Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]1[CH2:20][CH:19]2[N:4]([C:5](=[O:39])[CH:6]([NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:7][O:8][CH2:9][CH2:10][CH2:11][CH:12]=[CH:13][CH:14]3[C:16]([C:22]([NH:24][S:25]([CH:28]4[CH2:30][CH2:29]4)(=[O:27])=[O:26])=[O:23])([NH:17][C:18]2=[O:21])[CH2:15]3)[CH2:3]1.[O:40]([C:47]1[CH:55]=[CH:54][C:50]([C:51](Cl)=[O:52])=[CH:49][CH:48]=1)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>>[O:40]([C:47]1[CH:48]=[CH:49][C:50]([C:51]([O:1][CH:2]2[CH2:20][CH:19]3[N:4]([C:5](=[O:39])[CH:6]([NH:31][C:32]([O:34][C:35]([CH3:36])([CH3:38])[CH3:37])=[O:33])[CH2:7][O:8][CH2:9][CH2:10][CH2:11][CH:12]=[CH:13][CH:14]4[C:16]([C:22]([NH:24][S:25]([CH:28]5[CH2:29][CH2:30]5)(=[O:26])=[O:27])=[O:23])([NH:17][C:18]3=[O:21])[CH2:15]4)[CH2:3]2)=[O:52])=[CH:54][CH:55]=1)[C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1
Reactant: O=C(Cl)c1ccc(Oc2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)NC1COCCCC=CC2CC2(C(=O)NS(=O)(=O)C2CC2)NC(=O)C2CC(O)CN2C1=O
Product: CC(C)(C)OC(=O)NC1COCCCC=CC2CC2(C(=O)NS(=O)(=O)C2CC2)NC(=O)C2CC(OC(=O)c3ccc(Oc4ccccc4)cc3)CN2C1=O
Yield: 11.9 %

Procedure:
Prepared by way of method I using 18-hydroxy-14-tert-butoxycarbonylamino-4-cyclopropylsulfonylaminocarbonyl-2,15-dioxo-3,16-diaza-12-oxatricyclo[14.3.0.04,6]-nonadec-7-ene (100 mg, 0.175 mmol) and 4-phenoxybenzoyl chloride (111 mg, 0.53 mmol). The final trituration (diethyl ether/hexane) and filtration gave 16 mg (12%) of 18-(4-phenoxybenzoyloxy)-14-tert-butoxycarbonylamino-4-cyclopropylsulfonylaminocarbonyl-2,15-dioxo-3,16-diaza-12-oxatricyclo-[14.3.0.04,6]-nonadec-7-ene as a white powder: 97.5% pure (HPLC), MS m/z 765 (M−H)−, HRMS: calcd. 784.3228 and found 784.3208 (M+NH4)+, mp 207-209° C.
Reaction SMILES: [CH3:1][CH2:2][N:3]1[C:9]2[N:10]=[C:11]([N:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[N:12]=[CH:13][C:8]=2[C:6](=[O:7])[C:5]([C:20]([OH:22])=[O:21])=[CH:4]1.[F:23][C:24]([F:35])([F:34])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[N:31]=[C:32]=[S:33]>>[F:23][C:24]([F:34])([F:35])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[NH:31][C:32]([N:17]1[CH2:18][CH2:19][N:14]([C:11]2[N:12]=[CH:13][C:8]3[C:6](=[O:7])[C:5]([C:20]([OH:22])=[O:21])=[CH:4][N:3]([CH2:2][CH3:1])[C:9]=3[N:10]=2)[CH2:15][CH2:16]1)=[S:33]
Reactant: CCn1cc(C(=O)O)c(=O)c2cnc(N3CCNCC3)nc21
Reactant: FC(F)(F)c1ccccc1N=C=S
Product: CCn1cc(C(=O)O)c(=O)c2cnc(N3CCN(C(=S)Nc4ccccc4C(F)(F)F)CC3)nc21

Procedure:
Pipemidic acid (48 mg, 0.159 mmol) and 2-(trifluoromethyl)phenyl isothiocyanate (20 μL, 0.132 mmol) were used. Purification on silica yielded compound 12 in Table 1, below (55 mg, 82%). 1H NMR (300 MHz, CDCl3) δ 9.32 (s, 1H), 8.69 (s, 1H), 7.74-7.64 (m, 1H), 7.63-7.51 (m, 2H), 7.43-7.33 (m, 1H), 4.47-3.90 (m, 10H), 1.50 (t, J=6.86 Hz, 3H) ppm.
Reaction SMILES: [C:1]1(C)C=CC=CC=1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.C([O:28][CH2:29][CH2:30][CH:31]1[CH2:35][CH2:34][CH2:33][C:32]1=[O:36])(=O)C>CO>[CH3:1][O:36][C:32]12[CH2:33][CH2:34][CH2:35][CH:31]1[CH2:30][CH2:29][O:28]2
Reactant: Cc1ccccc1
Reactant: CC(=O)OCCC1CCCC1=O
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CO
Product: COC12CCCC1CCO2
Yield: 95 %

Procedure:
A reaction vessel was charged with 21 parts of anhydrous toluene, 0.6 parts of methanol, 0.2 part of pyridinium paratoluene sulfonate (PPTS), 2.0 parts of 2-(2-acetoxyethyl)cyclopentanone (8) obtained in Preparation Example 1 at room temperature. The mixture was refluxed for seven hours with stirring. After the reaction, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane: ethyl acetate=19:1) to obtain 1.6 parts of 1-methoxy-2-oxabicyclo[3.3.0]octane (9) (yield: 95%).
Reaction SMILES: [O:1]([CH2:8][CH2:9][CH2:10][C:11]#[C:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][OH:18])=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>CO.[Pd]>[O:1]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:14]=[CH:15][C:16]([CH2:17][OH:18])=[CH:19][CH:20]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [H][H]
Reactant: OCc1ccc(C#CCCCOc2ccccc2)cc1
Agent: [Pd]
Solvent: CO
Product: OCc1ccc(CCCCCOc2ccccc2)cc1
Yield: 96.7 %

Procedure:
A solution of 0.54 g of 4-(5-phenoxy-1-pentyn-1-yl)benzyl alcohol in 100 ml methanol was treated with 230 mg of 5% palladium on charcoal and 58 PSI hydrogen for 3.5 hours. The product mixture was filtered using celite and the filtrate was evaporated in vacuo to yield 0.53 g of the compound in the heading in the form of a light tan solid which was used without purification.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[S:5]1(=[O:7])=[O:6].[CH3:16][O:17][C:18](=[O:21])[CH2:19]Cl.Cl>CS(C)=O>[OH:15][C:14]1[C:13]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[S:5](=[O:7])(=[O:6])[N:4]([CH3:3])[C:19]=1[C:18]([O:17][CH3:16])=[O:21]
Reactant: CN1C(=O)c2ccccc2S1(=O)=O
Reactant: COC(=O)CCl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COC(=O)C1=C(O)c2ccccc2S(=O)(=O)N1C
Reaction time: 2 h

Procedure:
In a manner similar to Example 6, 864 mg. (0.036 mole) of 99% sodium hydride was added over a two hour period to a solution of 2.9 g. (0.015 mole) of N-methylsaccharin and 9.8 g. (0.09 mole) of methylchloroacetate in 10 ml. of dimethylsulfoxide at 40° C. Stirring was continued at 40°-45° C. for an additional two hours, and the reaction mixture was poured into 150 ml. of 5% hydrochloric acid solution. The precipitate was filtered and dried to give 3.07 (76%) of the desired product.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH2:12])[O:11][C:7]=2[C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:5][CH:4]=1.[CH3:19][O:20][CH2:21][CH2:22][N:23]([CH2:25][C:26]1[CH:34]=[CH:33][C:29]([C:30](Cl)=[O:31])=[CH:28][CH:27]=1)[CH3:24].C(N(CC)CC)C>CN(C1C=CN=CC=1)C.C1COCC1>[CH3:19][O:20][CH2:21][CH2:22][N:23]([CH2:25][C:26]1[CH:27]=[CH:28][C:29]([C:30]([NH:12][C:10]2[O:11][C:7]3[C:6]([C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=4)=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[C:8]=3[N:9]=2)=[O:31])=[CH:33][CH:34]=1)[CH3:24]
Reactant: COc1ccc(-c2ccccc2)c2oc(N)nc12
Reactant: COCCN(C)Cc1ccc(C(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COCCN(C)Cc1ccc(C(=O)Nc2nc3c(OC)ccc(-c4ccccc4)c3o2)cc1

Procedure:
From 4-methoxy-7-phenyl-benzooxazol-2-yl-amine with 4-{[(2-methoxy-ethyl)-methyl-amino]-methyl}-benzoyl chloride, triethylamine and N,N-dimethyl-4-aminopyridine in THF. ES-MS m/e (%): 446 (M+H+, 100).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([CH:12]([CH3:14])[CH3:13])[C:9](Cl)=[O:10])=[CH:4][CH:3]=1.[CH2:15]=[CH2:16].[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[C@@H:8]([CH:12]([CH3:14])[CH3:13])[C:9](=[O:10])[CH2:16][CH2:15]2
Reactant: C=C
Reactant: CC(C)[C@@H](C(=O)Cl)c1ccc(F)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(C)[C@H]1C(=O)CCc2cc(F)ccc21
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A solution of 54.8 g (0.255 mol) of [R]-(-)-2-(p-fluorophenyl)-3-methylbutyryl chloride in 950 ml of methylene chloride was saturated at -10° with ethylene gas. The temperature was then reduced to -56° and 47.5 g (0.356 mol) of aluminum chloride in one portion were added. After 15 minutes, 10.0 g (0.075 mol) more of aluminum chloride were added thereto and the reaction mixture was left to warm slowly to -20°. Then, 500 ml of ice-water were cautiously added, and the organic phase was separated and washed with 3N hydrochloric acid and water. After drying and evaporating the solvent under reduced pressure, 59.6 g of [R]-(+)-6-fluoro-3,4-dihydro-1-isopropyl-2(1H)-naphtone were obtained as a light yellow oil; [α]D20 =+189.5° (c=1, methanol).
Reaction SMILES: [N:1]1[C:6]2[NH:7][CH:8]=[CH:9][C:5]=2[C:4]([N:10]2[CH2:15][CH2:14][CH:13]([NH2:16])[CH2:12][CH2:11]2)=[N:3][CH:2]=1.[CH3:17][O:18][C:19]1[CH:24]=[C:23]([C:25](O)=[O:26])[CH:22]=[CH:21][N:20]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=NC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:17][O:18][C:19]1[CH:24]=[C:23]([C:25]([NH:16][CH:13]2[CH2:12][CH2:11][N:10]([C:4]3[N:3]=[CH:2][NH:1][C:6]4=[N:7][CH:8]=[CH:9][C:5]=34)[CH2:15][CH2:14]2)=[O:26])[CH:22]=[CH:21][N:20]=1
Reactant: COc1cc(C(=O)O)ccn1
Reactant: NC1CCN(c2ncnc3[nH]ccc23)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C(=O)NC2CCN(c3nc[nH]c4nccc3-4)CC2)ccn1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of 1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-4-piperidinamine D2 (65.2 mg), 2-(methyloxy)-4-pyridinecarboxylic acid (45.9 mg, 0.300 mmol), HATU (137 mg, 0.360 mmol) and HOAt (24.50 mg, 0180 mmol) in DMF (1.5 mL) was added DIPEA (252 μL, 1.440 mmol). The reaction mixture was stirred at room temperature for 3 hours then the solvent was removed in vacuo. The crude mixture was purified by MDAP using a high pH method to afford E15 (40 mg); 1H NMR (d6-DMSO) δ 11.70 (1H, brs), 8.50 (1H, d), 8.30 (1H, d), 8.17 (1H, s), 7.35 (1H, d), 7.20 (2H, d), 6.60 (1H, d), 4.67 (2H, dt), 4.15 (1H, m), 3.88 (3H, s), 3.20 (2H, dt), 1.90 (2H, m), 1.55 (2H, m), MS(ES+) 353 [M+H]+.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:19]=[CH:18][C:17]3[N:16]4[C@H:20]([CH3:25])[CH2:21][NH:22][C:23](=[O:24])[C:15]4=[CH:14][C:13]=3[CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[H-].[Na+].Cl.Cl[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=1>>[CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:19]=[CH:18][C:17]3[N:16]4[C@H:20]([CH3:25])[CH2:21][N:22]([CH2:30][C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=5)[C:23](=[O:24])[C:15]4=[CH:14][C:13]=3[CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3[C@H](C)CNC2=O)CC1
Reactant: ClCc1ccccn1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Product: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3[C@H](C)CN(Cc3ccccn3)C2=O)CC1
Yield: 67 %

Procedure:
The title compound was synthesized in analogy to example 17, from (R)-8-(1-isopropyl-piperidin-4-yloxy)-4-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (example 8), sodium hydride (2.4 equivalents) and 2-(chloromethyl)pyridine hydrochloride, to give the desired product as a light yellow foam (67%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][C:12](=O)[CH3:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C([BH3-])#[N:16].[Na+].Cl>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH:12]([NH2:16])[CH3:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: [BH3-]C#N
Reactant: COc1ccc(CC(C)=O)cc1OC
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COc1ccc(CC(C)N)cc1OC
Temperature: 25 °C
Reaction time: 67 h
Yield: 96.5 %

Procedure:
A mixture of 3,4-dimethoxyphenylactone (51.1 g., 0.26 m.) is dissolved in methanol (780 ml.), sodium cyanoborohydride (11.3 g., 0.18 m) is added and the mixture is stirred at room temperature for 67 hours. The reaction mixture is adjusted to pH 2 with concentrated HCl and the solvent is evaporated under reduced pressure. The residue is dissolved in H2O (250 ml.), the aqueous layer is extracted with ether (3X) and then rendered alkaline with KOH and extracted with CH2Cl2 (3X). After drying, the solvent is evaporated under reduced pressure and the product is distilled at 112°-5°/0.5 mm. to yield (VIII) (33.88 g., 67%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][NH2:23])=[CH:17][CH:16]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].CC(O)=O>C(Cl)Cl>[C:18]1([CH2:21][CH2:22][NH:23][CH:11]2[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][CH2:10]2)[CH:19]=[CH:20][CH:15]=[CH:16][CH:17]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: NCCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(NCCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of tert-butyl-4-oxo-1-piperidinecarboxylate in methylene chloride was added 2-phenethylamine, NaBH(OAc)3 and HOAc. The mixture was stirred at ambient temperature for 16 hours and quenched by addition of H2O. The aqueous layer was neutralized with NaHCO3 and extracted with CH2Cl2. The combined organic layer was washed with saturated NaHCO3 and brine and dried over MgSO4. Evaporation of solvent gave an off-white solid. This material was used without further purification. ESI-MS 305 (M+H); HPLC A: 2.54 min.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH:17]=2)[N:10]=1.[CH:27]1([CH2:33][OH:34])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>>[CH:27]1([CH2:33][O:34][C:2]2[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=2[C:9]2[N:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH:17]=3)[N:10]=2)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: OCC1CCCCC1
Reactant: CS(=O)(=O)Cc1cccc(Nc2ncnc(-c3ccc(F)cc3F)n2)c1
Product: CS(=O)(=O)Cc1cccc(Nc2ncnc(-c3ccc(F)cc3OCC3CCCCC3)n2)c1

Procedure:
Starting with 4-(2,4-difluorophenyl)-N-{3-[(methylsulfonyl)methyl]phenyl}-1,3,5-triazin-2-amine (50 mg; 0.129 mmol), intermediate 42.1, and cyclohexylmethanol (59.4 mg; 0.515 mmol), example 57 was prepared analogously to the procedure for the preparation of example 42.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[N:6]=[N:7][C:8]([Cl:11])=[CH:9][CH:10]=1)=O.[CH2:12]([O:14][C:15]([C:17]1[N:18]=[C:19]([NH2:22])[S:20][CH:21]=1)=[O:16])[CH3:13]>CC(CC)=O>[Cl:11][C:8]1[N:7]=[N:6][C:5]([C:3]2[N:22]=[C:19]3[N:18]([CH:2]=2)[C:17]([C:15]([O:14][CH2:12][CH3:13])=[O:16])=[CH:21][S:20]3)=[CH:10][CH:9]=1
Reactant: CCOC(=O)c1csc(N)n1
Reactant: O=C(CBr)c1ccc(Cl)nn1
Solvent: CCC(C)=O
Product: CCOC(=O)c1csc2nc(-c3ccc(Cl)nn3)cn12
Temperature: 90 °C
Reaction time: 8 h
Yield: 18 %

Procedure:
To a 20 dram vial was added 2-bromo-1-(6-chloropyridazin-3-yl)ethanone (4.2 g, 18 mmol), ethyl-2-aminothiazole-4-carboxylate (3.1 g, 18 mmol), and methylethylketone (40 mL). The mixture was heated to 90° C. and stirred overnight. The reaction was then concentrated and purified by silica gel chromatography (EtOAc/hex) to afford 1.0 g of ethyl 6-(6-chloropyridazin-3-yl)imidazo[2,1-b]thiazole-3-carboxylate as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:21]=[C:22]([Cl:24])[CH:23]=1)[CH2:5][N:6]1[CH:10]=[CH:9][N:8]=[C:7]1[CH2:11][NH:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=1.[Li]CCCC.CCCCCC.[C:36]([O:40][C:41]([N:43]1[CH2:48][CH2:47][N:46]([CH2:49][CH2:50]Cl)[CH2:45][CH2:44]1)=[O:42])([CH3:39])([CH3:38])[CH3:37]>C1COCC1>[C:36]([O:40][C:41]([N:43]1[CH2:48][CH2:47][N:46]([CH2:49][CH2:50][N:12]([CH2:11][C:7]2[N:6]([CH2:5][C:4]3[CH:21]=[C:22]([Cl:24])[CH:23]=[C:2]([Cl:1])[CH:3]=3)[CH:10]=[CH:9][N:8]=2)[CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)[CH2:45][CH2:44]1)=[O:42])([CH3:39])([CH3:38])[CH3:37]
Reactant: CC(C)(C)OC(=O)N1CCN(CCCl)CC1
Reactant: Fc1cccc(CNCc2nccn2Cc2cc(Cl)cc(Cl)c2)c1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(CCN(Cc2cccc(F)c2)Cc2nccn2Cc2cc(Cl)cc(Cl)c2)CC1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 44.2 %

Procedure:
To a solution of [1-(3,5-dichloro-benzyl)-1H-imidazol-2-ylmethyl]-(3-fluoro-benzyl)-amine (146 mg, 0.4 mmol) in THF (1 mL) at −78° C. was added dropwise a solution of n-BuLi in hexane (0.19 mL, 0.44 mmol) and the mixture stirred at −78° C. for 30 min. A solution of 4-(2-Chloro-ethyl)-piperazine-1-carboxylic acid tert-butyl ester (116 mg, 0.46 mmol) in THF (1 mL) was then added dropwise and the mixture allowed to warm to ambient temperature before stirring for an additional 24 h. The reaction was quenched with water (10 mL) and extracted with CH2Cl2 (2×40 mL). The combined CH2Cl2 extracts were dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel, 20:1 CH2Cl2/MeOH) to provide 4-{2-[[1-(3,5-dichloro-benzyl)-1H-imidazol-2-ylmethyl]-(3-fluoro-benzyl)-amino]-ethyl}-piperazine-1-carboxylic acid tert-butyl ester (102 mg, 44%) as a colorless viscous oil: ESI MS m/z 576 [C29H36Cl2FN5O2+H]+.
Reaction SMILES: O1CCO[CH:2]1[CH2:6][CH2:7][C:8]1[CH:29]=[CH:28][C:11]([O:12][CH2:13][C:14]([C:16]2[N:17]=[C:18]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[O:19][C:20]=2[CH3:21])=[O:15])=[CH:10][CH:9]=1.[O:30]1[CH2:34][C:33](=[O:35])[NH:32][C:31]1=[O:36].N1CCCCC1>C(O)(=O)C>[CH3:21][C:20]1[O:19][C:18]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[N:17][C:16]=1[C:14](=[O:15])[CH2:13][O:12][C:11]1[CH:28]=[CH:29][C:8]([CH2:7][CH2:6][CH:2]=[C:34]2[O:30][C:31](=[O:36])[NH:32][C:33]2=[O:35])=[CH:9][CH:10]=1
Reactant: Cc1oc(-c2ccccc2)nc1C(=O)COc1ccc(CCC2OCCO2)cc1
Reactant: O=C1COC(=O)N1
Solvent: CC(=O)O
Solvent: C1CCNCC1
Product: Cc1oc(-c2ccccc2)nc1C(=O)COc1ccc(CCC=C2OC(=O)NC2=O)cc1

Procedure:
A mixture of 4-[4-[2-(1,3-dioxolan-2-yl)ethyl]phenoxyacetyl]-5-methyl-2-phenyloxazole (1.8 g), 2,4-oxazolidinedione (0.925 g), piperidine (0.12 g) and acetic acid (30 ml) was heated for 15 hours under reflux. The reaction mixture was concentrated under reduced pressure. To the concentrate was added a saturated aqueous solution of sodium hydrogencarbonate, followed by extraction with chloroform. The chloroform layer was washed with water, dried (MgSO4), followed by distilling off the solvent. The oily residue was subjected to a silica gel column chromatography. From the fractions eluted with methanol-chloroform (1:30, v/v) was obtained 5-[3-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)-2-oxoethoxy]phenyl]propylidene]-2,4-oxazolidinedione. This compound was dissolved in tetrahydrofuran (THF) (30 ml), to which was added palladium-carbon (5%, 0.3 g). The mixture was subjected to catalytic hydrogenation. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The oily residue was subjected to a silica gel column chromatography. From the fractions eluted with ethyl acetate-hexane (1:1, v/v), 5-[3-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)-2-oxoethoxyaphenyl]propyl]-2,4-oxazolidinedione (0.32 g, 16%) was obtained as an oily product.
Reaction SMILES: [N+:1]([C:4]1[CH:26]=[CH:25][C:7]2[C:8](=[O:24])[N:9]([C@@H:11]([CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[S:10][C:6]=2[CH:5]=1)([O-])=O>C(O)(=O)C.[Fe]>[NH2:1][C:4]1[CH:26]=[CH:25][C:7]2[C:8](=[O:24])[N:9]([C@@H:11]([CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[S:10][C:6]=2[CH:5]=1
Reactant: CCOC(=O)CC[C@@H](C(=O)OCC)n1sc2cc([N+](=O)[O-])ccc2c1=O
Agent: [Fe]
Solvent: CC(=O)O
Product: CCOC(=O)CC[C@@H](C(=O)OCC)n1sc2cc(N)ccc2c1=O
Temperature: 55 °C
Reaction time: 1 h
Yield: 93.6 %

Procedure:
A solution of diethyl(S)-2-(2,3-dihydro-6-nitro-3-oxo-1,2-benzisothiazol-2-yl)glutarate (4.0 g, 10 mmol) and suspended iron (1.0 g, 18 mmol) in acetic acid (100 ml) was stirred under nitrogen for 1 hour at 55° C. Additional iron (3×0.25 g, 13 mmol) was added at intervals of 1, 1.25, and 1.75 hours. The reaction mixture was stirred 30 minutes after the last addition, filtered, concentrated in vacuo, and the residue absorbed onto silica gel (20 g) from a methylene chloride solution. Purification by chromatography on silica gel (150 g) eluting with ethyl acetate:hexane (1:1→2:1) gave diethyl(S)-2-(6-amino-2,3-dihydro-3-oxo-1,2-benzisothiazol-2-yl)glutarate (3.3 g) as an oil. 1H NMR (DMSO-d6, 300 MHz) δ: 1.15 (t, J=7 Hz, 3H, ester CH3), 1.17 (t, J=7 Hz, 3H, ester CH3), 1.95-2.38 (m, 4H, glu CH2CH2), 4.02 (q, J=7 Hz, 2H, ester CH2), 4.13 (q, J=7 Hz, 2H, ester CH2), 5.08-5.15 (m, 1H, glu CH), 6.09 (br s, 2H, NH2), 6.62 (dd, J=9,2 Hz, 1H, Ar), 6.84 (d, J=2 Hz, 1H, Ar), 7.50 (d, J=9 Hz, 1H, Ar). Mass spectrum (CI—CH4): 353 (M+1, 100%). Anal. Calculated for C16H20N2O5S: C, 54.53; H, 5.72; N, 7.95; S, 9.10. Found: C, 54.34; H, 5.73; N, 7.87; S, 9.00.
Reaction SMILES: CN(C)C=O.CS([O:10][CH2:11][CH2:12][C:13]([CH3:17])=[C:14]([F:16])[F:15])(=O)=O.[CH2:18]([C:25]1[N:30]=[C:29]([CH3:31])[C:28]([C:32](O)=[O:33])=[CH:27][N:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)([O-])O.[Na+]>O>[CH2:18]([C:25]1[N:30]=[C:29]([CH3:31])[C:28]([C:32]([O:10][CH2:11][CH2:12][C:13]([CH3:17])=[C:14]([F:16])[F:15])=[O:33])=[CH:27][N:26]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: Cc1nc(Cc2ccccc2)ncc1C(=O)O
Reactant: CC(CCOS(C)(=O)=O)=C(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(CCOC(=O)c1cnc(Cc2ccccc2)nc1C)=C(F)F
Temperature: 100 °C
Reaction time: 3 h
Yield: 78.2 %

Procedure:
To 10 ml of N,N-dimethylformamide were dissolved 1.00 g (5.0 mmol) of 4,4-difluoro-3-methyl-3-butenyl methanesulfonate and 1.30 g (5.5 mmol) of 2-benzyl-4-methylpyrimidine-5-carboxylic acid, followed by the addition of 0.50 g (6.0 mmol) of sodium hydrogencarbonate and stirring at 100° C. for 3 hours. The reaction liquid was then poured in water and extracted with diethyl ether. The organic layer was washed with water and a saturated saline solution in this order, followed by drying over an hydrous magnesium sulfate, the addition of “Florisil” and filtering. The solution was concentrated under reduced pressure to obtain 1.30 g (yield: 78%) of 4,4-difluoro-3-methyl-3-butenyl 2-benzyl-4-methylpyrimidine-5-carboxylate.
Reaction SMILES: Cl.[C:2](Cl)(=O)[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.[CH3:11][NH:12][C:13](=[S:16])[NH:14][NH2:15].[OH-].[Na+].Cl>N1C=CC=CC=1>[CH3:11][N:12]1[C:2]([C:3]2[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=2)=[N:15][NH:14][C:13]1=[S:16]
Reactant: CNC(=S)NN
Reactant: O=C(Cl)c1ccncc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Product: Cn1c(-c2ccncc2)n[nH]c1=S
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.2 %

Procedure:
Isonicotinoyl chloride hydrochloride (27.5 g, 154.5 mmol) and 4-methyl-3-thiosemicarbazide (16.4 g, 155.9 mmol) were mixed in pyridine (200 ml) and stirred under argon at ambient temperature overnight. After evaporation to dryness, aqueous sodium hydroxide (250 mL, 2M, 500 mmol) was added and the resulting solution was heated at 60° C. for 16 h. After cooling to room temperature, the solution was neutralized with 6N hydrochloric acid. The precipitate that formed was collected by filtration to give the title compound (pale yellow solid, 16.4 g, 55%). 1H NMR (DMSO-d6), δ (ppm): 8.78 (dd, 2H), 7.75 (dd, 2H), 3.59 (s, 3H).
Reaction SMILES: N1C=CC(NS(C2C=C3C(=CC=2)C(C2C=CC(C(F)(F)F)=CC=2[C:31]2[CH2:36][CH2:35][N:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:33][CH:32]=2)=CC=C3)(=O)=O)=NC=1.Cl[C:45]1[CH:50]=[C:49]([C:51]([F:54])([F:53])[F:52])[CH:48]=[CH:47][C:46]=1[C:55]1[CH:64]=[CH:63][CH:62]=[C:61]2[C:56]=1[CH:57]=[CH:58][C:59]([S:65]([N:68]([CH2:74][C:75]1[CH:80]=[CH:79][C:78]([O:81][CH3:82])=[CH:77][CH:76]=1)[C:69]1[S:70][CH:71]=[CH:72][N:73]=1)(=[O:67])=[O:66])=[CH:60]2>>[CH3:82][O:81][C:78]1[CH:77]=[CH:76][C:75]([CH2:74][N:68]([C:69]2[S:70][CH:71]=[CH:72][N:73]=2)[S:65]([C:59]2[CH:60]=[C:61]3[C:56](=[CH:57][CH:58]=2)[C:55]([C:46]2[CH:47]=[CH:48][C:49]([C:51]([F:52])([F:53])[F:54])=[CH:50][C:45]=2[C:31]2[CH2:36][CH2:35][N:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:33][CH:32]=2)=[CH:64][CH:63]=[CH:62]3)(=[O:67])=[O:66])=[CH:80][CH:79]=1
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(-c4ccc(C(F)(F)F)cc4Cl)cccc3c2)cc1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cc(C(F)(F)F)ccc2-c2cccc3cc(S(=O)(=O)Nc4ccncn4)ccc23)CC1
Product: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(-c4ccc(C(F)(F)F)cc4C4=CCN(C(=O)OC(C)(C)C)CC4)cccc3c2)cc1

Procedure:
The title compound was prepared in an analogous manner to that of intermediate Y, except that 5-(2-chloro-4-(trifluoromethyl)phenyl)-N-(4-methoxybenzyl)-N-(thiazol-2-yl)naphthalene-2-sulfonamide was used instead of 5-(2-chloro-4-(trifluoromethyl)phenyl)-N-(pyrimidin-4-yl)naphthalene-2-sulfonamide.