Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:23]2[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][CH:24]=2)([C:16]2[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=2)[C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[N:30]1[C:37](Cl)=[N:36][C:34]([Cl:35])=[N:33][C:31]=1[Cl:32].C([O-])([O-])=O.[Na+].[Na+].O>CC(C)=O>[Cl:35][C:34]1[N:33]=[C:31]([Cl:32])[N:30]=[C:37]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]([C:16]3[CH:21]=[CH:20][C:19]([NH:22][C:37]4[N:36]=[C:34]([Cl:35])[N:33]=[C:31]([Cl:32])[N:30]=4)=[CH:18][CH:17]=3)([C:23]3[CH:28]=[CH:27][C:26]([NH:29][C:37]4[N:36]=[C:34]([Cl:35])[N:33]=[C:31]([Cl:32])[N:30]=4)=[CH:25][CH:24]=3)[C:9]3[CH:10]=[CH:11][C:12]([NH:15][C:37]4[N:36]=[C:34]([Cl:35])[N:33]=[C:31]([Cl:32])[N:30]=4)=[CH:13][CH:14]=3)=[CH:6][CH:7]=2)[N:36]=1
Reactant: Nc1ccc(C(c2ccc(N)cc2)(c2ccc(N)cc2)c2ccc(N)cc2)cc1
Reactant: Clc1nc(Cl)nc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: Clc1nc(Cl)nc(Nc2ccc(C(c3ccc(Nc4nc(Cl)nc(Cl)n4)cc3)(c3ccc(Nc4nc(Cl)nc(Cl)n4)cc3)c3ccc(Nc4nc(Cl)nc(Cl)n4)cc3)cc2)n1
Reaction time: 1 h
Yield: 68.3 %

Procedure:
A solution of tetrakis(4-aminophenyl)methane (4.57 grams, 12.0 mmol; prepared as described in Example C) in acetone (96 milliliters) was added dropwise at 0° C. to a stirred solution of cyanuric chloride (9.06 grams, 49.1 mmol; obtained from Aldrich Chemical Co., Milwaukee, Wis.) in acetone (144 milliliters). The resulting mixture was kept at 0° C. for 1 hour, treated with Na2CO3 (5.21 grams, 49.2 mmol), and poured into water (960 milliliters). The precipitate was separated by filtration, washed with water, and dried to give the tetrakis[4-[(2,4-dichloro-1,3,5-triazin-6-yl)amino]phenyl]methane (7.97 grams, 8.20 mmol, 68 percent yield) as a colorless solid: mp>310° C.; 1H NMR (400 MHz, DMSO-d6, 25° C.) δ7.18 (d, 8H, 3J=8.7 Hz), 7.55 (d, 8H, 3J=8.7 Hz), 11.18 (s, 4H); 13C NMR (75.4 MHz, DMSO-d6, 25° C.)δ64.1, 121.7, 131.7, 135.8, 143.8, 164.6, 169.7, 170.7; MS (FAB, 2-nitrobenzyl alcohol) m/e 969. Anal. Calcd for C37H20Cl8N16: C, 45.71; H, 2.07; N, 23.05. Found: C, 46.03; H, 2.09; N, 22.61.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8](=[O:10])[CH3:9])[CH2:4][CH2:3]1.[Br:11][C:12]1[CH:13]=[C:14](O)[CH:15]=[N:16][CH:17]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1.C(Cl)Cl>[Br:11][C:12]1[CH:13]=[C:14]([O:1][CH:2]2[CH2:7][CH2:6][N:5]([C:8](=[O:10])[CH3:9])[CH2:4][CH2:3]2)[CH:15]=[N:16][CH:17]=1
Reactant: Oc1cncc(Br)c1
Reactant: CC(=O)N1CCC(O)CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(=O)N1CCC(Oc2cncc(Br)c2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 59.7 %

Procedure:
1-(4-Hydroxy-piperidin-1-yl)-ethanone (200 mg, 1.4 mmol) and 5-bromo-pyridin-3-ol (248 mg, 1.4 mmol) are added to a solution of PPh3 (606 mg, 2.3 mmol) in THF (30 mL). Then diisopropyl azodicarboxylate (462 mg, 2.3 mmol) is added and the mixture is stirred at room temperature for 16 hrs. The mixture is then diluted with DCM, washed with water, dried over Na2SO4, filtered and concentrated. The residue is purified by flash column chromatography to give 250 mg of 1-[4-(5-bromo-pyridin-3-yloxy)-piperidin-1-yl]-ethanone.
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C@@H:7]([CH2:8][CH2:9][C@:10]3([CH3:34])[C@@H:19]2[CH2:18][CH2:17][C@H:16]2[C@@:11]3([CH3:33])[CH2:12][CH2:13][C@@:14]3([C:30](O)=[O:31])[CH2:26][CH2:25][C@@H:24]([C:27]([CH3:29])=[CH2:28])[C@@H:15]32)[C:6]1([CH3:36])[CH3:35])(=[O:3])[CH3:2].C(Cl)(C(Cl)=O)=O.[NH2:43][C@H:44]1[CH2:47][C@@H:46]([C:48]([N:50]2[CH2:54][CH2:53][CH2:52][CH2:51]2)=[O:49])[C:45]1([CH3:56])[CH3:55].CCN(CC)CC>C(Cl)Cl>[C:1]([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C@@H:7]([CH2:8][CH2:9][C@:10]3([CH3:34])[C@@H:19]2[CH2:18][CH2:17][C@H:16]2[C@@:11]3([CH3:33])[CH2:12][CH2:13][C@@:14]3([C:30](=[O:31])[NH:43][C@H:44]4[CH2:47][C@@H:46]([C:48]([N:50]5[CH2:54][CH2:53][CH2:52][CH2:51]5)=[O:49])[C:45]4([CH3:56])[CH3:55])[CH2:26][CH2:25][C@@H:24]([C:27]([CH3:29])=[CH2:28])[C@@H:15]32)[C:6]1([CH3:36])[CH3:35])(=[O:3])[CH3:2]
Reactant: CC1(C)[C@@H](N)C[C@H]1C(=O)N1CCCC1
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](OC(C)=O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)N[C@H]3C[C@@H](C(=O)N4CCCC4)C3(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](OC(C)=O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 25 °C
Reaction time: 3 h
Yield: 56.5 %

Procedure:
To a stirred solution of (1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-9-acetoxy-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysene-3a-carboxylic acid (0.3 g, 0.602 mmol) in DCM (1 ml) a solution of (COCl)2 (0.52 ml, 6.02 mmol) in DCM (4 ml) was added at about 0° C. and the reaction mixture was allowed to stir at room temperature for about 3 hours. After completion of the reaction (monitored by TLC), the solvent was evaporated under nitrogen atmosphere and dissolved in DCM (4 ml), which was added to a stirred solution of ((1R,3S)-3-amino-2,2-dimethylcyclobutyl)(pyrrolidin-1-yl)methanone (Intermediate 13, 0.288 g, 1.023 mmol) in DCM (5 ml) and Et3N (0.16 ml, 1.204 mmol) at about 0° C. and allowed to stir at room temperature for about 16 hours. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with DCM and washed with water, 1N HCl, water, brine and dried over Na2SO4, the solvent was evaporated and purified by silica gel column (100-200 mesh, elution 20% EtOAc in hexane) to afford the title compound as an off white solid. Wt: 0.230 g; Yield: 56.5%; 1H NMR (300 MHz, CDCl3): δ 6.38 (d, 1H, J=8.4 Hz), 4.73 (s, 1H), 4.58 (s, 1H), 4.50-4.42 (m, 1H), 4.13-4.02 (m, 1H), 3.56-3.28 (m, 5H), 3.18-3.07 (m, 1H), 2.79 (t, 1H, J=7.2 Hz), 2.55-2.33 (m, 2H), 2.27-2.18 (m, 1H), 2.04 (s, 3H), 2.00-1.74 (m, 8H), 1.72-1.10 (m, 20H), 0.95, 0.92, 0.88, 0.83 (s, 22H); Mass: [M+Na]+ 714 (100%); IR (KBr, cm−1): 3372, 2943, 2864, 1736, 1730, 1652, 1636, 1623, 1501, 1459, 1444, 1369, 1248, 1192, 1024, 979, 881, 853; M.R: 125.4° C.-135.5° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[Cl:14])=[O:7])[CH3:2].S(Cl)([Cl:19])(=O)=O>CCOCC>[Cl:19][CH:5]([C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[Cl:14])=[O:7])[C:4]([O:3][CH2:1][CH3:2])=[O:15]
Reactant: O=S(=O)(Cl)Cl
Reactant: CCOC(=O)CC(=O)c1ccccc1Cl
Solvent: CCOCC
Product: CCOC(=O)C(Cl)C(=O)c1ccccc1Cl
Reaction time: 4 h
Yield: 93.6 %

Procedure:
To a stirred solution of 3-(2-chloro-phenyl)-3-oxo-propionicacidethylester (5.000 mL, 26.600 mmol) in ether (75.00 mL) was added dropwise sulfuryl chloride (2.800 mL, 34.600 mmol) and the resulting solution was stirred for 4 h. The reaction mixture was diluted with ether (50.0 mL) and quenched by the slow addition of a saturated aqueous solution of sodium bicarbonate (50.0 mL) and the mixture was vigorously stirred for 30 min. The organic phase was separated and dried over anhydrous MgSO4, filtered, and concentrated in vacuo to provide 6.500 g of crude product as a clear colorless oil (100%). The crude residue was used without further purification. LC/MS (AA) ES+ 261, 263. 1H NMR (400 MHz, d, CDCl3) δ: 12.47 (s, 1H), 7.49-7.32 (m, 4H), 4.39 (q, J=7.2 Hz, 2H), 1.41 (t, J=7.2 Hz, 3H).
Reaction SMILES: [CH3:1][S:2][C:3]1[O:4][C:5]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1.ClC1C=C(C=CC=1)C(OO)=[O:25]>C(Cl)(Cl)Cl>[CH3:1][S:2]([C:3]1[O:4][C:5]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1)=[O:25]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1nc(-c2ccccc2)c(-c2ccccc2)o1
Solvent: ClC(Cl)Cl
Product: CS(=O)c1nc(-c2ccccc2)c(-c2ccccc2)o1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a cooled (ice/water) solution of 5.21 g. of 2-methylthio-4,5-diphenyl-oxazole pre-dissolved in 50 ml. of chloroform is added in portions over 5 minutes, 4.35 g. of m-chloro-peroxybenzoic acid dissolved in 50 ml. of chloroform. After stirring the reaction mixture for 20 minutes, the ice/water bath is removed and the reaction mixture stirred at room temperature for an additional 60 minutes. The precipitated m-chloro-benzoic acid is filtered off, washed with chloroform and the combined chloroform solution is washed with a 10% solution of sodium carbonate, dried, evaporated in vacuo to dryness, and the residue recrystallized from benzene/ligroin to yield 2-methylsulfinyl-4,5-diphenyl-oxazole, m.p. 75°-78° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:18]#[C:19][CH2:20][OH:21])[C:5]2[O:9][C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[Cl:16])=[N:7][C:6]=2[CH:17]=1.[H][H]>C(OCC)(=O)C.[Ni]>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:18][CH2:19][CH2:20][OH:21])[C:5]2[O:9][C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[Cl:16])=[N:7][C:6]=2[CH:17]=1
Reactant: [H][H]
Reactant: OCC#Cc1cc(Cl)cc2nc(-c3ccccc3Cl)oc12
Agent: [Ni]
Solvent: CCOC(C)=O
Product: OCCCc1cc(Cl)cc2nc(-c3ccccc3Cl)oc12

Procedure:
A suspension of 11.07 g (34.8 mmol) of 5-chloro-2-(2-chlorophenyl)-7-(3-hydroxy-1-propynyl)-benzoxazole in 120 ml of ethyl acetate was treated with 3.70 g of neutral Raney-nickel. After the hydrogen uptake ceased, the nickel was filtered off and washed, and the solution evaporated in vacuo. Crystallization from dichloromethane/di-isopropyl ether gave the title compound in two crops (6.12 g (54.6%) and 1.61 g (14.4%)), mp 82-4° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([N:11]2[CH2:15][CH2:14][C@@H:13]([OH:16])[CH2:12]2)[S:9][CH:10]=1)=[O:5])[CH3:2].[Si:17](Cl)([C:30]([CH3:33])([CH3:32])[CH3:31])([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.N1C=CN=C1.C(O)C>CN(C)C=O>[Si:17]([O:16][C@@H:13]1[CH2:14][CH2:15][N:11]([C:8]2[S:9][CH:10]=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[N:7]=2)[CH2:12]1)([C:30]([CH3:33])([CH3:32])[CH3:31])([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCOC(=O)c1csc(N2CC[C@@H](O)C2)n1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: CCO
Solvent: CN(C)C=O
Product: CCOC(=O)c1csc(N2CC[C@@H](O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)C2)n1
Reaction time: 0.17 h
Yield: 98.1 %

Procedure:
To a solution of (3R)-1-(4-ethoxycarbonyl-1,3-thiazol-2-yl)-3-hydroxypyrrolidine (3.0 g, 12.4 mmol) (obtained as described in Reference Example 18(2)) in dimethylformamide (90 ml) were added t-butyldiphenylsilyl chloride (6.45 ml, 24.8 mmol) and imidazole (1.69 g, 24.8 mmol) in an ice bath. After stirring the mixture in an ice bath for 10 minutes, the resulting mixture was stirred at room temperature overnight. After checking the completion of the reaction, ethanol (2.59 ml) was added to the reaction mixture in an ice bath and the resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was partitioned between ethyl acetate and 10% aqueous sodium chloride solution. The organic layer was washed successively with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using n-hexane:ethyl acetate (4:1→1:1) as the eluant to afford (3R)-3-t-butyldiphenylsilyloxy-1-(4-ethoxycarbonyl-1,3-thiazol-2-yl)pyrrolidine (5.85 g, yield 90%) as a pale brown solid.
Reaction SMILES: [CH:1]([N:4]([CH3:25])[C@@H:5]1[CH2:10][CH2:9][C@H:8]([NH:11]C(=O)OCC2C=CC=CC=2)[C@H:7]([CH2:22][O:23][CH3:24])[CH2:6]1)([CH3:3])[CH3:2].C(OCC)C>Br.C(O)(=O)C>[CH:1]([N:4]([CH3:25])[C@@H:5]1[CH2:10][CH2:9][C@H:8]([NH2:11])[C@H:7]([CH2:22][O:23][CH3:24])[CH2:6]1)([CH3:3])[CH3:2]
Reactant: COC[C@@H]1C[C@H](N(C)C(C)C)CC[C@@H]1NC(=O)OCc1ccccc1
Agent: Br
Solvent: CC(=O)O
Solvent: CCOCC
Product: COC[C@@H]1C[C@H](N(C)C(C)C)CC[C@@H]1N
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 337.2 %

Procedure:
Benzyl(1S,2R,4R)-4-(isopropyl(methyl)amino)-2-(methoxymethyl)cyclohexylcarbamate (135 mg) was dissolved in 30% HBr in acetic acid (3 ml) and stirred at rt for 45 min. Diethyl ether was added and the resulting gum was isolated, washed with additional ether, stripped four times from benzene and dried under vacuum to provide the dihydrobromide salt of (1R,3R,4S)-N1-isopropyl-3-(methoxymethyl)-N1-methylcyclohexane-1,4-diamine (280 mg) as a gum, used without further purification. MS found: (M+H)+=215.2.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]([NH:15][NH2:16])=[O:14].[CH3:17][O:18][C:19]1[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:20]=1[C:21](O)=O>>[CH3:17][O:18][C:19]1[CH:27]=[C:26]([C:28]([F:29])([F:30])[F:31])[CH:25]=[CH:24][C:20]=1[C:21]1[O:14][C:13]([C:3]2[C:4]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)=[N:5][O:6][C:2]=2[CH3:1])=[N:15][N:16]=1
Reactant: Cc1onc(-c2ccccc2)c1C(=O)NN
Reactant: COc1cc(C(F)(F)F)ccc1C(=O)O
Product: COc1cc(C(F)(F)F)ccc1-c1nnc(-c2c(-c3ccccc3)noc2C)o1
Yield: 50 %

Procedure:
As described for example 2, 5-methyl-3-phenyl-isoxazole-4-carboxylic acid hydrazide (200 mg, 0.92 mmol) was converted using 2-methoxy-4-trifluoromethyl-benzoic acid instead of o-toluic acid to the title compound (SiO2, heptane:ethyl acetate:dichloromethane=70:10:20 to 40:40:20, 185 mg, 50%) which was obtained as a white solid. MS: m/e=402.1 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[C:11]([O:15][C:16](=[O:38])[CH2:17][N:18]1[C:22]2[CH:23]=[CH:24][C:25]([NH:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:26][C:21]=2[N:20]=[C:19]1[CH2:35][CH2:36][CH3:37])([CH3:14])([CH3:13])[CH3:12].CCN(C(C)C)C(C)C>CN(C1C=CN=CC=1)C.C(Cl)Cl.Cl>[C:11]([O:15][C:16](=[O:38])[CH2:17][N:18]1[C:22]2[CH:23]=[CH:24][C:25]([N:27]([CH2:28][C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:6](=[O:7])[C:5]3[CH:9]=[CH:10][C:2]([F:1])=[CH:3][CH:4]=3)=[CH:26][C:21]=2[N:20]=[C:19]1[CH2:35][CH2:36][CH3:37])([CH3:14])([CH3:13])[CH3:12]
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: CCCc1nc2cc(NCc3ccccc3)ccc2n1CC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCc1nc2cc(N(Cc3ccccc3)C(=O)c3ccc(F)cc3)ccc2n1CC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-Fluoro-benzoyl chloride (42 μL, 0.36 mmol) was added to a solution of (5-benzylamino-2-propyl-benzoimidazol-1-yl)-acetic acid tert-butyl ester (45 mg, 0.12 mmol), DIEA (41 μL, 0.24 mmol) and DMAP (15 mg, 0.12 mmol) in CH2Cl2 (1 mL), and stirred overnight at room temperature. The reaction solution was diluted with aqueous HCl (1.0 M) and filtered through an Extrelut column. The Extrelut column was washed with CH2Cl2, and the filtrate was concentrated to afford the subtitle compound that was used without further purification. MS calculated for C30H32FN3O3+H: 502, observed: 502.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]([OH:13])[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:23][C:24]1[CH:32]=[CH:31][C:27]([C:28](Cl)=[O:29])=[CH:26][CH:25]=1>C1(C)C=CC=CC=1>[Cl:23][C:24]1[CH:32]=[CH:31][C:27]([C:28]([O:13][CH:10]2[CH2:9][CH2:8][N:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:15][CH:14]=3)[CH2:12][CH2:11]2)=[O:29])=[CH:26][CH:25]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: OC1CCN(Cc2ccc(Cl)cc2)CC1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=C(OC1CCN(Cc2ccc(Cl)cc2)CC1)c1ccc(Cl)cc1
Yield: 76.9 %

Procedure:
0.226 g (0.001 mol) of 1-(4-chloro-benzyl)-piperidin-4-ol and 0.350 ml (0.0025 mol) of triethylamine were dissolved in 10 ml of toluene, treated with 0.16 ml (0.00125 mol) of 4-chloro-benzoyl chloride and boiled at reflux for 18 hrs. The reaction mixture was concentrated and the residue was chromatographed over silica gel with ethyl acetate/hexane (1:3). 0.28 g (77%) of 1-(4-chloro-benzyl)-piperidin-4-yl 4-chloro-benzoate was obtained as colorless crystals; m.p. 67°-69°.
Reaction SMILES: C(OC(=O)[N:7]([CH2:28][C:29]1[CH:38]=[CH:37][C:32]2[O:33][CH2:34][CH2:35][O:36][C:31]=2[CH:30]=1)[CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([Br:26])[CH:24]=3)[N:19]=[CH:18][C:17]2=[O:27])[CH2:10][CH2:9]1)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)(Cl)Cl>[O:33]1[C:32]2[CH:37]=[CH:38][C:29]([CH2:28][NH:7][CH:8]3[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][N:16]4[C:25]5[C:20](=[CH:21][CH:22]=[C:23]([Br:26])[CH:24]=5)[N:19]=[CH:18][C:17]4=[O:27])[CH2:12][CH2:13]3)=[CH:30][C:31]=2[O:36][CH2:35][CH2:34]1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCN(CCn2c(=O)cnc3ccc(Br)cc32)CC1
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: O=c1cnc2ccc(Br)cc2n1CCN1CCC(NCc2ccc3c(c2)OCCO3)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 71.5 %

Procedure:
To 20 mL of a chloroform solution containing 0.47 g of tert-butyl(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(7-bromo-2-oxoquinoxalin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate, 20 mL of trifluoroacetic acid was added and stirred at room temperature for 12 hours. After solvents of the reaction mixture were removed under reduced pressure and the residue was alkalized by aqueous saturated sodium hydrogen carbonate solution, it was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [Silica Gel; Kanto Chemical Co., Inc., Silica Gel 60N, eluent; chloroform:methanol=10:1], to give 280 mg of 1-(2-(4-((2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)piperidin-1-yl)ethyl)-7-bromoquinoxalin-2(1H)-one as a pale brown foam.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]=[O:18])=[CH:13][N:12]=1)[C:5]#[N:6].C(=O)([O-])[O-:20].[K+].[K+].OO.O>CS(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]=[O:18])=[CH:13][N:12]=1)[C:5]([NH2:6])=[O:20]
Reactant: O=C([O-])[O-]
Reactant: N#Cc1ccc(Oc2ccc(C=O)cn2)c(Br)c1
Agent: OO
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: NC(=O)c1ccc(Oc2ccc(C=O)cn2)c(Br)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 100.5 %

Procedure:
Combine 3-bromo-4-(5-formyl-pyridin-2-yloxy)-benzonitrile (1.60 g, 5.28 mmol) and potassium carbonate (365 mg, 2.64 mmol) in DMSO (40 mL). Cool the reaction mixture at 0° C. Add hydrogen peroxide (1.59 mL, 5.28 mmol) dropwise and let the reaction stir at room temperature for 2 h. Pour into water and triturate to a white solid with stirring. Filter the white solid and dry to give (852 mg, 82%) of the title compound.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[Al+3].[Cl-].[Cl-].[Cl-].[Cl:9][C:10]1[C:18]2[O:17][N:16]=[C:15]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[F:25])[C:14]=2[CH:13]=[CH:12][C:11]=1[O:26][CH2:27][C:28]#[N:29].O>C1COCC1>[Cl:9][C:10]1[C:18]2[O:17][N:16]=[C:15]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[F:25])[C:14]=2[CH:13]=[CH:12][C:11]=1[O:26][CH2:27][C:28]1[NH:29][N:3]=[N:2][N:1]=1
Reactant: [N-]=[N+]=[N-]
Reactant: N#CCOc1ccc2c(-c3ccccc3F)noc2c1Cl
Agent: [Al+3]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Fc1ccccc1-c1noc2c(Cl)c(OCc3nnn[nH]3)ccc12

Procedure:
3.35 g NaN3 and 2.25 g of AlCl3 are stirred in 50 ml THF at reflux for 0.5 hour. A solution of 5 g {[7-chloro-3-(2-fluorophenyl)-1,2-benzisoxazole-6-yl]oxy}acetonitrile, of Example 50, in 50 ml THF is added and the reaction mixture is stirred at reflux for about 120 hours. To the reaction mixture is added water and the solvent is removed. The residue is treated with dilute HCl and extracted with CHCl3. Upon attempted extraction of the chloroform solution with 15% NaOH a precipitate forms which is filtered, dissolved in hot water and acidified to afford 7-chloro-3-(2-fluorophenyl)-6-{[5-tetrazolylmethyl]oxy}-1,2-benzisoxazole, mp 198°-200° C.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][CH:4]([C:7]2[N:12]=[C:11]3[CH2:13][CH2:14][CH2:15][C:10]3=[C:9]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH2:23][C:24]([O:26]CC)=O)=[CH:19][CH:18]=3)[CH:8]=2)[CH2:3]1.[NH3:29]>CO>[OH:1][CH:2]1[CH2:6][CH2:5][CH:4]([C:7]2[N:12]=[C:11]3[CH2:13][CH2:14][CH2:15][C:10]3=[C:9]([NH:16][C:17]3[CH:18]=[CH:19][C:20]([CH2:23][C:24]([NH2:29])=[O:26])=[CH:21][CH:22]=3)[CH:8]=2)[CH2:3]1
Reactant: CCOC(=O)Cc1ccc(Nc2cc(C3CCC(O)C3)nc3c2CCC3)cc1
Reactant: N
Solvent: CO
Product: NC(=O)Cc1ccc(Nc2cc(C3CCC(O)C3)nc3c2CCC3)cc1
Temperature: 100 °C
Reaction time: 23 h
Yield: 25 %

Procedure:
A 10-mL vial was charged with ethyl 2-(4-((2-(3-hydroxycyclopentyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)phenyl)acetate (diastereomer A, 0.022 g, 0.058 mmol), methanol (2 mL) and ammonia (1.7 mL, 7N in methanol, 11.5 mmol). The vial was sealed and the resulting mixture was stirred at 100° C. for 23 h. After this time, LCMS analysis of the cooled reaction showed ˜88% conversion. Additional ammonia (1.0 mL, 7N in methanol, 7.0 mmol) was added and the mixture was heated at 100° C. for 2 h. Then, the cooled reaction mixture was concentrated under reduced pressure. The residue was absorbed on silica (2 g) and purified by chromatography on silica using dichloromethane/(80:20:1 dichloromethane/methanol/conc. NH4OH) (10:0 to 0:10) as eluent to afford the title compound (0.005 g, 25%) as a light brown solid. MW=351.44 1H NMR (DMSO-d6, 500 MHz) δ 7.86 (s, 1H), 7.41 (s, 1H), 7.23-7.19 (m, 2H), 7.12-7.08 (m, 2H), 6.84 (br s, 1H), 6.60 (s, 1H), 4.39 (d, J=4.0 Hz, 1H), 4.25-4.20 (m, 1H), 3.33 (s, 2H), 3.18 (quin, J=6.5 Hz, 1H), 2.78 (t, J=7.5 Hz, 2H), 2.73 (t, J=7.5 Hz, 2H), 2.05-1.88 (m, 4H), 1.83-1.72 (m, 2H), 1.67-1.56 (m, 1H), 1.53-1.45 (m, 1H); APCI m/z 352 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.[Cl:11][C:12]1[C:17]([CH3:18])=[C:16](Cl)[N:15]=[CH:14][N:13]=1.ClC1C(C)=C(C2C=CC(C(F)(F)F)=CC=2)N=CN=1>>[Cl:11][C:12]1[C:17]([CH3:18])=[C:16]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:15]=[CH:14][N:13]=1
Reactant: Cc1c(Cl)ncnc1Cl
Reactant: OB(O)c1ccc(Cl)cc1
Agent: Cc1c(Cl)ncnc1-c1ccc(C(F)(F)F)cc1
Product: Cc1c(Cl)ncnc1-c1ccc(Cl)cc1

Procedure:
Prepared from 4-chlorophenylboronic acid and 4,6-dichloro-5-methylpyrimidine using the procedure described for Intermediate 62.