Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][C:6]([CH2:19][N:20]3[CH:24]=[C:23]([C@@:25]([OH:32])([CH2:30][CH3:31])[C:26]([F:29])([F:28])[F:27])[N:22]=[N:21]3)=[CH:7][CH:8]=2)[N:3]=1.C([Sn](CCCC)(CCCC)[C:38]([O:40]CC)=[CH2:39])CCC.[Cl-].[Li+].C([O-])(O)=O.[Na+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:18][C:15]1[CH:16]=[CH:17][C:12]([C:10]2[C:9]3[C:4](=[CH:5][C:6]([CH2:19][N:20]4[CH:24]=[C:23]([C@:25]([OH:32])([C:26]([F:29])([F:28])[F:27])[CH2:30][CH3:31])[N:22]=[N:21]4)=[CH:7][CH:8]=3)[N:3]=[C:2]([C:38](=[O:40])[CH3:39])[CH:11]=2)=[CH:13][CH:14]=1
Reactant: CC[C@](O)(c1cn(Cc2ccc3c(-c4ccc(F)cc4)cc(Cl)nc3c2)nn1)C(F)(F)F
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: C1COCCO1
Product: CC[C@](O)(c1cn(Cc2ccc3c(-c4ccc(F)cc4)cc(C(C)=O)nc3c2)nn1)C(F)(F)F
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of (S)-2-(1-{[2-chloro-4-(4-fluorophenyl)quinolin-7-yl]methyl}-1H-1,2,3-triazol-4-yl)-1,1,1-trifluorobutan-2-ol (235 mg, 0.51 mmol), tributyl(1-ethoxyvinyl)tin (188 μL, 0.56 mmol), tetrakis(triphenylphosphine)palladium (30 mg, 0.025 mmol) and lithium chloride (64 mg, 1.5 mmol) was refluxed in dioxane (10 mL) overnight. An aqueous saturated solution of NaHCO3 was added and the mixture extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated under reduce pressure. THF (5 mL) and 3M HCl (2 mL) were added, and the solution was stirred at rt for 4 h. An aqueous saturated solution of NaHCO3 was added and the mixture extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduce pressure. Purification on silica gel (eluting with ethyl acetate/hexanes, 2:8) gave the title compound. MS (+ESI): 473 (M+H)+.
Reaction SMILES: [CH2:1]([CH:3]([CH2:24][CH2:25][CH2:26][CH3:27])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH:14]([CH2:19][CH3:20])[CH2:15][CH2:16][CH2:17][CH3:18])=[CH:8][C:7]=1[N+:21]([O-])=O)[CH3:2].C([O-])=O.[NH4+]>CC(O)C>[CH2:1]([CH:3]([CH2:24][CH2:25][CH2:26][CH3:27])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH:14]([CH2:19][CH3:20])[CH2:15][CH2:16][CH2:17][CH3:18])=[CH:8][C:7]=1[NH2:21])[CH3:2]
Reactant: CCCCC(CC)COc1ccc(OCC(CC)CCCC)c([N+](=O)[O-])c1
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CC(C)O
Product: CCCCC(CC)COc1ccc(OCC(CC)CCCC)c(N)c1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
1,4-Bis(2-ethylhexyloxy)-2-nitrobenzene (11.4 g, 0.03 mol) is dissolved in 2-propanol (100 ml) and degassed under vacuum, purging to nitrogen. 10% (w/w) Pd/C (0.52 g) is added and the mixture heated to 80° C. Water (10 ml) is added, followed by solid ammonium formate (18.9 g, 0.3 mol). After a further 1 hour at 80° C., the reaction mixture is allowed to cool then filtered to remove catalyst, to give a colourless solution which darkened rapidly on standing. The material is used immediately as an isopropanol solution (quant).
Reaction SMILES: C(Cl)CCl.[C:5]([CH2:9][C:10]([OH:12])=O)([CH3:8])([CH3:7])[CH3:6].ON1C2N=CC=CC=2N=N1.Cl.Cl.[NH:25]1[C:33]2[CH2:32][CH2:31][NH:30][CH2:29][C:28]=2[N:27]=[CH:26]1.C(N(C(C)C)C(C)C)C>ClCCl.C(OCC)(=O)C>[CH3:6][C:5]([CH3:8])([CH3:7])[CH2:9][C:10]([N:30]1[CH2:31][CH2:32][C:33]2[NH:25][CH:26]=[N:27][C:28]=2[CH2:29]1)=[O:12]
Reactant: c1nc2c([nH]1)CCNC2
Reactant: CC(C)(C)CC(=O)O
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CC(C)(C)CC(=O)N1CCc2[nH]cnc2C1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 24.6 %

Procedure:
At 0° C., EDC (0.45 g, 2.4 mmol) was added to a solution of tert-butylacetic acid (0.30 mL, 2.3 mmol), and 1-hydroxy-7-azabenzotriazole (0.32 g, 2.4 mmol) in dichloromethane (30 mL). The reaction mixture was stirred for 20 min at 0° C. 4,5,6,7-tetrahydroimidazo[4,5-c]pyridine dihydrochloride (0.50 g, 2.4 mmol) was added. Ethyldiisopropylamine (0.40 mL, 2.4 mmol) was added. The reaction mixture was stirred for 16 h at room temperature. The reaction mixture was diluted with ethyl acetate (100 mL) and washed with 10% aqueous sodium hydrogen sulfate solution (100 mL). A 1 N solution of sodium hydroxide was added to the aqueous solution until pH 12 was obtained. It was extracted with ethyl acetate (2×100 mL). These organic extracts were dried over magnesium sulfate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (40 g), using dichloromethane/methanol/25% aqueous ammonia (100:10:1) as eluent to give 125 mg of the title compound.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][C:10]1[NH:11][CH:12]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:17][CH:16]=2)[N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[Br-].[CH3:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39]>CN(C)C=O.O>[CH2:1]([N:8]([CH2:9][C:10]1[NH:11][CH:12]=[C:13]([C:15]2[CH:16]=[CH:17][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:19][CH:20]=2)[N:14]=1)[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(CNCc2nc(-c3ccc(-c4ccccc4)cc3)c[nH]2)cc1
Reactant: CCCCCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCN(Cc1ccccc1)Cc1nc(-c2ccc(-c3ccccc3)cc2)c[nH]1
Reaction time: 3 h
Yield: 13 %

Procedure:
N-benzyl(4-(1,1′-biphenyl)-4-yl-1H-imidazol-2-yl)methanamine (1 g; 0.0024 mol; prepared according to experimental conditions analogous to the preceding examples and using the appropriate starting compounds and reaction products) was diluted in 15 ml dimethylformamide. Potassium carbonate (1 g; 0.0073 mol) was added at about 23° C. and then hexane bromide (0.34 ml; 0.0024 mol) was added quite slowly. The reaction mixture was brought around the temperature of about 70° C. for about 3 hours before being poured in icy water. The mixture was extracted with ethyl acetate and the organic phase washed with water. After drying over magnesium sulfate, the solvents were concentrated using a rotative evaporator. After purification over a silica column (eluent: ethyl acetate-heptane/7-3), a light yellow solid was obtained in the form of a glue (yield of 13%). Free base. Melting point: 120-122° C. MH+=424.3.
Reaction SMILES: CI.[Cl:3][C:4]1[CH:5]=[C:6]([CH3:11])[C:7](=[O:10])[NH:8][N:9]=1.[C:12]([O-])([O-])=O.[K+].[K+].O>CN(C)C=O>[Cl:3][C:4]1[CH:5]=[C:6]([CH3:11])[C:7](=[O:10])[N:8]([CH3:12])[N:9]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1cc(Cl)n[nH]c1=O
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CI
Product: Cc1cc(Cl)nn(C)c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl iodide (1.3 mL) was added to a mixture of 6-chloro-4-methyl-2H-pyridazin-3-one (2.70 g) and K2CO3 (3.40 g) in dimethylformamide (27 mL). The resulting mixture was stirred at ambient temperature overnight. Then, water was added and the mixture was extracted with ethyl acetate. The combined organic extracts were washed with water and brine and dried (MgSO4). After removal of the solvent, the title compound was obtained as a solid. Yield: 2.97 g (100% of theory). Mass spectrum (ESI+): m/z=159/161 (CI) [M+H]+
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][O:15][C:16]1[CH:43]=[CH:42][C:19]([CH2:20][CH:21]([C:32]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[O:33])[C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])=[CH:18][CH:17]=1.[H-].[Na+].Br[CH2:47][C:48]([O:50][CH2:51][CH3:52])=[O:49].S([O-])(O)(=O)=O.[Na+]>O1CCCC1.O>[CH2:51]([O:50][C:48]([CH2:47][C:21]([CH2:20][C:19]1[CH:42]=[CH:43][C:16]([O:15][CH2:14][CH2:13][C:3]2[N:4]=[C:5]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[O:6][C:2]=2[CH3:1])=[CH:17][CH:18]=1)([C:32]([O:34][CH2:35][C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)=[O:33])[C:22]([O:24][CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)=[O:23])=[O:49])[CH3:52]
Reactant: CCOC(=O)CBr
Reactant: Cc1oc(-c2ccccc2)nc1CCOc1ccc(CC(C(=O)OCc2ccccc2)C(=O)OCc2ccccc2)cc1
Agent: O=S(=O)([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)CC(Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1)(C(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 101 %

Procedure:
Dibenzyl 2-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]benzyl]malonate (26.0 g, 45.2 mmol) synthesized according to the method described in WO95/18125 was dissolved in tetrahydrofuran (250 ml), and sodium hydride (60% in oil, 2.2 g, 54.2 mmol) was added at 0° C., which was followed by stirring at room temperature for 30 min. To the reaction mixture was added a solution of ethyl bromoacetate (15.3 ml, 135.6 mmol) in tetrahydrofuran (50 ml) at room temperature. After stirring for 1 hr, sodium hydride (60% in oil, 1.1 g, 27.1 mmol) and ethyl bromoacetate (5.1 ml, 45.2 mmol) were added. After stirring for 1 hr, sodium hydride (60% in oil, 2.2 g, 54.2 mmol) was added and the mixture was stirred for 1 hr. Water and 1N aqueous sodium hydrogensulfate solution were added to the reaction mixture and extracted three times with ethyl acetate (200 ml). The extracted organic layers were combined, washed with brine, dried over sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (developing solvent; hexane:ethyl acetate=5:1→3:1) to give the title compound (30.2 g, yield 100%) as an oil.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[CH2:15][CH2:14][CH2:13][C:12](=[O:17])[C:11]=2[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH:20](OCC)=[O:21].O1CCCC1>C(O)C.C(OCC)C.O>[CH2:1]([N:8]1[C:16]2[CH2:15][CH2:14][C:13](=[CH:20][OH:21])[C:12](=[O:17])[C:11]=2[CH:10]=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC=O
Reactant: O=C1CCCc2c1cnn2Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: O=C1C(=CO)CCc2c1cnn2Cc1ccccc1

Procedure:
A mixture of 7.8 grams of 1-benzyl-1,5,6,7-tetrahydro-4H-indazol-4-one, 2.8 grams of sodium hydride (60% suspension in mineral oil), 10 ml of ethyl formate, 2 drops of ethanol and 100 ml of tetrahydrofuran was stirred at reflux for 1 hour and then cooled. Water (300 ml) and 100 ml of ethyl ether were added and the mixture was stirred briefly. The layers were separated and the aqueous layer was washed with ethyl ether and acidified with concentrated hydrochloric acid to a pH of about 4. The resulting slurry was extracted several times with dichloromethane and the combined organic extracts were dried over magnesium sulfate and concentrated under reduced pressure to give 1-benzyl1,5,6,7-tetrahydro-5-hydroxymethylene 4H-indazol-4-one as an amber oil.
Reaction SMILES: O.O.P([O-])(O)(O)=O.[Na+].[Na+].P([O-])(O)(O)=O.[CH2:15]([O:17][C:18]([C@@H:20]([NH:29][C@H:30]([C:32]([OH:34])=[O:33])[CH3:31])[CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:19])[CH3:16].Cl[C:36](Cl)([O:38]C(=O)OC(Cl)(Cl)Cl)Cl.N1C=CC=CC=1>O.ClCCl>[CH3:16][CH2:15][O:17][C:18]([CH:20]([N:29]1[C:36](=[O:38])[O:34][C:32](=[O:33])[CH:30]1[CH3:31])[CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:19]
Reactant: CCOC(=O)[C@H](CCc1ccccc1)N[C@@H](C)C(=O)O
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: O
Product: CCOC(=O)C(CCc1ccccc1)N1C(=O)OC(=O)C1C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Disodium dihydrogen phosphate dihydrate (177 gms; 0.994 moles) was dissolved in water (300 ml) at 35° C. and cooled to ambient temperature. Dichloromethane (250 ml) was charged and stirred for 15 mins. N-[1-(S)-ethoxy carbonyl-3-phenyl propyl]-L-alanine (106 gms; 0.381 moles) was added to the above solution and the reaction mass was cooled to 15° C. Solution of triphosgene (52.8 gms; 0.177 moles) dissolved dichloromethane (40 ml) was added dropwise to the reaction mass in 40 mins at 15-20° C. The reaction mass was further stirred for 30 min. Pyridine (0.5 ml; 0.006 moles) was added and the reaction mass was stirred for 1 hr at 15-20° C. The reaction mass was settled and layers were separated. Organic layer was washed with 2N HCl till the neutral pH obtained. The organic layer was further washed with water and dried over sodium sulphate. The solvent was evaporated to residue (110 gms).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][CH:14]=1)[CH:5]([OH:11])[C:6]([O:8][CH2:9][CH3:10])=[O:7].[Br:15][CH2:16][CH2:17][CH2:18]Br.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:15][CH2:16][CH2:17][CH2:18][O:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][CH:14]=1)[CH:5]([OH:11])[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: BrCCCBr
Reactant: CCOC(=O)C(O)c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(O)c1cccc(OCCCBr)c1

Procedure:
A solution of ethyl 3-hydroxymandelate (10.0 g), 1,3-dibromopropane (41.16 g) and potassium carbonate (8.08 g) in dry DMF (150 mL) was stirred at 40° C. overnight. The reaction mixture was partitioned between ethyl acetate and 1.0 N HCl. The organic layer was washed twice with water, once with brine and then dried over sodium sulfate. The organic layer was then filtered and the solvent removed in vacuo. The resulting oil was chromatographed on silica gel, using a gradient of 100% hexane to methylene chloride-hexane to yield the titled compound.
Reaction SMILES: [CH:1](=O)[CH:2]([CH3:4])[CH3:3].[NH:6]1[CH2:11][CH2:10][CH:9]([O:12][C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:20]([N:22]3[CH2:30][C:29]4[CH:28]=[CH:27][N:26]=[CH:25][C:24]=4[CH2:23]3)=[O:21])=[CH:15][CH:14]=2)[CH2:8][CH2:7]1.N1CC=C(C2C=CC(NC(N3CC4C(=CC=CC=4)C3)=O)=CC=2)CC1>>[CH3:1][CH:2]([CH3:4])[CH2:3][N:6]1[CH2:11][CH2:10][CH:9]([O:12][C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:20]([N:22]3[CH2:30][C:29]4[CH:28]=[CH:27][N:26]=[CH:25][C:24]=4[CH2:23]3)=[O:21])=[CH:15][CH:14]=2)[CH2:8][CH2:7]1
Reactant: O=C(Nc1ccc(OC2CCNCC2)cc1)N1Cc2ccncc2C1
Reactant: CC(C)C=O
Agent: O=C(Nc1ccc(C2=CCNCC2)cc1)N1Cc2ccccc2C1
Product: CC(C)CN1CCC(Oc2ccc(NC(=O)N3Cc4ccncc4C3)cc2)CC1

Procedure:
The title compound was prepared as described in Example 429, substituting isobutyraldehyde for isobutyraldehyde and N-(4-(piperidin-4-yloxy)phenyl)-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxamide for N-(4-(1,2,3,6-tetrahydropyridin-4-yl)phenyl)isoindoline-2-carboxamide. 1H NMR (400 MHz, Pyridine-d5. Temp=90° C.) δ ppm 8.49-8.60 (m, 2H) 8.09 (s, 1H) 7.68-7.80 (m, 2H) 7.10 (d, J=5.19 Hz, 1H) 6.96-7.04 (m, 2H) 4.85 (s, 4H) 4.21-4.28 (m, 1H) 2.65-2.79 (m, 2H) 2.13-2.24 (m, 2H) 2.06 (m, 2H) 1.98 (s, 2H) 1.77-1.88 (m, 2H) 1.67-1.77 (m, 1H) 0.89 (d, J=6.71 Hz, 6H); MS (APCI(+)) m/e 395 (M+H)+.
Reaction SMILES: [Cl-].[Ca+2].[Cl-].[BH4-].[Na+].[CH3:6][O:7][C:8](=O)[C@@H:9]([NH:13][C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])[CH2:10][O:11]C>C(O)C>[CH2:17]([O:16][C:14](=[O:15])[NH:13][C@H:9]([CH2:10][OH:11])[CH2:8][O:7][CH3:6])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: COC[C@H](NC(=O)OCc1ccccc1)C(=O)OC
Agent: [BH4-]
Agent: [Ca+2]
Agent: [Cl-]
Solvent: CCO
Product: COC[C@@H](CO)NC(=O)OCc1ccccc1
Temperature: -20 °C
Reaction time: 3 h
Yield: 64.2 %

Procedure:
Calcium chloride (16.63 g, 149.8 mmol) is added to a stirring suspension of sodium borohydride (11.33 g, 299.6 mmol) in ethanol (300 mL) at −40° C. The heterogeneous mixture is warmed to −20° C. and stirred for 1 h. (S)-2-Benzyloxycarbonylamino-3-methoxy-propionic acid methyl ester (20 g, 74.9 mmol) in abs EtOH (250 mL) is then added via cannula transfer. The heterogeneous mixture is stirred at −20° C. for 3 h. The reaction is quenched with water (400 mL) and carefully acidified with 1.0 M HCl. The aqueous layer is extracted with CH2Cl2 (4×200 mL) and the combined organic phases are washed with brine (200 mL), dried over anhydrous Na2SO4 and concentrated to afford a colorless oil. The mixture is absorbed onto the silica gel and chromatographed on silica gel (hexane:EtOAc, 4:1>2:1>1:1>1:2) to afford 11.5 g (64%) of (R)-(1-hydroxymethyl-2-methoxy-ethyl)-carbamic acid benzyl ester as a colorless oil.
Reaction SMILES: [CH3:1][N:2]=[C:3]=[O:4].[CH:5]1[CH:10]=[C:9]2[CH:11]([OH:19])[C:12]3[C:17]([O:18][C:8]2=[CH:7][CH:6]=1)=[CH:16][CH:15]=[CH:14][CH:13]=3>C(N(CC)CC)C>[CH3:1][NH:2][C:3]([O:19][CH:11]1[C:9]2[CH:10]=[CH:5][CH:6]=[CH:7][C:8]=2[O:18][C:17]2[C:12]1=[CH:13][CH:14]=[CH:15][CH:16]=2)=[O:4]
Reactant: OC1c2ccccc2Oc2ccccc21
Reactant: CN=C=O
Solvent: CCN(CC)CC
Product: CNC(=O)OC1c2ccccc2Oc2ccccc21
Reaction time: 0.67 h

Procedure:
Methyl isocyanate (20 g.) was added slowly, with stirring, to a filtered solution of 30 g. of xanthydrol in 100 ml. of anhydrous triethylamine. After standing for 40 minutes in a 20° C. water bath, the mixture was filtered. The collected solid was washed with anhydrous diethyl ether and dried in vacuo to give 9-(N-methylcarbamoyloxy)xanthene.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[F:23][C:24]([F:56])([F:55])[CH:25]([C:27]1[N:28]([CH2:44][C:45]2[CH:50]=[CH:49][CH:48]=[C:47]([C:51]([F:54])([F:53])[F:52])[CH:46]=2)[C:29]2[C:34]([C:35]=1[C:36]1[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=1)=[CH:33][CH:32]=[CH:31][CH:30]=2)[OH:26]>ClCCl>[F:56][C:24]([F:23])([F:55])[C:25]([C:27]1[N:28]([CH2:44][C:45]2[CH:50]=[CH:49][CH:48]=[C:47]([C:51]([F:54])([F:53])[F:52])[CH:46]=2)[C:29]2[C:34]([C:35]=1[C:36]1[CH:37]=[CH:38][C:39]([O:42][CH3:43])=[CH:40][CH:41]=1)=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:26]
Reactant: COc1ccc(-c2c(C(O)C(F)(F)F)n(Cc3cccc(C(F)(F)F)c3)c3ccccc23)cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: COc1ccc(-c2c(C(=O)C(F)(F)F)n(Cc3cccc(C(F)(F)F)c3)c3ccccc23)cc1
Reaction time: 2 h
Yield: 70.7 %

Procedure:
Dess-Martin reagent (39 mg, 0.09 mmol) was added to a stirred solution of 2,2,2-trifluoro-1-(3-(4-methoxphenyl)-1-{[3-(trifluoromethyl)phenyl]methyl}indol-2-yl)ethan-1-ol (Example 219, 40 mg, 0.08 mmol) in dichloromethane (2 mL). The resulting solution was stirred for 2 hours, more oxidant was added, and then the mixture was left stirring for 18 h. The reaction was quenched with a mixed aqueous solution of saturated sodium bicarbonate and saturated sodium thio sulfate (1:1, 10 mL), and the mixture was extracted with ethyl acetate (2×10 mL). The combined organic extracts were washed with water, and brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. Silica gel flash chromatography using hexane/ethyl acetate (4/1) as the eluant gave 2,2,2-trifluoro-1-(3-(4-methoxyphenyl)-1-{[3-(trifluoromethyl)phenyl]methyl}indol-2-yl)ethan-1-one as an orange oil (27 mg, 70%): 1H NMR (300 MHz, DMSO-d6) δ 7.76 (d, 1H), 7.47-7.62 (m, 4H), 7.20-7.45 (m, 5H), 7.05 (d, 2H), 5.76 (s, 2H); MS (MH+) calcd for C25H18F6NO2: 478., found: 478.
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.[C:15]1(=[O:25])[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17](=[O:24])[NH:16]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:45][C:46]([F:61])([F:60])[C:47]1[CH:48]=[CH:49][C:50]([CH2:53][CH:54]2[CH2:58][CH2:57][CH2:56][CH:55]2O)=[N:51][CH:52]=1>C1COCC1>[F:61][C:46]([F:45])([F:60])[C:47]1[CH:48]=[CH:49][C:50]([CH2:53][CH:54]2[CH2:58][CH2:57][CH2:56][CH:55]2[N:16]2[C:17](=[O:24])[C:18]3[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:15]2=[O:25])=[N:51][CH:52]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: OC1CCCC1Cc1ccc(C(F)(F)F)cn1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1C1CCCC1Cc1ccc(C(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
DIAD (0.348 mL, 1.791 mmol) was added to a solution of 2,3-dihydro-1H-isoindole-1,3-dione (CAS number 136918-14-4; 0.263 g, 1.791 mmol), triphenylphosphine (0.470 g, 1.791 mmol) and 2-{[5-(trifluoromethyl)pyridin-2-yl]methyl}cyclopentan-1-ol (Diastereomer 2) (0.366 g, 1.492 mmol) in THF (2 ml) under nitrogen. The reaction was stirred at room temperature for 72 hours and then concentrated. The crude product was purified by column chromatography (silica, 0-20% ethyl acetate/petrol) to afford the title compound.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH:7]([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[C:11]([F:21])[CH:10]=2)[CH3:8])[N:6]=1.[C:22](Cl)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N(CC)CC)C>O1CCCC1>[C:22]([NH:1][C:2]1[S:3][CH:4]=[C:5]([CH:7]([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)=[C:11]([F:21])[CH:10]=2)[CH3:8])[N:6]=1)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CC(c1ccc(-c2ccccc2)c(F)c1)c1csc(N)n1
Reactant: O=C(Cl)c1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(c1ccc(-c2ccccc2)c(F)c1)c1csc(NC(=O)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.6 %

Procedure:
To 2-amino-4-(1-(2-fluoro-4-biphenylyl)ethyl)thiazole (300 mg, 1.01 mmol) in tetrahydrofuran (15 ml) was added benzoyl chloride (145 mg, 1.03 mmol) and triethylamine (101 mg, 1.00 mmol) and the mixture was stirred at room temperature overnight. After reaction, the reaction mixture was filterated and evaporated under reduced pressure to a residue, which was cromatographed to afford 2-benzamido-4-(1-(2-fluoro-4-biphenylyl)ethyl)thiazole (279 mg, 69% yield): mp 147°-147.5° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[N:3]=1.[N:20]1[CH:25]=[CH:24][CH:23]=[C:22](B2OC(C)(C)C(C)(C)O2)[CH:21]=1>CCCCCC.C(OCC)(=O)C>[N:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:2]2[N:7]=[C:6]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)[N:5]=[C:4]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:3]=2)[CH:21]=1
Reactant: Clc1nc(N2CCOCC2)nc(N2CCOCC2)n1
Reactant: CC1(C)OB(c2cccnc2)OC1(C)C
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: c1cncc(-c2nc(N3CCOCC3)nc(N3CCOCC3)n2)c1

Procedure:
Following the general procedure A, 4,4′-(6-chloro-1,3,5-triazine-2,4-diyl)dimorpholine was coupled with 3-pyridineboronic acid pinacol ester with reaction time of 15 h. Chromatography (hexane/ethyl acetate 1:1) gave the title compound as a colorless solid.
Reaction SMILES: [CH:1]([C:3]1[CH:14]=[CH:13][C:6]([CH:7]=[CH:8][C:9]([O:11][CH3:12])=[O:10])=[CH:5][CH:4]=1)=[O:2].[BH4-].[Na+].O>CO>[OH:2][CH2:1][C:3]1[CH:4]=[CH:5][C:6]([CH:7]=[CH:8][C:9]([O:11][CH3:12])=[O:10])=[CH:13][CH:14]=1
Reactant: COC(=O)C=Cc1ccc(C=O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)C=Cc1ccc(CO)cc1
Temperature: 25 °C
Yield: 93.5 %

Procedure:
To a solution of methyl 4-formylcinnamate (5.58 g) in methanol (100 ml) was added sodium borohydride (0.4 g), and the mixture was stirred at room temperature for an hour. The reaction mixture was poured into water and extracted with methylene chloride. The methylene chloride layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. Evaporation of the solvent under reduced pressure gave methyl 4-(hydroxymethyl)cinnamate (5.27 g).
Reaction SMILES: [Na].[C:2]1([NH:8][NH2:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:10](#[N:14])/[CH:11]=[CH:12]/[CH3:13]>C(O)C>[NH2:14][C:10]1[CH2:11][CH:12]([CH3:13])[N:8]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[N:9]=1
Reactant: C/C=C/C#N
Reactant: NNc1ccccc1
Agent: [Na]
Solvent: CCO
Product: CC1CC(N)=NN1c1ccccc1
Reaction time: 0.17 h

Procedure:
A 2.0 g. amount of sodium metal is dissolved in 200 ml. of absolute ethanol, then 32.4 g. of phenylhydrazine in 50 ml. of ethanol is added followed in 10 minutes by 20.1 g. of crotononitrile. The reaction mixture is refluxed for 5 hours. Most of the ethanol is removed in vacuo, water is added and the product is collected by filtration. The solid is dissolved in dichloromethane. This solution is passed through a short column of a hydrous magnesium silicate. The column effluent is then refluxed on a steam bath with the gradual addition of hexane to crystallize a product. The product is collected and recrystallized from acetone-hexane to give 26.9 g. of the product of the Example as colorless prisms, m.p. 103.5°-106° C.