Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]([NH:10][CH2:11][C:12]([O:14]CC2C=CC=CC=2)=[O:13])=[O:9])[CH2:4][CH2:3]1.[H][H].O>[Pd].CO>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([C:8]([NH:10][CH2:11][C:12]([OH:14])=[O:13])=[O:9])[CH2:6][CH2:7]1
Reactant: CN1CCN(C(=O)NCC(=O)OCc2ccccc2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: O
Product: CN1CCN(C(=O)NCC(=O)O)CC1
Yield: 92 %

Procedure:
2.36 g of benzyl N-(4-methylpiperazin-1-ylcarbonyl)glycinate are added, at 20° C., under an argon atmosphere, to 0.15 g of 5% palladium on carbon in suspension in 100 cm3 of methanol. After stirring for 2.5 hours at 22° C., under 1.6 bar of hydrogen, 50 cm3 of water are added and the mixture is filtered on Clarcel. The cake is washed with three times 70 cm3 of water at 60° C. The filtrate is then concentrated to dryness under reduced pressure (2.7 kPa) at 50° C. The residue is dried under reduced pressure (2.7 kPa) at 50° C. to give 1.5 g of N-(4-methylpiperazin-1-ylcarbonyl)glycine.
Reaction SMILES: [CH3:1][C:2]1[N:7]([CH2:8][CH2:9][CH3:10])[C:6](=[O:11])[N:5]([CH2:12][CH2:13][CH3:14])[C:4](=[O:15])[CH:3]=1.S(=O)(=O)(O)O.[N+:21]([O-])([OH:23])=[O:22]>>[CH3:1][C:2]1[N:7]([CH2:8][CH2:9][CH3:10])[C:6](=[O:11])[N:5]([CH2:12][CH2:13][CH3:14])[C:4](=[O:15])[C:3]=1[N+:21]([O-:23])=[O:22]
Reactant: O=[N+]([O-])O
Reactant: CCCn1c(C)cc(=O)n(CCC)c1=O
Agent: O=S(=O)(O)O
Product: CCCn1c(C)c([N+](=O)[O-])c(=O)n(CCC)c1=O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
1.2 g, 6 mmol, of 6-methyl-1,3-dipropyl-1,3-dihydropyrimidine-2,4-dione, as prepared in Example 1, was added in small portions to a cooled (0° C.) solution of concentrated sulfuric acid (3.0 ml) and nitric acid (2.0 ml). The reaction stirred at 0° C. for 2 hours. The reaction mixture was poured over ice and a green amorphous solid formed. The solid was removed by filtration and washed copiously with water. The solid was dissolved in dichloromethane and concentrated. The residue was purified using column chromatography (1:1.2 EtOAc:Hexanes) to yield 6-methyl-5-nitro-1,3-dipropyl-1,3-dihydropyrimidine-2,4-dione(0.430 g, HNMR)
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[CH2:4][CH:5]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]([F:19])([F:18])[F:17])[C:6](OC)=[O:7].O.[NH2:21][NH2:22]>C(O)C>[NH2:21][N:22]1[CH2:3][CH:2]([OH:1])[CH2:4][CH:5]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]([F:19])([F:18])[F:17])[C:6]1=[O:7]
Reactant: NN
Reactant: COC(=O)C(CC1CO1)c1ccccc1C(F)(F)F
Solvent: CCO
Solvent: O
Product: NN1CC(O)CC(c2ccccc2C(F)(F)F)C1=O

Procedure:
Methyl 3-oxiranyl-2-(2-trifluoromethylphenyl)propionate (2.61 g) was dissolved in ethanol (20 mL). Hydrazine monohydrate (2.3 mL) was added at room temperature, and the mixture was reacted for 24 hours. Concentration under reduced pressure gave an oil which was partitioned with methylene chloride and water. The aqueous layer was extracted with methylene chloride four times. After drying over magnesium sulfate, concentration under reduced pressure gave the title compound (1.8 g) as a pale yellow solid.
Reaction SMILES: [P:1]([O-:6])([O:4][CH3:5])[O:2][CH3:3].[CH:7](=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[F-].[K+]>C(Cl)Cl>[OH:14][CH:7]([P:1](=[O:6])([O:4][CH3:5])[O:2][CH3:3])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=Cc1ccccc1
Reactant: COP([O-])OC
Agent: [F-]
Agent: [K+]
Solvent: ClCCl
Product: COP(=O)(OC)C(O)c1ccccc1
Reaction time: 0.08 h
Yield: 102.3 %

Procedure:
Dimethyl phosphite (1.86 mL, 20.3 mmol, 1.03 eq) was added to benzaldehyde (2 mL, 19.8 mmol, 1 eq) and stirred for 5 min. KF (5.75 g, 99.0 mmol, 5 eq) was then added and the reaction mixture was stirred until it solidified (˜20 min). The crude product was then dissolved in DCM, filtered, and the solvent evaporated yielding 4 as a white powder (4.38 g, 100%). The product was dried under high vacuum over P2O5. No further purification was required. 1H NMR (400 MHz CDCl3) δ 7.53-7.45 (m, 2H), 7.43-7.23 (m, 3H), 5.05 (d, J=11.1 Hz, 1H), 3.67 (dd, J=14.3, 10.4 Hz, 6H). 13C NMR (101 MHz, CDCl3) δ 136.66 (s), 128.64 (s), 128.49 (s), 127.28 (d, JC-P=5.7 Hz), 70.86 (d, JC-P=159.6 Hz), 54.02 (dd, JC-P=28.4, 7.0 Hz). 31P NMR (162 MHz CDCl3) δ 24.71 (s). ESIMS calculated for C9H13O4PNa [M+Na]+239.06, found: 239.04; mp 85-86° C.
Reaction SMILES: Br[C:2]1[CH:17]=[CH:16][C:5]2[N:6]=[C:7]([O:9][CH:10]3[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]3)[S:8][C:4]=2[CH:3]=1.CC1(C)C(C)(C)OB([C:26]2[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH:27]=2)O1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.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>[NH:13]1[CH2:14][CH2:15][CH:10]([O:9][C:7]2[S:8][C:4]3[CH:3]=[C:2]([C:26]4[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH:27]=4)[CH:17]=[CH:16][C:5]=3[N:6]=2)[CH2:11][CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: Brc1ccc2nc(OC3CCNCC3)sc2c1
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: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CC=C(c2ccc3nc(OC4CCNCC4)sc3c2)CC1
Temperature: 100 °C
Reaction time: 8 h
Yield: 87.1 %

Procedure:
To a degassed solution of 6-bromo-2-(piperidin-4-yloxy)benzo[d]thiazole (800 mg, 2.55 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (1.185 g, 3.83 mmol) and potassium carbonate (1.412 g, 10.22 mmol) in dioxane (21 mL) and water (7 mL) was added Pd(Ph3P)4 (148 mg, 0.128 mmol). The reaction mixture was stirred at 100° C. overnight. The mixture was cooled to rt, diluted with water (60 mL), and extracted with CH2Cl2 (3×30 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated. The residue was purified by column chromatography (silica gel, CH2Cl2-MeOH gradient 0 to 20% MeOH) to afford tert-butyl 4-(2-(piperidin-4-yloxy)benzo[d]thiazol-6-yl)-5,6-dihydropyridine-1(2H)-carboxylate (923 mg, 2.221 mmol, 87% yield) as a white foam. LCMS (m/z)=416 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[CH:26]=[C:25]([C:27](=[O:38])[NH:28][C:29]5([C:32]6[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=6)[CH2:31][CH2:30]5)[CH:24]=[CH:23][C:22]=4[O:39]C)=[CH:17][C:11]=3[C:12]=2[C:13]([NH:15][CH3:16])=[O:14])=[CH:4][CH:3]=1.[B-](Br)(Br)(Br)[S+](C)C>ClCCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[CH:26]=[C:25]([C:27](=[O:38])[NH:28][C:29]5([C:32]6[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=6)[CH2:30][CH2:31]5)[CH:24]=[CH:23][C:22]=4[OH:39])=[CH:17][C:11]=3[C:12]=2[C:13]([NH:15][CH3:16])=[O:14])=[CH:4][CH:3]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)NC4(c5ccccn5)CC4)ccc3OC)cc12
Agent: C[S+](C)[B-](Br)(Br)Br
Solvent: ClCCCl
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)NC4(c5ccccn5)CC4)ccc3O)cc12
Temperature: 90 °C
Reaction time: 8 h
Yield: 60.1 %

Procedure:
To a 100 mL round-bottomed flask equipped with a reflux condenser was added 2-(4-fluorophenyl)-5-(2-methoxy-5-(1-(pyridin-2-yl)cyclopropylcarbamoyl)phenyl)-N-methylbenzofuran-3-carboxamide (400 mg, 0.747 mmol), DCE (42 mL) and boron tribromide-methyl sulfide complex (1868 mg, 5.97 mmol). The solution was placed under nitrogen and stirred overnight at 90° C. The reaction mixture was cooled to room temperature, quenched with methanol and evaporated to near dryness. The mixture was taken up in 10 mL of methanol and purified using a Shimadzu preparative HPLC employing methanol/water/0.1% trifluoroacetic acid where solvent A was 10% methanol/90% water/0.1% trifluoroacetic acid and solvent B was 10% water/90% methanol/0.1% trifluoroacetic acid with a PHENOMENEX® Luna 10 μm C18 30×100 mm column at a gradient of 40-100% B and a flow rate of 40 mL/min. over 10 minutes with a 5 minute hold. The solvent was evaporated giving 234 mgs (60% yield) of 2-(4-fluorophenyl)-5-(2-hydroxy-5-(1-(pyridin-2-yl)cyclopropylcarbamoyl)phenyl)-N-methylbenzofuran-3-carboxamide as a white solid. The LC/MS data was obtained on a Shimadzu analytical LC/MICROMASS® Platform LC (ESI+) at 220 nm using the following set of conditions: Sunfire 5 μm C18, 4.6×50 mm column, with a gradient of 0-100% B (B=90% HPLC grade methanol/0.1% trifluoroacetic acid/10% HPLC grade water), (A=90% HPLC grade water/0.1% trifluoroacetic acid/10% HPLC grade methanol), in 4 minutes with a 1 minute hold at a rate of 4 mL/minute. 1H NMR (400 MHz, THF-d8) δ ppm 1.25-1.31 (m, 2H), 1.59-1.66 (m, 2H), 2.90 (d, J=4.52 Hz, 3H), 6.91 (d, J=8.53 Hz, 1H), 7.08 (dd, J=6.90, 5.40 Hz, 1H), 7.17-7.24 (m, 2H), 7.45-7.65 (m, 5H), 7.79 (dd, J=8.41, 2.13 Hz, 1H), 7.88 (d, J=1.25 Hz, 1H), 7.93 (d, J=2.01 Hz, 1H), 8.08-8.17 (m, 2H), 8.39-8.45 (m, 1H), 8.49 (br. s., 1H). LCMS Rt=1.495 min., m/z 522.33 (M+H), 94% purity.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[C:4]([O:11][CH3:12])[CH:3]=1.Cl[C:14]([S:16]Cl)=[O:15].O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]2[O:7][C:14](=[O:15])[S:16][N:8]=2)=[C:4]([O:11][CH3:12])[CH:3]=1
Reactant: COc1cc(Cl)ccc1C(N)=O
Reactant: O=C(Cl)SCl
Solvent: Cc1ccccc1
Solvent: O
Product: COc1cc(Cl)ccc1-c1nsc(=O)o1
Temperature: 90 °C
Yield: 95.6 %

Procedure:
To a solution of 4-chloro-2-methoxybenzamide (0.82 g, 4.42 mmol) in toluene (20 ml) was added chlorocarbonylsulfenyl chloride (0.73 ml, 8.84 mmol) under nitrogen atmosphere and the resulting reaction mixture was refluxed at 90° C. for 2 h. After the completion of the reaction (TLC monitoring) water was added followed by extraction with ether (3×50 ml). The combined organics was then sequentially washed with water, 10% NaHCO3 (aqueous solution) and finally again with water. The organic layer was then dried over anhydrous Na2SO4, filtered and concentrated to get desired product (1.03 g, 96% crude yield) that was carried forward as such without further purification. MS: 244.16 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][C@@H:38]4[C@@H:36]([CH:37]4[C:40]([OH:42])=O)[CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:43][CH2:44][CH3:45])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:46][CH2:47][CH2:48][OH:49]>>[OH:49][CH2:48][CH2:47][NH:46][C:40]([CH:37]1[C@@H:36]2[C@H:38]1[CH2:39][N:34]([C:32]([N:12]1[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=[C:11]1[C:8]1[CH:9]=[N:10][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:6][C:7]=1[O:43][CH2:44][CH3:45])=[O:33])[CH2:35]2)=[O:42]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1C[C@@H]2C(C(=O)O)[C@@H]2C1
Reactant: NCCO
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1C[C@@H]2C(C(=O)NCCO)[C@@H]2C1

Procedure:
In a manner analogous to the method described in examples 99, (1S,5R)-3-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-3-aza-bicyclo[3.1.0]hexane-6-carboxylic acid (prepared from the ethyl ester, example 135) was coupled with 2-aminoethanol (Aldrich) to give the title compound. HR-MS (ES, m/z) calculated for C37H44Cl2N5O4 [(M+H)+] 692.2765, observed 692.2768.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.[N:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][C:26]=2[N:28]2[CH2:33][CH2:32][C:31](=O)[CH2:30][CH2:29]2)[CH:21]=[CH:20][CH:19]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClC(Cl)C>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([N:12]3[CH2:17][CH2:16][N:15]([CH:31]4[CH2:30][CH2:29][N:28]([C:26]5[CH:25]=[CH:24][CH:23]=[C:22]6[C:27]=5[N:18]=[CH:19][CH:20]=[CH:21]6)[CH2:33][CH2:32]4)[CH2:14][CH2:13]3)[CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2
Reactant: O=C1CCN(c2cccc3cccnc23)CC1
Reactant: Fc1cc(N2CCNCC2)c2ncccc2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: Fc1cc(N2CCN(C3CCN(c4cccc5cccnc45)CC3)CC2)c2ncccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.4 %

Procedure:
To a solution of 0.247 g of 6-fluoro-8-piperazino-quinoline (Step 3) in 10 mL of dichloroethane, was added 0.226 g of 1-quinolin-8-yl-piperidin-4-one (Example A, Step 6, above) followed by 0.274 g of sodium triacetoxyborohydride and 0.1 mL acetic acid. The reaction was stirred at room temperature overnight. It was quenched with 1N NaOH, and the product was extracted with CH2Cl2. The organic phase was washed with water and dried over magnesium sulfate. The product crystallized and filtered to give 0.200 g of the desired product. Mp: 211° C.; MS (ES) m/z (relative intensity): 442 (M++−H, 100).
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8][O:9][N:10]=[C:11]([C:15]1[N:16]=[C:17]([NH:20][CH:21]=[O:22])[S:18][CH:19]=1)[C:12]([OH:14])=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:23]1([C:29]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[N+]=[N-])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(OCC)(=O)C.O1CCCC1>[C:1]([O:5][C:6]([CH2:8][O:9][N:10]=[C:11]([C:15]1[N:16]=[C:17]([NH:20][CH:21]=[O:22])[S:18][CH:19]=1)[C:12]([O:14][CH:29]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:13])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: [N-]=[N+]=C(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)CON=C(C(=O)O)c1csc(NC=O)n1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)CON=C(C(=O)OC(c1ccccc1)c1ccccc1)c1csc(NC=O)n1

Procedure:
To a solution of 2-t-butoxycarbonylmethoxyimino-2-(2-formamidothiazol-4-yl)acetic acid (syn isomer) (65.9 g) in ethyl acetate (300 ml) and tetrahydrofuran (200 ml) was dropwise added a solution of diphenyldiazomethane in ethyl acetate (1 m mol/ml, 200 ml) at ambient temperature and the mixture was stirred for an hour. The resultant mixture was washed with saturated aqueous solution of sodium bicarbonate and brine, and dried over magnesium sulfate. The solution was evaporated to give benzhydryl 2-t-butoxycarbonylmethoxyimino-2-(2-formamidothiazol-4-yl)acetate (syn isomer) (99.3 g). To the solution of benzhydryl 2-t-butoxycarbonylmethoxyimino-2-(2-formamidothiazol-4-yl)acetate (syn isomer) (99.0 g) in methanol (500 ml) was added conc. hydrochloric acid (41.6 g) at ambient temperature and the mixture was stirred at the same temperature for 1.5 hours. The reaction mixture was poured into a solution of sodium bicarbonate (33.6 g) in water (2.5 l) and extracted with ethyl acetate. The extracts were washed with brine and dried over magnesium sulfate. The solution was evaporated and the residue was pulverized with ether to give benzhydryl 2-t-butoxycarbonylmethoxyimino-2-(2-aminothiazol-4-yl)acetate (syn isomer) (72.3 g).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[OH-].[Na+].Cl[C:11]1[N:16]=[C:15]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[N:14]=[C:13]([N:23]2[C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=3[N:25]=[C:24]2[CH:32]([F:34])[F:33])[N:12]=1.COCCOCCN(CCOCCOC)CCOCCOC>O.O1CCOCC1>[F:34][CH:32]([F:33])[C:24]1[N:23]([C:13]2[N:14]=[C:15]([N:17]3[CH2:18][CH2:19][O:20][CH2:21][CH2:22]3)[N:16]=[C:11]([O:1][C:2]3[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=3)[N:12]=2)[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[N:25]=1
Reactant: FC(F)c1nc2ccccc2n1-c1nc(Cl)nc(N2CCOCC2)n1
Reactant: Oc1cccnc1
Agent: COCCOCCN(CCOCCOC)CCOCCOC
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: FC(F)c1nc2ccccc2n1-c1nc(Oc2cccnc2)nc(N2CCOCC2)n1
Yield: 11.9 %

Procedure:
A mixture of 0.301 g (3.16 mmol) of 3-hydroxypyridine and 0.132 g (3.30 mmol) of NaOH was stirred in water until a clear solution was obtained. The water was removed and the residue was combined with a mixture of 0.301 g (3.16 mmol) of 1-[4-chloro-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-1H-benzimidazole and 0.02 g (0.06 mmol) of tris[2-(2-methoxyethoxy)ethyl]amine (TDA-1) in dioxane (12 mL). The resulting mixture was heated under reflux for 2 hr before being cooled, and diluted with water. The resulting precipitate was collected by filtration, and recrystallized from methanol to give 0.160 g (50% yield) of 2-(difluoromethyl)-1-[4-(4-morpholinyl)-6-(3-pyridinyloxy)-1,3,5-triazin-2-yl]-1H-benzimidazole: mp 229-231° C.; 1H NMR (CDCl3) δ8.63-8.60 (m, 2H), 8.12 (dd, J=7.1, 1.4 Hz, 1H), 7.87 (dd, J=7.1, 1.4 Hz, 1H), 7.59 (ddd, J=8.3, 2.7, 1.4 Hz, 1H), 7.45 (ddd, J=8.2, 4.6, 0.3 Hz, 1H), 7.41-7.34 (m, 2H), 7.25 (t, JHF=53.6 Hz, 1H), 3.99-3.96 (m, 2H), 3.89-3.83 (m, 4H), 3.79-3.77 (m, 2H); Anal. Calcd. for C20H17F2N7O2 0.7H2O: C, 54.8; H, 4.2; N, 22.4. Found: C, 54.5; H, 4.0; N, 22.0%.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([CH2:12][C:13]1[N:17]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][CH:20]=3)[CH:16]=[N:15][CH:14]=1)[CH2:7]2.[Cl:27][C:28]1[CH:33]=[C:32]([Cl:34])[CH:31]=[CH:30][C:29]=1B(O)O>COCCOC.O.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>[Cl:27][C:28]1[CH:33]=[C:32]([Cl:34])[CH:31]=[CH:30][C:29]=1[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([CH2:12][C:13]1[N:17]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][CH:20]=3)[CH:16]=[N:15][CH:14]=1)[CH2:7]2
Reactant: N#Cc1ccc(Cn2cncc2CN2CCc3c(Br)cccc3C2)cc1
Reactant: OB(O)c1ccc(Cl)cc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: COCCOC
Product: N#Cc1ccc(Cn2cncc2CN2CCc3c(cccc3-c3ccc(Cl)cc3Cl)C2)cc1

Procedure:
A solution of 5-bromo-2-(1-(4-cyanobenzyl)-5-imidazolylmethyl)-1,2,3,4-tetrahydroisoquinoline (Example 10; 100 mg, 250 0.25 mmol), 2,4-dichlorophenyl boronic acid (53 mg, 0.275 mmol) and tetrakis(triphenylphosphine)palladium(0) in DME (2 mL) and water (0.5 mL) was heated to 80° C. for 20 h. The mixture was partitioned between water and EtOAc, washed with aqueous NaHCO3, water (2×), dried and evaporated. Column chromatography of the residue (silica gel; CHCl3 /MeOH 80:1) afforded the title compound as a white solid. FAB ms (m+1) 473.2
Reaction SMILES: [CH:1]1([C:6]2([CH2:14][CH2:15][C:16]3[CH:21]=[C:20]([CH2:22][CH3:23])[C:19]([OH:24])=[CH:18][C:17]=3[O:25][CH3:26])[O:11][C:10](=[O:12])[CH2:9][C:8](=[O:13])[CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:27]([C:29]1[NH:30][C:31]([CH:35]=O)=[C:32]([CH3:34])[N:33]=1)[CH3:28].CC1C=NC2N(N=C(C=O)N=2)C=1>>[CH:1]1([C:6]2([CH2:14][CH2:15][C:16]3[CH:21]=[C:20]([CH2:22][CH3:23])[C:19]([OH:24])=[CH:18][C:17]=3[O:25][CH3:26])[O:11][C:10](=[O:12])[C:9]([CH2:35][C:31]3[N:30]=[C:29]([CH2:27][CH3:28])[NH:33][C:32]=3[CH3:34])=[C:8]([OH:13])[CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCc1cc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)c(OC)cc1O
Reactant: CCc1nc(C)c(C=O)[nH]1
Agent: Cc1cnc2nc(C=O)nn2c1
Product: CCc1nc(CC2=C(O)CC(CCc3cc(CC)c(O)cc3OC)(C3CCCC3)OC2=O)c(C)[nH]1

Procedure:
The title compound was prepared analogously to Example A(126), where 6-Cyclopentyl-6-[2-(5-ethyl-4-hydroxy-2-methoxy-phenyl)-ethyl]-dihydro-pyran-2,4-dione was substituted in place of 6-Cyclopentyl-6-[2-(3-ethyl-4-hydroxy-phenyl)-ethyl-dihydro-pyran-2,4-dione and 2-ethyl-5-formyl-4-methylimidazole was substituted in place of 6-Methyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde of that example. 1H NMR (400 MHz, DMSO-d6): δ 1.07-1.34 (m, 6H), 1.49-1.81 (m, 10H), 2.13 (s, 3H), 2.28-2.35 (m, 1H), 2.39-2.68 (m, 8H), 3.40 (d, J=6.9 Hz, 2H), 3.68 (s, 3H), 6.41 (s, 1H), 6.74 (s, 1H). Anal. Calcd. For C28H38N2O5.1H2O: C, 67.18; H, 8.05; N, 5.60. Found: C, 67.50; H, 8.09; N, 5.60. MS(ESI): 483.2 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4]([N:7]([CH2:10][CH3:11])[CH2:8][CH3:9])[C:3]=1[C:12]#[N:13].[CH3:14][N:15]=[C:16]=[O:17]>C([O-])(=O)C.C([O-])(=O)C.C([Sn+2]CCCC)CCC.O1CCCC1>[CH3:14][NH:15][C:16]([NH:1][C:2]1[S:6][N:5]=[C:4]([N:7]([CH2:8][CH3:9])[CH2:10][CH3:11])[C:3]=1[C:12]#[N:13])=[O:17]
Reactant: CN=C=O
Reactant: CCN(CC)c1nsc(N)c1C#N
Agent: CC(=O)[O-]
Agent: CCCC[Sn+2]CCCC
Solvent: C1CCOC1
Product: CCN(CC)c1nsc(NC(=O)NC)c1C#N

Procedure:
A mixture of 9.8 g of 5-amino-4-cyano-3-(diethylamino)isothiazole, 20 drops of dibutyltin diacetate, and about 15 ml of methyl isocyanate in 50 ml of dry tetrahydrofuran was heated under reflux for 21 hours, at which time thin-layer chromatographic analysis indicated reaction to be complete. The solution was concentrated under reduced pressure and the residue was recrystallized from ethanol to give 11.7 g of white 1-methyl-3-(4-cyano-3-(diethylamino)-5-isothiazolyl)urea, m.p. 182°-183°. The nmr spectrum was consistent with the assigned structure.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][C:13]([F:16])([F:15])[F:14])=[CH:9][CH:10]=2)[N+:5]([O-:17])=[CH:4][CH:3]=1.[OH-:18].[K+]>>[OH:18][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][C:13]([F:16])([F:15])[F:14])=[CH:9][CH:10]=2)[N+:5]([O-:17])=[CH:4][CH:3]=1
Reactant: [OH-]
Reactant: [O-][n+]1ccc(Cl)c2ccc(OC(F)(F)F)cc21
Agent: [K+]
Product: [O-][n+]1ccc(O)c2ccc(OC(F)(F)F)cc21

Procedure:
4-Chloro-7-trifluoromethoxyquinoline-1-oxide (9.4 g) and potassium hydroxide (20.0 g) were dissolved in industrial methylated spirit (320 ml) and the solution was heated under reflux for 90 minutes. The solvent was removed by evaporation and the residue dissolved in water (100 ml). Glacial acetic acid (40 ml) was added at 0 to 5°, the precipitate collected, washed with water (2×10 ml) and crystallised from methanol (120 ml) to give the novel compound 4-hydroxy-7-trifluoromethoxyquinoline-1-oxide, m.p. 80°-181°.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:3]=1[NH2:4].CCN(C(C)C)C(C)C.[C:21](Cl)(=[O:23])[CH3:22]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Br:1][C:2]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:3]=1[NH:4][C:21](=[O:23])[CH3:22]
Reactant: CC(=O)Cl
Reactant: Nc1cc([N+](=O)[O-])ccc1Br
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)Nc1cc([N+](=O)[O-])ccc1Br
Temperature: 0 °C
Reaction time: 3 h

Procedure:
2-Bromo-5-nitroaniline (10 g) was dissolved in 500 mL of CH2Cl2, DIEA (6.6 g) was added to the mixture, followed by DMAP (100 mg). The mixture was cooled to 0° C. in ice bath. Acetyl chloride (4 g in 50 mL CH2Cl2) was added dropwise to the reaction mixture. After the mixture was stirred at RT over 3 h, extracted once with saturated NaHCO3 solution and once with brine, the resulting organic layer was dried over MgSO4, filtered and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel with 1:1 EtOAc:Hexane to 100% EtOAc to afford N-(2-bromo-5-nitrophenyl)acetamide as a white solid. MS: 258 (M−1). Calc'd. for C8H7BrN2O3—259.06.
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[F:15][C:16]1[CH:21]=[CH:20][C:19]([CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[CH:18][CH:17]=1.[C:28]([OH:33])(=[O:32])[C:29]([OH:31])=[O:30].CO>C(OCC)(=O)C>[C:28]([OH:33])(=[O:32])[C:29]([OH:31])=[O:30].[NH:10]1[C:11]2[C:7](=[C:6]([O:5][CH2:4][C@@H:2]([OH:1])[CH2:3][N:25]3[CH2:26][CH2:27][CH:22]([C:19]4[CH:18]=[CH:17][C:16]([F:15])=[CH:21][CH:20]=4)[CH2:23][CH2:24]3)[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: Fc1ccc(C2CCNCC2)cc1
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Agent: O=C(O)C(=O)O
Solvent: CO
Solvent: CCOC(C)=O
Product: O[C@H](COc1cccc2[nH]ccc12)CN1CCC(c2ccc(F)cc2)CC1

Procedure:
The title compound was prepared in similar fashion from (S)-(+)-4-(oxiranylmethoxy)-1H-indole and 4-(4-fluorophenyl)piperidine. The resulting free base was dissolved in ethyl acetate, and precipitated with one equivalent of oxalic acid in ethyl acetate in 30% overall yield. FDMS m/e=369 (M+ of free base). α[D]589 =-2.49 (c=0.24, methanol).