Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CSC(SC)=[C:4]([C:7]#N)[C:5]#[N:6].CS[C:13](SC)=[C:14]([C:18]#[N:19])[C:15]([NH2:17])=[O:16]>CO>[O:16]1[C:15]2[CH:14]=[CH:13][CH:7]=[CH:4][C:5]=2[NH:6][C:13]1=[C:14]([C:18]#[N:19])[C:15]([NH2:17])=[O:16]
Reactant: CSC(SC)=C(C#N)C(N)=O
Reactant: CSC(SC)=C(C#N)C#N
Solvent: CO
Product: N#CC(C(N)=O)=C1Nc2ccccc2O1

Procedure:
The procedure described in Example 1 is repeated using, instead of 3,3-bis(methylthio)-2-cyanoacrylonitrile, an equivalent amount of 3,3-bis(methylthio)-2-cyanoacrylamide and holding the mixture under reflux for 12 hours to obtain 2-benzoxazolinylidene-cyanoacetic acid amide of melting point 220°-222° C. (dec.) (from methanol).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:4][CH:3]=1.[Cl-].[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:27]=[CH:28][C:29]=1[O:30][CH3:31])[CH:23]=[N+:24]([CH3:26])[CH3:25].COC1C=C(C=CC=1OC)C=O.CNC>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[NH:9][C:10]3[C:15]([C:16]=2[CH:23]([N:24]([CH3:26])[CH3:25])[C:22]2[CH:27]=[CH:28][C:29]([O:30][CH3:31])=[C:20]([O:19][CH3:18])[CH:21]=2)=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:6][CH:7]=1
Reactant: Clc1ccc(-c2cc3ccccc3[nH]2)cc1
Reactant: COc1ccc(C=[N+](C)C)cc1OC
Agent: CNC
Agent: COc1ccc(C=O)cc1OC
Agent: [Cl-]
Product: COc1ccc(C(c2c(-c3ccc(Cl)cc3)[nH]c3ccccc23)N(C)C)cc1OC

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 2-(4-chloro-phenyl)-1H-indole and (3,4-dimethoxy-benzylidene)-dimethylammonium chloride, which had been prepared in accordance with example 44 from 3,4-dimethoxy-benzaldehyde and dimethylamine.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[C:11](=[C:14]([CH3:16])[CH3:15])/[C:10](=[C:17](\[C:19]3[CH:23]=[C:22]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[S:21][C:20]=3[CH3:30])/[CH3:18])/[C:9]2=[O:31])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:39](Cl)(=[O:43])[C:40]([CH3:42])=[CH2:41]>ClCCl>[C:39]([O:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[C:11](=[C:14]([CH3:15])[CH3:16])/[C:10](=[C:17](\[C:19]3[CH:23]=[C:22]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[S:21][C:20]=3[CH3:30])/[CH3:18])/[C:9]2=[O:31])=[CH:4][CH:3]=1)(=[O:43])[C:40]([CH3:42])=[CH2:41]
Reactant: CC(C)=C1C(=O)N(c2ccc(O)cc2)C(=O)/C1=C(\C)c1cc(-c2ccccc2)sc1C
Reactant: C=C(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)Oc1ccc(N2C(=O)C(=C(C)C)/C(=C(/C)c3cc(-c4ccccc4)sc3C)C2=O)cc1
Reaction time: 1 h
Yield: 44 %

Procedure:
To a solution obtained by dissolving 430 mg of N-(4-hydroxyphenyl)-2-[(E)-1-(2-methyl-5-phenyl-3-thienyl)ethylidene]-3-isopropylidenesuccinimide obtained in Example 8 in 10 ml of dichloromethane, 202 mg of triethylamine was added, followed by dropwise addition of 209 mg of methacryloyl chloride in 10 minutes. The reaction was carried out at room temperature for further 1 hour. After the reaction, the reaction solution was washed with water, dried over anhydrous magnesium sulfate, and subjected to removal of the solvent by distillation. The resulting residue was purified by column chromatography (filler: Wakogel C-300, eluent: a mixed solution of n-hexane and ethyl acetate) to give organce crystals of N-(4-methacryloyloxyphenyl)-2-[(E)-1-(2-methyl-5-phenyl-3-thienyl)ethylidene]-3-isopropylidenesuccinimide in yield of 44.0%.
Reaction SMILES: C(OC([NH:8][CH2:9][CH:10]1[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([O:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:16]=2)[CH2:11]1)=O)(C)(C)C.FC(F)(F)C(O)=O.C(=O)([O-])[O-].[K+].[K+].[C:39]1([S:45](Cl)(=[O:47])=[O:46])[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>C(Cl)Cl.O>[C:39]1([S:45]([NH:8][CH2:9][CH:10]2[CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:16]=3)[CH2:11]2)(=[O:47])=[O:46])[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CCOC(=O)COc1ccc2c(c1)CC(CNC(=O)OC(C)(C)C)C2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)COc1ccc2c(c1)CC(CNS(=O)(=O)c1ccccc1)C2
Temperature: 0 °C
Reaction time: 1 h
Yield: 88 %

Procedure:
Dissolved in 6 ml of methylene chloride were 1.77 g (5.00 mmol) of ethyl [2-(t-butoxycarbonylaminomethyl)indane-5-oxy]acetate, and 4 ml of trifluoroacetic acid were added under chilling with ice water, followed by stirring for 1 hour. The liquid reaction mixture was diluted with 40 ml of methylene chloride, and a solution of 8.37 g (60 mmol) of potassium carbonate in 40 ml of water was added, followed by vigorous stirring. After 10 minutes, 1.07 g (6.00 mmol) of phenyl-sulfonyl chloride were added, and the resultant mixture was stirred further for 1.5 hours. An organic layer separated was taken out, dried and then concentrated, and the residue was purified by column chromatography on silica gel (ethyl acetate: hexane=1:1), thereby obtaining 1.68 g of a colorless oily substance. Yield: 88%.
Reaction SMILES: [CH3:1][C:2]1[C:14]2[CH:13]([CH2:15][CH2:16][CH:17]3[O:21]CC[O:18]3)[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.C(OCC)(=O)C.CCCCCC>CC(C)=O>[CH3:1][C:2]1[C:14]2[CH:13]([CH2:15][CH2:16][C:17]([OH:21])=[O:18])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc2c1C(CCC1OCCO1)c1ccccc1-2
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CC(C)=O
Product: Cc1cccc2c1C(CCC(=O)O)c1ccccc1-2
Temperature: 25 °C
Reaction time: 6 h
Yield: 59.9 %

Procedure:
2-[2-(1-Methylfluoren-9-yl)ethyl]-1,3-dioxolane (4.8 g, 17.2 mmol) in 100 mL of acetone was charged slowly with John's reagent (CrO3 : H2SO4 :H2O 4:4:50 by weight) at room temperature. The reaction was monitored by TLC (silica, 10% ethyl acetate/hexane). The reaction mixture was stirred for 6 hr at room temperature, the acetone was evaporated and the residual water was extracted with ethyl acetate twice. The combined organic layers were washed with water until water became colorless. The organic solution was then extracted with 1N aqueous solution of sodium hydroxide. The basic aqueous solution was washed with ethyl acetate, acidified and extracted with ethyl acetate again. The ethyl acetate solution was dried over magnesium sulfate and evaporated. Purification of the crude by short path chromatography (silica, 25% ethyl acetate/hexane) afforded 2.6 g (59.9%) of 3-(1-methylfluoren-9-yl)propionic acid.
Reaction SMILES: N(OC(C)(C)C)=O.[F:8][C:9]1[C:15]([CH3:16])=[C:14]([F:17])[C:13]([F:18])=[C:12]([N+:19]([O-:21])=[O:20])[C:10]=1N>CN(C)C=O>[F:17][C:14]1[C:13]([F:18])=[C:12]([N+:19]([O-:21])=[O:20])[CH:10]=[C:9]([F:8])[C:15]=1[CH3:16]
Reactant: Cc1c(F)c(N)c([N+](=O)[O-])c(F)c1F
Agent: CC(C)(C)ON=O
Solvent: CN(C)C=O
Product: Cc1c(F)cc([N+](=O)[O-])c(F)c1F
Temperature: 0 °C
Yield: 36.8 %

Procedure:
To a solution of t-butyl nitrite (1.87 g) in anhydrous dimethylformamide (10.9 ml) is added dropwise a solution of 2,4,5-trifluoro-3-methyl-6-nitroaniline (2.05 g) in anhydrous dimethylformamide (16.4 ml) with stirring at 50°-52° C. and the mixture is stirred at the same temperature for 30 minutes. After cooling, the reaction mixture is poured into ice-water, extracted with diethyl ether, and the extract is washed with water and dried. The solvent is distilled off under reduced pressure and the obtained residue is purified by silica-gel column-chromatography (eluent; dichloromethane : n-hexane=1 : 4) to give 2,3,6-trifluoro-4-nitrotoluene (0.7 g).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27]Br)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[Br:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]2[CH:40]=[CH:39][NH:38][N:37]=2)=[CH:32][CH:31]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27][N:38]4[CH:39]=[CH:40][C:36]([C:33]5[CH:32]=[CH:31][C:30]([Br:29])=[CH:35][CH:34]=5)=[N:37]4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CBr)cc3)cc2)CC1
Reactant: Brc1ccc(-c2cc[nH]n2)cc1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Cn4ccc(-c5ccc(Br)cc5)n4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 5, Step 3, using 1-[4′-(4-bromomethyl-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and 3-(4-bromo-phenyl)-1H-pyrazole.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([CH2:24]OS(C3C=CC(C)=CC=3)(=O)=O)[N:20]=2)[CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:36][O:37][CH2:38][CH2:39][CH2:40][NH2:41]>>[CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([CH2:24][NH:41][CH2:40][CH2:39][CH2:38][O:37][CH3:36])[N:20]=2)[CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:16])[CH3:17])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COCCCN
Reactant: Cc1ccc(S(=O)(=O)OCc2noc([C@H](CCCC3CCCCC3)CC(=O)OC(C)(C)C)n2)cc1
Product: COCCCNCc1noc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1

Procedure:
Method as for preparation 5 using tert-butyl (3R)-6-cyclohexyl-3-[3-({[(4-methylphenyl)sulfonyl]oxy}methyl)-1,2,4-oxadiazol-5-yl]hexanoate (preparation 177) (488 mg, 0.96 mmol) and 3-methoxypropylamine (325 mg, 3.84 mmol) as starting materials.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH2:8][N:9]2[C:13]([CH3:14])=[N:12][C:11]([C:15]3[O:16][C:17]([C:20]4[CH:25]=[CH:24][C:23]([O:26][C:27]([F:30])([F:29])[F:28])=[CH:22][CH:21]=4)=[CH:18][N:19]=3)=[N:10]2)[CH:5]=[CH:4][N:3]=1.[CH3:31][N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>CS(C)=O>[CH3:31][N:32]1[CH2:37][CH2:36][N:35]([C:2]2[CH:7]=[C:6]([CH2:8][N:9]3[C:13]([CH3:14])=[N:12][C:11]([C:15]4[O:16][C:17]([C:20]5[CH:21]=[CH:22][C:23]([O:26][C:27]([F:30])([F:28])[F:29])=[CH:24][CH:25]=5)=[CH:18][N:19]=4)=[N:10]3)[CH:5]=[CH:4][N:3]=2)[CH2:34][CH2:33]1
Reactant: Cc1nc(-c2ncc(-c3ccc(OC(F)(F)F)cc3)o2)nn1Cc1ccnc(Cl)c1
Reactant: CN1CCNCC1
Solvent: CS(C)=O
Product: Cc1nc(-c2ncc(-c3ccc(OC(F)(F)F)cc3)o2)nn1Cc1ccnc(N2CCN(C)CC2)c1
Temperature: 140 °C
Reaction time: 16 h

Procedure:
A mixture of 2-(1-((2-chloropyridin-4-yl)methyl)-5-methyl-1H-1,2,4-triazol-3-yl)-5-(4-(trifluoromethoxy)phenyl)oxazole (60 mg, 0.14 mmol) and 1-methyl-piperazine (1 mL) in DMSO (2 mL) was stirred at 140° C. for 16 h under Ar atmosphere. The mixture was then cooled to RT, and purified by prep-HPLC (Mobile phase: A=0.1% TFA/H2O, B=MeCN; Gradient: B=5%-95% in 8 min; Column: XBridge C18, 5 um, 30 mm×150 mm) to afford the title compound a solid. MS (ES+) C24H24F3N7O2 requires: 499. found: 500 [M+H]+; 1H NMR (500 MHz, CDCl3) δ 8.18 (d, J=5.0 Hz, 1H), 7.80 (d, J=9.0 Hz, 2H), 7.51 (s, 1H), 7.29 (d, J=9.0 Hz, 2H), 6.48 (d, J=5.0 Hz, 1H), 6.38 (s, 1H), 5.32 (s, 2H), 3.62 (m, 4H), 2.67 (m, 4H), 2.50 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C@@H:12]2[CH2:17][C@H:16]([C:18]3[O:22][NH:21][C:20](=[O:23])[CH:19]=3)[CH2:15][CH2:14][N:13]2C(OC)=O)[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].Br>>[CH3:1][C:2]1[CH:3]=[C:4]([C@@H:12]2[CH2:17][C@H:16]([C:18]3[O:22][NH:21][C:20](=[O:23])[CH:19]=3)[CH2:15][CH2:14][NH:13]2)[CH:5]=[CH:6][C:7]=1[C:8]([F:9])([F:10])[F:11]
Reactant: COC(=O)N1CC[C@@H](c2cc(=O)[nH]o2)C[C@H]1c1ccc(C(F)(F)F)c(C)c1
Agent: Br
Product: Cc1cc([C@@H]2C[C@H](c3cc(=O)[nH]o3)CCN2)ccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.4 %

Procedure:
(2S,4R)-Methyl 2-(3-methyl-4-(trifluoromethyl)phenyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)-piperidine-1-carboxylate (0.168 g, 0.44 mmol) (from example 67, step 3) was dissolved in HBr (33% in acetic acid, 5.6 g, 22.84 mmol) and the mixture was stirred at room temperature overnight. The solvent was evaporated and the residue purified by preparative HPLC (Instrument: FractionLynx II, Mobilphase: gradient 5-95% MeCN in 0.2% NH3, pH 10, Column: Xbridge Prep C18 5 μm OBD 19*150 mm) to yield 5-((2S,4R)-2-(3-methyl-4-(trifluoromethyl)phenyl)piperidin-4-yl)isoxazol-3(2H)-one (0.068 g, 48%). 1H NMR (600 MHz, dmso) δ 1.31-1.40 (m, 1H), 1.41-1.50 (m, 1H), 1.85-1.90 (m, 1H), 1.95-2.00 (m, 1H), 2.40 (s, 3H), 2.69-2.76 (m, 1H), 2.83-2.90 (m, 1H), 3.08-3.13 (m, 1H), 3.68 (d, 1H), 5.73 (s, 1H), 7.36 (d, 1H), 7.43 (s, 1H), 7.57 (d, 1H). HRMS Calcd for [C16H17F3N2O2+H]+: 327.1320. Found: 327.1318.
Reaction SMILES: [CH2:1]([Zn]CC)C.FC(F)(F)C(O)=O.C(I)I.[Br:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH:24]=[CH2:25])=[C:19]([Cl:26])[CH:18]=1>C(Cl)Cl>[Br:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH:24]2[CH2:1][CH2:25]2)=[C:19]([Cl:26])[CH:18]=1
Reactant: CC[Zn]CC
Reactant: C=COc1ccc(Br)cc1Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: ICI
Product: Clc1cc(Br)ccc1OC1CC1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To an ice-cooled solution of diethylzinc solution (1.0 M in hexanes) (8.25 mL, 8.25 mmol, 2.75 eq.) in DCM (15 mL), trifluoroacetic acid (0.6 mL, 7.80 mmol, 2.60 eq.) was added slowly (gas evolution). Upon addition completion, the mixture was stirred at 0° C. for 10 min. Methyleniodid (0.7 mL, 8.70 mmol, 2.90 eq.) was added dropwise and the mixture was stirred at 0° C. for 10 min. A solution of 4-bromo-2-chloro-1-vinyloxy-benzene (700 mg, 3.00 mmol, 1.00 eq.) in DCM (5 mL) was added dropwise. The reaction mixture was stirred at 0° C. for 30 min and further at r.t. for 1 hour, then quenched with 2N aq. HCl soln. (15 mL) and water (5 mL). The layers were separated. The aq. layer was extracted with DCM (1×25 mL). The comb. org. phases were dried over MgSO4 and concentrated in vacuo. The residue was purified by flashmaster (column: 100 g, flow: 45 mL/min, 30 fractions of 45 mL, Heptane to Heptane+5% AcOEt) to yield 4-bromo-2-chloro-1-cyclopropoxy-benzene as a colorless oil.
Reaction SMILES: [CH:1](=O)[CH3:2].[N+:4]([C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:21][CH2:20][C:15]3([NH:19][CH2:18][CH2:17][CH2:16]3)[CH2:14]2)=[CH:9][C:8]=1[O:22][CH:23]([CH3:25])[CH3:24])([O-:6])=[O:5].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CCOCC>[CH2:1]([N:19]1[C:15]2([CH2:20][CH2:21][N:13]([C:10]3[CH:11]=[CH:12][C:7]([N+:4]([O-:6])=[O:5])=[C:8]([O:22][CH:23]([CH3:25])[CH3:24])[CH:9]=3)[CH2:14]2)[CH2:16][CH2:17][CH2:18]1)[CH3:2]
Reactant: CC=O
Reactant: CC(C)Oc1cc(N2CCC3(CCCN3)C2)ccc1[N+](=O)[O-]
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOCC
Product: CCN1CCCC12CCN(c1ccc([N+](=O)[O-])c(OC(C)C)c1)C2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1.0 ml of acetaldehyde is added to a solution of 500 mg of 7-[4-nitro-3-(propan-2-yloxy)phenyl]-1,7-diazaspiro[4.4]nonane in 20 ml of 1,4-dichloroethane, cooled in a bath of ice-cold water. After 30 minutes, 1.12 g of sodium triacetoxyborohydride are added in small portions and the mixture is left to return to ambient temperature. The mixture is stirred at ambient temperature for 15 hours. 1 ml of acetaldehyde is then added and the mixture is stirred for 7 h. The mixture is concentrated to dryness under reduced pressure and the residue is diluted in 100 ml of dichloromethane. The organic phase is washed three times with 50 ml of water and the organic phase is dried over anhydrous magnesium sulfate, filtered and then concentrated to dryness under reduced pressure. The residue is purified by chromatography on silica gel, elution being carried out with a dichloromethane/isopropanol gradient: 100/0 to 50/50, and then by further chromatography on silica gel, elution being carried out with a dichloromethane/acetone gradient: 100/0 to 50/50, so as to obtain a yellow oil. This oil is taken up with ether, and the precipitate obtained is filtered off. The filtrate is concentrated to dryness under reduced pressure, so as to give 250 mg of 1-ethyl-7-[4-nitro-3-(propan-2-yloxy)phenyl]-1,7-diazaspiro[4.4]nonane in the form of a yellow oil.
Reaction SMILES: Cl[C:2](=[CH2:5])[C:3]#[N:4].Br.[CH2:7]([O:9][C:10]([C:12]([NH2:14])=[NH:13])=[O:11])[CH3:8].C(N(CC)CC)C>C(O)C>[NH2:4][C:3]1[CH:2]=[CH:5][N:14]=[C:12]([C:10]([O:9][CH2:7][CH3:8])=[O:11])[N:13]=1
Reactant: C=C(Cl)C#N
Reactant: CCOC(=O)C(=N)N
Agent: Br
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)c1nccc(N)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 57.5 %

Procedure:
To a solution of 2-chloroacrylonitrile (437 mg) and 1-ethoxycarbonylformamidine hydrobromide (985 mg) in ethanol (5 ml) was added dropwise triethylamine (1.01 g) at 0° C. The reaction mixture was stirred for 4 hours at ambient temperature and evaporated to dryness. The residue was dissolved in a mixture of ethyl acetate and water, and extracted with ethyl acetate three times. The combined extracts were dried over anhydrous magnesium sulfate and evaporated to dryness. The residue was triturated with diethyl ether to give ethyl 4-aminopyrimidine-2-carboxylate (480 mg), which was recrystallized from a mixture of ethyl acetate and benzene, mp. 101°-104° C.
Reaction SMILES: [CH3:1][S:2][C:3]1[C:8]([N+:9]([O-])=O)=[CH:7][CH:6]=[C:5]([O:12][CH3:13])[C:4]=1OC.S(S([O-])=O)([O-])=O.[Na+].[Na+].C(O)C.[C:27](=[O:30])([O-])[O-].[K+].[K+]>O>[CH3:1][S:2][C:3]1[CH:4]=[C:5]([O:12][CH3:13])[C:6]([O:30][CH3:27])=[CH:7][C:8]=1[NH2:9]
Reactant: O=C([O-])[O-]
Reactant: COc1ccc([N+](=O)[O-])c(SC)c1OC
Agent: O=S([O-])S(=O)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COc1cc(N)c(SC)cc1OC

Procedure:
A reaction mixture was prepared containing 68.7 g. of 3-methylthio-4-nitroveratrole, 261 g. sodium dithionite (Na2S2O4), 1500 ml. of ethanol and 2250 ml. of water. The reaction mixture was heated at reflux temperature for about 1 hour and then cooled. The reaction mixture was then made basic with potassium carbonate and the resulting alkaline solution concentrated in vacuo to one-half its original volume. The aqueous solution was extracted twice with 2 l. portions of ether. The ether extracts were combined, dried, and the ether removed therefrom by evaporation in vacuo. The solid residue, comprising 2-methylthio-4,5-dimethoxy aniline formed in the above reaction, was recrystallized from a benzene-hexane solvent mixture to yield 33.6 g. of crystalline material melting at 69°-72° C.
Reaction SMILES: C1[C:6]([C:7]([OH:9])=[O:8])=[CH:5][C:4]2C([O:12][C:13](=[O:14])[C:3]=2C=1)=O.C(C1C=CC=CC=1)(=O)C>>[C:13]([OH:14])(=[O:12])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8]
Reactant: O=C(O)c1ccc2c(c1)C(=O)OC2=O
Solvent: CC(=O)c1ccccc1
Product: O=C(O)CCCCC(=O)O
Yield: 49.1 %

Procedure:
A solution is formed by mixing 128.6 grams of trimellitic acid anhydride and 257.5 grams of p,p' diphenyl methane diisocyanate and 109.0 grams of acetophenone by heating the mixture. At approximately 135°C. a clear homogeneous solution is obtained. Once clarity is obtained 48.0 grams of adipic acid are added slowly. The temperature of the mixture is raised to approximately 180°C. and slow reflux is maintained. After approximately 60 minutes, a yellow viscous resin is obtained and 530.5 grams of cresylic acid and 530.5 grams of phenol, previously mixed, (1061.0 grams in total) are added to quench and stop the reaction. The solution is maintained at 135°C. until all the resin is dissolved. The resultant solution is cooled to room temperature and filtered. The viscosity of the product at 25°C. was measured at about 3000 cps, utilizing a Brookfield viscometer, and a resin solution of approximately 25% weight resin.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:32])[CH2:10][CH2:11][N:12]1[C:16]2([CH2:21][CH2:20][C:19](=[CH:22][CH2:23][CH:24]([CH3:26])[CH3:25])[CH2:18][CH2:17]2)[S:15][CH:14]([CH2:27]C(O)=O)[C:13]1=[O:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)(Cl)=O.O.[C:38]([OH:41])(=[O:40])[CH3:39]>C(Cl)Cl.C(OCC)(=O)C>[CH2:1]([O:8][C:9](=[O:32])[CH2:10][CH2:11][N:12]1[C:16]2([CH2:17][CH2:18][C:19](=[CH:22][CH2:23][CH:24]([CH3:26])[CH3:25])[CH2:20][CH2:21]2)[S:15][CH:14]([CH2:27][CH2:39][C:38]([OH:41])=[O:40])[C:13]1=[O:31])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)CC=C1CCC2(CC1)SC(CC(=O)O)C(=O)N2CCC(=O)OCc1ccccc1
Reactant: CC(=O)O
Solvent: O=S(Cl)Cl
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)CC=C1CCC2(CC1)SC(CCC(=O)O)C(=O)N2CCC(=O)OCc1ccccc1
Reaction time: 1 h

Procedure:
In 10 ml of methylene chloride was dissolved 0.96 g of 2-[4-[3-(benzyloxy)-3-oxopropyl]-8-(3-methylbutylidene)-3-oxo-1-thia-4-azaspiro[4.5]decan-2-yl]-acetic acid. After adding 0.18 ml of thionyl chloride at ambient temperature, the resulting mixture was stirred for one hour under reflux. The reaction mixture was concentrated under reduced pressure, and the concentrate was dissolved in 10 ml of dioxane. The resulting solution was dropwise added at 0-5° C. to an ethyl ether solution containing diazomethane prepared from 5.00 g of N-methylnitrosourea, 3.00 g of potassium hydroxide, 4.00 ml of water and 15 ml of ethyl ether, and the resulting mixture was stirred at ambient temperature for 30 minutes. The reaction mixture was poured into a mixture of water, acetic acid and ethyl acetate, and the organic layer was separated. The organic layer thus obtained was washed successively with water, saturated aqueous solution of sodium hydrogen carbonate and saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was dissolved in a mixture of 10 ml dioxane and 10 ml water, and the resulting solution was added to a mixture of 0.16 g of silver benzoate and 3.00 ml of triethylamine at ambient temperature and stirred for 2 hours. The reaction mixture was poured into a mixture of water and ethyl acetate, pH was adjusted to 2.0 with 2 mol/L hydrochloric acid, and the organic layer was separated. The organic layer thus obtained was washed successively with water and saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Purification of the residue by column chromatography [eluent: chloroform:ethanol=80:1] gave 0.36 g of 3-[4-[3-(benzyloxy)-3-oxopropyl]-8-(3-methylbutylidene)-3-oxo-1-thia-4-azaspiro[4.5]decan-2-yl]-propionic acid as a light yellow oily product.
Reaction SMILES: [OH-].[Zr+4:2].[OH-].[OH-].[OH-].[Zr].[P:7](=[O:11])([OH:10])([OH:9])[OH:8].[P]>O>[P:7]([O-:11])([O-:10])([O-:9])=[O:8].[Zr+4:2].[P:7]([O-:11])([O-:10])([O-:9])=[O:8].[P:7]([O-:11])([O-:10])([O-:9])=[O:8].[P:7]([O-:11])([O-:10])([O-:9])=[O:8].[Zr+4:2].[Zr+4:2]
Reactant: O=P(O)(O)O
Agent: [Zr+4]
Agent: [Zr]
Agent: [OH-]
Solvent: O
Product: O=P([O-])([O-])[O-]
Temperature: 80 °C
Reaction time: 2 h

Procedure:
Catalyst preparation. A zirconium phosphate based catalyst was prepared by a co-precipitation method. A solution of zirconium hydroxide (Zr(OH)4) as a zirconium precursor was dissolved in deionized water. To this solution, a stoichiometric amount of phosphoric acid as a phosphorus precursor was added. The resulting mixture was heated at 80° C. for 2 hours to remove water, and a paste was obtained. The resulting paste was then dried in an oven at 100° C. overnight (about 12-18 hours) to remove the bulk of any remaining water, and to provide a powder. The powder was then calcined at 350° C. for 2 hours to obtain powdered zirconium phosphate.