Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1](Cl)(Cl)=[O:2].[OH:5][N:6]=[C:7]([NH2:20])[CH2:8][C:9]1[CH2:18][CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]=1[Cl:19].N1C=CC=CC=1>C(Cl)Cl>[Cl:19][C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:17][CH2:18][C:9]=1[CH2:8][C:7]1[NH:20][S:1](=[O:2])[O:5][N:6]=1
Reactant: NC(CC1=C(Cl)c2ccccc2CC1)=NO
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=S1NC(CC2=C(Cl)c3ccccc3CC2)=NO1
Yield: 31.8 %

Procedure:
Thionyl chloride (0.55 mL, 7.5 mmol) was added dropwise to a mixture of N'-hydroxy-(1-chloro-3,4-dihydro-2-naphthalenyl)ethanimidamide (1.6 g, 6.8 mmol) and pyridine (1.10 mL, 13.6 mmol) in dry CH2Cl2 (25 mL) at 0° C. After the addition, the reaction was concentrated under reduced pressure, diluted with water (50 mL), and extracted with ether (3×50 mL). The organics were washed with brine, dried (MgSO4), and concentrated to obtain a black froth. The froth was chromatographed on silica gel (twice: eluant 4% MeOH/CH3Cl2 and eluant 2% MeOH/CH2Cl2) to yield 612 mg (32%) of an off-white solid, m.p. 90.5°-91.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH:9]2[CH2:12][N:11]([C:13](Cl)=[O:14])[CH2:10]2)=[CH:4][CH:3]=1.[CH3:16][NH:17][CH3:18]>O1CCCC1.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH:9]2[CH2:12][N:11]([C:13]([N:17]([CH3:18])[CH3:16])=[O:14])[CH2:10]2)=[CH:4][CH:3]=1
Reactant: CNC
Reactant: O=C(Cl)N1CC(Sc2ccc(Cl)cc2)C1
Solvent: O
Solvent: C1CCOC1
Product: CN(C)C(=O)N1CC(Sc2ccc(Cl)cc2)C1
Reaction time: 3 h
Yield: 73.9 %

Procedure:
A solution of 2.6 g (0.01 mole) of 3-[(4-chlorophenyl)thio]-1-azetidinecarbonyl chloride in 20 ml of tetrahydrofuran was stirred while cooling in a water bath and treated with 2.5 ml (0.02 mole) of 40% dimethylamine in water. After stirring for 3 hr, the reaction mixture was diluted with 200 ml of water and the resulting product collected by filtration (2.6 g). Recrystallization from acetone/isopropyl ether yielded 2 g (74.1%) of fine white crystals, m.p. 96°-97° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:10]=[CH:9][N:8]([C@@H:11]3[CH2:15][C@H:14]([CH2:16][OH:17])[C@@H:13]([OH:18])[C@H:12]3[OH:19])[C:4]=2[N:5]=[CH:6][N:7]=1.CO[C:22](OC)([CH3:24])[CH3:23].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C([O-])(O)=O.[Na+]>>[Cl:1][C:2]1[C:3]2[CH:10]=[CH:9][N:8]([C@H:11]3[C@@H:12]4[O:19][C:22]([CH3:24])([CH3:23])[O:18][C@@H:13]4[C@@H:14]([CH2:16][OH:17])[CH2:15]3)[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: COC(C)(C)OC
Reactant: OC[C@H]1C[C@@H](n2ccc3c(Cl)ncnc32)[C@H](O)[C@@H]1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CC1(C)O[C@@H]2[C@@H](CO)C[C@@H](n3ccc4c(Cl)ncnc43)[C@@H]2O1
Reaction time: 1.25 h
Yield: 67.6 %

Procedure:
A mixture of crude (1R,2S,3R,5R)-3-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-(hydroxymethyl)cyclopentane-1,2-diol (10 g, ˜20 mmol, 54% pure by NMR) and 2,2-dimethoxypropane (100 mL, 800 mmol) was treated with p-toluenesulfonic acid monohydrate (7.28 g, 38.3 mmol) and the yellow-brown reaction mixture was stirred vigorously for 1.25 h, at which time the only solids were a fine tan precipitate; HPLC indicated nearly complete consumption of the starting material. The reaction mixture was diluted with water (30 mL) and neutralized with solid NaHCO3 (4.80 g, 57.1 mmol). The volatiles were carefully removed in vacuo and the resulting brown aqueous solution was extracted with EtOAc (3×100 mL). The combined organics were dried (Na2SO4) and concentrated in vacuo to afford a tan paste. Purification by column chromatography (4×22 cm silica; 0-66% EtOAc/Hex) afforded the title compound (4.38 g, 70%, one step) as a colorless foam/glass: MS (ESI+) for C15H18ClN3O3 m/z 324.2 (M+H)+; MS (ESI−) for C15H18ClN3O3 m/z 368.2 (M+HCO2)−; HPLC purity>95% (ret. time, 3.034 min).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)[CH:5]=[CH:6][CH:7]=1.[C:16]([C:24]1[CH:29]=[CH:28][C:27]([C:30]2[O:31][CH:32]=[C:33]([CH2:35]Cl)[N:34]=2)=[CH:26][CH:25]=1)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[C:16]([C:24]1[CH:29]=[CH:28][C:27]([C:30]2[O:31][CH:32]=[C:33]([CH2:35][O:1][C:2]3[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][CH2:9][CH2:10][N:11]4[CH:15]=[CH:14][N:13]=[CH:12]4)[CH:3]=3)[N:34]=2)=[CH:26][CH:25]=1)(=[O:23])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: Oc1cccc(CCCn2ccnc2)c1
Reactant: O=C(c1ccccc1)c1ccc(-c2nc(CCl)co2)cc1
Product: O=C(c1ccccc1)c1ccc(-c2nc(COc3cccc(CCCn4ccnc4)c3)co2)cc1
Yield: 85 %

Procedure:
In substantially the same manner as in Working Example 72, 1-[3-(3-hydroxyphenyl)propyl]imidazole was allowed to react with 2-(4-benzoylphenyl)-4-chloromethyloxazole to gave 2-(4-benzoylphenyl)-4-[3-[3-(1-imidazolyl)propyl]phenoxymethyl]oxazole. The yield was 85%. Recrystallization from ethyl acetate-hexane gave colorless prisms, mp 97-98° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11]1[CH:15]=[C:14]([CH2:16][CH2:17][CH:18]=O)[O:13][N:12]=1.[CH2:20]([N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11]1[CH:15]=[C:14]([CH2:16][CH2:17][CH2:18][N:30]2[CH2:31][CH2:32][N:27]([CH2:20][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH2:28][CH2:29]2)[O:13][N:12]=1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: COc1ccc(-c2cc(CCC=O)on2)c(OC)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc(-c2cc(CCCN3CCN(Cc4ccccc4)CC3)on2)c(OC)c1
Yield: 80.1 %

Procedure:
About 2 min after dissolving 3-[3-(2,4-dimethoxyphenyl)isoxazol-5-yl]propanal (10 mg, 0.04 mmol) and 1-benylpiperazine (6.7, 0.04 mmol) in 2 mL of dry methylene chloride, were added NaBH(OAc)3 (24 mg, 0.12 mmol) and molecular sieves (5 beads). The reaction mixture was reacted for 3.5 hr and followed the same processes as in Example 1 to obtain 13.5 mg (83.6%) of the target compound.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7](Br)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH2:15]([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][CH3:26])=[CH:19][C:18]=1[OH:27])[CH3:16]>CN(C=O)C>[CH2:7]([O:27][C:18]1[CH:19]=[C:20]([O:23][CH2:24][CH2:25][CH3:26])[CH:21]=[CH:22][C:17]=1[CH2:15][CH3:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CCCOc1ccc(CC)c(O)c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCOc1ccc(CC)c(OCc2ccccc2)c1
Temperature: 45 °C
Reaction time: 15 h
Yield: 52.6 %

Procedure:
Potassium carbonate (17.8 g, 0.13 mol) followed by benzyl bromide (5.12 mL, 42.9 mmol) were added to a solution of 2-ethyl-5-propoxy-phenol (7.74 g, 42.9 mmol) in DMF (60 mL). The mixture was stirred at 45° C. for 15 hours and then partitioned between H2O and EtOAc. The organic layer was washed with 1N HCl, brine, dried over Na2SO4 and concentrated to a brown oil. Purification by flash column chromatography (0% to 20% EtOAc in hexanes) gave the product as a clear oil (6.1 g, 55%). 1H NMR (400 MHz, CDCl3): δ 1.02 (t, J=7.6 Hz, 3 H), 1.19 (t, J=7.6 Hz, 3 H), 1.78 (q, J=7.6 Hz, 2 H), 2.63 (q, J=7.6 Hz, 2 H), 3.88 (t, J=6.6 Hz, 2 H), 5.05 (s, 2 H), 6.44 (dd, J=8.1, 2.3 Hz, 1 H), 6.51 (dd, J=2.3 Hz, 1 H), 7.05 (d, J=8.3 Hz, 1 H), 7.31 (m, 1 H), 7.38 (m, 2 H), 7.44 (m, 2 H).
Reaction SMILES: S(=O)(=O)(O)[OH:2].[CH:6]([N:9]=[N:10][C:11]1([C:17]#[N:18])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)([CH3:8])[CH3:7]>>[CH:6]([N:9]=[N:10][C:11]1([C:17](=[O:2])[NH2:18])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)([CH3:8])[CH3:7]
Reactant: CC(C)N=NC1(C#N)CCCCC1
Reactant: O=S(=O)(O)O
Product: CC(C)N=NC1(C(N)=O)CCCCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 100 ml of 96% sulfuric acid cooled to 0° C in an ice bath was added 13.5 grams (.0755 moles) of 1-isopropylazo-1-cyanocylohexane (from Example 4-b-6) dropwise over 1/2 hour while holding the temperature at 0° C. After the addition was complete the temperature was allowed to rise to 10° C over 1/2 hour and to 25° C over another 1/2 hour and then stirred another 1/2 hour at 25° C. The reaction mixture was poured onto 1/2 liter of ice and stirred until all of the ice dissolved. A white solid that formed was filtered off and the aqueous acid filtrate was extracted with 200 ml of methylene chloride. The methylene chloride extract was washed with saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered and the methylene chloride evaporated under reduced pressure on a rotating evaporator. The product was a light brown liquid and weighed 5.0 grams (33.7% crude yield). The infrared spectrum of the product was in agreement with the structure of 1-isopropylazo-1-carbamylcyclohexane (strong broad carbonyl band at 1675-1750 cm-1 and NH band at 3500 cm-1).
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]([C:12]1[CH:13]=[N:14][C:15]([O:18][CH3:19])=[N:16][CH:17]=1)O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C1C=CC(OP(OC2C=CC=CC=2)([N:29]=[N+:30]=[N-:31])=O)=CC=1.N12CCCN=C1CCCCC2>C1(C)C=CC=CC=1>[N:29]([C@@H:10]([C:12]1[CH:13]=[N:14][C:15]([O:18][CH3:19])=[N:16][CH:17]=1)[CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])=[N+:30]=[N-:31]
Reactant: [N-]=[N+]=NP(=O)(Oc1ccccc1)Oc1ccccc1
Reactant: COc1ncc([C@@H](O)CO[Si](C)(C)C(C)(C)C)cn1
Solvent: C1CCC2=NCCCN2CC1
Solvent: Cc1ccccc1
Product: COc1ncc([C@@H](CO[Si](C)(C)C(C)(C)C)N=[N+]=[N-])cn1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A mixture of (R)-2-(tert-butyldimethylsilyloxy)-1-(2-methoxypyrimidin-5-yl)ethanol (4.4 g, 15 mmol) and diphenylphosphonic azide (16.7 mL, 77.3 mmol) was dissolved in toluene (53 mL). The mixture was cooled to 0° C. and neat 1,8-diazabicyclo[5.4.0]undec-7-ene (11.8 mL, 77.3 mmol) was added. The reaction was stirred for 30 minutes at 0° C. and then reacted at 60° C. overnight. The mixture was washed with water (50 mL) and 5% HCl (50 mL). The organic layer was concentrated in vacuo and purified by silica gel chromatography (0-25% EtOAc/hexane) to afford a colorless oil.
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:9][CH:10]=[C:5]2[N:4]=[C:3]1[CH2:17][O:18][C:19]1[CH:51]=[CH:50][C:22]([CH2:23][CH:24]2[S:28][C:27](=[O:29])[N:26](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[C:25]2=[O:49])=[CH:21][CH:20]=1.C(O)(=O)C>O>[CH3:1][N:2]1[C:6]2=[N:7][C:8]([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)=[CH:9][CH:10]=[C:5]2[N:4]=[C:3]1[CH2:17][O:18][C:19]1[CH:51]=[CH:50][C:22]([CH2:23][CH:24]2[S:28][C:27](=[O:29])[NH:26][C:25]2=[O:49])=[CH:21][CH:20]=1
Reactant: Cn1c(COc2ccc(CC3SC(=O)N(C(c4ccccc4)(c4ccccc4)c4ccccc4)C3=O)cc2)nc2ccc(-c3ccccc3)nc21
Solvent: CC(=O)O
Solvent: O
Product: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2ccc(-c3ccccc3)nc21
Yield: 72.1 %

Procedure:
A procedure similar to that described in Example 12 was repeated, except that 0.9 g of 5-{4-(3-methyl-5-phenylimidazo[5,4-b]pyridin-2-ylmethoxy)benzyl}-3-triphenylmethylthiazolidine-2,4-dione (prepared as described in Preparation 111) was treated with 36 ml of a 3:1 by volume mixture of acetic acid and water. After working up the product as described in Example 12, the resulting crude product was crystallized by trituration with ethyl acetate, to give 420 mg of the title compound, melting at 211-213° C.
Reaction SMILES: N1C=CC=CC=1.[F:7][C:8]([F:21])([F:20])[S:9]([O:12]S(C(F)(F)F)(=O)=O)(=[O:11])=[O:10].O[C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[CH:28]([CH2:32][C:33]([O:35][CH3:36])=[O:34])[CH2:27][CH2:26]2>ClCCl>[F:7][C:8]([F:21])([F:20])[S:9]([O:12][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[CH:28]([CH2:32][C:33]([O:35][CH3:36])=[O:34])[CH2:27][CH2:26]2)(=[O:11])=[O:10]
Reactant: COC(=O)CC1CCc2cc(O)ccc21
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)CC1CCc2cc(OS(=O)(=O)C(F)(F)F)ccc21
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 92.1 %

Procedure:
To a solution of pyridine (820 μL, 10.1 mmol) in dichloromethane (10 mL) cooled to 0° C. trifluoromethanesulfonic anhydride (1.56 mL, 9.28 mmol) was added. The resulting mixture was stirred for 5 min, and methyl (R/S)-(5-hydroxy-indan-1-yl)acetate (1.74 g, 8.44 mmol, from Step C) was added. The reaction mixture was warmed to ambient temperature, stirred for 1 hr and diluted with dichloromethane. The organic layer was washed with H2O, brine and dried over MgSO4. The mixture was filtered and concentrated in vacuo. Purification by flash chromatography (10% EtOAc/hexanes) on SiO2 gave 2.63 g of the title compound as a pale yellow liquid: 1H NMR (CDCl3) δ 1.83-1.88 (m, 1H), 2.47-2.55 (m, 2H), 2.78 (dd, 1H, J=6.0, 15.8 Hz), 2.92-3.01 (m, 2H), 3.62-3.65 (m, 1H), 3.76 (s, 3H), 7.09 (dd, 1H, J=2.3, 8.3 Hz), 7.16 (s, 1H), 7.25 (d, 1H, J=8.2 Hz).
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[NH:6][C:5](=[O:7])[N:4]([C:8]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][CH:11]=2)=[O:9])[C:3]1=[O:20].[H-].[Na+].[Cl:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29]Br)=[CH:27][CH:26]=1.C(OCC)(=O)C>CN(C=O)C>[Cl:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][N:6]2[C:2]([CH3:21])([CH3:1])[C:3](=[O:20])[N:4]([C:8]([C:10]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[CH:13]=[CH:12][CH:11]=3)=[O:9])[C:5]2=[O:7])=[CH:27][CH:26]=1
Reactant: CC1(C)NC(=O)N(C(=O)c2cccc3ccccc23)C1=O
Reactant: Clc1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC1(C)C(=O)N(C(=O)c2cccc3ccccc23)C(=O)N1Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.6 %

Procedure:
5,5-Dimethyl-3-naphthylcarbonylimidazolidine-2,4-dione (35 mg) was dissolved in DMF (0.4 mL), and sodium hydride (60%, in oil) (5 mg) was added. Then, 4-chlorobenzyl bromide (26 mg) was added, and the mixture was stirred at room temperature overnight. Ethyl acetate (9.5 mL) was added to the reaction solution, separated out white precipitates were filtered, and the filtrate was concentrated and purified by silica gel chromatography (hexane:ethyl acetate=2:1) to obtain 20 mg of white crystals.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([Cl:11])[CH:10]=1)[NH:7][C:6]([C:12]([N:14]1[CH2:19][CH2:18][C:17]([F:21])([F:20])[CH2:16][CH2:15]1)=[O:13])=[CH:5]2.C(N(CC)CC)C.[C:29]([O:32][CH2:33]C)(=[O:31])C>C(O)C.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[CH3:33][O:32][C:29]([C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([Cl:11])[CH:10]=1)[NH:7][C:6]([C:12]([N:14]1[CH2:19][CH2:18][C:17]([F:21])([F:20])[CH2:16][CH2:15]1)=[O:13])=[CH:5]2)=[O:31]
Reactant: CCOC(C)=O
Reactant: O=C(c1cc2cc(Br)cc(Cl)c2[nH]1)N1CCC(F)(F)CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CCN(CC)CC
Solvent: CCO
Product: COC(=O)c1cc(Cl)c2[nH]c(C(=O)N3CCC(F)(F)CC3)cc2c1
Temperature: 25 °C
Yield: 69 %

Procedure:
The mixture consistent of 100 mg (0.265 mmol) (5-bromo-7-chloro-1H-indol-2-yl)-(4,4-difluoro-piperidin-1-yl)-methanone, 15 mg (0.0184 mmol) 1,1′-bis(diphenylphosphino)ferrocene palladium dichloride and 55.6 μL (0.398 mmol) triethylamine in 1 mL ethanol and 1 mL ethyl acetate was stirred overnight at 100° C. under an atmosphere of carbon monoxide (120 bar). After cooling to room temperature the reaction mixture is filtered, evaporated and chromatographed on silica gel with ethyl acetate:n-heptane (1:2 v/v) as eluant to give the desired compound as a colorless solid (69%).
Reaction SMILES: [H-].[Na+].[CH2:3]([N:5]([CH2:21][CH3:22])[C:6](=[O:20])[O:7][C:8]1[C:17]([Cl:18])=[C:16]2[C:11]([CH2:12][CH2:13][NH:14][C:15]2=[O:19])=[CH:10][CH:9]=1)[CH3:4].[CH2:23]([O:30][C:31]1[C:36]([CH2:37]Cl)=[C:35]([CH3:39])[CH:34]=[C:33]([CH3:40])[N:32]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.O>CN(C=O)C>[CH2:21]([N:5]([CH2:3][CH3:4])[C:6](=[O:20])[O:7][C:8]1[C:17]([Cl:18])=[C:16]2[C:11]([CH2:12][CH2:13][N:14]([CH2:37][C:36]3[C:31]([O:30][CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[N:32][C:33]([CH3:40])=[CH:34][C:35]=3[CH3:39])[C:15]2=[O:19])=[CH:10][CH:9]=1)[CH3:22]
Reactant: Cc1cc(C)c(CCl)c(OCc2ccccc2)n1
Reactant: CCN(CC)C(=O)Oc1ccc2c(c1Cl)C(=O)NCC2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCN(CC)C(=O)Oc1ccc2c(c1Cl)C(=O)N(Cc1c(C)cc(C)nc1OCc1ccccc1)CC2
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 99.3 %

Procedure:
To a suspension of NaH (2.2 g, 54 mmol, 60% in oil) in dry DMF (20 mL) was added dropwise a solution of 8-chloro-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl diethylcarbamate (1f, 8.0 g, 27 mmol) in dry DMF (40 mL) at 0° C. under N2. The mixture was stirred at 0° C. for 15 minutes. 2-(Benzyloxy)-3-(chloromethyl)-4,6-dimethylpyridine (Cpd Z, 8.5 g, 32.4 mmol) was added. The mixture was stirred at room temperature overnight. To the reaction mixture was added dropwise H2O (200 mL) carefully. The mixture was extracted with EtOAc (2×150 mL). The combined organic layers were washed with brine (4×200 mL), dried over Na2SO4, and concentrated under vacuum. The residue was purified by column chromatography (petroleum ether/EtOAc, 3:1) to give 2-{[2-(benzyloxy)-4,6-dimethylpyridin-3-yl]methyl}-8-chloro-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl diethylcarbamate (1g, 14 g, 99%) as yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH:17]([C:18]3[N:19]([CH3:25])[C:20]([CH3:24])=[C:21]([CH3:23])[N:22]=3)[C:16](=O)[C:15]3[C:14]([C:27]([O:29]CC)=O)=[CH:13][CH:12]=[CH:11][C:10]=3[NH:9]2)=[CH:4][CH:3]=1.O.[NH2:33][NH2:34]>CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[NH:9][C:10]3[C:15]4[C:16](=[N:33][NH:34][C:27](=[O:29])[C:14]=4[CH:13]=[CH:12][CH:11]=3)[CH:17]2[C:18]2[N:19]([CH3:25])[C:20]([CH3:24])=[C:21]([CH3:23])[N:22]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cccc2c1C(=O)C(c1nc(C)c(C)n1C)C(c1ccc(F)cc1)N2
Reactant: NN
Solvent: O
Solvent: CO
Product: Cc1nc(C2c3n[nH]c(=O)c4cccc(c34)NC2c2ccc(F)cc2)n(C)c1C
Temperature: 25 °C
Reaction time: 48 h
Yield: 65 %

Procedure:
A mixture of ethyl 2-(4-fluorophenyl)-4-oxo-3-(1,4,5-trimethyl-1H-imidazol-2-yl)-1,2,3,4-tetrahydroquinoline-5-carboxylate (150 mg) in 85% hydrazine monohydrate (85%, 3 mL) and methanol (5 mL) was stirred at room temperature for 2 days. The result suspension was filtered and washed the water (20 mL) and methanol (5 ml) to obtain a white solid. The solid was dried in vacuum at 50° C. to afford the title compound (90 mg, yield 65%). 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 1.91-1.96 (d, J=18 Hz, 6H), 3.25 (s, 3H), 4.59-4.62 (d, J=10.8 Hz, 1H), 4.92-4.95 (d, J=10.8 Hz, 1H), 7.09-7.15 (m, 3H), 7.22 (s, 1H), 7.36-7.38 (d, J=7.6 Hz, 1H), 7.43-7.46 (m, 2H), 7.54-7.58 (t, J=8 Hz, 1H), 12.13 (s, 1H); LC-MS (ESI) m/z: 390 (M+1)+.
Reaction SMILES: C([O:3][C:4](=[O:16])[CH:5]([S:7][C:8]1[N:13]=[C:12]([Cl:14])[CH:11]=[C:10](Cl)[N:9]=1)[CH3:6])C.[Cl:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][NH2:23])=[CH:20][CH:19]=1.C(=O)([O-])[O-].[Na+].[Na+].Cl>C(O)C>[Cl:14][C:12]1[CH:11]=[C:10]([NH:23][CH2:22][C:21]2[CH:24]=[CH:25][C:18]([Cl:17])=[CH:19][CH:20]=2)[N:9]=[C:8]([S:7][CH:5]([CH3:6])[C:4]([OH:3])=[O:16])[N:13]=1
Reactant: CCOC(=O)C(C)Sc1nc(Cl)cc(Cl)n1
Reactant: NCc1ccc(Cl)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CC(Sc1nc(Cl)cc(NCc2ccc(Cl)cc2)n1)C(=O)O

Procedure:
A stirred mixture of 5.6 g of 2-(4,6-dichloro-2-pyrimidinylthio) propionic acid ethyl ester, 2.9 g of p-chlorobenzylamine and 2.1 g of anhydrous sodium carbonate in 50 ml. of ethanol were heated under reflux for 6 hr. The reaction mixture was filtered and taken to dryness on a rotary evaporator. The residue was dissolved in ether and filtered free of insoluble material. The ether was removed on a rotary evaporator and the residue was treated with approximately 10 ml. of 30% sodium hydroxide solution to which was added enough ethanol until a clear solution was obtained. The reaction mixture was heated on a steam bath for a few minutes then acidified with concentrated hydrochloric acid solution. The precipitate which was formed was recrystallized from 95% ethanol affording 5.0 g of product, mp. 133°-136°C.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][N:19]([C:22]3[C:26]4[CH:27]=[C:28]([F:32])[CH:29]=[C:30]([F:31])[C:25]=4[O:24][N:23]=3)[CH2:18][CH2:17]2)[CH2:10][CH2:9]1)(C)(C)C.[ClH:34].O1CCOCC1>C(Cl)Cl>[ClH:34].[F:32][C:28]1[CH:29]=[C:30]([F:31])[C:25]2[O:24][N:23]=[C:22]([N:19]3[CH2:18][CH2:17][N:16]([CH2:15][CH2:14][C@H:11]4[CH2:12][CH2:13][C@H:8]([NH2:7])[CH2:9][CH2:10]4)[CH2:21][CH2:20]3)[C:26]=2[CH:27]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CCN2CCN(c3noc4c(F)cc(F)cc34)CC2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: N[C@H]1CC[C@H](CCN2CCN(c3noc4c(F)cc(F)cc34)CC2)CC1
Temperature: 25 °C

Procedure:
trans-(4-{2-[4-(5,7-Difluoro-benzo[d]isoxazol-3-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-carbamic acid tert-butyl ester (2.59 g, 5.6 mmol) was dissolved in CH2Cl2 (40 ml) and 4 N HCl in dioxane (27.9 ml, 112 mmol) was slowly added. The resulting mixture was stirred over night at r.t. After dilution with iPr2O the product was collected by filtration and washed with one portion of iPr2O before drying it under high vacuum at 50° C. to obtain 1.98 g (88%) as a white solid. m/z=365.2 ([M+H]+).
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH2:9])=[O:8])=[CH:5][CH:4]=1)#[N:2].[Cl:12][CH2:13][C:14]([CH2:16]Cl)=O>>[Cl:12][CH2:13][C:14]1[N:9]=[C:7]([C:6]2[CH:10]=[CH:11][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)[O:8][CH:16]=1
Reactant: N#Cc1ccc(C(N)=O)cc1
Reactant: O=C(CCl)CCl
Product: N#Cc1ccc(-c2nc(CCl)co2)cc1
Yield: 41 %

Procedure:
In substantially the same manner as in Reference Example 31, 4-cyanobenzamide was allowed to react with 1,3-dichloroacetone to give 4-chloromethyl-2-(4-cyanophenyl)oxazole. The yield was 41%. Recrystallization form ethyl acetate-hexane gave colorless prisms, mp 134-135° C.
Reaction SMILES: [F:1][C:2]([F:15])([C:11]([F:14])([F:13])[F:12])[CH2:3][CH2:4][S:5]([CH2:8][C:9]#[N:10])(=[O:7])=[O:6].[F:16][C:17]([S:20][CH2:21][CH2:22]OS(C(F)(F)F)(=O)=O)([F:19])[F:18].C([O-])([O-])=O.[K+].[K+]>COCCOC.O>[F:15][C:2]([F:1])([C:11]([F:12])([F:13])[F:14])[CH2:3][CH2:4][S:5]([CH:8]([CH2:22][CH2:21][S:20][C:17]([F:19])([F:18])[F:16])[C:9]#[N:10])(=[O:6])=[O:7]
Reactant: O=S(=O)(OCCSC(F)(F)F)C(F)(F)F
Reactant: N#CCS(=O)(=O)CCC(F)(F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: N#CC(CCSC(F)(F)F)S(=O)(=O)CCC(F)(F)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of (3,3,4,4,4-Pentafluoro-butane-1-sulfonyl)-acetonitrile (WO2007/060839) (0.50 g, 1.99 mmol), trifluoro-methanesulfonic acid 2-trifluoromethylsulfanyl-ethyl ester (WO 2007/147888) (0.55 g, 1.99 mmol), and K2CO3 (0.82 g, 5.97 mmol) in 1,2-dimethoxyethane (20 mL) was stirred under nitrogen at room temperature overnight. The reaction mixture was diluted with H2O (50 mL) and extracted with ethyl acetate (2×50 mL). The combined organic extracts were washed with brine (100 mL), dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, hexanes/EtOAc 19:1) to afford compound II-1 (0.28 g, 37%) as a white solid.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:11]=[CH:10][C:9]([CH:12]([CH3:15])[CH2:13][NH2:14])=[CH:8][CH:7]=2)=[CH:2]1.[N:16]1([C:22](Cl)=[O:23])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1>>[S:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:11]=[CH:10][C:9]([CH:12]([CH3:15])[CH2:13][NH:14][C:22]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[O:23])=[CH:8][CH:7]=2)=[CH:2]1
Reactant: O=C(Cl)N1CCOCC1
Reactant: CC(CN)c1ccc(-c2ccsc2)cc1
Product: CC(CNC(=O)N1CCOCC1)c1ccc(-c2ccsc2)cc1

Procedure:
The title compound was prepared from 2-(4-(3-thienyl)phenyl)propylamine (see example 14) and 4-morpholine carbonyl chloride in a manner analogous to the procedure described in example 14. The NMR spectrum was consistent with the proposed title structure.