Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([C:11]([C:16]2[CH:21]=[CH:20][C:19]([O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])=[C:18]([CH3:30])[CH:17]=2)([CH2:14][CH3:15])[CH2:12][CH3:13])=[CH:8][C:9]=1[CH3:10])=O.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[C:26]([Si:23]([CH3:25])([CH3:24])[O:22][C:19]1[CH:20]=[CH:21][C:16]([C:11]([C:7]2[S:6][C:5]([CH2:3][OH:2])=[C:9]([CH3:10])[CH:8]=2)([CH2:14][CH3:15])[CH2:12][CH3:13])=[CH:17][C:18]=1[CH3:30])([CH3:28])([CH3:27])[CH3:29]
Reactant: CCC(CC)(c1ccc(O[Si](C)(C)C(C)(C)C)c(C)c1)c1cc(C)c(C(=O)OC)s1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCC(CC)(c1ccc(O[Si](C)(C)C(C)(C)C)c(C)c1)c1cc(C)c(CO)s1
Temperature: 25 °C
Yield: 74.7 %

Procedure:
To a 0° C. solution of 5-{1-[4-(tert-butyl-dimethyl-silanyloxy)-3-methyl-phenyl]-1-ethyl-propyl}-3-methyl-thiophene-2-carboxylic acid methyl ester (10.0 g, 22.39 mmol) in THF (200 ml) is added portionwise lithium aluminum hydride (1.70 g, 44.78 mmol) and the reaction mixture is warmed to RT for 1 h. The reaction is quenched with water (1.7 ml), 5N NaOH (1.7 ml), and water (5.1 ml). The reaction mixture is filtered, concentrated and chromatographed (120 g SiO2, 10% EtOAc/Hex) to yield the title compound (7.0 g, 75%).
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].FC(F)(F)S(O[C:13]1[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH:18]=1)(=O)=O.[C:28]([NH:31][C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][CH:37]=1)(=[O:30])[CH3:29]>C(COC)OC>[C:28]([NH:31][C:32]1[CH:37]=[C:36]([C:13]2[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH:18]=2)[CH:35]=[CH:34][CH:33]=1)(=[O:30])[CH3:29]
Reactant: CC(=O)Nc1cccc(B(O)O)c1
Reactant: CC(C)(C)OC(=O)N1CC=C(OS(=O)(=O)C(F)(F)F)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(=O)Nc1cccc(C2=CCN(C(=O)OC(C)(C)C)CC2)c1

Procedure:
A mixture of saturated of aqueous Na2CO3 solution (25 mL), tert-butyl 4-{[(trifluoromethyl)sulfonyl]oxy}-1,2,3,6-tetrahydro-1-pyridine-carboxylate (20 mmol), 3-acetamidophenylboronic acid (30 mmol) and tetrakis-triphenylphosphine palladium (0) (1.15 g) and dimethoxyethane (40 mL) was heated at reflux temperature overnight. The organic layer of the cooled reaction mixture was separated and the aqueous layer was washed with ethyl acetate (3×). The combined organic extracts were dried and concentrated in vacuo. The crude product was chromatograghed, giving the desired product 1H NMR δ 8.11 (br s, 1 H), 7.57 (br s, 1 H), 7.41 (br d, 1 H, J=7.8 Hz), 7.25 (apparent t, 1 H, J=7.8 Hz), 7.08 (br d, 1 H, J=7.8 Hz), 5.99 (b s, 1 H), 4.03 (br m, 2 H, J=2.7 Hz), 3.59 (t, 2 H, J=5.7 Hz), 2.46 (m, 2 H,), 2.16 (s, 3 H), 1.49 (s, 9 H).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[C:5]([CH2:13][C:14](OC)=[O:15])[C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2.[H-].C([Al+]CC(C)C)C(C)C>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[N:4]=[C:5]([CH2:13][CH:14]=[O:15])[C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2
Reactant: COC(=O)Cc1nc(OC)cc2ccccc12
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Product: COc1cc2ccccc2c(CC=O)n1
Reaction time: 1 h

Procedure:
To 1 part of methyl 3-methoxy-2-azanaphthaleneacetate in 25 parts by volume of toluene at -78° C is slowly added 0.33 part of diisobutylaluminum hydride in toluene. The reaction is stirred for 1 hour and allowed to come to room temperature. The reaction is quenched with ethylacetate followed by ice water. The organic layer is washed with saturated sodium chloride, dried with anhydrous sodium sulfate, and 3-methoxy-2-azanaphthaleneacetaldehyde is isolated. This compound has the following structural formula ##SPC24##
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][CH:10]([C:13]([OH:16])([CH3:15])[CH3:14])[CH2:9]1)C1C=CC=CC=1.[H][H]>[Pd].CCO>[NH:8]1[CH2:12][CH2:11][CH:10]([C:13]([OH:16])([CH3:15])[CH3:14])[CH2:9]1
Reactant: CC(C)(O)C1CCN(Cc2ccccc2)C1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC(C)(O)C1CCNC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A pressure vessel was charged with 2-(1-benzylpyrrolidin-3-yl)propan-2-ol (1.013 g, 4.62 mmol), palladium, 10 wt. % (dry basis) on activated carbon (wet) (0.904 g, 0.425 mmol) and EtOH (20 mL). The reaction vessel was pressurized (50 psi) with hydrogen and purged 3 times. The vessel was pressurized at 50 psi and allowed to stir overnight at rt. The reaction was filtered and the filtrate was concentrated to dryness.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[C:14](=[O:18])[CH2:13][CH2:12]3)O1.Br[C:21]1[S:22][CH:23]=[CH:24][N:25]=1>COCCOC>[S:22]1[CH:23]=[CH:24][N:25]=[C:21]1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[C:14](=[O:18])[CH2:13][CH2:12]2
Reactant: CC1(C)OB(c2ccc3c(c2)CCC3=O)OC1(C)C
Reactant: Brc1nccs1
Solvent: COCCOC
Product: O=C1CCc2cc(-c3nccs3)ccc21
Reaction time: 8 h

Procedure:
5-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)indan-1-one (SM-1a, 350 mg, 0.95 mmol) and 2-bromothiazole (156 mg, 0.95 mmol) were combined in DME (10 mL), and the mixture was purged with nitrogen for 10 minutes. Aqueous sodium carbonate solution (2M, 0.95 mL) and Pd(dppf)Cl2 (34 mg, 5 mol %) were added. The solution was purged with nitrogen for 10 minutes and was heated at reflux for 5 hours. The reaction was cooled and held at room temperature overnight. The reaction mixture was partitioned between ethyl acetate and water and separated. The aqueous layer was washed with 15 mL ethyl acetate (2×), and the combined organic portions were washed with brine and dried over MgSO4. Filtration and solvent removal afforded the crude product as a brown paste which was purified by silica chromatography on Combiflash ISCO purification system (Teledyne Corp., Lincoln Nebr.) eluting with a heptanes/ethyl acetate gradient. The final product was obtained as a light yellow flaky solid (SM-1f, 195 mg, 95%). MS (ES+) 216.2, 1H NMR (CDCl3) δ 2.72-2.75 (m, 2H), 3.20 (t, 2H), 7.42 (d, 1H), 7.80 (d, 1H), 7.92 (d, 1H), 7.94-7.97 (m, 1H), 8.10 (br s, 1H).
Reaction SMILES: [CH:1]1([C:7]2[CH:8]=[C:9]([C:19]([OH:21])=O)[CH:10]=[N:11][C:12]=2[O:13][CH2:14][C:15]([F:18])([F:17])[F:16])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:22][N:23]1[CH2:28][CH2:27][CH:26]([OH:29])[CH2:25][CH2:24]1>>[CH:1]1([C:7]2[CH:8]=[C:9]([C:19]([NH:22][N:23]3[CH2:28][CH2:27][CH:26]([OH:29])[CH2:25][CH2:24]3)=[O:21])[CH:10]=[N:11][C:12]=2[O:13][CH2:14][C:15]([F:16])([F:18])[F:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: NN1CCC(O)CC1
Reactant: O=C(O)c1cnc(OCC(F)(F)F)c(C2CCCCC2)c1
Product: O=C(NN1CCC(O)CC1)c1cnc(OCC(F)(F)F)c(C2CCCCC2)c1

Procedure:
The title compound was synthesized in analogy to Example 1 using 5-cyclohexyl-6-(2,2,2-trifluoro-ethoxy)-3-pyridinecarboxylic acid and 1-amino-4-piperidinol (CAN 79414-82-7) as starting materials; LC-MS (UV peak area/ESI) 96.4%, 402.1991 (M+H)+.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1/[CH:11]=[CH:12]/[C:13]([OH:15])=O.C(N(CC)CC)C.Cl.[NH2:24][OH:25].Cl>CN(C)C=O.O>[OH:25][NH:24][C:13](=[O:15])/[CH:12]=[CH:11]/[C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:1]=1
Reactant: NO
Reactant: O=C(O)/C=C/c1ccc2ccccc2n1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(/C=C/c1ccc2ccccc2n1)NO
Reaction time: 2 h

Procedure:
To a solution of (E)-3-(2quinolinyl)-2-propenoic acid L3) (0.4 g, 2.0 mmol) in dry dimethylformamide (3 ml), at ice bath temperature (˜0° C.), under an atmosphere of argon, N,N′-carbonyldiimidazole (0.65 g, 4.0 mmol) was added over 15 minutes and the reaction mixture was stirred at this temperature for 2 hours. Triethylamine (0.85 ml, 6.0 mmol), followed by hydroxylamine hydrochloride (0.42 g, 6.0 mmol), were added to the reaction, and the obtained mixture was stirred at ice bath temperature for 1 hour, and then at room temperature overnight. The reaction mixture was poured into water (30 ml), acidified with 1 N HCl to pH 5 and extracted with ethyl acetate (3×40 ml). The combined extracts were washed with water (50 ml), brine (20 ml), and dried (Na2SO4). The solvent was evaporated and the residue was chromatographed on silica gel with acetonitrile-water (20:1) as eluent to give the title compound as white crystals. M.p. 159.5-160.5° C. 1H NMR (DMSO-d6, HMDSO), δ: 7.12 (1H, d, J=16.0 Hz); 7.49-8.18 (6H, m); 8.44 (1H, d, J=8.0 Hz); 10.13 (2H, br s). HPLC analysis on Symmetry C8 column: impurities 2.0% (column size 3.9×150 mm; mobile phase acetonitrile—0.1M phosphate buffer, pH 2.5, 20:80; detector UV 254 nm; flow rate 1.2 ml/min; sample concentration 0.5 mg/ml). Anal. Calcd for C12H10N2O2*H2O: C, 62.06; H, 5.21; N, 12.06. Found, %: C, 61.95; H, 4.91; N, 12.07.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[CH2:3][O:4][C:5]1[N:10]=[CH:9][C:8]([CH:11]([OH:14])[CH2:12][OH:13])=[CH:7][CH:6]=1.[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1.N1C=CC=CC=1.O>ClCCl>[CH3:27][C:17]1[CH:22]=[CH:21][C:20]([S:23]([O:13][CH2:12][CH:11]([OH:14])[C:8]2[CH:9]=[N:10][C:5]([O:4][CH2:3][C:2]([F:1])([F:15])[F:16])=[CH:6][CH:7]=2)(=[O:25])=[O:24])=[CH:19][CH:18]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCC(O)c1ccc(OCC(F)(F)F)nc1
Solvent: O
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCC(O)c2ccc(OCC(F)(F)F)nc2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 98.8 %

Procedure:
A mixture of 1-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethane-1,2-diol (1.01 g, 4.24 mmol, Step-3, single enantiomer), p-toluenesulfonyl chloride (0.97 g, 5.09 mmol) and pyridine (3.43 mL, 42.4 mmol) in dichloromethane (21 mL) is stirred at room temperature for 20 hours. Then p-toluenesulfonyl chloride (0.97 g, 5.09 mmol) is added to the reaction mixture and stirred for 24 hours. The reaction mixture is poured into water and extracted with ethyl acetate and dried over sodium sulfate and concentrated in vacuo. The residue is purified by column chromatography on silica gel eluting with n-hexane/ethyl acetate (2:1 to 1:1) to give 1.64 g (99% yield) of the title compound as colorless oil.
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([NH:9][C:10]2[S:11][C:12]3[CH:18]=[C:17]([C:19]4[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=4)[CH:16]=[CH:15][C:13]=3[N:14]=2)[CH:4]=1.O=P(Cl)(Cl)[Cl:27]>>[Cl:27][CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([NH:9][C:10]2[S:11][C:12]3[CH:18]=[C:17]([C:19]4[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=4)[CH:16]=[CH:15][C:13]=3[N:14]=2)[CH:4]=1
Reactant: OCc1ccnc(Nc2nc3ccc(-c4ccncc4)cc3s2)c1
Reactant: O=P(Cl)(Cl)Cl
Product: ClCc1ccnc(Nc2nc3ccc(-c4ccncc4)cc3s2)c1
Temperature: 110 °C
Reaction time: 2 h
Yield: 63 %

Procedure:
(2-((6-(Pyridin-4-yl)benzo[d]thiazol-2-yl)amino)pyridin-4-yl)methanol 101 (0.12 g, 0.36 mmol, 1 eq.) was dissolved in POCl3 (3 mL) under N2, and the suspension was stirred at 110° C. for 2 hours. After cooling, POCl3 was evaporated under reduced pressure and the residue was basified with sat. Na2CO3 solution, then extracted with DCM, dried and concentrated in vacuo to afford N-(4-(chloromethyl)pyridin-2-yl)-6-(pyridin-4-yl)benzo[d]thiazol-2-amine (80 mg, 63%) which was used directly in the next step.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][C:9]2[NH:8][CH2:7][C@@H:6]3[CH2:12][O:13][CH2:14][CH2:15][N:5]3[C:4]=2[N:3]=1.CC(C)([O-])C.[Na+].Cl[CH2:23][C:24]1[O:28][CH:27]=[N:26][CH:25]=1>CS(C)=O>[Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH2:23][C:24]3[O:28][CH:27]=[N:26][CH:25]=3)[CH2:7][C@@H:6]3[CH2:12][O:13][CH2:14][CH2:15][N:5]3[C:4]=2[N:3]=1
Reactant: ClCc1cnco1
Reactant: Clc1ncc2c(n1)N1CCOC[C@H]1CN2
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: Clc1ncc2c(n1)N1CCOC[C@H]1CN2Cc1cnco1

Procedure:
The title compound was prepared in a manner similar to PREPARATION x5 using (R)-2-chloro-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridine (PREPARATION x2, 351 mg, 1.547 mmol) in DMSO (10 mL), sodium tert-butoxide (178 mg, 1.856 mmol) and 5-(chloromethyl)oxazole (200 mg, 1.702 mmol) (171 mg, 36%). ESI-MS m/z [M+H]+ calc'd for C13H14ClN5O2, 308.09; found 308.1.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[N:11]=[N:12][N:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]([N:23]3[CH2:28][CH2:27][CH:26]([OH:29])[CH2:25][CH2:24]3)=[N:15][C:14]=12.[CH3:30]I>CN(C)C(=O)C.O>[F:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[N:11]=[N:12][N:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]([N:23]3[CH2:24][CH2:25][CH:26]([O:29][CH3:30])[CH2:27][CH2:28]3)=[N:15][C:14]=12
Reactant: CI
Reactant: OC1CCN(c2nc3c(-c4ccccc4F)nnn3c3ccccc23)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: COC1CCN(c2nc3c(-c4ccccc4F)nnn3c3ccccc23)CC1
Reaction time: 18 h
Yield: 65.7 %

Procedure:
Sodium hydride (60% dispersion in oil) (0.044 g, 1.10 mmol) was added to a solution of 3-(2-fluorophenyl)-5-(4-hydroxypiperidin-1-yl)-[1,2,3]triazolo[1,5-α]quinazoline (Example 9) (10 g, 0.27 mmol) in N,N-dimethylacetamide (4 ml). The mixture was stirred for 30 min before addition of methyl iodide (0.17 ml, 2.8 mmol) and then stirred for a further 18 h. The mixture was diluted with water (20 ml) and extracted with CH2Cl2 (2×50 ml). The combined organic extracts were washed with brine (20 ml), dried over MgSO4 and evaporated to give a colourless oil. Purification by preparative thin layer chromatography eluting with CH2Cl2:MeOH:NH3(c) (95:5:0.5) gave 3-(2-fluorophenyl)-5-(4-methoxypiperidin-1-yl)-[1,2,3]triazolo[1,5-α]quinazoline (0.067 g, 65%) as a yellow solid. δH (360 MHz; CDCl3) 1.84-1.90 (2H, m), 2.11-2.16 (2H, m), 3.36-3.41 (2H, m), 3.42 (3H, s), 3.51-3.54 (1H, m), 3.88-3.95 (2H, m), 7.19-7.29 (2H, m), 7.32-7.37 (1H, m), 7.60 (1H, ddd, J=8, 8 and 1), 7.88 (1H, ddd, J=8, 8 and 1), 8.01 (1H, d, J=8), 8.15 (1H, ddd, J=7, 7 and 2), 8.67 (1H, dd, J=8 and 1); m/z (ES+) 378 (M+H+).
Reaction SMILES: [C:1]1([C@H:7]([CH3:11])[C:8]([OH:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)(O)[O-].[Na+].[CH2:17](O)[CH3:18]>S(=O)(=O)(O)O>[C:1]1([C@H:7]([CH3:11])[C:8]([O:10][CH2:17][CH3:18])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[C@H](C(=O)O)c1ccccc1
Reactant: CCO
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CCOC(=O)[C@@H](C)c1ccccc1
Yield: 84 %

Procedure:
To a solution consisting of (S)-2-phenylpropanoic acid (1.0 g, 6.7 mmol, from Chem-Impex) in ethanol (30 mL) was added concentrated sulfuric acid (4 drops). The reaction mixture was stirred at reflux overnight in a vessel equipped with a Dean-Stark condenser. To the mixture was added solid sodium bicarbonate and the resulting mixture was filtered and concentrated under vacuum to afford the title compound (1.0 g, 84%) as a colorless oil; TLC Rf 0.5 (solvent system: 15:85:1 v/v/v ethyl acetate-heptane-acetic acid). The product was carried directly onto the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:27])[C:15]([NH:17][CH:18]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:19][OH:20])=O.CC[N+](S(N=C(OC)[O-])(=O)=O)(CC)CC>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14]([C:15]1[O:20][CH2:19][CH:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:17]=1)=[O:27]
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)C(=O)NC(CO)c1ccccc1
Agent: CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC
Solvent: C1CCOC1
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)C1=NC(c2ccccc2)CO1
Temperature: 80 °C
Reaction time: 20 h
Yield: 3.5 %

Procedure:
A sealed tube containing (N1-(2-(5-chloro-1H-indol-3-yl)ethyl)-N2-(2-hydroxy-1-phenylethyl)oxalamide (0.211 g, 0.546 mmol) and Burgess reagent [(methoxycarbonylsulfamoyl)triethylammonium hydroxide inner salt (0.161 g; 0.656 mmol)] in dry THF (6 mL) was stirred at 80° C. for 20 hours. The solution was evaporated and the resulting residue was purified by flash chromatography on silica gel (eluent 7 to 60% ethyl acetate in dichloromethane) to give 0.007 g (4%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4-phenyl-4,5-dihydrooxazole-2-carboxamide as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:29])[N:19]([CH2:23][C:24]5[NH:25][CH:26]=[CH:27][N:28]=5)[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:32]([F:35])([F:34])[F:33])[CH:3]=1.[F:36][C:37]([F:43])([F:42])[S:38](Cl)(=[O:40])=[O:39]>>[Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:29])[N:19]([CH2:23][C:24]5[N:25]([S:38]([C:37]([F:43])([F:42])[F:36])(=[O:40])=[O:39])[CH:26]=[CH:27][N:28]=5)[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:32]([F:35])([F:34])[F:33])[CH:3]=1
Reactant: O=C1S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C(=O)N1Cc1ncc[nH]1
Reactant: O=S(=O)(Cl)C(F)(F)F
Product: O=C1S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C(=O)N1Cc1nccn1S(=O)(=O)C(F)(F)F

Procedure:
(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-({1-[(trifluoromethyl)sulfonyl]-1H-imidazol-2-yl}methyl)-1,3-thiazolidine-2,4-dione was prepared from (5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-(1H-imidazol-2-ylmethyl)-1,3-thiazolidine-2,4-dione (from Example 403) and trifluoromethanesulfonyl chloride following General Procedure U.
Reaction SMILES: BrC1C=CC=C2C=1C=CN2.[F:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:20]=1[NH:19][C:18](=[O:21])[C:17]2=[O:22].BrCCCCC.Br[CH2:30][C:31]1[O:32][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:34][CH:35]=1>>[F:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:20]=1[N:19]([CH2:30][C:31]1[O:32][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:34][CH:35]=1)[C:18](=[O:21])[C:17]2=[O:22]
Reactant: O=C1Nc2c(F)cccc2C1=O
Reactant: FC(F)(F)c1ccc(CBr)o1
Agent: Brc1cccc2[nH]ccc12
Solvent: CCCCCBr
Product: O=C1C(=O)N(Cc2ccc(C(F)(F)F)o2)c2c(F)cccc21

Procedure:
Following the procedure as described in PREPARATION 1A, and making non-critical variations to replace 4-bromoindole with 7-fluoroisatin, and 1-bromopentane with 2-(bromomethyl)-5-(trifluoromethyl)furan, the title compound was obtained (34%): MS (ES+) m/z 336.2 (M+23).
Reaction SMILES: [CH2:1]([CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[O:11])[CH2:6][CH2:5]1)[C:2]#[CH:3].I[C:22]1[N:23]=[C:24]([NH2:40])[C:25]2[N:26]=[CH:27][N:28]([C:38]=2[N:39]=1)[C@@H:29]1[O:37][C@H:34]([CH2:35][OH:36])[C@@H:32]([OH:33])[C@H:30]1[OH:31]>>[CH3:20][O:19][C:16]1[CH:17]=[CH:18][C:13]([O:12][C:10]([N:7]2[CH2:8][CH2:9][CH:4]([CH2:1][C:2]#[C:3][C:22]3[N:23]=[C:24]([NH2:40])[C:25]4[N:26]=[CH:27][N:28]([C:38]=4[N:39]=3)[C@@H:29]3[O:37][C@H:34]([CH2:35][OH:36])[C@@H:32]([OH:33])[C@H:30]3[OH:31])[CH2:5][CH2:6]2)=[O:11])=[CH:14][CH:15]=1
Reactant: Nc1nc(I)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Reactant: C#CCC1CCN(C(=O)Oc2ccc(OC)cc2)CC1
Product: COc1ccc(OC(=O)N2CCC(CC#Cc3nc(N)c4ncn([C@@H]5O[C@H](CO)[C@@H](O)[C@H]5O)c4n3)CC2)cc1

Procedure:
Batch: AB-10-017. 4-methoxyphenyl 4-(prop-2-ynyl)piperidine-1-carboxylate, batch JR28-103 (597 g, 2.184 mmol) was added to a solution of 2-iodoadenosine (0.649 g, 1.651 mmol) according to general procedure 2. Yield: 0.294 g, 33%. 1H NMR (CD3OD) δ 8.30 (s, 1H), 7.00-6.87 (2×m, 4H), 5.94 (d, 1H), 4.73 (m, 2H), 4.33-4.14 (2×m, 3H), 3.92-3.76 (2×d, 5H), 3.10-2.90 (2×bt, 4H), 2.46 (d, 5H), 1.91-1.40 (2×m, 5H). m/z MH+=539.14. HPLC rt=5.5 min.
Reaction SMILES: [NH2:1][C:2]1[CH:30]=[CH:29][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]3[CH2:21][CH2:20][CH:19]([N:22]4[CH2:25][CH:24]([N:26]([CH3:28])[CH3:27])[CH2:23]4)[CH2:18][CH2:17]3)=[O:15])[CH:8]=2)=[C:4]([F:31])[CH:3]=1.[C:32]1([CH2:38][C:39]([N:41]=[C:42]=[O:43])=[O:40])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C(OCC)C>O1CCCC1.CCCCCC>[F:31][C:4]1[CH:3]=[C:2]([NH:1][C:42]([NH:41][C:39](=[O:40])[CH2:38][C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)=[O:43])[CH:30]=[CH:29][C:5]=1[O:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]2[CH2:21][CH2:20][CH:19]([N:22]3[CH2:23][CH:24]([N:26]([CH3:27])[CH3:28])[CH2:25]3)[CH2:18][CH2:17]2)=[O:15])[CH:8]=1
Reactant: O=C=NC(=O)Cc1ccccc1
Reactant: CN(C)C1CN(C2CCN(C(=O)Nc3cc(Oc4ccc(N)cc4F)ccn3)CC2)C1
Solvent: CCOCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CN(C)C1CN(C2CCN(C(=O)Nc3cc(Oc4ccc(NC(=O)NC(=O)Cc5ccccc5)cc4F)ccn3)CC2)C1
Temperature: 25 °C
Reaction time: 11 h
Yield: 33 %

Procedure:
To a solution of 4-(3-dimethylaminoazetidin-1-yl)piperidine-1-carboxylic acid [4-(4-amino-2-fluorophenoxy)pyridin-2-yl]amide (78 mg) in tetrahydrofuran (6.0 ml) was added a solution of 2-phenylacetyl isocyanate in hexane (0.25 M, 1.82 ml), followed by stirring at room temperature for 11 hrs. The reaction mixture was partitioned between ethyl acetate and a saturated aqueous solution of sodium hydrogencarbonate. The aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with brine, and dried over anhydrous sodium sulfate. The organic layer was concentrated to give a residue, which was then purified by silica gel column chromatography (FUJI Silysia NH, eluent; ethyl acetate:methanol=100:7). Fractions containing a target compound were concentrated to give a residue, to which diethyl ether (2 ml) and hexane (2 ml) were added to give a precipitate. The precipitate was suspended in the solvent. Then the precipitate was filtered off, washed with diethyl ether, and dried under aeration to provide the titled compound (34.9 mg, 33%) as pale yellow powder.
Reaction SMILES: Cl[CH2:2][N:3]1[C:13](=[O:14])[C:12]2[C:7](=[C:8]([O:21][CH3:22])[C:9]([CH2:18][CH2:19][CH3:20])=[CH:10][C:11]=2[O:15][CH2:16][CH3:17])[S:4]1(=[O:6])=[O:5].[Na].[C:24]1([N:30]2[C:34]([SH:35])=[N:33][N:32]=[N:31]2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[C:24]1([N:30]2[C:34]([S:35][CH2:2][N:3]3[C:13](=[O:14])[C:12]4[C:7](=[C:8]([O:21][CH3:22])[C:9]([CH2:18][CH2:19][CH3:20])=[CH:10][C:11]=4[O:15][CH2:16][CH3:17])[S:4]3(=[O:6])=[O:5])=[N:33][N:32]=[N:31]2)[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CCCc1cc(OCC)c2c(c1OC)S(=O)(=O)N(CCl)C2=O
Reactant: Sc1nnnn1-c1ccccc1
Agent: [Na]
Product: CCCc1cc(OCC)c2c(c1OC)S(=O)(=O)N(CSc1nnnn1-c1ccccc1)C2=O
Yield: 71 %

Procedure:
By the method of part F of Example 45 condensation of 2-chloromethyl-4-ethoxy-6-propyl-7-methoxysaccharin (0.62 g) and 1-phenyltetrazol-5-thiol sodium salt (0.36 g initially and a small amount more after 3.5 hours reaction time, total reaction time 8 hours) and isolation of the oily product by extraction with dichloromethane and purification thereof first by column chromatography on silica gel using dichloromethane as eluant and then by crystallization of the resulting oil (0.62 g., 71% yield) from ethanol gave 2-(1-phenyltetrazol-5-yl)thiomethyl-4-ethoxy-6-propyl-7-methoxysaccharin, mp 110°-111° C.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][C:16]3[O:19][CH:20]=[CH:21][C:15]=3[C:14]2=[O:22])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:23][NH:24][CH3:25].[CH2:26]=O>C(O)(=O)C>[CH3:23][N:24]([CH2:26][C:20]1[O:19][C:16]2[CH2:17][CH2:18][N:13]([CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:14](=[O:22])[C:15]=2[CH:21]=1)[CH3:25]
Reactant: C=O
Reactant: CNC
Reactant: O=C1c2ccoc2CCN1CCCCCCc1ccccc1
Solvent: CC(=O)O
Product: CN(C)Cc1cc2c(o1)CCN(CCCCCCc1ccccc1)C2=O
Reaction time: 8 h

Procedure:
To a solution of 0.242 g (0.814 mmol) of 5-(6-phenylhexyl)-6,7-dihydro-5H-furo[3,2-c]pyridin-4-one in 10 ml of acetic acid, 0.37 g (4.1 mmol) of 50% aqueous dimethylamine and 0.33 g (4.1 mmol) of 37% aqueous formaldehyde were added, followed by overnight refluxing. After the solvent was distilled off under reduced pressure, the residual solution was alkalified with aqueous sodium hydroxide and extracted with ethyl acetate 3 times. The combined organic layer was dried over anhydrous magnesium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (ethyl acetate to ethyl acetate/methanol=4/1) to yield the desired product.