Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:26][CH2:27][CH2:28][CH3:29])=[C:8]([C:10]2[NH:15][C:14](=[O:16])[C:13]3=[C:17]([CH3:25])[N:18]=[C:19]([CH:20]4[CH2:24][CH2:23][CH2:22][CH2:21]4)[N:12]3[N:11]=2)[CH:9]=1)([O-])=O>O1CCCC1.C(O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([O:26][CH2:27][CH2:28][CH3:29])=[C:8]([C:10]2[NH:15][C:14](=[O:16])[C:13]3=[C:17]([CH3:25])[N:18]=[C:19]([CH:20]4[CH2:24][CH2:23][CH2:22][CH2:21]4)[N:12]3[N:11]=2)[CH:9]=1
Reactant: CCCOc1ccc([N+](=O)[O-])cc1-c1nn2c(C3CCCC3)nc(C)c2c(=O)[nH]1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CCCOc1ccc(N)cc1-c1nn2c(C3CCCC3)nc(C)c2c(=O)[nH]1

Procedure:
Analogously to the procedure of example 42A, 5.13 g (12.96 mmol) of the compound from example 43A are hydrogenated in tetrahydrofuran/ethanol (1:1) using 1.11 g of 10% Pd/C. The product is purified by silica gel chromalography using toluene and ethyl acetate as solvent gradient.
Reaction SMILES: [C:1]1([C:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:8][C:9](Cl)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:24][CH:25]1[CH2:30][CH:29]2[CH2:31][CH2:32][CH:26]1[CH2:27][NH:28]2>>[C:1]1([C:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:8][C:9]([N:28]2[CH2:27][CH:26]3[CH2:32][CH2:31][CH:29]2[CH2:30][CH:25]3[OH:24])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)CC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: OC1CC2CCC1CN2
Product: O=C(CC(c1ccccc1)(c1ccccc1)c1ccccc1)N1CC2CCC1CC2O

Procedure:
Following the procedures set out in Example 1, 1 part of 3,3,3-triphenylpropionyl chloride and 2 parts of 5-hydroxy-2-azabicyclo[2.2.2]octane are reacted to provide 2-(3,3,3-triphenylpropionyl)-5-hydroxy-2-azabicyclo[2.2.2]octane. 0.23 Parts of this material is reacted with 0.05 parts of lithium aluminum hydride in 3.0 parts by volume of ethyl ether to provide 2-(3,3,3-triphenylpropyl)-5-hydroxy-2-azabicyclo[2. 2. 2]octane. This compound, isolated as the hydrochloride salt, has the following structural formula. ##STR42## Administration of this material inhibits diarrhea in animals in need of antidiarrheal treatment.
Reaction SMILES: C(O)(=O)C.Cl[C:6]1[N:11]=[C:10]([CH3:12])[CH:9]=[CH:8][N:7]=1.[Br:13][C:14]1[CH:15]=[C:16]([CH:18]=[C:19]([CH3:21])[CH:20]=1)[NH2:17]>O1CCOCC1>[Br:13][C:14]1[CH:15]=[C:16]([NH:17][C:6]2[N:11]=[C:10]([CH3:12])[CH:9]=[CH:8][N:7]=2)[CH:18]=[C:19]([CH3:21])[CH:20]=1
Reactant: Cc1cc(N)cc(Br)c1
Reactant: Cc1ccnc(Cl)n1
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: Cc1cc(Br)cc(Nc2nccc(C)n2)c1
Temperature: 120 °C
Yield: 100 %

Procedure:
Acetic acid (0.234 mL, 4.08 mmol) was added to 2-chloro-4-methylpyrimidine (0.5 g, 3.89 mmol) and 3-bromo-5-methylaniline (1.096 g, 3.89 mmol) suspended in dioxane (7.78 mL). The reaction was heated to 120° C. overnight. Then, the reaction was cooled to room temperature and was directly purified by column chromatography on silica gel eluting with ethyl acetate/hexanes to give N-(3-bromo-5-methylphenyl)-4-methylpyrimidin-2-amine (1.08 g, 3.89 mmol, quant.) as a white solid. MS ESI: [M+H]+ m/z 278.0 and 280.0.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)=[N:9][CH:10]=[C:4]2[CH:3]=1.C([Li])CCC.[F:23][C:24]([F:38])([F:37])[C:25]([C:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[N:29]([CH3:36])[CH:28]=1)=[O:26]>C1COCC1>[F:38][C:24]([F:23])([F:37])[C:25]([C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)=[N:9][CH:10]=[C:4]2[CH:3]=1)([C:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[N:29]([CH3:36])[CH:28]=1)[OH:26]
Reactant: Cn1cc(C(=O)C(F)(F)F)c2ccccc21
Reactant: Fc1ccc(-c2ncc3cc(Br)ccn23)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cn1cc(C(O)(c2ccn3c(-c4ccc(F)cc4)ncc3c2)C(F)(F)F)c2ccccc21
Reaction time: 0.02 h
Yield: 34.1 %

Procedure:
To a chilled (−78° C.) solution of 7-bromo-3-(4-fluorophenyl)imidazo[1,5-a]pyridine (58 mg, 0.2 mmol) in anhydrous THF (1 mL) was added n-butyllithium (0.1 mL of a 2.5 M solution in hexanes, 2.5 mmol). After 1 minute, a chilled (−78° C.) solution of 2,2,2-trifluoro-1-(1-methyl-1H-indol-3-yl)ethanone (68 mg, 0.3 mmol) in 1 mL of THF was added. After 5 minutes, the reaction mixture was quenched with 50 mL of brine solution and extracted with three 25 mL portions of methylene chloride. The combined organic extracts were washed with water, dried over anhydrous sodium sulfate, and concentrated in vacuo to afford a yellow oil. The residue was purified by column chromatography over silica gel eluting with 0-70% ethyl acetate to afford 30 mg of the title compound as a light yellow solid. MS m/z 440 (MH+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[CH2:16][CH:15]3[CH2:17][N:11]4[CH2:12][CH:13]([CH2:18][CH:9]2[CH2:10]4)[CH2:14]3)[CH:5]=[N:6][CH:7]=1.[O:19]1[CH:23]=[CH:22][CH:21]=[C:20]1B(O)O>>[O:19]1[CH:23]=[CH:22][CH:21]=[C:20]1[C:2]1[CH:3]=[C:4]([N:8]2[CH2:16][CH:15]3[CH2:17][N:11]4[CH2:12][CH:13]([CH2:18][CH:9]2[CH2:10]4)[CH2:14]3)[CH:5]=[N:6][CH:7]=1
Reactant: Brc1cncc(N2CC3CC4CC2CN(C4)C3)c1
Reactant: OB(O)c1ccco1
Product: c1coc(-c2cncc(N3CC4CC5CC3CN(C5)C4)c2)c1

Procedure:
The title compound was prepared from the product of Example 65A and 2-furylboronic acid according to General Method B: LC-MS Method B (ESI+) m/z 296.0 (M+H)+, retention time 1.72 minutes.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)([OH:23])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][CH:11]=[C:10]([O:21][CH3:22])[CH:9]=2)=[O:5])C.[OH-].[Na+]>C1COCC1.C(O)C>[CH:24]1([C:7]2([OH:23])[C:8]3[C:13](=[CH:12][CH:11]=[C:10]([O:21][CH3:22])[CH:9]=3)[C:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[C:6]2[C:4]([OH:5])=[O:3])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]1
Reactant: CCOC(=O)C1=C(c2ccccc2)c2ccc(OC)cc2C1(O)C1CCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1ccc2c(c1)C(O)(C1CCCCC1)C(C(=O)O)=C2c1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 80.7 %

Procedure:
1-Cyclohexyl-1-hydroxy-6-methoxy-3-phenyl-1H-indene-2-carboxylic acid ethyl ester (20 mg, 0.051 mmol) prepared in Example 6 was dissolved in THF, and an excess amount of sodium hydroxide dissolved in aqueous ethanol was added thereto in such a way not to cause layer separation. The mixture was stirred for 24 hrs at RT, and the pH was adjusted to 3˜4 using 2N hydrochloric acid. The resulting mixture was extracted with ethyl acetate. The organic layer was separated, dried over anhydrous MgSO4 and concentrated under a reduced pressure, to obtain 15 mg of the titled compound (yield: 80%).
Reaction SMILES: [CH3:1][N:2]1[C:6](=[S:7])[N:5]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)[C:4](=[O:15])[NH:3]1.[H-].[Na+].[CH3:18][O:19][CH2:20]Br>CN(C=O)C.C(Cl)Cl>[CH3:1][N:2]1[C:6](=[S:7])[N:5]([C:8]2[CH:9]=[CH:10][C:11]([Cl:14])=[CH:12][CH:13]=2)[C:4](=[O:15])[N:3]1[CH2:18][O:19][CH3:20]
Reactant: COCBr
Reactant: Cn1[nH]c(=O)n(-c2ccc(Cl)cc2)c1=S
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COCn1c(=O)n(-c2ccc(Cl)cc2)c(=S)n1C
Reaction time: 0.5 h

Procedure:
To 1-methyl-4-(4-chlorophenyl)-1,2,4-triazolidin-3-one-5-thione (5 g) in 200 ml dry DMF was added 0.91 g sodium hydride. After stirring for 30 minutes, bromomethyl methyl ether (2.63 g) was added dropwise, then heated to reflux for 30 minutes, and stirred overnight at room temperature. The solvent was stripped and the residue was dissolved in methylene chloride, washed with water, and chromatographed on a silica gel column (200 g) by elution with methylene chloride, followed by 2.5% methanol in methylene chloride. Yield: 4.8 g.
Reaction SMILES: C1COCC1.Cl[C:7]1[C:12]([C:13]([F:16])([F:15])[F:14])=[CH:11][C:10]([Cl:17])=[CH:9][N:8]=1.[H-].[Na+].[CH3:20][O:21][N:22]=[C:23]([C:32]1[CH:36]=[C:35]([CH3:37])[O:34][N:33]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH2:30][OH:31]>O>[CH3:20][O:21][N:22]=[C:23]([C:32]1[CH:36]=[C:35]([CH3:37])[O:34][N:33]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH2:30][O:31][C:7]1[C:12]([C:13]([F:16])([F:15])[F:14])=[CH:11][C:10]([Cl:17])=[CH:9][N:8]=1
Reactant: CON=C(c1cc(C)on1)c1ccccc1CO
Reactant: FC(F)(F)c1cc(Cl)cnc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CON=C(c1cc(C)on1)c1ccccc1COc1ncc(Cl)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.3 %

Procedure:
THF (3 ml), 2,5-dichloro-3-trifluoromethylpyridine (0.32 g, 1.5 mmol) and 60% sodium hydride (0.05 g, 1.2 mmol) were added to 2-hydroxymethylphenyl 5-methylisoxazol-3-yl ketone O-methyloxime (0.25 g, 1.0 mmol) under ice-cooling, and the mixture was stirred at room temperature overnight. Water (100 ml) was added to the reaction mixture, and the mixture was extracted with ether (150 ml). The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate/n-hexane) to give 2-(5-chloro-3-trifluoromethyl-2-pyridyloxymethyl)phenyl 5-methylisoxazol-3-yl ketone O-methyloxime (0.41 g, yield: 96.3%) as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[O:9]1[CH2:14][CH2:13]OCC1>>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:14](=[O:9])[C:13]2[CH:8]=[CH:2][CH:3]=[CH:4][C:5]=2[NH2:6])=[CH:4][CH:3]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: C1COCCO1
Product: Nc1ccccc1C(=O)Nc1ccc(Cl)cc1

Procedure:
A mixture of benzoxazine-2,4-dione (1.6 g, 10 mmol) and 4-chloroaniline (2.5 g, 20 mmol) in 1,4-dioxane (30 mL) was heated at reflux for 15 hours. After cooling the solid was filtered, and the filtrate was concentrated, washed with ethyl ether. The washing was concentrated further to a solid. Additional washing with cold ethyl ether (10 mL) afforded N-(4-chlorophenyl)-2-aminobenzamide as a tan solid; NMR (DMSO-d6) 10.1 (s, 1), 7.8 (d, 2), 7.6 (d, 1), 7.4 (d, 2), 7.2 (t, 1), 6.8 (d, 1), 6.6 (t, 1), 6.3 (s, 2) ppm.
Reaction SMILES: [Si:1](Cl)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:19][CH2:20][C:21]1([C@H:24]2[CH2:28][C:27](=[O:29])[N:26]([C@H:30]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH3:31])[CH2:25]2)[CH2:23][CH2:22]1.N1C=CN=C1>CN(C)C=O.C(OCC)(=O)C>[O:19]([CH2:20][C:21]1([C@H:24]2[CH2:28][C:27](=[O:29])[N:26]([C@H:30]([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[CH3:31])[CH2:25]2)[CH2:22][CH2:23]1)[Si:1]([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@@H](c1ccccc1)N1C[C@@H](C2(CO)CC2)CC1=O
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C[C@@H](c1ccccc1)N1C[C@@H](C2(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)CC2)CC1=O
Temperature: 25 °C
Reaction time: 20 h
Yield: 86 %

Procedure:
tert-Butyldiphenylsilyl chloride (2.83 ml, 10.88 mmol) was added to a solution of (3R)-3-[1-(hydroxymethyl)cyclopropan-1-yl]-5-oxo-1-[(1S)-1-phenylethyl]pyrrolidine (2.35 g, 9.06 mmol) and imidazole (925 mg, 13.59 mmol) in N,N-dimethylformamide (30 mL), and the mixture was stirred at room temperature for 20 hours. The reaction solution was diluted with ethyl acetate (150 mL), washed with water (50 mL×2) and brine (50 mL×2), dried over anhydrous sodium sulfate, and then filtered. The solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:19→1:9→1:4→1:1) to give 3.88 g (86%) of the title compound as a colorless transparent gummy solid.
Reaction SMILES: [C:1]1([OH:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.Cl.Cl[CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1.[OH-].[Na+]>C(O)C>[C:1]1([O:11][CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: Oc1cccc2ccccc12
Reactant: ClCCN1CCOCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: c1ccc2c(OCCN3CCOCC3)cccc2c1
Reaction time: 3 h

Procedure:
441 g of 1-naphthol and 648 g of N-(2-chloroethyl)morpholine hydrochloride are initially charged in 2680 ml of ethanol at 50° C. 554 g of 50% aqueous sodium hydroxide are added dropwise within 3 h. Stirring is then continued at 50° C. for 3 h and then for 1 h under reflux.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][CH2:9][C:10]([CH3:25])([S:21]([CH3:24])(=[O:23])=[O:22])[C:11]([NH:13][O:14]C1CCCCO1)=[O:12].Cl>ClCCl.O1CCOCC1>[F:1][C:2]1[CH:3]=[C:4]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][CH2:9][C:10]([CH3:25])([S:21]([CH3:24])(=[O:23])=[O:22])[C:11]([NH:13][OH:14])=[O:12]
Reactant: CC(CCc1ccc(-c2ccccc2)cc1F)(C(=O)NOC1CCCCO1)S(C)(=O)=O
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC(CCc1ccc(-c2ccccc2)cc1F)(C(=O)NO)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 17.5 %

Procedure:
4-(3-Fluorobiphenyl-4-yl)-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide (170 mg, 0.382 mmol) was dissolved in 5 mL of dichloromethane at ambient temperature. To this solution was added 4M HCl (2.86 mL, 11.5 mmol) in dioxane and the solution was stirred at ambient temperature for 5 minutes. The reaction was quenched by the addition of 0.5 mL of methanol. After stirring for an additional 5 minutes, the reaction was concentrated in vacuo. Purification was performed using Shimadzu prep HPLC to provide the title compound (24.4 mg, 14.5%) LC-MS m/z 366.5 (M+1) 1H NMR (400 MHz, METHANOL-d4) δ ppm 1.68 (s, 3H) 2.06-2.16 (m, 1H) 2.53-2.59 (m, 1H) 2.60-2.67 (m, 1H) 2.79-2.89 (m, 1H) 3.06 (s, 3H) 7.30-7.33 (m, 1H) 7.31-7.33 (m, 1H) 7.34-7.37 (m, 1H) 7.38 (d, J=3.12 Hz, 1H) 7.40-7.42 (m, 1H) 7.43-7.46 (m, 2H) 7.58-7.64 (m, 2H)
Reaction SMILES: Cl.[CH2:2]([N:6]1[C:10](CC#N)=[C:9]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:8]=[C:7]1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:3][CH2:4][CH3:5].O.[C:27]([O:30][CH2:31]C)(=[O:29])[CH3:28]>CO>[CH3:31][O:30][C:27](=[O:29])[CH2:28][C:10]1[N:6]([CH2:2][CH2:3][CH2:4][CH3:5])[C:7]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[N:8][C:9]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CCCCn1c(-c2ccccc2)nc(-c2ccccc2)c1CC#N
Reactant: CCOC(C)=O
Agent: Cl
Solvent: CO
Solvent: O
Product: CCCCn1c(-c2ccccc2)nc(-c2ccccc2)c1CC(=O)OC
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
Hydrogen chloride gas is bubbled into solution of (3-butyl-2,5-diphenyl-3H-imidazol-4-yl)-acetonitrile (187) (640 mg, 2.03 mmol) in methanol (30 mL) at 0° C. for 10 minutes, followed by stirring for 30 minutes. Water (0.0365 ml, 2.03 mmol) is then added and the reaction refluxed at 80° C. for 2 hours. The methanol is then removed in vacuo, the reaction crude is dissolved in ethyl acetate (100 mL), and the organic layer is washed with saturated sodium bicarbonate (1×100 mL), brine (1×100 mL), and dried over magnesium sulfate. The sample is filtered, concentrated and purified by flash chromatography on SiO2 using an eluent of 2:3 ethyl acetate:hexane to afford (3-butyl-2,5-diphenyl-3H-imidazol-4-yl)-acetic acid methyl ester (188) as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:17]([O-:19])=[O:18])[CH:5]=[C:6]2[C:11]=1[N:10]([CH2:12][CH2:13][N:14](C)[CH3:15])[CH2:9][CH2:8][CH2:7]2.Cl[C:21]([O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:22]>ClCCl.O.C(=O)([O-])[O-].[K+].[K+]>[F:1][C:2]1[CH:3]=[C:4]([N+:17]([O-:19])=[O:18])[CH:5]=[C:6]2[C:11]=1[N:10]([CH2:12][CH2:13][N:14]([CH3:15])[C:21](=[O:22])[O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:9][CH2:8][CH2:7]2
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CN(C)CCN1CCCc2cc([N+](=O)[O-])cc(F)c21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: CN(CCN1CCCc2cc([N+](=O)[O-])cc(F)c21)C(=O)Oc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.5 %

Procedure:
To a stirred solution of 2-(8-fluoro-6-nitro-3,4-dihydroquinolin-1(2H)-yl)-N,N-dimethylethanamine (500 mg, 1.871 mmol) in Dichloromethane (8 ml) at room temperature was added phenyl chloroformate (0.352 ml, 2.81 mmol) via a syringe dropwise, slowly. The resulting solution was stirred overnight at room temperature. The reaction mixture was then diluted with water and potassium carbonate (dilute) and extracted with dichloromethane (3×). The combined organics were dried, filtered and concentrated, then chromatographed in 0-50% ethyl acetate in hexanes, giving the desired phenyl 2-(8-fluoro-6-nitro-3,4-dihydroquinolin-1(2H)-yl)ethyl(methyl)carbamate (576 mg, 1.543 mmol, 82% yield). 1H NMR (DMSO-d6) δ 7.85-7.76 (m, 1H); 7.75-7.70 (m, 1H); 7.34 (t, J=7 Hz, 1H); 7.22-7.16 (m, 1H); 6.99-6.95 (m, 2H); 3.77-3.65 (m, 3H); 3.60-3.54 (m, 1H); 3.43 (t, J=5.5 Hz, 2H); 3.02, 2.93 (2s, 3H); 2.75 (t, J=5.8, 2H); 1.90-1.81 (m, 2H). ESI-MS (m/z, %): 374 (MH+, 100).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:10]2[N:11]=[C:12]3[N:16]([C:17]=2[C:18]2[CH:23]=[CH:22][N:21]=[C:20]([NH:24][C@@H:25]4[CH2:30][CH2:29][CH2:28][NH:27][CH2:26]4)[N:19]=2)[CH:15]=[CH:14][S:13]3)[CH:7]=[CH:8][CH:9]=1.CCN(C(C)C)C(C)C.[Cl:40][C:41]1[CH:46]=[CH:45][C:44]([S:47](Cl)(=[O:49])=[O:48])=[CH:43][CH:42]=1>C(Cl)Cl>[Cl:40][C:41]1[CH:46]=[CH:45][C:44]([S:47]([N:27]2[CH2:28][CH2:29][CH2:30][C@@H:25]([NH:24][C:20]3[N:19]=[C:18]([C:17]4[N:16]5[C:12]([S:13][CH:14]=[CH:15]5)=[N:11][C:10]=4[C:6]4[CH:7]=[CH:8][CH:9]=[C:4]([O:3][CH3:2])[CH:5]=4)[CH:23]=[CH:22][N:21]=3)[CH2:26]2)(=[O:49])=[O:48])=[CH:43][CH:42]=1
Reactant: COc1cccc(-c2nc3sccn3c2-c2ccnc(N[C@@H]3CCCNC3)n2)c1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc(-c2nc3sccn3c2-c2ccnc(N[C@@H]3CCCN(S(=O)(=O)c4ccc(Cl)cc4)C3)n2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84.6 %

Procedure:
The 4-[6-(3-methoxyphenyl)imidazo[2,1-b][1,3]thiazol-5-yl]-N-[(3R)-piperidin-3-yl]pyrimidin-2-amine hydrochloride (6.81 g, 14.2 mmol) in methylene chloride (DCM) (60 ml) was cooled to 0° C. and was treated with Hunig's base (9.9 ml, 56.8 mmol). The mixture was kept at 0° C. for 30 minutes then the 4-chlorophenylsulfonyl chloride (3.3 g, 15.6 mmol) was added. The reaction mixture was stirred at room temperature overnight. The mixture was diluted with methylene chloride (100 ml) and was washed water (100 ml) and a saturated aqueous sodium chloride solution (100 ml). The organic phase was dried over sodium sulfate and concentrated in vacuo. The crude product was purified by flash chromatography using a gradient (ethyl acetate/hexanes, 40-100%), affording 6.98 g (85%) of the title compound as a pale yellow solid. 400 MHz 1H NMR (DMSO-d6 at 60° C.) δ: 8.42 (br. s, 1H), 8.12 (d, J=5.1 Hz, 1H), 7.8-7.75 (m, 2H), 7.7-7.65 (m, 2H), 7.43-7.39 (m, 1H), 7.36 (d, J=7.8 Hz, 1H), 7.18-7.1 (m, 2H), 7.05-6.98 (m, 1H), 6.42 (d, J=5.1 Hz, 1H), 4.0-3.9 (m, 1H), 3.78 (s, 3H), 3.74 (d, J=11.7 Hz, 1H), 3.48 (d, J=11.7 Hz, 1H), 2.5-2.4 (m, 1H), 2.33 (t, J=5.3 Hz, 1H), 1.95-1.8 (m, 2H), 1.65-1.5 (m, 1H), 1.45-1.4 (m, 1H). LCMS: 581 [M+H].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][N:3]=1.C1C=C(Cl)C=C(C(OO)=[O:18])C=1>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][N+:3]=1[O-:18]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1ccc(Cl)nc1
Solvent: ClCCl
Product: COc1ccc(Cl)[n+]([O-])c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 63.1 %

Procedure:
2-chloro-5-methoxy-pyridine (200 mg, 1.39 mmol) and mCPBA (360 mg, 2.09 mmol) was dissolved in CH2Cl2 (10 ml). The mixture was stirred at room temperature for 2 days. The mixture was then diluted with CH2Cl2 and washed with 10% aqueous K2CO3 and brine and dried over Na2SO4. The solvent were removed in vacuo affording 140 mg (63%) of the title compound as white crystals.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=[C:11]([CH2:19][S:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[C:10]=1[CH3:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:37])C=1.[OH-].[Na+]>ClCCl>[CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=[C:11]([CH2:19][S:20]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:37])[C:10]=1[CH3:28])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCCCCSCc1nc2ccccc2c(OCc2ccccc2)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CCCCCCCS(=O)Cc1nc2ccccc2c(OCc2ccccc2)c1C
Temperature: 25 °C
Reaction time: 5 h
Yield: 68 %

Procedure:
To a solution of 4-(benzyloxy)-2-[(heptylsulfanyl)methyl]-3-methylquinoline (106 mg) in dichloromethane (5 mL) was added m-chloroperbenzoic acid (75%, 68 mg) at −30° C., followed by stirring for 5 hours while warming to room temperature. A 0.2M aqueous sodium hydroxide solution (20 mL) was added to the reaction mixture, followed by extraction with chloroform (50 mL). The organic layer was washed sequentially with water and saturated brine and then dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform/methanol=10/1) to obtain 4-(benzyloxy)-2-[(heptylsulfinyl)methyl]-3-methylquinoline (75 mg).
Reaction SMILES: [O:1]1[C:3]2([CH2:8][CH2:7][N:6](C(OCC3C=CC=CC=3)=O)[CH2:5][CH2:4]2)[CH2:2]1.[NH3:19]>>[NH2:19][CH2:2][C:3]1([OH:1])[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1
Reactant: N
Reactant: O=C(OCc1ccccc1)N1CCC2(CC1)CO2
Product: NCC1(O)CCNCC1

Procedure:
The synthesis of 1-oxa-4,9-diaza-spiro[5.5]undecan-3-ones is described in Scheme 8A (see R. D. Clark, J. M. Caroon, D. B. Repke, A. M. Strosberg, S. M. Bitter, M. D. Okada, A. D. Michel, R. L. Whiting, J. Med. Chem. 1983, 26, 855). N-protected 4-methylenepiperidine epoxides like benzyl 1-oxa-6-aza-spiro[2.5]octane-6-carboxylate are opened by heating with a methanolic solution of ammonia to give the corresponding 4-aminomethyl-4-hydroxypiperidine. The spiro-bicyclic nucleus is formed by the following condensation with chloroacetyl chloride. After removal of the benzyloxycarbonyl group with HBr in acetic acid the spiropiperidine is acylated with 4-cyanobenzoyl chloride. The subsequent steps of alkylation with ω-halogenoalkanoates, formation of the amidine, and cleavage of the ester are carried out as described in the previous Schemes.
Reaction SMILES: [NH2:1][C@@H:2]([C:4]([OH:6])=[O:5])[CH3:3].[CH2:7]([O:14][C:15](Cl)=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[OH-].[Na+]>>[CH2:7]([O:14][C:15]([NH:1][C@@H:2]([C:4]([OH:6])=[O:5])[CH3:3])=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: C[C@@H](N)C(=O)O
Agent: [Na+]
Agent: [OH-]
Product: C[C@@H](NC(=O)OCc1ccccc1)C(=O)O

Procedure:
D-alanine is reacted (12.5 g., 0.14 mol) with 26 g., 0.14 mol + 2 g. excess. of benzyloxycarbonyl chloride and 0.28 mol of sodium hydroxide. The D-alanine is dissolved in one equivalent of sodium hydroxide solution, cooled in ice, and treated slowly with the acid chloride and the second equivalent of sodium hydroxide while maintaining pH 10-12. The reaction is stirred for an additional hour with cooling and is worked up by extraction with ether and acidification of the aqueous solution. A precipitate soon solidifies and is collected and dried; 23.5 g.; m.p. 82°-85° C.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]([N:13]1[C:17]2[N:18]=[C:19]([Cl:22])[N:20]=[CH:21][C:16]=2[C:15](I)=[CH:14]1)([CH3:12])[CH3:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Br:24][C:25]1[CH:26]=[N:27][CH:28]=[C:29]([CH:36]=1)[C:30](N(OC)C)=[O:31]>>[Br:24][C:25]1[CH:36]=[C:29]([C:30]([C:15]2[C:16]3[CH:21]=[N:20][C:19]([Cl:22])=[N:18][C:17]=3[N:13]([C:10]([CH3:12])([CH3:11])[CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[CH:14]=2)=[O:31])[CH:28]=[N:27][CH:26]=1
Reactant: CC(C)(CO[Si](C)(C)C(C)(C)C)n1cc(I)c2cnc(Cl)nc21
Reactant: CON(C)C(=O)c1cncc(Br)c1
Product: CC(C)(CO[Si](C)(C)C(C)(C)C)n1cc(C(=O)c2cncc(Br)c2)c2cnc(Cl)nc21

Procedure:
The title compound was prepared according to the method described for Preparation 28 using 7-(2-{[tert-butyl(dimethyl)silyl]oxy}-1,1-dimethylethyl)-2-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (see Preparation 44) and 5-bromo-N-methoxy-N-methylnicotinamide to afford the title compound as a yellow solid in 42% yield, 1.40 g.