Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.[OH-].[Na+].C([O:6][C:7]([C:9]1[CH:10]=[N:11][N:12]([C:15]2[C:20]([Cl:21])=[CH:19][C:18]([CH:22]3[CH2:24][CH2:23]3)=[CH:17][N:16]=2)[C:13]=1[CH3:14])=[O:8])C.Cl>C(O)C>[Cl:21][C:20]1[C:15]([N:12]2[C:13]([CH3:14])=[C:9]([C:7]([OH:8])=[O:6])[CH:10]=[N:11]2)=[N:16][CH:17]=[C:18]([CH:22]2[CH2:23][CH2:24]2)[CH:19]=1
Reactant: CCOC(=O)c1cnn(-c2ncc(C3CC3)cc2Cl)c1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1c(C(=O)O)cnn1-c1ncc(C2CC2)cc1Cl
Temperature: 90 °C
Reaction time: 6 h
Yield: 72 %

Procedure:
Water (2 ml) and 4N aqueous solution of sodium hydroxide (2 ml) were added to a solution of 1-(3-chloro-5-cyclopropylpyridin-2-yl)-5-methyl-1H-pyrazole-4-carboxylic acid ethyl ester (240 mg) in ethanol (4 ml) at room temperature, and stirred at 90° C. for six hours. After completion of the reaction, the reaction solution was cooled to 0° C. and 1N hydrochloric acid aqueous solution (9 ml) was added. The precipitated solid was collected by filtration to give the titled compound (157 mg) as a light brown solid.
Reaction SMILES: [CH2:1]([CH:3]1[O:5][CH2:4]1)Cl.[CH3:6][C:7]1[CH:14]=[C:13](O)[CH:12]=[CH:11][C:8]=1[CH:9]=[O:10]>[OH-].[Na+]>[CH3:6][C:7]1[CH:14]=[C:13]([CH2:1][CH:3]2[O:5][CH2:4]2)[CH:12]=[CH:11][C:8]=1[CH:9]=[O:10]
Reactant: Cc1cc(O)ccc1C=O
Reactant: ClCC1CO1
Agent: [Na+]
Agent: [OH-]
Product: Cc1cc(CC2CO2)ccc1C=O
Temperature: 55 °C
Reaction time: 3 h
Yield: 71.4 %

Procedure:
To epichlorohydrin (20 g., 0.216 mole) heated at 55° C. is added dropwise a solution of 2-methyl-4-hydroxybenzaldehyde (9.0 g., 0.066 mole) in 2.5N sodium hydroxide solution (40 ml.). After the addition, the solution is allowed to stir an additional 3 hours at 55° C. and then at room temperature overnight. The oil is distilled to give 8.3 g of 2-methyl-4-(2,3-epoxypropyl)benzaldehyde, m.p. 160°-170° C. at 1 mm. Hg.
Reaction SMILES: O.[CH3:2][N:3]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:5]([CH2:6][C@@H:7]([C:9]([OH:11])=[O:10])[NH2:8])=[CH:4]1.C(=O)([O-])O.[Na+].[C:23]([C:25](=[CH:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[F:43])[C:26](ON1C(=O)CCC1=O)=[O:27])#[N:24]>O1CCOCC1>[C:23]([C:25](=[CH:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[F:43])[C:26]([NH:8][C@H:7]([C:9]([OH:11])=[O:10])[CH2:6][C:5]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:3]([CH3:2])[CH:4]=1)=[O:27])#[N:24]
Reactant: N#CC(=Cc1ccccc1F)C(=O)ON1C(=O)CCC1=O
Reactant: Cn1cc(C[C@H](N)C(=O)O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Cn1cc(C[C@H](NC(=O)C(C#N)=Cc2ccccc2F)C(=O)O)c2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 16.7 %

Procedure:
To water (60 mL)-dioxane (60 mL) suspension of 1-methyl-L-tryptophan (2.1 g) was added sodium hydrogencarbonate (0.8 g) at 0° C., and the mixture was stirred for 30 minutes at room temperature. Dioxane (80 mL) solution of the compound obtained in Example 120 (2.6 g, 9.2 mmol) was added dropwise to the reaction mixture at 0° C., and the mixture was stirred for 21 hours at room temperature. The reaction mixture was concentrated to a ⅓ volume under a reduced pressure, water was added thereto, and the mixture was washed with diethyl ether. The aqueous layer was made acidic with a 10% aqueous citric acid solution, and thereafter extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, and thereafter dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under a reduced pressure was purified with silica gel chromatography (BW-127ZH, chloroform:methanol=50:1), to give the captioned compound (0.6 g, 17%) as an amorphous solid product.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7](=[O:20])[N:8]([CH2:12][CH2:13][N:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)[CH2:9][CH2:10][CH2:11][C:5]=2[NH:4][C:3]=1[CH:21]=O.[F:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[NH:29][C:28](=[O:33])[CH2:27]2.N1CCCCC1>C(O)C>[F:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[NH:29][C:28](=[O:33])/[C:27]/2=[CH:21]\[C:3]1[NH:4][C:5]2[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][CH2:13][N:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)[C:7](=[O:20])[C:6]=2[C:2]=1[CH3:1]
Reactant: O=C1Cc2cc(F)ccc2N1
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN1CCCCC1)CCC2
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1c(/C=C2\C(=O)Nc3ccc(F)cc32)[nH]c2c1C(=O)N(CCN1CCCCC1)CCC2
Temperature: 25 °C
Yield: 58034.5 %

Procedure:
3-Methyl-4-oxo-5-(2-piperidin-1-yl-ethyl)-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-carbaldehyde 32d (50 mg, 0.165 mmol) and 5-fluoro-1,3-dihydro-indol-2-one (22.4 mg, 0.15 mmol) were dissolved in 0.3 ml of ethanol under stirring, and added with piperidine (0.05 ml, 0.5 mmol) to the solution at room temperature. Upon completion of the addition, the mixture was stirred at 40˜50° C. in an oil bath for 5 hours. After thin lay chromatography showed the disappearance of starting materials, the reaction mixture was filtered to obtain yellow solid. The solid was dissolved in ethanol (2 ml), heated to reflux for 30 minutes, cooled down to room temperature and filtered to obtain the title compound (Z)-2-(5-fluoro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-3-methyl-5-(2-piperidin-1-yl-ethyl)-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-c]azepin-4-one 32 (38 g, yield 58%) as a yellow solid.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[CH:9][C:10]3[O:14][C:13](=S)[NH:12][C:11]=3[CH:16]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:18]>P(Cl)(Cl)(Cl)=O>[Cl:18][C:13]1[O:14][C:10]2[CH:9]=[CH:8][C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[CH:16][C:11]=2[N:12]=1
Reactant: S=c1[nH]c2cc(-c3ccccc3)ccc2o1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: Clc1nc2cc(-c3ccccc3)ccc2o1
Temperature: 25 °C
Reaction time: 3 h
Yield: 640.1 %

Procedure:
5-Phenyl-3H-benzooxazole-2thione (227 mg, 1.0 mmol) was dissolved in phosphorus oxychloride (1.6 mL). Phosphorus pentachloride (208 mg, 1.0 mmol) was added and the mixture was placed in an oil bath at 100° C. for 3 h. The mixture was allowed to cool to RT and concentrated. The crude residue was concentrated from CH2Cl2 (3×). The crude reaction product was triturated with hexanes (40 mL), and the resulting solids were collected by filtration. The solids were washed with hexanes (20 mL×3) and dried to afford 1.47 g (73%) of the title compound: 1H NMR (CDCl3, 400 MHz) δ 7.86 (d, 1H, J=1.3 Hz), 7.60-7.56 (m, 3H), 7.55-7.52 (m, 1H), 7.49-7.44 (m, 2H), 7.40-7.36 (m, 1H), 13C NMR (CDCl3, 100 MHz) δ 151.6, 151.4, 141.9, 140.7, 139.3, 129.2, 127.8, 127.7, 125.2, 118.4, 110.7; MS (Cl) m/z 230.1 (M+1); HPLC retention time=5.41 min.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[O:8][CH3:9])(=O)[CH3:2].BrC1C=[CH:25][C:17]([C:18]([N:20]([CH2:23][CH3:24])[CH2:21][CH3:22])=[O:19])=[CH:16][CH:15]=1.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl.[Cu]I>[CH2:23]([N:20]([CH2:21][CH3:22])[C:18](=[O:19])[C:17]1[CH:16]=[CH:15][C:1]([NH:4][C:5]2[CH:12]=[CH:11][CH:10]=[C:7]([O:8][CH3:9])[CH:6]=2)=[CH:2][CH:25]=1)[CH3:24]
Reactant: COc1cccc(NC(C)=O)c1
Reactant: CCN(CC)C(=O)c1ccc(Br)cc1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CCN(CC)C(=O)c1ccc(Nc2cccc(OC)c2)cc1
Temperature: 250 °C
Yield: 437.1 %

Procedure:
3.7 g (2.3 mmol) of N-acetyl-m-anisidine, 10.6 g (41.4 mmol) of 4-bromo-N,N-diethylbenzamide and 0.42 g of CuI were heated to 1000° C.; 3 g (22.3 mmol) of K2CO3 were added and the resulting mixture was heated to 250° C. for 2 hours. The residue was dissolved in CH2Cl2 and washed with H2O, the organic layer was dried over Na2SO4 and the solvent was removed in vacuo. The resulting residue was dissolved in 20 ml of absolute EtOH and refluxed for 2 h. The solvent was removed in vacuo, the residue was taken up in H2O and the aqueous layer extracted with AcOEt. The organic layer was dried over Na2SO4 and the solvent removed in vacuo. The resulting residue was purified by flash chromatography (AcOEt/Hexane 6:4), yielding 3 g of the title compound.
Reaction SMILES: [CH2:1]([S:3][C@@H:4]1[NH:7][C:6](=[O:8])[C@H:5]1[NH:9][C:10](=[O:19])[CH2:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH3:2].OO.O.C(OCC)(=[O:25])C>CO>[CH2:1]([S:3]([C@@H:4]1[NH:7][C:6](=[O:8])[C@H:5]1[NH:9][C:10](=[O:19])[CH2:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:25])[CH3:2]
Reactant: CCOC(C)=O
Reactant: CCS[C@@H]1NC(=O)[C@H]1NC(=O)COc1ccccc1
Agent: OO
Solvent: CO
Solvent: O
Product: CCS(=O)[C@@H]1NC(=O)[C@H]1NC(=O)COc1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 0.224 g of (3R,4S)-4-ethylthio-3-phenoxyacetamido-2-oxoazetidine in 3 ml of methanol is added 0.16 ml of 30% aqueous hydrogen peroxide and the mixture is stirred at room temperature for 4 hours. Then, 0.1 ml of 30% aqueous hydrogen peroxide is added, and the mixture is further stirred for 4 hours, followed by addition of 10 ml of water Extraction is carried out with ethyl acetate. The organic layer is washed with water, dried over magnesium sulfate and concentrated under reduced pressure to give 0.20 g of (3R,4S)-4-ethylsulfinyl-3-phenoxyacetamido-2-oxoazetidine.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[Br:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:17])[O:14][CH2:15][CH3:16])=[C:8]([C:18]([F:21])([F:20])[F:19])[CH:7]=1.C(O)(=O)C>S(=O)(=O)(O)O.C(OC(=O)C)(=O)C>[Br:5][C:6]1[CH:7]=[C:8]([C:18]([F:20])([F:21])[F:19])[C:9]([NH:12][C:13](=[O:17])[O:14][CH2:15][CH3:16])=[C:10]([N+:1]([O-:4])=[O:2])[CH:11]=1
Reactant: CCOC(=O)Nc1ccc(Br)cc1C(F)(F)F
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CCOC(=O)Nc1c([N+](=O)[O-])cc(Br)cc1C(F)(F)F
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 61 %

Procedure:
To acetic anhydride (10 ml) was added dropwise conc. nitric acid (d=1.42, 1.300 ml) during 10 minutes in an ice bath and added one drop of conc. sulfuric acid (96%). To this solution was added a solution of ethyl 4-bromo-2-(trifluoromethyl)phenylcarbamate in acetic anhydride (7 ml)/acetic acid (1 ml) during 30 minutes in an ice bath. After stirring for 2.5 hours, the reaction mixture was poured into ice-water, and the precipitated solid product was filtered. The resultant solid product was purified by silica gel column (120 g, hexane:ethyl acetate=15:1) to give the title compound (2.3265 g, 61%).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1([CH3:13])[O:8][C@@H:7]([CH2:9][OH:10])[C@H:6]([CH2:11][OH:12])[O:5]1.[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(O)(=O)C>CN(C)C=O>[CH2:14]([O:12][CH2:11][C@@H:6]1[O:5][C:4]([CH3:13])([CH3:3])[O:8][C@H:7]1[CH2:9][OH:10])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: BrCc1ccccc1
Reactant: CC1(C)O[C@@H](CO)[C@H](CO)O1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CC1(C)O[C@@H](CO)[C@H](COCc2ccccc2)O1
Reaction time: 1 h
Yield: 73.2 %

Procedure:
7.71 g of sodium hydride (content: 60%) (193 mmol) was added portionwise to a solution of 30.92 g of (+)-2,3-O-isopropylidene-L-threitol (191 mmol) in N,N-dimethylformamide (285 ml) under a nitrogen atmosphere and under ice-cooling over 45 minutes, and the mixture was stirred at the same temperature for one hour. 23.8 ml of benzyl bromide (200 mmol) was added to the reaction mixture over 30 minutes, and the mixture was stirred at the same temperature for three hours. 2.2 ml of acetic acid (38 mmol) was added to the reaction mixture, and the mixture was further stirred at room temperature for one hour. The reaction mixture was concentrated under reduced pressure and diluted with water, followed by extraction with ethyl acetate. Then, the organic layer was washed with water and brine and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent:n-hexane/ethyl acetate=2/1-1/1) to obtain 35.27 g of the title compound (yield: 73%).
Reaction SMILES: [CH:1]([C:4]1([CH2:9][CH2:10][OH:11])[O:8][CH2:7][CH2:6][O:5]1)([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>C(Cl)Cl>[CH3:19][S:20]([O:11][CH2:10][CH2:9][C:4]1([CH:1]([CH3:3])[CH3:2])[O:8][CH2:7][CH2:6][O:5]1)(=[O:22])=[O:21]
Reactant: CC(C)C1(CCO)OCCO1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)C1(CCOS(C)(=O)=O)OCCO1
Temperature: 25 °C
Yield: 100.7 %

Procedure:
To a solution of 2-(2-isopropyl-1,3-dioxolan-2-yl)-ethanol (8.0 g, 50 mmol) and triethylamine (23.5 mL, 170 mmol) in anhydrous CH2Cl2 (120 mL) was added methanesulfonyl chloride (11.6 mL, 150 mmol) at 0° C., and the reaction mixture was stirred at rt till the reaction was finished. The reaction mixture was washed with water and brine, dried over Na2SO4, filtered, and concentrated to give the crude 2-(2-isopropyl-1,3-dioxolan-2-yl)ethyl methanesulfonate (12 g, crude), which was used for the next step without further purification.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[CH:10][C:9]=1[Cl:20])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[Cl:20][C:9]1[CH:10]=[C:11]([N:14]2[CH2:15][CH2:16][O:17][CH2:18][CH2:19]2)[CH:12]=[CH:13][C:8]=1[NH2:7]
Reactant: CC(C)(C)OC(=O)Nc1ccc(N2CCOCC2)cc1Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1ccc(N2CCOCC2)cc1Cl
Temperature: 25 °C
Reaction time: 24 h
Yield: 39.9 %

Procedure:
A solution of impure (2-chloro-4-morpholin-4-yl-phenyl)-carbamic acid tert-butyl ester (2.84 g) in dichloromethane (30 mL) was treated with trifluoroacetic acid (3.5 mL), stirred at room temperature for 24 h and evaporated. The residue was dissolved in ethyl acetate, was washed with 1N NaOH, water, and brine, was dried (sodium sulfate) and evaporated. Purification by flash chromatography (SiO2) eluted with 35:65 ethyl acetate:hexanes provided 2-chloro-4-morpholin-4-yl-phenylamine (0.77 g, 40% yield) as an off-white solid. 1H-NMR (CDCl3, 500 MHz) 6.92 (br, 1H), 6.77 (br, 2H), 3.89 (m, 6H), 3.05 (m, 4H) ppm; MS (FIA) 213.1 (M+H); HPLC (Method A) 1.975 min.
Reaction SMILES: [C:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1)(=[O:4])[CH2:2][CH3:3].[C:14]([O-])(O)=O.[Na+].IC>CN(C=O)C.[Na+].[Cl-]>[CH3:14][O:10][C:9](=[O:11])[C:8]1[CH:12]=[CH:13][C:5]([C:1](=[O:4])[CH2:2][CH3:3])=[CH:6][CH:7]=1
Reactant: O=C([O-])O
Reactant: CCC(=O)c1ccc(C(=O)O)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: CCC(=O)c1ccc(C(=O)OC)cc1
Yield: 77.4 %

Procedure:
4-propionylbenzoic acid (890 mg, 5 mmol), NaHCO3 (1.26 g, 15 mmol), and iodomethane (935 μL, 15 mmol) in DMF (10 mL) were stirred at RT overnight. The mixture was diluted with saturated aqueous NaCl (50 mL) and extracted with ether (3×50 mL). The organic phase was washed with water (50 mL), dried, and evaporated. Flash chromatography (90 g silica, 2/1 petroleum ether—EtOAc) gave white solids of 4-Propionyl-benzoic acid methyl ester (744 mg, 77%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][NH:8][C:9]([O:11][CH2:12][C:13]1([CH2:18][O:19][C:20]([NH:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])=[O:21])[CH2:17][CH2:16][CH2:15][O:14]1)=[O:10].C(N(CC)CC)C.[C:48](OC(=O)C)(=[O:50])[CH3:49]>C(Cl)(Cl)Cl.CN(C)C1C=CN=CC=1>[C:48]([N:8]([CH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)[C:9]([O:11][CH2:12][C:13]1([CH2:18][O:19][C:20]([NH:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])=[O:21])[CH2:17][CH2:16][CH2:15][O:14]1)=[O:10])(=[O:50])[CH3:49]
Reactant: CCCCCCCCCCCCCCCCCCNC(=O)OCC1(COC(=O)NCc2ccccn2)CCCO1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCCCCCNC(=O)OCC1(COC(=O)N(Cc2ccccn2)C(C)=O)CCCO1

Procedure:
To 3.2 g (5.7 mmol) of the compound prepared in (b) above dissolved in 25 ml of chloroform was added, with stirring and under a nitrogen atmosphere, 18.15 g (180 mmol) of triethylamine, 11.63 g (114 mmol) of acetic anhydride and 0.035 g (0.29 mmol) of 4-dimethylaminopyridine. The resultant mixture was then heated to reflux and maintained at the reflux temperature for 72 hours. The volatiles were then removed under high vacuum and the resultant residue was dissolved in methylene chloride and washed rapidly with a saturated aqueous sodium bicarbonate solution. The organic layer was then dried over sodium sulfate, filtered and concentrated. The resultant residue was then chromatographed on silica gel employing a mixture of petroleum ether and ethyl acetate in a ratio of 1:1 by volume initially, with the product being eluted when the eluent was pure ethyl acetate. The resultant solution was then concentrated to obtain a semi-solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH2:18][C:19]1[N:23]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:22]=[C:21]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH:20]=1.CCN(C(C)C)C(C)C.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>CC1CCCO1>[Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[CH:7][C:3]=1[C:4]([NH:18][C:19]1[N:23]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:22]=[C:21]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH:20]=1)=[O:6]
Reactant: CCOC(=O)c1cc(N)n(-c2ccccc2)n1
Reactant: O=C(O)c1cc(-c2ccccn2)c(Cl)cc1Cl
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CC1CCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cc(NC(=O)c2cc(-c3ccccn3)c(Cl)cc2Cl)n(-c2ccccc2)n1
Temperature: 95 °C
Reaction time: 18 h
Yield: 84.8 %

Procedure:
To a solution of 2,4-dichloro-5-(pyridin-2-yl)benzoic acid (Preparation 30, 3.76 g, 14.02 mmol) and ethyl 5-amino-1-phenyl-1H-pyrazole-3-carboxylate (3.89 g, 16.83 mmol) in 2-methyltetrahydrofuran (150 mL) was added DIPEA (7.33 mL, 42 mmol) and the reaction was heated to 95° C. T3P (50% solution in EtOAc, 16.53 mL, 28 mmol) was added and the reaction was stirred at 95° C. for 18 hours. The reaction was cooled and partitioned between saturated aqueous sodium carbonate solution (200 mL) and EtOAc (200 mL). The organic layer was collected, washed with brine, dried over magnesium sulphate and concentrated in vacuo. The residue was triturated with TBME to afford the title compound (5.72 g, 85%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[C@@H:15]([OH:16])[C:14](=[O:17])[NH:13][C:12]3[CH:18]=[CH:19][C:20]([Cl:22])=[CH:21][C:11]=3[S:10]2)=[CH:5][CH:4]=1.Cl.[CH3:24][N:25]([CH2:29][CH2:30]Cl)[CH2:26][CH2:27][CH3:28].[BrH:32]>>[BrH:32].[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[C@@H:15]([OH:16])[C:14](=[O:17])[N:13]([CH2:30][CH2:29][N:25]([CH3:24])[CH2:26][CH2:27][CH3:28])[C:12]3[CH:18]=[CH:19][C:20]([Cl:22])=[CH:21][C:11]=3[S:10]2)=[CH:5][CH:4]=1
Reactant: CCCN(C)CCCl
Reactant: COc1ccc([C@@H]2Sc3cc(Cl)ccc3NC(=O)[C@@H]2O)cc1
Agent: Br
Agent: Cl
Product: CCCN(C)CCN1C(=O)[C@H](O)[C@H](c2ccc(OC)cc2)Sc2cc(Cl)ccc21

Procedure:
2 g of (±)-cis-2-(4-methoxyphenyl)-3-hydroxy-8-chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one and 1.13 g of 2-(N-methyl-N-n-propylamino)ethyl chloride hydrochloride are treated in the same manner as described in Example 5. The product is converted to its hydrobromide and recrystallized from a mixture of ethanol and ether. 2.1 g of (±)-cis-2-(4-methoxyphenyl)-3-hydroxy-5-[2-(N-methyl-N-n-propylamino)ethyl]-8-chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one hydrobromide are thereby obtained as colorless prisms.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[S:11]([O-:14])(=[O:13])=[O:12].[Na+:15].[Si]([O-])([O-])([O-])[O-].[Na+].[Na+].[Na+].[Na+].[OH-].[Na+].[CH2:27]([O:30][CH2:31][CH2:32][OH:33])[CH2:28][CH3:29]>O>[CH2:27]([O:30][CH2:31][CH2:32][O:33][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[S:11]([O-:14])(=[O:13])=[O:12])[CH2:28][CH3:29].[Na+:15]
Reactant: CCCOCCO
Reactant: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)[O-])c1
Agent: [Na+]
Agent: [O-][Si]([O-])([O-])[O-]
Agent: [OH-]
Solvent: O
Product: CCCOCCOc1ccc([N+](=O)[O-])cc1S(=O)(=O)[O-]

Procedure:
26.0 g of sodium 2-chloro-5-nitrobenzenesulfonate and 5.0 g of sodium silicate (Na2O.nSiO2 wherein n is about 3) were suspended in 120 ml of 2-propoxyethanol. To the suspension was added dropwise with stirring a solution containing 5.0 g of sodium hydroxide dissolved in 5 ml of water at 65° C. for 10 minutes. After completion of the addition, the reaction mixture was stirred at 65° C. for 3 hours and the insoluble materials were removed by filtration under suction. The solids which deposited from the filtrate upon standing were removed by filtration. The filtrate was concentrated to a dry solid. 100 ml of ethanol was added to the residue to form crystals. The crystals were recovered by filtration, washed with isopropyl alcohol and dried at 50° C. Yield: 14.1 g. The compound at first melted at 70° to 74° C., then solidified at about 130° C. and again melted at 206° to 209° C.
Reaction SMILES: [OH:1][CH:2]([CH2:20][CH3:21])[C:3]([N:5]1[CH2:10][CH2:9][C:8]2[N:11]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[O:13][C:7]=2[CH2:6]1)=[O:4].N1C=CN=C1.[C:27]([Si:31](Cl)([CH3:33])[CH3:32])([CH3:30])([CH3:29])[CH3:28].C(Cl)Cl>CN(C=O)C.CN(C1C=CN=CC=1)C>[C:27]([Si:31]([CH3:33])([CH3:32])[O:1][CH:2]([CH2:20][CH3:21])[C:3]([N:5]1[CH2:10][CH2:9][C:8]2[N:11]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[O:13][C:7]=2[CH2:6]1)=[O:4])([CH3:30])([CH3:29])[CH3:28]
Reactant: CCC(O)C(=O)N1CCc2nc(-c3ccccc3)oc2C1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCC(O[Si](C)(C)C(C)(C)C)C(=O)N1CCc2nc(-c3ccccc3)oc2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
710.00 mg (2.48 mmol) 2-hydroxy-1-(2-phenyl-6,7-dihydro-4H-oxazolo[5,4-c]pyridin-5-yl)-butan-1-one are placed in 10 mL DMF and combined with 340.00 mg (4.99 mmol) imidazole. Then 600.00 mg (3.98 mmol) tert.-butyl-chloro-dimethyl-silane and 30.00 mg (0.25 mmol) DMAP are added and the mixture is stirred overnight at RT. The DMF is eliminated i.V., the residue is added to DCM and extracted 1 time each with H2O, 1N HCl and saturated sodium chloride solution. The solvent of the org. phase is eliminated in vacuo and the residue is purified on silica gel. (Eluant: cyclohexane/EA).
Reaction SMILES: [C:1]([Si:5]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[O:6][CH2:7][CH2:8][C:9]1[N:10]=[C:11]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)[O:12][C:13]=1[CH3:14])([CH3:4])([CH3:3])[CH3:2].Br.Br[CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=1.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[C:1]([Si:5]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[O:6][CH2:7][CH2:8][C:9]1[N:10]=[C:11]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=3)=[CH:17][CH:16]=2)[O:12][C:13]=1[CH3:14])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1oc(-c2ccc(O)cc2)nc1CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Reactant: BrCc1ccccn1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1oc(-c2ccc(OCc3ccccn3)cc2)nc1CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Yield: 78.6 %

Procedure:
A mixture of 4-{4-[2-(tert-Butyl-diphenyl-silanyloxy)-ethyl]-5-methyl-oxazol-2-yl}-phenol (1.0 g, 2.25 mmol), 2-bromomethylpyridine hydrobromide (0.85 g, 3.4 mmol), and K2CO3 (1.1 g, 7.9 mmol) in acetone (20 mL) is heated at reflux for 12 h. The mixture is filtered, and the solvent is removed in vacuo. The residue is partitioned between EtOAc and water. The organic phase is washed with water and brine, dried (Na2SO4), and concentrated. The residue is purified by flash chromatography (90 g SiO2, elute 10% to 50% EtOAc/hexane) to yield 0.97 g of the title compound. MS (ES+) 549.3
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:10][C:11]([OH:13])=[O:12])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].Cl.[CH3:15]O>>[CH3:15][O:12][C:11](=[O:13])[CH2:10][C:4]1[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([Br:1])[CH:3]=1
Reactant: CO
Reactant: COc1ccc(CC(=O)O)cc1Br
Agent: Cl
Product: COC(=O)Cc1ccc(OC)c(Br)c1

Procedure:
To 3-bromo-4-methoxyphenylacetic acid (1.0 g, 4.1 mmol) in MeOH (20 mL) was added HCl (4N in 1,4-dioxane; 5 mL, 20 mmol), and the reaction was refluxed overnight. The mixture was concentrated to give the title compound.