Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]#[C:6][CH2:7][CH2:8][C:9](=[O:11])[CH3:10].C(O)C.[C-:15]#[N:16].[Na+]>O.CCOCC.[OH-].[Na+]>[C:15]([CH2:2][CH2:3][CH2:4][C:5]#[C:6][CH2:7][CH2:8][C:9](=[O:11])[CH3:10])#[N:16]
Reactant: [C-]#N
Reactant: CC(=O)CCC#CCCCCl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: CCOCC
Product: CC(=O)CCC#CCCCC#N

Procedure:
To a solution consisting of 2.77 parts of 9-chloro-5-nonyn-2-one in 8 parts by volume of ethanol is added a solution containing 2.77 parts of sodium cyanide, dissolved in 4 parts of water. The resulting reaction mixture is heated at 80°-100° for about 24 hours, then is cooled and diluted with ether, whereupon 20 parts by volume of dilute aqueous sodium hydroxide is added with stirring. The layers are separated and the alkaline layer is extracted with ether. The ether extracts are combined, then washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford 9-cyano-5-nonyn-2-one. This compound exhibits an infrared absorption maximum at 2250 reciprocal centimeters and nuclear magnetic resonance peak at δ2.81 and δ2.50.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([S:13]([NH:16][C:17]3([C:23]([OH:25])=[O:24])[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)(=[O:15])=[O:14])=[CH:10][CH:11]=2)[C:6]([NH:26][C:27]([NH2:29])=[NH:28])=[N:5][CH:4]=1.Cl.N[C:32](N)=N.ClC1C2C(=CC=C(S(NC3(C(OC)=O)CCOCC3)(=O)=O)C=2)C(Cl)=CN=1.NC(N)=N>CS(C)=O.O>[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([S:13]([NH:16][C:17]3([C:23]([O:25][CH3:32])=[O:24])[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)(=[O:15])=[O:14])=[CH:10][CH:11]=2)[C:6]([NH:26][C:27]([NH2:29])=[NH:28])=[N:5][CH:4]=1
Reactant: N=C(N)Nc1ncc(Cl)c2ccc(S(=O)(=O)NC3(C(=O)O)CCOCC3)cc12
Reactant: N=C(N)N
Agent: COC(=O)C1(NS(=O)(=O)c2ccc3c(Cl)cnc(Cl)c3c2)CCOCC1
Agent: Cl
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)C1(NS(=O)(=O)c2ccc3c(Cl)cnc(NC(=N)N)c3c2)CCOCC1
Temperature: 50 °C
Yield: 16.6 %

Procedure:
4-{[(4-Chloro-1-guanidino-7-isoquinolinyl)sulphonyl]amino}tetrahydro-2H-pyran-4-carboxylic acid hydrochloride ##STR55## NaH (33.5 mg, 80% dispersion by wt in mineral oil, 1.12 mmol) was added in one portion to a stirred solution of guanidine hydrochloride (176 mg, 1.84 mmol) in DMSO (3.0 mL) under N2 and the mixture was heated at 50° C. for 15 min. Methyl 4-{[(1,4-dichloro-7-isoquinolinyl)sulphonyl]amino}tetrahydro-2H-pyran-4-carboxylate (187 mg, 0.446 mmol) was added in one portion and the mixture heated at 80° C. for 8 h. A second portion of guanidine (0.45 mmol) [prepared from guanidine hydrochloride and NaH] in DMSO (1.0 mL) was added and the mixture heated at 90° C. for an additional 4 h. The cooled mixture was poured into water (100 mL), extracted with EtOAc (3×50 mL) and the combined organic extracts were washed with brine, dried (Na2SO4). The solvents were evaporated in vacuo and the residue purified by column chromatography upon silica gel using CH2Cl2 -MeOH-0.880NH3 (95:5:0.5) as eluant, and then crystallised with EtOAc, to give to give methyl 4-{[(4-chloro-1-guanidino-7-isoquinolinyl)sulphonyl]amino}tetrahydro-2H-pyran-4-carboxylate (83 mg, 0.186 mmol) as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)[S:4][C:3]=1[C:13]([NH2:15])=[O:14].[S:16]1[CH2:21][CH2:20][C:19](=O)[CH2:18][CH2:17]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C([O-])(O)=O.[Na+]>C(O)(=O)C>[N:10]1[CH:9]=[CH:8][C:7]([C:5]2[S:4][C:3]3[C:13](=[O:14])[NH:15][C:19]4([CH2:20][CH2:21][S:16][CH2:17][CH2:18]4)[NH:1][C:2]=3[CH:6]=2)=[CH:12][CH:11]=1
Reactant: NC(=O)c1sc(-c2ccncc2)cc1N
Reactant: O=C1CCSCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=C1NC2(CCSCC2)Nc2cc(-c3ccncc3)sc21
Temperature: 80 °C
Yield: 91 %

Procedure:
To a solution of 3-amino-5-(pyridin-4-yl)thiophene-2-carboxamide (0.200 g, 0.910 mmol) and tetrahydrothiopyran-4-one (0.528 g, 4.55 mmol) in glacial acetic acid (6 mL) was added p-toluenesulfonic acid monohydrate (0.017 g, 0.091 mmol). The mixture was heated at 80° C. overnight. Then, the mixture was concentrated, and then the residue was dissolved in methanol (20 mL). Solid NaHCO3 (1.00 g, 11.9 mmol) was added, and the mixture was stirred briefly. The solvent was then removed, and the obtained residue was chromatographed (Combiflash, silica gel, dichloromethane to 93:7 dichloromethane/methanol) to give the title compound (0.263 g, 91%) as a yellow solid:
Reaction SMILES: [C:1]1(=[O:8])[NH:6][C:5](=[O:7])[CH2:4][CH2:3][CH2:2]1.[C:9]1(=O)N[C:12](=O)[CH2:11][CH2:10]1>>[CH2:9]([N:6]1[C:5](=[O:7])[CH2:4][CH2:3][CH2:2][C:1]1=[O:8])[CH2:10][CH2:11][CH2:12][CH2:1][CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: O=C1CCC(=O)N1
Reactant: O=C1CCCC(=O)N1
Product: CCCCCCCCCN1C(=O)CCCC1=O

Procedure:
The procedure of Example 1 was repeated except that glutarimide replaced the succinimide.
Reaction SMILES: [C:1]([C:4](=[CH:17][C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=1)[C:5]([NH:7][CH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:6])(=O)[CH3:2].Cl.[C:27]([NH2:35])(=[NH:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C([O-])(=O)C.[Na+].C(OCC)(=O)C>CN(C=O)C>[C:11]1([CH2:10][CH2:9][CH2:8][NH:7][C:5]([C:4]2[CH:17]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=3)[N:34]=[C:27]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[NH:35][C:1]=2[CH3:2])=[O:6])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CC(=O)C(=Cc1ccc(Cl)c(Cl)c1)C(=O)NCCCc1ccccc1
Reactant: N=C(N)c1ccccc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC1=C(C(=O)NCCCc2ccccc2)C(c2ccc(Cl)c(Cl)c2)N=C(c2ccccc2)N1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
100 mg (0.266 mmol) of 2-acetyl-3-(3,4-dichlorophenyl)-N-(3-phenylpropyl)acrylamide was dissolved in 2 ml of DMF. 63.0 mg (0.400 mmol) of benzamidine hydrochloride and 26.0 mg (0.317 mmol) of sodium acetate were added to the obtained solution, and they were stirred at 60° C. overnight. Ethyl acetate was added to the reaction mixture and then the obtained mixture was washed with 1 N hydrochloric acid, saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by the silica gel chromatography (hexane/ethyl acetate=1/3) to obtain the title compound.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[C:11]([NH:30][C@@H:31]([CH2:34][CH3:35])[CH2:32][OH:33])([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CCN(CC)CC>C(Cl)Cl.CCCCCC.CCOCC>[C:11]([NH:30][C@@H:31]([CH2:34][CH3:35])[CH:32]=[O:33])([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC[C@@H](CO)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CC[C@@H](C=O)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: -45 °C
Reaction time: 1 h
Yield: 91.5 %

Procedure:
To a stirred solution of DMSO (2.4 mL, 33.82 mmol) in CH2Cl2 (30 mL) under an argon atmosphere at −45° C., was added oxalyl chloride (2M in CH2Cl2, 8.45 mL, 16.9 mmol) dropwise. The reaction mixture was stirred at −45° C. for 1 h, after which time a solution of (S)-2-(trityl-amino)-butan-1-ol (4 g, 12.07 mmol) in CH2Cl2 (30 mL) was added dropwise with stirring. Stirring was continued at this temperature for 3 h, when TLC (8:2 hexane/Et2O) indicated that the reaction had gone to completion. Et3N (8.4 mL, 60.27 mmol) in CH2Cl2 (30 mL) was added and the solution was allowed to warm to RT over 16 h. It was diluted with more CH2Cl2 (100 mL) and was washed with H2O. (250 ml). The aqueous phase was extracted with CH2Cl2 (3×50 mL.) and the combined organic phases were washed with brine (50 mL), dried (MgSO4), and evaporated in vacuo. The residue was dissolved in Et2O (30 mL), the solid precipitate was removed by filtration, and the filtrate was evaporated in vacuo. The residue was dissolved in hexane (50 mL), the solid precipitate was removed by filtration, and the filtrate was evaporated in vacuo to afford the title compound as a light yellow oil (3.64 g, 91%). 1H-NMR (d6-DMSO, 250 M): δ 0.77 (t, 3H, J=7.42 Hz, —NHCH(CH2CH3)CHO), 1.37-1.59 (m, 2H, —NHCH(CH2CH3)CHO), 2.93 (m, 1H, —NHCH(CH2CH3)CHO), 3.62 (d, 1H, J=5.84 Hz, —NHCH(CH2CH3)CHO), 7.16-7.46 (m, 15H, 3×Bz), 8.77 (d, 1H, J=3.00 Hz, —NHCH(CH2CH3)CHO).
Reaction SMILES: [OH-].[Na+].O1CCOCC1.C([O:12][C:13]1[CH:40]=[CH:39][C:16]([C:17]([NH:19][C:20]2[CH:32]=[C:31]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH:30]=[CH:29][C:21]=2[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[O:18])=[C:15]([O:41][CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH:14]=1)(=O)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(OCC)(=O)C>[CH2:42]([O:41][C:15]1[CH:14]=[C:13]([OH:12])[CH:40]=[CH:39][C:16]=1[C:17]([NH:19][C:20]1[CH:32]=[C:31]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:30]=[CH:29][C:21]=1[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[O:18])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1
Reactant: CC(=O)Oc1ccc(C(=O)Nc2cc(-c3ccccc3)ccc2C(=O)OC(C)(C)C)c(OCc2ccccc2)c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1ccc(O)cc1OCc1ccccc1
Temperature: 52.5 °C
Reaction time: 2 h
Yield: 92.5 %

Procedure:
A 4 mol/L aqueous solution of sodium hydroxide (0.47 mL) was added to a dioxane (5.0 mL) solution of the obtained tert-butyl 2-(4-acetoxy-2-(benzyloxy)benzamido)-4-phenylbenzoate (0.34 g), followed by stirring at 50 to 55° C. for 2 hours. The reaction mixture was cooled to room temperature, and a 10% aqueous solution of citric acid (15 mL) and ethyl acetate were added thereto. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. Diisopropyl ether was added to the obtained residue, and the solid substance was collected by filtration to obtain 0.29 g of tert-butyl 2-(2-(benzyloxy)-4-hydroxybenzamido)-4-phenylbenzoate as a white solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:12])[NH:7][CH2:8][CH2:9][CH2:10][NH2:11])([CH3:4])([CH3:3])[CH3:2].[CH2:13]([O:20][C:21]([NH:23][CH2:24][C:25](O)=[O:26])=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.CN1CCOCC1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C)C=O>[C:1]([O:5][C:6](=[O:12])[NH:7][CH2:8][CH2:9][CH2:10][NH:11][C:25](=[O:26])[CH2:24][NH:23][C:21]([O:20][CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)=[O:22])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCCN
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)NCCCNC(=O)CNC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To 3 grams of (3-Amino-propyl)-carbamic acid tert-butyl ester in 15 ml of dimethylformamide was added 3 grams of N-benzyloxycarbonyl glycine, 4.7 mL of N-methylmorpholine and 5.06 grams of TBTU. The reaction was cooled to 0 degrees C. for 30 minutes then allowed to stir at room temperature overnight. The volatiles were removed under reduced pressure and the resulting material was dissolved in ethyl acetate and washed with 10% citric acid. The aqueous was extracted an additional two times with ethyl acetate, combined and washed with water, saturated aqueous sodium bicarbonate, water, brine and dried over MgSO4. The volatiles were removed under reduced pressure and the resulting material was crystallized from EtOAc/hexane affording 4.55 grams of the desired product as a tan solid. LRMS found 388.3=(M+Na)+.
Reaction SMILES: [Cl:1][C:2]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[S:12]([NH2:15])(=[O:14])=[O:13])=[CH:3][Cl:4].[CH3:16][N:17]=[C:18]=[S:19].N12CCCN=C1CCCCC2.CS(O)(=O)=O>C(#N)C.O>[Cl:1][C:2]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[S:12]([NH:15][C:18]([NH:17][CH3:16])=[S:19])(=[O:13])=[O:14])=[CH:3][Cl:4]
Reactant: CN=C=S
Reactant: NS(=O)(=O)c1ccccc1OC(Cl)=CCl
Agent: CS(=O)(=O)O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Solvent: O
Product: CNC(=S)NS(=O)(=O)c1ccccc1OC(Cl)=CCl
Reaction time: 24 h

Procedure:
13.4 g of 2-(1,2-dichlorovinyloxy)phenylsulfonamide and 3.65 g of methyl isothiocyanate are dissolved in 50 ml of acetonitrile, and 7.8 g of 1,8-diazabicyclo[5.4.0]undec-7-ene are added with cooling (0° to 5° C.) and stirring. The resulting red reaction solution is left to stand for 24 hours, 4.8 g of methanesulfonic acid are then added and the mixture is diluted with water to a volume of 1 liter. The crystals which separate out are filtered off, washed with methanol and dried. Yield: 15 g. Melting point: 185°-187° (decomposition).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([OH:8])[C:5]([CH2:9][CH2:10][CH2:11][C:12]([C:14]2[CH:22]=[CH:21][C:17]([C:18]([OH:20])=O)=[CH:16][CH:15]=2)=[CH2:13])=[C:4]([NH2:23])[N:3]=1.CN1CCOCC1.COC1N=C(OC)N=C(Cl)N=1.Cl.[CH3:43][O:44][C:45](=[O:54])[C@H:46]([CH2:48][CH2:49][C:50]([O:52][CH3:53])=[O:51])[NH2:47]>O1CCCC1>[NH2:1][C:2]1[N:7]=[C:6]([OH:8])[C:5]([CH2:9][CH2:10][CH2:11][C:12]([C:14]2[CH:15]=[CH:16][C:17]([C:18]([NH:47][C@H:46]([C:45]([O:44][CH3:43])=[O:54])[CH2:48][CH2:49][C:50]([O:52][CH3:53])=[O:51])=[O:20])=[CH:21][CH:22]=2)=[CH2:13])=[C:4]([NH2:23])[N:3]=1
Reactant: C=C(CCCc1c(N)nc(N)nc1O)c1ccc(C(=O)O)cc1
Reactant: COC(=O)CC[C@H](N)C(=O)OC
Agent: COc1nc(Cl)nc(OC)n1
Agent: Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: C=C(CCCc1c(N)nc(N)nc1O)c1ccc(C(=O)N[C@@H](CCC(=O)OC)C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A mixture of 270 mg (1 eq) of 4-[5-(2,6-diamino-4-hydroxypyrimidin-5-yl)-pent-1-en-2-yl]benzoic acid and 104 mg (1.2 eq) of N-methylmorpholine in 4.0 ml of anhydrous tetrahydrofuran, was vigorously stirred for 5 minutes at room temperature. To this mixture, 165 mg (1.1 eq) of 2,4-dimethoxy-6-chloro-1,3,5-triazine were added and the sol was stirred for 40 minutes at room temperature. An additional 104 mg (1.2 eq) of N-methylmorpholine were introduced followed by 236 mg (1.3 eq) of dry dimethyl-L-glutamate hydrochloride. The solution then was continuously stirred for 4 hours at room temperature. The solvent was removed under reduced pressure and the residue dissolved in chloroform. Extraction with saturated aqueous sodium bicarbonate removed unreacted acid, triazine and triazinone. The organic layer was dried over magnesium sulfate, filtered and evaporated to dryness to yield the product which was further purified by flash chromatography eluting with 1:10 methanol:chloroform. M.S.:m/z=471.2081 (M+, calc. for C23H29N5O6 : 471.2118). 1H-N.M.R. (CDCl3, 300 MHz): 1.41(quin, 2H, CH2 --CH2 --CH2, J=7.5 Hz); 2.00-2.55(m, 8H, 4×--CH2 --); 3.56(s, 3H, CH3O); 3.68(s, 3H, CH3O); 4.68 (dt, 1H, CH, J=6, 7.5 Hz); 4.84 (s (broad), 2H, NH2); 4.97 (s, 1Holef.); 5.18 (s, 1Holef.); 5.86 (s (broad), 2H, NH2); 7.29 (d, 2Harom., J=9 Hz); 7.62 (m, (broad), 1H, NHglu); 7.64 (d, 2Harom., J=9 Hz); 11.20 (s (broad), 1H, NHpyr).
Reaction SMILES: N(C(C)C)C(C)C.C([Li])CCC.[F:13][C:14]([F:28])([F:27])[C:15]([NH:17][C:18]1[CH:22]=[CH:21][S:20][C:19]=1[C:23]([O:25][CH3:26])=[O:24])=[O:16].[Br:29]CCBr.C([O-])(O)=O.[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>C1COCC1.CO>[Br:29][C:21]1[S:20][C:19]([C:23]([O:25][CH3:26])=[O:24])=[C:18]([NH:17][C:15](=[O:16])[C:14]([F:13])([F:27])[F:28])[CH:22]=1
Reactant: COC(=O)c1sccc1NC(=O)C(F)(F)F
Reactant: BrCCBr
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CO
Solvent: CC(C)NC(C)C
Product: COC(=O)c1sc(Br)cc1NC(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 21 %

Procedure:
To a stirred solution of i-Pr2NH (6.2 mL, 3.2 mmol) in THF (100 mL) in a dry ice-i-PrOH bath was added, dropwise, n-butyllithium (2.5 N in hexanes, 17 mL, 43 mmol). After 5 min, the mixture was placed in an ice-water bath. After an additional 5 min, the mixture was cooled in a dry ice-i-PrOH bath. To this stirred solution was added, dropwise over 2 min, a solution of the methyl 3-(trifluoroacetylamino)-2-thiophenecarboxylate (3.5 g, 14 mmol) in THF (15 mL). After 5 min, 1,2-dibromoethane (4 mL) was added in one portion. After 5 min, MeOH (3.5 mL) and saturated NaHCO3 (150 mL) containing sodium thiosulfate (5 g) were sequentially added. The mixture was removed from the cold bath and allowed to warm to room temperature whereupon EtOAc (250 mL) was added. After partition, the aqueous layer was extracted with EtOAc (2×100 mL). The three combined organic layers were washed with brine (2×100 mL), dried (MgSO4) and concentrated in vacuo. The residue was absorbed onto Celite® 545 and chromatographed (12 g silica gel, 10% EtOAc-hexanes to 25% EtOAc/hexanes, 50 mL/min). The product-containing fractions were combined and rechromatographed (12 g silica gel, 10% EtOAc-hexanes, 50 mL/min) to provide methyl 5-bromo-3-(trifluoroacetylamino)-2-thiophenecarboxylate as a pale yellow solid 0.98 g (21%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:12][C:13]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[C:23]([OH:31])(=[O:30])[C:24]([CH2:26][C:27](O)=[O:28])=[CH2:25]>>[O:28]=[C:27]1[N:1]([C:2]2[CH:7]=[C:6]([C:8]([F:10])([F:11])[F:9])[CH:5]=[C:4]([NH:12][C:13]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[O:14])[CH:3]=2)[CH2:25][CH:24]([C:23]([OH:31])=[O:30])[CH2:26]1
Reactant: Nc1cc(NC(=O)NCc2ccccc2)cc(C(F)(F)F)c1
Reactant: C=C(CC(=O)O)C(=O)O
Product: O=C(NCc1ccccc1)Nc1cc(N2CC(C(=O)O)CC2=O)cc(C(F)(F)F)c1
Reaction time: 10 h

Procedure:
A mixture of N-(3-amino-5-(trifluoromethyl)phenyl)(benzylamino)carboxamide and itaconic acid was fused at 110° C. for 10 hours. The resulted solid was washed with methanol and then dried at 50° C. for 12 hours.
Reaction SMILES: [Cu:1].[CH2:2]1[C@H](N[C@@H]2[C@H](O)[C@@H](O)[C@H](O)C(CO)=C2)[C@H](O)[C@@H](O)[C@H](O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)[C@H]1CO.[Cu].C1[C@H](N[C@@H]2[C@H](O)[C@@H](O)[C@H](O)C(CO)=C2)[C@H](O)[C@@H](O)[C@H](O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)[C@H]1CO.C1OC(=O)C2C(Cl)=C(Cl)C(Cl)=C(Cl)C1=2.[Cu].CO/N=C(/C1C=CC(Cl)=CC=1Cl)\CC1C=CC=NC=1.[Cu+].[CH3:106][C:107]1([CH:122]=[CH2:123])O[C:111](=[O:112])[N:110]([C:114]2[CH:115]=[C:116]([Cl:121])[CH:117]=[C:118]([Cl:120])[CH:119]=2)[C:108]1=[O:109].[Cu].C1OC(=O)C2C(Cl)=C(Cl)C(Cl)=C(Cl)C1=2>>[Cu:1].[CH3:2][C:107]12[C:108](=[O:109])[N:110]([C:114]3[CH:115]=[C:116]([Cl:121])[CH:117]=[C:118]([Cl:120])[CH:119]=3)[C:111](=[O:112])[C:122]1([CH3:123])[CH2:106]2
Reactant: OCC1=C[C@H](N[C@H]2C[C@H](CO)[C@@H](O[C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)[C@H](O)[C@H]2O)[C@H](O)[C@@H](O)[C@@H]1O
Reactant: C=CC1(C)OC(=O)N(c2cc(Cl)cc(Cl)c2)C1=O
Agent: [Cu+]
Agent: [Cu]
Agent: CO/N=C(\Cc1cccnc1)c1ccc(Cl)cc1Cl
Product: CC12CC1(C)C(=O)N(c1cc(Cl)cc(Cl)c1)C2=O

Procedure:
The fungicidal preparations containing the inorganic copper fungicide and chemicals (such as fungicides, etc.) other than ingredients (a) and (b) include a Bordeaux mixture containing basic copper calcium sulfate; copper-sulfur fungicides, such as Engei Bordeaux (trade name, produced by Sankei Chemical Co., Ltd.), etc.; copper-validamycin fungicides; copper-validamycin-fthalide fungicides; copper-pyrifenox fungicides; copper (I)-vinclozolin fungicides; copper-fthalide fungicides; copper-procymidone fungicides, such as Scletane Wettable Powder (trade name, produced by Hokko Chemical Industry Co., Ltd.); copper (I)-fosetyl wettable powders; copper-metalaxyl fungicides, such as Ridomil Copper Wettable Powder (trade name, produced by Nihon Nohyaku Co., Ltd.); iprodione copper (I) fungicides, such as Daisedo Wettable Powder (trade name, produced by Yashima Chemical Industry Co., Ltd.); iminoctadine triacetate-copper fungicides; oxadixyl copper (I) fungicides; oxolinic acid-copper fungicides; Ad kasugamycin-copper fungicides, such as Kasumin Bordeaux Dust 3DL (trade name, produced by Hokko Chemical Industry Co., Ltd.), Kasumin Bordeaux (trade name, produced by Dai-ichi Noyaku K.K. and Hokko Chemical Industry Co., Ltd.), etc.; Dithianon copper (I) fungicides; streptomycin-copper fungicides, such as Do-Stomy Wettable Powder (trade name, produced by Nihon Nohyaku Co., Ltd.), etc.; sodium hydrogencarbonate-copper fungicides, such as G-Fine Wettable Powder (trade name, produced by Yashima Chemical Industry Co., Ltd.); and copper-organocopper fungicides, such as Oxy Bordeaux (trade name, produced by Sankyo Co., Ltd.), Kinset Wettable Powder (trade name, produced by Agro-Kanesho Co., Ltd.), Kinset Wettable Powder 80 (trade name, produced by Agro-Kanesho Co., Ltd.), etc.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[CH2:7][NH2:8].[CH3:9][NH:10][S:11]([C:14]1[CH:15]=[C:16]([C:24](Cl)=[O:25])[C:17]2[O:22][CH2:21][CH2:20][O:19][C:18]=2[CH:23]=1)(=[O:13])=[O:12].O>C(Cl)(Cl)Cl>[CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[CH2:7][NH:8][C:24]([C:16]1[C:17]2[O:22][CH2:21][CH2:20][O:19][C:18]=2[CH:23]=[C:14]([S:11](=[O:13])(=[O:12])[NH:10][CH3:9])[CH:15]=1)=[O:25]
Reactant: CN1CCCC1CN
Reactant: CNS(=O)(=O)c1cc2c(c(C(=O)Cl)c1)OCCO2
Solvent: ClC(Cl)Cl
Solvent: O
Product: CNS(=O)(=O)c1cc2c(c(C(=O)NCC3CCCN3C)c1)OCCO2
Yield: 78.5 %

Procedure:
61 g of dextrorotatory 1-methyl-2-aminomethylpyrrolidine, 465 ccm of chloroform and, in portions, 155 g of 7-methylsulfamoyl-1,4-benzodioxane-5-carbonyl chloride, with the temperature being maintained at 5°-10° C., were introduced into a balloon flask provided with an agitator and a thermometer. After agitation of the mixture and the addition of 1,850 cm3 of water, chloroform was distilled and the remaining solution was filtered. The base was precipitated by the addition of 65 cm3 of 20% ammonia. The crystals formed were dried off, washed and dried. 154 g of dextrorotatory-N-(1-methyl-2-pyrrolidylmethyl)-7-methylsulfamoyl-1,4-benzodioxane-5-carboxamide was produced (M.P.: 187°-188° C.; yield: 78.5%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:45]=[C:46]([C:48]([F:51])([F:50])[F:49])[CH:47]=1)[CH2:6][N:7]([CH2:25][C:26]1[CH:31]=[C:30]([O:32][CH3:33])[C:29]([O:34][CH3:35])=[CH:28][C:27]=1B1OC(C)(C)C(C)(C)O1)[C:8]1[N:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[CH:10][N:9]=1)#[N:2].Br[C:53]1[C:58]([O:59][CH3:60])=[CH:57][CH:56]=[C:55]([C:61]([CH3:63])=[CH2:62])[N:54]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>O1CCOCC1.O>[C:1]([C:3]1[CH:4]=[C:5]([CH:45]=[C:46]([C:48]([F:51])([F:50])[F:49])[CH:47]=1)[CH2:6][N:7]([CH2:25][C:26]1[CH:31]=[C:30]([O:32][CH3:33])[C:29]([O:34][CH3:35])=[CH:28][C:27]=1[C:53]1[C:58]([O:59][CH3:60])=[CH:57][CH:56]=[C:55]([C:61]([CH3:63])=[CH2:62])[N:54]=1)[C:8]1[N:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][C:21]([CH3:23])([CH3:24])[CH3:22])=[O:19])=[CH:10][N:9]=1)#[N:2]
Reactant: COc1cc(CN(Cc2cc(C#N)cc(C(F)(F)F)c2)c2ncc(OCCCC(=O)OC(C)(C)C)cn2)c(B2OC(C)(C)C(C)(C)O2)cc1OC
Reactant: C=C(C)c1ccc(OC)c(Br)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: C=C(C)c1ccc(OC)c(-c2cc(OC)c(OC)cc2CN(Cc2cc(C#N)cc(C(F)(F)F)c2)c2ncc(OCCCC(=O)OC(C)(C)C)cn2)n1
Temperature: 80 °C
Reaction time: 8 h
Yield: 27.5 %

Procedure:
Tert-butyl 4-(2-{(3-cyano-5-trifluoromethyl-benzyl)-[4,5-dimethoxy-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzyl]-amino}-pyrimidin-5-yloxy)-butyrate (60 mg) is dissolved in 1,4-dioxane (1.5 ml) and thereto are added 2-bromo-6-isopropenyl-3-methoxy-pyridine (38 mg), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (7 mg) and cesium carbonate (55 mg), and the mixture is stirred under nitrogen atmosphere at 80° C. overnight. The reaction solution is cooled to room temperature, and thereto are added ethyl acetate and water, and the mixture is separated and the organic layer is filtered by NH— silica gel and the mixture is extracted with ethyl acetate and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=85:15→70:30) to give tert-butyl 4-(2-{(3-cyano-5-trifluoromethyl-benzyl)-[2-(6-isopropenyl-3-methoxy-pyridin-2-yl)-4,5-dimethoxy-benzyl]-amino}-pyrimidin-5-yloxy)-butyrate (17 mg). MS (m/z): 734 [M+H]+