Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:18][CH:19]1[CH2:22][N:21]([C:23]2[S:24][CH:25]=[C:26]([C:28](OCC)=[O:29])[N:27]=2)[CH2:20]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Si:33]([O:50][CH2:51][C@@H:52]([NH2:57])[C@@H:53]([CH3:56])[CH2:54][CH3:55])([C:46]([CH3:49])([CH3:48])[CH3:47])([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.C[Al](C)C.C(O)(=O)C.C(OCC)(=O)C>C1C=CC=CC=1>[Si:1]([O:18][CH:19]1[CH2:22][N:21]([C:23]2[S:24][CH:25]=[C:26]([C:28](=[O:29])[NH:57][C@H:52]([CH2:51][O:50][Si:33]([C:46]([CH3:48])([CH3:47])[CH3:49])([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[C@@H:53]([CH3:56])[CH2:54][CH3:55])[N:27]=2)[CH2:20]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC[C@H](C)[C@H](N)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Reactant: CCOC(=O)c1csc(N2CC(O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)C2)n1
Agent: C[Al](C)C
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Solvent: CC(=O)O
Product: CC[C@H](C)[C@@H](CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)NC(=O)c1csc(N2CC(O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)C2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 57 %

Procedure:
Subsequently, to a solution of 3-t-butyldiphenylsilyloxy-1-(4-ethoxycarbonyl-1,3-thiazol-2-yl)azetidine (2.00 g, 4.29 mmol) (obtained as described in Reference Example 2(1)) in benzene (100 ml) was added a solution of 0.67M (1S,2S)-1-(t-butyldiphenylsilyloxymethyl)-2-methylbutylamine-trimethylaluminium in benzene (12.9 ml) at room temperature under an atmosphere of nitrogen. The mixture was heated under reflux overnight. After checking the completion of the reaction, 10% aqueous acetic acid solution (100 ml) and ethyl acetate (200 ml) were added to the reaction mixture in an ice bath, and the resulting mixture was stirred at room temperature for 30 minutes. After adding ethyl acetate thereto, the reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed successively with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using n-hexane:ethyl acetate (6:1→1:3) as the eluant to afford 3-t-butyldiphenylsilyloxy-1-{4-[(1S,2S)-1-(t-butyldiphenylsilyloxymethyl)-2-methylbutylcarbamoyl]-1,3-thiazol-2-yl}azetidine (1.89 g, yield 57%) as a pale brown solid.
Reaction SMILES: CON(C)[C:4](=[O:15])[C@@H:5]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH3:6].[Cl:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[Mg]Cl>>[Cl:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:4](=[O:15])[C@@H:5]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:12])[CH3:13])[CH3:6]
Reactant: Cl[Mg]c1ccccc1Cl
Reactant: CON(C)C(=O)[C@H](C)NC(=O)OC(C)(C)C
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)c1ccccc1Cl

Procedure:
Prepared as described in Example 6 using (S)-tert-butyl 1-(methoxy(methyl)amino)-1-oxopropan-2-ylcarbamate (182 mg, 0.78 mmol) and (2-chlorophenyl)magnesium chloride (403 mg, 2.35 mmol). Yield 110 mg (50%).
Reaction SMILES: B(C1CCCCC1)C1CCCCC1.[CH3:14][C:15]([CH3:19])([CH3:18])[C:16]#[CH:17].[Zn](CC)CC.[CH:25](=[O:28])[CH2:26][CH3:27]>>[CH3:14][C:15]([CH3:19])([CH3:18])[CH:16]=[CH:17][C@@H:25]([OH:28])[CH2:26][CH3:27]
Reactant: C#CC(C)(C)C
Reactant: CCC=O
Agent: B(C1CCCCC1)C1CCCCC1
Agent: CC[Zn]CC
Product: CC[C@H](O)C=CC(C)(C)C
Yield: 68 %

Procedure:
The product was prepared by General procedure S using 196 mg (1.1 mmol) Cy2BH, 137 μL (1.1 mmol) 3,3-dimethyl-1-butyne, 1.1 mL (2.1 mmol, 2.0 M in hexanes) Et2Zn, 9.6 mg (0.04 mmol) (−)-MIB, and 72 μL (1.0 mmol) propanal. The crude product was purified by column chromatography (5% ethyl acetate in hexanes) to afford the title compound as a colorless oil in 68% yield (96 mg, 0.68 mmol). [α]D20=−60.3 (c=0.63, CHCl3, 77% ee); 1H NMR (CDCl3, 500 MHz): δ 0.86 (t, 3H, J=7.4 Hz), 0.98 (s, 9H), 1.26 (br s, 1H), 1.44-1.59 (m, 2H), 3.93 (dt, 1H, J=6.6, 6.6 Hz), 5.31 (dd, 1H, J=15.7, 7.1 Hz), and 5.62 (d, 1H, J=15.7 Hz) ppm; 13C{1H} NMR (CDCl3, 125 MHz): δ 9.7, 22.6, 29.5, 30.2, 74.7, 127.4, and 143.2 ppm; IR (neat): 3360, 3025, 2960, 2866, 1660, 1478, 1463, 1414, 1384, 1363, 1331, and 1262 cm−1; HRMS-CI m/z 141.1274 [(M−H)+; calcd for C9H17O: 141.1279].
Reaction SMILES: [N:1]1([C:6]2[CH:18]=[CH:17][C:9]([O:10][C@@H:11]3[CH2:16][CH2:15][CH2:14][NH:13][CH2:12]3)=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.Cl[CH2:20][C:21]1[CH:29]=[CH:28][C:24]2[O:25][CH2:26][O:27][C:23]=2[CH:22]=1.C([O-])([O-])=O.[K+].[K+].N[C@H](C(O)=O)CC1C=C2C(C=CC=C2)=CC=1>CN(C=O)C.C(OCC)(=O)C.CO>[N:1]1([C:6]2[CH:18]=[CH:17][C:9]([O:10][C@@H:11]3[CH2:16][CH2:15][CH2:14][N:13]([CH2:20][C:21]4[CH:29]=[CH:28][C:24]5[O:25][CH2:26][O:27][C:23]=5[CH:22]=4)[CH2:12]3)=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: c1cn(-c2ccc(O[C@@H]3CCCNC3)cc2)cn1
Reactant: ClCc1ccc2c(c1)OCO2
Agent: N[C@@H](Cc1ccc2ccccc2c1)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: c1cn(-c2ccc(O[C@@H]3CCCN(Cc4ccc5c(c4)OCO5)C3)cc2)cn1
Temperature: 50 °C

Procedure:
(3R)-3-[4-(Imidazol-1-yl)phenoxy]piperidine (150 mg, 0.61 mmol) was dissolved in DMF (2 mL) and was added to a solution of 5-chloromethyl-1,3-benzodioxole (0.16 ml in 50% methylene chloride, 1.0 eq.) in DMF, followed by the addition of K2CO3 (2.5 eq.) and Nal (0.1 eq.). The resulting mixture was heated at 50° C. for 1 hour. The solvent was evaporated and flash column chromatography on silical gel with 3% methanol in methylene chloride gave a crude product (112 mg). Additional flash chromatography with 3% methanol in ethyl acetate afforded (3R)-3-[4-(imidazol-1-yl)phenoxy]-1-[(1,3-benzodioxol-5-yl)methyl]piperidine (70 mg), 1H NMR (CDCl3) 7.75 (s, 1), 7.30 (d, 2), 7.20 (d, 2), 7.00 (d, 2), 6.85 (s, 1), 6.75 (d, 2), 5.90 (s, 2), 4.40 (m, 1), 3.50 (s, 2), 3.00 (m, 1), 2.70 (m, 1), 2.20 (m, 3), 1.85 (m, 1), 1.50 (m, 2) ppm.
Reaction SMILES: C(C1OC[C@H](C(C)(C)C)N=1)C1OC[C@H](C(C)(C)C)N=1.[Cl:20][C:21]([F:23])=[CH2:22].[N+](=[CH:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[N-]>C1CCCCC1.FC(F)(F)S([O-])(=O)=O.[Cu+2].FC(F)(F)S([O-])(=O)=O>[Cl:20][C:21]1([F:23])[CH2:22][CH:26]1[C:27]([O:29][CH2:30][CH3:31])=[O:28]
Reactant: C=C(F)Cl
Reactant: CCOC(=O)C=[N+]=[N-]
Agent: [Cu+2]
Agent: CC(C)(C)[C@H]1COC(CC2=N[C@@H](C(C)(C)C)CO2)=N1
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: C1CCCCC1
Product: CCOC(=O)C1CC1(F)Cl
Temperature: 30 °C
Reaction time: 1 h

Procedure:
Cyclohexane (76.6 g), 2,2′-methylenebis[(4S)-4-tert-butyl-2-oxazoline] (293 mg, 1.1 mmol), and copper (II) trifluoromethanesulfonate (361 mg, 1.0 mmol) were added in an autoclave, and then 1-chloro-1-fluoroethylene (80 g, 1.0 mol) was charged under elevated pressure. After the mixture was warmed to 30° C., a mixed solution containing 95% of ethyl diazoacetate (12.01 g, 100 mmol) and cyclohexane (50 g) was charged under elevated pressure over five hours. Cyclohexane (20 ml) was further charged under elevated pressure and stirring was continued at the same temperature for 1 hour, and then the internal pressure was released to obtain a solution of ethyl 2-chloro-2-fluorocyclopropane-carboxylate in cyclohexane (183.86 g). The content of the ethyl 2-chloro-2-fluorocyclopropanecarboxylate was 4.92% (yield based on ethyl diazoacetate: 54.3%), and the ratio of cis-isomer/trans-isomer was 59.5/40.5. The optical purity of the cis-isomer was 71% e.e. (1S,2R), and the optical purity of the trans-isomer was 19% e.e. (1S,2S).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([NH:10][CH2:11][C@@H:12]3[C@H:17]([CH3:18])[CH2:16][CH2:15][CH2:14][N:13]3C(OCC=C)=O)=[N:7][C:6]=2[CH:25]=1.N1CCOCC1>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([NH:10][CH2:11][C@@H:12]3[C@H:17]([CH3:18])[CH2:16][CH2:15][CH2:14][NH:13]3)=[N:7][C:6]=2[CH:25]=1
Reactant: C=CCOC(=O)N1CCC[C@@H](C)[C@H]1CNc1nc2cc(Cl)ccc2o1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCN1
Solvent: C1CCOC1
Product: C[C@@H]1CCCN[C@@H]1CNc1nc2cc(Cl)ccc2o1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (2S,3R)-allyl 2-(((5-chlorobenzo[d]oxazol-2-yl)amino)methyl)-3-methylpiperidine-1-carboxylate (1.18 g, 3.248 mmol) and morpholine (2.8 mL, 32.48 mmol) in THF (30 mL) was added Pd(PPh3)4 (0.375 g, 0.32 mmol). The mixture was stirred at rt for 2 h. The solvent was removed in vacuo. The crude was purified via silica gel with 0˜100% EtOAc/DCM to obtain the title compound. ESI-MS (m/z): 280 [M+1]+.
Reaction SMILES: C(NC(=O)C(C(C)(C)C)=O)(=[O:3])C.C(N[C:17](=[O:26])[C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:19])(=O)C>>[C:20]1([C:18](=[O:19])[C:17]([OH:26])=[O:3])[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CC(=O)NC(=O)C(=O)C(C)(C)C
Reactant: CC(=O)NC(=O)C(=O)c1ccccc1
Product: O=C(O)C(=O)c1ccccc1
Yield: 89.3 %

Procedure:
The procedure followed is as described in Example B 2. (a), but instead of trimethylpyruvic acid N-acetylamide, the equivalent amount (0.1 mole) of phenylglyoxylic acid N-acetylamide was employed. 13.4 g (89.3% of theory) of phenylglyoxylic acid were obtained.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([C:11]([F:14])([F:13])[F:12])=[CH:4][N:3]=1.[C:15]([O:22][CH3:23])(=[O:21])[CH2:16][C:17]([O:19][CH3:20])=[O:18].[H-].[Na+]>C1COCC1.CCOC(C)=O>[N+:8]([C:7]1[C:2]([CH:16]([C:15]([O:22][CH3:23])=[O:21])[C:17]([O:19][CH3:20])=[O:18])=[N:3][CH:4]=[C:5]([C:11]([F:14])([F:13])[F:12])[CH:6]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)cnc1Cl
Reactant: COC(=O)CC(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)C(C(=O)OC)c1ncc(C(F)(F)F)cc1[N+](=O)[O-]
Yield: 56.2 %

Procedure:
A solution of 2-chloro-3-nitro-5-(trifluoromethyl)pyridine from Example B16 (400 mg, 1.766 mmol) in THF (5 mL) was treated sequentially with dimethyl malonate (250 μl, 2.187 mmol) and sodium hydride (60%, 85 mg, 2.119 mmol). The resultant mixture was stirred at RT overnight. The mixture was diluted with EtOAc and washed with 0.1 M aq HCl, water, and brine, dried (MgSO4), concentrated in vacuo and purified by silica gel chromatography to provide dimethyl 2-(3-nitro-5-(trifluoromethyl)pyridin-2-yl)malonate (320 mg, 56% yield) of sufficient purity for the next step. MS (ESI) m/z: 323.0 (M+H+).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C[Al](C)C.[F:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[C:13]=1[N:19]1[C:24]2[N:25]=[C:26]([NH:37][CH2:38][C:39](OC)=[O:40])[N:27]=[C:28]([C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][C:30]=3[CH3:36])[C:23]=2[CH:22]=[CH:21][C:20]1=[O:43]>ClCCl.CCOC(C)=O>[F:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[C:13]=1[N:19]1[C:24]2[N:25]=[C:26]([NH:37][CH2:38][C:39]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[O:40])[N:27]=[C:28]([C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][C:30]=3[CH3:36])[C:23]=2[CH:22]=[CH:21][C:20]1=[O:43]
Reactant: C1COCCN1
Reactant: COC(=O)CNc1nc(-c2ccc(F)cc2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Agent: C[Al](C)C
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1cc(F)ccc1-c1nc(NCC(=O)N2CCOCC2)nc2c1ccc(=O)n2-c1c(F)cccc1F
Reaction time: 16 h
Yield: 31.2 %

Procedure:
Under Ar, a soln of morpholine (58 mg, 0.66 mmol) and trimethylaluminum (2M in toluene) (0.33 mL, 0.66 mmol) in dichloromethane was stirred for 10 min. A soln of the product of Example 190 (100 mg, 0.22 mmol) in dichloromethane (2 mL) was added. The resulting mixture was stirred for 16 h, diluted with EtOAc and washed with H2O to give the crude material. Purification by Flash chromatography on silica gel, eluting with EtOAc/hexane/triethylamine (70/30/2, v/v/v), followed by recrystallization from dichloromethane and hexane, gave the desired product (35 mg, 31%). LC-MS: 510.10 (MH+, m/z), 1.96 (Rt, min).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH:13]([CH:14]([O:16][C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)[CH3:15])[CH2:12][NH:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].CCN(CC)CC.[Br:34][CH2:35][C:36](Cl)=[O:37]>C(Cl)Cl>[Br:34][CH2:35][C:36]([N:11]1[CH2:12][CH:13]([CH:14]([O:16][C:17]2[CH:18]=[CH:19][C:20]([C:23]([F:25])([F:26])[F:24])=[CH:21][CH:22]=2)[CH3:15])[CH:9]([C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[CH2:10]1)=[O:37]
Reactant: O=C(Cl)CBr
Reactant: CC(Oc1ccc(C(F)(F)F)cc1)C1CNCC1c1ccc(Cl)c(Cl)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(Oc1ccc(C(F)(F)F)cc1)C1CN(C(=O)CBr)CC1c1ccc(Cl)c(Cl)c1
Yield: 84.5 %

Procedure:
To a stirred solution of (3RS,4SR)-3-(3,4-dichloro-phenyl)-4-[(RS)-1-(4-trifluoromethyl-phenoxy)-ethyl]-pyrrolidine (XV-B-1) 0.25 g (0.62 mmol) in CH2Cl2 (30 mL) at RT, 0.10 ml (0.74 mmol) of Et3N and 0.062 mL (0.74 mmol) of bromo-acetyl chloride were added. Stirring was continued over night and then concentrated under vacuo. The crude residue was dissolved in EtOAc, washed with H2O. The organic phase was dried over Na2SO4 and the product was purified by flash chromatography (SiO2, EtOAc) to yield the title product 0.275 g (85%) as a colorless oil.
Reaction SMILES: COCC1C=C[C:7]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18]C)=[CH:14][CH:13]=2)=C([N+]([O-])=O)C=1.F[C:24](F)(F)C(O)=O>C(Cl)Cl>[CH3:24][C:14]1[CH:13]=[C:12]([CH2:11][O:10][CH3:7])[CH:17]=[CH:16][C:15]=1[OH:18]
Reactant: O=C(O)C(F)(F)F
Reactant: COCc1ccc(OCc2ccc(OC)cc2)c([N+](=O)[O-])c1
Solvent: ClCCl
Product: COCc1ccc(O)c(C)c1

Procedure:
To a solution of 4-[(methyloxy)methyl]-1-({[4-(methyloxy)phenyl]methyl}oxy)-2-nitrobenzene D54 (1.57 g, 5.18 mmol) in DCM (80 mL) was added trifluoroacetic acid (3.99 mL, 51.80 mmol). After 1 hr the mixture was washed with water (3×25 mL) and then extracted with 10% aq potassium carbonate solution (3×20 mL). The combined extracts were back washed with diethyl ether (20 mL) and then the pH was adjusted to 1 with 2N HCl, the mixture was extracted with DCM (3×25 mL), the combined extracts were washed with water (25 mL) and brine (25 mL), dried(MgSO4), filtered and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with 5-40% EtOAc in isohexane to afford the title compound as a bright yellow oil. 0.72 g, 76% 1H NMR δ (CDCl3): 3.41 (3H, s), 4.42 (2H, d), 7.15 (1H, d, J=8.4 Hz), 7.56 (1H, m), 8.08 (1H, d).
Reaction SMILES: [CH3:1][C:2]([C:4]([O:6]CCO)=[O:5])=[CH2:3].C(C1C=CC(S(O)(=O)=[O:29])=CC=1)CCCCCCCCCCC.[CH3:32][CH2:33][CH2:34]CCCC>C(OCC)(=O)C>[C:4]([OH:6])(=[O:5])[C:2]1[C:1](=[CH:32][CH:33]=[CH:34][CH:3]=1)[OH:29]
Reactant: C=C(C)C(=O)OCCO
Reactant: CCCCCCCCCCCCc1ccc(S(=O)(=O)O)cc1
Reactant: CCCCCCC
Solvent: CCOC(C)=O
Product: O=C(O)c1ccccc1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2 g of HEMA, 1.5 g of 10% p-dodecylbenzene sulfonic acid (DBSA) in heptane and 15 ml of ethyl acetate was added to the polymeric stabilizer precursor solution prepared above. The reaction mixture was stirred at room temperature overnight. The IR spectra of a dry film of the polymeric solution showed the disappearance of the azlactone carbonyl peak, indicating the completion of the reaction of the azlactone with HEMA.
Reaction SMILES: [SH:1][C:2]1[NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]=1.Cl[CH2:12][C:13]1[CH:18]=[C:17]([O:19][CH2:20][CH2:21][CH2:22][O:23][CH3:24])[CH:16]=[CH:15][N:14]=1.[OH-].[Na+]>C(O)C>[CH3:24][O:23][CH2:22][CH2:21][CH2:20][O:19][C:17]1[CH:16]=[CH:15][N:14]=[C:13]([CH2:12][S:1][C:2]2[NH:6][C:5]3[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=3[N:3]=2)[CH:18]=1
Reactant: Sc1nc2ccccc2[nH]1
Reactant: COCCCOc1ccnc(CCl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COCCCOc1ccnc(CSc2nc3ccccc3[nH]2)c1
Yield: 99.3 %

Procedure:
A mixture comprising 1.50 g (0.01 mol) of 2-mercapto-1H-benzimidazole, 3.20 g (0.015 mol) of 2-chloromethyl-4-(3-methoxypropoxy)pyridine, 0.51 g (0.012 mol) of 95% sodium hydroxide and 60 ml of ethanol was stirred at 40° C. for 0.5 hour and filtered. The filtrate was concentrated under a reduced pressure and purified by silica gel column chromatography (ethyl acetate/n-hexane) to obtain 3.27 g of the title compound as a colorless crystal.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[N:10][N:11]3[CH:16]=[CH:15][C:14]([C:17]([OH:19])=O)=[N:13][C:12]=23)[CH:5]=[CH:6][CH:7]=1.C1([C:26]2[CH:32]=[CH:31][CH:30]=[CH:29][C:27]=2[NH2:28])CCCCC1.N1[C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=2N=N1.Cl.C(N=C=NCCCN(C)C)C>O.CN(C)C=O>[CH2:26]1[CH2:32][CH2:31][CH2:30][CH2:29][CH:27]1[NH:28][C:17]([C:14]1[CH:15]=[CH:16][N:11]2[N:10]=[C:9]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)=[C:12]2[N:13]=1)=[O:19]
Reactant: c1ccc2[nH]nnc2c1
Reactant: Nc1ccccc1C1CCCCC1
Reactant: O=C(O)c1ccn2ncc(-c3cccc(Cl)c3)c2n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NC1CCCCC1)c1ccn2nc(-c3ccccc3)c(-c3cccc(Cl)c3)c2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 63.5 %

Procedure:
To a mixture of 3-(3-chlorophenyl)-pyrazolo-[1,5-a]-pyrimidine-5-carboxylic acid (0.08 g), 2-cyclohexylaniline (0.06 g), and 2 ml of N,N-dimethylformamide, 1-hyhdroxy benzotriazol (0.05 g) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.07 g) were added, and stirred at room temperature over 2 hours. The reactant was poured into 20 ml of water, and extracted with 80 ml of ethyl acetate. The extract was washed saturated saline solution, dried with magnesium sulfate, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (ethyl acetate:toluene=1:1), and recrystallized with ethyl acetate to yield N-2-cyclohexylphenyl-3-(3-chlorophenyl)-pyrazolo-[1,5-a]-pyrimidine-5-amide (0.08 g, 64%) as a yellow needle crystal. mp: 160.2-161.4° C.
Reaction SMILES: C([O:8][C:9](=[O:17])[NH:10][C@H:11]1[CH2:15][CH2:14][NH:13][C:12]1=[O:16])C1C=CC=CC=1.[H-].[Na+].O([C:27]1[C:36]2[C:31](=[CH:32][C:33]([CH2:37]Br)=[CH:34][CH:35]=2)[CH:30]=[CH:29][N:28]=1)C1C=CC=CC=1.[NH4+].[Cl-:40]>C1COCC1.C(Cl)Cl.CN(C=O)C>[Cl:40][C:27]1[C:36]2[C:31](=[CH:32][C:33]([CH2:37][N:13]3[CH2:14][CH2:15][C@H:11]([NH:10][C:9](=[O:17])[OH:8])[C:12]3=[O:16])=[CH:34][CH:35]=2)[CH:30]=[CH:29][N:28]=1
Reactant: BrCc1ccc2c(Oc3ccccc3)nccc2c1
Reactant: O=C(N[C@H]1CCNC1=O)OCc1ccccc1
Reactant: [Cl-]
Agent: [H-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=C(O)N[C@H]1CCN(Cc2ccc3c(Cl)nccc3c2)C1=O
Temperature: 120 °C
Reaction time: 16 h

Procedure:
To a solution of (2-oxopyrrolidin-3-(S)-yl)-carbamic acid benzyl ester (0.15 g, 0.64 mmol) in 6 mL of 10:1 THF:DMF at 0° C. is added a 60% NaH dispersion (0.03 g, 0.71 mmol) followed by 1-phenoxy-6-bromomethyl-isoquinoline (0.2 g, 0.64 mmol). After 16 hours, the solution is treated with 10 mL of saturated NH4Cl. The solution is diluted with CH2Cl2. The organic layer is washed with H2O and saturated NaCl. The resulting product is suspended in 5 g of NH4OAc and heated to 120° C. After 36 hours, the solution is cooled to ambient temperatures. The solution is diluted with H2O and CH2Cl2. The organic layer is washed with H2O and saturated NaCl. The organic layer is dried over MgSO4, filtered and concentrated. The residue is purified by column chromatography eluting with 5% MeOH/CH2Cl2 to 10% MeOH/CH2Cl2 to give the product as a white solid (0.043 g, 0.11 mmol).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)([CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[OH:9])=[CH:4][CH:3]=1.Br[CH2:24][CH2:25][CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([NH:34][C:35]([NH:37][CH3:38])=[O:36])=[CH:30][CH:29]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:16]2[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=2)([OH:9])[CH:10]2[CH2:11][CH2:12][N:13]([CH2:24][CH2:25][CH2:26][O:27][C:28]3[CH:33]=[CH:32][C:31]([NH:34][C:35]([NH:37][CH3:38])=[O:36])=[CH:30][CH:29]=3)[CH2:14][CH2:15]2)=[CH:4][CH:3]=1
Reactant: OC(c1ccc(F)cc1)(c1ccc(F)cc1)C1CCNCC1
Reactant: CNC(=O)Nc1ccc(OCCCBr)cc1
Product: CNC(=O)Nc1ccc(OCCCN2CCC(C(O)(c3ccc(F)cc3)c3ccc(F)cc3)CC2)cc1

Procedure:
Following the procedure of Example 1, [α,α-bis(p-fluorophenyl)]-4-piperidinemethanol and N-[4-(3-bromopropoxy)phenyl]-N'-methylurea are reacted to give the title compound.
Reaction SMILES: F[C:2]1[C:9]([C:10](=O)[C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=2)=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:19][CH3:20])[CH:3]=1.O.[NH2:22][NH2:23].O>O1CCCC1.CO>[F:17][C:13]1[CH:12]=[C:11]([C:10]2[C:9]3[C:2](=[CH:3][C:4]([O:19][CH3:20])=[C:5]([C:6]#[N:7])[CH:8]=3)[NH:23][N:22]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: NN
Reactant: COc1cc(F)c(C(=O)c2cccc(F)c2)cc1C#N
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: COc1cc2[nH]nc(-c3cccc(F)c3)c2cc1C#N

Procedure:
A total of 203 mg of 4-fluoro-5-(3-fluoro-benzoyl)-2-methoxy-benzonitrile obtained in Production Example II-1-c was dissolved in 3 ml of tetrahydrofuran and 3 ml of methanol, 7.4 ml of hydrazine monohydrate was added at room temperature under stirring, and the mixture was stirred at room temperature for 14 hours. Then, water was added and the mixture was extracted with ethyl acetate. The resulting organic layer was washed with 1 N hydrochloric acid, saturated aqueous sodium hydrogencarbonate solution and brine, dried over magnesium sulfate and the solvent was evaporated. The resulting crystals were washed with diethyl ether, to give 172 mg of the title compound as pale yellow crystals.
Reaction SMILES: [Na].Cl[C:3]1[N:4]=[N:5][C:6]([S:9][CH2:10][CH:11]=[CH2:12])=[CH:7][CH:8]=1.[CH:13]1[C:18]([OH:19])=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:20]>>[CH3:20][C:14]1[CH:13]=[C:18]([CH:17]=[CH:16][CH:15]=1)[O:19][C:3]1[N:4]=[N:5][C:6]([S:9][CH2:10][CH:11]=[CH2:12])=[CH:7][CH:8]=1
Reactant: C=CCSc1ccc(Cl)nn1
Reactant: Cc1cccc(O)c1
Agent: [Na]
Product: C=CCSc1ccc(Oc2cccc(C)c2)nn1
Temperature: 100 °C
Reaction time: 5 h

Procedure:
0.23 g(0.01 mol) of metallic sodium was dissolved in 30 ml of dry m-cresol. To the resulting solution was added 1.87 g(0.01 mol) of 3-chloro-6-allylthiopyridazine. The reaction solution was stirred for 5 hours at 100±5° C. and then treated according to the same manner as Example 23 to obtain the title compound as a pale white needle crystal.
Reaction SMILES: [CH2:1]([S-:3])[CH3:2].[Na+].ClC1C=CC(N[C:11]2[C:20]3[C:15](=[CH:16][C:17]([O:23][CH2:24][CH2:25][CH2:26]Cl)=[C:18]([O:21][CH3:22])[CH:19]=3)[N:14]=[CH:13][N:12]=2)=C(F)C=1>CN(C=O)C.O>[CH2:1]([S:3][CH2:26][CH2:25][CH2:24][O:23][C:17]1[CH:16]=[C:15]2[C:20]([CH:11]=[N:12][CH:13]=[N:14]2)=[CH:19][C:18]=1[O:21][CH3:22])[CH3:2]
Reactant: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1OCCCCl
Reactant: CC[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCSCCCOc1cc2ncncc2cc1OC
Temperature: 70 °C
Yield: 54.2 %

Procedure:
A mixture of sodium ethanethiolate (120 mg, 1.5 mmol) and 4-(4chloro-2-fluoroanilino)7-(3-chloropropoxy)-6-methoxyquinazoline (227 mg, 0.57 mmol) in DMF (10 ml) was stirred and heated at 70° C. for 3 hours. The reaction mixture was allowed to cool, was diluted with water and extracted with ethyl acetate (3×75 ml). The extracts were combined, washed with water (×2), and then brine, and dried (MgSO4). The solvent was removed by evaporation and the residue was recrystallised from ethyl acetate/hexane to give 4chloro-2-fluoroanilino)-7-(3-(ethylthio)propoxy)6-methoxyquinazoline (86 mg, 40%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]([NH2:12])=[S:11].[Br:13][CH2:14][C:15](=O)[C:16]([O:18][CH2:19][CH3:20])=[O:17]>C(O)C>[BrH:13].[OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[S:11][CH:14]=[C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:12]=1
Reactant: Cc1ccc(NC(N)=S)c(O)c1
Reactant: CCOC(=O)C(=O)CBr
Solvent: CCO
Product: Br
Product: CCOC(=O)c1csc(Nc2ccc(C)cc2O)n1
Yield: 65 %

Procedure:
0.065 mole of 1-(2-hydroxy-4-methylphenyl)-2-thiourea and 0.077 mole of ethyl bromopyruvate in 100 ml of 95° strength ethanol are brought to reflux for 3 hours. After evaporation of the solvent, crystallization of the residual oil is induced in diethyl ether. The product is then recrystallized in an ethanol/ether mixture. (M.p. 158°-60° C.) yield: 65%.