Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:12]=[C:11]([N+:13]([O-])=O)[CH:10]=[CH:9][C:3]=1[C:4]([N:6]([CH3:8])[CH3:7])=[O:5].O.O.Cl[Sn]Cl>CCO>[NH2:13][C:11]1[CH:10]=[CH:9][C:3]([C:4]([N:6]([CH3:8])[CH3:7])=[O:5])=[C:2]([F:1])[CH:12]=1
Reactant: CN(C)C(=O)c1ccc([N+](=O)[O-])cc1F
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Product: CN(C)C(=O)c1ccc(N)cc1F
Temperature: 85 °C
Yield: 104 %

Procedure:
To a 50 mL round bottom flask was added 2-fluoro-N,N-dimethyl-4-nitro benzamide (2.8 g, 0.0132 mol) and EtOH (20 mL). To the same flask, SnCl2.2H2O (11.9 g, 0.0528 mol) was added and the reaction mixture was maintained at 85° C. for 2 h. The reaction mass was cooled to room temperature and the volatiles were evaporated under reduced pressure. The residue was dissolved in water and ethyl acetate. Aqueous saturated sodium bicarbonate was added to adjust to a pH of 7.0. The reaction mixture was filtered through a pad of Celite® reagent and washed with ethyl acetate. The organic layer was separated, dried over anhydrous sodium sulfate and evaporated under reduced pressure to obtain the title compound [2.5 g, 100%]. 1H NMR (300 MHz, CDCl3): δ 7.21 (t, J=7.8 Hz, 1H), 6.46 (dd, J′=8.4 Hz, J″=2.4 Hz, 1H), 6.34 (d, J′=11.4 Hz, J″=1.8 Hz, 1H), 3.95 (brs, 2H), 3.08 (s, 3H), 2.95 (d, J=1.8 Hz, 3H); LC-MS (ESI): Calculated mass: 182.1; Observed mass: 183.1 (RT: 0.17 min).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4](F)[CH:3]=1.[NH2:12][C@H:13]([C:15]([OH:17])=[O:16])[CH3:14].C(=O)([O-])[O-].[K+].[K+].Cl>C(O)C.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([NH:12][C@H:13]([C:15]([OH:17])=[O:16])[CH3:14])[CH:3]=1
Reactant: O=[N+]([O-])c1ccc(Br)cc1F
Reactant: C[C@H](N)C(=O)O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: C[C@H](Nc1cc(Br)ccc1[N+](=O)[O-])C(=O)O
Temperature: 25 °C
Yield: 100 %

Procedure:
A mixture of 4-bromo-2-fluoro-1-nitro-benzene (22 g, 100 mmol), L-alanine (8.9 g, 100 mmol), and potassium carbonate (17.5 g, 125 mmol) in ethanol (250 ml), and water (200 ml) was heated to reflux for 5 hours. After cooling to room temperature, the mixture was diluted with water, and acidified with 1N hydrochloric acid. The precipitate was collected on a funnel and dried to afford N-(5-bromo-2-nitrophenyl)-alanine (28.9 g, 100%). A sample was recrystallized from ethanol: m.p. 183-187° C.; 1H-NMR (DMSO-d6) δ 1.44 (d, J=6.9 Hz, 3H), 4.56 (m, 1H), 6.87 (d, J=6 Hz, 1H), 7.21 (d, J=1.7 Hz, 1H), 7.99 (d, J=7 Hz, 1H), 8.36 (d, J=7 Hz, 1H), 13.27 (s, 1H).
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:10]([OH:12])=[O:11])[CH2:4][C:5]1[N:9]=[CH:8][NH:7][CH:6]=1.[CH3:13][C:14]1([S:26]([O-:29])(=[O:28])=[O:27])[C:24](=[O:25])[C:23]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[C:16](=[O:17])[CH2:15]1.O.O.O.[Na+]>Cl>[CH3:13][C:14]1([S:26]([OH:29])(=[O:28])=[O:27])[C:24](=[O:25])[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:16](=[O:17])[CH2:15]1.[NH2:2][C@H:3]([C:10]([OH:12])=[O:11])[CH2:4][C:5]1[N:9]=[CH:8][NH:7][CH:6]=1
Reactant: CC1(S(=O)(=O)[O-])CC(=O)c2ccccc2C1=O
Agent: Cl
Agent: N[C@@H](Cc1c[nH]cn1)C(=O)O
Agent: [Na+]
Solvent: O
Product: CC1(S(=O)(=O)O)CC(=O)c2ccccc2C1=O

Procedure:
16 g of histidine hydrochloride was dissolved in 50 g of a 6% solution of hydrochloric acid. To this solution, 25 g of powdery menadione sodium bisulfite was added within about 1/2 hour. A white, very fine precipitate was obtained, which, after filtering, washing and vacuum drying, weighed 26 g and had the following analysis:
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:28])[C:6]1[C:11]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([I:19])=[CH:15][C:14]=2[F:20])=[CH:10][N:9]=[CH:8][C:7]=1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[F:27]>CO>[F:27][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[C:7]1[CH:8]=[N:9][CH:10]=[C:11]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([I:19])=[CH:15][C:14]=2[F:20])[C:6]=1[C:5]([OH:28])=[O:4]
Reactant: COC(=O)c1c(Nc2ccc(I)cc2F)cncc1-c1ccccc1F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1c(Nc2ccc(I)cc2F)cncc1-c1ccccc1F
Temperature: 60 °C
Reaction time: 8 h
Yield: 74.3 %

Procedure:
NaOH (3.2 mL, 2M solution in H2O, 6.4 mmol) was added to a solution of 3-(2-fluoro-phenyl)-5-(2-fluoro-4-iodo-phenylamino)-isonicotinic acid methyl ester (300 mg, 0.64 mmol) in MeOH (3 mL) and stirred overnight at 60° C. The MeOH was removed and the aqueous solution was acidified with concentrated HCl. The resulting precipitate was filtered, washed with H2O, and dried under vacuum to afford the desired product (215 mg, 74%). LC-MS (M+H=453, obsd.=453).
Reaction SMILES: [O-]CC.[Na+].[Na].[CH3:6][C:7]([C:10]1[CH:15]=[C:14]([SH:16])[CH:13]=[C:12]([C:17]([CH3:20])([CH3:19])[CH3:18])[C:11]=1[OH:21])([CH3:9])[CH3:8].[CH3:22][C:23]1([CH3:26])[O:25][CH2:24]1>C(O)C>[CH3:18][C:17]([C:12]1[CH:13]=[C:14]([S:16][CH2:22][C:23]([OH:25])([CH3:26])[CH3:24])[CH:15]=[C:10]([C:7]([CH3:6])([CH3:8])[CH3:9])[C:11]=1[OH:21])([CH3:20])[CH3:19]
Reactant: CC1(C)CO1
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Product: CC(C)(O)CSc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Temperature: 5 °C
Reaction time: 1 h

Procedure:
To a solution of sodium ethoxide, freshly prepared from sodium (1.31 g, 57.2 mmole) in ethyl alcohol (200 ml), was added 2,6-bis(1,1-dimethylethyl)-4-mercaptophenol (6.8 g, 28.6 mmole) and the mixture was stirred for one hour. After cooling to 5° C. with an ice bath, 1,1-dimethylethylene oxide (2.06 g, 28.6 mmole) was added and the ice bath removed. After stirring for 5.5 hours the reaction mixture was poured into 10% hydrochloric acid. The ethyl alcohol was removed in vacuo and the aqueous residue was extracted with ethyl acetate. The extracts were combined, dried over sodium sulfate, filtered, and concentrated to give 2,6-bis (1,1-dimethylethyl)-4-[(2-hydroxy-2-methylpropyl)thio]phenol. Trifluoroacetic acid (3 ml) was added to a solution of the phenol intermediate (2.2 g, 7 mmole), followed by addition by syringe of methyl thioglycolate (0.7 g, 6.7 mmole). After three hours the mixture was poured into water (100 ml) and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to an oil. Chromatography on silica gel gave the title dithio compound, m.p. 64°-68°.
Reaction SMILES: [OH:1][C@@H:2]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C@@H:3]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1.[H-].[Na+].CS(O[CH2:29][CH2:30][CH2:31][O:32][CH3:33])(=O)=O.O>C1COCC1>[CH3:33][O:32][CH2:31][CH2:30][CH2:29][O:1][C@@H:2]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C@@H:3]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:10])[CH2:4]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]([C@@H](O)c2ccccc2)C1
Reactant: COCCCOS(C)(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COCCCO[C@@H](c1ccccc1)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 96.8 %

Procedure:
An oven dried flask was charged with (R)-tert-butyl 3-((R)-hydroxy(phenyl)-methyl)piperidine-1-carboxylate (162 mg, 0.557 mmol) and 60% NaH in mineral oil (112 mg, 5 equiv.). The flask was purged with N2 gas, cooled to 0° C. and anhydrous THF (6 mL) was added slowly. After 5 min, the reaction mixture was allowed to warn to rt slowly. A solution of 3-methoxypropyl methanesulfonate (468 mg, 4 equiv.) in anhydrous THF (5 mL) was added. The mixture was heated at reflux for 4 h. LC-MS indicated the reaction was complete. The reaction mixture was cooled to 0° C. and water was added dropwise. After separation, the aqueous layer was extracted with ether (3×). The combined organic layers were washed with 5% aq HCl, satd aq NaHCO3 and brine, and dried over Na2SO4. After concentration, the crude product was purified by flash chromatography on a 4-g silica gel cartridge eluted with a 0-35% EtOAc in hexanes gradient to afford (R)-tert-butyl 3-((R)-(3-methoxypropoxy)(phenyl)-methyl)piperidine-1-carboxylate (196 mg, 97% yield) as a clear oil. LC-MS (3 min) tR=2.19 min, m/z 386 (M+Na).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[O:9][C:10]([F:16])([F:15])[C:11](Br)([F:13])[F:12].N1C=CC=CC=1C1C=CC=CN=1>CS(C)=O.C(OCC)C.CCCCC.[Cu]>[F:15][C:10]1([F:16])[C:11]([F:13])([F:12])[C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=2[O:9]1
Reactant: Fc1cccc(Br)c1OC(F)(F)C(F)(F)Br
Agent: [Cu]
Agent: c1ccc(-c2ccccn2)nc1
Solvent: CCCCC
Solvent: CCOCC
Solvent: CS(C)=O
Product: Fc1cccc2c1OC(F)(F)C2(F)F
Temperature: 150 °C
Yield: 63.9 %

Procedure:
1-Bromo-2-(2-bromo-1,1,2,2-tetrafluoroethoxy)-3-fluorobenzene (14 g, 38 mmol), copper powder (12.2 g, 192 mmol) and 2,2′-bipyridine (610 mg, 3.9 mmol) were combined in dry DMSO (55 mL) and heated to 150° C. for 1.5 h. Vacuum (ca 20 mm) was applied to the reactor and distillate was taken overhead until the pot temperature reached 100° C. The distillate containing the product and DMSO was diluted with 1:1 diethyl ether-pentane (30 mL) and washed (3×5 mL) with water, dried, and distilled at 1 atmosphere (atm) through a 200 mm Vigreux column to remove the bulk of the solvents. Vacuum (ca 20 mmHg) was applied and the fraction boiling at 60-65° C. was collected to afford the title compound as a clear liquid (5.1 g, 64%): 1H NMR (400 MHz, CDCl3) δ 7.40-7.31 (m, 2H), 7.25-7.17 (m, 1H); EIMS m/z 210.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4](F)[C:3]=1[CH:12]=[CH2:13].[CH3:14][CH:15]([NH2:18])[CH:16]=[CH2:17].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(O)C>[F:1][C:2]1[C:3]([CH:12]=[CH2:13])=[C:4]([NH:18][CH:15]([CH3:14])[CH:16]=[CH2:17])[C:5]([N+:8]([O-:10])=[O:9])=[CH:6][CH:7]=1
Reactant: C=Cc1c(F)ccc([N+](=O)[O-])c1F
Reactant: C=CC(C)N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: CN(C)C=O
Product: C=Cc1c(F)ccc([N+](=O)[O-])c1NC(C)C=C
Temperature: 25 °C
Reaction time: 1 h
Yield: 70 %

Procedure:
To a solution of 1,3-difluoro-4-nitro-2-vinylbenzene (150 mg, 0.81 mmol) in DMF (3 mL) was added a mixture of 1-methylallylamine in ethanol (0.4 mL). Potassium carbonate (0.224 g, 1.62 mmol) was added and the mixture stirred at RT for 1 h. A further portion of 1-methylallylamine in ethanol (0.3 mL) was added and stirring was continued for 1 h, and then the reaction mixture was partitioned between water and EtOAc. The aqueous phase was extracted with EtOAc and the combined organic layers were washed with water, followed by brine, then dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, eluant 2-6% EtOAc in cyclohexane) affording the title compound as a yellow oil (134 mg, 70%). 1H NMR (CDCl3, 300 MHz): 8.06 (1H, dd J=9.4, 5.7 Hz), 7.23 (1H, bs), 6.62 (1H, t, J=9.3 Hz), 6.48 (1H, dd, J=18.0, 11.6 Hz), 5.81-5.62 (2H, m), 5.64 (1H, dt, J=11.6, 1.3 Hz), 5.12-5.00 (2H, m), 4.38-4.25 (1H, m), 1.27 (3H, d, J=6.6 Hz)
Reaction SMILES: [H][H].C([O:10][C:11]([C:13]1[CH:22]=[CH:21][C:20]2[CH2:19][CH:18]([O:23][C:24](=[O:42])[C:25]3[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])=[CH:27][CH:26]=3)[CH2:17][CH2:16][C:15]=2[CH:14]=1)=[O:12])C1C=CC=CC=1>[Pd].O1CCCC1>[CH2:32]([O:31][C:28]1[CH:29]=[CH:30][C:25]([C:24]([O:23][CH:18]2[CH2:17][CH2:16][C:15]3[CH:14]=[C:13]([C:11]([OH:12])=[O:10])[CH:22]=[CH:21][C:20]=3[CH2:19]2)=[O:42])=[CH:26][CH:27]=1)[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41]
Reactant: CCCCCCCCCCOc1ccc(C(=O)OC2CCc3cc(C(=O)OCc4ccccc4)ccc3C2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: CCCCCCCCCCOc1ccc(C(=O)OC2CCc3cc(C(=O)O)ccc3C2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 93 %

Procedure:
Hydrogen gas was blown into a mixture of 0.53 g (1.0 mmol) of 6-(4'-decyloxybenzoyloxy)-5,6,7,8-tetrahydronaphthalene-2-carboxylic acid benzyl ester, 0.11 g of 5% palladium/carbon and 10 ml of tetrahydrofuran with stirring at room temperature and ordinary pressure for 15 hours. The reaction mixture was filtered using Celite as a filter aid, and the filtrate was concentrated to obtain 0.42 g (0.93 mmol) of 6-(4'-decyloxybenzoyloxy)-5,6,7,8-tetrahydronaphthalene-2-carboxylic acid.
Reaction SMILES: [I:1][C:2]1[N:3]=[CH:4][N:5](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:6]=1.Br[CH2:27][C:28]1[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[CH:30][C:29]=1[F:36]>>[F:36][C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][C:28]=1[CH2:27][N:3]1[C:2]([I:1])=[CH:6][N:5]=[CH:4]1)[C:32]#[N:33]
Reactant: N#Cc1ccc(CBr)c(F)c1
Reactant: Ic1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Product: N#Cc1ccc(Cn2cncc2I)c(F)c1
Temperature: 25 °C
Reaction time: 168 h

Procedure:
A mixture of 4-iodo-1-trityl-1H-imidazole (17.1 g, 39.2 mmol) and 4-bromomethyl-3-fluorobenzonitrile (9.65 g, 45.08 mmol) in 150 mL of dry actetonitrile is stirred at room temperature for 7 days. After concentration, the residue is mixed with methanol, and heated to reflux for 1.5 h. The solvent is subsequently removed and the residue is treated with 1M HCl (300 mL). The resulting suspension is filtered and the washed with HCl (1M). The combined solution is adjusted to PH 9-10 by saturated NaHCO3 solution. The resulting precipitation is collected by filtration, dried in vacuum oven. MS (ESI) m/z (M+H) 328.1.
Reaction SMILES: CCN(CC)CC.[CH3:8][S:9](Cl)(=[O:11])=[O:10].[NH2:13][C:14]1[CH:15]=[C:16]([CH:40]=[CH:41][CH:42]=1)[CH2:17][C:18]1[C:19](=[O:39])[O:20][C:21]2[CH:31]=[C:30]([O:32][C:33](=[O:37])[N:34]([CH3:36])[CH3:35])[C:29]([Cl:38])=[CH:28][C:22]=2[C:23]=1[CH2:24][C:25](=[O:27])[NH2:26]>C(Cl)Cl>[C:25]([CH2:24][C:23]1[C:22]2[CH:28]=[C:29]([Cl:38])[C:30]([O:32][C:33](=[O:37])[N:34]([CH3:35])[CH3:36])=[CH:31][C:21]=2[O:20][C:19](=[O:39])[C:18]=1[CH2:17][C:16]1[CH:40]=[CH:41][CH:42]=[C:14]([NH:13][S:9]([CH3:8])(=[O:11])=[O:10])[CH:15]=1)(=[O:27])[NH2:26]
Reactant: CS(=O)(=O)Cl
Reactant: CN(C)C(=O)Oc1cc2oc(=O)c(Cc3cccc(N)c3)c(CC(N)=O)c2cc1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)C(=O)Oc1cc2oc(=O)c(Cc3cccc(NS(C)(=O)=O)c3)c(CC(N)=O)c2cc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 20.9 %

Procedure:
Et3N (13 •L, 0.093 mmol) and methanesulfonyl chloride (3.6 •L, 0.050 mmol) were added to a solution of dimethylcarbamic acid 3-(3-aminobenzyl)-4-carbamoylmethyl-6-chloro-2-oxo-2H-1-benzopyran-7-yl ester (20 mg, 0.047 mmol) in methylene chloride (1.0 mL), and the mixture was stirred at room temperature for 2 hours. The solvent was distilled away by concentration under reduced pressure, and the resultant residue was purified by column chromatography to yield the title compound (5.0 mg, 22%) as a white solid.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:27])=[C:11]([N:14]4[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]4)[CH:12]=3)[C:7](=[O:28])[C:6]([C:29](=[O:34])[CH2:30][N+:31]([O-:33])=[O:32])=[CH:5]2)[CH2:3][CH2:2]1.CC(C)=O.[F:39][C:40]([F:45])([F:44])[C:41]([OH:43])=[O:42]>>[F:39][C:40]([F:45])([F:44])[C:41]([OH:43])=[O:42].[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:27])=[C:11]([N:14]4[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]4)[CH:12]=3)[C:7](=[O:28])[C:6]([C:29](=[O:34])[CH2:30][N+:31]([O-:33])=[O:32])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc3c(cc2F)c(=O)c(C(=O)C[N+](=O)[O-])cn3C2CC2)CC1
Solvent: CC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: O=C(C[N+](=O)[O-])c1cn(C2CC2)c2cc(N3CCNCC3)c(F)cc2c1=O
Reaction time: 0.17 h
Yield: 87 %

Procedure:
4.7 g of 1-cyclopropyl-6-fluoro-7-(4-t-butoxycarbonylpiperazin-1-yl)-3-(2-nitroacetyl)-1,4-dihydro-4-oxoquinoline obtained from Example 3 was dissolved in 20 ml of trifluoroacetic acid and then stirred for 10 minutes. The solvent was removed, and the solid formed after addition of 50 ml of acetone was filtered and then dried to obtain 4.25 g of the object compound
Reaction SMILES: [CH:1]1([C:7]2[CH:20]=[CH:19][C:10]([O:11][CH2:12][CH:13]3[O:17][C:16]([NH2:18])=[N:15][CH2:14]3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:21](OCC)(=[O:25])[C:22]#[C:23][CH3:24]>C(O)C>[CH:1]1([C:7]2[CH:20]=[CH:19][C:10]([O:11][CH2:12][CH:13]3[O:17][C:16]4=[N:18][C:21](=[O:25])[CH:22]=[C:23]([CH3:24])[N:15]4[CH2:14]3)=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: NC1=NCC(COc2ccc(C3CCCCC3)cc2)O1
Reactant: CC#CC(=O)OCC
Solvent: CCO
Product: Cc1cc(=O)nc2n1CC(COc1ccc(C3CCCCC3)cc1)O2
Temperature: 150 °C
Reaction time: 0.33 h
Yield: 51 %

Procedure:
To a solution of 5-(4-cyclohexyl-phenoxymethyl)-4,5-dihydro-oxazol-2-ylamine (300 mg, 1.095 mmol) in ethanol (6 mL) was added ethyl 2-butynoate (246 mg, 2.19 mmol). The reaction mixture was heated in a microwave oven at 150° C. for 30 min, then at 160° C. for 20 min, and at 170° C. for 30 min. Solvent was removed under vacuum, and the residue purified via flash column chromatography (silica gel, 1-18% EtOH/CH2Cl2) to afford 190 mg of 2-(4-cyclohexyl-phenoxymethyl)-5-methyl-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7-one as a white solid.
Reaction SMILES: CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.Cl[C:44]1[CH:49]=[C:48]([C:50]([F:53])([F:52])[F:51])[CH:47]=[C:46]([C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][C:55]=2[Cl:60])[N:45]=1.[F:61][C:62]1[CH:63]=[C:64]2[C:70]([NH2:71])=[N:69][N:68](COCC[Si](C)(C)C)[C:65]2=[N:66][CH:67]=1.C(=O)([O-])[O-].[K+].[K+].Cl>O1CCOCC1.C1COCC1.CC([O-])=O.CC([O-])=O.[Pd+2].CCOC(C)=O>[Cl:60][C:55]1[CH:56]=[CH:57][CH:58]=[CH:59][C:54]=1[C:46]1[N:45]=[C:44]([NH:71][C:70]2[C:64]3[C:65](=[N:66][CH:67]=[C:62]([F:61])[CH:63]=3)[NH:68][N:69]=2)[CH:49]=[C:48]([C:50]([F:53])([F:52])[F:51])[CH:47]=1
Reactant: FC(F)(F)c1cc(Cl)nc(-c2ccccc2Cl)c1
Reactant: C[Si](C)(C)CCOCn1nc(N)c2cc(F)cnc21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Fc1cnc2[nH]nc(Nc3cc(C(F)(F)F)cc(-c4ccccc4Cl)n3)c2c1
Reaction time: 0.05 h
Yield: 11.3 %

Procedure:
Xantphos (37.7 mg, 0.065 mmol) was added to Pd(OAc)2 (7.3 mg, 0.033 mmol) in dioxane (2 mL). After 3 min, this solution was added (with the aid of 1 mL dioxane) to a mixture of 2-chloro-6-(2-chlorophenyl)-4-(trifluoromethyl)pyridine (85.4 mg, 0.359 mmol), 5-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-b]pyridin-3-amine (92 mg, 0.326 mmol) and potassium carbonate (225 mg, 1.63 mmol) in dioxane (15 mL) under nitrogen. The reaction mixture was heated and stirred at reflux for 80 min. EtOAc was added, the solids were filtered off and the filtrate was concentrated. Purification by column chromatography (1/2 Petroleum ether/EtOAc) gave a residue that was dissolved in THF (2 mL) and treated with aq. HCl (2M, 8 mL). After 90 min at 100° C., the mixture was concentrated. The residue was partitioned between EtOAc and aq. sat. NaHCO3. The organic layer was separated, dried (MgSO4), filtered and concentrated. The residue was purified by Fractionlynx mass-directed prep. HPLC (with aq. TFA/MeCN mixtures) and the fractions passed through a bicarbonate Stratosphere cartridge. Concentration gave the aminopyridine (15 mg, 11%) as a white solid. 1H NMR (400 MHz, DMSO): 7.36 (1H, s), 7.48-7.51 (2H, m), 7.60-7.64 (2H, m), 8.31 (1H, s), 8.43 (1H, d), 8.56 (1H, s), 10.61 (1H, s), 13.17 (1H, s).
Reaction SMILES: [CH3:1]SCCC(Cl)=O.[CH3:8][S:9][CH2:10][CH2:11][C:12]([N:14]=[C:15]=[S:16])=[O:13].[CH3:17][O:18][C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][C:28]=1[O:29][CH3:30])[N:25]=[CH:24]N=[C:22]2[O:31][C:32]1[CH:38]=[CH:37][C:35]([NH2:36])=[CH:34][C:33]=1[F:39].C1(C)C=CC=CC=1>C(O)C>[CH3:8][S:9][CH2:10][CH2:11][C:12]([N:14]=[C:15]=[S:16])=[O:13].[CH3:17][O:18][C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][C:28]=1[O:29][CH3:30])[N:25]=[CH:24][CH:1]=[C:22]2[O:31][C:32]1[CH:38]=[CH:37][C:35]([NH:36][C:15]([NH:14][C:12](=[O:13])[CH2:11][CH2:10][S:9][CH3:8])=[S:16])=[CH:34][C:33]=1[F:39]
Reactant: CSCCC(=O)Cl
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3F)c2cc1OC
Agent: CSCCC(=O)N=C=S
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)CCSC)cc3F)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 50 %

Procedure:
3-(Methylsulfanyl)propanoyl isothiocyanate was prepared using commercially available 3-(methylsulfanyl)propanoyl chloride (80 mg) as a starting compound according to the description of the literature. 3-(Methylsulfanyl)propanoyl isothiocyanate was dissolved in ethanol (1 ml) to prepare a solution. 4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]-3-fluoroaniline (50 mg), toluene (5 ml), and ethanol (1 ml) were added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (38 mg, yield 50%).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([O:8][CH2:9][C:10]2[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[C:11]=2[C:12]([O:14]C)=[O:13])[CH2:3]1.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([C:31]2[O:32][C:33]([CH3:38])=[C:34]([CH2:36]I)[N:35]=2)[CH:26]=[CH:27][C:28]=1[O:29][CH3:30]>>[CH3:21][O:22][C:23]1[CH:24]=[C:25]([C:31]2[O:32][C:33]([CH3:38])=[C:34]([CH2:36][O:1][CH:2]3[CH2:7][CH2:6][CH2:5][CH:4]([O:8][CH2:9][C:10]4[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[C:11]=4[C:12]([OH:14])=[O:13])[CH2:3]3)[N:35]=2)[CH:26]=[CH:27][C:28]=1[O:29][CH3:30]
Reactant: COc1ccc(-c2nc(CI)c(C)o2)cc1OC
Reactant: COC(=O)c1c(C)cccc1COC1CCCC(O)C1
Product: COc1ccc(-c2nc(COC3CCCC(OCc4cccc(C)c4C(=O)O)C3)c(C)o2)cc1OC

Procedure:
Using methyl 2-(3-hydroxycyclohexyloxymethyl)-6-methylbenzoate and 2-(3,4-dimethoxyphenyl)-4-iodomethyl-5-methyloxazol as starting materials in the procedure of Example XXXI, gave the product 67 of molecular weight 495.58 (C28H33NO7), MS(ESI): 496.20 (M+H+).
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:17][C:18](=[O:20])[CH3:19]>C1(C)C=CC=CC=1>[CH2:3]([N:2]([CH3:1])[CH2:17][C:18]([CH3:19])=[O:20])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(=O)CCl
Reactant: CNCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CC(=O)CN(C)Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Put 12.118 g (100 mmol) N-methylbenzylamine with 16.584 g (120 mmol) potassium carbonate in 100 ml toluene. Add dropwise 11.103 g (120 mmol) chloroacetone and stir overnight under reflux. Then cool to RT, filter to remove the salt and concentrate by evaporation. Purify the residue by chromatography on silica gel (solvent: cyclohexane/ethyl acetate 8:2), obtaining 9.0 g (50.8% of theor.) of the target compound.
Reaction SMILES: [C:1]([CH2:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1)=[O:5])#[N:2].C(O/[CH:17]=[CH:18]/[C:19](=O)[C:20]([F:23])([F:22])[F:21])C.N12CCN(CC1)CC2>COCCO.Cl.C(OCC)(=O)C>[F:13][C:10]1[CH:9]=[CH:8][C:7]([N:6]2[C:19]([C:20]([F:23])([F:22])[F:21])=[CH:18][CH:17]=[C:3]([C:1]#[N:2])[C:4]2=[O:5])=[CH:12][CH:11]=1
Reactant: N#CCC(=O)Nc1ccc(F)cc1
Reactant: CCO/C=C/C(=O)C(F)(F)F
Agent: C1CN2CCN1CC2
Agent: Cl
Solvent: CCOC(C)=O
Solvent: COCCO
Product: N#Cc1ccc(C(F)(F)F)n(-c2ccc(F)cc2)c1=O
Temperature: 120 °C
Reaction time: 6 h
Yield: 7.3 %

Procedure:
To a solution of 2-cyano-N-(4-fluorophenyl)acetamide (2 g, 11.2 mmol) and (3E)-4-ethoxy-1,1,1-trifluorobut-3-en-2-one (2.26 g, 13.4 mmol) in dimethyleneglycol monomethylether (20 mL) was added 1,4-diazabicyclo[2.2.2]octane (1.26 g, 11.2 mmol), and the mixture was stirred at 120° C. for 6 hr. The reaction mixture was diluted with 1N hydrochloric acid and ethyl acetate, and the mixture was extracted 3 times with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (NH silica gel, ethyl acetate/hexane=1/2→1/1) to give a white solid. The white solid was washed with ethyl acetate and collected by filtration to give the title compound (230 mg, 7.2%) as a white solid.