Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=C(Cl)[O:3][C:4](Cl)(Cl)Cl.[F:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][CH2:17][C:18]2[C:19]([NH:26][CH3:27])=[N:20][C:21]([S:24][CH3:25])=[N:22][CH:23]=2)=[CH:12][C:11]=1[N+:28]([O-:30])=[O:29].CCN(CC)CC>O1CCOCC1>[F:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH2:17][C:18]3[C:19](=[N:20][C:21]([S:24][CH3:25])=[N:22][CH:23]=3)[N:26]([CH3:27])[C:4]2=[O:3])=[CH:12][C:11]=1[N+:28]([O-:30])=[O:29]
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: CNc1nc(SC)ncc1CNc1ccc(F)c([N+](=O)[O-])c1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CSc1ncc2c(n1)N(C)C(=O)N(c1ccc(F)c([N+](=O)[O-])c1)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.9 %

Procedure:
To a solution of diphosgene (3.5 g, 17.7 mmol) in dioxane (350 mL) at 0° C. was slowly added a solution comprised of 5-((4-fluoro-3-nitrophenylamino)methyl)-N-methyl-2-(methylthio)pyrimidin-4-amine (5.2 g, 16.1 mmol) and Et3N (4.5 mL, 32.1 mmol) in dioxane (250 mL). The resultant reaction mixture was stirred at RT overnight. The solvent was removed in vacuo and the residue was partitioned between EtOAc and H2O. The combined organics were dried (Na2SO4) and concentrated to give crude product, which was washed with cold MeOH (5 mL) to give 3-(4-fluoro-3-nitrophenyl)-1-methyl-7-(methylthio)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (5.0 g, 89% yield) as a brown solid. 1H NMR (300 MHz, DMSO-d6): δ 8.26 (s, 1 H), 8.20 (m, 1 H), 7.82 (m, 1 H), 7.64 (dd, J=6.9, 8.4 Hz, 1 H), 4.82 (s, 2 H), 3.29 (s, 3 H), 2.50 (s, 3 H); MS (ESI) m/z: 350.3 (M+H+).
Reaction SMILES: O.[OH-].[Li+:3].[OH-].[Ca+2:5].[OH-].[OH:7][CH:8]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20]>>[OH:7][CH:8]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O-:21])=[O:20].[Ca+2:5].[Li+:3].[OH:7][CH:8]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O-:21])=[O:20].[OH:7][CH:8]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O-:21])=[O:20]
Reactant: CCCCCCC(O)CCCCCCCCCCC(=O)O
Agent: [Ca+2]
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: CCCCCCC(O)CCCCCCCCCCC(=O)[O-]
Temperature: 100 °C
Reaction time: 1 h

Procedure:
A grease kettle equipped with stirring, heating and an external recirculation system, capable of pumping the contents from the bottom of the kettle to the top, was charged with 4428.6 grams of high viscosity index (HVI) mineral oil of viscosity 110 mm2 /s (cSt) at 40° C., 50.0 grams of lithium hydroxide monohydrate and 21.4 grams of hydrated lime. The mixture was stirred and heated to 100° C. while the heating rate was maintained to control foaming. After foaming stopped, recirculation was started and the mixture was stirred and heated at 140° C. Over a 10 to 15 minute period, 500 grams of 12-hydroxystearic acid was added slowly to control foaming. After the neutralization step was complete, the charge was heated to 150° C. with stirring and recirculation. The charge was held at this temperature for approximately one hour until the product began to thicken. The heat was then shut off and the charge allowed to cool to below 100° C. while stirring and recirculation were maintained. A portion of the resulting grease. having a soap thickener content of about 1O% w, was then passed through a Mantin Gaulin homogenizer at a pressure of 41000 kPa. The resulting smooth grease was designated Grease I-A.
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)OC1.[C:13](=[O:16])(O)[O-].[Na+]>>[NH2:2][CH:3]1[CH2:12][CH2:11][C:10]2[C:13](=[CH:6][CH:7]=[CH:8][CH:9]=2)[O:16]1
Reactant: O=C([O-])O
Reactant: NC1COc2ccccc2C1
Agent: Cl
Agent: [Na+]
Product: NC1CCc2ccccc2O1

Procedure:
3-aminochroman hydrochloride (0.37 g, 2 mmol) was neutralized with aqueous sodium bicarbonate, extracted with diethyl ether, dried with magnesium sulfate, and the solvent evaporated to give 2-aminochroman.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:15]=[CH:14][CH:13]=[CH:12][C:7]=1[C:8]([O:10]C)=[O:9])[CH:2]([CH3:4])[CH3:3].[OH-].[Na+].C(OCC)(=O)C.Cl>CO.O>[CH2:1]([O:5][C:6]1[CH:15]=[CH:14][CH:13]=[CH:12][C:7]=1[C:8]([OH:10])=[O:9])[CH:2]([CH3:4])[CH3:3]
Reactant: COC(=O)c1ccccc1OCC(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: O
Product: CC(C)COc1ccccc1C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 102 %

Procedure:
In 20 ml of methanol is dissolved 4.1 g of methyl 2-isobutoxybenzoate. After adding 6 ml of 5 mol/L solution of sodium hydroxide, the mixture thus obtained is stirred at ambient temperature for 2 hours. Ethyl acetate and water are added to the reaction mixture, pH is adjusted to 2 with 2 mol/L hydrochloric acid, and the organic layer is separated. The organic layer thus obtained is washed with water and saturated aqueous solution of sodium chloride successively and dried over anhydrous magnesium sulfate, and then the solvent is distilled off under reduced pressure. Thus, 3.9 g of 2-isobutoxybenzoic acid is obtained as a colorless crystalline product.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([C:15]([OH:17])=O)=[CH:10][CH:9]=2)=[O:5].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[CH:40]1([N:45]2[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]2)[CH2:44][CH2:43][CH2:42][CH2:41]1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH2:2]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([C:15]([N:48]1[CH2:49][CH2:50][N:45]([CH:40]3[CH2:44][CH2:43][CH2:42][CH2:41]3)[CH2:46][CH2:47]1)=[O:17])=[CH:10][CH:9]=2)=[O:5])[CH3:1]
Reactant: CCOC(=O)c1cc2cc(C(=O)O)ccc2[nH]1
Reactant: C1CCC(N2CCNCC2)C1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2cc(C(=O)N3CCN(C4CCCC4)CC3)ccc2[nH]1
Yield: 74 %

Procedure:
The title compound was synthesized in analogy to example 1, intermediate 1 a), from 1H-indole-2,5-dicarboxylic acid 2-ethyl ester, O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (commercially available), 1-cyclopentylpiperazine (commercially available) and N,N-diisopropylethylamine in N,N-dimethylformamide, to give the desired product as a light brown solid (74%).
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)Cl.[Cl:7][C:8]1[C:9]([C:23](=O)[NH:24][CH3:25])=[C:10]2[C:15](=[CH:16][C:17]=1[Cl:18])[N:14]=[C:13]([O:19][CH3:20])[C:12]([O:21][CH3:22])=[N:11]2.C[Si]([N:31]=[N+:32]=[N-:33])(C)C.N>C1(C)C=CC=CC=1>[Cl:7][C:8]1[C:9]([C:23]2[N:24]([CH3:25])[N:33]=[N:32][N:31]=2)=[C:10]2[C:15](=[CH:16][C:17]=1[Cl:18])[N:14]=[C:13]([O:19][CH3:20])[C:12]([O:21][CH3:22])=[N:11]2
Reactant: CNC(=O)c1c(Cl)c(Cl)cc2nc(OC)c(OC)nc12
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: N
Solvent: Cc1ccccc1
Product: COc1nc2cc(Cl)c(Cl)c(-c3nnnn3C)c2nc1OC
Temperature: 25 °C
Reaction time: 18 h
Yield: 37.8 %

Procedure:
Phosphorous pentachloride (0.136 g, 0.65 mmol) was added to a solution of 6,7-dichloro-2,3-dimethoxy-5-(N-methylcarbamoyl)quinoxaline (Preparation 7, 0.197 g, 0.62 mmol) in toluene (7 mL) and the mixture was heated under reflux under nitrogen for 1 hour. The reaction was cooled to room temperature and trimethylsilyl azide (123 μL, 0.107 g, 0.93 mmol) was added. After stirring at room temperature for 18 hours, dilute aqueous ammonia solution (20 mL) was added and the mixture was extracted with dichloromethane (3×50 mL). The combined organic extracts were dried (MgSO4) and evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel, eluting with dichloromethane to give the title compound (0.080 g, 38%) as a white solid.
Reaction SMILES: [C:1]([O:6][CH2:7][CH3:8])(=[O:5])[CH:2]([CH3:4])[CH3:3].C1COCC1.[Li+].CC([N-]C(C)C)C.[Br:22][CH2:23][CH2:24][CH2:25][CH2:26]Br>CN(P(N(C)C)(N(C)C)=O)C>[Br:22][CH2:23][CH2:24][CH2:25][CH2:26][C:2]([C:1]([O:6][CH2:7][CH3:8])=[O:5])([CH3:4])[CH3:3]
Reactant: BrCCCCBr
Reactant: CCOC(=O)C(C)C
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: CCOC(=O)C(C)(C)CCCCBr
Temperature: -78 °C
Reaction time: 1 h
Yield: 66.5 %

Procedure:
In a 1-L 3-neck round-bottomed flask fitted with condenser, dropping funnel pressure equalizer and magnetic stirrer, purged with argon and maintained under argon, were added ethyl isobutyrate (84 ml, 0.63 mol) and THF (120 ml). The mixture was cooled to −78° C., when a solution of LDA (300 ml, 2.0 M in THF/heptane) was added dropwise with a syringe. After the addition was complete, the reaction mixture was stirred at −78° C. for 1 hr. To this mixture, 1,4-dibromobutane (105 ml, 0.84 mol) was added at −78° C., followed by HMPA (90 ml). The reaction mixture was stirred for 30 min at −78° C., then the cooling was stopped. The reaction was left to warm to room temperature, and was quenched with a saturated NH4Cl solution (1.8 L). The aqueous layer was extracted with ethyl acetate (3×100 ml), the organic extracts combined were washed with brine (100 ml), 5% HCl (100 ml) and saturated NaHCO3 (100 ml). The organic phase was dried (MgSO4) and the solvent was evaporated under vacuum. The residue was distilled under reduced pressure to provide the above-titled compound (105.2 g, 70%) (bp 65° C./0.15 mmHg). 1H NMR CDCl3, δ (ppm): 4.15 (q, J=4 Hz, 2H), 3.41 (t, J=5.3 Hz, 2H), 1.85 (qv, J=4 Hz, 2H), 1.60-1.45 (m, 2H), 1.40-1.30 (m, 2H), 1.28 (t, J=4 Hz, 3H), 1.20 (s, 6H); 13C NMR CDCl3, δ (ppm): 177.3, 60.0, 41.8; 39.4, 33.2, 32.9, 24.9, 23.34, 14.02.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:30]=[CH:29][CH:28]=[CH:27][C:4]=1[O:5][C:6]1[C:13]([O:14][CH2:15][CH2:16][O:17]C2CCCCO2)=[CH:12][C:9]([C:10]#[N:11])=[CH:8][C:7]=1[N+:24]([O-])=O.O.O.[Sn](Cl)Cl>C(O)C.Cl>[NH2:24][C:7]1[CH:8]=[C:9]([CH:12]=[C:13]([O:14][CH2:15][CH2:16][OH:17])[C:6]=1[O:5][C:4]1[CH:27]=[CH:28][CH:29]=[CH:30][C:3]=1[O:2][CH3:1])[C:10]#[N:11]
Reactant: COc1ccccc1Oc1c(OCCOC2CCCCO2)cc(C#N)cc1[N+](=O)[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Product: COc1ccccc1Oc1c(N)cc(C#N)cc1OCCO
Temperature: 25 °C
Reaction time: 12 h

Procedure:
3.5 g of 4-(2-methoxy-phenoxy)-3-nitro-5-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-benzonitrile were dissolved in ethanol (100 ml), a solution of tin dichloride dihydrate (7.6 g) in 37% HCl (17 ml) was added dropwise thereto at room temperature and the mixture was subsequently stirred at room temperature for 12 hours. The mixture was poured on to ice-water, adjusted to pH 7 and the product was extracted with ethyl acetate. After usual processing of the organic phase there was obtained 3-amino-5-(2-hydroxy-ethoxy)-4-(2-methoxy-phenoxy)-benzonitrile as a crystalline solid.
Reaction SMILES: [CH:1]1[C:12]2[CH2:11][CH2:10][C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[CH2:7][NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:17]([C:25]1[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[CH:27][CH:26]=1)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[C:17]([C:25]1[CH:26]=[CH:27][C:28]([C:29]([N:6]2[CH2:7][C:8]3[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=3[CH2:10][CH2:11][C:12]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]2=3)=[O:30])=[CH:32][CH:33]=1)(=[O:24])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: c1ccc2c(c1)CCc1ccccc1NC2
Reactant: O=C(Cl)c1ccc(C(=O)c2ccccc2)cc1
Product: O=C(c1ccccc1)c1ccc(C(=O)N2Cc3ccccc3CCc3ccccc32)cc1

Procedure:
As described for Example 26, 5,6,11,12-tetrahydrodibenz[b,f]azocine is reacted with 4-(benzoyl)benzoyl chloride to give the product as a solid, m.p. 89°-92° C., Mass spectrum (CI), 418(MH+)
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:5]=[C:6](N)[C:7]2[C:8]([N:23]=1)=[N:9][C:10]([C:13]1[C:18]([C:19]([F:22])([F:21])[F:20])=[CH:17][CH:16]=[CH:15][N:14]=1)=[CH:11][N:12]=2.N([O-])=[O:26].[Na+]>C(O)(=O)C.O>[CH3:1][O:2][CH2:3][C:4]1[CH:5]=[C:6]([OH:26])[C:7]2[C:8]([N:23]=1)=[N:9][C:10]([C:13]1[C:18]([C:19]([F:22])([F:21])[F:20])=[CH:17][CH:16]=[CH:15][N:14]=1)=[CH:11][N:12]=2
Reactant: O=N[O-]
Reactant: COCc1cc(N)c2ncc(-c3ncccc3C(F)(F)F)nc2n1
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COCc1cc(O)c2ncc(-c3ncccc3C(F)(F)F)nc2n1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
6-Methoxymethyl-3-(3-trifluoromethyl-pyridin-2-yl)-pyrido-[2,3-b]pyrazin-8-ylamine (252 mg, 0.751 mmol) is dissolved in a solution of acetic acid (2 mL) and water (5 mL). The mixture is heated to 50° C. and sodium nitrite (362 mg, 5.26 mmol) is added in portions over 1 hour. The solution is warmed to 70° C. and stirred overnight. Water (20 mL) is added and the aqueous mixture is extracted with EtOAc (4×50 mL). The combined organic extracts are washed with brine and dried over Na2SO4. The solvent is removed under reduced pressure. The crude product is chromatographed on silica gel eluting with hexanes/acetone (1:1) to afford the title compound as a white solid.
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[CH:4]=[C:5]([CH:22]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:24]=1)[CH2:6][O:7][CH2:8][C:9]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:15][CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.[CH:31]1([CH:34]=O)[CH2:33][CH2:32]1.C([BH3-])#N.[Na+]>CO.FC(F)(F)C(O)=O>[F:30][C:2]([F:29])([F:1])[C:3]1[CH:4]=[C:5]([CH:22]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:24]=1)[CH2:6][O:7][CH2:8][C:9]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:15][CH2:14][CH2:13][N:12]([CH2:34][CH:31]2[CH2:33][CH2:32]2)[CH2:11][CH2:10]1
Reactant: FC(F)(F)c1cc(COCC2(c3ccccc3)CCCNCC2)cc(C(F)(F)F)c1
Reactant: O=CC1CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: FC(F)(F)c1cc(COCC2(c3ccccc3)CCCN(CC3CC3)CC2)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 41.5 %

Procedure:
Mixture of isomer A of 4-((3,5-bis(trifluoromethyl)benzyloxy)methyl)-4-phenylazepane (3 mg) and cyclopropanecarbaldehyde (1.4 mg) in methanol (0.15 mL) was stirred at room temperature for 0.5 hr, then sodium cyanoborohydride (1.0 M solution in THF, 0.02 mL) was added followed by 1 drop of trifluoroacetic acid. The mixture was stirred at room temperature for overnight and concentrated under vacuum. Then saturated sodium bicarbonate and dichloromethane was added to the mixture and the organic layer was separated. The aqueous layer was extracted with dichloromethane 2 times and the combined organic layers were dried over magnesium sulfate, filtered and concentrated under vacuum to give the product as a clear sticky oil (1.4 mg, 41% yield).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][C@@H:15]([C:34]([NH:36][C@H:37]1[CH2:41][CH2:40][CH2:39][C@H:38]1[C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])=[O:35])[NH:16]C(OCC1C2C=CC=CC=2C2C1=CC=CC=2)=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1CCCCC1>C(Cl)(Cl)Cl>[CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][C@@H:15]([C:34]([NH:36][C@H:37]1[CH2:41][CH2:40][CH2:39][C@H:38]1[C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])=[O:35])[NH2:16])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)[C@@H]1CCC[C@@H]1NC(=O)[C@H](CCCNC(=O)OCc1ccccc1)NC(=O)OCC1c2ccccc2-c2ccccc21
Solvent: ClC(Cl)Cl
Solvent: C1CCNCC1
Product: CC(C)(C)OC(=O)[C@@H]1CCC[C@@H]1NC(=O)[C@@H](N)CCCNC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 13 h
Yield: 98.3 %

Procedure:
To a mixture of tert-butyl (1R,2S)-2-({N5-[(benzyloxy)carbonyl]-N2-[(9H-fluorene -9-ylmethoxy)carbonyl]-L-ornithyl}amino)cyclopentanecarboxylate (4.0 g) and chloroform(80 ml) was added piperidine (6.0 ml) under ice-cooling, followed by stirring at room temperature for 13 hours. The reaction mixture was washed with a saturated sodium bicarbonate solution, water, and saturated brine in this order, and the organic layer was dried over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1, and then 0→2→5% methanol/chloroform) to obtain tert-butyl (1R,2S)-2-({N5-[(benzyloxy)carbonyl]-L-ornithyl}amino)cyclopentanecarboxylate (2.6 g).
Reaction SMILES: C(O[C:4]([C:6]1[CH:20]=[CH:19][C:9]2[N:10]=[C:11]([NH:13][C:14]([NH:16][CH2:17][CH3:18])=[O:15])[S:12][C:8]=2[CH:7]=1)=[O:5])C.[C:21](#[N:23])[CH3:22].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.C1COCC1>CN(C=O)C>[C:21]([CH2:22][C:4]([C:6]1[CH:20]=[CH:19][C:9]2[N:10]=[C:11]([NH:13][C:14]([NH:16][CH2:17][CH3:18])=[O:15])[S:12][C:8]=2[CH:7]=1)=[O:5])#[N:23]
Reactant: CC#N
Reactant: CCNC(=O)Nc1nc2ccc(C(=O)OCC)cc2s1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCNC(=O)Nc1nc2ccc(C(=O)CC#N)cc2s1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 54 %

Procedure:
A solution of 1-(6-ethoxycarbonyl-2-benzothiazolyl)-3-ethylurea (1.20 g, 4.09 mmol) in 5 mL of anhydrous DMF was treated with 2 mL of acetonitrile, cooled down to about 0° C., followed by treatment with 1 M LiHMDS in THF (13.1 mL, 13.1 mmol, 3.2 eq). It was stirred at the temperature for about 0.5 hour, then warmed up to room temperature, and stirred for another 4 hours. More LiHMDS (4 mL, 4.0 mmol, 1.0 eq) was added after the first hour. The mixture was quenched with MeOH and water, concentrated, and purified by flash chromatography on SiO2 with MeOH and methylene chloride (1/50) to give the desired compound 0.640 g (54%). LC/MS 288.9 (M+1); LC retention time 2.56 min.
Reaction SMILES: C[O:2][C:3](=[O:22])[C:4]1[CH:9]=[C:8]([O:10][C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=2[F:18])[CH:7]=[CH:6][C:5]=1[N+:19]([O-:21])=[O:20].[OH-].[Na+].Cl>O.CO>[F:18][C:12]1[CH:13]=[C:14]([F:17])[CH:15]=[CH:16][C:11]=1[O:10][C:8]1[CH:7]=[CH:6][C:5]([N+:19]([O-:21])=[O:20])=[C:4]([CH:9]=1)[C:3]([OH:22])=[O:2]
Reactant: COC(=O)c1cc(Oc2ccc(F)cc2F)ccc1[N+](=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1cc(Oc2ccc(F)cc2F)ccc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 85.5 %

Procedure:
To a solution of compound (1A) (66 g, 0.21 mol) in water/MeOH (180/180 mL) was added NaOH (27 g, 0.68 mol), and the mixture was heated to reflux for 2 h. After cooling to room temperature, the reaction was acidified with 10% HCl and extracted into EtOAc. The organic layer was washed with brine, dried over sodium sulfate, concentrated in vacuo, and crystallized from ether/hexane to afford 53 g of 5-(2,4-difluoro-phenoxy)-2-nitro-benzoic acid (1B).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][N:24]=1)[C:5]([NH:7][C:8]1[S:9][CH:10]=[C:11]([C:13]2[C:18]([CH3:19])=[CH:17][C:16]([CH3:20])=[CH:15][C:14]=2[CH3:21])[N:12]=1)=[O:6].C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:31][NH:32][CH3:33].C1COCC1>CN(C=O)C.O>[CH3:31][N:32]([CH3:33])[C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][N:24]=1)[C:5]([NH:7][C:8]1[S:9][CH:10]=[C:11]([C:13]2[C:18]([CH3:19])=[CH:17][C:16]([CH3:20])=[CH:15][C:14]=2[CH3:21])[N:12]=1)=[O:6]
Reactant: CNC
Reactant: Cc1cc(C)c(-c2csc(NC(=O)c3ccnc(Cl)c3)n2)c(C)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(C)c(-c2csc(NC(=O)c3ccnc(N(C)C)c3)n2)c(C)c1
Yield: 3 %

Procedure:
A mixture of 2-chloro-N-(4-mesitylthiazol-2-yl)isonicotinamide (200 mg, 0.60 mmol, 1.0 equiv), cesium carbonate (2.73 g, 0.6 mmol, 15 equiv) and 2.0 M dimethylamine in THF (3.4 mL, 6.7 mmol, 12 equiv) in DMF (6.0 mL) was heated at reflux for 16 h. The mixture was poured into icy H2O (10.0 mL) and extracted with EtOAc. The organic layer was collected, dried over MgSO4(s), and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (15% EtOAc in hexanes as eluant) to provide 2-(dimethylamino)-N-(4-mesityl-thiazol-2-yl)isonicotinamide (5.5 mg, 0.10 mmol) as yellow solids in 3.0% yield: 1H NMR (CDCl3, 500 MHz) δ 8.32 (d, J=5.1 Hz, 1 H), 7.02 (s, 1 H), 6.92 (s, 2 H), 6.85 (d, J=5.1 Hz, 1 H), 6.80 (s, 1 H), 3.16 (s, 6 H), 2.31 (s, 3 H), 2.09 (s, 6 H); ESI-MS: m/z 367.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9](F)[CH:10]=2)[CH:5]=[N:4][CH:3]=1.C(OC(=O)[NH:19][C@H:20]1[CH2:25][CH2:24][C@@H:23]([OH:26])[CH2:22][CH2:21]1)(C)(C)C>>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:26][C@@H:23]3[CH2:24][CH2:25][C@H:20]([NH2:19])[CH2:21][CH2:22]3)[CH:10]=2)[CH:5]=[N:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](O)CC1
Reactant: Fc1ccc2cncc(Cl)c2c1
Product: N[C@H]1CC[C@@H](Oc2ccc3cncc(Cl)c3c2)CC1

Procedure:
Starting from 4-chloro-6-fluoro-isoquinoline (9) and cis-(4-hydroxy-cyclohexyl)-carbamic acid tert-butyl ester the title compound was prepared as hydrochloride by the method described for trans-[4-(5-chloro-isoquinolin-6-yloxy)-cyclohexyl]-carbamic acid tert-butyl ester (10) followed by deprotection using 4M hydrochloric acid in isopropanol. Rt=0.79 min (Method #1). Detected mass: 277.1/279.1 (M+H+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5](/[C:8](=[N:14]/[O:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]3[N:26]=[C:27]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[O:28][C:29]=3[CH3:30])=[CH:19][CH:18]=2)/[C:9]([O:11]CC)=[O:10])=[CH:4][CH:3]=1.[S:37]1[CH:41]=[CH:40][C:39](B(O)O)=[CH:38]1.C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC=CC=1>O.C(O)C>[CH3:30][C:29]1[O:28][C:27]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[N:26][C:25]=1[CH2:24][O:23][C:20]1[CH:21]=[CH:22][C:17]([CH2:16][O:15]/[N:14]=[C:8](/[C:5]2[CH:6]=[CH:7][C:2]([C:39]3[CH:40]=[CH:41][S:37][CH:38]=3)=[CH:3][CH:4]=2)\[C:9]([OH:11])=[O:10])=[CH:18][CH:19]=1
Reactant: CCOC(=O)/C(=N\OCc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1)c1ccc(Br)cc1
Reactant: OB(O)c1ccsc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(CO/N=C(\C(=O)O)c2ccc(-c3ccsc3)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 57.9 %

Procedure:
A mixture of ethyl Z-2-(4-bromophenyl)-2-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]acetate (800 mg), 3-thienylboronic acid (224 mg), potassium carbonate (604 mg), toluene (20 ml), ethanol (2 ml) and water (2 ml) was stirred under an argon atmosphere for 30 minutes at room temperature. Tetrakis (triphenylphosphine)palladium (0) (101 mg) was added and the mixture was heated under reflux for 14 hours. The reaction mixture was washed with saturated aqueous sodium chloride, dried (MgSO4) and then concentrated. The residue was subjected to column chromatography on silica gel to obtain an oil from a fraction eluted with ethyl acetate-hexane (1:3, v/v). This oil was dissolved in tetrahydrofuran (10 ml)-methanol (5 ml), and 1N aqueous solution of sodium hydroxide (5 ml) was added and the mixture was stirred for 2 hours at 40° C. 1N HCl (5.5 ml) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride, dried (MgSO4) and then concentrated. The residual crystal was recrystallized from ethyl acetate-hexane to obtain Z-2-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-2-[4-(3-thienyl)phenyl]acetic acid (442 mg, yield 58%) as pale-yellow crystals. m.p. 205-206° C. (decomposition)
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH2:10][CH2:11][CH2:12][C:13]2[CH:14]=[C:15]([C:23]([O:25][CH3:26])=[O:24])[C:16](=[CH:21][CH:22]=2)[C:17]([O:19][CH3:20])=[O:18])[CH:6]=[CH:7][C:8]=1[OH:9])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:34][C:35](=[O:40])[C:36]([CH3:39])([CH3:38])[CH3:37]>CC(=O)CC>[CH3:37][C:36]([CH3:39])([CH3:38])[C:35](=[O:40])[CH2:34][O:9][C:8]1[CH:7]=[CH:6][C:5]([CH2:10][CH2:11][CH2:12][C:13]2[CH:14]=[C:15]([C:23]([O:25][CH3:26])=[O:24])[C:16](=[CH:21][CH:22]=2)[C:17]([O:19][CH3:20])=[O:18])=[CH:4][C:3]=1[CH2:1][CH3:2]
Reactant: CC(C)(C)C(=O)CBr
Reactant: CCc1cc(CCCc2ccc(C(=O)OC)c(C(=O)OC)c2)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCc1cc(CCCc2ccc(C(=O)OC)c(C(=O)OC)c2)ccc1OCC(=O)C(C)(C)C

Procedure:
800 mg (2.2 mmol) of dimethyl 4-[3-(3-ethyl-4-hydroxyphenyl)propyl}phthalate are dissolved in 40 ml of 2-butanone. 340 mg (2.5 mmol) of potassium carbonate and 330 μl (2.5 mmol) of 1-bromopinacolone are added. The reaction medium is heated under reflux for 8 hours, and is then filtered on celite. The residue obtained is purified by chromatography on a silica column (eluent ethyl acetate 20/heptane 80). A colorless oil is obtained (m=920 mg; y=90%).