 0.8465 mmol) was reacted with 4-bromo-1-trityl-1H-pyrazole (369.3 mg, 0.8465 mmol), 1,4-dioxane (50 mL), copper iodide (16 mg, 0.08465 mmol), trans-1,2-diamino cyclohexane (29 mg, 0.2539 mmol) and potassium carbonate (468 mg, 3.3860 mmol) to afford the crude product. Purification by column chromatography on silica gel (2% MeOH in chloroform) afforded 250 mg of 1-(4-Methyl-pyridin-3-yl)-3-(1-trityl-1H-pyrazol-4-yl)-imidazolidin-2-one (60% yield). Dioxane hydrochloride (10 mL) was added to a stirred solution of 1-(4-methyl-pyridin-3-yl)-3-(1-trityl-1H-pyrazol-4-yl)-imidazolidin-2-one (250 mg, 0.51484 mmol) in dioxane under nitrogen atmosphere at 0° C. The reaction mixture was stirred at room temperature for 2 hours with TLC monitoring (10% MeOH in DCM). The solvent was distilled from the reaction mixture and washed with ether. The precipitate was collected and dried under reduced pressure to afford 80 mg of the product (55% yield).
Reaction SMILES: [C:1]([C:4]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6])(=O)[CH3:2].[C:21]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])#[N:22].C([O-])(=O)C.[NH4+]>C(OCC)(=O)C.C(O)(=O)C.C1C=CC=CC=1>[CH2:27]([O:26][C:24](=[O:25])[C:23]([C:21]#[N:22])=[C:1]([CH3:2])[C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH3:28]
Reactant: CCOC(=O)C(C(C)=O)(C(=O)OCC)c1ccccc1
Reactant: CCOC(=O)CC#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Solvent: CC(=O)O
Product: CCOC(=O)C(C#N)=C(C)C(C(=O)OCC)(C(=O)OCC)c1ccccc1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
A mixture of diethyl 2-acetyl-2-phenylmalonate (50 mmol, Example 32, Part A), ethyl cyanoacetate (50 mmol), acetic acid (1.14 mL) ammonium acetate (400 mg), and benzene (50 mL) is heated to reflux in a Dean-Stark apparatus. After approximately 10 hours, additional ethyl cyanoacetate (50 mmol), acetic acid (1.14 mL), and ammonium acetate (400 mg) are added. After an additional 10 hours, the reaction is cooled to room temperature, diluted with ethyl acetate (30 mL), washed with water (240 mL), brine (40 mL), and dried (Na2SO4). After filtering, the extract is concentrated in vacuo and the desired product, as a mixture of E and Z-isomers, is isolated by column chromatography on silica gel, eluting with 5% ethyl acetate in petroleum ether.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]#[N:12])[CH:9]=2)[N:4]([CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][O:14]2)[N:3]=1.ClCCl.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C(O[CH2:34][CH3:35])(=O)C>COCCOC>[NH2:3][C:2]1[CH:10]=[C:9]([C:2]2[C:10]3[C:5](=[CH:6][CH:7]=[C:8]([C:11]#[N:12])[CH:9]=3)[N:4]([CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][O:14]3)[N:3]=2)[CH:8]=[CH:34][CH:35]=1
Reactant: N#Cc1ccc2c(c1)c(Br)nn2C1CCCCO1
Reactant: CCOC(C)=O
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: ClCCl
Product: N#Cc1ccc2c(c1)c(-c1cccc(N)c1)nn2C1CCCCO1

Procedure:
The title compound was prepared as described in example 161 using 3-bromo-1-perhydro-2H-pyran-2-yl-1H-indazole-5-carbonitrile (1.7 g, 5.55 mmol), in ethylene glycol dimethyl ether (60 mL), 3-amino boronic acid (1.72 g, 11.10 mmol), [1,1′-bis(diphenylphosphino)-ferrocene]complex with dichloromethane (1:1) (0.641 g, 0.555 mmol), and potassium phosphate (5.89 g, 27.75 mmol). A second batch was prepared using 3-bromo-1-perhydro-2H-pyran-2-yl-1H-indazole-5-carbonitrile (2.0 g, 6.53 mmol), in ethylene glycol dimethyl ether (70 mL), 3-amino boronic acid (2.025 g, 13.06 mmol), [1,1′-bis(diphenylphosphino)-ferrocene]complex with dichloromethane (1:1) (0.755 g, 0.653 mmol), and potassium phosphate (6.92 g, 32.65 mmol). The crude compounds were combined and purified by column chromatography using 30% ethyl acetate in hexanes (3.2 g, 82% yield): ES-MS (m/z) 319 [M+H]+.
Reaction SMILES: [C:1]1([C@H:7]([CH3:20])[CH2:8][O:9][S:10]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)(=[O:12])=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1([C@@H](C)CO)C=CC=CC=1>>[C:1]1([C@@H:7]([CH3:20])[CH2:8][O:9][S:10]([C:13]2[CH:14]=[CH:15][C:16]([CH3:19])=[CH:17][CH:18]=2)(=[O:12])=[O:11])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H](C)c2ccccc2)cc1
Agent: C[C@@H](CO)c1ccccc1
Product: Cc1ccc(S(=O)(=O)OC[C@H](C)c2ccccc2)cc1

Procedure:
Following the procedure analogous to that used for the synthesis of toluene-4-sulfonic acid (S)-2-phenyl-propyl ester, but using (R)-2-phenyl-1-propanol as starting compound, the title compound was prepared.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[C@@H:15]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:14](=[O:23])OC1C1C=CC(OC)=CC=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:33][Cl:34].O1CCCC1.S([O-])(O)(=O)=O.[K+]>CCCCCC>[CH2:1]([O:8][C:9]([NH:11][C@@H:15]([CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[C:14](=[O:23])[CH2:33][Cl:34])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(C2OC(=O)[C@H](Cc3ccccc3)N2C(=O)OCc2ccccc2)cc1
Reactant: ClCBr
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=C(N[C@@H](Cc1ccccc1)C(=O)CCl)OCc1ccccc1
Temperature: -78 °C
Reaction time: 0.55 h
Yield: 62 %

Procedure:
(4S)-N-benzyloxycarbonyl-2-(p-methoxyphenyl)-4-phenylmethyloxazolidin-5-one (Tetrahedron Lett. 1995, 36, 42, 7761) (700 mg) and bromochloromethane (0.142 ml) were added to dehydrated tetrahydrofuran (16.8 ml), and they were cooled to −78° C. 1.54 Mn-butyllithium solution (1.42 ml) in hexane was added to the obtained mixture, and they were stirred for 33 minutes. 5% aqueous potassium hydrogensulfate solution was added to the reaction mixture to terminate the reaction. After the extraction with ethyl acetate at room temperature twice followed by drying over anhydrous magnesium sulfate, magnesium sulfate was removed. The obtained solution in ethyl acetate was analyzed by HPLC to find that (3S)-3-benzyloxycarbonylamino-1-chloro-4-phenyl-2-butanone (347 mg) was obtained in a yield of 62%.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=2)[C:5]([F:16])=[CH:4][N:3]=1.[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH:23]=[C:24]([O:28][CH3:29])[C:25]=1[O:26][CH3:27])[NH2:22]>>[F:16][C:5]1[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=2)=[N:7][C:2]([NH:22][C:21]2[CH:23]=[C:24]([O:28][CH3:29])[C:25]([O:26][CH3:27])=[C:19]([O:18][CH3:17])[CH:20]=2)=[N:3][CH:4]=1
Reactant: COc1cc(N)cc(OC)c1OC
Reactant: Oc1cccc(Nc2nc(Cl)ncc2F)c1
Product: COc1cc(Nc2ncc(F)c(Nc3cccc(O)c3)n2)cc(OC)c1OC

Procedure:
In a like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, 2-chloro-5-fluoro-N4-(3-hydroxyphenyl)-4-pyrimidineamine and 3,4,5-trimethoxyaniline were reacted to produce 5-fluoro-N4-(3-hydroxyphenyl)-N2-(3,4,5-trimethoxyphenyl)-2,4-pyrimidinediamine. 1H NMR (DMSO-d6): δ 9.33 (s, 1H), 9.17 (s, 1H), 8.99 (s, 1H), 8.06 (d, 1H, J=3.3 Hz), 7.27 (d, 1H, J=7.5 Hz), 7.08-7.02 (m, 4H), 6.46 (dd, 1H, J=1.8 and 7.8 Hz), 3.60 (s, 6H), 3.57 (s, 3H); LCMS: purity: 99%; MS (m/e): 387 (MH+).
Reaction SMILES: C(O[C:4]([C:6]1[C:7]([N:19]([CH2:21][CH3:22])[CH3:20])=[N:8][C:9]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:10][C:11]=1[CH3:12])=[O:5])C.[F:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][NH2:29])=[CH:26][CH:25]=1.C[Al](C)C.[OH-].[Na+]>C1(C)C=CC=CC=1.O.CCOC(C)=O>[CH2:21]([N:19]([CH3:20])[C:7]1[C:6]([C:4]([NH:29][CH2:28][C:27]2[CH:30]=[CH:31][C:24]([F:23])=[CH:25][CH:26]=2)=[O:5])=[C:11]([CH3:12])[CH:10]=[C:9]([N:13]2[CH2:14][CH2:15][O:16][CH2:17][CH2:18]2)[N:8]=1)[CH3:22]
Reactant: NCc1ccc(F)cc1
Reactant: CCOC(=O)c1c(C)cc(N2CCOCC2)nc1N(C)CC
Agent: C[Al](C)C
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: CCN(C)c1nc(N2CCOCC2)cc(C)c1C(=O)NCc1ccc(F)cc1
Temperature: 120 °C
Yield: 40.7 %

Procedure:
A solution of 249 mg (0.81 mmol) 2-(ethyl(methyl)amino)-4-methyl-6-morpholino-pyridine-3-carboxylic acid ethylester and 924 μl (8.1 mmol) 4-fluoro-benzylamine in toluene (17 ml) was treated with 2.85 ml (2M in toluene, 5.7 mmol) AlMe3 and was subsequently heated to 120° C. for 4 d. Then the solution was diluted with water, a 1M aq. NaOH sol. and EtOAc. The organic layer was separated, washed with a 2M aq. NaOH sol. and brine, dried over MgSO4 and concentrated in vacuo. Purification of the residue by CC (hexane/EtOAc 3:1) provided 127 mg (0.33 mmol, 40%) 2-(Ethyl-methyl-amino)-N-[(4-fluorophenyl)-methyl]-4-methyl-6-morpholin-4-yl-pyridine-3-carboxylic acid amide (example 174). [M+H]+ 387.2
Reaction SMILES: [CH2:1]([N:8]([CH2:21][C:22]1[CH:39]=[CH:38][C:25]([O:26][C:27]2[CH:32]=[CH:31][C:30]([CH2:33][CH2:34][C:35](O)=[O:36])=[CH:29][CH:28]=2)=[CH:24][CH:23]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[C:10]=1[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C[O:42][C:43](=[O:46])[CH2:44][NH2:45].C(N(C(C)C)CC)(C)C.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.C(OCC)C>[CH2:1]([N:8]([CH2:21][C:22]1[CH:23]=[CH:24][C:25]([O:26][C:27]2[CH:28]=[CH:29][C:30]([CH2:33][CH2:34][C:35]([NH:45][CH2:44][C:43]([OH:46])=[O:42])=[O:36])=[CH:31][CH:32]=2)=[CH:38][CH:39]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:17])=[O:18])[C:10]=1[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2ccc(CCC(=O)O)cc2)cc1
Reactant: COC(=O)CN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOCC
Product: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2ccc(CCC(=O)NCC(=O)O)cc2)cc1
Reaction time: 12 h
Yield: 87.3 %

Procedure:
A solution of the product from Example 104A (0.065 g, 0.119 mmoles), glycine methyl ester hydrochloride (0.0300 g, 0.24 mmoles), and diisopropylethylamine (0.042 mL, 0.24 mmoles) in DMF (0.3 mL) was treated with EDAC (0.032 g, 0.167 mmoles) and HOBT (0.0225 g, 0.167 mmoles). The resulting mixture was shaken for 12 h. The crude products were diluted with diethyl ether, extracted with sat. NH4Cl, extracted with H2O (2×), rinsed with brine, dried (Na2SO4), and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel. The product was dissolved in EtOH (0.5 mL) and THF (0.5 mL) and treated with 2N NaOH (1.0 mL) for 4 h. The resulting mixture was poured into 3N HCl and extracted with ethyl acetate (2×). The combined organics were rinsed with brine, dried (Na2SO4), and concentrated under reduced pressure. Purification by preparative HPLC (CH3CN:0.1% trifluoroacetic acid in H2O) on a YMC ODS Guardpak column yielded the title compound (0.0625 g, 87%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ8.97 (s, 1 H), 8.18 (t, 1 H), 7.23 (m, 9 H), 7.00 (m, 3 H), 6.86 (m, 4 H), 4.05 (s, 2 H), 4.01 (s, 2 H), 3.73 (d, 2 H), 2.91 (s, 3 H), 2.79 (t, 2 H), 2.40 (m, 3 H), 2.39 (s, 3 H); MS (APCI) m/z 602 (M+H+).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@H:10]([OH:15])[CH2:11][CH:12]=[CH:13][CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:16]([O:18][CH:19]([O:35][CH2:36][CH3:37])[CH2:20]O[C@H](CC=C)COCC1C=CC=CC=1)[CH3:17]>>[CH2:16]([O:18][CH:19]([O:35][CH2:36][CH3:37])[CH2:20][O:15][C@H:10]([CH2:11][CH:12]=[CH:13][CH3:14])[CH2:9][O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH3:17]
Reactant: CC=CC[C@@H](O)COCc1ccccc1
Reactant: C=CC[C@H](COCc1ccccc1)OCC(OCC)OCC
Product: CC=CC[C@H](COCc1ccccc1)OCC(OCC)OCC

Procedure:
(2R)-1-(Benzyloxy)hex-4-en-2-ol (C12) (150 g, 0.73 mol) was converted to the product according to the method used for synthesis of ({[(2R)-2-(2,2-diethoxyethoxyl)pent-4-en-1-yl]oxy}methyl)benzene (C2) in Preparation P1, except that the initial combination of reagents was carried out at 0° C. The product was obtained as a brown oil (400 g, ≦0.73 mol), which was used for the next step without further purification. By 1H NMR analysis, this material contained a roughly 1:1 mixture of geometric isomers. 1H NMR (400 MHz, CDCl3), characteristic peaks for product: δ 7.25-7.38 (m, 5H), 5.38-5.60 (m, 2H), 4.55 and 4.55 (2 s, total 2H), 2.22-2.37 (m, 2H), 1.60-1.68 (m, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[CH3:9].C1C(=O)N(Br)C(=O)C1.[CH3:18][N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>C(Cl)(Cl)(Cl)Cl.CCO>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[CH2:9][N:22]1[CH2:23][CH2:24][N:19]([CH3:18])[CH2:20][CH2:21]1
Reactant: Cc1ccc(I)cc1F
Reactant: CN1CCNCC1
Agent: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCO
Product: CN1CCN(Cc2ccc(I)cc2F)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.6 %

Procedure:
To a mixture of 2-fluoro-4-iodotoluene (0.94 g, 4.0 mmol) in CCl4 (40 mL) were added BPO (0.02 g, 0.08 mmol) and NBS (0.78 g, 4.4 mmol) under N2. The reaction mixture was refluxed for 5 h, then cooled and concentrated in vacuo. To the residue was added a solution of methylpiperazine (2.00 g, 20 mmol) in EtOH (40 mL) under N2. The mixture was stirred at rt overnight and concentrated in vacuo. The resulting residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=10:1) to give the title compound as a white solid (0.69 g, 52%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](I)=[C:6]([CH2:8][NH2:9])[CH:7]=1.C(N(CC)C(C)C)(C)C.[C:20](#[N:24])[CH2:21][C:22]#[N:23].N>CN(C)C=O.CCOCC>[NH2:24][C:20]1[N:9]=[CH:8][C:6]2[C:5]([C:21]=1[C:22]#[N:23])=[CH:4][CH:3]=[C:2]([Br:1])[CH:7]=2
Reactant: N#CCC#N
Reactant: NCc1cc(Br)ccc1I
Agent: N
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Product: N#Cc1c(N)ncc2cc(Br)ccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.5 %

Procedure:
To a stirred solution of (5-bromo-2-iodophenyl)methanamine (40 g, 0.129 mol) in N,N-dimethylformamide (500 mL) was sequentially added N,N-diisopropylethylamine (33.3 g, 0.257 mol), malononitrile (16.9 g, 0.257 mol) and CuBr (36.9 g, 0.257 mol). The mixture was stirred at room temperature overnight. After that, to the reaction mixture was added ether and 10% NH3 (1 L, 1:1) and stirred at room temperature overnight open to the air. The mixture was separated and the residue was extracted with ethyl acetate three times, and the combined organic extracts were washed with brine, filtered, and evaporated to yield 20 g (62%) of 3-amino-7-bromoisoquinoline-4-carbonitrile. LCMS (ESI): M+H=247.7; 1H NMR (400 MHz, DMSO-d6) δ 9.03 (s, 1H), 8.23 (d, J=2.0 Hz, 1H), 7.81 (dd, J=2.0, 9.2 Hz, 1H), 7.56 (d, J=9.2 Hz, 1H), 7.42 (s, 2H).
Reaction SMILES: [CH3:1][CH:2]1[C:7]2=[N:8][C:9]3[CH:10]=[N+:11]([O-])[C:12]4[C:17]([C:18]=3[N:6]2[C@@H:5]([CH3:20])[CH2:4][O:3]1)=[CH:16][CH:15]=[CH:14][CH:13]=4.[OH-].[NH4+:22].C1(C)C=CC(S(Cl)(=O)=O)=CC=1.O>C(Cl)Cl.C(Cl)(Cl)Cl>[CH3:1][CH:2]1[C:7]2=[N:8][C:9]3[C:10]([NH2:22])=[N:11][C:12]4[C:17]([C:18]=3[N:6]2[C@@H:5]([CH3:20])[CH2:4][O:3]1)=[CH:16][CH:15]=[CH:14][CH:13]=4
Reactant: [NH4+]
Reactant: CC1OC[C@H](C)n2c1nc1c[n+]([O-])c3ccccc3c12
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [OH-]
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: O
Product: CC1OC[C@H](C)n2c1nc1c(N)nc3ccccc3c12

Procedure:
A solution of (11S)-8,11-dimethyl-10,11-dihydro-8H-[1,4]oxazino[4′,3′:1,2]imidazo[4,5-c]quinoline 5-oxide (85 mg, 0.316 mmol) in 5 mL of CH2Cl2 was treated with 1 mL of concentrated aqueous ammonium hydroxide and stirred vigorously. p-Toluenesulfonyl chloride (60 mg, 0.316 mmol) was added in one portion. The following day the reaction was treated with 5 mL of H2O and 10 mL of CH2Cl2, and the layers were separated. The organic layer was washed sequentially with saturated NaHCO3 solution (2×) and brine, dried over Na2SO4, filtered, and concentrated to give a light yellow solid. Chromatography (AFC, SiO2, 0-20% CMA/CHCl3) afforded (11s)-8,11-dimethyl-10,11-dihydro-8H-[1,4]oxazino[4′,3′:1,2]imidazo[4,5-c]quinolin-6-amine (25 mg) as a white solid, m.p. 218-223° C.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[Cl:5][C:6]1[CH:12]=[C:11]([Cl:13])[C:10]([Cl:14])=[CH:9][C:7]=1[NH2:8]>ClCCl>[CH3:2][C:1]([NH:8][C:7]1[C:6]([Cl:5])=[CH:12][C:11]([Cl:13])=[C:10]([Cl:14])[CH:9]=1)=[O:3]
Reactant: Nc1cc(Cl)c(Cl)cc1Cl
Reactant: CC(=O)Cl
Solvent: ClCCl
Product: CC(=O)Nc1cc(Cl)c(Cl)cc1Cl
Temperature: 50 °C

Procedure:
Acetyl chloride (2.13 mls; 0.03 mole) is added dropwise to a suspension of 2,4,5-trichloroaniline (4.91 g; 0.025 mole) and powdered 3A molecular sieves (7.4 g) in dichloromethane (25 mls), at room temperature, under a nitrogen atmosphere. When addition is completed, the mixture is heated to 50° C. for 1.5 hours and then cooled to room temperature. The 3A sieves are separated by filtration and washed with dichloromethane. All dichloromethane solutions are combined and evaporated to obtain 4.1 grams (69% of theoretical) of the solid product; m.p. 188°-190° C. after recrystallized from toluene.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]#[C:10][C:11]2[CH:16]=[CH:15][C:14](Br)=[CH:13][CH:12]=2)=[CH:5][CH:4]=1)#[N:2].CN1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.C(=O)([O-])[O-].[K+].[K+].[OH-].[Na+].OO>O1CCCC1.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>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]#[C:10][C:11]2[CH:16]=[CH:15][C:14](/[CH:20]=[CH:21]/[CH2:22][CH2:23][CH3:24])=[CH:13][CH:12]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: CN1CCCCC1
Reactant: N#Cc1ccc(C#Cc2ccc(Br)cc2)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: OO
Solvent: C1CCOC1
Product: CCC/C=C/c1ccc(C#Cc2ccc(C#N)cc2)cc1
Temperature: 25 °C
Yield: 82.9 %

Procedure:
In a four necked flask equipped with a stirrer, a reflux condenser and a thermometer which had been replaced by a nitrogen atmosphere, 1-(4-cyanophenyl)-2-(4-bromophenyl)acetylene (3.4 g, 12 mmol), tetrakis(triphenylphosphine)palladium (0.23 g, 0.2 mmol), N-methylpiperidine (5 g), potassium carbonate (5.5 g, 40 mmol) and tetrahydrofuran (60 ml) were charged. Then, to the mixture, a solution of E-1-pentenylcatecholborane (20 mmol) in tetrahydrofuran (50 ml) was dropwise added at room temperature, followed by heat refluxing for 6 hours while stirring. After cooling the reaction mixture to room temperature, 10% aqueous solution of sodium hydroxide (5 ml) and 30% aqueous hydrogen peroxide (2 ml) were added to the mixture, followed by stirring for 1 hour. The mixture was extracted with ethyl ether. The organic layer was washed with saturated aqueous solution of sodium chloride (20 ml each) twice and dried over anhydrous magnesium sulfate. After evaporating the solvent off, the residue was purified by silica gel column chromatography to obtain 1-(4-cyanophenyl)-2-[4-(1-trans-pentenyl)phenyl]acetylene (2.7 g). Yield: 84%.