Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:21]([O:23][C:24](=[O:33])[CH2:25][S:26][C:27]1[S:31][C:30]([NH2:32])=[N:29][CH:28]=1)[CH3:22]>>[CH2:21]([O:23][C:24](=[O:33])[CH2:25][S:26][C:27]1[S:31][C:30]([NH:32][C:8](=[O:10])[CH:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=2)[CH2:6][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)=[N:29][CH:28]=1)[CH3:22]
Reactant: CCOC(=O)CSc1cnc(N)s1
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)O)cc1
Product: CCOC(=O)CSc1cnc(NC(=O)C(CC2CCCC2)c2ccc(S(C)(=O)=O)cc2)s1

Procedure:
{2-[3-Cyclopentyl-2-(4-methanesulfonyl-phenyl)-propionylamino]-thiazol-5-ylsulfanyl}-acetic acid ethyl ester was prepared from 3-cyclopentyl-2-(4-methanesulfonylphenyl)propionic acid and (2-aminothiazol-5-ylsulfanyl)-acetic acid ethyl ester as described in Example 1. 1H-NMR (CDCl3): δ 11.78 (broad s, 1H), 7.88 (d, 2H), 7.57 (d, 2H), 7.54 (s, 1H), 4.18 (q, 2H), 3.80 (t, 1H), 3.46 (s, 2H), 3.05 (s, 3H), 2.31-2.23 (m, 1H), 1.92-1.85 (m, 1H), 1.80-1.40 (m, 7H), 1.26 (t, 3H), 1.12 (m, 2H); HPLC-MS: m/z=497 (M+1).
Reaction SMILES: [Si:1]([O:8][C@@H:9]([C@@H:11]1[C@@H:14]([CH2:15][C:16]([S:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=O)[N:13]([CH2:25][CH2:26][O:27][CH2:28][C:29]2[CH:34]=[CH:33][C:32]([N+:35]([O-:37])=[O:36])=[CH:31][CH:30]=2)[C:12]1=[O:38])[CH3:10])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].P(OCC)(OCC)(OCC)=[O:40]>C1(C)C=CC=CC=1>[Si:1]([O:8][C@@H:9]([C@H:11]1[C:12](=[O:38])[N:13]2[C:25]([C:26]([O:27][CH2:28][C:29]3[CH:30]=[CH:31][C:32]([N+:35]([O-:37])=[O:36])=[CH:33][CH:34]=3)=[O:40])=[C:16]([S:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:15][C@H:14]12)[CH3:10])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N(CCOCc2ccc([N+](=O)[O-])cc2)[C@@H]1CC(=O)Sc1ccccc1
Reactant: CCOP(=O)(OCC)OCC
Solvent: Cc1ccccc1
Product: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(Sc3ccccc3)C[C@H]12
Temperature: 100 °C
Reaction time: 18 h
Yield: 88.3 %

Procedure:
A mixture of 114 mg (0.194 mmole) of (3S, 4R)-3-[(R)-1-t-butyldimethylsilyloxyethyl]-1-(p-nitrobenzyloxyethyl)-4-[(phenylthio)carbonylmethyl]-2-azetidinone, 258 mg (1.55 mmole) of triethyl phosphate and 10 ml of toluene was stirred at 100° C. for 18 hours under a nitrogen atmosphere. The solvent was distilled off, and the residue was purified by the procedure described in Example 5, to give 95 mg (yield 88%) of the title product , in the form of crystals.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41](O)=[O:42])[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:47][N:48]([CH3:55])[CH:49]1[CH2:54][CH2:53][NH:52][CH2:51][CH2:50]1>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:35][CH2:36][CH:37]([CH2:40][C:41]([N:52]4[CH2:53][CH2:54][CH:49]([N:48]([CH3:55])[CH3:47])[CH2:50][CH2:51]4)=[O:42])[CH2:38][CH2:39]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)C1CCNCC1
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)O)CC1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)N2CCC(N(C)C)CC2)CC1

Procedure:
In a manner analogous to the method described in example 163, {1-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperidin-4-yl}-acetic acid was reacted with 4-dimethylamino-piperidine (Oakwood) to give the title compound. LC-MS (ES+) 775 [(M+H)+].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]([CH3:34])[C:12]2[N:17]=[C:16]([N:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[N:15]=[C:14]([NH:24][CH2:25][CH2:26][C:27]3[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=3)[N:13]=2)=[CH:4][CH:3]=1.Cl.Cl[CH2:37][C:38]1[N:39]=[C:40]([CH3:43])[S:41][CH:42]=1>C(Cl)Cl.CCOC(C)=O.CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]([CH3:34])[C:12]2[N:17]=[C:16]([N:18]3[CH2:19][CH2:20][N:21]([CH2:37][C:38]4[N:39]=[C:40]([CH3:43])[S:41][CH:42]=4)[CH2:22][CH2:23]3)[N:15]=[C:14]([NH:24][CH2:25][CH2:26][C:27]3[CH:28]=[CH:29][C:30]([OH:33])=[CH:31][CH:32]=3)[N:13]=2)=[CH:4][CH:3]=1
Reactant: Cc1nc(CCl)cs1
Reactant: CN(CCCc1ccc(Cl)cc1)c1nc(NCCc2ccc(O)cc2)nc(N2CCNCC2)n1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1nc(CN2CCN(c3nc(NCCc4ccc(O)cc4)nc(N(C)CCCc4ccc(Cl)cc4)n3)CC2)cs1
Yield: 50 %

Procedure:
The title compound was prepared in 50% yield via the procedure outlined for example 5 using 4-(2-{[4-[[3-(4-chlorophenyl)propyl](methyl)amino]-6-(1-piperazinyl)-1,3,5-triazin-2-yl]amino}ethyl)phenol and 4-chloromethyl-2-methylthiazole hydrochloride to give an off-white glass: 1H NMR (CDCl3, 400 MHz) δ 7.18 (d, 2H, J=8.0), 7.10-7.02 (m, 2H), 6.98-6.95 (m, 3H), 6.64 (d, 2H, J=8.0), 3.85-3.45 (m, 10H), 3.02 (s, 3H), 2.78-2.68 (m, 5H), 2.55-2.50 (m, 2H), 2.50-2.46 (m, 4H), 1.92-1.80 (m, 2H); low resolution MS (ES+) m/e 594 (MH+); TLC (CH2Cl2/EtOAc/MeOH (5:5:1)): Rf=0.50; Anal. calcd. for C30H37N8OSCl: C, 60.74; H, 6.29; N, 18.89. Found: C, 60.64; H, 6.26; N, 18.81.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[CH:8][C:3]=1[C:4]([NH:6][CH3:7])=[O:5].[Cl:18]N1C(=O)CCC1=O>CN(C)C=O>[Cl:18][C:10]1[C:9]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[CH:8][C:3]([C:4]([NH:6][CH3:7])=[O:5])=[C:2]([CH3:1])[CH:11]=1
Reactant: CNC(=O)c1cc(N2CCOCC2)ccc1C
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Product: CNC(=O)c1cc(N2CCOCC2)c(Cl)cc1C
Temperature: 50 °C
Reaction time: 1 h
Yield: 47.5 %

Procedure:
100 mg (0.427 mmol) of 2,N-dimethyl-5-morpholin-4-ylbenzamide prepared in Step A was dissolved in 3 ml of N,N-dimethylformamide, and thereafter, 63 mg (0.47 mmol) of N-chlorosuccinimide was added thereto under cooling on ice. The obtained mixture was stirred at 50° C. for 1 hour. Thereafter, the reaction solution was concentrated, and water was then added thereto. The mixture was extracted with ethyl acetate. The extract was washed with water and a saturated saline solution, and was then dried over anhydrous sodium sulfate. The extract was concentrated, and the obtained residue was then purified by silica gel column chromatography (ethyl acetate:methylene chloride=1:5), so as to obtain 54.5 mg (47%) of 4-chloro-2,N-dimethyl-5-morpholin-4-ylbenzamide in the form of a colorless solid, as well as 46 mg (40%) of 2-chloro-6,N-dimethyl-3-morpholin-4-ylbenzamide in the form of a colorless solid.
Reaction SMILES: [CH:1]1([C:4]2[CH:25]=[CH:24][C:7]3[N:8](COC)[C:9]([CH2:11][N:12](C)[C:13](=O)OC(C)(C)C)=[N:10][C:6]=3[CH:5]=2)[CH2:3][CH2:2]1.C1(C2C=CC3N=C(CN(C)C(=O)OC(C)(C)C)N(COC)C=3C=2)CC1.[ClH:51].O1CCOCC1>C1COCC1.CCO>[ClH:51].[ClH:51].[CH:1]1([C:4]2[CH:25]=[CH:24][C:7]3[NH:8][C:9]([CH2:11][NH:12][CH3:13])=[N:10][C:6]=3[CH:5]=2)[CH2:2][CH2:3]1
Reactant: COCn1c(CN(C)C(=O)OC(C)(C)C)nc2cc(C3CC3)ccc21
Agent: COCn1c(CN(C)C(=O)OC(C)(C)C)nc2ccc(C3CC3)cc21
Agent: Cl
Solvent: C1COCCO1
Solvent: CCO
Solvent: C1CCOC1
Product: CNCc1nc2cc(C3CC3)ccc2[nH]1
Temperature: 80 °C
Reaction time: 5 h

Procedure:
To a mixture of a mixture (501 mg) of tert-butyl {[5-cyclopropyl-1-(methoxymethyl)-1H-benzimidazol-2-yl]methyl}methylcarbamate and tert-butyl {[6-cyclopropyl-1-(methoxymethyl)-1H-benzimidazol-2-yl]methyl}methylcarbamate and EtOH/water (1/1, 6 mL) was added 4 M hydrogen chloride/1,4-dioxane (6 mL), followed by heating and stirring at 80° C. for 5 hours and then concentrating under reduced pressure to obtain 1-(5-cyclopropyl-1H-benzimidazol-2-yl)-N-methylmethanamine dihydrochloride (328 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]([CH:16]1[CH2:20][C:19](=[O:21])[NH:18][C:17]1=[O:22])[C:13]([OH:15])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+](=[CH2:25])=[N-]>CO>[CH3:25][O:14][C:13](=[O:15])[CH:12]([CH:16]1[CH2:20][C:19](=[O:21])[NH:18][C:17]1=[O:22])[NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10]
Reactant: C=[N+]=[N-]
Reactant: O=C1CC(C(NC(=O)OCc2ccccc2)C(=O)O)C(=O)N1
Solvent: CO
Product: COC(=O)C(NC(=O)OCc1ccccc1)C1CC(=O)NC1=O

Procedure:
In 300 ml of methanol was dissolved 2 g of benzyloxycarbonyl-2-(2,5-dioxopyrrolidin-3-yl)glycine and under ice-cooling an excess of an ethereal solution of diazomethane was added. The mixture was stirred under ice-cooling for 2 hours and then concentrated under reduced pressure. The concentrate was chromatographed on a silica gel column and eluted with toluene-acetone (4:1). The eluate was concentrated under reduced pressure and after addition of ethyl ether to the residue, the mixture was allowed to stand in a refrigerator overnight to give crystals. Yield 1.3 g.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:45][CH:46]([F:48])[F:47])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][C:26]([N:28]3[CH2:33][CH2:32][CH:31]([C:34]([O:36][CH2:37][CH:38]4[CH2:43][CH2:42][N:41]([CH3:44])[CH2:40][CH2:39]4)=[O:35])[CH2:30][CH2:29]3)=[O:27])[N:9]=2)[CH:7]=1.[C:49](OC(N1CCC(C)(C(O)=O)CC1)=O)(C)(C)C>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:45][CH:46]([F:48])[F:47])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][C:26]([N:28]3[CH2:29][CH2:30][C:31]([CH3:49])([C:34]([O:36][CH2:37][CH:38]4[CH2:43][CH2:42][N:41]([CH3:44])[CH2:40][CH2:39]4)=[O:35])[CH2:32][CH2:33]3)=[O:27])[N:9]=2)[CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C)(C(=O)O)CC1
Reactant: CN1CCC(COC(=O)C2CCN(C(=O)Cn3cc(NC(=O)c4cnn5cccnc45)c(-c4cc(Cl)ccc4OC(F)F)n3)CC2)CC1
Product: CN1CCC(COC(=O)C2(C)CCN(C(=O)Cn3cc(NC(=O)c4cnn5cccnc45)c(-c4cc(Cl)ccc4OC(F)F)n3)CC2)CC1

Procedure:
Using synthetic method analogous to that of (1-methylpiperidin-4-yl)methyl 1-(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidine-3-amido]-1H-pyrazol-1-yl]acetyl)piperidine-4-carboxylate, the title compound was prepared from 1-[(tert-butoxy)carbonyl]-4-methylpiperidine-4-carboxylic acid. LCMS (Method 28) [M+H]+=699.2, RT=0.95 min. 1H NMR (400 MHz, DMSO-d6) δ: (ppm) 9.75 (s, 1H), 9.34 (dd, 1H, J=1.6, 7.2 Hz), 8.69-8.68 (m, 2H), 8.31 (s, 1H), 7.63 (dd, 1H, J=2.4, 8.8 Hz), 7.55 (d, 1H, J=2.8 Hz), 7.46 (d, 1H, J=8.8 Hz), 7.29 (dd, 1H, J=4.0, 6.8 Hz), 7.08 (t, 1H, J=73.2 Hz), 5.24 (s, 2H), 3.99-3.96 (m, 2H), 3.94-3.88 (m, 1H), 3.78-3.71 (m, 1H), 3.26-3.20 (m, 1H), 3.08-3.00 (m, 1H), 2.85-2.80 (m, 2H), 2.20 (s, 3H), 2.02-1.94 (m, 4H), 1.68-1.59 (m, 4H), 1.54-1.48 (m, 1H), 1.41-1.34 (m, 1H), 1.28-1.23 (m, 2H), 1.18 (s, 3H).
Reaction SMILES: F[B-](F)(F)F.[N+:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([O-:8])=[O:7].[F:15]C1C=C([N+]([O-])=O)C=CC=1.FC1C=CC=CC=1[N+]([O-])=O>ClC1C=CC=CC=1.C1C=CC=CC=1>[F:15][C:12]1[CH:13]=[CH:14][C:9]([N+:6]([O-:8])=[O:7])=[CH:10][CH:11]=1
Reactant: O=[N+]([O-])c1ccccc1
Reactant: O=[N+]([O-])c1cccc(F)c1
Agent: F[B-](F)(F)F
Agent: O=[N+]([O-])c1ccccc1F
Solvent: Clc1ccccc1
Solvent: c1ccccc1
Product: O=[N+]([O-])c1ccc(F)cc1
Temperature: 90 °C

Procedure:
A homogeneous reaction mixture was obtained in this experiment, whereas in the aforementioned fluorinations of benzene and chlorobenzene, the reaction mixtures contained suspended [(ClCN)3F]+BF4−. In order to drive the fluorination of nitrobenzene to completion, the reaction mixture was heated at 90° C. for 2 hours before it was tested with KI solution and gave a negative result. G.C. analysis revealed the presence of only 3-fluoronitrobenzene and 2-fluoronitrobenzene with no marked change in ratio (about 2:1 ratio). Despite the presence of the 2-fluoro derivative, no evidence were obtained for the presence of 4-fluoronitrobenzene. The absence of 4-fluoronitrobenzene may have resulted from loss of this isomer during the reaction or subsequent handling operations via nucleophilic displacement of the highly mobile fluorine. In this connection, the reaction vessel became etched during the reaction.
Reaction SMILES: Cl[N:2]1[C:10]2[C:5](=[CH:6][C:7]([N+:11]([O-:13])=[O:12])=[CH:8][CH:9]=2)[C:4](=[O:14])[NH:3]1.C([O-])([O-])=O.[K+].[K+].[Cl:21][C:22]1[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=1[CH2:24]Br.[ClH:30]>O>[Cl:30][C:8]1[CH:9]=[C:10]2[C:5]([C:4](=[O:14])[NH:3][N:2]2[CH2:24][C:23]2[CH:26]=[CH:27][CH:28]=[CH:29][C:22]=2[Cl:21])=[CH:6][C:7]=1[N+:11]([O-:13])=[O:12]
Reactant: Clc1ccccc1CBr
Reactant: Cl
Reactant: O=c1[nH]n(Cl)c2ccc([N+](=O)[O-])cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: O=c1[nH]n(Cc2ccccc2Cl)c2cc(Cl)c([N+](=O)[O-])cc12
Temperature: 50 °C
Reaction time: 8 h

Procedure:
Chloro-5-nitro-1,2-dihydro-indazol-3-one (prepared in analogy to Org. Synth. 1949, 29, 54 or Chem Ber. 1942, 75, 1104 from 4-chloro-2-fluoro-5-nitro-benzoic acid over two steps) (0.6 g) was suspended in water (5 mL) and 2N K2CO3 (aq.) (1 g) was added to the flask and the mixture was heated to 50° C. for 10 minutes. 2-Chlorobenzylbromide (0.40 g) was then added dropwise. The reaction was stirred overnight and was neutralized with 2 N HCl (aq.) while cooling in an ice bath. The precipitate was collected by filtration and triturated with diethylether to afford pure desired 6-chloro-1-(2-chloro-benzyl)-5-nitro-1,2-dihydro-indazol-3-one as a brown solid. MS (ESI−:336.3[M−H]−).
Reaction SMILES: [C:1](OCC)(=O)[CH:2]=[CH2:3].[C:8]([O:13][CH3:14])(=[O:12])[C:9]([CH3:11])=[CH2:10].[C:15]([OH:20])(=O)[C:16]([CH3:18])=[CH2:17]>>[CH3:1][CH:2]([CH:15]([OH:20])[C:16]([CH2:14][O:13][C:8]([CH:9]([CH3:11])[CH3:10])=[O:12])([CH3:18])[CH3:17])[CH3:3]
Reactant: C=C(C)C(=O)O
Reactant: C=CC(=O)OCC
Reactant: C=C(C)C(=O)OC
Product: CC(C)C(=O)OCC(C)(C)C(O)C(C)C

Procedure:
The composition of the polymer component of the dispersion Plextol B500 is 69.2% ethyl acrylate, 29.6% methyl methacrylate and 1.2% methacrylic acid
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([F:14])[C:11]([F:15])=[C:10]([F:16])[CH:9]=2)=[C:4]([F:17])[CH:3]=1.C([Li])CCC.[B:23](OC)([O:26]C)[O:24]C.Cl>CCCCCC.C1COCC1.C(OCC)C>[F:17][C:4]1([B:23]([OH:26])[OH:24])[CH2:3][CH:2]=[CH:7][CH:6]=[C:5]1[C:8]1[CH:13]=[C:12]([F:14])[C:11]([F:15])=[C:10]([F:16])[CH:9]=1
Reactant: COB(OC)OC
Reactant: Fc1cc(Br)ccc1-c1cc(F)c(F)c(F)c1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CCCCCC
Product: OB(O)C1(F)CC=CC=C1c1cc(F)c(F)c(F)c1
Temperature: -74 °C
Reaction time: 2 h

Procedure:
4-Bromo-2,3′,4′,5′-tetrafluoro-1,1′-biphenyl (T-39) (12.0 g) and diethyl ether (220 ml) were put into a reaction vessel under a nitrogen atmosphere and cooled to −74° C. 1.57M of n-butyl lithium in n-hexane solution (31.5 ml) was added dropwise thereto in the temperature range of −74° C. to −68° C. and stirred another 120 minutes. Then, trimethyl borate (6.70 ml) in THF (20 ml) solution was added dropwise in the temperature range of −75° C. to −68° C. and the stirring was continued for another 180 minutes while the reaction mixture was allowed to come to 25° C. Then, the reaction mixture was cooled to −30° C. and 6N-hydrochloric acid (40 ml) was slowly added dropwise thereto, and the mixture was stirred for another 180 minutes. After the reaction thus obtained had been allowed to come to 25° C., it was poured into ice-water (200 ml) and mixed. Organic and aqueous layers were separated by adding ethyl acetate 200 ml). The aqueous layer was extracted with toluene. The organic layers combined were washed sequentially with water, a saturated aqueous solution of sodium hydrogencarbonate and brine, and dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure and 2,3′,4′,5′-tetrafluoro-1,1′-biphenylboronic acid (T-40) (8.91 g) was obtained. The yield based on the compound (T-39) was 85%.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:5]=[C:4]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:3]=1.[N:22]12[CH2:29][CH2:28][CH:25]([CH2:26][CH2:27]1)[CH:24]([OH:30])[CH2:23]2>>[Cl-:1].[O:15]([C:4]1[N:5]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:7]=[C:2]([N+:22]23[CH2:29][CH2:28][CH:25]([CH2:26][CH2:27]2)[CH:24]([OH:30])[CH2:23]3)[N:3]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Clc1nc(Oc2ccccc2)nc(Oc2ccccc2)n1
Reactant: OC1CN2CCC1CC2
Product: OC1C[N+]2(c3nc(Oc4ccccc4)nc(Oc4ccccc4)n3)CCC1CC2
Product: [Cl-]

Procedure:
The operation was carried out in the same manner as in Preparation Example 1 but using 6.00 g (0.02 mols) of a 2-chloro-4,6-diphenoxy-1,3,5-triazine and 2.54 g (0.02 mols) of a 3-quinuclidinol to obtain 8.38 g (yield, 98.1%) of white crystals of a 1-(4,6-diphenoxy-1,3,5-triazin-2-yl)-3-hydroxyquinuclidinium chloride represented by the following general formula (XIV)
Reaction SMILES: C1CO[C:3]2([C:6]([Sn:7]([CH2:16][CH2:17][CH2:18][CH3:19])([CH2:12][CH2:13][CH2:14][CH3:15])[CH2:8][CH2:9][CH2:10][CH3:11])=[C:5]([CH3:20])[C:4]2=[O:21])[O:2]1.O1CCCC1.S(=O)(=O)(O)O.O>O>[CH3:20][C:5]1[C:4](=[O:21])[C:3](=[O:2])[C:6]=1[Sn:7]([CH2:16][CH2:17][CH2:18][CH3:19])([CH2:8][CH2:9][CH2:10][CH3:11])[CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCC[Sn](CCCC)(CCCC)C1=C(C)C(=O)C12OCCO2
Agent: O=S(=O)(O)O
Solvent: O
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1c(C)c(=O)c1=O
Temperature: 22 °C
Reaction time: 2.5 h
Yield: 35.9 %

Procedure:
2,2-Ethylenedioxy-4-methyl-3-(tri-n-butylstannyl)cyclobut-3-ene-1-one (450 mg) was added to a stirred mixture of tetrahydrofuran (4 mL) and sulfuric acid-H2O (3 mL of 1:1). The mixture was stirred at 22° C. for 2.5 hrs and then was diluted with H2O. The mixture was extracted with n-heptane (2×). The combined extracts were sequentially washed with H2O (2×) and saturated NaCl, dried (Na2SO4), and concentrated to leave the title compound (145 mg, 36% yield) as a yellow oil.
Reaction SMILES: C(N=C[C:7]1([F:19])[C:12]([F:14])([F:13])[O:11][C:10]2[CH:15]=[CH:16][CH:17]=[CH:18][C:9]=2[O:8]1)CCC.[C:20]([O:23][CH2:24][C:25](=[O:32])[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])(=[O:22])[CH3:21].[C:33](OC(=O)C)(=O)C>>[F:14][C:12]1([F:13])[O:11][C:10]2[CH:15]=[CH:16][CH:17]=[C:18]([CH:33]=[C:26]([C:25]([CH2:24][O:23][C:20](=[O:22])[CH3:21])=[O:32])[C:27]([O:29][CH2:30][CH3:31])=[O:28])[C:9]=2[O:8][CH:7]1[F:19]
Reactant: CCCCN=CC1(F)Oc2ccccc2OC1(F)F
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)CC(=O)COC(C)=O
Product: CCOC(=O)C(=Cc1cccc2c1OC(F)C(F)(F)O2)C(=O)COC(C)=O
Temperature: 0 °C

Procedure:
50 mmol of 5-(butyliminomethyl-2,2,3-trifluoro-1,4-benzodioxane and 50 mmol of ethyl 4-acetoxy-acetoacetate are stirred in 80 ml of acetic anhydride for 24 hours. The mixture is hydrolyzed with about 1 l of ice-water and the oil which has separated out is separated off, taken up in methylene chloride, dried and used as the crude product.
Reaction SMILES: [CH3:1][N:2]([CH3:21])[CH2:3][CH2:4][NH:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17](F)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7].C(N1C=CN=C1)(N1C=CN=C1)=O.CN(CCN)C.[N+:40](C1C=CC(N2CCNCC2)=CC=1)([O-:42])=[O:41]>O1CCCC1>[CH3:1][N:2]([CH3:21])[CH2:3][CH2:4][NH:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([N+:40]([O-:42])=[O:41])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7]
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)cc1
Reactant: CN(C)CCNC(=O)N1CCN(c2ccc(F)cc2)CC1
Agent: CN(C)CCN
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CN(C)CCNC(=O)N1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Yield: 54 %

Procedure:
This compound was prepared according to the procedure used to synthesize the compound of Example 11. A mixture of 5.5 g (0.03 mole) of 1,1'-carbonyldiimidazole, 3.0 g (0.03 mole) of unsym-dimethylethylenediamine and 7.0 g (0.03 mole) of 1-(4-nitrophenyl)piperazine in a total volume of 200 ml of tetrahydrofuran gave an oil that solidified. The solid was recrystallized from benzene to give 5.8 g (54%) of the title compound as a yellow solid, m.p. 115°-120° C.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:10])[N:4]([CH3:9])[N:5]=[CH:6][C:7]=1Br.[CH3:11][O-:12].[Na+]>CO>[Br:1][C:2]1[C:3](=[O:10])[N:4]([CH3:9])[N:5]=[CH:6][C:7]=1[O:12][CH3:11]
Reactant: Cn1ncc(Br)c(Br)c1=O
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1cnn(C)c(=O)c1Br
Temperature: 23 °C
Reaction time: 3 h

Procedure:
4,5-Dibromo-2-methyl-3(2H)-pyridazinone (20 g, Maybridge Chemical Company) was cooled in an ice bath and treated successively with methanol (200 mL) and sodium methoxide (12 mL of a 30% solution in methanol). The ice bath was removed and the reaction was allowed to stir at 23° C. for 3 h. The methanol was removed by evaporation at reduced pressure. The residue was partitioned between dichloromethane and water. The organic layer was dried over magnesium sulfate and concentrated to provide the desired product 17 g as a whim solid melting at 146°-147° C. 1 H NMR (CDCl3): 7.7 (1H), 4.0 (3H), 3.8 (3H).
Reaction SMILES: [Cl-].[C:2]([O:7][CH3:8])(=[O:6])[C:3]([O-])=[O:4].[Cl:9][C:10]1[CH:16]=[CH:15][C:13]([NH2:14])=[CH:12][CH:11]=1.N1C=CC=CC=1>C(Cl)Cl>[Cl:9][C:10]1[CH:16]=[CH:15][C:13]([NH:14][C:3](=[O:4])[C:2]([O:7][CH3:8])=[O:6])=[CH:12][CH:11]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: COC(=O)C(=O)[O-]
Agent: [Cl-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)C(=O)Nc1ccc(Cl)cc1
Yield: 100.6 %

Procedure:
With stirring, 6.7 g of monomethyl oxalate chloride are added dropwise at 0° to 5° C. to a solution of 6.4 g of 4-chloroaniline and 7.9 g pyridine in 150 ml of dry methylene chloride. When the addition is complete, the suspension is stirred for 30 minutes at room temperature, then diluted with 100 ml of methylene chloride, washed twice with 3N hydrochloric acid and once with saturated sodium bicarbonate solution, dried and concentrated. The residual oil crystallises on trituration, affording 10.4 g of crystalline title compound with a melting point of 162°-164° C.
Reaction SMILES: [I-].C1([P+](C2C=CC=CC=2)(C2C=CC=CC=2)[CH2:9][CH:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)C=CC=CC=1.[CH2:28]([O:30][C:31](=[O:45])[C:32]([C:34]1[CH:39]=[CH:38][C:37]([S:40][CH:41]2[CH2:43][CH2:42]2)=[C:36]([Br:44])[CH:35]=1)=O)[CH3:29].Cl>C1COCC1>[Br:44][C:36]1[CH:35]=[C:34]([C:32](=[CH:9][CH:10]2[CH2:11][CH2:12][O:13][CH2:14][CH2:15]2)[C:31]([O:30][CH2:28][CH3:29])=[O:45])[CH:39]=[CH:38][C:37]=1[S:40][CH:41]1[CH2:43][CH2:42]1
Reactant: c1ccc([P+](CC2CCOCC2)(c2ccccc2)c2ccccc2)cc1
Reactant: CCOC(=O)C(=O)c1ccc(SC2CC2)c(Br)c1
Agent: Cl
Agent: [I-]
Solvent: C1CCOC1
Product: CCOC(=O)C(=CC1CCOCC1)c1ccc(SC2CC2)c(Br)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 73.1 %

Procedure:
To a suspension of triphenyl(tetrahydro-2H-pyran-4-yl-methyl)phosphonium iodide (9.27 g) in THF (70 mL) was added dropwise lithium-1,1,1,3,3,3-hexamethyldisilazide (1 M THF solution, 19.0 mL) at 0° C. or lower, followed by stirring at around 0° C. for 1 hour. To the reaction mixture was added dropwise a solution of ethyl[3-bromo-4-(cyclopropylsulfanyl)phenyl](oxo)acetate (5.0 g) in THF (10 mL) at 2° C. or lower. The reaction mixture was stirred for 30 minutes under ice-cooling and then stirred at room temperature for 15 hours. 4 M Hydrochloric acid was added dropwise thereto at 10° C. or lower, adjusted to pH 7, and then concentrated under reduced pressure. To the residue was added diethyl ether and the resulting solid was separated by filtration. The filtrate was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain ethyl 2-[3-bromo-4-(cyclopropylsulfanyl)phenyl]-3-(tetrahydro-2H-pyran-4-yl)acrylate (4.57 g) as an (E)/(Z)-mixture of olefin.