Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.[I-].[CH3:7][P+:8]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[OH:27][C:28]1[C:37]([CH3:38])=[CH:36][CH:35]=[CH:34][C:29]=1[C:30](OC)=[O:31]>CCCCCC.C1COCC1>[OH:27][C:28]1[C:37]([CH3:38])=[CH:36][CH:35]=[CH:34][C:29]=1[C:30](=[O:31])[CH:7]=[P:8]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COC(=O)c1cccc(C)c1O
Reactant: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [I-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1cccc(C(=O)C=P(c2ccccc2)(c2ccccc2)c2ccccc2)c1O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
206.8 ml (330.9 mmol) of a 1.6 molar n-butyllithium solution in n-hexane are slowly added to 97.3 g (240.7 mmol) of methyltriphenylphosphonium iodide in 800 ml of absolute THF under argon. The mixture is stirred at room temperature for 3 h. Then 20.0 g (120.3 mmol) of methyl 2-hydroxy-3-methylbenzoate in 200 ml of absolute THF are added dropwise to the reaction mixture. The mixture is stirred at 60° C. for 3 h. After cooling to room temperature, the precipitated lithium iodide is filtered off. The filtrate is concentrated in vacuo, and the residue is recrystallized from methanol. 27 g (56% of theory) of the title compound are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][C:11]([F:14])([F:13])[F:12])[CH:5]=O.[CH3:15][C:16]([S@:19]([NH2:21])=[O:20])([CH3:18])[CH3:17].C1COCC1>C(O[Ti](OCC)(OCC)OCC)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][C:11]([F:14])([F:13])[F:12])/[CH:5]=[N:21]/[S@@:19]([C:16]([CH3:18])([CH3:17])[CH3:15])=[O:20]
Reactant: CC(C)(C)[S@](N)=O
Reactant: O=Cc1ccc(OC(F)(F)F)c(Cl)c1
Agent: CCO[Ti](OCC)(OCC)OCC
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)[S@@](=O)/N=C/c1ccc(OC(F)(F)F)c(Cl)c1
Temperature: 65 °C
Yield: 96.6 %

Procedure:
To a solution of 3-chloro-4-(trifluoromethoxy)benzaldehyde (2.8 g, 12 mmol) and (R)-2-methylpropane-2-sulfinamide (2.7 g, 22 mmol) and THF (25 mL) at RT was added tetraethoxytitanium (9.3 mL, 45 mmol) and the reaction was heated to 65° C. for 12 h. The reaction was cooled to RT, water (100 mL) was added and the solids were filtered and discarded. The filtrate was extracted with EtOAc, the organic fraction was dried, filtered, and concentrated in vacuo. The crude product was purified by SiO2 chromatography eluting with DCM/MeOH (500:10) to afford 3.8 g (98%) of (R,E)-N-(3-chloro-4-(trifluoromethoxy)benzylidene)-2-methylpropane-2-sulfinamide (218).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:11]3([C:15](=[O:16])[NH:14][C:13](=O)[NH:12]3)[CH2:10][CH:9]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[O:8][C:5]2=[CH:6][CH:7]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:33])=CC=1>O1CCOCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:11]3([C:15](=[O:16])[NH:14][C:13](=[S:33])[NH:12]3)[CH2:10][CH:9]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[O:8][C:5]2=[CH:6][CH:7]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: O=C1NC(=O)C2(CC(c3ccccc3)Oc3ccc(Br)cc32)N1
Solvent: C1COCCO1
Product: O=C1NC(=S)NC12CC(c1ccccc1)Oc1ccc(Br)cc12
Temperature: 110 °C
Yield: 51.8 %

Procedure:
To a solution of 6-bromo-2-phenylspiro[chroman-4,4′-imidazolidine]-2′,5′-dione (440 mg, 1.18 mmol) in 1,4-dioxane (3.6 mL) in a 10 mL CEM microwave test tube, there is added Lawesson's reagent (477 mg, 1.18 mmol). The resulting mixture is heated in a CEM microwave reactor at 110° C. for 40 min and cooled to rt. The solvent is removed in vacuo, and the residue is purified by flash chromatography column to give 6-bromo-2-phenyl-2′-thioxospiro[chroman-4,4′-imidazolidin]-5′-one (238 mg, 52%). MS m/z 389 (M+H+).
Reaction SMILES: [C:1]([C:3]1[CH:31]=[CH:30][C:29]([O:32][CH2:33][C:34]2[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=2)=[CH:28][C:4]=1[O:5][CH:6]([C:12]1[CH:17]=[C:16]([O:18]COCC[Si](C)(C)C)[CH:15]=[CH:14][C:13]=1[CH3:27])[CH2:7][CH2:8][C:9]([OH:11])=[O:10])#[N:2].Cl>O1CCCC1>[C:1]([C:3]1[CH:31]=[CH:30][C:29]([O:32][CH2:33][C:34]2[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=2)=[CH:28][C:4]=1[O:5][CH:6]([C:12]1[CH:17]=[C:16]([OH:18])[CH:15]=[CH:14][C:13]=1[CH3:27])[CH2:7][CH2:8][C:9]([OH:11])=[O:10])#[N:2]
Reactant: Cc1ccc(OCOCC[Si](C)(C)C)cc1C(CCC(=O)O)Oc1cc(OCc2cccnc2)ccc1C#N
Agent: Cl
Solvent: C1CCOC1
Product: Cc1ccc(O)cc1C(CCC(=O)O)Oc1cc(OCc2cccnc2)ccc1C#N
Yield: 36.4 %

Procedure:
A solution of (RS)-4-[2-cyano-5-(3-pyridylmethoxy)phenoxy]-4-(2-methyl-5-(2-(trimethylsilyl)ethoxymethoxy)phenyl)butanoic acid (1.8 g) in tetrahydrofuran (150 mL) is treated with 1 N hydrochloric acid (10 mL) and the mixture heated at reflux for 1 hour. The reaction mixture is evaporated and the residue partitioned between ethyl acetate (200 mL) and water (100 mL). The organic phase is washed with water (100 mL), brine (100 mL), dried over magnesium sulphate and evaporated. The residual brown gum (1.25 g) is recrystallised from acetonitrile to give (RS)-4-[2-cyano-5-(3-pyridylmethoxy)phenoxy]-4-(5-hydroxy-2-methylphenyl)butanoic acid (0.5 g) as a cream solid, m.p. 198-200° C. [Elemental analysis:- C,68.32; H,5.45; N,6.93%. Calculated:- C,68.89; H,5.30; N,6.69%]
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].[O:10]=[C:11](Cl)OC(Cl)(Cl)Cl>O1CCCC1>[CH3:5][CH:4]([CH3:6])[CH2:3][C@H:2]1[C:7](=[O:9])[O:8][C:11](=[O:10])[NH:1]1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: CC(C)C[C@H](N)C(=O)O
Solvent: C1CCOC1
Product: CC(C)C[C@@H]1NC(=O)OC1=O

Procedure:
The title compound is prepared by the procedure of Example 262 using 3.93 g of L-leucine, 2.7 ml of diphosgene, 0.075 g of activated carbon, and 40 ml of dry tetrahydrofuran to give 2.74 g of the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:11]2[CH2:14][CH:13]([O:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:12]2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.Cl.[NH2:23][C:24]1([C:27]2[CH:36]=[CH:35][C:30]([C:31]([O:33][CH3:34])=[O:32])=[CH:29][CH:28]=2)[CH2:26][CH2:25]1>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:11]2[CH2:14][CH:13]([O:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:12]2)=[C:6]([CH:10]=1)[C:7]([NH:23][C:24]1([C:27]2[CH:36]=[CH:35][C:30]([C:31]([O:33][CH3:34])=[O:32])=[CH:29][CH:28]=2)[CH2:26][CH2:25]1)=[O:9]
Reactant: COC(=O)c1ccc(C2(N)CC2)cc1
Reactant: O=C(O)c1cc(Cl)cnc1N1CC(Oc2ccccc2)C1
Agent: Cl
Product: COC(=O)c1ccc(C2(NC(=O)c3cc(Cl)cnc3N3CC(Oc4ccccc4)C3)CC2)cc1
Yield: 117.7 %

Procedure:
The title compound (D145) (225 mg) was prepared according to the experimental procedure described in Description 142 starting from 5-chloro-2-(3-phenoxyazetidin-1-yl)nicotinic acid (D101) (140 mg, 0.46 mmol) and methyl 4-(1-aminocyclopropyl)benzoate hydrochloride (D7) (104 mg, 0.40 mmol).
Reaction SMILES: Br[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=1[Cl:13].[NH:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1.CC(C)([O-])C.[Na+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:13][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:2]=1[N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: C1CCNC1
Reactant: CCOC(=O)c1ccc(Br)c(Cl)c1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccc(N2CCCC2)c(Cl)c1
Yield: 24.6 %

Procedure:
A mixture of ethyl 4-bromo-3-chlorobenzoate (D16) (2.53 g, 9.62 mmol), pyrrolidine (1.03 mL, 12.5 mmol), sodium tert-butoxide (1.29 g, 13.5 mmol), BINAP (196 mg, 0.29 mmol) and tris(dibenzylideneacetone)dipalladium(0) (58 mg, 0.10 mmol) in toluene (120 mL) was heated to reflux under argon for 3 h. The reaction was allowed to cool and was filtered. The solid was washed with toluene and then the filtrate was concentrated. The residue was partitioned between ethyl acetate (150 mL) and water (100 mL) with aqueous sodium bicarbonate (50 mL) added. The organic phase was dried (phase separator) and concentrated to give an orange oil. The oil was purified by reverse phase chromatography, eluting 5-100% acetonitrile in water to give the title compound as an orange oil (600 mg). This contained some impurities. MS (ES): C13H1635ClNO2 requires 253; found 254 (MH+).
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[F:12][C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=1[NH:20][C:21](=[O:41])[C:22]([N:25]1[C:30](=[O:31])[C:29]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[C:28]([CH2:38][S:39][CH3:40])[O:27][CH2:26]1)([CH3:24])[CH3:23]>ClCCl>[F:12][C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=1[NH:20][C:21](=[O:41])[C:22]([N:25]1[C:30](=[O:31])[C:29]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[C:28]([CH2:38][S:39]([CH3:40])=[O:6])[O:27][CH2:26]1)([CH3:24])[CH3:23]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSCC1=C(c2ccccc2)C(=O)N(C(C)(C)C(=O)Nc2cc(F)ccc2F)CO1
Solvent: ClCCl
Product: CS(=O)CC1=C(c2ccccc2)C(=O)N(C(C)(C)C(=O)Nc2cc(F)ccc2F)CO1
Temperature: -20 °C
Reaction time: 1 h
Yield: 36.3 %

Procedure:
m-Chloroperoxybenzoic acid (75% pure, 0.54 g) was added to a stirred solution of N-(2,5-difluorophenyl)-2-(2,3-dihydro-6-methylthiomethyl-4-oxo-5-phenyl-4H-1,3-oxazin-3-yl)-2-methylpropanamide (compound 1, 100 g) in dichloromethane at -20° C. The mixture was stirred at -20° C. for 1 hour, diluted with dichloromethane, washed with 1M sodium carbonate, dried (magnesium sulphate) and solvent evaporated under reduced pressure. The residue was triturated with diethyl ether to give N-(2,5-difluorophenyl)-2-(2,3-dihydro-6-methylsulphinylmethyl-4-oxo-5-phenyl-4H-1,3-oxazin-3-yl)-2-methylpropanamide (compound 5, 0.51 g) as a white solid, m.p. 124-128° C.
Reaction SMILES: CN(C)[C:3]1[S:4][C:5]2[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[CH:25][C:6]=2[C:7]=1[C:8]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)=[CH:12][CH:11]=1)=[O:9].C1COCC1.[CH3:37][C:38]1[CH:39]=[C:40]([Mg]Br)[CH:41]=[CH:42][C:43]=1[O:44][CH3:45].CO>ClC1C=CC=CC=1.C(Cl)Cl>[CH3:37][C:38]1[CH:39]=[C:40]([C:3]2[S:4][C:5]3[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[CH:25][C:6]=3[C:7]=2[C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][N:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)=[CH:12][CH:11]=2)=[O:9])[CH:41]=[CH:42][C:43]=1[O:44][CH3:45]
Reactant: COc1ccc2c(C(=O)c3ccc(OCCN4CCCCC4)cc3)c(N(C)C)sc2c1
Reactant: COc1ccc([Mg]Br)cc1C
Solvent: CO
Solvent: ClCCl
Solvent: C1CCOC1
Product: COc1ccc2c(C(=O)c3ccc(OCCN4CCCCC4)cc3)c(-c3ccc(OC)c(C)c3)sc2c1
Yield: 68.3 %

Procedure:
By the method described in Example 1, [2-dimethylamino-6-methoxybenzothien-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]-methanone (1.0 g, 2.3 mmol) in chlorobenzene (10 mL) was treated with a 0.69 M THF solution of 3-methyl-4-methoxyphenylmagnesium bromide (11 mL, 7.6 mmol) (prepared from 4-bromo-2-methylanisole, catalytic iodine, and magnesium turnings in THF) to provide, after chromatography (silica gel, 5-10% MeOH in CH2Cl2) 810 mg (69%) of the title compound as a yellow oil: 1H NMR d 1.43 (m, 2H), 1.58 (m, 4H), 2.11 (s, 3H), 2.46 (m, 4H), 2.71 (t, J=5.8 Hz, 2H), 3.75 (s, 3H), 3.86 (s, 3H), 4.06 (t, J=5.8 Hz, 2H), 6.64 (d, J=8.9 Hz, 1H), 6.75 (d, J=8.6 Hz, 2H), 6.95 (d, J=8.9 Hz, 1H), 7.20 (s, 2H), 7.31 (s, 1H), 7.54 (d, J=8.9 Hz, 1H), 7.77 (d, J=8.6 Hz, 2H); 13C NMR d 16.4, 24.4, 26.1, 55.3, 55.6, 55.9, 57.9, 66.4, 104.8, 110.2, 114.5, 115.0, 124.3, 125.8, 127.1, 128.0, 130.6, 130.8, 131.6, 132.5, 134.3, 140.3, 143.2, 157.9, 158.3, 163.2, 193.6; MS (FD) m/e 515 (M+); Anal. calc'd. for C31H33NO4S: C, 72.21; H, 6.45; N, 2.72. Found: C, 72.43; H, 6.53; N, 2.95.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]2[N:6]=[CH:7][S:8][C:4]=2[C:3]=1[NH2:11].O.O.[C:14](O)(=[O:18])[C:15](O)=[O:16]>Cl>[OH:16][C:15]1[C:14]([OH:18])=[N:11][C:3]2[C:2](=[CH:10][CH:9]=[C:5]3[N:6]=[CH:7][S:8][C:4]3=2)[N:1]=1
Reactant: Nc1ccc2ncsc2c1N
Reactant: O=C(O)C(=O)O
Agent: Cl
Solvent: O
Product: Oc1nc2ccc3ncsc3c2nc1O
Yield: 87.8 %

Procedure:
A solution of 6,7-diaminobenzothiazole (1.3 g, 7.9 mmol) and oxalic acid dihydrate (1.3 g, 10.3 mmol) in 40 ml of 4M hydrochloric acid was refluxed on an oil bath for 11/2 h, and cooled. The resulting precipitate was collected by filtration and washed successively with water and ethanol to give 1.52 g (88%) of the title compound; m.p. >360° C.; IR (KBr): 1700 cm-1 ; 1H-NMR (DMSO-d6): ca. 6.3 (very broad s, lH, OH), 7.40 (d, J=9 Hz, lH, ArH), 7.87 (d, J=9 Hz, lH, ArH), 9.33 (s, lH, H-2), 12.07 (broad s, lH, OH).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[C:11]([O:15][C:16]([NH:18][C@@H:19]([CH2:24][CH:25]1[CH2:30][CH2:29][CH:28]([OH:31])[CH2:27][CH2:26]1)[C:20]([O:22][CH3:23])=[O:21])=[O:17])([CH3:14])([CH3:13])[CH3:12].C([O-])(O)=O.[Na+]>C(Cl)Cl.CCN(CC)CC>[C:11]([O:15][C:16]([NH:18][C@@H:19]([CH2:24][CH:25]1[CH2:30][CH2:29][C:28](=[O:31])[CH2:27][CH2:26]1)[C:20]([O:22][CH3:23])=[O:21])=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: COC(=O)[C@H](CC1CCC(O)CC1)NC(=O)OC(C)(C)C
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: COC(=O)[C@H](CC1CCC(=O)CC1)NC(=O)OC(C)(C)C
Temperature: -40 °C
Reaction time: 5 h
Yield: 67 %

Procedure:
To a solution of oxalyl dichloride (49.5 g, 0.39 mol) in dry CH2Cl2 (480 mL) was added dropwise a solution of dry DMSO (60.8 g, 0.78 mol) in dry CH2Cl2 (200 mL) at −65° C. for about 0.5-1 hr. Then a solution of (S)-methyl 2-(tert-butoxycarbonylamino)-3-(4-hydroxycyclohexyl)propanoate (59.5 g, 0.197 mol) in dry CH2Cl2 (600 mL) was added dropwise to the above mixture for about 0.5-1 hr. It was allowed to stir for 4-6 hr at −50-−30° C. Upon completion of the reaction, 158 mL of Et3N was added dropwise and the mixture was warmed to rt. The solution was added sat. NaHCO3, extracted by EtOAc, washed with H2O, brine, dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatograph to give (S)-methyl 2-(tert-butoxycarbonylamino)-3-(4-oxocyclohexyl)propanoate (39.5 g, 67%). 1H NMR (CDCl3, 400 MHz) δ 5.00 (d, J=8.0H, 1H), 4.39 (m, 1H), 3.74 (s, 3H), 2.40-1.30 (m, 11H), 1.44 (s, 9H). MS ESI +ve m/z 301 (M+1).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([F:20])=[C:15](F)[C:16]=3[Cl:18])[C:11](=[O:21])[C:10]([C:22]([OH:24])=[O:23])=[CH:9]2)[C:5]([F:25])=[CH:4][C:3]=1[F:26].[NH2:27][CH2:28][CH2:29][CH2:30][OH:31].C(N(CC)CC)C>N1C=CC=CC=1>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([F:20])=[C:15]([NH:27][CH2:28][CH2:29][CH2:30][OH:31])[C:16]=3[Cl:18])[C:11](=[O:21])[C:10]([C:22]([OH:24])=[O:23])=[CH:9]2)[C:5]([F:25])=[CH:4][C:3]=1[F:26]
Reactant: NCCCO
Reactant: Nc1nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(Cl)c32)c(F)cc1F
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: Nc1nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(NCCCO)c(Cl)c32)c(F)cc1F
Temperature: 40 °C
Reaction time: 65 h
Yield: 49.6 %

Procedure:
1-(6-Amino-3,5-difluoropyridin-2-yl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (150 mg), 3-amino-1-propanol (75 mg) and triethylamine (110 mg) were added to pyridine (400 mg), and the mixture was stirred at 40° C. for 65 hours. The reaction mixture was concentrated under reduced pressure. A process of adding ethanol (2 ml) to the residue and then concentrating the mixture under reduced pressure was conducted twice repeatedly. Concentrated hydrochloric acid (100 mg) was added to the residue, and the mixture was concentrated under reduced pressure. Ethanol (1.5 ml) was added to the resultant residue, and deposits were collected by filtration and washed with ethanol and diisopropyl ether in that order to obtain the title compound (85 mg) as a pale yellow powder.
Reaction SMILES: [CH3:1][N:2]1[C:7]2=[CH:8][N:9]([C@@H:17]([CH2:28][CH2:29][C:30]([O:32]CC3C=CC=CC=3)=[O:31])[C:18]([O:20]CC3C=CC=CC=3)=[O:19])[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[C:6]2[C:5](=[O:40])[N:4]([CH3:41])[C:3]1=[O:42]>[Pd].C(O)C>[CH3:1][N:2]1[C:7]2=[CH:8][N:9]([C@@H:17]([CH2:28][CH2:29][C:30]([OH:32])=[O:31])[C:18]([OH:20])=[O:19])[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[C:6]2[C:5](=[O:40])[N:4]([CH3:41])[C:3]1=[O:42]
Reactant: Cn1c(=O)c2c(-c3ccccc3)n([C@@H](CCC(=O)OCc3ccccc3)C(=O)OCc3ccccc3)cc2n(C)c1=O
Agent: [Pd]
Solvent: CCO
Product: Cn1c(=O)c2c(-c3ccccc3)n([C@@H](CCC(=O)O)C(=O)O)cc2n(C)c1=O
Reaction time: 2.33 h

Procedure:
A suspension of (S)-dibenzyl 2-(1,3-dimethyl-2,4-dioxo-5-phenyl-3,4-dihydro-1H-pyrrolo[3,4-d]pyrimidin-6(2H)-yl)pentanedioate (3 g, 5.30 mmol) and 10% palladium on carbon (0.564 g, 0.530 mmol) in ethanol (100 mL) was stirred under a hydrogen atmosphere for 140 mins. The mixture was filtered through a Celite® cartridge (10 g, filter material) and the residue rinsed well with methanol and 7N NH3/methanol. The combined filtrates were evaporated under vacuum to afford the title compound.
Reaction SMILES: [N:1]1[N:2]=[C:3]([C:12]2([C:17]3[S:18][CH:19]=[CH:20][CH:21]=3)[CH2:15][CH:14]([OH:16])[CH2:13]2)[N:4]2[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][C:5]=12.C[N+]1([O-])CCOCC1>C(Cl)Cl>[N:1]1[N:2]=[C:3]([C:12]2([C:17]3[S:18][CH:19]=[CH:20][CH:21]=3)[CH2:13][C:14](=[O:16])[CH2:15]2)[N:4]2[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][C:5]=12
Reactant: OC1CC(c2cccs2)(c2nnc3n2CCCCCC3)C1
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Product: O=C1CC(c2cccs2)(c2nnc3n2CCCCCC3)C1
Temperature: 25 °C
Reaction time: 15 h
Yield: 79.7 %

Procedure:
3-(5,6,7,8,9,10-hexahydro[1,2,4]triazolo[4,3-a]azocin-3-yl)-3-(2-thienyl)cyclobutanol (2.73 g) was dissolved in methylene chloride (330 ml) and then tetra-n-propylammonium perruthenate(VII) (316 mg) and NMO (1.58 g) were added thereto, followed by stirring at room temperature for 15 hours. The reaction solution was subjected to evaporation under reduced pressure and the resulting residue was purified by column chromatography (methanol:chloroform=3:97) to obtain 2.16 g of 3-(5,6,7,8,9,10-hexahydro[1,2,4]triazolo[4,3-a]azocin-3-yl)-3-(2-thienyl)cyclobutanone (pale yellow solid).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[C:11]([C:14]([OH:16])=O)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[NH2:17][C:18]1[CH:19]=[CH:20][C:21]([N:26]2[CH2:31][CH2:30][CH:29]([N:32]([CH3:34])[CH3:33])[CH2:28][CH2:27]2)=[C:22]([CH:25]=1)[C:23]#[N:24]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([CH3:13])=[C:11]([C:14]([NH:17][C:18]3[CH:19]=[CH:20][C:21]([N:26]4[CH2:27][CH2:28][CH:29]([N:32]([CH3:33])[CH3:34])[CH2:30][CH2:31]4)=[C:22]([C:23]#[N:24])[CH:25]=3)=[O:16])[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: CN(C)C1CCN(c2ccc(N)cc2C#N)CC1
Reactant: Cc1c(C(=O)O)cnn1-c1ccc(Cl)cc1
Product: Cc1c(C(=O)Nc2ccc(N3CCC(N(C)C)CC3)c(C#N)c2)cnn1-c1ccc(Cl)cc1
Yield: 30.9 %

Procedure:
By the reaction and treatment in the same manner as in Example 64 using 1-(4-chlorophenyl)-5-methylpyrazole-4-carboxylic acid (3.3 g) and 5-amino-2-[4-(N,N-dimethylamino)piperidin-1-yl]benzonitrile (2.9 g), the title compound (1.7 g) was obtained, melting point: 210–213° C.
Reaction SMILES: [C:1]([C:4]1([NH:10][S:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)(=[O:13])=[O:12])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1)(=O)[CH3:2].ClC1C=CC(CS(Cl)(=O)=O)=CC=1.C(NC1CCCCC1)#C.C(N(CC)CC)C>O1CCCC1.C(OCC)(=O)C>[Cl:21][C:18]1[CH:17]=[CH:16][C:15]([CH2:14][S:11]([NH:10][C:4]2([C:1]#[CH:2])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]2)(=[O:13])=[O:12])=[CH:20][CH:19]=1
Reactant: CC(=O)C1(NS(=O)(=O)Cc2ccc(Cl)cc2)CCCCC1
Agent: C#CNC1CCCCC1
Agent: O=S(=O)(Cl)Cc1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C#CC1(NS(=O)(=O)Cc2ccc(Cl)cc2)CCCCC1
Yield: 80 %

Procedure:
The preparation of N-(1-acetylcyclohexyl)-4-chlorophenyl-methanesulfonamide, shown below, was performed as described in Pestic. Sci. 1993, 39, 185–192. 4-chloro-phenylmethanesulfonyl chloride (1.37 g, 6 mmol) and ethynylcyclohexylamine (0.73 g, 6 mmol) were stirred in tetrahydrofuran (10 mL) with triethylamine (0.9 mL, 6.6 mmol) for several hours at room temperature. The mixture was diluted with ethyl acetate, washed with water, dried (Na2SO4) and evaporated. Recrystallisation from ethanol yielded 4-chlorophenyl-N-(1-ethynylcyclohexyl)methane-sulfonamide (1.5 g, 80%) as a solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:36]=[CH:35][C:6]([CH2:7][N:8]2[C:14](=[O:15])[C:13](=[N:16]NC3C=CC=CC=3)[C:12](=[O:24])[N:11]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:10]3[CH:31]=[CH:32][CH:33]=[CH:34][C:9]2=3)=[CH:5][CH:4]=1>C(O)(=O)C.CC(OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=O.[Zn]>[NH2:16][CH:13]1[C:14](=[O:15])[N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:36][CH:35]=2)[C:9]2[CH:34]=[CH:33][CH:32]=[CH:31][C:10]=2[N:11]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:12]1=[O:24]
Reactant: COc1ccc(Cn2c(=O)c(=NNc3ccccc3)c(=O)n(-c3ccccc3)c3ccccc32)cc1
Agent: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Agent: [Zn]
Solvent: CC(=O)O
Product: COc1ccc(CN2C(=O)C(N)C(=O)N(c3ccccc3)c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 102.2 %

Procedure:
To a vigorously stirred slurry of zinc dust (6.49 g) in acetic acid (50 ml) cooled to 10° C., was added a slurry of 1 -(4-Methoxybenzyl)-5-phenyl-3-(phenylhydrazono)-1,5-dihydrobenzo [b] [1, 4] diazepine-2, 4-dione (5.75 g,12.1 mmol) in acetic add (30 ml) over a fifteen minute period. After complete addition, the solution was warmed to room temperature and stirred three hours. The zinc was separated by filtration and washed with ethyl acetate (75 ml). The filtrate was concentrated in vacuo and partitioned between H2O (60 ml) and ethyl acetate (100 ml). The pH was adjusted to 9 with saturated aqueous sodium carbonate and the phases separated. The aqueous phase was extracted with ethyl acetate (2×75 ml), the organic layers combined, dried with magnesium sulfate, filtered and concentrated in vacuo to give a yellow oil which was dried in vacuo to give the title compound (4.79 g) NMR (300 MHz, CDCl3): d 3.05 (s, 2H), 3.75 (s, 3H), 4.35 (s, 1H), 4.64 (d, J=14.7 Hz, 1H), 5.82 (d, J=14.7 Hz, 1H), 6.59-6.85 (m, 6H), 7.06-7.29 (m, 6H), 7.51(d, J=7.4 Hz. 1H); MS (FAB): m/z=388.2 (MH+); TLC (CH2Cl2 /CH3OH (9:1)): Rf =0.50.
Reaction SMILES: BrC1C=CC(C(N2CCN(C3C(C)=CC(CC)=CN=3)CC2)=O)=C(F)C=1.COC1C=CC(CN2CC(C)NC2=O)=CC=1.[CH2:42]([C:44]1[CH:45]=[C:46]([CH3:81])[C:47]([N:50]2[CH2:55][CH2:54][N:53]([C:56]([C:58]3[CH:63]=[CH:62][C:61]([N:64]4[CH:68]([CH3:69])[CH2:67][N:66](CC5C=CC(OC)=CC=5)[C:65]4=[O:79])=[CH:60][C:59]=3[F:80])=[O:57])[CH2:52][CH2:51]2)=[N:48][CH:49]=1)[CH3:43]>>[CH2:42]([C:44]1[CH:45]=[C:46]([CH3:81])[C:47]([N:50]2[CH2:55][CH2:54][N:53]([C:56]([C:58]3[CH:63]=[CH:62][C:61]([N:64]4[CH:68]([CH3:69])[CH2:67][NH:66][C:65]4=[O:79])=[CH:60][C:59]=3[F:80])=[O:57])[CH2:52][CH2:51]2)=[N:48][CH:49]=1)[CH3:43]
Reactant: CCc1cnc(N2CCN(C(=O)c3ccc(N4C(=O)N(Cc5ccc(OC)cc5)CC4C)cc3F)CC2)c(C)c1
Agent: CCc1cnc(N2CCN(C(=O)c3ccc(Br)cc3F)CC2)c(C)c1
Agent: COc1ccc(CN2CC(C)NC2=O)cc1
Product: CCc1cnc(N2CCN(C(=O)c3ccc(N4C(=O)NCC4C)cc3F)CC2)c(C)c1

Procedure:
Using (4-bromo-2-fluorophenyl)[4-(5-ethyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone (163 mg) described in Preparation Example 211 and 1-(4-methoxybenzyl)-4-methylimidazolidin-2-one (88 mg) described in Preparation Example 52 and by the reaction and treatment in the same manner as in Example 506, the title compound (89 mg) was obtained via 3-{4-[4-(5-ethyl-3-methylpyridin-2-yl)piperazine-1-carbonyl]-3-fluorophenyl}-1-(4-methoxybenzyl)-4-methylimidazolidin-2-one.