Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1C=CN=C1.[C:6]([Si:10]([CH3:13])([CH3:12])Cl)([CH3:9])([CH3:8])[CH3:7].[Br:14][CH2:15][CH2:16][CH2:17][OH:18].CCOC(C)=O>C1COCC1>[Br:14][CH2:15][CH2:16][CH2:17][O:18][Si:10]([CH3:13])([CH3:12])[C:6]([CH3:9])([CH3:8])[CH3:7]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCCCBr
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OCCCBr
Temperature: 25 °C
Reaction time: 20 h
Yield: 21.8 %

Procedure:
Imidazole (0.52 g, 7.6 mmol) and t-butyldimethylchlorosilane (5.80 g, 38 mmol) were added successively to a solution of 1-bromo-3-propanol (5.35 g, 38 mmol) in dry THF (10 mL) at room temperature. The resulting suspension was stirred at room temperature for 20 hours. EtOAc (25 mL) was added. The solution was washed with water, dried over Na2SO4, filtered and concentrated in vacuo at room temperature. The residue was chromatographed on silica gel eluting with 1:10 EtOAc:Hex to give the title compound 2.1 g (22%) as a colorless volatile liquid. 1H NMR (300 MHz, CDCl3) δ 3.74 (t, J=5.7 Hz, 2H), 3.52 (t, J=6.5 Hz, 2H), 2.02-2.06 (mult, 2H), 0.90 (s, 9H), 0.07 (s, 6H); 13C NMR (75 MHz, CDCl3) δ 60.6, 35.7, 30.8, 26.1, −5.2.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].C1(C)C=CC=CC=1.[CH3:12][C:13]([C:16]1[CH:17]=[C:18]([S:27][CH2:28][CH2:29][C:30]([NH:32][NH2:33])=[O:31])[CH:19]=[C:20]([C:23]([CH3:26])([CH3:25])[CH3:24])[C:21]=1[OH:22])([CH3:15])[CH3:14].C(=O)(O)[O-].[Na+]>O1CCCC1.C(OCC)(=O)C>[CH3:15][C:13]([C:16]1[CH:17]=[C:18]([S:27][CH2:28][CH2:29][C:30]2[O:31][C:1](=[O:2])[NH:33][N:32]=2)[CH:19]=[C:20]([C:23]([CH3:24])([CH3:25])[CH3:26])[C:21]=1[OH:22])([CH3:12])[CH3:14]
Reactant: O=C(Cl)Cl
Reactant: CC(C)(C)c1cc(SCCC(=O)NN)cc(C(C)(C)C)c1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(SCCc2n[nH]c(=O)o2)cc(C(C)(C)C)c1O
Reaction time: 0.17 h
Yield: 63 %

Procedure:
A 12.5% solution of phosgene in toluene (5.5 mL, 6.2 mmol) is added dropwise to a -78° C. solution of 3-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]thio]propanoic acid hydrazide (1.0 g, 2.94 mmol) in tetrahydrofuran (100 mL). The reaction mixture is stirred for 10 minutes then poured into a separatory funnel containing ethyl acetate and aqueous sodium bicarbonate. The organic phase is washed three times with water and once with brine. Drying the organic phase over magnesium sulfate and evaporation gives a heavy oil which is chromatographed on a 100 g column of silica with methanol/chloroform (3/97). After coevaporation with dichloromethane the product solidifies affording 0.64 g (63%) of 5-[2-[[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]thio]ethyl]-1,3,4-oxadiazol-2(3H)-one, mp 86.0°-87.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]=[CH:7][C:8]([OH:10])=[O:9])=[CH:4][CH:3]=1>C1COCC1.[Pd]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH2:7][C:8]([OH:10])=[O:9])=[CH:11][CH:12]=1
Reactant: O=C(O)C=Cc1ccc(Cl)cc1
Agent: [Pd]
Solvent: C1CCOC1
Product: O=C(O)CCc1ccc(Cl)cc1
Yield: 98 %

Procedure:
To a solution of 1.80 g (10 mmol) of 4-chlorocinnamic acid in 50 mL of THF was added Pd/C (1.04 g, 5% w/w) and the solution was stirred under a hydrogen atmosphere until no further H2 take-up was observed (~1 h). The solution was filtered through Celite and the solvent removed under reduced pressure to yield 1.82 g (9.8 mmol, 98%) of a white solid: mp. 103°-105° C.; 1H NMR (DMSO-d6) δ2.51 (t, 2H, β--CH2), 2.79 (t, 2H, (α--CH2), 7.28 (dd, 4H, aromatic CH's), 12.12 (s, 1H, COOH); MS (EI, calculated for C9H9ClO2, 184.0291) m/e 184.0288 (M+).
Reaction SMILES: [C:1]([O:4][C:5](=O)[CH3:6])(=[O:3])[CH3:2].[C:8]([C:16]1[CH:17]=[C:18]([CH:22]=CC=1O)[C:19]([OH:21])=[O:20])(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[OH-].[Na+]>O>[C:8]([C:16]1[CH:17]=[C:18]([CH:22]=[CH:6][C:5]=1[O:4][C:1](=[O:3])[CH3:2])[C:19]([OH:21])=[O:20])(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC(=O)OC(C)=O
Reactant: O=C(O)c1ccc(O)c(C(=O)c2ccccc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)Oc1ccc(C(=O)O)cc1C(=O)c1ccccc1
Temperature: 8 °C
Reaction time: 1 h

Procedure:
Acetic anhydride (10.5 g, 0.103 mmol) was added to a solution of 3-benzoyl-4-hydroxybenzoic acid (12.5 g, 51.6 mole) and NaOH (4.33 g, 0.108 mmol) in 250 ml of water under nitrogen. The clear colorless solution was stirred at 8° C. for one hour. The product separated initially as a colorless oil which soon crystallized to a white solid. The slurry was made strongly acidic by adding concentrated HCl, and was extracted with ether. The ether extract was washed with water, and dried with MgSO4 and evaporated to dryness providing crude acetoxy acid. The crude product was recrystallized from a mixture of 200 ml of toluene and 150 ml of cyclohexane to give 3-benzoyl-4-acetoxybenzoic acid with a m.p. of 162.5° C. to 163° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH:12][C:13]([C:15]3[CH:20]=[CH:19][NH:18][C:17](=[O:21])[CH:16]=3)=[O:14])[S:11][C:7]=2[C:6]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[CH:5][CH:4]=1.[H-].[Na+].[Br-].[Li+].Cl[CH2:33][C:34]([N:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1)=[O:35]>CN(C=O)C.COCCOC.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH:12][C:13]([C:15]3[CH:20]=[CH:19][N:18]([CH2:33][C:34]([N:36]4[CH2:41][CH2:40][O:39][CH2:38][CH2:37]4)=[O:35])[C:17](=[O:21])[CH:16]=3)=[O:14])[S:11][C:7]=2[C:6]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[CH:5][CH:4]=1
Reactant: O=C(CCl)N1CCOCC1
Reactant: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3cc[nH]c(=O)c3)nc12
Agent: [Br-]
Agent: [H-]
Agent: [Li+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccn(CC(=O)N4CCOCC4)c(=O)c3)nc12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 31.1 %

Procedure:
To a stirred solution of 200 mg (0.52 mmol) 2-oxo-1,2-dihydro-pyridine-4-carboxylic acid (4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-amide in 1 ml DMF and 4 ml 1,2-dimethoxyethane was added 44 mg (1.04 mmol) sodium hydride (60% dispersion in mineral oil). After stirring for 15 min at room temperature, 90 mg (1.04 mmol) lithium bromide was added and stirring continued for a further 15 min. 95 mg (0.58 mmol) 4-(2-chloroacetyl)morpholine was then added and the mixture was stirred at room temperature for 16 h. The reaction mixture was then diluted with ethyl acetate, and washed sequentially with 0.5 M hydrochloric acid, saturated sodium bicarbonate solution and saturated brine. The combined aqueous phases were filtered, and the filter cake washed with ether, then resuspended in toluene and concentrated in vacuo. Flash chromatography (MeOH/CH2Cl2) followed by trituration in ethyl acetate afforded 83 mg (31%) 1-(2-morpholin-4-yl-2-oxo-ethyl)-2-oxo-1,2-dihydro-pyridine-4-carboxylic acid (4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-amide as a yellow crystalline solid. ES-MS m/e (%): 536 (M+Na+, 25), 514 (M+H+, 100).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[C:9](=[O:13])O[CH:11]=[N:12][C:7]=2[CH:6]=[C:5]([O:14][CH3:15])[CH:4]=1.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][CH:19]=1>C1(C)C(C)=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:14][CH3:15])[CH:6]=[C:7]2[C:8]=1[C:9](=[O:13])[N:24]([C:21]1[CH:22]=[CH:23][C:18]([O:17][CH3:16])=[CH:19][CH:20]=1)[CH:11]=[N:12]2
Reactant: COc1ccc(N)cc1
Reactant: COc1cc(OC)c2c(=O)ocnc2c1
Solvent: Cc1ccccc1C
Product: COc1ccc(-n2cnc3cc(OC)cc(OC)c3c2=O)cc1
Yield: 39.6 %

Procedure:
A mixture of 200 mg (0.97 mmol) of the benzoxazinone prepared in Example 4 and 119 mg (0.97 mmol) of p-anisidine in 5 ml of xylene was refluxed for 4 hours. The solvent was removed and the target compound purified by flash chromatography on silica gel (loaded with CH2Cl2 and eluted with 40% EtOAc in hexane) to obtain 120 mg of 5,7-dimethoxy-3-(4-methoxyphenyl)-4(3H)-quinazolinone (40% yield) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:14]([Cl:15])=[C:13]([C:16]([C:18]2[N:22](COCC)[N:21]=[CH:20][CH:19]=2)=[O:17])[CH:12]=[CH:11][C:3]=1[O:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].Cl.C(=O)(O)[O-].[Na+]>C(O)C>[Cl:1][C:2]1[C:14]([Cl:15])=[C:13]([C:16]([C:18]2[NH:22][N:21]=[CH:20][CH:19]=2)=[O:17])[CH:12]=[CH:11][C:3]=1[O:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOCn1nccc1C(=O)c1ccc(OCC(=O)OCC)c(Cl)c1Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)COc1ccc(C(=O)c2ccn[nH]2)c(Cl)c1Cl
Reaction time: 3.5 h
Yield: 61.3 %

Procedure:
1.03 g of ethyl [2,3-dichloro-4-(1-ethoxymethyl-5-pyrazolylcarbonyl)phenoxy]acetate are dissolved in 25 ml of ethanol, and 6 ml of concentrated hydrochloric acid are added thereto. The mixture is stirred at 60°-65° C. for 3.5 hours. The reaction mixture is cooled, adjusted to pH 8-9 by addition of an aqueous saturated sodium bicarbonate solution under ice-cooling, and then extracted with ethyl acetate. The extract is washed successively with an aqueous saturated sodium bicarbonate solution and water, dried and evaporated to remove solvent. The residue is purified by silica gel column chromatography (solvent; benzene-ethyl acetate) and crystallized with a mixture of benzene and chloroform to give 0.54 g of ethyl [2,3-dichloro-4-(5-pyrazolylcarbonyl)phenoxy]acetate.
Reaction SMILES: [Cl:1][C:2](=[CH2:22])[CH2:3][C:4]1[C:17]([F:18])=[C:16]([F:19])[C:7]([CH2:8][O:9]C2CCCCO2)=[C:6]([F:20])[C:5]=1[F:21].O>CO.Cl>[Cl:1][C:2](=[CH2:22])[CH2:3][C:4]1[C:5]([F:21])=[C:6]([F:20])[C:7]([CH2:8][OH:9])=[C:16]([F:19])[C:17]=1[F:18]
Reactant: C=C(Cl)Cc1c(F)c(F)c(COC2CCCCO2)c(F)c1F
Agent: Cl
Solvent: O
Solvent: CO
Product: C=C(Cl)Cc1c(F)c(F)c(CO)c(F)c1F
Reaction time: 6 h
Yield: 99.8 %

Procedure:
The tetrahydropyranyl ether prepared in stage (i) (0.2 g), was dissolved in methanol (6 cm3), and to the stirred solution was added concentrated hydrochloric acid (several drops). After stirring for 6 hours, and standing for a further 14 hours, the reaction mixture was poured into water, and extracted into ethyl acetate. The organic layer was washed with water and brine, dried, and the solvent evaporated under reduced pressure to give 4-(2-chloroprop-2-en-1-yl)-2,3,5,6-tetrafluorobenzyl alcohol as an orange oil (0.15 g).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:6]2[N:5]=[CH:4][C:3]=1[C:16]([O:18][CH3:19])=[O:17].[F:20][C:21]1[CH:22]=[C:23]([CH:25]=[CH:26][C:27]=1[CH3:28])[NH2:24]>>[CH2:14]([O:13][C:11]([C:10]1[CH:9]=[N:8][N:7]2[C:2]([NH:24][C:23]3[CH:25]=[CH:26][C:27]([CH3:28])=[C:21]([F:20])[CH:22]=3)=[C:3]([C:16]([O:18][CH3:19])=[O:17])[CH:4]=[N:5][C:6]=12)=[O:12])[CH3:15]
Reactant: Cc1ccc(N)cc1F
Reactant: CCOC(=O)c1cnn2c(Cl)c(C(=O)OC)cnc12
Product: CCOC(=O)c1cnn2c(Nc3ccc(C)c(F)c3)c(C(=O)OC)cnc12
Yield: 93 %

Procedure:
In the same manner as in Example 1, step 4 and using methyl 7-chloro-3-ethoxycarbonylpyrazolo[1,5-a]pyrimidine-6-carboxylate (3.00 g, 10.6 mmol) obtained in Example 21, step 2 and 3-fluoro-4-methylaniline (1.43 ml, 12.7 mmol), the title compound (3.67 g, 94%) was obtained.
Reaction SMILES: [C:1]([C:4]1[CH:24]=[CH:23][C:7]([C:8]([NH:10][C:11]2[CH:21]=[C:20]([NH2:22])[CH:19]=[CH:18][C:12]=2[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:9])=[CH:6][CH:5]=1)([OH:3])=[O:2].[C:25](Cl)(=[O:28])[CH2:26][CH3:27].O.Cl>N1C=CC=CC=1>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([C:8]([NH:10][C:11]2[CH:21]=[C:20]([NH:22][C:25](=[O:28])[CH2:26][CH3:27])[CH:19]=[CH:18][C:12]=2[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:9])=[CH:23][CH:24]=1)([OH:3])=[O:2]
Reactant: CCC(=O)Cl
Reactant: CCOC(=O)c1ccc(N)cc1NC(=O)c1ccc(C(=O)O)cc1
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: CCOC(=O)c1ccc(NC(=O)CC)cc1NC(=O)c1ccc(C(=O)O)cc1
Reaction time: 3 h
Yield: 62.6 %

Procedure:
A solution of 3 g of ethyl 2-(4-carboxybenzamido)-4-aminobenzoate in 30 ml of pyridine was mixed with 3 g of propionyl chloride, and the mixture was held at 40° to 50° C. for a period of 3 hours. Subsequently, 20 ml of water was gradually added to the mixture which was held at the temperature for a period of one hour. After further addition of 100 ml of water, hydrochloric acid was used to control the pH of the reaction mixture between 1 and 2, and the precipitating crystal was filtered, washed with water, and recrystallized from a solvent mixture of ethanol and water to thereby produce 2.2 g of ethyl 2-(4-carboxybenzamido)-4-propionamidobenzoate having a melting point in the range of from 246° to 248° C.
Reaction SMILES: C[O:2][C:3](=[O:41])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][N:11]([C:13]2[C:14]([CH3:40])=[N:15][C:16]([O:19][CH2:20][C:21]3[N:22]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[O:35][C:36]([F:39])([F:38])[F:37])[N:23]=[CH:24][C:25]=3[CH:26]([CH3:28])[CH3:27])=[CH:17][CH:18]=2)[CH3:12])[CH:5]=1.[OH-].[Li+]>O1CCOCC1>[CH:26]([C:25]1[CH:24]=[N:23][N:22]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[O:35][C:36]([F:38])([F:39])[F:37])[C:21]=1[CH2:20][O:19][C:16]1[N:15]=[C:14]([CH3:40])[C:13]([N:11]([CH2:10][C:6]2[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=2)[C:3]([OH:41])=[O:2])[CH3:12])=[CH:18][CH:17]=1)([CH3:28])[CH3:27]
Reactant: COC(=O)c1cccc(CN(C)c2ccc(OCc3c(C(C)C)cnn3-c3ccccc3OC(F)(F)F)nc2C)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Cc1nc(OCc2c(C(C)C)cnn2-c2ccccc2OC(F)(F)F)ccc1N(C)Cc1cccc(C(=O)O)c1
Temperature: 50 °C
Yield: 96 %

Procedure:
To an ambient temperature solution of 3-[({6-[4-Isopropyl-2-(2-trifluoromethoxy-phenyl)-2H-pyrazol-3-ylmethoxy]-2-methyl-pyridin-3-yl}-methyl-amino)-methyl]-benzoic acid methyl ester (106 mg, 0.186 mmol) in dioxane (2 mL) is added a solution of lithium hydroxide (279 μL, 0.558 mmol, 2.0N in water). The reaction mixture is heated to 50° C. The reaction is concentrated under reduced pressure and the residue is partitioned between Et2O and water. The aqueous layer pH is adjusted to approximately 7 and is extracted with a second portion of Et2O. The combined organic layers are washed with water, dried (MgSO4), filtered, and concentrated to yield the title compound (99 mg, 96%). ES/MS m/e 555.3 (M+1)
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH:2]=[CH2:3].[CH2:6]([N:9](CC=C)[CH:10]=[CH:11][CH:12]=[C:13]([C:16]#[N:17])[C:14]#[N:15])[CH:7]=[CH2:8]>C(O)C>[C:1]([OH:5])(=[O:4])[CH:2]=[CH2:3].[CH2:6]([NH:9][CH:10]=[CH:11][CH:12]=[C:13]([C:14]#[N:15])[C:16]#[N:17])[CH:7]=[CH2:8]
Reactant: C=CCN(C=CC=C(C#N)C#N)CC=C
Agent: C=CC(=O)O
Solvent: CCO
Product: C=CCNC=CC=C(C#N)C#N

Procedure:
A solution of 60 g.=56 cc. of acrylic acid and 60 g. of 3-diallylaminoallylidenemalononitrile (A) in 250 cc. of ethanol was refluxed. 6 g. of AZBN were added and it was reflux-washed for 18 hours. It was cooled, saturated with ether and precipitated in ether, washed with ether and vacuum dried at 50° C. The yield was 92 g. of a product containing about 27% of aminoallylidenemalononitrile units in weight, whose solution at 6% in water and NaOH at pH7 was diluted at 1:8000 with water had an optical density of 0.60 at 382 nm. All subsequent optical density readings are given at this wavelength unless otherwise stated.
Reaction SMILES: [Br:1][C:2]1[CH:13]=[CH:12][C:5]([CH2:6][CH:7]([C:10]#[N:11])[C:8]#[N:9])=[C:4]([F:14])[CH:3]=1.[H-].[Na+].Br[CH2:18][CH2:19][F:20]>CN(C)C=O>[Br:1][C:2]1[CH:13]=[CH:12][C:5]([CH2:6][C:7]([CH2:18][CH2:19][F:20])([C:8]#[N:9])[C:10]#[N:11])=[C:4]([F:14])[CH:3]=1
Reactant: N#CC(C#N)Cc1ccc(Br)cc1F
Reactant: FCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CC(C#N)(CCF)Cc1ccc(Br)cc1F
Yield: 33.8 %

Procedure:
Using 0.25 g of (4-bromo-2-fluorobenzyl)malononitrile, 3 ml of N,N-dimethylformamide, 0.10 g of sodium hydride (60% in oil), and 0.13 g of 1-bromo-2-fluoroethane, and according to the process described in the Production Example 1, there was obtained 0.10 g of 2-(4-bromo-2-fluorobenzyl)-2-(2-fluoroethyl)malononitrile (the present compound (67)).
Reaction SMILES: [CH2:1]([N:3]([CH2:24][CH3:25])[CH2:4][CH2:5][N:6]1[C:14]2[CH:13]=[CH:12][C:11]([CH2:15][OH:16])=[C:10]3[S:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[C:8]([C:9]=23)=[N:7]1)[CH3:2].[OH:26]O>CC(C)=O>[CH2:24]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][N:6]1[C:14]2[CH:13]=[CH:12][C:11]([CH2:15][OH:16])=[C:10]3[S:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[C:8]([C:9]=23)=[N+:7]1[O-:26])[CH3:25]
Reactant: CCN(CC)CCn1nc2c3c(c(CO)ccc31)Sc1ccccc1-2
Reactant: OO
Solvent: CC(C)=O
Product: CCN(CC)CCn1c2ccc(CO)c3c2c([n+]1[O-])-c1ccccc1S3
Reaction time: 8 h

Procedure:
To a solution of 2-(2-(diethylamino)ethyl)-2H(1)benzothiopyrano[4,3,2-cd]indazole-5-methanol (0.18 g.) in acetone (3 ml.) was added 30% aqueous hydrogen peroxide (0.21 ml.) and the mixture left overnight at room temperature. Evaporation under reduced pressure and crystallization from ethanol-ethyl acetate gave 2-(2-(diethylamino)ethyl)-2H(1)benzothiopyrano[4,3,2-cd]indazole-5-methanol N-oxide one-third hydrate which melted at 142°-143° (decomp.).
Reaction SMILES: [OH:1][C@@H:2]1[C@H:6]2[O:7][CH2:8][C@:3]1([CH2:18][OH:19])[O:4][C@H:5]2[N:9]1[CH:17]=[C:15]([CH3:16])[C:13](=[O:14])[NH:12][C:10]1=[O:11].[CH3:20][O:21][C:22]1[CH:43]=[CH:42][C:25]([C:26](Cl)([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)=[CH:24][CH:23]=1.C(=O)([O-])O.[Na+]>N1C=CC=CC=1>[CH3:34][O:33][C:30]1[CH:29]=[CH:28][C:27]([C:26]([O:19][CH2:18][C@@:3]23[C@H:2]([OH:1])[C@@H:6]([O:7][CH2:8]2)[C@H:5]([N:9]2[CH:17]=[C:15]([CH3:16])[C:13](=[O:14])[NH:12][C:10]2=[O:11])[O:4]3)([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:25]2[CH:42]=[CH:43][C:22]([O:21][CH3:20])=[CH:23][CH:24]=2)=[CH:32][CH:31]=1
Reactant: Cc1cn([C@@H]2O[C@@]3(CO)CO[C@@H]2[C@H]3O)c(=O)[nH]c1=O
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccc(OC)cc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: COc1ccc(C(OC[C@@]23CO[C@@H]([C@H](n4cc(C)c(=O)[nH]c4=O)O2)[C@H]3O)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 21 h
Yield: 50 %

Procedure:
To a stirred solution of nucleoside 9 (0.500 g, 1.85 mmol) in anhydrous pyridine (10 cm3) was added 4,4′-dimethoxytrityl chloride (0.941 g, 2.78 mmol) and the mixture was stirred for 25 h at room temperature for 25 h after which additional 4,4′-dimethoxytrityl chloride (0.062 g, 0.18 mmol) was added and stirring at room temperature was continued for another 21 h. A saturated aqueous solution of sodium hydrogen carbonate (50 cm3) was added and extraction was performed using dichloromethane (3×25 cm3). The combined organic phase was washed with saturated aqueous solutions of sodium hydrogen carbonate (3×20 cm3) and brine (3×25 cm3), dried (Na2SO4) and evaporated to dryness under reduced pressure. The residue was purified by silica gel column chromatography using dichloromethane/methanol/pyridine (1–4% methanol, 0.5% pyridine, v/v/v) as eluent to give nucleoside 10 (0.53 g, 50%) as a white solid material after evaporation of the solvents under reduced pressure (0.307 g, 28.9%).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([C:7]([OH:9])=O)[NH:4][N:3]=1.Cl.[Cl:11][C:12]1[CH:13]=[C:14]([C:19]2[O:23][C:22]([CH2:24][CH2:25][NH2:26])=[CH:21][CH:20]=2)[CH:15]=[CH:16][C:17]=1[Cl:18]>>[Cl:11][C:12]1[CH:13]=[C:14]([C:19]2[O:23][C:22]([CH2:24][CH2:25][NH:26][C:7]([C:5]3[NH:4][N:3]=[C:2]([CH3:1])[CH:6]=3)=[O:9])=[CH:21][CH:20]=2)[CH:15]=[CH:16][C:17]=1[Cl:18]
Reactant: NCCc1ccc(-c2ccc(Cl)c(Cl)c2)o1
Reactant: Cc1cc(C(=O)O)[nH]n1
Agent: Cl
Product: Cc1cc(C(=O)NCCc2ccc(-c3ccc(Cl)c(Cl)c3)o2)[nH]n1
Yield: 28 %

Procedure:
The title compound was prepared using the method of Example 20 starting from 3-methyl-1H-pyrazole-5-carboxylic acid and 2-(5-(3,4-dichlorophenyl)furan-2-yl)ethanamine hydrochloride. Crude product was purified by chromatography (CombiFlash, silica column, eluent: 0-100% EtOAc/heptane) to obtain 301 mg (28%) of the title compound. 1H-NMR (400 MHz; d6-DMSO): δ 2.25 (s, 3H), 2.92 (t, 2H), 3.53 (q, 2H), 6.32 (d, 1H), 6.34 (s, 1H), 7.01 (d, 1H), 7.63 (m, 2H), 7.85 (s, 1H), 8.16 (t, 1H), 13.86 (s, 1H).
Reaction SMILES: CN(OC)[C:3]([C:5]1[CH:9]=[CH:8][O:7][CH:6]=1)=[O:4].C[Mg]Br.Cl.[CH2:16]1COC[CH2:17]1>CCOCC>[O:7]1[CH:8]=[CH:9][C:5]([C:3](=[O:4])[CH2:16][CH3:17])=[CH:6]1
Reactant: C1CCOC1
Reactant: CON(C)C(=O)c1ccoc1
Agent: C[Mg]Br
Agent: Cl
Solvent: CCOCC
Product: CCC(=O)c1ccoc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70.2 %

Procedure:
To a solution of 3-(N-methyl-N-methoxycarbamoyl)furan (14 g, 0.09 mol) in 150 mL of THF cooled to -78° C. was added in portions 36.1 mL (0.108 mol) of 3M methylmagnesium bromide in ether and the mixture was heated to warm to room temperature, and then stirred for 30 min. To the above mixture was added a cold 2N HCl (100 mL) and the aqueous layer was extracted with ether (3×100 mL), the combined organic layer was washed with brine, dried over sodium sulfate, and concentrated in vacuo to yield a pale-yellow oil. The above oil was chromatographed on silica (methylene chloride/hexane 2:1) to afford 6.95 g (70.2 %) of 1-(3-furyl)-1-propanone as a colorless oil which crystallized as a white solid.
Reaction SMILES: C(OC(=O)[C@@H](OC)CC1C=CC(OCC(O)=O)=CC=1)C.O(C1C=CC(CCN)=CC=1)C1C=CC=CC=1.[CH2:37]([O:39][C@@H:40]([CH2:44][C:45]1[CH:50]=[CH:49][C:48]([O:51][C@@H:52]([C:54](=[O:71])[NH:55][CH2:56][CH2:57][C:58]2[CH:63]=[CH:62][C:61]([O:64][C:65]3[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=3)=[CH:60][CH:59]=2)C)=[CH:47][CH:46]=1)[C:41]([OH:43])=[O:42])C>>[CH3:37][O:39][C@@H:40]([CH2:44][C:45]1[CH:46]=[CH:47][C:48]([O:51][CH2:52][C:54](=[O:71])[NH:55][CH2:56][CH2:57][C:58]2[CH:59]=[CH:60][C:61]([O:64][C:65]3[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=3)=[CH:62][CH:63]=2)=[CH:49][CH:50]=1)[C:41]([OH:43])=[O:42]
Reactant: CCO[C@@H](Cc1ccc(O[C@H](C)C(=O)NCCc2ccc(Oc3ccccc3)cc2)cc1)C(=O)O
Agent: CCOC(=O)[C@H](Cc1ccc(OCC(=O)O)cc1)OC
Agent: NCCc1ccc(Oc2ccccc2)cc1
Product: CO[C@@H](Cc1ccc(OCC(=O)NCCc2ccc(Oc3ccccc3)cc2)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-(4-carboxymethoxy-phenyl)-2-methoxy-propionic acid ethyl ester (PREPARATION 3, step 2) and 2-(4-phenoxy-phenyl)-ethylamine via the same procedure used for the preparation of (2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionic acid (Example 1, step 3) to produce a colorless oil. MS (ES) for C26H27NO6 [M+H]+: 450.
Reaction SMILES: B(Cl)([C@@H]1[C@@H](C)[C@H]2C(C)(C)[C@H](C2)C1)[C@@H]1[C@@H](C)[C@H]2C(C)(C)[C@H](C2)C1.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:31](=[O:33])[CH3:32]>O1CCCC1>[CH3:23][O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C@H:31]([OH:33])[CH3:32]
Reactant: COc1ccccc1C(C)=O
Agent: C[C@@H]1[C@@H](B(Cl)[C@H]2C[C@H]3C[C@@H]([C@@H]2C)C3(C)C)C[C@H]2C[C@@H]1C2(C)C
Solvent: C1CCOC1
Product: COc1ccccc1[C@@H](C)O
Temperature: -25 °C
Reaction time: 1 h
Yield: 75.2 %

Procedure:
To a solution of (+)-B-chlorodiisopinocampheylborane (10.5 g) in tetrahydrofuran (50 ml) was added dropwise 2′methoxyacetophenone (10.5 g) at −25° C. The mixture was stirred at −25° C. for 1 hr and concentrated under reduced pressure. To the residue were added diethyl ether (100 ml) and diethanolamine (18.1 g) and the reaction mixture was stirred at room temperature for 2 hr. The precipitated solid was filtered off. The filtrate was concentrated under reduced pressure and purified by distillation under reduced pressure (bp 74–77° C./1 mmHg) to give the title compound (8.00 g).