Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[N:21]=[CH:20][CH:19]=[C:18]3[N:25]2[CH2:30][CH2:29][CH2:28][C@H:27]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[CH2:26]2)[N:10]=1)C1C=CC=CC=1>[Pd].CCO.CCOC(C)=O>[O:8]=[C:9]1[NH:10][C:11]([C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[N:21]=[CH:20][CH:19]=[C:18]3[N:25]2[CH2:30][CH2:29][CH2:28][C@H:27]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:36])([CH3:35])[CH3:37])[CH2:26]2)=[N:12][CH:13]=[CH:14]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCN(c2ccnc3ccc(-c4nccc(OCc5ccccc5)n4)cc23)C1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@H]1CCCN(c2ccnc3ccc(-c4nccc(=O)[nH]4)cc23)C1
Reaction time: 12 h
Yield: 87 %

Procedure:
To a solution of (S)-tert-butyl 1-(6-(4-(benzyloxy)pyrimidin-2-yl)quinolin-4-yl)piperidin-3-ylcarbamate (1.0 equiv.) in 4:1 EtOH/EtOAc (0.6 M), was added 10% palladium on carbon (0.2 eq.). The resulting heterogeneous solution was stirred for 12 hours under an atmosphere of hydrogen. The mixture was then filtered through a pad of celite eluting with EtOAc. The volatiles were removed in vacuo yielding (S)-tert-butyl 1-(6-(6-oxo-1,6-dihydropyrimidin-2-yl)quinolin-4-yl)piperidin-3-ylcarbamate (87%). LCMS (m/z): 422.1 (MH+); LC Rt=2.14 min.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH2:9][CH:8]([C:11]([OH:13])=O)[CH2:7][CH2:6]1)=[O:4].[C:14]([O:17][CH2:18][CH3:19])(=[O:16])[CH3:15].C1N=CN(C(N2C=NC=C2)=O)C=1>C1COCC1>[CH3:1][O:2][C:3]([CH:5]1[CH2:6][CH2:7][CH:8]([C:11](=[O:13])[CH2:15][C:14]([O:17][CH2:18][CH3:19])=[O:16])[CH2:9][CH2:10]1)=[O:4]
Reactant: CCOC(C)=O
Reactant: COC(=O)C1CCC(C(=O)O)CC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)C1CCC(C(=O)OC)CC1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
Cyclohexane-1,4-dicarboxylic acid monomethyl ester (26.9 mmol, 5.0 g) and N,N′-carbonyldiimidazole (33.6 mmol, 5.44 g) in anhydrous THF (80 mL) were stirred 16 h at room temperature under argon. In a separate, sealed and argon-flushed flask, lithium HMDS (1.0 M in THF, 56.5 ml) is added to 40 mL anhydrous THF stirring at −78° C. To this solution is added dropwise anhydrous ethyl acetate (57.8 mmol, 5.65 mL). This solution is allowed to stir at −78° C. for 1 hour prior to dropwise addition of original CDI/acid solution that had been stirring overnight. The reaction mixture was allowed to stir and warm to room temperature overnight. The reaction is then quenched with saturated NH4Cl(aq) (200 mL) and extracted with Et2O (100×2). The combined organics are then washed with water, saturated brine, and dried over Na2SO4. The solvent was removed in vacuo and the crude residue (8.5 g) was used in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[C:8]([OH:9])=[CH:7][CH:6]=[CH:5][C:3]=1[OH:4].C(O)(=O)[CH:11]([CH2:13][C:14](O)=O)[OH:12]>S(=O)(=O)(O)O>[OH:4][C:3]1[C:2]([CH3:1])=[C:8]2[C:7]([CH:14]=[CH:13][C:11](=[O:12])[O:9]2)=[CH:6][CH:5]=1
Reactant: O=C(O)CC(O)C(=O)O
Reactant: Cc1c(O)cccc1O
Agent: O=S(=O)(O)O
Product: Cc1c(O)ccc2ccc(=O)oc12
Temperature: 80 °C
Reaction time: 24 h
Yield: 20.64 %

Procedure:
2-methyl resorcinol (0.161 mmol, 20.024 g) and malic acid (0.165 mmol, 22.129 g) were dissolved in concentrated sulfuric acid. The reaction mixture was stirred at 80° C. for 24 h. The resulting solution was then poured over crushed ice, and the precipitate was collected by vacuum filtration. The precipitate was then washed with 5% NaHCO3 and again collected by vacuum filtration yielding an orange-yellow solid in a 20.64% yield.
Reaction SMILES: O.O.O.O.O.[OH-].C[N+](C)(C)C.CN(C=O)C.[C:17]([OH:20])(=[O:19])[CH3:18].[CH2:21]([O:23][C:24]([C:26]1[CH:31]=[CH:30][C:29]([C:32]2[CH:37]=[CH:36][C:35]([O:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50]Br)=[CH:34][CH:33]=2)=[CH:28][CH:27]=1)=[O:25])[CH3:22]>CCOCC>[CH2:21]([O:23][C:24]([C:26]1[CH:31]=[CH:30][C:29]([C:32]2[CH:37]=[CH:36][C:35]([O:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][O:20][C:17](=[O:19])[CH3:18])=[CH:34][CH:33]=2)=[CH:28][CH:27]=1)=[O:25])[CH3:22]
Reactant: CCOC(=O)c1ccc(-c2ccc(OCCCCCCCCCCCCBr)cc2)cc1
Reactant: CC(=O)O
Agent: C[N+](C)(C)C
Agent: [OH-]
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1ccc(-c2ccc(OCCCCCCCCCCCCOC(C)=O)cc2)cc1
Reaction time: 1 h
Yield: 66.9 %

Procedure:
60 m moles (10.9 g) of tetramethylammonium hydroxide pentahydrate was added to a DMF solution of 60 m moles (3.6 g) of acetic acid, and stirred for one hour, then 50 m moles (24.5 g) of the above 4'-(12-bromododecyloxy)biphenyl-4-carboxylic acid ethyl ester was added thereto, and stirred for 12 hours. After the reaction, the reaction solution was ether extracted. The extrate was concentrated, and then purified by column chromatography, to obtain 15.7 g of 4'-(12-acetyloxydodecyloxy)biphenyl-4-carboxylic acid ethyl ester [m.p. 80.1°-81.5° C⟧ (yield: 67%)
Reaction SMILES: [CH:1](=[N:8][C:9]1[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[Li].BrC1C=CC=CN=1>CCOCC>[N:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH:1]([NH:8][C:9]1[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C(=Nc1ccncc1)c1ccccc1
Reactant: [Li]c1ccccn1
Agent: Brc1ccccn1
Solvent: CCOCC
Product: c1ccc(C(Nc2ccncc2)c2ccccn2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 34.7 %

Procedure:
4.55 Grams (0.025 mole) of 4-benzylideneaminopyridine in 50 milliliters of dry ether was added dropwise to a stirred solution of 2-pyridyl lithium (prepared from 0.03 mole of butyl lithium and 4.74 grams [0.03 mole] of 2-bromopyridine) in 100 ml. of hexane-ether cooled to -30° C. under nitrogen. A purple precipitate was formed which was stirred for 4 hours while allowing the product to warm up to room temperature. The mixture was poured onto ice and the organic layer was separated and extracted with 2 N hydrochloric acid. The acid extracts were combined with the aqueous layer and the combined aqueous medium was basified with 5 N sodium hydroxide and extracted into dichloromethane. After drying over magnesium sulphate, the solvent was removed to leave a solid which was recrystallized from a mixture of toluene and light petroleum (b.p. 100°-120° C.) to afford 2.27 grams of the title compound as free base, m.p. 114°-115° C. The base was converted to its colourless dihydrobromide salt, m.p. 230° (decomposition), by dissolution in the minimum quantity of 2-propanol and adding a solution of hydrogen bromide in dry ether.
Reaction SMILES: [BH4-].[Na+].[CH:3]([C:5]1[N:6]([C:10]2[CH:11]=[C:12]([CH:17]=[CH:18][C:19]=2[OH:20])[C:13]([O:15][CH3:16])=[O:14])[CH:7]=[CH:8][CH:9]=1)=[O:4].C(OCC)(=O)C.Cl>O1CCCC1.O>[OH:20][C:19]1[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][C:10]=1[N:6]1[CH:7]=[CH:8][CH:9]=[C:5]1[CH2:3][OH:4]
Reactant: COC(=O)c1ccc(O)c(-n2cccc2C=O)c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1ccc(O)c(-n2cccc2CO)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84 %

Procedure:
Sodium borohydride (0.46 g) was added to a solution of methyl 3-(2-formylpyrrol-1-yl)-4-hydroxybenzoate (3.0 g) in tetrahydrofuran (30 ml) and the mixture was stirred for 1 hour at ambient temperature. The reaction mixture was added to the mixture of ethyl acetate and water and adjusted to pH 7.5 with 6N-hydrochloric acid. The separated organic layer was washed with water, dried over magnesium sulfate and evaporated in vacuo to give methyl 4-hydroxy-3-(2-hydroxymethylpyrrol-1-yl)benzoate (2.54 g).
Reaction SMILES: Cl[CH2:2][CH:3]=[O:4].[N:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11][C:12](=[S:14])[S-:13].C([NH+](CC)CC)C>CN(C)C=O>[OH:4][CH:3]1[CH2:2][S:14][C:12](=[S:13])[N:11]1[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][N:5]=1
Reactant: O=CCCl
Reactant: S=C([S-])Nc1ccccn1
Agent: CC[NH+](CC)CC
Solvent: CN(C)C=O
Product: OC1CSC(=S)N1c1ccccn1
Temperature: 2 °C
Reaction time: 16 h
Yield: 34.8 %

Procedure:
A 50% by weight aqueous solution of chloroacetaldehyde (37.7 g) is added at 10° C., to a solution of triethylammonium pyrid-2-yldithiocarbamate (65.4 g) in dimethylformamide (300 cc). The reaction is allowed to proceed for 16 hours at 20° C. After evaporating off the solvents under pressure (0.1 mm Hg) at 50° C., the residual oil is treated with chloroform (750 cc). The chloroform solution is washed twice with distilled water (200 cc in total), dried over sodium sulphate and evaporated. The oily residue (38 g) is dissolved in boiling ethanol (180 cc), and boiling isopropyl ether (180 cc) and decolourising charcoal (1 g) are added. After filtering the boiling solution and then cooling for 2 hours at 2° C., the crystals which have appeared are filtered off, washed with an ice-cooled mixture (50 cc in total) of ethanol (25 cc) and isopropyl ether (25 cc) and dried under reduced pressure (0.1 mm Hg) at 45° C. 4-Hydroxy-3-(pyrid-2-yl)thiazolidine-2-thione (17.8 g), which melts at 110° C., is thus obtained.
Reaction SMILES: FC(F)(F)C([O-])=O.[CH3:8][O:9][P:10]([CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)(=[O:13])[O:11][CH3:12].C(N(C(C)C)CC)(C)C.[CH:31]([O:44][C:45]1[C:54]2[N:53]=[CH:52][CH:51]=[CH:50][C:49]=2[C:48]([C:55](O)=[O:56])=[C:47]2[CH2:58][N:59]([CH2:62][C:63]3[CH:68]=[CH:67][C:66]([F:69])=[CH:65][CH:64]=3)[C:60](=[O:61])[C:46]=12)([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CCOC(C)=O>[CH3:12][O:11][P:10]([CH2:14][CH2:15][N:16]1[CH2:17][CH2:18][N:19]([C:55]([C:48]2[C:49]3[CH:50]=[CH:51][CH:52]=[N:53][C:54]=3[C:45]([O:44][CH:31]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)=[C:46]3[C:60](=[O:61])[N:59]([CH2:62][C:63]4[CH:64]=[CH:65][C:66]([F:69])=[CH:67][CH:68]=4)[CH2:58][C:47]=23)=[O:56])[CH2:20][CH2:21]1)(=[O:13])[O:9][CH3:8]
Reactant: O=C(O)c1c2c(c(OC(c3ccccc3)c3ccccc3)c3ncccc13)C(=O)N(Cc1ccc(F)cc1)C2
Reactant: COP(=O)(CCN1CCNCC1)OC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])C(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COP(=O)(CCN1CCN(C(=O)c2c3c(c(OC(c4ccccc4)c4ccccc4)c4ncccc24)C(=O)N(Cc2ccc(F)cc2)C3)CC1)OC
Yield: 72.8 %

Procedure:
To a solution of the trifluoroacetate salt of (2-piperazin-1-yl-ethyl)-phosphonic acid dimethyl ester 187 (0.023 g, 0.077 mmol) in 1 ml DMF was added diisopropylethylamine (33 μL, 0.192 mmol). This mixture was added to a solution of 9-benzhydryloxy-7-(4-fluoro-benzyl)-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g]quinoline-5-carboxylic acid 213 (0.020 g, 0.038 mmol) that had been mixed with HATU (0.0293 g, 0.077 mmol) in 1 ml of DMF. The reaction was stirred at rt under inert atmosphere for 3 h, at which time TLC in 100% EtOAc showed complete consumption of starting material. The reaction mixture was introduced directly onto silica gel (99/1 EtOH/Et3N) to give 20 mg of (2-{4-[9-benzhydryloxy-7-(4-fluoro-benzyl)-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g]quinoline-5-carbonyl]-piperazin-1-yl}-ethyl)-phosphonic acid dimethyl ester 291 after flash chromatography.
Reaction SMILES: [NH3:1].[F:2][C:3]1[CH:8]=[C:7]([N:9]=[C:10]=[S:11])[CH:6]=[CH:5][C:4]=1[N:12]1[C:16]([CH3:17])=[N:15][CH:14]=[N:13]1>>[F:2][C:3]1[CH:8]=[C:7]([NH:9][C:10]([NH2:1])=[S:11])[CH:6]=[CH:5][C:4]=1[N:12]1[C:16]([CH3:17])=[N:15][CH:14]=[N:13]1
Reactant: N
Reactant: Cc1ncnn1-c1ccc(N=C=S)cc1F
Product: Cc1ncnn1-c1ccc(NC(N)=S)cc1F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 93.9 %

Procedure:
Step C (4): Methanolic ammonia (1.0 M, 100 mL, 100 mmol) was added to a flask charged with 1-(2-fluoro-4-isothiocyanatophenyl)-5-methyl-1H-1,2,4-triazole (3.18 g, 13.6 mmol) in a ice-water bath. After the addition was complete, the resulting slurry was stirred for 10 min and then allowed to warm to rt. After 24 h, the reaction mixture was concentrated in vacuo. The resulting solid was dried under high vacuum to afford 1-(3-fluoro-4-(5-methyl-1H-1,2,4-triazol-1-yl)phenyl)thiourea (3.21 g, 94% yield) as an off-white solid. LC-MS (M+H)+ 252.1. 1H NMR (500 MHz, DMSO-d6) δ ppm 8.06 (s, 1 H), 7.93 (dd, J=12.8, 2.1 Hz, 1 H), 7.54 (t, J=8.7 Hz, 1 H), 7.37 (dd, J=8.5, 1.8 Hz, 1 H), 2.32 (s, 3 H)
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:16])[N:4]([CH2:13][CH2:14][CH3:15])[C:5](=[O:12])[N:6]([CH2:9][CH2:10][CH3:11])[C:7]=1[NH2:8].[O:17]1[C:22]2[CH:23]=[CH:24][C:25]([CH:27]=[CH:28][C:29](O)=O)=[CH:26][C:21]=2[O:20][CH2:19][CH2:18]1>>[O:17]1[C:22]2[CH:23]=[CH:24][C:25](/[CH:27]=[CH:28]/[C:29]3[NH:1][C:2]4[C:3](=[O:16])[N:4]([CH2:13][CH2:14][CH3:15])[C:5](=[O:12])[N:6]([CH2:9][CH2:10][CH3:11])[C:7]=4[N:8]=3)=[CH:26][C:21]=2[O:20][CH2:19][CH2:18]1
Reactant: CCCn1c(N)c(N)c(=O)n(CCC)c1=O
Reactant: O=C(O)C=Cc1ccc2c(c1)OCCO2
Product: CCCn1c(=O)c2[nH]c(/C=C/c3ccc4c(c3)OCCO4)nc2n(CCC)c1=O
Yield: 65.2 %

Procedure:
Substantially the same procedure as in Reference Example 1 was repeated using 1.35 g (5.96 mmol) of 5,6-diamino-1,3-dipropyluracil and 1.35 g (6.55 mmol) of 3-(1,4-benzodioxan-6-yl)acrylic acid. Then, the resultant crude crystals were recrystallized from ethanol/water to give 1.54 g (yield 65%) of Compound 17 as white needles.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]([C:5]1[N:9]2[CH:10]=[CH:11][CH:12]=[C:13]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][N:19]3[C:23](=[O:24])[CH2:22][S:21][C:20]3=[O:25])[C:8]2=[N:7][CH:6]=1)=[O:4].[CH:28](=O)[CH2:29][CH2:30][CH3:31].N1CCCCC1>C(O)C>[CH:28](=[C:22]1[S:21][C:20](=[O:25])[N:19]([CH2:18][CH2:17][CH2:16][CH2:15][O:14][C:13]2[C:8]3[N:9]([C:5]([C:3](=[O:4])[C:2]([F:1])([F:26])[F:27])=[CH:6][N:7]=3)[CH:10]=[CH:11][CH:12]=2)[C:23]1=[O:24])[CH2:29][CH2:30][CH3:31]
Reactant: O=C1CSC(=O)N1CCCCOc1cccn2c(C(=O)C(F)(F)F)cnc12
Reactant: CCCC=O
Solvent: CCO
Solvent: C1CCNCC1
Product: CCCC=C1SC(=O)N(CCCCOc2cccn3c(C(=O)C(F)(F)F)cnc23)C1=O

Procedure:
To a solution of 271 mg (0.69 mmol) of 3-[4-(3-trifluoroacetylimidazo[1,2-a]pyridin-8-yloxy)butyl]thiazolidine-2,4-dione and 69 μl (0.69 mmol) of n-butyraldehyde in 5 ml of ethanol, 7 μl (0.07 mmol) of piperidine was added, followed by refluxing for 1 hour. After the reaction mixture was cooled, the solvent was distilled off. The residue was dissolved in chloroform, washed with water and dried, after which the solvent was distilled off. The residue was purified by column chromatography (eluent, n-hexane/ethyl acetate=2/1) to yield 250 mg (79.7%, light yellow oily substance) of the desired product.
Reaction SMILES: [CH2:1]([NH:4][CH2:5][CH:6]([OH:8])[CH3:7])[CH2:2][CH3:3].[C:9]([Si:13](Cl)([CH3:15])[CH3:14])([CH3:12])([CH3:11])[CH3:10].O>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Si:13]([O:8][CH:6]([CH3:7])[CH2:5][NH:4][CH2:1][CH2:2][CH3:3])([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:15])[CH3:14]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CCCNCC(C)O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: O
Product: CCCNCC(C)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 1-(propylamino)propan-2-ol (8.00 g, 68.3 mmol), tert-butylchlorodimethylsilane (10.9 g, 72.4 mmol), and catalytic amount of DMAP in CH2Cl2 (68 mL) at 0° C. was added dropwise TEA (9.61 ml, 68.3 mmol). The reaction mixture was warmed to room temperature and stirred for 20 h. Additional 1 mL of TEA was added and stirred for additional 20 h. Water (60 mL) was added. The layers were separated. The aqueous layer was extracted with EtOAc (1×). The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure to give the crude material that was filtered again to afford quantitatively 2-(tert-butyldimethylsilyloxy)-N-propylpropan-1-amine that was used directly without further purification.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[F:18][C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21](Cl)=[O:22]>>[F:18][C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21]([NH:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1)=[O:22]
Reactant: O=C(Cl)c1ccccc1F
Reactant: CN1CCC(c2c[nH]c3ccc(N)nc23)CC1
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)c4ccccc4F)nc23)CC1
Yield: 81.5 %

Procedure:
Beginning with 0.085 gm (0.369 mMol) 5-amino-3-(1-methylpiperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.093 mL (0.776 mMol) 2-fluorobenzoyl chloride, 0.106 gm (82%) of the title compound was recovered as a crystalline solid by the procedure described in Example 16.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.Cl.C=O.[C:11]([O-])(=O)C.[Na+].[CH3:16][N:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[C:18]1[CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=1>C(OCC)(=O)C>[CH3:16][N:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]([CH2:11][N:5]2[CH2:6][CH2:7][CH:2]([CH3:1])[CH2:3][CH2:4]2)=[C:18]1[CH2:26][O:27][C:28]1[CH:29]=[CH:30][C:31]([Cl:34])=[CH:32][CH:33]=1
Reactant: CC(=O)[O-]
Reactant: Cn1c(COc2ccc(Cl)cc2)cc2ccccc21
Reactant: CC1CCNCC1
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CC1CCN(Cc2c(COc3ccc(Cl)cc3)n(C)c3ccccc23)CC1

Procedure:
Under a nitrogen atmosphere 4-methylpiperidine (0.109 ml, 0.09 g, 0.92 mmol), dissolved in 2.0 ml of ethyl acetate, was added to a round bottom flask which was then placed in an ice bath. Concentrated hydrochloric acid (0.084 ml) was then added and the reaction mixture was removed from the ice bath. To the reaction mixture were added formaldehyde (0.304 g, 1.01 mmol), sodium acetate (0.113 g, 1.38 mmol), and 1-methyl-2-(4-chlorophenoxymethyl)-1H-indole (0.250 g, 0.92 mmol). The resulting mixture was then heated to reflux and maintained at this temperature overnight. The progress of the reaction was monitored by thin layer chromatography.
Reaction SMILES: [Cl-].[Cl-].[Ca+2:3].[Na].[CH3:5][O:6][C:7]1[CH:28]=[CH:27][C:10]2[NH:11][C:12]([S:14]([CH2:16][C:17]3[C:22]([CH3:23])=[C:21]([O:24][CH3:25])[C:20]([CH3:26])=[CH:19][N:18]=3)=[O:15])=[N:13][C:9]=2[CH:8]=1>O>[CH3:26][C:20]1[CH:19]=[N:18][C:17]([CH2:16][S+:14]([O-:15])[C:12]2[NH:11][C:10]3[CH:27]=[CH:28][C:7]([O:6][CH3:5])=[CH:8][C:9]=3[N:13]=2)=[C:22]([CH3:23])[C:21]=1[O:24][CH3:25].[Ca:3]
Reactant: [Ca+2]
Reactant: COc1ccc2[nH]c(S(=O)Cc3ncc(C)c(OC)c3C)nc2c1
Agent: [Cl-]
Agent: [Na]
Solvent: O
Product: COc1ccc2[nH]c([S+]([O-])Cc3ncc(C)c(OC)c3C)nc2c1
Product: [Ca]
Reaction time: 1 h
Yield: 0.2 %

Procedure:
Anhydrous CaCl2 (17.9 g, 0.161 mol) dissolved in deionized water (200 ml) was added dropwise under viogorous stirring to a solution of omeprazole sodium salt (125 g, 0.340 mole) in deionized water (1250 ml) and then stirring was continued for 1 h at room temperature. The precipitate was centrifuged down and washed with deionized water until no Cl- was detectable (AgNO3). After drying in the air and grinding, the crystals were dried in vacuum at 40° for 20 h yielding omeprazole calcium salt dihydrate (104 mg, 80%), mp 182°-184° C., NMR: δ(CDCl3 1 drop of DMSO-d6) 2.0(s, 3H), 2.15(s, 3H), 3.6(s, 3H), 3.7(s, 3H), 4.5(s, 2H), 6.7(dd, 1H), 7.1(d, 1H), 7.6(d, 1H, 8.15(s, 1H).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH:12]2[OH:24])=[CH:7][CH:6]=1)[CH:2]=[CH2:3].Cl[CH2:26][C:27]1[CH:36]=[C:35]2[C:30]([CH2:31][CH2:32][C:33](=[O:42])[N:34]2[CH2:37][CH2:38][CH2:39][O:40][CH3:41])=[CH:29][CH:28]=1>>[CH2:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH:12]2[O:24][CH2:26][C:27]2[CH:36]=[C:35]3[C:30]([CH2:31][CH2:32][C:33](=[O:42])[N:34]3[CH2:37][CH2:38][CH2:39][O:40][CH3:41])=[CH:29][CH:28]=2)=[CH:9][CH:10]=1)[CH:2]=[CH2:3]
Reactant: COCCCN1C(=O)CCc2ccc(CCl)cc21
Reactant: C=CCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2O)cc1
Product: C=CCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCc2ccc3c(c2)N(CCCOC)C(=O)CC3)cc1

Procedure:
Analogously to Method D, 3.26 g of tert-butyl 4-(4-allyloxyphenyl)-3-hydroxypiperidine-1-carboxylate and 2.62 g of 7-chloromethyl-1-(3-methoxypropyl)-3,4-dihydro-1H-quinolin-2-one are reacted. The title compound is obtained as a slightly yellowish oil. Rf=0.16 (1:1 EtOAc-heptane); Rt=5.50.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[CH:10]=[CH:11][C:12]3[O:17][CH:16](O)[CH2:15][CH2:14][C:13]=3[CH:19]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:20]([CH:25]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:22][CH2:23][CH3:24])=[O:21]>C1(C)C=CC=CC=1>[CH2:23]([O:22][C:20](=[O:21])[CH2:25][CH:16]1[CH2:15][CH2:14][C:13]2[CH:19]=[C:9]([O:8][CH2:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH:10]=[CH:11][C:12]=2[O:17]1)[CH3:24]
Reactant: OC1CCc2cc(OCc3ccccc3)ccc2O1
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: CCOC(=O)CC1CCc2cc(OCc3ccccc3)ccc2O1
Yield: 74.2 %

Procedure:
A solution of 1.8 g of racemic-3,4-dihydro-6-(phenylmethoxy)-2H-1-benzopyran-2-ol and 2.6 g of (carbethoxymethylene)triphenylphosphorane in 20 ml of toluene was stirred and refluxed for 22 hours. The solution was cooled and placed on a column of 50 g of silica gel packed in toluene. Elution with toluene and 19:1 toluene-ethyl acetate gave 1.7 g (74.2%) of racemic-3,4-dihydro-6-(phenylmethoxy)-2H-1-benzopyran-2-acetic acid ethyl ester as a pale-yellow oil. This material was dissolved in 25 ml of absolute ethanol and the solution was stirred in the presence of 0.2 g of 10% palladium on carbon, at room temperature, in an atmosphere of hydrogen. After 1.5 hours, hydrogen uptake ceased and the catalyst was removed by filtration. The filtrate was concentrated in vacuo to give 1.2 g (97.6%) of racemic-3,4-dihydro-6-hydroxy-2H-1-benzopyran-2-acetic acid ethyl ester as a pale-yellow oil.
Reaction SMILES: [CH3:1][N:2]([CH3:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[F:10][C:11](I)([C:16](F)(F)[F:17])[C:12]([F:15])([F:14])[F:13].C([O-])(O)=O.[Na+].NC1C=CC=CC=1>O.CN(C)C=O>[F:17][CH2:16][C:11]([F:10])([C:6]1[CH:7]=[CH:8][C:3]([N:2]([CH3:9])[CH3:1])=[CH:4][CH:5]=1)[C:12]([F:15])([F:14])[F:13]
Reactant: CN(C)c1ccccc1
Reactant: FC(F)(F)C(F)(I)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Nc1ccccc1
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)c1ccc(C(F)(CF)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-(Pentafluoroisopropyl)-N,N-dimethylaniline was prepared as follows. A flask was charged with N,N-dimethylaniline (10.2 g), perfluoroisopropyl iodide (25 g), N,N-dimethyl formamide (35 mL) and water (15 mL). To the flask was slowly added a mixture of NaS2O4 (17.5 g) and NaHCO3 (8.5 g). The reaction started immediately when the mixture of NaS2O4/NaHCO3 was introduced, thus the flask was cooled with an ice-water bath. After addition, the mixture was stirred at room temperature overnight. The mixture was poured into 200 mL water. The mixture was then extracted with diethyl ether (4×50 mL). The ether solution was dried over MgSO4. The ether was removed under reduced pressure to give a crude mixture of ortho- and para-substituted perfluoroisopropyl aniline and a bit of the starting aniline (10.0 g). The higher boiling point liquid was distilled to produce a fraction at 38-45° C. (at 0.05 mm Hg) (a mixture of para- and ortho-substituted products as a yellow liquid, 5.5 g). and a fraction at 45-48° C. (at 0.05 mm Hg) (para-substituted perfluoroisopropyl-N,N-dimethylaniline, 3.8 g). The liquid was sampled and analyzed by 1H and 19F NMR. 1H NMR: δ7.35 (d, 2H, J=8 Hz), 6.64 (d, 2H, J=8 Hz), 2.94 (s, 6H); 19F NMR: δ−75.3 (6F), −174.2 (F).