Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si]([N:8]1[C:16]2[C:11](=[C:12](B3OC(C)(C)C(C)(C)O3)[C:13]([F:17])=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)(C(C)(C)C)(C)C.Cl[C:28]1[N:29]=[C:30]([N:49]2[CH2:54][CH2:53][O:52][CH2:51][CH2:50]2)[C:31]2[N:37]=[C:36]([CH2:38][N:39]3[CH2:44][CH2:43][CH:42]([C:45]([OH:48])([CH3:47])[CH3:46])[CH2:41][CH2:40]3)[CH:35]=[CH:34][C:32]=2[N:33]=1>>[F:17][C:13]1[C:12]([C:28]2[N:29]=[C:30]([N:49]3[CH2:54][CH2:53][O:52][CH2:51][CH2:50]3)[C:31]3[N:37]=[C:36]([CH2:38][N:39]4[CH2:44][CH2:43][CH:42]([C:45]([OH:48])([CH3:47])[CH3:46])[CH2:41][CH2:40]4)[CH:35]=[CH:34][C:32]=3[N:33]=2)=[C:11]2[C:16](=[CH:15][CH:14]=1)[NH:8][CH:9]=[CH:10]2
Reactant: CC1(C)OB(c2c(F)ccc3c2ccn3[Si](C)(C)C(C)(C)C)OC1(C)C
Reactant: CC(C)(O)C1CCN(Cc2ccc3nc(Cl)nc(N4CCOCC4)c3n2)CC1
Product: CC(C)(O)C1CCN(Cc2ccc3nc(-c4c(F)ccc5[nH]ccc45)nc(N4CCOCC4)c3n2)CC1

Procedure:
Following General Procedure A, 1-(tert-butyldimethylsilyl)-5-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole and 2-(1-((2-chloro-4-morpholinopyrido[3,2-d]pyrimidin-6-yl)methyl)piperidin-4-yl)propan-2-ol from Example 8 were reacted to give 105. LCMS (MH+)=505.2. 1H-NMR (DMSO-d6): δ 11.2 (s, 1H), 8.15 (d, 1H), 7.87 (d, 1H), 7.47 (m, 1H), 7.44 (s, 1H), 7.01 (m, 1H), 6.75 (s, 1H), 4.49 (s, 4H), 4.02 (s, 1H), 3.80 (m, 4H), 3.73 (s, 2H), 2.93 (m, 2H), 1.99 (m, 2H), 1.66 (m, 2H), 1.28 (m, 3H), 1.04 (s, 6H)
Reaction SMILES: [NH2:1][CH2:2][C:3]([OH:5])=[O:4].C(=O)([O-])O.[Na+].O1CCOCC1.[NH:17]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[C@H:18]([C:23](ON1C(=O)CCC1=O)=[O:24])[CH2:19][CH:20]([CH3:22])[CH3:21]>O.C(OCC)(=O)C.CCCCCC>[NH:17]([C:33]([O:35][C:36]([CH3:38])([CH3:37])[CH3:39])=[O:34])[C@H:18]([C:23]([NH:1][CH2:2][C:3]([OH:5])=[O:4])=[O:24])[CH2:19][CH:20]([CH3:22])[CH3:21]
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)ON1C(=O)CCC1=O
Reactant: NCC(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCCC
Solvent: O
Solvent: C1COCCO1
Product: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)NCC(=O)O
Reaction time: 0.5 h
Yield: 75.7 %

Procedure:
2.63 Grams of H-Gly-OH and 3.50 g of sodium hydrogen carbonate were suspended in 50 ml of water, to this supension was added, under ice-cooling condition, 50 ml of dioxane solution containing 10.0 g of Boc-Leu-OSu, and stirred for 30 minutes, then this mixture was further stirred at room temperature for 15 hours. The reaction mixture was concentrated under reduced pressure, and the residue thus obtained was extracted with ethyl acetate (70 ml). The ethyl acetate layer was washed with 1N-hydrochloric acid, and with a saturated sodium chloride aqueous solution, then was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue thus obtained was recrystalled from ethyl acetate-n-hexane to obtain 6.65 g (yield: 75.7%) of the above-mentioned objective product.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]([OH:11])=[O:10])[CH2:5][CH2:4]1.C([O-])([O-])=O.[K+].[K+].[CH2:18]([O:25][C:26](Cl)=[O:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.Cl>O.O1CCOCC1>[CH2:18]([O:25][C:26]([NH:1][CH2:2][C@H:3]1[CH2:4][CH2:5][C@H:6]([C:9]([OH:11])=[O:10])[CH2:7][CH2:8]1)=[O:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NC[C@H]1CC[C@H](C(=O)O)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: O=C(NC[C@H]1CC[C@H](C(=O)O)CC1)OCc1ccccc1

Procedure:
A 1L 3-neck flask was charged with 25.09 (160 mmol) trans-4-aminomethyl-cyclohexanecarboxylic acid, 77.4 g (560 mmol) K2CO3, 250 mL dioxane and 250 mL water. The suspension was stirred, then 28.5 mL (200 mmol) benzylchloroformate was added dropwise. The reaction mixture was then stirred at room temperature for 6.5 hours then poured into 800 mL water and acidified (slowly) with 1N HCl. The resulting white precipitate was filtered and dried-45.6 g.
Reaction SMILES: [NH2:1][CH:2]1[CH2:8][N:7]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:6][CH2:5][NH:4][C:3]1=O.CSC>C1COCC1>[NH2:1][CH:2]1[CH2:8][N:7]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:6][CH2:5][NH:4][CH2:3]1
Reactant: NC1CN(C(=O)OCc2ccccc2)CCNC1=O
Solvent: CSC
Solvent: C1CCOC1
Product: NC1CNCCN(C(=O)OCc2ccccc2)C1
Reaction time: 15 h

Procedure:
A solution of benzyl 6-amino-5-oxo-1,4-diazepane-1-carboxylate (12.86 g, 47.4 mmol) in THF (158 mL) was treated dropwise with BH3.DMS (22.5 mL, 237 mmol). The mixture was warmed to reflux and stirred for 15 hours. The mixture was then cooled to 0 OC, quenched by the slow addition of MeOH (50 mL; vigorous H2 evolution observed) and treated over 10 min with concentrated HCl (12 mL). The reaction vessel was then heated to reflux for 8 hours. The volatiles were partially removed under reduced pressure and the mixture was basified to pH 11 with solid Na2CO3. The aqueous layer was extracted with CH2Cl2 (2×), the organic phase was dried (Na2SO4), and concentrated in vacuo to afford benzyl 6-amino-1,4-diazepane-1-carboxylate (I-54a). MS calculated for C13H20N3O2 (M+H+) 250.15. found 250.1. The crude was used in the next step without further purification.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([S:10](Cl)(=[O:12])=[O:11])=[CH:9][C:4]=2[CH:3]=[CH:2]1.[O:14]1[CH:18]2[O:19][CH2:20][CH2:21][CH:17]2[CH:16]([O:22][C:23](=[O:41])[NH:24][CH:25]([CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:26]([OH:33])[CH2:27][NH:28][CH2:29][CH:30]([CH3:32])[CH3:31])[CH2:15]1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[O:14]1[CH:18]2[O:19][CH2:20][CH2:21][CH:17]2[CH:16]([O:22][C:23](=[O:41])[NH:24][CH:25]([CH2:34][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:26]([OH:33])[CH2:27][N:28]([S:10]([C:8]2[CH:7]=[CH:6][C:5]3[O:1][CH:2]=[CH:3][C:4]=3[CH:9]=2)(=[O:12])=[O:11])[CH2:29][CH:30]([CH3:32])[CH3:31])[CH2:15]1
Reactant: CC(C)CNCC(O)C(Cc1ccccc1)NC(=O)OC1COC2OCCC12
Reactant: O=S(=O)(Cl)c1ccc2occc2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)CN(CC(O)C(Cc1ccccc1)NC(=O)OC1COC2OCCC12)S(=O)(=O)c1ccc2occc2c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Benzofuran-5-sulfonyl chloride 148 mg (0.68 mmol) was dissolved in 5 mL of methylene chloride. (1-Benzyl-2-hydroxy-3-isobutylamino-propyl)-carbamic acid hexahydro-furo[2,3-b]furan-3-yl ester 19 (244 mg, 0.62 mmol) was added followed by 0.63 mL 10% NaHCO3 solution (0.75 mmol). The reaction was stirred at room temperature for 16 hours. The organic phase was separated and loaded onto silica gel in methylene chloride. The excess of benzofuran-5-sulfonyl chloride was washed out by several portions of methylene chloride. The final product was obtained by eluting with 3/1 ethyl acetate/methylene chloride. Concentration in vacuo afforded 350 mg (98.5% yield) of the final product with HPLC purity of >97% (220 nm). The product can be recrystallized from ethyl acetate/hexanes to get colorless crystals m.p. 122-124° C. MS 573 (MH)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:14]=1[S:20](Cl)(=[O:22])=[O:21]>CN(C1C=CN=CC=1)C>[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:14]=1[S:20]([NH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2)(=[O:22])=[O:21]
Reactant: Nc1cccc2cccnc12
Reactant: O=S(=O)(Cl)c1c(Cl)cccc1Cl
Agent: CN(C)c1ccncc1
Product: O=S(=O)(Nc1cccc2cccnc12)c1c(Cl)cccc1Cl
Yield: 40.4 %

Procedure:
In a similar fashion using route 14 general procedure 27, 8-aminoquinoline (100 mg, 0.70 mmol), 2,6-dichlorobenzenesulfonyl chloride (190 mg, 0.83 mmol) and DMAP (cat.) gave the title compound (100 mg, 41%) after purification by column chromatography with DCM as the eluent.
Reaction SMILES: N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O.[F:17][C:18]1[C:23]([CH2:24]O)=[CH:22][CH:21]=[CH:20][N:19]=1.[F:26][C:27]1[CH:45]=[C:44]([F:46])[CH:43]=[CH:42][C:28]=1[O:29][C:30]1[CH:35]=[CH:34][C:33]([NH:36][S:37]([CH2:40][CH3:41])(=[O:39])=[O:38])=[CH:32][CH:31]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[F:26][C:27]1[CH:45]=[C:44]([F:46])[CH:43]=[CH:42][C:28]=1[O:29][C:30]1[CH:31]=[CH:32][C:33]([N:36]([CH2:24][C:23]2[C:18]([F:17])=[N:19][CH:20]=[CH:21][CH:22]=2)[S:37]([CH2:40][CH3:41])(=[O:38])=[O:39])=[CH:34][CH:35]=1
Reactant: OCc1cccnc1F
Reactant: CCS(=O)(=O)Nc1ccc(Oc2ccc(F)cc2F)cc1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCS(=O)(=O)N(Cc1cccnc1F)c1ccc(Oc2ccc(F)cc2F)cc1
Temperature: 25 °C
Reaction time: 19 h
Yield: 42.5 %

Procedure:
Di-tert-butyl azodicarboxylate (0.36 g, 1.57 mmol) was added to a suspension of (2-fluoropyridin-3-yl)methanol (10, 0.20 g, 1.57 mmol), N-(4-(2,4-difluorophenoxy)phenyl)-N-ethylsulfonylamine (0.49 g, 1.56 mmol) and polystyrene resin-bound triphenylphosphine (0.52 g, 1.57 mmol, ˜3 mmol/g) in anhydrous tetrahydrofuran (5 mL) at 0° C. under nitrogen. The resulting yellow suspension was warmed to room temperature and stirred for 19 h, after which additional polystyrene resin bound triphenylphosphine (0.52 g, 1.57 mmol, ˜3 mmol/g) and di-tert-butyl azodicarboxylate (0.36 g, 1.57 mmol) were added. This solution was stirred for 24 h after which the suspension was diluted with anhydrous tetrahydrofuran (100 mL) and the solids were removed by vacuum filtration. The filtrate solvent was removed under reduced pressure to provide the crude product as a yellow oil. This oil was purified by medium pressure liquid chromatography on silica gel, eluting with hexanes/ethyl acetate (7:3), to provide a colorless oil. This oil was triturated with hexanes/ethyl acetate (4-5 mL) to give the title compound as a white powder (0.28 g, 53%): mp 110-112° C.; TLC Rf (3:2 hexanes/ethyl acetate)=0.44; 1H NMR (300 MHz) 8.11 (m, 1H), 7.90 (m, 1H), 7.24-7.15 (m, 3H), 7.11-7.03 (m, 1H), 6.98-6.86 (m, 2H), 6.84 (d, J=6.8 Hz, 2H), 4.91 (s, 2H), 3.15-3.07 (q, J=7.4 Hz, 2H), 1.43 (t, J=7.4 Hz, 1H) ppm; 13C NMR (75 MHz) 163.3, 161.3, 160.1, 157.8, 156.5, 153.1, 147.5 (d, J=14.9 Hz), 141.7, 139.1, 133.6, 130.5, 123.8 (d, J=9.7 Hz), 122.1, 119.1 (d, J=29.2 Hz), 117.5, 112.0 (d, J=22.9 Hz), 106.0 (t, J=24.3 Hz), 49.1, 46.0, 8.44 ppm; APCI MS m/z 423 [C20H17F3N2O3S+H]+. Anal. Calcd. for C20H17F3N2O3S: C, 56.87; H, 4.06; N, 6.63. Found: C, 56.90; H, 4.10; N, 6.45.
Reaction SMILES: [CH:1]1([C:4]2[C:12]([N:13]([CH2:18][CH2:19][OH:20])[S:14]([CH3:17])(=[O:16])=[O:15])=[CH:11][C:10]3[C:6](=[C:7]([C:28]([NH:30][CH3:31])=[O:29])[N:8]([C:21]4[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][N:22]=4)[N:9]=3)[CH:5]=2)[CH2:3][CH2:2]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[CH:1]1([C:4]2[C:12]([N:13]([S:14]([CH3:17])(=[O:15])=[O:16])[CH2:18][CH:19]=[O:20])=[CH:11][C:10]3[C:6](=[C:7]([C:28]([NH:30][CH3:31])=[O:29])[N:8]([C:21]4[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][N:22]=4)[N:9]=3)[CH:5]=2)[CH2:3][CH2:2]1
Reactant: CNC(=O)c1c2cc(C3CC3)c(N(CCO)S(C)(=O)=O)cc2nn1-c1ccc(C)cn1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CNC(=O)c1c2cc(C3CC3)c(N(CC=O)S(C)(=O)=O)cc2nn1-c1ccc(C)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.7 %

Procedure:
To a stirred solution of Compound (2) (278 mg) in DCM (6 mL) was added Dess-Martin periodinane (400 mg, 0.94 mmol). The mixture was stirred at room temperature for 1 h and then diluted with DCM (10 mL) and washed with aq. saturated NaHCO3 solution (10 mL) and water (10 mL). The organic phase was filtered to remove insoluble impurities, dried (MgSO4) and concentrated in vacuo to afford (i) (276 mg) which was used in the next step without further purification. ESI-MS m/z calculated for [M+MeOH]+: 474.2. found: 474.2.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[C:9]([Cl:31])=[C:10]([NH:16][C:17]3[N:22]=[C:21]([NH:23][CH2:24][CH3:25])[C:20]4=[N:26][CH:27]=[C:28]([C:29]#[N:30])[N:19]4[N:18]=3)[CH:11]=[C:12]([C:14]#[N:15])[CH:13]=2)[CH2:4][CH2:3]1.C(N(CC)C(C)C)(C)C.[C:41](Cl)(=[O:44])[O:42][CH3:43]>CO.C1COCC1>[Cl:31][C:9]1[C:10]([NH:16][C:17]2[N:22]=[C:21]([NH:23][CH2:24][CH3:25])[C:20]3=[N:26][CH:27]=[C:28]([C:29]#[N:30])[N:19]3[N:18]=2)=[CH:11][C:12]([C:14]#[N:15])=[CH:13][C:8]=1[N:5]1[CH2:6][CH2:7][CH:2]([NH:1][C:41](=[O:44])[O:42][CH3:43])[CH2:3][CH2:4]1
Reactant: COC(=O)Cl
Reactant: CCNc1nc(Nc2cc(C#N)cc(N3CCC(N)CC3)c2Cl)nn2c(C#N)cnc12
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: C1CCOC1
Product: CCNc1nc(Nc2cc(C#N)cc(N3CCC(NC(=O)OC)CC3)c2Cl)nn2c(C#N)cnc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.6 %

Procedure:
2-((3-(4-aminopiperidin-1-yl)-2-chloro-5-cyanophenyl)amino)-4-(ethylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (Example 329) (40 mg, 0.092 mmol) was mixed with N,N-diisopropylethylamine (0.2 ml, 1.145 mmol) in MeOH (1 ml) and THF (1 ml). methyl carbonochloridate (0.05 ml, 0.646 mmol) was added. The mixture was stirred at r.t. for 1 hr. LC/MS showed product formation. The white precipitate was formed and collected by filtration, washed with cold MeOH (15 ml), then water (5 ml) and dried with air-suction to give 31.7 mg of desired product.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[Br:12]Br>C(Cl)(Cl)Cl.ClCCl>[Br:12][C:9]1[CH:10]=[CH:11][C:2]([OH:1])=[C:3]([CH:8]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1ccccc1O
Reactant: BrBr
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: COC(=O)c1cc(Br)ccc1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.1 %

Procedure:
To a solution of methyl 2-hydroxybenzoate (152 g, 1.0 mol) in chloroform (500 mL) was added dropwise with stirring a solution of bromine (172 g, 1.08 mol) in chloroform (300 mL) at 10° C. After the addition, the solution was stirred at room temperature overnight. The mixture was diluted with dichloromethane (500 mL), washed with water (1 L×3), saturated sodium bicarbonate solution (500 mL), brine (500 mL), dried over anhydrous sodium sulfate and concentrated to give crude product. The crude product was re-crystallized from methanol to give methyl 5-bromo-2-hydroxybenzoate (192 g, yield 83%) as a white solid. 1H-NMR (400 MHz, CDCl3) δ 3.96 (s, 3H), 6.89 (d, J=8.8 Hz, 1H), 7.52-7.55 (dd, J=8.8 Hz, J=2 Hz, 1H), 7.96 (d, J=2.8 Hz, 1H), 10.7 (s, 1H); LC-MS (ESI) m/z 233 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:9][C:10]([C:12]1[CH:17]=[CH:16][C:15]([CH:18]([CH3:22])[C:19]([OH:21])=[O:20])=[CH:14][CH:13]=1)=[O:11].[CH2:23](O)[CH:24]([CH3:26])[CH3:25].O>O1CCCC1>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:9][C:10]([C:12]1[CH:17]=[CH:16][C:15]([CH:18]([CH3:22])[C:19]([O:21][CH2:23][CH:24]([CH3:26])[CH3:25])=[O:20])=[CH:14][CH:13]=1)=[O:11]
Reactant: CC(C)CO
Reactant: CC(C(=O)O)c1ccc(C(=O)Nc2cccc(Cl)c2Cl)cc1
Solvent: O
Solvent: C1CCOC1
Product: CC(C)COC(=O)C(C)c1ccc(C(=O)Nc2cccc(Cl)c2Cl)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 80 %

Procedure:
3.38 g of 2-[4-(2,3-dichlorophenylcarbamoyl)-phenyl]propionic acid was dissolved in 30 ml of anhydrous tetrahydrofuran. While cooling the solution with ice water, 2.43 g of N,N'-carbonyldiimidazole was added thereto, and the mixture was stirred for 30 minutes. Thereafter, 0.74 g of isobutyl alcohol was added thereto. The mixture was returned to room temperature and stirred for 5 hours. After completion of the reaction, the reaction solution was poured into 300 ml of water, and the resulting crystals were collected by filtration, washed with water and dried, and then recrystallized from toluene-hexane to obtain 3.15 g of desired isobutyl 2-[4-(2,3-dichloropheylcarbamoyl)-phenyl]-propionate. The yield was 80%, and the melting point of this compound was from 70° to 72° C.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[C:24](I)[CH:25]=3)[N:20]=[CH:19][N:18]=2)=[CH:12][CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C([Sn](CCCC)(CCCC)[C:33]1[C:34]([CH3:38])=[N:35][O:36][CH:37]=1)CCC.C(N(CC)CC)C>O1CCOCC1.[Ag]=O>[CH2:2]([O:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([C:33]4[C:34]([CH3:38])=[N:35][O:36][CH:37]=4)[CH:25]=3)[N:20]=[CH:19][N:18]=2)=[CH:12][CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Ic1ccc2ncnc(Nc3ccc(OCc4ccccc4)cc3)c2c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1conc1C
Agent: O=[Ag]
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: Cc1nocc1-c1ccc2ncnc(Nc3ccc(OCc4ccccc4)cc3)c2c1

Procedure:
(4-Benzyloxy-phenyl)-(6-iodoquinazolin-4-yl)-amine hydrochloride (0.35 g) in dioxan (10 ml) under nitrogen was treated with 4-tributylstannyl-3-methylisoxazole (prepapred according to the literature method: Heterocycles, (1996), 43(6), 1301-1304) (0.4 g), silver oxide (0.092 g), triethylamine (0.1 ml) and [1.4-bis(diphenylphosphino)butane]palladium (II) chloride (0.1 g) at 90° C. for 16 hours. The mixture was cooled, adsorbed onto silica and purified by chromatography. Trituration from hexane and filtration gave the title compound (0.20 g); δH [2H6]DMSO 9.78(1H,bs), 9.22(l H,s), 8.57(1H,s), 8.53(1H,s), 7.98(1H,d), 7.83(1H,d), 7.67(2H,d), 7.42(5H,m), 7.09(1H,d), 5.64(2H,s) 2.51 (3H,s); m/z (M+1)+ 409.
Reaction SMILES: [I:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][N:7]([C:11]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[O:12])[CH2:8]2)=[CH:4][C:3]=1[C:21](OC)=[O:22].[Li+].[B-](CC)(CC)CC>C1COCC1>[OH:22][CH2:21][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:2]=1[I:1])[CH2:8][N:7]([C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])[CH2:6]2
Reactant: COC(=O)c1cc2c(cc1I)CN(C(=O)OCc1ccccc1)C2
Agent: CC[B-](CC)CC
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)N1Cc2cc(I)c(CO)cc2C1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a solution of 2-benzyl 5-methyl 6-iodo-1,3-dihydro-2H-isoindole-2,5-dicarboxylate (104 mg, 0.238 mmol) in THF (5 mL) at −78° C. under N2, was added dropwise 1N Super Hydride in THF (476 uL, 0.476 mmol). The mixture was stirred at −78° C. for 2 h. The reaction mixture was quenched with 1N HCl. The aqueous layer was extracted with EtOAc (3×). The combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel to provide benzyl 5-(hydroxymethyl)-6-iodo-1,3-dihydro-2H-isoindole-2-carboxylate. LCMS calc.=432.0; found=431.9 (M+Na)+. 1H NMR (500 MHz, CDCl3): δ 7.76-7.70 (2 s, 1H); 7.45-7.35 (m, 6H); 5.24 (s, 2H); 4.76-4.67 (m, 4H); 2.18 (br s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][N:5]([CH3:16])[C:6]=1[C:7]1[CH:8]=[C:9]([C:13]([OH:15])=O)[S:10][C:11]=1[CH3:12].[NH2:17][C@@H:18]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[CH:33]=1)[CH2:19][N:20]1[C:28](=[O:29])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]1=[O:30].CC(OC(N[C@H](C(O)=O)CC1C=CC=CC=1C(F)(F)F)=O)(C)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[N:4][N:5]([CH3:16])[C:6]=1[C:7]1[CH:8]=[C:9]([C:13]([NH:17][C@@H:18]([CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[CH:33]=2)[CH2:19][N:20]2[C:28](=[O:29])[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]2=[O:30])=[O:15])[S:10][C:11]=1[CH3:12]
Reactant: Cc1sc(C(=O)O)cc1-c1c(Br)cnn1C
Reactant: N[C@@H](Cc1cccc(F)c1)CN1C(=O)c2ccccc2C1=O
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1C(F)(F)F)C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: Cc1sc(C(=O)N[C@@H](Cc2cccc(F)c2)CN2C(=O)c3ccccc3C2=O)cc1-c1c(Br)cnn1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.8 %

Procedure:
To a 50 mL round-bottomed flask was added 4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxylic acid (191 mg, 0.63 mmol) [prepared according to the procedure of Example 159], 2-[(2S)-2-amino-3-(3-fluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione (209 mg, 0.62 mmol) [prepared according to the procedure of Preparation 6 except substituting N-{[(1,1-dimethylethyl)oxy]carbonyl}-3-fluoro-L-phenylalanine (5.03 g, 17.8 mmol) for N-{[(1,1-dimethylethyl)oxy]carbonyl}-2-(trifluoromethyl)-L-phenylalanine] and PyBrop (359 mg, 0.77 mmol) in chloroform (7 mL). DIEA (560 μL, 3.21 mmol) was added and the reaction stirred overnight at room temperature. The mixture was adsorbed onto silica and purified via column chromatography (25-70% EtOAc/Hex) affording the title compound (171 mg, 0.29 mmol, 46%): LC-MS (ES) m/z=583 (M+H)+.
Reaction SMILES: CC1C=CC(S(OCC2CC3C=CC=C(C4C=CC5C(=CC=CC=5)C=4)C=3O2)(=O)=O)=CC=1.[N-]=[N+]=[N-].[Na+].[N:36]([CH2:39][CH:40]1[CH2:44][C:43]2[CH:45]=[CH:46][CH:47]=[C:48]([C:49]3[CH:58]=[CH:57][C:56]4[C:51](=[CH:52][CH:53]=[CH:54][CH:55]=4)[CH:50]=3)[C:42]=2[O:41]1)=[N+]=[N-].[N-]=[N+]=[N-]>[Pd]>[CH:50]1[C:51]2[C:56](=[CH:55][CH:54]=[CH:53][CH:52]=2)[CH:57]=[CH:58][C:49]=1[C:48]1[C:42]2[O:41][CH:40]([CH2:39][NH2:36])[CH2:44][C:43]=2[CH:45]=[CH:46][CH:47]=1
Reactant: [N-]=[N+]=NCC1Cc2cccc(-c3ccc4ccccc4c3)c2O1
Agent: [Pd]
Agent: Cc1ccc(S(=O)(=O)OCC2Cc3cccc(-c4ccc5ccccc5c4)c3O2)cc1
Agent: [N-]=[N+]=[N-]
Product: NCC1Cc2cccc(-c3ccc4ccccc4c3)c2O1
Yield: 48 %

Procedure:
Treatment of (±)-[7-(2-naphthyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.51 g, 1.23 mmol) with sodium azide (0.20 g, 3.08 mmol) generally according to the procedure described for Intermediate 98 provided (±)-2-(azidomethyl)-7-(2-naphthyl)-2,3-dihydro-1-benzofuran. Treatment of the azide with palladium on carbon (0.050 g, 10 wt. %) generally according to the procedure described for Example 1 afforded 0.183 g (48%) of (±)-1-[7-(2-naphthyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine as a white solid, hydrochloride salt. mp 135-140° C.; Anal. calcd. for C19H17NOHCl.0.3H2O: C, 71.94; H, 5.91 N, 4.42. Found: C, 71.67; H, 5.95; N, 4.25.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[NH:9][C:8](=[O:13])[C:7]3[S:14][CH:15]=[CH:16][C:6]=3[C:5]=2[C:4]=1[C:17]1[CH:26]=[C:25]2[C:20]([CH2:21][CH2:22][N:23](C(OC(C)(C)C)=O)[CH2:24]2)=[CH:19][CH:18]=1.C(O)(C(F)(F)F)=O>>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[NH:9][C:8](=[O:13])[C:7]3[S:14][CH:15]=[CH:16][C:6]=3[C:5]=2[C:4]=1[C:17]1[CH:26]=[C:25]2[C:20]([CH2:21][CH2:22][NH:23][CH2:24]2)=[CH:19][CH:18]=1
Reactant: COc1ccc2[nH]c(=O)c3sccc3c2c1-c1ccc2c(c1)CN(C(=O)OC(C)(C)C)CC2
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2[nH]c(=O)c3sccc3c2c1-c1ccc2c(c1)CNCC2
Yield: 93.7 %

Procedure:
Following General Procedure C, tert-Butyl 7-(8-Methoxy-4-oxo-4,5-dihydrothieno[2,3-c]quinolin-9-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (260 mg, 0.53 mmol) was reacted with TFA (5 mL) afford the desired product (180 mg, 20%) as a white solid: 1H NMR (500 MHz, CD3OD) δ 7.61-7.56 (m, 1H), 7.55 (dd, J=9.0, 3.2 Hz, 1H), 7.44 (d, J=7.8 Hz, 1H), 7.41-7.36 (m, 1H), 7.22 (d, J=7.8 Hz, 1H), 7.16 (s, 1H), 6.13 (d, J=5.4 Hz, 1H), 4.42 (s, 2H), 3.73 (s, 3H), 3.68-3.54 (m, 2H), 3.29-3.20 (m, 2H).
Reaction SMILES: [NH:1]1[CH2:11][CH2:10][CH2:9][CH:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH2:2]1.[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>ClCCl>[CH2:12]([N:1]1[CH2:11][CH2:10][CH2:9][CH:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH2:2]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCOC(=O)C1CCCNC1
Reactant: BrCc1ccccc1
Solvent: ClCCl
Product: CCOC(=O)C1CCCN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 20 h
Yield: 78.9 %

Procedure:
Commercially available ethyl nipecotate (509.7 mg; 3.25 mmol) was dissolved in dichloromethane (12 ml). Dilsopropylethylamine (570 μl; 3.27 mmol) was added, followed by commercially available benzyl bromide (386 μl; 3.25 mmol) and the mixture stirred at ambient temperature for approximately 20 hours. The mixture was then evaporated at ambient temperature under reduced pressure. The crude product was purified by chromatography on silica eluting with 80% ethyl acetate in hexane, giving ethyl 1-benzyl-3-piperidinecarboxylate (634.4 mg) as a colorless oil. MS m/z (positive ion) 248 (MH+; 100).