Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:23]=[CH:22][CH:21]=[CH:20][C:3]=1[CH2:4][N:5]1[C:10]2[N:11]=[C:12](S(C)(=O)=O)[N:13]=[CH:14][C:9]=2[CH:8]=[CH:7][C:6]1=[O:19].[CH3:24][N:25]1[CH2:30][CH2:29][N:28]([C:31]2[CH:37]=[CH:36][C:34]([NH2:35])=[CH:33][CH:32]=2)[CH2:27][CH2:26]1>ClCCl>[Br:1][C:2]1[CH:23]=[CH:22][CH:21]=[CH:20][C:3]=1[CH2:4][N:5]1[C:10]2[N:11]=[C:12]([NH:35][C:34]3[CH:33]=[CH:32][C:31]([N:28]4[CH2:27][CH2:26][N:25]([CH3:24])[CH2:30][CH2:29]4)=[CH:37][CH:36]=3)[N:13]=[CH:14][C:9]=2[CH:8]=[CH:7][C:6]1=[O:19]
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Reactant: CS(=O)(=O)c1ncc2ccc(=O)n(Cc3ccccc3Br)c2n1
Solvent: ClCCl
Product: CN1CCN(c2ccc(Nc3ncc4ccc(=O)n(Cc5ccccc5Br)c4n3)cc2)CC1
Yield: 9.3 %

Procedure:
8-(2-bromobenzyl)-2-(methylsulfonyl)pyrido[2,3-d]pyrimidin-7(8H)-one (0.17 g, 0.43 mmol) and 4-(4-methylpiperazino)aniline (0.08 g, 0.43 mmol) were stirred at 140° C. for 4 h. The reaction mixture was dissolved in dichloromethane (20 mL) and washed with 10% sodium hydroxide solution (1×10 mL) then with water (1×10 mL). The organic layer was dried over sodium sulfate, filtered and evaporated. The residue was purified by silica gel column chromatography using dichloromethane:methanol (95:5) and the product was recrystallized from isopropanol to give the title compound (19 mg, 0.04 mmol, 9.3%). ESMS m/z 505 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 8.53 (s, 1H), 7.64 (dd, J=7.7, 1.4 Hz, 1H), 7.61 (d, J=9.3 Hz, 1H), 7.06-7.25 (m, 5H), 6.82 (d, J=8.8 Hz, 2H), 6.66 (br. s., 1H), 6.54 (d, J=9.3 Hz, 1H), 5.59 (s, 2H), 3.14-3.21 (m, 4H), 2.55-2.63 (m, 4H), 2.36 (s, 3H).
Reaction SMILES: [NH2:1][CH:2]([C:26]([OH:28])=[O:27])[CH2:3][CH2:4][CH2:5][C:6]([NH:8][CH:9]1[C:24](=[O:25])[N:11]2[C:12]([C:21]([OH:23])=[O:22])=[C:13]([CH2:16][O:17][C:18](=[O:20])[NH2:19])[CH2:14][S:15][C@H:10]12)=[O:7].C(N1[C:38](=[O:39])[C:37]2=[CH:40][CH:41]=[CH:42][CH:43]=[C:36]2[C:35]1=[O:44])(OCC)=O.P(=O)(O)(O)O>P([O-])([O-])(O)=O.[K+].[K+].CC(C)=O.O>[C:35]1(=[O:44])[N:1]([CH:2]([C:26]([OH:28])=[O:27])[CH2:3][CH2:4][CH2:5][C:6]([NH:8][CH:9]2[C:24](=[O:25])[N:11]3[C:12]([C:21]([OH:23])=[O:22])=[C:13]([CH2:16][O:17][C:18](=[O:20])[NH2:19])[CH2:14][S:15][C@H:10]23)=[O:7])[C:38](=[O:39])[C:37]2=[CH:40][CH:41]=[CH:42][CH:43]=[C:36]12
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Reactant: NC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)CCCC(N)C(=O)O)[C@H]2SC1
Agent: O=P(O)(O)O
Agent: O=P([O-])([O-])O
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: NC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)CCCC(C(=O)O)N3C(=O)c4ccccc4C3=O)[C@H]2SC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 15 grams of 7-(5-amino-5-carboxyvaleramido)-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid in 150 milliliters of 10 percent potassium hydrogen phosphate buffer solution (adjusted to pH 9.1 by addition of 25 percent potassium phosphate solution) was added 9.9 grams of N-carbethoxy phthalimide in 75 milliliters of acetone. The reaction mixture was stirred at room temperature for one hour at pH 9.1, diluted with water to 300 milliliters, and the pH adjusted to 7.0 by addition of phosphoric acid. The acetone was then evaporated and the reaction mixture extracted with ethyl acetate:ethanol (88:12) to remove the phthalimide. The pH of the aqueous layers was adjusted to 2 by addition of phosphoric acid and the mixture extracted with ethyl acetate:ethanol (88:12). The extract was dried with anhydrous magnesium sulfate and filtered, and the filtrate evaporated to dryness, leaving as a residue the desired 7-(5-phthalimido-5-carboxyvaleramido)-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid as a foam. It was digested three times with 500-milliliter aliquots of ether. The ether washed product amounted to 17.05 grams.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]2[C:8]3[CH2:14][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:12][CH2:11][C:9]=3[N:10]=[C:4]2[CH:3]=1.[CH2:22]([O:29][C:30]1[CH:35]=[CH:34][NH:33][C:32](=[O:36])[CH:31]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH2:22]([O:29][C:30]1[CH:35]=[CH:34][N:33]([C:2]2[CH:7]=[CH:6][N:5]3[C:8]4[CH2:14][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:12][CH2:11][C:9]=4[N:10]=[C:4]3[CH:3]=2)[C:32](=[O:36])[CH:31]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: O=c1cc(OCc2ccccc2)cc[nH]1
Reactant: CC(C)(C)OC(=O)N1CCc2nc3cc(Br)ccn3c2C1
Product: CC(C)(C)OC(=O)N1CCc2nc3cc(-n4ccc(OCc5ccccc5)cc4=O)ccn3c2C1
Yield: 60.7 %

Procedure:
tert-Butyl 7-bromo-3,4-dihydropyrido[4′,3′:4,5]imidazo[1,2-a]pyridine-2(1H)-carboxylate (591 mg, 1.68 mmol) and 4-(benzyloxy)pyridin-2(1H)-one (338 mg, 1.68 mmol) were reacted according to Example 18 (step g) to provide the title compound (482 mg, 61%) as a brown solid: ESI MS m/z 473 [M+H]+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:7]([NH:11][C:12]([C:14]1[S:47][C:17]2[N:18]=[C:19]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[N:20]=[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([NH:28][C:29](OC4C=CC([N+]([O-])=O)=CC=4)=[O:30])[CH:23]=3)[C:16]=2[C:15]=1[NH2:48])=[O:13])([CH3:10])([CH3:9])[CH3:8]>ClCCl>[C:7]([NH:11][C:12]([C:14]1[S:47][C:17]2[N:18]=[C:19]([C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=3)[N:20]=[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([NH:28][C:29]([N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)=[O:30])[CH:23]=3)[C:16]=2[C:15]=1[NH2:48])=[O:13])([CH3:10])([CH3:8])[CH3:9]
Reactant: CC(C)(C)NC(=O)c1sc2nc(-c3ccccc3)nc(-c3cccc(NC(=O)Oc4ccc([N+](=O)[O-])cc4)c3)c2c1N
Reactant: C1COCCN1
Solvent: ClCCl
Product: CC(C)(C)NC(=O)c1sc2nc(-c3ccccc3)nc(-c3cccc(NC(=O)N4CCOCC4)c3)c2c1N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Morpholine (250 mg) was added to a solution of tert-butyl 5-amino-2-phenyl-4-(3-(p-nitro-phenoxycarbonylamino)-phenyl)-thieno[2,3-d]pyrimidine-6-carboxamide (example 31(h), 150 mg) in dichloromethane (5 ml) and the reaction mixture was stirred at room temperature overnight. Subsequently, the reaction mixture was diluted with CH2Cl2 and washed with H2O. The organic layer was concentrated under reduced pressure. The title compound was purified by HPLC using a Luna C-18 column with the following gradient: H2O/CH3CN=80/20 to 0/100 (v/v) in 45 min. The title compound was then lyophilized from a mixture of 1,4-dioxane and H2O.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:22]=[CH:21][C:17]([C:18](Cl)=[O:19])=[CH:16][C:15]=3[CH3:23])=[CH:7][C:6]=2[C:5]2[CH:24]=[CH:25][C:26]([CH3:28])=[CH:27][C:4]=2[N:3]=1.[NH3:29]>>[NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:22]=[CH:21][C:17]([C:18]([NH2:29])=[O:19])=[CH:16][C:15]=3[CH3:23])=[CH:7][C:6]=2[C:5]2[CH:24]=[CH:25][C:26]([CH3:28])=[CH:27][C:4]=2[N:3]=1
Reactant: Cc1ccc2c(c1)nc(N)c1ncc(CCc3ccc(C(=O)Cl)cc3C)cc12
Reactant: N
Product: Cc1ccc2c(c1)nc(N)c1ncc(CCc3ccc(C(N)=O)cc3C)cc12

Procedure:
4-(2-(5-Amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylbenzamide was prepared from 4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylbenzoyl chloride (Example 116/Step 2) and ammonia following the procedures described for Example 117. 1H NMR (CDCl3): δ 8.60 (s, 1H), 8.35 (s, 1H), 8.05 (d, 1H), 7.65 (s, 1H), 7.51-7.53 (m, 2H), 7.13-7.21 (m, 2H), 3.09-3.16 (m, 4H), 2.51 (s, 3H), 2.34 (s, 3H). LRMS [M+H]=371.2
Reaction SMILES: [Na].[CH:2]([CH:4]([CH2:7][NH:8][CH:9]=[O:10])[C:5]#[N:6])=O.[Cl-].[CH3:12][NH2+:13][CH3:14].C(Cl)(Cl)Cl>O>[CH3:12][N:13]([CH:2]=[C:4]([CH2:7][NH:8][CH:9]=[O:10])[C:5]#[N:6])[CH3:14]
Reactant: C[NH2+]C
Reactant: N#CC(C=O)CNC=O
Agent: [Cl-]
Agent: [Na]
Solvent: O
Solvent: ClC(Cl)Cl
Product: CN(C)C=C(C#N)CNC=O

Procedure:
98.6 parts of 75 percent pure sodium salt of α-formyl-β-formylaminopropionitrile and 81.5 parts of dimethylammonium chloride in 700 parts by volume of chloroform are refluxed for 1.5 hours, during which time 8.5 parts (theory: 9 parts) of water are eliminated. The mixture is filtered, the filtrate is concentrated to dryness and the product is recrystallized from methanol. 43.0 parts of α-dimethylaminomethylene-β-formylaminopropionitrile of melting point 90° C. are obtained.
Reaction SMILES: [C:1]([C:4]1[NH:5][CH:6]=[NH+:7][C:8]=1[O-:9])(=[O:3])[NH2:2].[Br:10][C:11]1[CH:19]=[CH:18][C:14]([C:15](Cl)=[O:16])=[CH:13][CH:12]=1>N1C=CC=CC=1>[Br:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([O:9][C:8]2[N:7]=[CH:6][NH:5][C:4]=2[C:1](=[O:3])[NH2:2])=[O:16])=[CH:13][CH:12]=1
Reactant: NC(=O)c1[nH]c[nH+]c1[O-]
Reactant: O=C(Cl)c1ccc(Br)cc1
Solvent: c1ccncc1
Product: NC(=O)c1[nH]cnc1OC(=O)c1ccc(Br)cc1
Reaction time: 2.5 h
Yield: 84.9 %

Procedure:
To a suspension of 5.084 g of 4-carbamoyl-imidazolium-5-olate in 104 ml of dry pyridine was added 11.41 g of p-bromobenzoyl chloride at room temperature. After addition was over, the mixture was stirred at 40°-45° C. for 2.5 hours. The separated crystals were filtered off, washed with chloroform and diisopropyl ether, dried under vacuum to give 10.535 g of 5-carbamoyl-1H-imidazol-4-yl p-bromobenzoate, m.p. 232°-233° C. (dec.)
Reaction SMILES: [F:1][CH2:2][C:3]([CH2:5][F:6])=[O:4].[F:7][C:8]1[CH:9]=[CH:10][C:11](O)=[C:12]([C:14](=[O:16])[CH3:15])[CH:13]=1.N1CCCC1>CO>[F:7][C:8]1[CH:13]=[C:12]2[C:11](=[CH:10][CH:9]=1)[O:4][C:3]([CH2:5][F:6])([CH2:2][F:1])[CH2:15][C:14]2=[O:16]
Reactant: CC(=O)c1cc(F)ccc1O
Reactant: O=C(CF)CF
Solvent: CO
Solvent: C1CCNC1
Product: O=C1CC(CF)(CF)Oc2ccc(F)cc21
Temperature: 60 °C
Yield: 67.1 %

Procedure:
A solution of 1,3-difluoroacetone (4.90 g, 52.1 mmol), MeOH (100 mL), and 1-(5-fluoro-2-hydroxyphenyl)ethanone (6.69 g, 43.4 mmol, Aldrich Chemical) was stirred at ambient temperature and pyrrolidine (4.31 mL, 52.1 mmol) was added. The reaction was heated at 60° C. for 21 hours, then concentrated and purified by silica gel chromatography (gradient elution, 0-25% EtOAc/hexanes) to provide the title compound (6.70 g, 29.1 mmol, 67%) as a brown oil. MS (DCI) m/z 248 (M+NH4)+.
Reaction SMILES: [C:1]12([NH:11][C:12]3[N:17]=[C:16](Cl)[CH:15]=[C:14]([N:19]4[CH2:23][CH2:22][CH2:21][CH2:20]4)[N:13]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[NH:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>>[C:1]12([NH:11][C:12]3[N:17]=[C:16]([N:24]4[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]4)[CH:15]=[C:14]([N:19]4[CH2:23][CH2:22][CH2:21][CH2:20]4)[N:13]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: Clc1cc(N2CCCC2)nc(NC23CC4CC(CC(C4)C2)C3)n1
Reactant: C1CNCCN1
Product: c1c(N2CCCC2)nc(NC23CC4CC(CC(C4)C2)C3)nc1N1CCNCC1
Yield: 69.7 %

Procedure:
By reacting 2-(1-adamantylamino)-4-chloro-6-pyrrolidinopyrimidine with piperazine as described in Example 4, the title compound is obtained in a yield of 69.7%, m.p.: 160°-164° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([Cl:10])=[CH:4][C:3]=1[CH2:11]Br.[C-:13]#[N:14].[Na+]>O.CO>[Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([Cl:10])=[CH:4][C:3]=1[CH2:11][C:13]#[N:14]
Reactant: [C-]#N
Reactant: COc1cc(Cl)cc(CBr)c1Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1cc(Cl)cc(CC#N)c1Cl
Yield: 97.4 %

Procedure:
By the method of Example 1, Step C, 15.40 grams (0.057 mole) of 2,5-dichloro-3-methoxyphenylmethyl bromide and 3.63 grams (0.074 mole ) of sodium cyanide were reacted in 70 mL of water and 65 mL of methanol, yielding 12.0 g of 2,5-dichloro-3-methoxyphenylacetonitrile as an oil that solidified on standing, m.p. 53°-57° C. The NMR and IR spectra were consistent with the proposed structure.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([S:8][C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)[CH:5]=[CH:4][C:3]=1[N+:16]([O-])=O.Cl.C(O)(=O)C.C(=O)(O)[O-].[K+]>C(Cl)(Cl)Cl>[NH2:16][C:3]1[CH:4]=[CH:5][C:6]([S:8][C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)=[CH:7][C:2]=1[NH2:1]
Reactant: Cc1ccc(Sc2ccc([N+](=O)[O-])c(N)c2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [K+]
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: Cc1ccc(Sc2ccc(N)c(N)c2)cc1

Procedure:
3.5 G. of 2-amino-4-(p-methylphenylthio)-1-nitrobenzene in 8 ml. concentrated hydrochloric acid is treated with a solution of 16 g. stannous chloride in 8 ml. concentrated hydrochloric acid in 20 ml. acetic acid. The mixture is heated for 1 hour on a steam bath, cooled and treated with potassium bicarbonate and chloroform. The mixture is filtered and the chloroform layer evaporated. The residue is triturated with hot cyclohexane giving 1,2-diamino-4-(p-methylphenylthio)-benzene.
Reaction SMILES: [OH:1][CH:2]([CH3:15])[CH2:3][C:4]([CH:6]1[C:11]([CH3:13])([CH3:12])[CH2:10][CH:9]=[CH:8][CH:7]1[CH3:14])=[O:5].N1C=CC=CC=1.Cl[C:23]([O:25][CH2:26][CH3:27])=[O:24].Cl>>[C:23](=[O:24])([O:1][CH:2]([CH3:15])[CH2:3][C:4](=[O:5])[C@@H:6]1[C:11]([CH3:13])([CH3:12])[CH2:10][CH:9]=[CH:8][C@H:7]1[CH3:14])[O:25][CH2:26][CH3:27]
Reactant: CCOC(=O)Cl
Reactant: CC(O)CC(=O)C1C(C)C=CCC1(C)C
Agent: Cl
Solvent: c1ccncc1
Product: CCOC(=O)OC(C)CC(=O)[C@H]1[C@H](C)C=CCC1(C)C
Temperature: 25 °C
Reaction time: 36 h

Procedure:
A solution of 3-hydroxy-1-(2,6,6-trimethyl-3-cyclohexen-1-yl)-1-butanone (2.00 g, 84% pure, 8.0 mmol) in pyridine (1.85 g, 23.4 mmol) was treated at 0° C. with ethyl chloroformate (1.24 g, 23.4 mmol). The reaction solution was stirred at room temperature for 36 hours, treated with aqueous 5% HCl and extracted twice with ether, washed with water, saturated aqueous NaHCO3, then with saturated aqueous NaCl, dried over Na2SO4 and concentrated. The oil thus obtained was purified by flash-chromatography (cyclohexane/AcOEt=98:2), using SiO2 (100 g). Yield: 2.06 g (78%).
Reaction SMILES: [C:1]([C:4]1([OH:13])[CH:12]=[CH:11][CH:10]=[CH:9][CH:5]1[C:6]([OH:8])=[O:7])(=[O:3])[CH3:2].C(N(CC)CC)C.Br[CH:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:24](=[O:25])[O:23]1>CC(C)=O>[C:1]([C:4]1([OH:13])[CH:12]=[CH:11][CH:10]=[CH:9][CH:5]1[C:6]([O:8][CH:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:24](=[O:25])[O:23]1)=[O:7])(=[O:3])[CH3:2]
Reactant: O=C1OC(Br)c2ccccc21
Reactant: CC(=O)C1(O)C=CC=CC1C(=O)O
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: CC(=O)C1(O)C=CC=CC1C(=O)OC1OC(=O)c2ccccc21
Temperature: 25 °C
Yield: 84.4 %

Procedure:
o-Acetylsalicylic acid (18 g) and triethylamine (21 ml) were stirred at a temperature of 20°-25° C. for 30 minutes in 500 ml of acetone. When dissolution was completed, 3-bromophthalide (32 g) was added and the mixture refluxed 2 hours. The reaction mixture was then cooled to 20°-25° C. and poured into distilled water (500 ml). The resulting mixture was extracted with 200 ml of dichloromethane twice, discarding the acetone layer. After the organic solution was washed with 200 ml portions of distilled water twice, 5 g of anhydrous sodium sulfate were added and the mixture filtered. After filtration the organic filtrate was evaporated, the residue was taken up with previously warmed methanol. Decolorizing carbon (1 g) and filtering aid (1 g) were added. The methanolic solution was filtered, and the filtrate was cooled, first to room temperature, and subsequently in an ice/water bath. The solid precipitate was collected by filtration, and dried under vacuum at 40° C. to obtain a yield (83.9%; 26.2 g) of crude phthalidyl o-acetylsalicylate (m.p. 85° C.-88° C.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([S:13]([CH3:15])=[O:14])=[CH:9][C:4]=1[C:5]([O:7]C)=[O:6].[OH-].[K+].Cl>ClCCl>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([S:13]([CH3:15])=[O:14])=[CH:9][C:4]=1[C:5]([OH:7])=[O:6]
Reactant: COC(=O)c1cc(S(C)=O)ccc1OC
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Product: COc1ccc(S(C)=O)cc1C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Combine methyl 2-methoxy-5-methylsulfinylbenzoate (2.37 g, 12.0 mmol) and a 1 M aqueous solution of potassium hydroxide (13 mL, 13 mmol). Heat to reflux. After 2 hours, cool to ambient temperature and adjust the pH to about 2 using a 1 M aqueous hydrochloric acid (14.5 mL, 14.5 mmol. Evaporate in vacuo to give a solid. Combine the solid and dichloromethane and stir. Decant the solvent and add more dichloromethane. Again decant and combine with the first decantate, dry over Na2SO4, filter, and evaporate in vacuo to to give the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:44])[CH:5]([CH2:11][C:12]([F:43])([F:42])[CH2:13][C@H:14]([C@@H:16]1[C@:33]2([CH3:34])[C@H:19]([C@H:20]3[C@H:30]([CH2:31][CH2:32]2)[C@:28]2([CH3:29])[C:23]([CH2:24][C@@H:25]([O:35][CH:36]4[CH2:41][CH2:40][CH2:39][CH2:38][O:37]4)[CH2:26][CH2:27]2)=[CH:22][CH2:21]3)[CH2:18][CH2:17]1)[CH3:15])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].[H-].[Na+].[Cl:47]N1C(=O)CCC1=O>C(COC)OC>[CH2:1]([O:3][C:4](=[O:44])[C:5]([Cl:47])([CH2:11][C:12]([F:42])([F:43])[CH2:13][C@H:14]([C@@H:16]1[C@:33]2([CH3:34])[C@H:19]([C@H:20]3[C@H:30]([CH2:31][CH2:32]2)[C@:28]2([CH3:29])[C:23]([CH2:24][C@@H:25]([O:35][CH:36]4[CH2:41][CH2:40][CH2:39][CH2:38][O:37]4)[CH2:26][CH2:27]2)=[CH:22][CH2:21]3)[CH2:18][CH2:17]1)[CH3:15])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2]
Reactant: CCOC(=O)C(CC(F)(F)C[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OC5CCCCO5)CC[C@]4(C)[C@H]3CC[C@]12C)C(=O)OCC
Reactant: O=C1CCC(=O)N1Cl
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CCOC(=O)C(Cl)(CC(F)(F)C[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OC5CCCCO5)CC[C@]4(C)[C@H]3CC[C@]12C)C(=O)OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.7 %

Procedure:
The diester (9) (700 mg, 1.125 mmol) was treated with sodium hydride (39 mg, 1.625 mmol) in dimethoxyethane (20 ml) at room temperature under argon atmosphere for 1 hr. Then, to this solution N-chlorosuccinimide (180 mg, 1.35 mmol) was added and the mixture was stirred at room temperature for 1 hr. The usual work-up (ether for extraction) gave a crude product, which was applied to a column of silica gel (20 g). Elution with n-hexane-ether (10:1) provided tthe chlorodiester (10) (730 mg, 99%), glass. 1H-NMR: 0.72 (3H, s, 18-H3), 1.02 (3H, s, 19-H3), 1.10 (3H, d, J=6 Hz, 21-H3), 1.30 (6H, t, J=7.5 Hz, --CO2CH2CH3), 2.95 (2H, t, J=15 Hz, 24-H2), 3.52 (2H, m, THP), 3.88 (1H, m, 3-H), 4.32 (4H, q, J=7.5 Hz, --CO2CO2CH3), 4.72 (1H, m. THP), 5.38 (1H, m, 6-H). MS m/z: 554, 520.
Reaction SMILES: [H-].[Na+].[C:3]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])(=[O:9])[CH2:4][C:5]([O:7][CH3:8])=[O:6].Cl[C:16]1[N:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][C:17]=1[C:18]#[N:19]>C1COCC1>[C:18]([C:17]1[C:16]([CH:4]([C:5]([O:7][CH3:8])=[O:6])[C:3]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=[N:23][CH:22]=[C:21]([C:24]([F:27])([F:25])[F:26])[CH:20]=1)#[N:19]
Reactant: COC(=O)CC(=O)OC(C)(C)C
Reactant: N#Cc1cc(C(F)(F)F)cnc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)C(C(=O)OC(C)(C)C)c1ncc(C(F)(F)F)cc1C#N
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.1 %

Procedure:
To a suspension of sodium hydride (0.752 g, 29.8 mmol) in THF (18 mL) under nitrogen was added dropwise a solution of tert-butyl methyl malonate (3.18 mL, 17.9 mmol) in dry THF (15 mL) via syringe during a period of 15 min. The reaction mixture was stirred for 30 min before a solution of 2-chloro-5-(trifluoromethyl)nicotinonitrile (4.0 g, 14.5 mmol) in THF (30 mL) was added slowly. After being stirred at room temperature overnight, the reaction mixture was quenched with aqueous NH4Cl. THF was removed in vacuo and the aqueous solution was extracted with EtOAc three times. The combined organic layers were dried over MgSO4, filtered, and evaporated in vacuo. The crude brown product (7.1 g) was purified by flash chromatography (10:90 EtOAc/hexanes) to afford 4.20 g (84%) of desired product as a yellow oil. LC-MS calculated for C15H15F3N2O4: (M+H)+345; found 245.0 (M−CO2tBu+H+1)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:33])=[C:5]([C:24]([O:31][CH3:32])=[C:25]([O:29][CH3:30])[C:26]=1[O:27][CH3:28])[CH2:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[C:9]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:8]=1.[CH3:34][Si](C=[N+]=[N-])(C)C.C(O)(=O)C>CO>[CH3:1][O:2][C:3]1[C:4]([CH3:33])=[C:5]([C:24]([O:31][CH3:32])=[C:25]([O:29][CH3:30])[C:26]=1[O:27][CH3:28])[CH2:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([O:13][CH3:34])=[O:12])=[C:9]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:8]=1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: COc1c(C)c(Cc2ccc(C(=O)O)c(OCc3ccccc3)c2)c(OC)c(OC)c1OC
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)c1ccc(Cc2c(C)c(OC)c(OC)c(OC)c2OC)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.9 %

Procedure:
4-(3,4,5,6-Tetramethoxy-2-methylbenzyl)-2-benzyloxybenzoic acid (525 mg, 1.1615 mmol) was dissolved in methanol (20 ml), trimethylsilyl diazomethane (15.9 g, 10% solution in hexane, 13.9473 mmol) was added thereto under cooling with ice and the mixture was stirred at room temperature for 2 hours. To the reaction solution was added acetic acid (2 ml) and the mixture was allowed to stand so as to decompose an excessive reagent. The reaction solution was concentrated to give the title compound (530 mg, 1.1373 mmol, 98%).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]([C:16](=[O:18])[CH3:17])[CH:9]=[CH:10][C:11]=2[O:12][CH:13]([F:15])[F:14])[CH2:3][CH2:2]1.CO[CH:21](OC)[N:22]([CH3:24])[CH3:23]>C1(C)C=CC=CC=1>[CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]([C:16](=[O:18])[CH:17]=[CH:21][N:22]([CH3:24])[CH3:23])[CH:9]=[CH:10][C:11]=2[O:12][CH:13]([F:15])[F:14])[CH2:3][CH2:2]1
Reactant: COC(OC)N(C)C
Reactant: CC(=O)c1ccc(OC(F)F)c(OCC2CC2)c1
Solvent: Cc1ccccc1
Product: CN(C)C=CC(=O)c1ccc(OC(F)F)c(OCC2CC2)c1
Yield: 90.6 %

Procedure:
In toluene, dissolved were 1-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl]ethanone (10 g, 39 mmol) and DMFDMA (N,N-dimethyl formamide dimethyl acetal) (13.9 g, 117 mmol), and the mixture was heated under reflux. The reaction mixture was extracted with EA, and the extract was washed twice with brine, dried over MgSO4, filtered and evaporated under reduced pressure to remove solvent. The mixture was purified via column chromatography (MC/MeOH=10/1) to obtain 1-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl]-3-(dimethylamino)prop-2-en-1-one (11 g, 92%).
Reaction SMILES: C(O)=O.C([O:11][CH2:12][C:13]1[C:21]2[C:20](=[O:22])[NH:19][C:18]([C:23]3[C:24]([O:40][CH2:41][CH3:42])=[N:25][CH:26]=[C:27]([S:29]([N:32]4[CH2:37][CH2:36][N:35]([CH2:38][CH3:39])[CH2:34][CH2:33]4)(=[O:31])=[O:30])[CH:28]=3)=[N:17][C:16]=2[N:15]([CH2:43][CH3:44])[N:14]=1)C1C=CC=CC=1>[Pd].C(OCC)(=O)C>[CH2:41]([O:40][C:24]1[C:23]([C:18]2[NH:19][C:20](=[O:22])[C:21]3[C:13]([CH2:12][OH:11])=[N:14][N:15]([CH2:43][CH3:44])[C:16]=3[N:17]=2)=[CH:28][C:27]([S:29]([N:32]2[CH2:33][CH2:34][N:35]([CH2:38][CH3:39])[CH2:36][CH2:37]2)(=[O:31])=[O:30])=[CH:26][N:25]=1)[CH3:42]
Reactant: CCOc1ncc(S(=O)(=O)N2CCN(CC)CC2)cc1-c1nc2c(c(COCc3ccccc3)nn2CC)c(=O)[nH]1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: O=CO
Product: CCOc1ncc(S(=O)(=O)N2CCN(CC)CC2)cc1-c1nc2c(c(CO)nn2CC)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 24 h
Yield: 58.7 %

Procedure:
Formic acid (1.5 ml) was added to a mixture of the title compound of example 23 (750 mg, 1.3 mmol) and 10% palladium on charcoal (750 mg) in ethyl acetate (15 ml), and the reaction stirred under a nitrogen atmosphere at room temperature for 24 hours. The reaction mixture was filtered through Arbocel, the filter pad washed with water (30 ml) and ethyl acetate (30 ml), and the filtrate basified using 2N sodium hydroxide solution. The layers were separated, the aqueous extracted with dichloromethane (3×100 ml), and the combined organic solutions dried (MgSO4) and evaporated under reduced pressure. The residue was triturated with ether, to afford the title compound as a white solid, (375 mg).
Reaction SMILES: [CH3:1][NH:2][CH3:3].[Cl:4][C:5]1[CH:20]=[C:19]([N:21]=[C:22]=[O:23])[CH:18]=[CH:17][C:6]=1[O:7][C:8]1[CH:9]=[CH:10][C:11]2[S:15][N:14]=[CH:13][C:12]=2[CH:16]=1>C(OCC)C>[Cl:4][C:5]1[CH:20]=[C:19]([NH:21][C:22]([N:2]([CH3:3])[CH3:1])=[O:23])[CH:18]=[CH:17][C:6]=1[O:7][C:8]1[CH:9]=[CH:10][C:11]2[S:15][N:14]=[CH:13][C:12]=2[CH:16]=1
Reactant: CNC
Reactant: O=C=Nc1ccc(Oc2ccc3sncc3c2)c(Cl)c1
Solvent: CCOCC
Product: CN(C)C(=O)Nc1ccc(Oc2ccc3sncc3c2)c(Cl)c1
Reaction time: 12 h
Yield: 70 %

Procedure:
5 parts of gaseous dimethylamine were passed into 30.3 parts of 5-(2'-chloro-4'-isocyanatophenoxy)-benzisothiazole and 300 parts of diethyl ether at from 20° to 30° C., the mixture was stirred for 12 hours at this temperature and the resulting precipitate was then isolated and dried. 27.5 parts (70% of theory) of 5-(2'-chloro-4'-dimethylaminocarbonylaminophenoxy)-benzisothiazole of melting point 149° C. were obtained.