Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][CH2:8][CH2:9][NH:10][C:11]1[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:12]=1[N+:19]([O-])=O)([CH3:4])([CH3:3])[CH3:2]>[OH-].[OH-].[Pd+2].O1CCOCC1>[C:1]([O:5][C:6](=[O:22])[NH:7][CH2:8][CH2:9][NH:10][C:11]1[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:12]=1[NH2:19])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc([N+](=O)[O-])c(NCCNC(=O)OC(C)(C)C)c1
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1COCCO1
Product: COc1ccc(N)c(NCCNC(=O)OC(C)(C)C)c1
Reaction time: 12 h

Procedure:
A 2 L round bottom flask equipped with a stir bar was charged with a suspension of 20% Pd(OH)2 (5 g) and 1,4-dioxane (800 mL). [2-(5-Methoxy-2-nitrophenylamino)-ethyl]-carbamic acid tert-butyl ester (100 g, 0.32 mol) was added to the suspension. The reaction mixture was hydrogenated (balloon) for 48 h (until the starting material had been consumed) followed by the addition of K2CO3 (100 g) was added to the mixture and stirred for an additional 12 h to remove traces of water. The suspension was filtered to remove the Pd(OH)2 and K2CO3. The filtrate was used in the next step without further purification (yield not determined).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([F:20])[C:5]([Cl:19])=[C:6]([O:8][C:9]2[C:10]([F:18])=[C:11]([CH2:16][NH2:17])[CH:12]=[CH:13][C:14]=2[Cl:15])[CH:7]=1.[C:21]([Zn]C#N)#[N:22].CN(C=O)C>C(O)CC.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>[NH2:17][CH2:16][C:11]1[C:10]([F:18])=[C:9]([O:8][C:6]2[CH:7]=[C:2]([CH:3]=[C:4]([F:20])[C:5]=2[Cl:19])[C:21]#[N:22])[C:14]([Cl:15])=[CH:13][CH:12]=1
Reactant: N#C[Zn]C#N
Reactant: NCc1ccc(Cl)c(Oc2cc(Br)cc(F)c2Cl)c1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCCO
Product: N#Cc1cc(F)c(Cl)c(Oc2c(Cl)ccc(CN)c2F)c1
Temperature: 120 °C
Yield: 89.8 %

Procedure:
({3-[(5-bromo-2-chloro-3-fluorophenyl)oxy]-4-chloro-2-fluorophenyl}methyl)amine (3.00 g, 7.83 mmol) was combined with dicyanozinc (0.460 g, 3.92 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.453 g, 0.392 mmol) in n-propanol (15 mL) and heated at 120° C. for 25 min in a microwave reactor under an inert atmosphere. DMF (8 mL) was added and the reaction mixture was again heated at 120° C. for 90 min in a microwave reactor at which time LC-MS indicated complete conversion. The reaction mixture was concentrated to remove the n-propanol, diluted with EtOAc, washed four times with saturated aqueous NaHCO3, dried over MgSO4, filtered and concentrated to dryness. The residue was purified on 80 g silica gel eluted successively with EtOAc followed by 0 to 10% CH3OH/DCM to give 3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-4-chloro-5-fluorobenzonitrile (1.16 g, 3.52 mmol, 45.0% yield) as a pale yellow oil which crystallized on standing. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.92 (dd, J=8.65, 1.51 Hz, 1H), 7.47-7.58 (m, 2 H), 7.25 (s, 1H), 3.77 (s, 2H), 1.93 (br. s., 2H). LC-MS (ES−) m/z 326.96, 329.05 [M−1]. LC-MS (ES+) m/z 329.00, 330.96 [M+H].
Reaction SMILES: C(O[C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH2:10]1)=O)(C)(C)C.[C:25]([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O>[CH2:6]([NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH2:10]1)[CH3:25]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCN(C(=O)OCc2ccccc2)C1
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CCN[C@H]1CCCN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
A solution of (S)-benzyl 3-(tert-butoxycarbonylamino)piperidine-1-carboxylate (300 mg, 0.82 mmol) in 1,4-dioxane (2.5 mL) was treated with dioxane. HCl (5 mL) and the solution was stirred at rt 1 h. The solvent was reduced in vacuo to afford a residue which was then dissolved in water (5 mL). The aqueous solution was treated with solid Na2CO3 and the aqueous solution was extracted with EtOAc (3×15 mL). The combined organic layer was dried over Na2SO4, concentrated in vacuo to yield titled intermediate (217 mg, 92%), which was used in the next step without further purification. 1H NMR (400 MHz, CDCl3): δ 7.36-7.26 (m, 5H), 5.13 (s, 2H), 4.20-3.82 (m, 2H), 2.94-2.60 (m, 5H), 1.94-1.92 (m, 1H), 1.69-1.68 (m, 1H), 1.47-1.28 (m, 3H), 1.09 (t, J=6.8 Hz, 3H). ES-MS: m/z [M+1]=263.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH2:16][C:17]2[N:18]=[C:19]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[O:20][C:21]=2[CH3:22])=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4].[C:29]([CH2:37][C:38](=O)[CH3:39])(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[CH3:39]/[C:38](/[NH:1][C@@H:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH2:16][C:17]2[N:18]=[C:19]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[O:20][C:21]=2[CH3:22])=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4])=[CH:37]/[C:29](=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CC(=O)CC(=O)c1ccccc1
Reactant: Cc1oc(-c2ccccc2)nc1CCCOc1ccc(C[C@H](N)C(=O)O)cc1
Product: C/C(=C/C(=O)c1ccccc1)N[C@@H](Cc1ccc(OCCCc2nc(-c3ccccc3)oc2C)cc1)C(=O)O

Procedure:
The title compound was prepared (as described above for the preparation of example 1) from a suspension of 205 mg (0.54 mmol) of Intermediate 55 and 88 mg (0.54 mmol) of benzoylacetone to yield 142 mg (50% yield) of example 57: TLC (DCM/MeOH, 4/1): Rf=0.66; 1H NMR (DMSO-d6, 300 MHz) δ11.44 (d, 1H, J=9.0), 7.88-7.85 (m, 2H), 7.78-7.75 (m, 2H), 7.49-7.43 (m, 3H), 7.37-7.32 (m, 3H), 7.12 (d, 2H, J=8.4), 6.78 (d, 2H, J=8.4), 5.54 (s, 1H), 4.13 (m, 1H), 3.87 (t, 1H, J=6.0), 3.22-3.16 (m, 1H), 2.77 (d, 1H, J=14.4, 9.2), 2.56 (t, 2H, J=7.2), 2.22 (s, 3H), 2.00-1.93 (m, 2H), 1.66 (s, 3H); low resolution MS (ES+)m/e 525.15 (MH+).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([C:18]4[CH:19]=[C:20]5[C:25](=[CH:26][CH:27]=4)[N:24]=[CH:23][CH:22]=[CH:21]5)=[CH2:17])=[CH:14][N:15]=3)[N:12]=2)[CH:4]=[N:3]1>C(O)C.[Pd]>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([CH:16]([C:18]4[CH:19]=[C:20]5[C:25](=[CH:26][CH:27]=4)[NH:24][CH2:23][CH2:22][CH2:21]5)[CH3:17])=[CH:14][N:15]=3)[N:12]=2)[CH:4]=[N:3]1
Reactant: C=C(c1ccc2ncccc2c1)c1cnc2ccc(-c3cnn(C)c3)nn12
Agent: [Pd]
Solvent: CCO
Product: CC(c1ccc2c(c1)CCCN2)c1cnc2ccc(-c3cnn(C)c3)nn12
Reaction time: 10 h

Procedure:
6-{1-[6-(1-Methyl-1H-pyrazol-4-yl)-imidazo[1,2-b]pyridazin-3-yl]-vinyl}-quinoline (Example 155, 2.2 g, 6.24 mmol) was dissolved in ethanol (300 mL) and hydrogenated under H2 atm. at rt in presence of Pd 15% C. After 10 h, the RM was filtered over Celite and the filtrate evaporated under vacuo. The residue was dried over night under vacuo and eluted on a silica gel column with EtOAc/MeOH=9:1 then 85:15 to afford, after evaporation of the solvent, crystals of the title compound (tR 3.24 min (conditions 3), MH+=359).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[CH:14]=[CH:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:5]=2[N:6]=1.[Br:15]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:15][CH2:1][C:2]1[S:3][C:4]2[CH:14]=[CH:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:5]=2[N:6]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1nc2c(ccc3ccccc32)s1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1nc2c(ccc3ccccc32)s1
Reaction time: 6 h
Yield: 63 %

Procedure:
To 3.98 g of 2-methylnaphtho[1,2-d]thiazole dissolved in carbon tetrachloride (40 ml) was added 3.56 g of N-bromosuccinimide and 0.20 g of benzoyl peroxide, followed by 6 hours of heating under reflux. After cooling the reaction solution, insoluble matter was removed by filtration, and the solvent was evaporated. The residue was subjected to silica gel column chromatography eluted with hexane-chloroform (5:1) to obtain 3.50 g (63%) of 2-bromomethylnaphtho[1,2-d]thiazole.
Reaction SMILES: Br[C:2]1[C:3](=[O:28])[C:4]2[C:9]([C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=1[F:18])=[CH:8][CH:7]=[C:6]([O:19][CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1)[CH:5]=2.O1CCN(CCOC2C=C3C(C(C4C=CC=CC=4)=C(Br)C3=O)=CC=2)CC1.[F:55][C:56]1[CH:57]=[C:58](B(O)O)[CH:59]=[CH:60][C:61]=1[O:62][CH3:63]>>[F:55][C:56]1[CH:57]=[C:58]([C:2]2[C:3](=[O:28])[C:4]3[C:9]([C:10]=2[C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=2[F:18])=[CH:8][CH:7]=[C:6]([O:19][CH2:20][CH2:21][N:22]2[CH2:23][CH2:24][O:25][CH2:26][CH2:27]2)[CH:5]=3)[CH:59]=[CH:60][C:61]=1[O:62][CH3:63]
Reactant: COc1ccc(B(O)O)cc1F
Reactant: O=C1C(Br)=C(c2ccc(F)cc2F)c2ccc(OCCN3CCOCC3)cc21
Agent: O=C1C(Br)=C(c2ccccc2)c2ccc(OCCN3CCOCC3)cc21
Product: COc1ccc(C2=C(c3ccc(F)cc3F)c3ccc(OCCN4CCOCC4)cc3C2=O)cc1F
Yield: 81 %

Procedure:
The procedure of Step 7 of Example 1 was repeated except for using 2-bromo-3-(2,4-difluorophenyl)-6-{2-(morpholin-4-yl)ethoxy}-1H-inden-1-one obtained in Step 1 of Example 124 as a starting material instead of 6-(2-morpholinoethoxy)-2-bromo-3-phenyl-1H-inden-1-one and 3-fluoro-4-methoxyphenylboronic acid instead of 3-pyridinylboronic acid to obtain the title compound (81%).
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:8][CH2:7][N:6]([CH2:9][CH2:10][N:11]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([O:21][CH3:22])[CH:19]=3)[CH:14]=[CH:13][C:12]2=[O:23])[CH2:5][CH2:4]1.C[O-].[Na+].CO.[CH2:29]([C:31]1[C:38]([F:39])=[CH:37][C:34]([CH:35]=O)=[CH:33][N:32]=1)[CH3:30].C([BH3-])#N.[Na+].C(=O)([O-])O.[Na+]>CO.C(Cl)(Cl)Cl.C(O)(=O)C>[CH2:29]([C:31]1[N:32]=[CH:33][C:34]([CH2:35][NH:2][CH:3]2[CH2:4][CH2:5][N:6]([CH2:9][CH2:10][N:11]3[C:20]4[C:15](=[N:16][CH:17]=[C:18]([O:21][CH3:22])[CH:19]=4)[CH:14]=[CH:13][C:12]3=[O:23])[CH2:7][CH2:8]2)=[CH:37][C:38]=1[F:39])[CH3:30]
Reactant: CCc1ncc(C=O)cc1F
Reactant: COc1cnc2ccc(=O)n(CCN3CCC(N)CC3)c2c1
Agent: C[O-]
Agent: Cl
Agent: O=C([O-])O
Solvent: CO
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: CCc1ncc(CNC2CCN(CCn3c(=O)ccc4ncc(OC)cc43)CC2)cc1F
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 34.8 %

Procedure:
To a suspension of 0.14 g of 1-(2-(4-aminopiperidin-1-yl)ethyl)-7-methoxy-1,5-naphthyridin-2(1H)-one hydrochloride in 2 mL of methanol, 0.20 g of a 28% sodium methoxide/methanol solution, 53 mg of 6-ethyl-5-fluoronicotinaldehyde and 20 μL of acetic acid were added. Then, 43 mg of sodium cyanoborohydride was added thereto, and the mixture was stirred at room temperature for 1 hour 20 minutes. Thereto was further added 43 mg of sodium cyanoborohydride, and the mixture was stirred at room temperature for 1 hour, and then stirred at 30 to 40° C. for 1 hour. To the reaction mixture, chloroform and a saturated aqueous sodium hydrogen carbonate solution were added. The organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and the extract were combined, the resultant solution was washed with water and a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resultant residue was purified by basic silica gel column chromatography using gradient elution with chloroform:methanol=93:7 to 9:1 to obtain 53 mg of 1-(2-(4-(((6-ethyl-5-fluoropyridin-3-yl)methyl)amino)piperidin-1-yl)ethyl)-7-methoxy-1,5-naphthyridin-2(1H)-one as a light yellow oily substance.
Reaction SMILES: Cl.[CH3:2][NH:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[C:11]([CH3:13])[C:10]([OH:14])=[CH:9][C:8]=1[CH:15]([CH3:17])[CH3:16].[CH2:18]([O:20][C:21]1[C:28]([CH3:29])=[C:27]([CH3:30])[C:26]([OH:31])=[C:25]([CH3:32])[C:22]=1[CH2:23][Cl:24])[CH3:19].C(N(CC)CC)C>CN(C)C=O>[ClH:24].[CH2:18]([O:20][C:21]1[C:28]([CH3:29])=[C:27]([CH3:30])[C:26]([OH:31])=[C:25]([CH3:32])[C:22]=1[CH2:23][N:3]([CH2:4][CH2:5][O:6][C:7]1[CH:12]=[C:11]([CH3:13])[C:10]([OH:14])=[CH:9][C:8]=1[CH:15]([CH3:17])[CH3:16])[CH3:2])[CH3:19]
Reactant: CCOc1c(C)c(C)c(O)c(C)c1CCl
Reactant: CNCCOc1cc(C)c(O)cc1C(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOc1c(C)c(C)c(O)c(C)c1CN(C)CCOc1cc(C)c(O)cc1C(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 5 %

Procedure:
N-Methyl-2-(4-hydroxy-2-isopropyl-5-methylphenoxy)ethylamine hydrochloride (10.4 g), 2-ethoxy-5-hydroxy-3,4,6-trimethylbenzyl chloride (9.15 g) and triethylamine (8.10 g) were dissolved in N,N-dimethylformamide (80 ml), and the mixture was stirred at room temperature for 4 hours. After the reaction, the solvent was distilled off and water was added. The mixture was extracted with ethyl acetate, and the extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The resulting liquid (1.0 g) was dissolved in methanol and conc. hydrochloric acid (0.2 ml) was added. The mixture was concentrated to dryness under reduced pressure. Recrystallization from ethanol-diethyl ether gave 910 mg of the title compound.
Reaction SMILES: Br[C:2]1[C:9]([O:10][CH2:11][CH3:12])=[C:8]([O:13][CH2:14][CH3:15])[C:7]([N+:16]([O-:18])=[O:17])=[CH:6][C:3]=1[CH:4]=O.[C:19]([O:23][CH3:24])(=[O:22])[CH2:20][SH:21].C(N(CC)CC)C.Cl>CN(C)C=O>[CH3:24][O:23][C:19]([C:20]1[S:21][C:2]2[C:9]([O:10][CH2:11][CH3:12])=[C:8]([O:13][CH2:14][CH3:15])[C:7]([N+:16]([O-:18])=[O:17])=[CH:6][C:3]=2[CH:4]=1)=[O:22]
Reactant: CCOc1c([N+](=O)[O-])cc(C=O)c(Br)c1OCC
Reactant: COC(=O)CS
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOc1c([N+](=O)[O-])cc2cc(C(=O)OC)sc2c1OCC
Reaction time: 8 h

Procedure:
To a solution of 2-bromo-3,4-diethoxy-5-nitrobenzaldehyde (1.5 g) in N,N-dimethylformamide (5 ml) were added methyl thioglycolate (1.5 g) and triethylamine (2.2 ml) at 0° C. Stirring was continued at room temperature overnight. 1 M HCl was added and the product was extracted with ether. The organic phase was dried with Na2SO4 and evaporated. The crude product was triturated with methanol.
Reaction SMILES: [CH:1]([OH:4])([CH3:3])[CH3:2].[H-].[Na+].Cl[C:8]1[CH:9]=[CH:10][C:11]2[CH2:12][N:13]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:14][CH2:15][O:16][C:17]=2[N:18]=1.O>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC(C)=CC=2)C2C=CC(C)=CC=2)C2C=CC(C)=CC=2)=CC=1>[CH:1]([O:4][C:8]1[CH:9]=[CH:10][C:11]2[CH2:12][N:13]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:14][CH2:15][O:16][C:17]=2[N:18]=1)([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCOc2nc(Cl)ccc2C1
Reactant: CC(C)O
Agent: [Pd]
Agent: Cc1ccc(P(c2ccc(C)cc2)c2ccc3ccccc3c2-c2c(P(c3ccc(C)cc3)c3ccc(C)cc3)ccc3ccccc23)cc1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)Oc1ccc2c(n1)OCCN(C(=O)OC(C)(C)C)C2
Temperature: 70 °C
Reaction time: 0.25 h
Yield: 64 %

Procedure:
To a solution of isopropyl alcohol (0.081 mL) in toluene (2 mL) was added sodium hydride (0.084 g), and the resulting mixture was stirred at 70° C. for 15 min under a nitrogen atmosphere. A mixture of tert-butyl 8-chloro-2,3-dihydropyrido[3,2-f][1,4]oxazepine-4(5H)-carboxylate (0.30 g), (S)-tol-BINAP (0.022 g), Pd2(dba)3 (0.015 g) and toluene (2 mL) was added, and the resulting mixture was stirred at 100° C. for 16 hr under an argon atmosphere. The reaction solution was poured into water, and the resulting product was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (solvent gradient; 0→40% ethyl acetate/hexane) to give tert-butyl 8-isopropoxy-2,3-dihydropyrido[3,2-f][1,4]oxazepine-4(5H)-carboxylate (0.21 g, 64%) as a colorless oil.
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]([OH:8])([CH3:7])[C:4](O)=[O:5].S(Cl)(Cl)=O.[Cl:15][C:16]1[C:21]([NH2:22])=[CH:20][C:19]([S:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)(=[O:25])=[O:24])=[CH:18][CH:17]=1.[OH-].[Na+]>CN(C)C(=O)C>[F:1][C:2]([F:10])([F:9])[C:3]([OH:8])([CH3:7])[C:4]([NH:22][C:21]1[C:16]([Cl:15])=[CH:17][CH:18]=[C:19]([S:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)(=[O:25])=[O:24])[CH:20]=1)=[O:5]
Reactant: Nc1cc(S(=O)(=O)c2ccccc2)ccc1Cl
Reactant: CC(O)(C(=O)O)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)N(C)C
Solvent: O=S(Cl)Cl
Product: CC(O)(C(=O)Nc1cc(S(=O)(=O)c2ccccc2)ccc1Cl)C(F)(F)F
Temperature: -20 °C
Reaction time: 1 h
Yield: 33.9 %

Procedure:
To a solution containing 3,3,3-trifluoro-2-hydroxy-2-methylpropanoic acid (2.00 g) in N,N-dimethylacetamide (40 mL) cooled to -20° C. was added thionyl chloride (1.50 g) and the mixture was stirred for 1.0 hour. 6-chloro-3-phenylsulfonylaniline (2.42 g) was added in one portion and mixture was stirred for 48 hours at room temperature. The reaction mixture was poured into aqueous sodium hydroxide (1.0N, 250 mL) and extracted with ethyl acetate. The combined ethyl acetate extracts were washed (aqueous sodium hydroxide, brine) and evaporated. Chromatography, with hexane:ethyl acetate as the eluent (4:1 then 2:1) yielded the title compound as a white solid (1.25 g); mp: 79°-80° C.; NMR (250 MHz): 1.61 (s,3), 7.69 (m,3), 7.82 (m,2), 7.94 (d,1, J=9), 7.98 (m,2), 8.52 (s,1), 9.93 (s,1); MS: m/z=408(M+1). Analysis for C16H13ClF3NO4S: Calculated: C, 47.11; H, 3.19; N, 3.44; Found: C, 47.10; H, 3.28; N, 3.38.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:15]=[CH:16][C:17]=1[NH2:18])[C:7]([C:9]1[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=1)=[O:8])([O-])=O.[H][H]>O1CCCC1.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([CH:15]=[CH:16][C:17]=1[NH2:18])[C:7]([C:9]1[CH:10]=[CH:11][N:12]=[CH:13][CH:14]=1)=[O:8]
Reactant: [H][H]
Reactant: Nc1ccc(C(=O)c2ccncc2)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: C1CCOC1
Product: Nc1ccc(C(=O)c2ccncc2)cc1N

Procedure:
A suspension of 20 g. (0.082 mol) of 4-(3-nitro-4-aminobenzoyl)pyridine in 1 liter of tetrahydrofuran containing 5 g. of 5% palladium on carbon was reduced with hydrogen under a pressure of 3 atmospheres. The resulting mixture was filtered and concentrated in vacuo to reddish oil which was dissolved in a minimum amount of methylene chloride and diluted with petroleum ether to yield 4-(3,4-diaminobenzoyl)pyridine as an unstable orange solid, mp. 210° -214° C. (water-Norite).
Reaction SMILES: [CH2:1]([N:4]1[CH2:7][CH:6]([C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)[CH2:5]1)[CH2:2][CH3:3].[F:15][C:16]([F:30])([F:29])[CH:17]([C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1)[CH3:18]>C(Cl)Cl.N1C=CC=CC=1>[CH2:1]([N:4]1[CH2:5][CH:6]([C:8]2[CH:9]=[CH:10][C:11]([NH:14][S:25]([C:22]3[CH:21]=[CH:20][C:19]([CH:17]([CH3:18])[C:16]([F:15])([F:29])[F:30])=[CH:24][CH:23]=3)(=[O:27])=[O:26])=[CH:12][CH:13]=2)[CH2:7]1)[CH2:2][CH3:3]
Reactant: CCCN1CC(c2ccc(N)cc2)C1
Reactant: CC(c1ccc(S(=O)(=O)Cl)cc1)C(F)(F)F
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCN1CC(c2ccc(NS(=O)(=O)c3ccc(C(C)C(F)(F)F)cc3)cc2)C1
Yield: 18 %

Procedure:
Following the same procedure as described in example 55, 4-(1-propyl-azetidin-3-yl)phenylamine (100 mg, 0.52 mmol) in CH2Cl2/pyridine 9:1 (15 ml) was treated with 4-(2,2,2-trifluoro-1-methyl-ethyl)-benzenesulfonyl chloride (145 mg, 0.52 mmol). Purification of the crude product by flash column chromatography (CH2Cl2:methanol, 95:5) provided the title compound (40 mg, 18%) as a pale yellow gum.
Reaction SMILES: [C:1]([OH:11])(=[O:10])[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[I:12]I.[N+]([O-])(O)=O>C(O)(=O)C.OS(O)(=O)=O.O>[I:12][C:6]1[CH:7]=[C:2]([CH:3]=[CH:4][C:5]=1[O:8][CH3:9])[C:1]([OH:11])=[O:10]
Reactant: COc1ccc(C(=O)O)cc1
Reactant: II
Agent: O=S(=O)(O)O
Solvent: O
Solvent: O=[N+]([O-])O
Solvent: CC(=O)O
Product: COc1ccc(C(=O)O)cc1I
Temperature: 45 °C
Reaction time: 0.5 h
Yield: 65.2 %

Procedure:
To a mechanically stirred suspension of p-anisic acid (59.90 g, 394 mmol) and iodine (100.0 g, 394 mmol) in a mixture of 325 mL glacial acetic acid and 60 g conc H2SO4, heated to 45° C. with a water bath, was added dropwise a solution of 40 g conc HNO3 in 60 mL HOAc at such a rate that the temperature was maintained between 40-50° C. (ca. 90 min). After addition, the mixture was stirred for 30 min at 50° C., then diluted with 400 mL H2O, which produced a pink solid. The material was collected on a Büchner funnel, rinsed with 1 L 10% Na2S2O4 and 1 L H2O, then air dried. Recrystallization from 700 mL pyridine/MeOH (1:1) provided colorless plates. The crystals were collected on a Büchner funnel, rinsed with 500 mL MeOH, then allowed to air dry. After drying under high vacuum overnight, 71.4 g (65.2%) of the desired product was obtained; mp 243-244° C. (lit.10 mp 238° C.); 1H NMR (DMSO-d6) δ 3.91 (s, 3 H), 7.00 (d, 1 H, J=8.7 Hz), 7.95 (dd, 1 H, J=8.7, 1.8 Hz), 8.27 (d, 1 H, J=1.8 Hz), 12.89 (br s, 1 H).
Reaction SMILES: O=C(C(=O)O)O.[CH2:7]([N:14]1[CH2:23][CH2:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]1[C:24]([NH2:26])=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>>[NH2:26][CH2:24][CH:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:22][CH2:23][N:14]1[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: NC(=O)C1c2ccccc2CCN1Cc1ccccc1
Agent: O=C(O)C(=O)O
Agent: [Al+3]
Agent: [H-]
Product: NCC1c2ccccc2CCN1Cc1ccccc1
Yield: 59.8 %

Procedure:
Title Compound I, in which R=CH2C6H5 ; R'=H; A=CH; pY=C2H2O4, q=0 and n=1, was prepared by reducing 2-benzyl-1,2,3,4-tetrahydroisoquinoline-1-carboxamide (6.7 g; 0.025 mole) with LiAlH4 by the same procedure as used in Example I to obtain 3.77 g (60% theory) of 1-aminomethyl-2-benzyl-1,2,3,4-tetrahydroisoquinoline as a yellow oil. This compound was reacted with benzaldehyde and reduced as in Example II. The resultant 1-(N-benzyl)aminomethyl-2-benzyl-1,2,3,4-tetrahydroisoquinoline was propionylated as in Example I and the oxalate (having a melting range of 159°-61°) formed.
Reaction SMILES: C(O)(=O)C.C([O:9][C:10](=[O:43])[CH2:11][N:12]([C:22](=[O:42])[C@H:23]([CH3:41])[NH:24][C@H:25]([C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH2:26][CH2:27][CH2:28][CH2:29][CH:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)[CH:13]1[CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14]1)(C)(C)C.[BrH:44].C(O)(=O)C>C(OCC)C>[BrH:44].[BrH:44].[CH2:39]([O:38][C:36]([C@@H:25]([NH:24][C@H:23]([C:22]([N:12]([CH:13]1[CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14]1)[CH2:11][C:10]([OH:43])=[O:9])=[O:42])[CH3:41])[CH2:26][CH2:27][CH2:28][CH2:29][CH:30]1[CH2:31][CH2:32][NH:33][CH2:34][CH2:35]1)=[O:37])[CH3:40]
Reactant: CCOC(=O)[C@H](CCCCC1CCNCC1)N[C@@H](C)C(=O)N(CC(=O)OC(C)(C)C)C1Cc2ccccc2C1
Agent: Br
Solvent: CC(=O)O
Solvent: CCOCC
Product: CCOC(=O)[C@H](CCCCC1CCNCC1)N[C@@H](C)C(=O)N(CC(=O)O)C1Cc2ccccc2C1
Reaction time: 0.5 h

Procedure:
In 2 mol of acetic acid is dissolved 0.3 g of N-[N-[(S)-5-(4-piperidyl)-1-ethoxycarbonylpentyl]-L-alanyl]-N-(indan-2yl)glycine tert-butyl ester, and 1 ml of hydrogen bromide-acetic acid solution is added to the solution, followed by standing at room temperature for 30 minutes. 50 ml of ethyl ether is added to the reaction solution, followed by shaking, and the supernatant layer is removed by decantation. The precipitate is collected and dried under reduced pressure to give 0.3 g of N-[N-[(S)-1-ethoxycarbonyl-5-(4-piperidyl)pentyl]-L-alanyl]-N-(indan-2-yl)glycine.dihydrobromide as a colorless powder.