Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:11])[NH:7][CH2:8][C:9]#[CH:10])([CH3:4])([CH3:3])[CH3:2].[CH3:12][O:13][C:14]([C:16]1[S:17][C:18](Br)=[CH:19][CH:20]=1)=[O:15]>CCOC(C)=O.[Pd].C(N(CC)CC)C>[CH3:12][O:13][C:14]([C:16]1[S:17][C:18]([C:10]#[C:9][CH2:8][NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:11])=[CH:19][CH:20]=1)=[O:15]
Reactant: C#CCNC(=O)OC(C)(C)C
Reactant: COC(=O)c1ccc(Br)s1
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(C#CCNC(=O)OC(C)(C)C)s1
Temperature: 25 °C
Yield: 63406.2 %

Procedure:
A mixture of prop-2-ynyl-carbamic acid tert-butyl ester (from Preparation 41, 1.67 mmol, 0.011 mmol), 5-bromo-thiophene-2-carboxylic acid methyl ester (2.50 g, 0.011 mmol), tetrakistriphenylpyosphine(O) palladium (0.622 g, 0.0538 mmol), Cul (0.102 g, 0.538 mmol) and triethylamine (1.57 mL, 0.011 mmol) in 50 mL acetronitrile was heated at reflux for 16 h. The reaction was cooled to room temperature, diluted with 75 mL EtOAc, washed with 5.5% HCl, water and brine, dried over MgSO4, filtered and concentrated in vacuo to an oil. The product was purified via flash chromatography (9:1 to 4:1 hexanes:EtOAc) to afford the title compound of Step A as an oil (2.06 g). MS 313 (M+18).
Reaction SMILES: [C:1]1([C:7]2[O:11][N:10]=[C:9]([C:12](F)=[O:13])[C:8]=2[C:15]([F:18])([F:17])[F:16])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O/[N:20]=[C:21](/[C:23]1[CH:40]=[CH:39][C:26]([CH2:27][N:28]2[CH2:31][CH:30]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:29]2)=[CH:25][CH:24]=1)\[NH2:22].CCN(C(C)C)C(C)C>C(#N)C>[C:1]1([C:7]2[O:11][N:10]=[C:9]([C:12]3[O:13][N:22]=[C:21]([C:23]4[CH:24]=[CH:25][C:26]([CH2:27][N:28]5[CH2:29][CH:30]([C:32]([O:34][C:35]([CH3:36])([CH3:38])[CH3:37])=[O:33])[CH2:31]5)=[CH:39][CH:40]=4)[N:20]=3)[C:8]=2[C:15]([F:18])([F:17])[F:16])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)C1CN(Cc2ccc(/C(N)=N/O)cc2)C1
Reactant: O=C(F)c1noc(-c2ccccc2)c1C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)(C)OC(=O)C1CN(Cc2ccc(-c3noc(-c4noc(-c5ccccc5)c4C(F)(F)F)n3)cc2)C1
Temperature: 25 °C
Reaction time: 72 h
Yield: 86 %

Procedure:
To a mixture of 5-phenyl-4-(trifluoromethyl)isoxazole-3-carbonyl fluoride (100 mg, 0.386 mmol) and (Z)-tert-butyl 1-(4-(N′-hydroxycarbamimidoyl)benzyl)azetidine-3-carboxylate (Int.1, 118 mg, 0.386 mmol) in acetonitrile (2 mL) at room temperature was added Hunig's Base (0.081 mL, 0.463 mmol). The reaction mixture was stirred at room temperature for 3 days. The volatiles were removed under reduced pressure, and the residue was partitioned between dichloromethane (30 mL) and a saturated aqueous solution of sodium bicarbonate (30 mL). The aqueous layer was extracted with dichloromethane (2×20 mL), and the combined organic layers were dried over anhydrous magnesium sulfate and concentrated to afford a light yellow oil. The compound was purified by flash silica gel chromatography using a mixture of ethyl acetate/hexane (0-70%) to give tert-butyl 1-(4-(5-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-1,2,4-oxadiazol-3-yl)benzyl)azetidine-3-carboxylate (175 mg, 0.332 mmol, 86% yield) as a white, crystalline solid. The compound had an HPLC retention time=3.34 minutes (YMC-Combi 4.6×50 mm S-5 ODS column) eluting with 10-90% aqueous methanol+0.2% phosphoric acid over a 4 minute gradient. MS: (M+H)=527.13. 1H NMR (400 MHz, CDCl3) δ ppm 1.47 (s, 9H), 3.26-3.33 (m, 3H), 3.54-3.59 (m, 2H), 3.70 (s, 2H), 7.46 (d, J=8.28 Hz, 2H), 7.56-7.62 (m, 2H), 7.63-7.68 (m, 1H), 7.78 (d, J=7.28 Hz, 2H), and 8.16 (d, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[CH2:10][CH2:9][CH:8]([CH2:11][CH2:12][C:13]([OH:15])=O)[CH2:7][CH2:6]1)=[O:4].C(Cl)(=O)C([Cl:19])=O>>[Cl:19][C:13]([CH2:12][CH2:11][CH:8]1[CH2:9][CH2:10][N:5]([C:3]([O:2][CH3:1])=[O:4])[CH2:6][CH2:7]1)=[O:15]
Reactant: O=C(Cl)C(=O)Cl
Reactant: COC(=O)N1CCC(CCC(=O)O)CC1
Product: COC(=O)N1CCC(CCC(=O)Cl)CC1

Procedure:
PCT Publication No WO 97/22584 reports preparation of Donepezil HCl by reacting pyridine-4-aldehyde with malonic acid. The resulting 3-(pyridin-4-yl)-2-propenoic acid was reduced with rodium on carbon under hydrogen atmosphere to give 3-(piperidin-4-yl)-2-propionic acid which on reaction with methyl chlorocarbonate gave 3-[N-(methoxycarbonyl)piperidin-4-yl]propionic acid. On reacting 3-[N-(methoxycarbonyl)piperidin-4-yl]propionic acid with oxalyl chloride, methyl 4-(2-chlorocarbonylethyl)piperidin-1-carboxylate is obtained which on reaction with 1,2-dimethoxy benzene in the presence of aluminium chloride afforded 4-[3-(3,4-dimethoxyphenyl)-3-oxopropyl]piperidin-1-carboxylate. On reacting 4-[3-(3,4-dimethoxyphenyl)-3-oxopropyl]piperidin-1-carboxylate with tetramethyl diamino methane, 4-[2-(3,4-dimethoxy benzoyl)allyl]piperidin-1-carboxylate is obtained which on treatment with sulphuric acid gave methyl 4-(5,6-dimethoxy-1-indanon-2-yl methyl)piperidin-1-carboxylate. On decarboxylating 4-(5,6-dimethoxy-1-indanon-2-yl methyl)piperidin-1-carboxylate, 5,6-dimethoxy-2-(piperidin-4-yl methyl)-1-indanone is obtained which on treatment with benzyl bromide afforded Donepezil HCl (Example 1 to 6). Overall yield of Donepezil HCl 19.3% (70%×84%×100%×68%×79%×61%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([N+:24]([O-])=O)[CH:19]=2)=[CH:12][CH:11]=1.[ClH:27]>CCOC(C)=O.CCO.[Pd]>[ClH:27].[F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]2[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=2)=[CH:12][CH:11]=1
Reactant: O=[N+]([O-])c1cccc(COc2ccc(-c3cc(F)c(F)cc3F)cc2)c1
Agent: [Pd]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Product: Nc1cccc(COc2ccc(-c3cc(F)c(F)cc3F)cc2)c1

Procedure:
A solution of 2,4,5-trifluoro-4′-(3-nitro-benzyloxy)-biphenyl (150 mg, 0.418 mmol) and 10% Pd/C (40 mg) in EtOAc (2 mL), EtOH (10 mL) and 6N HCl (100 uL) was hydrogenated at 50 psi for 1.25 hrs. The reaction mixture was filtered through Celite and evaporated to dryness to give 3-(2′,4′,5′-trifluoro-biphenyl-4-yloxymethyl)-phenylamine hydrochloride. LC-MS (ES) calculated for C19H14F3NO, 329.32; found m/z 330 [M+H]+.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]2=[O:21].[C:22]([O:26][C:27](=[O:32])[NH:28][CH2:29][CH2:30][NH2:31])([CH3:25])([CH3:24])[CH3:23]>>[C:22]([O:26][C:27](=[O:32])[NH:28][CH2:29][CH2:30][NH:31][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]2=[O:21])([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: CS(=O)(=O)Nn1c(=O)[nH]c2cc([N+](=O)[O-])c(F)cc2c1=O
Product: CC(C)(C)OC(=O)NCCNc1cc2c(=O)n(NS(C)(=O)=O)c(=O)[nH]c2cc1[N+](=O)[O-]
Yield: 62 %

Procedure:
N-(6-Fluoro-7-nitro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-methanesulfonamide (30 mg, 0.0943 mmol) is reacted with (2-amino-ethyl)-carbamic acid tert-butyl ester according to the GPA affording 27 mg (62%) of a red powder. Rt=4.43 min.
Reaction SMILES: [Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[K+].[K+].ClCC(N[C:17]1[CH:26]=[C:25]([NH:27][C:28](=[O:31])[CH2:29][Cl:30])[C:24]([OH:32])=[C:23]2[C:18]=1[CH:19]=[CH:20][C:21]([CH3:33])=[N:22]2)=O.[OH2:34]>C(O)(=O)C>[Cl:30][CH2:29][C:28]([NH:27][C:25]1[C:24](=[O:32])[C:23]2[N:22]=[C:21]([CH3:33])[CH:20]=[CH:19][C:18]=2[C:17](=[O:34])[CH:26]=1)=[O:31]
Reactant: O
Reactant: Cc1ccc2c(NC(=O)CCl)cc(NC(=O)CCl)c(O)c2n1
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: [K+]
Solvent: CC(=O)O
Product: Cc1ccc2c(n1)C(=O)C(NC(=O)CCl)=CC2=O
Temperature: 25 °C
Yield: 59 %

Procedure:
This compound was prepared by the oxidation of the corresponding acylamido with potassium dichromate in glacial acetic acid. In a 500 ml. round-bottom flask equipped with a magnetic bar, 5,7-bis(chloroacetamido)-8-hydroxy-2-methylquinoline (32) (prepared as described in Example 32) (3.42 g., 0.01 mol) was suspended in 122 ml. of glacial acetic acid. A solution of potassium dichromate (8.8 g., 0.03 mol) in 115 ml. of water was added and the resulting dark solution was stirred at room temperature over-night. The solution was extracted with dichloromethane (12×50 ml.). The organic extracts were washed with 3% sodium bicarbonate solution (200 ml.), dried with magnesium sulfate, and rotoevaporated to yield a bright yellow solid. After vacuum drying, the nearly pure product weighed 1.56 g. (yield of 59%). The product was recrystallized from ethyl acetate: mp 196°-200° C. (dec.); 1H NMR (CDCl3) δ2.76 (3H, s, C-2CH3), 4.23 (2H, s, C-7NHCOCH2Cl), 7.56 (1H, d, J=8.1 Hz, C-3H), 7.89 (1H, s, C-6H), 8.30 (1H, d, J=8.1 Hz, C-4H), 9.48 (1H, br. s, C-7NH); IR (KBr) vmax 3299, 3078, 2948, 1712, 1683, 1641, 1614, 1588, 1515, 1398, 1384, 1323, 1130 cm-1 ; EIMS, m/e (relative intensity) 264/266 (M+, 2.9/1, 67) 229 (62), 215 (74), 201 (43), 188 (86), 161 (base), 132 (21); HRMS, m/e for C14H9ClN2O3, calculated 264.030170, found 264.029824; analysis for C14H9ClN2O3 calculated: C, 54.46; H, 3.43; Cl, 13.40; N, 10.58; found: C, 54.19; H, 3.37; C1, 13.29; N, 10.36.
Reaction SMILES: C([O:3][C:4](=[O:30])[CH2:5][NH:6][C:7](=[O:29])[CH2:8][O:9][N:10]=[C:11]1[C:23]2[C:18](=[N:19][C:20]([C:26](=[O:28])[NH2:27])=[C:21]([C:24]#[N:25])[N:22]=2)[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]1=2)C.O[Li].O.Cl>C1COCC1.O>[C:26]([C:20]1[N:19]=[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[C:11](=[N:10][O:9][CH2:8][C:7]([NH:6][CH2:5][C:4]([OH:30])=[O:3])=[O:29])[C:23]2=[N:22][C:21]=1[C:24]#[N:25])(=[O:28])[NH2:27]
Reactant: CCOC(=O)CNC(=O)CON=C1c2ccccc2-c2nc(C(N)=O)c(C#N)nc21
Agent: Cl
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1nc2c(nc1C(N)=O)-c1ccccc1C2=NOCC(=O)NCC(=O)O
Temperature: 0 °C
Yield: 70.1 %

Procedure:
To a solution of 40 (60 mg, 0.15 mmol) in THF/H2O (1:1, 15 ml) LiOH.H2O (30 mg, 0.71 mmol) was added. The mixture was stirred at room temperature and after 2 h 2N HCl was added up to pH=5. The solvent was removed under reduced pressure and a 1:1 mixture of CH2Cl2/MeOH (10 ml) was added. The solution was cooled at 0° C. and the precipitate was collected by filtration, affording 41 (40 mg, 70%) as green solid. 1H NMR (300 MHz, DMSO d6+TFA): δ 8.35 (t, 1H), 8.13 (dd, 1H), 7.91 (m, 2H), 7.78 (ddd, 1H), 4.92 (s, 2H), 3.87 (d, 2H). ESI+MS: calcd for C17H12N6O5: 380.32; found: 381.4 (MH+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C@@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]2[NH:15][C@H:16]2[CH2:21][CH2:20][CH2:19][N:18]([C:22]3[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=3)[CH2:17]2)[CH:3]=1.[F:31][C:32]([F:44])([F:43])[O:33][C:34]1[CH:35]=[C:36](B(O)O)[CH:37]=[CH:38][CH:39]=1>>[N+:28]([C:25]1[CH:26]=[CH:27][C:22]([N:18]2[CH2:19][CH2:20][CH2:21][C@H:16]([NH:15][C@@H:10]3[CH2:11][CH2:12][CH2:13][CH2:14][C@H:9]3[NH:8][C:4]3[CH:3]=[C:2]([C:36]4[CH:37]=[CH:38][CH:39]=[C:34]([O:33][C:32]([F:31])([F:43])[F:44])[CH:35]=4)[CH:7]=[CH:6][N:5]=3)[CH2:17]2)=[CH:23][CH:24]=1)([O-:30])=[O:29]
Reactant: OB(O)c1cccc(OC(F)(F)F)c1
Reactant: O=[N+]([O-])c1ccc(N2CCC[C@H](N[C@@H]3CCCC[C@H]3Nc3cc(Br)ccn3)C2)cc1
Product: O=[N+]([O-])c1ccc(N2CCC[C@H](N[C@@H]3CCCC[C@H]3Nc3cc(-c4cccc(OC(F)(F)F)c4)ccn3)C2)cc1

Procedure:
(1R,2R)—N1-((S)-1-(4-Nitrophenyl)piperidin-3-yl)-N2-(4-(3-(trifluoromethoxy)phenyl)pyridin-2-yl)cyclohexane-1,2-diamine (1.6 mg, 0.003 mmol, 6.8% yield) was synthesized as described in General Procedure I using (1R,2R)—N1-(4-bromopyridin-2-yl)-N2-((S)-1-(4-nitrophenyl)piperidin-3-yl)cyclohexane-1,2-diamine (20 mg, 0.04 mmol) and 3-(trifluoromethoxy)phenylboronic acid (12.2 mg, 0.04 mmol). The desired fraction from RP prep-HPLC method D was concentrated to give the title compound as a pale yellow solid. Anal. Calcd. for C29H32F3N5O3 m/z 555.2, found: 556.2 (M+H)+; 1H NMR (400 MHz, CD3OD) δ ppm 8.05 (d, J=2.0 Hz, 1H), 7.80 (m, 2H), 7.51 (m, 1H), 7.39 (m, 1H), 7.33 (m, 2H), 6.89 (dd, J=5.6 Hz, J=1.6 Hz, 1H), 6.77 (m, 2H), 6.47 (m, 1H), 4.09 (m, 1H), 3.70 (m, 3H), 3.23 (m, 1H), 3.11 (m, 1H), 2.92 (m, 1H), 2.36 (m, 1H), 2.11 (m, 3H), 1.92 (m, 4H), 1.64 (m, 2H), 1.44 (m, 2H).
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([N:11]2[N:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:21])[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:22][C:23]1[CH:27]=[CH:26][N:25]([CH2:28][C:29]([CH3:32])([OH:31])[CH3:30])[N:24]=1>>[CH:1]1([CH2:6][CH:7]([N:11]2[N:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:21])[C:8]([NH:22][C:23]2[CH:27]=[CH:26][N:25]([CH2:28][C:29]([OH:31])([CH3:30])[CH3:32])[N:24]=2)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(O)C(CC1CCCC1)n1ncc2ccccc2c1=O
Reactant: CC(C)(O)Cn1ccc(N)n1
Product: CC(C)(O)Cn1ccc(NC(=O)C(CC2CCCC2)n2ncc3ccccc3c2=O)n1
Yield: 11 %

Procedure:
Using the method described in Example 83, Step 3,3-cyclopentyl-2-(1-oxo-1H-phthalazin-2-yl)-propionic acid (as prepared in Example 83, Step 2) and 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (Intermediate 1) afforded 3-cyclopentyl-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-2-(1-oxo-1H-phthalazin-2-yl)-propionamide as a white solid (48 mg, 11%); ES+-HRMS m/e calcd for C23H29N5O3 [M+H+] 319.1223 found 319.1223. 1H-NMR (300 MHz, DMSO-d6) δ ppm 1.03 (s, 6H), 1.04-1.17 (m, 1H), 1.24-1.72 (m, 8H), 1.93-2.10 (m, 1H), 2.21-2.35 (m, 1H), 3.86 (s, 2H), 4.64 (s, 1H), 5.61 (dd, J=10.7, 4.1 Hz, 1H), 6.39 (d, J=2.1 Hz, 1H), 7.50 (d, J=2.1 Hz, 1H), 7.79-7.91 (m, 1H), 7.91-7.98 (m, 2H), 8.24 (d, J=7.5 Hz, 1H), 8.48 (s, 1H), 10.66 (s, 1H).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:8][C@H:7]([CH3:9])[CH2:6][N:5]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:4]1.[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1.CCN(C(C)C)C(C)C.O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:9][C@H:7]1[CH2:8][C@@H:3]([CH2:2][O:1][S:23]([C:20]2[CH:21]=[CH:22][C:17]([CH3:27])=[CH:18][CH:19]=2)(=[O:25])=[O:24])[CH2:4][N:5]([C:10]([O:12][C:13]([CH3:15])([CH3:14])[CH3:16])=[O:11])[CH2:6]1
Reactant: C[C@H]1C[C@@H](CO)CN(C(=O)OC(C)(C)C)C1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OC[C@@H]2C[C@H](C)CN(C(=O)OC(C)(C)C)C2)cc1
Reaction time: 0.25 h
Yield: 65.9 %

Procedure:
To a stirred solution of (3R,5S)-tert-butyl 3-(hydroxymethyl)-5-methylpiperidine-1-carboxylate (0.783 g, 3.385 mmol) in DCM (5 mL) was added p-toluenesulfonyl chloride (0.968 g, 5.078 mmol) followed by DMAP (40 mg, 0.33 mmol) and DIPEA (1.18 mL, 6.77 mmol) at rt. The reaction mixture was stirred at rt for 3 h after which time water (5 mL) was added followed by stifling an additional 15 min. The resultant organic layer was washed with 0.1 N HCl (5 mL), brine (3 mL), dried over MgSO4, filtered and concentrated to dryness. The crude product was purified over silica gel (Biotage, eluting with 3:1 heptanes: EtOAc) to provide (3S,5R)-tert-butyl 3-methyl-5-((tosyloxy)methyl)piperidine-1-carboxylate (0.8602 g, 2.232 mmol, 65.9% yield).
Reaction SMILES: Cl[C:2]1[C:7]2[C:8]3[CH2:14][CH2:13][CH2:12][CH2:11][C:9]=3[Se:10][C:6]=2[N:5]=[CH:4][N:3]=1.[NH2:15][C:16]1[CH:17]=[N:18][CH:19]=[C:20]([Br:22])[CH:21]=1.[OH-].[Na+].O>CN(C=O)C>[Br:22][C:20]1[CH:21]=[C:16]([NH:15][C:2]2[C:7]3[C:8]4[CH2:14][CH2:13][CH2:12][CH2:11][C:9]=4[Se:10][C:6]=3[N:5]=[CH:4][N:3]=2)[CH:17]=[N:18][CH:19]=1
Reactant: Nc1cncc(Br)c1
Reactant: Clc1ncnc2[se]c3c(c12)CCCC3
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: Brc1cncc(Nc2ncnc3[se]c4c(c23)CCCC4)c1
Temperature: 25 °C
Reaction time: 36 h
Yield: 66.6 %

Procedure:
To a solution of 4-chloro-5,6,7,8-tetrahydrobenzo[1,2-b]pyrimidino[5,4-d]selenophene (500 mg, 1.84 mmol, from step b of example 1) in DMF (10 mL) was added sequentially 3-amino-5-bromopyridine (380 mg, 2.19 mmol) and powdered NaOH (220 mg, 5.5 mmol) at rt and the mixture was stirred at rt for 36 h. The mixture was poured into ice cooled water and stirred for 10 min. The precipitated solid was filtered, washed with water and dried. The crude solid was chromatographed over silica gel column using hexane-EtOAc (70:30) as eluents to give the product as an off-white color solid (500 mg, 67%), which was recrystallized from acetonitrile, mp 170-172° C. 1H NMR (400 MHz, CDCl3): δ 8.66 (1H, t, J=2.0 Hz), 8.56 (1H, d, J=2.4 Hz), 8.49 (1H, s), 8.39 (1H, d, J=1.6 Hz), 7.24 (1H, s, exchangeable with D2O), 3.08 (2H, t, J=6.2 Hz), 2.96 (2H, t, J=6.0 Hz), 2.00-2.06 (2H, m), 1.92-1.98 (2H, m); 13C NMR (100 MHz, CDCl3): δ 171.7, 154.7, 151.6, 145.3, 140.8, 140.0, 136.4, 130.3, 126.4, 120.5, 120.0, 28.4, 28.1, 22.7, 22.3; LC-MS (positive ion mode): m/z 407, 409, 411 (M+H)+.
Reaction SMILES: Cl.[CH3:2][N:3]([CH2:5][CH:6]1[C:21](=[O:22])[C:10]2[C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[F:20])=[N:12][O:13][C:9]=2[CH2:8][CH2:7]1)[CH3:4].Cl.[F:24][C:25]1[CH:38]=[CH:37][C:28]([C:29]([CH:31]2[CH2:36]CNC[CH2:32]2)=[O:30])=[CH:27][CH:26]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>O>[F:24][C:25]1[CH:26]=[CH:27][C:28]([C:29]([CH:31]2[CH2:32][CH2:2][N:3]([CH2:5][CH:6]3[C:21](=[O:22])[C:10]4[C:11]([C:14]5[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=5[F:20])=[N:12][O:13][C:9]=4[CH2:8][CH2:7]3)[CH2:4][CH2:36]2)=[O:30])=[CH:37][CH:38]=1
Reactant: O=C(c1ccc(F)cc1)C1CCNCC1
Reactant: CN(C)CC1CCc2onc(-c3ccccc3F)c2C1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(c1ccc(F)cc1)C1CCN(CC2CCc3onc(-c4ccccc4F)c3C2=O)CC1
Temperature: 25 °C
Yield: 8.1 %

Procedure:
To a solution consisting of 6,7-dihydro-5-dimethylaminomethyl-3-(2-fluorophenyl)-1,2-benzisoxazol-4(5H)-one hydrochloride (1. 86 g) in distilled water (18.5 ml) was added 4-(4-fluorobenzoyl)piperidine hydrochloride (2.7 8 g) and potassium carbonate (0.80 g). The reaction mixture was heated at reflux for 3 hours. Upon cooling to room temperature, ethyl acetate was added and the layers were separated. The aqueous phase was extracted twice with ethyl acetate. The combined organic layers were washed with brine and dried (MgSO4). Filtration and concentration gave the crude product. Purification via flash column chromatography (silica gel, 40% ethyl acetate/hexane) afforded 1.20 g of 6,7-dihydro-5-(4-(4-fluorobenzoyl) -1-piperidinyl)methyl-3-(2-fluorophenyl)-1,2-benzisoxazol-4(5H)-one. The compound was flushed through alumina with dichloromethane to give an oil which solidified on standing. The product was then recrystallized from ether/hexane, m.p. 99°-102° C.
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]1([N:16]2[CH:20]=[C:19]([C:21]([OH:23])=O)[N:18]=[N:17]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[NH2:46][CH2:47][C:48]([N:50]1[CH2:55][CH2:54][CH:53]([O:56][C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][C:58]=2[Cl:63])[CH2:52][CH2:51]1)=[O:49]>CN(C=O)C.O>[Cl:63][C:58]1[CH:59]=[CH:60][CH:61]=[CH:62][C:57]=1[O:56][CH:53]1[CH2:52][CH2:51][N:50]([C:48](=[O:49])[CH2:47][NH:46][C:21]([C:19]2[N:18]=[N:17][N:16]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:20]=2)=[O:23])[CH2:55][CH2:54]1
Reactant: NCC(=O)N1CCC(Oc2ccccc2Cl)CC1
Reactant: O=C(O)c1cn(-c2ccccc2)nn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NCC(=O)N1CCC(Oc2ccccc2Cl)CC1)c1cn(-c2ccccc2)nn1
Reaction time: 0.03 h
Yield: 76.6 %

Procedure:
DIPEA (200 mg, 0.27 mL, 1.55 mmol) was added to a stirred solution of 1-phenyl-1H-[1,2,3]triazole-4-carboxylic acid (60 mg, 0.32 mmol) in DMF (5 mL) followed by HOBt (47.6 mg, 0.35 mmol) and EDCI (153 mg, 0.8 mmol). After 2 minutes of stirring, 2-amino-1-[4-(2-chloro-phenoxy)-piperidin-1-yl]-ethanone hydrochloride (prepared according to Step 1 and 5 of the General Scheme) (107 mg, 0.35 mmol) was added and the resulting mixture was stirred at room temperature overnight. Cold water was then added and the precipitate formed was collected to afford 108 mg (76.6% Yield) of 1-phenyl-1H-[1,2,3]triazole-4-carboxylic acid {2-[4-(2-chloro-phenoxy)-piperidin-1-yl]-2-oxo-ethyl}-amide. LC/MS [M+H]+: 440.14, 95.71%. 1H NMR (300 MHz, DMSO-d6): δ 9.36 (s, 1H), 8.5 (t, 1H), 8.02 (d, 2H), 7.68 (m, 3H), 7.48 (d, 1H), 7.36-7.22 (m, 2H), 7.0 (t, 1H), 4.8 (m, 1H), 4.3 (d, 2H), 3.8 (t, 2H), 3.6 (s, 2H), 2.1 (d, 2H), 1.8 (d, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH2:8][CH3:9])[N:5]=[C:4]([CH2:10][CH3:11])[C:3]=1[CH:12]=O.N1CCCCC1.[CH3:20][CH:21](C(OCC)=O)[C:22](OCC)=[O:23]>>[CH2:10]([C:4]1[N:5]=[C:6]([CH2:8][CH3:9])[CH:7]=[C:2]2[C:3]=1[CH:12]=[C:21]([CH3:20])[C:22](=[O:23])[NH:1]2)[CH3:11]
Reactant: CCc1cc(N)c(C=O)c(CC)n1
Reactant: CCOC(=O)C(C)C(=O)OCC
Solvent: C1CCNCC1
Product: CCc1cc2[nH]c(=O)c(C)cc2c(CC)n1
Temperature: 120 °C

Procedure:
A mixture of 4-amino-2,6-diethylpyridine-3-carbaldehyde (2.0 g), piperidine (0.5 ml) and diethyl methylmalonate (3.0 ml) was heated together at 120° C. for 24 hours. The mixture was then purified by flash chromatography, eluting with ether, to give 5,7-diethyl-3-methyl-1,6-naphthyridin-2(1H)-one as a solid (0.265 g); m.p. 163°-166° C. dec. (after recrystallisation from acetone): NMR (d6 -DMSO): 1.22(t, 3H), 1.24(t, 3H), 2.11(s, 3H), 2.71(q, 2H), 2.99(q, 2H), 6.88(s, 1H), 7.96(s, 1H), 11.84(broad, 1H); mass spectrum (CI, ammonia): 217 (M+H)+ ; microanalysis, found: C, 72.3; H, 7.4; N, 13.1%; C13H16N2O requires: C, 72.2; H, 7.5; N, 13.0%.
Reaction SMILES: [CH2:1]([NH:8][CH:9]1[CH:15]=[CH:14][C:13]2[CH:16]=[C:17]([N+:20]([O-])=O)[CH:18]=[CH:19][C:12]=2[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[NH4+].O>C(O)C.O1CCOCC1.[Fe]>[CH2:1]([NH:8][CH:9]1[CH:15]=[CH:14][C:13]2[CH:16]=[C:17]([NH2:20])[CH:18]=[CH:19][C:12]=2[CH2:11][CH2:10]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccc2c(c1)C=CC(NCc1ccccc1)CC2
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Solvent: C1COCCO1
Product: Nc1ccc2c(c1)C=CC(NCc1ccccc1)CC2
Yield: 92.6 %

Procedure:
A solution of N-benzyl-6,7-dihydro-2-nitro-5H-benzocyclohepten-7-amine (3.03 g) in ethanol (19 ml) and dioxane (19 ml) was added dropwise to a stirred mixture of iron powder (3.03 g) and ammonium chloride (0.36 g), in ethanol (15 ml), dioxane (15 ml), and water (15 ml) under reflux over 20 minutes. The resulting mixture was stirred under reflux for 20 minutes and the hot reaction mixture was filtered. The filtrate was evaporated in vacuo and the residue was partitioned between ethyl acetate and sodium bicarbonate aqueous solution. The organic layer was washed with brine, dried over magnesium sulfate, evaporated in vacuo, and chromatographed over silica gel using dichloromethane and methanol to afford N7 -benzyl-6,7-dihydro-5H-benzocyclohepten-2,7-diamine (2.52 g) as a brown oil.
Reaction SMILES: C([O:9][C:10]1[C:15](=[O:16])[N:14]([CH3:17])[C:13]([CH:18]2[CH2:27][CH2:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]2[C:28]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=2)=[O:29])=[N:12][C:11]=1[C:36](OC)=[O:37])(=O)C1C=CC=CC=1.[F:40][C:41]1[CH:48]=[CH:47][C:44]([CH2:45][NH2:46])=[CH:43][CH:42]=1>CN(C=O)C>[F:40][C:41]1[CH:48]=[CH:47][C:44]([CH2:45][NH:46][C:36]([C:11]2[N:12]=[C:13]([CH:18]3[CH2:27][CH2:26][C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[N:19]3[C:28]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=3)=[O:29])[N:14]([CH3:17])[C:15](=[O:16])[C:10]=2[OH:9])=[O:37])=[CH:43][CH:42]=1
Reactant: COC(=O)c1nc(C2CCc3ccccc3N2C(=O)c2ccccn2)n(C)c(=O)c1OC(=O)c1ccccc1
Reactant: NCc1ccc(F)cc1
Solvent: CN(C)C=O
Product: Cn1c(C2CCc3ccccc3N2C(=O)c2ccccn2)nc(C(=O)NCc2ccc(F)cc2)c(O)c1=O
Temperature: 90 °C

Procedure:
The residue of Step 2 was dissolved in DMF and 4-fluorobenzylamine (3 eq.) was added. The reaction mixture was stirred at 90° C. for 1 H. The title compound was purified by preparative HPLC and isolated as its trifluoroacetic salt (C18, gradient of CH3CN/H2O+0.01% TFA).