Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([O:11][CH3:12])[CH2:9][NH2:10])=[CH:4][CH:3]=1.[Cl:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][C:23]=1[O:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](O)=[O:30])=[CH:27][CH:26]=1)[O:20][CH2:19][CH2:18][CH:17]2[C:34]([O:36][CH2:37][CH3:38])=[O:35].N1C2C(=NC=CC=2)N(O)N=1.Cl.C(N=C=NCCCN(C)C)C>CN(C=O)C.CCOC(C)=O>[Cl:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][C:23]=1[O:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](=[O:30])[NH:10][CH2:9][CH:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[O:11][CH3:12])=[CH:27][CH:26]=1)[O:20][CH2:19][CH2:18][CH:17]2[C:34]([O:36][CH2:37][CH3:38])=[O:35]
Reactant: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)O)cc3)c(Cl)cc21
Reactant: COC(CN)c1ccc(Cl)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)NCC(OC)c4ccc(Cl)cc4)cc3)c(Cl)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.9 %

Procedure:
To a solution of 2-(4-chlorophenyl)-2-methoxyethanamine (0.071 g, 0.38 mmol), 4-(6-chloro-4-(ethoxycarbonyl)chroman-7-yloxy)benzoic acid (0.060 g, 0.16 mmol), and 3H-[1,2,3]triazolo[4,5-b]pyridin-3-ol (0.022 g, 0.16 mmol) in DMF (1 ml) was added N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (0.037 g, 0.19 mmol), and the reaction was stirred at ambient temperature overnight. The reaction was diluted with EtOAc and washed with 1M hydrochloric acid, saturated sodium bicarbonate, and saturated sodium chloride. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude material was loaded onto a Biotage SP1 system, eluting with a linear gradient of 5-70% EtOAc in hexanes to yield 67 mg of the title compound (77% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[Cl:13]N1C(=O)CCC1=O>ClCCl>[Cl:13][C:12]1[CH:11]=[C:5]([CH:4]=[CH:3][C:2]=1[NH2:1])[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClCCl
Product: CCOC(=O)c1ccc(N)c(Cl)c1
Yield: 73.9 %

Procedure:
A mixture of 8.26 g of ethyl 4-aminobenzoate, 8.26 g of N-chlorosuccinimide in 50 ml of dichloromethane is refluxed overnight. The mixture is washed with saturated NaHCO3 solution and dried Na2SO4). The solution is passed through a thin pad of hydrous magnesium silicate and the filter cake washed with dichloromethane. The filtrate is concentrated and hexane added. Chilling gives 7.38 g of ethyl 3-chloro-4-aminobenzoate, m.p. 82°-83° C.
Reaction SMILES: Br[C:2]1[S:3][C:4]2[CH:10]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:8]=[CH:7][C:5]=2[N:6]=1.[C:16]([N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17].C(=O)([O-])[O-].[K+].[K+].C(#N)C>O>[C:19]([O:18][C:16]([N:23]1[CH2:28][CH2:27][N:26]([C:2]2[S:3][C:4]3[CH:10]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:8]=[CH:7][C:5]=3[N:6]=2)[CH2:25][CH2:24]1)=[O:17])([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CCOC(=O)c1ccc2nc(Br)sc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CCOC(=O)c1ccc2nc(N3CCN(C(=O)OC(C)(C)C)CC3)sc2c1
Temperature: 25 °C

Procedure:
The ethyl 2-bromobenzo[d]thiazole-6-carboxylate (11.1 g), BOC-piperazine (9.03 g), potassium carbonate (11.7 g) and acetonitrile (400 mL) were combined and heated to reflux overnight. The resulting mixture was cooled to room temperature, diluted with water and extracted with EtOAc. The organics were concentrated to a yellow solid, which was recrystallized from EtOAc/heptane to yield a ethyl 2-(4-(tert-butoxycarbonyl)piperazin-1-yl)benzo[d]thiazole-6-carboxylate as a white powder, which was collected by filtration.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:14]([C:15]([OH:17])=O)[CH2:13][C:10]2([CH2:12][CH2:11]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH3:18]>>[C:15]([CH:14]1[CH2:13][C:10]2([CH2:12][CH2:11]2)[CH2:9][N:8]1[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])(=[O:17])[NH2:18]
Reactant: CC(C)(C)OC(=O)N1CC2(CC2)CC1C(=O)O
Reactant: N
Product: CC(C)(C)OC(=O)N1CC2(CC2)CC1C(N)=O
Yield: 78 %

Procedure:
In analogy to the procedure described in Example 127 c), 5-(tert-butoxycarbonyl)-5-azaspiro[2.4]heptane-6-carboxylic acid (CAN 1454843-77-6, 112 mg, 464 μmol) was condensed with ammonia to give the title compound (87 mg, 78%) as colorless liquid, MS (EI): m/e=240.0 [M+].
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][N:5]([C:7](=[O:31])[CH2:8][C:9]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[C@H:4]([C:32]([N:34]2[CH2:38][CH2:37][CH2:36][C@@H:35]2[C:39]([NH:41][CH2:42][CH:43]2[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]2)=[O:40])=[O:33])[CH2:3]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[C:57](#N)[CH3:58]>C(Cl)(Cl)Cl>[CH:57]1([CH2:58][N:46]2[CH2:45][CH2:44][CH:43]([CH2:42][NH:41][C:39]([C@H:35]3[CH2:36][CH2:37][CH2:38][N:34]3[C:32]([C@@H:4]3[CH2:3][C@@H:2]([OH:1])[CH2:6][N:5]3[C:7](=[O:31])[CH2:8][C:9]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[C:10]3[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=3)=[O:33])=[O:40])[CH2:48][CH2:47]2)[CH2:4][CH2:3][CH2:2][CH2:6]1
Reactant: O=C(NCC1CCNCC1)[C@H]1CCCN1C(=O)[C@@H]1C[C@@H](O)CN1C(=O)CC(c1ccc(F)cc1)(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: CC#N
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: O=C(NCC1CCN(CC2CCCC2)CC1)[C@H]1CCCN1C(=O)[C@@H]1C[C@@H](O)CN1C(=O)CC(c1ccc(F)cc1)(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 80 °C
Reaction time: 24 h

Procedure:
To a solution of 19 mg of (2R)-1-((2S,4R)-4-hydroxy-1-{3,3,3-tris(4-fluorophenyl)propanoyl}pyrrolidin-2-yl)carbonyl-N-(4-piperidylmethyl)pyrrolidine-2-carboxamide in 1.5 ml of acetonitrile, 14 mg of methanesulfonic acid-cyclopentylmethyl, 13 mg of potassium carbonate and 5 mg of potassium iodide were added at room temperature, followed by 24 hours' stirring at 80° C. under heating. The reaction liquid was diluted with chloroform, washed successively with water and 1N aqueous sodium hydroxide solution, and drired over anhydrous sodium sulfate. Distilling the solvent off under reduced pressure, the resultant residue was purified by preparative thin-layer chromatography [Kieselgel™ 60F254, Art 5744 (Merck), chloroform/methanol/28% aqueous ammonia=100/10/1) to provide 16 mg of the title compound as a white solid.
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])=[N:5][CH:6]=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9].[C:19]([O-:22])(=[O:21])[CH3:20].[Na+].O>CC(N(C)C)=O>[C:19]([O:22][CH2:2][C:3]1[C:4]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])=[N:5][CH:6]=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9])(=[O:21])[CH3:20]
Reactant: CC(=O)[O-]
Reactant: COC(=O)c1cnc(OCC(F)(F)F)c(CBr)c1
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: COC(=O)c1cnc(OCC(F)(F)F)c(COC(C)=O)c1
Temperature: 130 °C
Reaction time: 2 h
Yield: 55 %

Procedure:
A mixture of methyl 5-(bromomethyl)-6-(2,2,2-trifluoroethoxy)nicotinate (0.68 g, 2.07 mmol, Step-2) and sodium acetate (0.51 g, 6.20 mmol) in DMA (10 mL) is stirred at 130° C. for 2 hours. After cooling to room temperature, the reaction mixture is poured into water, extracted with ethyl acetate and dried over sodium sulfate and concentrated in vacuo. The residue is purified by column chromatography on silica gel eluting with n-Hexane/ethyl acetate (6:1) to give 0.35 g (56% yield) of the title compound as colorless oil.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][N:9]=2)[CH2:4][CH2:3][CH2:2]1.[Br:11]N1C(=O)CCC1=O.C([O-])([O-])=O.[K+].[K+]>C(O)(=O)C>[Br:11][N:9]1[C:10]2[NH:1][CH2:2][CH2:3][CH2:4][C:5]=2[CH:6]=[CH:7][CH2:8]1
Reactant: O=C1CCC(=O)N1Br
Reactant: c1cnc2c(c1)CCCN2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Product: BrN1CC=CC2=C1NCCC2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 0.6730 g (5.02 mmol) 32 in 20 mL glacial acetic acid was added 1.0701 g (6.01 mmol) N-bromosuccinimide. After 16 h at 65° C., the reaction mixture was cooled to room temperature and poured onto 50 mL ice water. This was brought to pH 11 with K2CO3 and extracted with 4×100 mL CHCl3. The combined CHCl3 extracts were washed with 100 mL brine, dried over Na2SO4, filtered and concentrated in vacuo. Purification by flash chromatography (50×115 mm silica gel, linear gradient 2-5% (10% NH4H:MeOH):CH2Cl2) yielded 33. 1H NMR (CDCl3, 400 MHz) δ 8.175 (s, 1H, ArH); 7.877 (s, 1H, ArH); 3.458-3.423 (m, 2H, CH2); 2.725 (t, 2H, J=6.26 Hz, CH2); 1.970-1.911 (m, 2H, CH2); MS (Electrospray): m/z 212.9, 214.8 (M+H, 79Br, 81Br).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](OS(C(F)(F)F)(=O)=O)[C:5]([C:16]#[N:17])=[C:4]([C:18]2[O:19][CH:20]=[CH:21][CH:22]=2)[N:3]=1.[C:23]1([C:29]#[CH:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[NH2:1][C:2]1[N:3]=[C:4]([C:18]2[O:19][CH:20]=[CH:21][CH:22]=2)[C:5]([C:16]#[N:17])=[C:6]([C:30]#[C:29][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:7]=1
Reactant: C#Cc1ccccc1
Reactant: N#Cc1c(OS(=O)(=O)C(F)(F)F)nc(N)nc1-c1ccco1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: N#Cc1c(C#Cc2ccccc2)nc(N)nc1-c1ccco1

Procedure:
From trifluoromethanesulfonic acid 2-amino-5-cyano-6-furan-2-yl-pyrimidin-4-yl ester, phenylacetylene, bis(triphenylphosphine)palladium(II) chloride, triphenylphosphine, triethylamine and copper (I) iodide in THF. EI-MS m/e (%): 286 (M+, 100).
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:9][C@H:8]2[C:10](Cl)=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:13][CH2:14][CH2:15][CH2:16][N:17]1[C:25]2[C:24]([CH3:26])=[C:23]([CH3:27])[N:22]=[C:21]([NH2:28])[C:20]=2[N:19]=[C:18]1[CH3:29]>>[NH2:28][C:21]1[C:20]2[N:19]=[C:18]([CH3:29])[N:17]([CH2:16][CH2:15][CH2:14][NH:13][C:10]([C@@H:8]3[CH2:9][C@H:7]3[C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[O:11])[C:25]=2[C:24]([CH3:26])=[C:23]([CH3:27])[N:22]=1
Reactant: Cc1nc(N)c2nc(C)n(CCCN)c2c1C
Reactant: O=C(Cl)[C@@H]1C[C@H]1c1ccccc1
Product: Cc1nc(N)c2nc(C)n(CCCNC(=O)[C@@H]3C[C@H]3c3ccccc3)c2c1C

Procedure:
Using the method of Examples 78–92, trans-2-phenyl-1-cyclopropanecarbonyl chloride was reacted with 1-(3-aminopropyl)-2,6,7-trimethyl-1H-imidazo[4,5-c]pyridin-4-amine to provide the desired product. The observed accurate mass was 378.2298.
Reaction SMILES: Cl.C(O[N:5]=[CH:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][N:11]=[C:10]2[C:16]1[CH:17]=[C:18]([NH:22][C:23](=[O:32])[C@H:24]([OH:31])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:19]=[CH:20][CH:21]=1)C.[NH2:33][NH:34][C:35](=O)[CH2:36][N:37]([CH3:39])[CH3:38].C[O-].[Na+]>CO>[CH3:38][N:37]([CH2:36][C:35]1[NH:34][N:33]=[C:6]([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[NH:12][N:11]=[C:10]3[C:16]2[CH:17]=[C:18]([NH:22][C:23](=[O:32])[C@H:24]([OH:31])[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:19]=[CH:20][CH:21]=2)[N:5]=1)[CH3:39]
Reactant: CN(C)CC(=O)NN
Reactant: CCON=Cc1ccc2[nH]nc(-c3cccc(NC(=O)[C@H](O)c4ccccc4)c3)c2c1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CN(C)Cc1nc(-c2ccc3[nH]nc(-c4cccc(NC(=O)[C@H](O)c5ccccc5)c4)c3c2)n[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 9 %

Procedure:
To a suspension of (2R)-N-{3-[5-(ethoxyiminomethyl)(1H-indazol-3-yl)]phenyl}-2-hydroxy-2-phenylacetamide hydrochloride (0.500 g, 1.11 mmol) in methanol (10 mL) were added 3 equivalents of N-amino-2-(dimethylamino)acetamide (0.390 g, 3.33 mmol) and 2.5 equivalents of sodium methoxide in methanol (0.635 mL, 4.3 M). After stirring at room temperature for 1 h, the reaction mixture was heated to 95° C. for 48 hours. The reaction was then quenched with water, the pH adjusted to neutral and the crude product extracted with ethyl acetate. The title compound was purified by preparative HPLC (0.050 g, 9% yield): 1H NMR (CD3OD) δ 8.72 (s, 1H), 8.23 (s, 1H), 8.08 (d, 1H), 7.89 (d, 2H), 7.68 (d, 1H), 7.58 (d, 2H), 7.51 (t, 1H), 7.40–7.32 (m, 3H), 5.21 (s, 1H), 3.71 (s, 2H), 2.37 (s, 6H); ES-MS (m/z) 468 [M+H]+.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C:2]1=[O:6].Br[CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[H-].[Na+]>CN(C)C=O>[C:10]1([CH:9]([N:1]2[CH2:5][CH2:4][CH2:3][C:2]2=[O:6])[CH3:8])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: BrCCc1ccccc1
Reactant: O=C1CCCN1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(c1ccccc1)N1CCCC1=O

Procedure:
1-Phenylethyl-2-pyrrolidone is prepared from 2-pyrrolidone and 2-bromoethylbenzene in N,N-dimethylformamide in the presence of sodium hydride (M. Matsukawa et al. NeuroToxicology 2004, 25, 293-302).
Reaction SMILES: [N:1]1([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH:9]=[CH:10][NH:11]3)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.I[CH2:17][CH2:18][CH:19]1[CH2:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20]1.C(C(C)=O)C(C)C>CN1CCCC1=O>[CH2:20]1[C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:27][CH:19]1[CH2:18][CH2:17][N:4]1[CH2:3][CH2:2][N:1]([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH:9]=[CH:10][NH:11]3)[CH2:6][CH2:5]1
Reactant: c1cc(N2CCNCC2)c2cc[nH]c2c1
Reactant: ICCC1Cc2ccccc2C1
Solvent: CC(=O)CC(C)C
Solvent: CN1CCCC1=O
Product: c1ccc2c(c1)CC(CCN1CCN(c3cccc4[nH]ccc34)CC1)C2
Temperature: 25 °C
Yield: 47.3 %

Procedure:
A mixture of 4-(piperazin-1-yl)-1H-indole (1.5 g), 2-(2-iodoethyl)indane (2.0 g), K2C(3, methyl isobutyl ketone (150 ml), and N-methylpyrrolidone (10 ml ) was boiled under reflux for 3 h. The mixture was allowed to cool to room temperature, filtered, and concentrated in vacuo. The residue was purified on silica gel eluted with ethyl acetate-heptane (1:2) to give a crystalline compound, which was recrystallized (ethyl acetate) to give the title compound (1.2 g, 47%). Mp 146-147° C. 1H NMR (CDCl3) δ 1.70-1.85 (m, 2H), 2.40-2.70 (m, 5H), 2.75 (broad s, 4H), 3.00-3.15 (m, 2H), 3.30 (broad s, 4H), 6.55 (s, 1H), 6.60 (d, 1H), 7.00-7.30 (m, 711), 8.20 (broad s, 1H). MS m/z (%): 346 (MH+, 34%), 159 (88%), 145 (100%).
Reaction SMILES: [C:1](Cl)(=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5].[C:8]([NH2:17])(=[O:16])[C:9]1[C:10](=[CH:12][CH:13]=[CH:14][CH:15]=1)[NH2:11].C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>O1CCCC1>[O:6]=[C:1]([NH:11][C:10]1[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=1[C:8]([NH2:17])=[O:16])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCC(=O)Cl
Reactant: NC(=O)c1ccccc1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCC(=O)Nc1ccccc1C(N)=O
Temperature: 25 °C
Reaction time: 19 h
Yield: 89.9 %

Procedure:
Valeryl chloride (6.0 mL, 50 mmol) was added to a mixture of anthranilamide (6.8 g, 50 mmol) and triethylamine (7.0 mL, 50 mmol) in tetrahydrofuran (100 mL) at 25° C. A rapid, exothermic reaction was observed, but no external cooling was required to prevent reflux. The mixture was stirred at ambient temperature for 19 hours, after which it was poured into excess aqueous sodium bicarbonate solution, extracted with ethyl acetate, dried (magnesium sulfate), and concentrated in vacuo. The residue was triturated with hexane/ether to give the title compound as a tan solid (9.9 g, 90%); M.p. 119° C.-120° C.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=[CH:17][C:15]2=[O:16])[CH:10]([CH3:25])[CH2:9]1)C1C=CC=CC=1>[C].[Pd].C(O)(=O)C>[CH3:25][CH:10]1[CH:11]([N:14]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH2:18][CH2:17][C:15]2=[O:16])[CH2:12][CH2:13][NH:8][CH2:9]1
Reactant: CC1CN(Cc2ccccc2)CCC1n1c(=O)ccc2ccccc21
Agent: [Pd]
Solvent: CC(=O)O
Product: CC1CNCCC1N1C(=O)CCc2ccccc21
Yield: 65.4 %

Procedure:
Acetic acid (30 ml) and 1-(1-benzyl-3-methyl-4-piperidinyl)carbostyril (2.1 g) are added to 10% palladiumcarbon (0.5 g) and the mixture is subjected to catalytic reduction at 80° C. under atmospheric pressure. After the catalytic reduction, 10% palladium-carbon is filtered off and the filtrate is concentrated under reduced pressure. Water is added to the residue and the mixture is basified with aqueous sodium hydroxide solution and then extracted with dichloromethane. After washed with water, the extract is dried with magnesium sulfate and the solvent is distilled off under reduced pressure to give 1-(3-methyl-4-piperidinyl)-3,4-dihydrocarbostyril (1.01 g).
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([C@H:13]([O:15][C@H:16]2[CH2:21][CH2:20][C@H:19]([CH2:22][OH:23])[C@@H:18]([CH2:24][OH:25])[C@@H:17]2[C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH3:35][S:36](Cl)(=[O:38])=[O:37]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:35][S:36]([O:23][CH2:22][C@H:19]1[CH2:20][CH2:21][C@H:16]([O:15][C@@H:13]([C:5]2[CH:4]=[C:3]([C:2]([F:1])([F:33])[F:34])[CH:8]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:6]=2)[CH3:14])[C@@H:17]([C:26]2[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=2)[C@@H:18]1[CH2:24][O:25][S:36]([CH3:35])(=[O:38])=[O:37])(=[O:38])=[O:37]
Reactant: C[C@@H](O[C@H]1CC[C@H](CO)[C@@H](CO)[C@@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: C[C@@H](O[C@H]1CC[C@H](COS(C)(=O)=O)[C@@H](COS(C)(=O)=O)[C@@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: -5 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1.82 g (3.7 mmol) [(1S,2R,3R,4S)-4-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}-3-(4-fluorophenyl)cyclohexane-1,2-diyl]dimethanol (step G) in 50 mL methylene chloride cooled to −5° C. in an ice/salt bath was added 1.0 mL (3.5 equiv.) methane-sulfonyl chloride; 2.1 mL (4 equiv.) TEA and 44 mg (0.1 equiv.) DMAP. The reaction mixture was stirred at −5° C. for 30 min then quenched at that temperature by the addition of 20 mL sat. aq. NaHCO3. The mixture was warmed to RT. The organic layer was separated and the aqueous layer extracted with additional 50 mL methylene chloride. The combined organic layer was washed with 20 mL 2N aq. HCl, 30 mL sat. aq. NaHCO3, brine, dried over MgSO4 drying agent, filtered and the solvent evaporated under vacuum to give the title compound as an oil which was used without further purification.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[CH2:9][O:8][C:7](=[O:11])[C:6]=2[CH:5]=[CH:4][C:3]=1[C@H:12]1[CH2:14][O:13]1.[CH3:15][C:16]1[C:20](=[O:21])[O:19][CH2:18][C:17]=1[N:22]1[CH2:26][CH2:25][C:24]2([CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[C:23]1=[O:32].CCN(C(C)C)C(C)C>CCO>[OH:13][C@@H:12]([C:3]1[CH:4]=[CH:5][C:6]2[C:7](=[O:11])[O:8][CH2:9][C:10]=2[C:2]=1[CH3:1])[CH2:14][N:29]1[CH2:30][CH2:31][C:24]2([C:23](=[O:32])[N:22]([C:17]3[CH2:18][O:19][C:20](=[O:21])[C:16]=3[CH3:15])[CH2:26][CH2:25]2)[CH2:27][CH2:28]1
Reactant: CC1=C(N2CCC3(CCNCC3)C2=O)COC1=O
Reactant: Cc1c([C@H]2CO2)ccc2c1COC2=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CC1=C(N2CCC3(CCN(C[C@@H](O)c4ccc5c(c4C)COC5=O)CC3)C2=O)COC1=O
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a suspension of 4-methyl-5-[(2S)-oxiran-2-yl]-2-benzofuran-1(3H)-one (I-4A)(200 mg, 1.05 mmol) and 2-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-2,8-diazaspiro[4.5]decan-1-one (300 mg, 1.05 mmol) in 10 mL of EtOH was added DIPEA (271 mg, 2.10 mmol). The resulting mixture was stirred at 80° C. overnight, and then cooled to room temperature; the solvent was removed under vacuum. The residue was purified by flash chromatography (ethyl acetate: MeOH=20:1) to afford title compound. MS-ESI (m/z): 441 (M+1)
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[N:16]=[CH:17][C:18]([C:21]([OH:23])=O)=[N:19][CH:20]=1.[C:24]([NH2:28])([CH3:27])([CH3:26])[CH3:25]>>[C:24]([NH:28][C:21]([C:18]1[CH:17]=[N:16][C:15]([O:14][CH2:13][C:3]2[C:4]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)=[N:5][O:6][C:2]=2[CH3:1])=[CH:20][N:19]=1)=[O:23])([CH3:27])([CH3:26])[CH3:25]
Reactant: CC(C)(C)N
Reactant: Cc1onc(-c2ccccc2)c1COc1cnc(C(=O)O)cn1
Product: Cc1onc(-c2ccccc2)c1COc1cnc(C(=O)NC(C)(C)C)cn1
Yield: 20 %

Procedure:
As described for example 2b, 5-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyrazine-2-carboxylic acid (100 mg, 0.32 mmol) was converted using tert-butylamine instead of aminomethylcyclopropane, to the title compound (SiO2, heptane:ethyl acetate=90:10 to 60:40, 24 mg, 20%) which was obtained as a colorless gum. MS: m/e=367.2 [M+H]+.
Reaction SMILES: [SH:1][C:2]1[CH:9]=[C:8]([C:10]2[C:11]([C:15]([F:18])([F:17])[F:16])=[N:12][NH:13][CH:14]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].O>CS(C)=O>[S:1]([C:6]1[CH:7]=[C:8]([C:10]2[C:11]([C:15]([F:16])([F:17])[F:18])=[N:12][NH:13][CH:14]=2)[CH:9]=[CH:2][C:3]=1[C:4]#[N:5])[C:2]1[CH:9]=[C:8]([C:10]2[C:11]([C:15]([F:16])([F:18])[F:17])=[N:12][NH:13][CH:14]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1ccc(-c2c[nH]nc2C(F)(F)F)cc1S
Solvent: O
Solvent: CS(C)=O
Product: N#Cc1ccc(-c2c[nH]nc2C(F)(F)F)cc1Sc1cc(-c2c[nH]nc2C(F)(F)F)ccc1C#N
Temperature: 25 °C
Yield: 46.4 %

Procedure:
3.0 g (11.1 mmol) of 2-mercapto-4-(3-trifluoromethylpyrazolyl)benzonitrile in 5 ml of dimethyl sulfoxide was stirred at 50° C. for 2 hours. The reaction mixture was cooled to room temperature and poured into 50 ml of water, and the organic matters were extracted with 20 ml of ethyl acetate twice. The ethyl acetate layers were combined, then washed with 30 ml of water twice and dried over anhydrous magnesium sulfate, and the ethyl acetate was distilled off under reduced pressure. Purification of the residue afforded 1.3 g of 1,1′-thiodi-[2-cyano-5-(3-trifluoromethylpyrazolyl)benzene] (yield 42.4%) as a yellow solid, which was used in Example 2 (3) as the starting material.
Reaction SMILES: Cl[C:2]1[N:6]=[C:5]([N:7]2[CH2:12][CH2:11][CH:10]([N:13]([CH:27]3[CH2:29][CH2:28]3)[C:14](=[O:26])[C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][CH:24]=[N:23][CH:22]=4)=[CH:17][CH:16]=3)[CH2:9][CH2:8]2)[S:4][N:3]=1.[CH:30]([OH:33])([CH3:32])[CH3:31].C(=O)([O-])[O-].[Cs+].[Cs+]>CN1CCCC1=O>[CH:27]1([N:13]([CH:10]2[CH2:11][CH2:12][N:7]([C:5]3[S:4][N:3]=[C:2]([O:33][CH:30]([CH3:32])[CH3:31])[N:6]=3)[CH2:8][CH2:9]2)[C:14](=[O:26])[C:15]2[CH:20]=[CH:19][C:18]([C:21]3[O:25][CH:24]=[N:23][CH:22]=3)=[CH:17][CH:16]=2)[CH2:29][CH2:28]1
Reactant: CC(C)O
Reactant: O=C(c1ccc(-c2cnco2)cc1)N(C1CC1)C1CCN(c2nc(Cl)ns2)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: CC(C)Oc1nsc(N2CCC(N(C(=O)c3ccc(-c4cnco4)cc3)C3CC3)CC2)n1
Temperature: 125 °C
Reaction time: 72 h

Procedure:
A mixture of N-[1-(3-chloro-[1,2,4]thiadiazol-5-yl)-piperidin-4-yl]-N-cyclopropyl-4-oxazol-5-yl-benzamide (43 mg), isopropanol (2.0 mL), and cesium carbonate (98 mg) in N-methyl-2-pyrrolidinon (2.0 mL) is stirred at 125° C. for three days. The mixture is separated by HPLC (MeOH/H2O/TFA) to give the title compound. LC (method 5): tR=2.14 min; Mass spectrum (ESI+): m/z=454 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][C:7]2=[O:12].[C:13](Cl)(=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15].Cl>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[C:13]([O:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][C:7]2=[O:12])(=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15]
Reactant: O=C1CCCc2c(O)cccc21
Reactant: CC(C)(C)C(=O)Cl
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: c1ccncc1
Product: CC(C)(C)C(=O)Oc1cccc2c1CCCC2=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a pyridine (180 ml) solution of 5-hydroxy-1-tetralone (30.0 g), 4-dimethylaminopyridine (1.13 g) was added, and pivaloyl chloride (25.0 ml) was added thereto under ice-cooling, followed by stirring at room temperature overnight. The reaction mixture was ice-cooled, and a concentrated hydrochloric acid was added thereto, followed by extracting with ethyl acetate. The extract was washed with water and saturated saline in this order, dried with anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1 to 5:1) to thereby obtain the title compound (45.4 g) having the following physical data.