Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:10]([S:11](=[O:14])(=[O:13])[NH2:12])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16].[OH-].[Na+].[C:20]([NH:23][C:24]1[CH:29]=[CH:28][C:27]([SH:30])=[CH:26][CH:25]=1)(=[O:22])[CH3:21]>>[C:20]([NH:23][C:24]1[CH:29]=[CH:28][C:27]([S:30][C:2]2[C:10]([S:11](=[O:14])(=[O:13])[NH2:12])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=2[N+:15]([O-:17])=[O:16])=[CH:26][CH:25]=1)(=[O:22])[CH3:21]
Reactant: NS(=O)(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1Cl
Reactant: CC(=O)Nc1ccc(S)cc1
Agent: [Na+]
Agent: [OH-]
Product: CC(=O)Nc1ccc(Sc2c([N+](=O)[O-])cc(C(=O)O)cc2S(N)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
The starting material is prepared as follows: The mixture of 19.6 g of 4-chloro-3-nitro-5-sulfamoylbenzoic acid, 280 ml of N aqueous sodium hydroxide and 11.8 g of 4-acetamidothiophenol is stirred for 24 hours at room temperature under nitrogen. It is filtered, the filtrate made strongly acidic with concentrated hydrochloric acid, the precipitate formed filtered off and recrystallized from 50% aqueous ethanol, to yield the 4-(4-acetamidophenylmercapto)-3-nitro-5-sulfamoylbenzoic acid, melting at 168°. 8.2 g thereof are added portionwise to the mixture of 16 g of iron powder, 1.7 g of ammonium chloride, 70 ml of water and 0.8 ml of N hydrochloric acid while stirring. After heating it for 4 hours at the steam bath it is filtered hot, the precipitate taken up in 200 ml of N aqueous sodium hydroxide and the solution filtered. The filtrates are acidified with concentrated hydrochloric acid and the precipitate formed recrystallized from 50% aqueous ethanol, to yield the 4-(4-acetamidophenylmercapto)-3-amino-5-sulfamoylbenzoic acid melting at 207°.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([C:8]1[CH:13]=[C:12]([NH2:14])[C:11]([O:15][CH3:16])=[CH:10][C:9]=1[O:17][CH3:18])=[O:7].[F:19][C:20]([F:31])([F:30])[C:21]1[CH:26]=[CH:25][C:24]([N:27]=[C:28]=[O:29])=[CH:23][CH:22]=1.C1(C)C=CC=CC=1>C(OCC)(=O)C>[Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([C:8]1[C:9]([O:17][CH3:18])=[CH:10][C:11]([O:15][CH3:16])=[C:12]([NH:14][C:28]([NH:27][C:24]2[CH:23]=[CH:22][C:21]([C:20]([F:19])([F:30])[F:31])=[CH:26][CH:25]=2)=[O:29])[CH:13]=1)=[O:7]
Reactant: COc1cc(OC)c(C(=O)CCCCCl)cc1N
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COc1cc(OC)c(C(=O)CCCCCl)cc1NC(=O)Nc1ccc(C(F)(F)F)cc1
Temperature: 50 °C
Yield: 94 %

Procedure:
A mixture of 5-chloro-1-(5-amino-2,4-dimethoxyphenyl)-1-pentanone (0.27 g, 1 mmol), prepared as in Example 14, α,α,α-trifluoro-p-tolyl isocyanate (0.16 mL, 1.1 mmol), toluene (3 mL) and ethyl acetate (0.5 mL) was heated 10 minutes with stirring at approximately 50° C. The mixture was concentrated and the residue was recrystallized from hexane/ethyl acetate. The solids were collected and dried at 70° C. to give 1-[5-(5-chloropentanoyl)-2,4-dimethoxyphenyl]-3-(4-trifluoromethylphenyl)urea (0.43 g, 0.94 mmol), m.p. 154°-156° C.
Reaction SMILES: [Na].[N+:2]([C:5]1[CH:10]=[C:9]([N+]([O-])=O)[CH:8]=[C:7]([N+:14]([O-:16])=[O:15])[CH:6]=1)([O-:4])=[O:3].[CH3:17][OH:18]>>[N+:2]([C:5]1[CH:10]=[C:9]([O:18][CH3:17])[CH:8]=[C:7]([N+:14]([O-:16])=[O:15])[CH:6]=1)([O-:4])=[O:3]
Reactant: CO
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Agent: [Na]
Product: COc1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Reaction time: 8 h

Procedure:
Sodium (575 mg, 25 mmol) was dissolved in absolute methanol (100 ml). 1,3,5-Trinitrobenzene (4.26 g, 20 mmol) was then added and the solution was stirred overnight. After evaporation of the solvent, water was added and the precipitate was filtered off, washed with water and dried. The material was used without purification in the next step. Yield: 3.4 g (86%).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([C:10](=O)[CH3:11])=[N:2]1.Cl.[NH2:14][OH:15].N1C=CC=CC=1>C(OCC)(=O)C>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([C:10](=[N:14][OH:15])[CH3:11])=[N:2]1
Reactant: NO
Reactant: CC(=O)c1noc2ccccc12
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(=NO)c1noc2ccccc12
Temperature: 0 °C

Procedure:
A mixture of 1.4 g of 1-(1,2-benzisoxazol-3-yl)ethanone, 0.7 g of hydroxylamine hydrochloride and 10 ml of pyridine is refluxed for 1 h. The reaction mixture is then poured onto a mixture of ice/water and the precipitated product is isolated by filtration. The product is dissolved in ethyl acetate, the solution is washed once with water, then twice with a saturated solution of sodium chloride and finally dried over sodium sulfate. The solvent is stripped off under vacuum, to give pure 1-(1,2-benzisoxazol-3-yl)ethanone oxime having a melting point of 193°-195° C.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[O:7][C:6](=[O:8])[N:5]([C:9]2[CH:18]=[C:17]3[C:12]([CH:13]=[C:14]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[CH2:26][C:27](C)=[CH2:28])[NH:15][C:16]3=[O:19])=[CH:11][CH:10]=2)[CH2:4]1.I([O-])(=O)(=O)=[O:31].[Na+].O.[BH4-].[Na+]>C1COCC1.O.[Os]=O>[OH:1][CH2:2][C@@H:3]1[O:7][C:6](=[O:8])[N:5]([C:9]2[CH:18]=[C:17]3[C:12]([CH:13]=[C:14]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[CH2:26][CH:27]([OH:31])[CH3:28])[NH:15][C:16]3=[O:19])=[CH:11][CH:10]=2)[CH2:4]1
Reactant: C=C(C)Cc1ccccc1-c1cc2ccc(N3C[C@H](CO)OC3=O)cc2c(=O)[nH]1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os]
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(O)Cc1ccccc1-c1cc2ccc(N3C[C@H](CO)OC3=O)cc2c(=O)[nH]1
Temperature: 25 °C
Reaction time: 15 h
Yield: 60.6 %

Procedure:
The 7-((R)-5-hydroxymethyl-2-oxooxazolidin-3-yl)-3-[2-(2-methylallyl)phenyl]-2H-isoquinolin-1-one (25 mg, 0.064 mmol) obtained in Example 2-40 was dissolved in THF-water (3 ml-1 ml). Thereafter, an osmium oxide aqueous solution (0.1 mmol/ml, 0.032 ml, 0.0032 mmol) and sodium periodate (55 mg, 0.26 mmol) were added to the solution, and the obtained mixture was then stirred at a room temperature for 15 hours. Thereafter, water was added to the reaction mixture, followed by extraction with methylene chloride. The extract was dried over magnesium sulfate, and was then concentrated under reduced pressure. The thus obtained ketone body (24 mg) that was a roughly purified product was dissolved in methanol (2 ml) without being further purified. Thereafter, sodium borohydride (7.3 mg, 0.19 mmol) was added to the obtained solution under cooling on ice. The obtained mixture was stirred at a room temperature for 2 hours. Thereafter, the reaction solution was concentrated, and was then purified by preparative TLC (methylene chloride:methanol=10:1), so as to obtain 7-((R)-5-hydroxymethyl-2-oxooxazolidin-3-yl)-3-[2-(2-hydroxypropyl)phenyl]-2H-isoquinolin-1-one (15.3 mg, 61%, two-stage) in the form of white powders.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([N:13]3[CH2:17][CH2:16][CH2:15][CH:14]3[CH3:18])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH2:19].[NH:20]1[C:28]2[C:23](=[CH:24][C:25]([C:29](O)=[O:30])=[CH:26][CH:27]=2)[CH:22]=[CH:21]1>>[CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([N:13]3[CH2:17][CH2:16][CH2:15][CH:14]3[CH3:18])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH:19][C:29]([C:25]1[CH:24]=[C:23]2[C:28](=[CH:27][CH:26]=1)[NH:20][CH:21]=[CH:22]2)=[O:30]
Reactant: Cc1cc(N2CCC(N3CCCC3C)C2)ccc1N
Reactant: O=C(O)c1ccc2[nH]ccc2c1
Product: Cc1cc(N2CCC(N3CCCC3C)C2)ccc1NC(=O)c1ccc2[nH]ccc2c1

Procedure:
The title compound was prepared in a manner substantially the same as example 1 by coupling 2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine with 1H-indole-5-carboxylic acid. MS: 403.3 (M+H).
Reaction SMILES: [Br:1][C:2]1[C:3]([NH:11][C:12]([NH:14]C(OCC)=O)=S)=[N:4][CH:5]=[C:6]([CH:8]2[CH2:10][CH2:9]2)[CH:7]=1.Cl.NO.C([N:26](C(C)C)CC)(C)C>CO>[Br:1][C:2]1[C:3]2[N:4]([N:26]=[C:12]([NH2:14])[N:11]=2)[CH:5]=[C:6]([CH:8]2[CH2:9][CH2:10]2)[CH:7]=1
Reactant: CCOC(=O)NC(=S)Nc1ncc(C2CC2)cc1Br
Reactant: CCN(C(C)C)C(C)C
Agent: Cl
Agent: NO
Solvent: CO
Product: Nc1nc2c(Br)cc(C3CC3)cn2n1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of N-(3-bromo-5-cyclopropyl-pyridin-2-yl)-N′-ethoxycarbonyl-thiourea (1.5 g, 4.36 mmol) in dry methanol (20 mL) were added hydroxylamine hydrochloride (1.41 g, 21.8 mmol) and diisopropyl ethylamine (12.14 mL, 13.08 mmol) under an argon atmosphere and stirred at room temperature for 6 hours. Methanol was evaporated and the residue purified by silica gel chromatography using ethyl acetate/hexane as eluent. The title compound was obtained as off white solid (910 mg, 82%).
Reaction SMILES: [CH:1]1([CH2:5][CH:6]([C:8]([OH:10])=[O:9])[NH2:7])[CH2:4][CH2:3][CH2:2]1.Cl[C:12]([O:14][CH2:15][CH3:16])=[O:13]>[OH-].[Na+]>[CH2:15]([O:14][C:12]([NH:7][CH:6]([C:8]([OH:10])=[O:9])[CH2:5][CH:1]1[CH2:4][CH2:3][CH2:2]1)=[O:13])[CH3:16]
Reactant: NC(CC1CCC1)C(=O)O
Reactant: CCOC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Product: CCOC(=O)NC(CC1CCC1)C(=O)O
Reaction time: 2 h

Procedure:
10 g (70 mmol) of 3-cyclobutyl-DL-alanine [A. Burger et al., J. Med. Chem. 6, 221 (1963)] is dissolved, in 70 ml of 2M NaOH solution, cooled to +5° C. and 11.1 ml (116.2 mmol) of ethyl chloroformate is added in drops with constant stirring. Stirring is continued for 2 hours at this temperature, and for further 2 hours at room temperature. The reaction mixture is then washed with 20 ml of diethyl ether and after acidifying the solution to pH1 extracted with 3×20 ml of ethyl acetate. The pooled extracts are washed with brine, dried over anhydrous sodium sulphate and the solvent is evaporated at a pressure of 2.0-2.5 kPa. The resulted oil is considered to be the pure product [Yield: 13.1 g (87%), Rf(7)=0.8] and is used without further treatment in the next step.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[C:11]([C:15]1[CH:16]=[C:17]([CH:21]=[C:22]([C:25]([CH3:28])([CH3:27])[CH3:26])[C:23]=1[OH:24])[C:18](Cl)=[O:19])([CH3:14])([CH3:13])[CH3:12]>COCCOC>[C:6]([C:5]1[CH:9]=[CH:10][C:2]([NH:1][C:18](=[O:19])[C:17]2[CH:21]=[C:22]([C:25]([CH3:26])([CH3:27])[CH3:28])[C:23]([OH:24])=[C:15]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:16]=2)=[CH:3][CH:4]=1)([OH:8])=[O:7]
Reactant: Nc1ccc(C(=O)O)cc1
Reactant: CC(C)(C)c1cc(C(=O)Cl)cc(C(C)(C)C)c1O
Solvent: COCCOC
Product: CC(C)(C)c1cc(C(=O)Nc2ccc(C(=O)O)cc2)cc(C(C)(C)C)c1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 32.7 %

Procedure:
A solution of 8.6g (0.063 mole) of p-aminobenzoic acid in 100 ml of 1,2-dimethoxyethane was added to a suspension of 8.0g (0.0298 mole) of 3,5-di-t-butyl-4-hydroxybenzoyl chloride in 100 ml of 1,2-dimethoxyethane, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was then filtered. The filtrate was thereafter diluted with 200 ml of water and chilled. The resulting precipitate was collected, and was then recrystallized from a mixture of ethanol and water to give 3.6g of white needles of N-(4-carboxyphenyl)-3,5-di-t-butyl-4-hydroxybenzamide, m.p. 265°-266° C. Analysis: Calculated for C22H27NO4 : %C, 71.5; %H, 7.4; %N, 3.8; Found: %C, 71.7; %H, 7.3; %N, 3.6.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([O:13]CC2C=CC=CC=2)=[CH:5][C:4]=1[CH3:21].[H][H]>[Pd].C(OCC)(=O)C>[CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([OH:13])=[CH:5][C:4]=1[CH3:21]
Reactant: COc1c(C)cc(OCc2ccccc2)c2ccccc12
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COc1c(C)cc(O)c2ccccc12

Procedure:
The 1-methoxy-2-methyl-4-benzyloxynaphthalene, in an amount of 925 milligrams, is added to a mixture of 286 milligrams of a 10 percent palladium/carbon catalyst in 20 milliliters of ethyl acetate. The resultant mixture is subjected to hydrogenolysis by contact with a mixture of hydrogen and nitrogen at atmospheric pressure for 38 hours. Subsequent to the hydrogenolysis, the catalyst is removed by centrifugation, and the crude product is obtained by solvent evaporation. Crystallization of the product from benzene/petroleum ether gives 4-methoxy-3-methyl-1-naphthol in an amount of 473 milligrams.
Reaction SMILES: [I:1][C:2]1[CH:11]=[N:10][C:5]2[NH:6][CH2:7][CH2:8][NH:9][C:4]=2[CH:3]=1.[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[S:19](Cl)(=[O:21])=[O:20]>N1C=CC=CC=1>[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[S:19]([N:9]1[CH2:8][CH2:7][NH:6][C:5]2[N:10]=[CH:11][C:2]([I:1])=[CH:3][C:4]1=2)(=[O:21])=[O:20]
Reactant: Ic1cnc2c(c1)NCCN2
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Solvent: c1ccncc1
Product: O=S(=O)(c1ccccc1Cl)N1CCNc2ncc(I)cc21
Temperature: 100 °C
Yield: 10 %

Procedure:
7-Iodo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine (300 mg) was dissolved in anhydrous pyridine. 2-chlorobenzene sulfonyl chloride (1.0 eq) was added and the reaction mixture was heated to 100° C. in a microwave oven for 10 minutes. Silica gel chromatography gave the title compound as a pale orange solid (10% yield). M.p. 146-147° C., LCMS: m/z=435.94 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 3.30-3.35 (m, 2H), 3.80 (t, J=5.0 Hz, 2H), 5.02 (bs, 1H), 7.42-4.57 (m, 3H), 7.81 (d, J=1.8 Hz, 1H), 8.00 (d, J=1.8 Hz, 1H), 8.10 (dd, J=8.6 Hz, 1.5 Hz, 1H).
Reaction SMILES: C[O:2][C:3](=[O:19])[CH:4]([O:17][CH3:18])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH2:13][CH2:14][CH2:15]Br)[CH:7]=1.[CH:20]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[OH:29])([CH3:22])[CH3:21].CO[C@@H](CC1C=CC(OCCCOC2C=CC=CC=2)=CC=1)C(O)=O>>[CH:20]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[O:29][CH2:15][CH2:14][CH2:13][O:12][C:8]1[CH:7]=[C:6]([CH2:5][CH:4]([O:17][CH3:18])[C:3]([OH:2])=[O:19])[CH:11]=[CH:10][CH:9]=1)([CH3:22])[CH3:21]
Reactant: CC(C)c1ccccc1O
Reactant: COC(=O)C(Cc1cccc(OCCCBr)c1)OC
Agent: CO[C@@H](Cc1ccc(OCCCOc2ccccc2)cc1)C(=O)O
Product: COC(Cc1cccc(OCCCOc2ccccc2C(C)C)c1)C(=O)O

Procedure:
The title compound-was prepared from 3-[3-(3-bromo-propoxy)-phenyl]-2-methoxy-propionic acid methyl ester (Example 323, Step 1) and 2-isopropylphenol via the same procedure used for the preparation of (2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid (Example 285, Step 1). The enatiomers were separated by chiral HPLC. MS (ES) for C22H28O5 [M+Na]+: 395.4.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11](=O)[CH:12]=[CH:13][C:14](=O)[CH3:15])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[O:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[C:23]1[CH:29]=[CH:28][C:26]([NH2:27])=[CH:25][CH:24]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[O:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[C:23]1[CH:29]=[CH:28][C:26]([N:27]2[C:11]([C:8]3[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:6][CH:7]=3)=[CH:12][CH:13]=[C:14]2[CH3:15])=[CH:25][CH:24]=1
Reactant: Nc1ccc(-c2ccco2)cc1
Reactant: CC(=O)C=CC(=O)c1ccc(S(C)(=O)=O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2ccc(S(C)(=O)=O)cc2)n1-c1ccc(-c2ccco2)cc1
Yield: 24.3 %

Procedure:
A mixture of 1-[4-(methylsulfonyl)phenyl]pentene-1,4-dione (0.305 g, 1.2 mmol prepared according to the method of J. Med. Chem., 1997, 40 , 1619), 4-(2-furyl)aniline (0.35 g, 2 mmol), and p-toluenesulfonic acid monohydrate (0.015 g) in toluene (40 mL) was heated at reflux temperature for 16 hours using Dean-Stark apparatus. After cooling, volatiles were removed by evaporation. The residue was purified by flash chromatography eluting with hexane/ethyl acetate (4/1). The resulting solid was recrystallized from CH2Cl2/hexane to give the title compound (0.11 g, 24.3% yield).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]#[N:11])=[CH:4][CH:3]=1.[CH3:12][N:13]1[C:17]([C:18]#[N:19])=[CH:16][CH:15]=[C:14]1B(O)O.C(=O)([O-])[O-].[K+].[K+].COC(OC)COCC(OC)OC.O>O>[C:18]([C:17]1[N:13]([CH3:12])[C:14]([C:2]2[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]#[N:11])=[CH:4][CH:3]=2)=[CH:15][CH:16]=1)#[N:19]
Reactant: N#CNCc1ccc(Br)cc1
Reactant: Cn1c(C#N)ccc1B(O)O
Agent: COC(COCC(OC)OC)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Cn1c(C#N)ccc1-c1ccc(CNC#N)cc1
Temperature: 10 °C
Yield: 27 %

Procedure:
(4-bromophenyl)methyl cyanamide (0.100 g, 0.47 mmol) tetrakis(triphenylphosphine)palladium(0) (0.050 g, 0.043 mmol), N-methyl-5-cyanopyrroleboronic acid (0.150 g, 1 mmol), potassium carbonate (0.345 g, 2.5 mmol) and dimethoxyethylether/water 3:1 were placed in a microwave reaction vial fitted with a septa. The vial was then filled with a continuous flow of nitrogen. Using microwave assisted conditions, the mixture was heated to 10° C. for 15 minutes. The mixture was poured into water, extracted with ethyl acetate, the ethylacetate dried over magnesium sulfate, and evaporated in vacuo. The residue was flash chromatographed using 9/1 Hexane/ethylacetate to give [4-(5-cyano-1-methyl-1H-pyrrol-2-yl)phenyl]methylcyanamide (0.030 g, 27%). HPLC purity 100% at 210-370 nm, 10 min.; the Xterra™ RP18 instrument, 3.5μ, 150×4.6 mm column, 1.2 mL/min., 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for 10 min., hold 4 min. HRMS: calcd for C14H12N4+H+, 237.11347; found (ESI, [M+H]+), 237.1127.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[NH:13][C:14](=[O:41])[N:15]([C:17]1[N:22]=[CH:21][N:20]=[C:19]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([N:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)=[CH:26][C:25]=2[NH:36][C:37](=[O:40])[CH:38]=[CH2:39])[CH:18]=1)[CH3:16].CCN(C(C)C)C(C)C.[C:51](Cl)(=[O:53])[CH3:52]>C(Cl)Cl>[C:51]([N:33]1[CH2:32][CH2:31][N:30]([C:27]2[CH:28]=[CH:29][C:24]([NH:23][C:19]3[CH:18]=[C:17]([N:15]([CH3:16])[C:14]([NH:13][C:3]4[C:2]([Cl:1])=[C:7]([O:8][CH3:9])[CH:6]=[C:5]([O:10][CH3:11])[C:4]=4[Cl:12])=[O:41])[N:22]=[CH:21][N:20]=3)=[C:25]([NH:36][C:37](=[O:40])[CH:38]=[CH2:39])[CH:26]=2)[CH2:35][CH2:34]1)(=[O:53])[CH3:52]
Reactant: CC(=O)Cl
Reactant: C=CC(=O)Nc1cc(N2CCNCC2)ccc1Nc1cc(N(C)C(=O)Nc2c(Cl)c(OC)cc(OC)c2Cl)ncn1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CC(=O)Nc1cc(N2CCN(C(C)=O)CC2)ccc1Nc1cc(N(C)C(=O)Nc2c(Cl)c(OC)cc(OC)c2Cl)ncn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 15.5 %

Procedure:
N-(2-((6-(3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-methylureido)pyrimidin-4-yl)amino)-5-(piperazin-1-yl)phenyl)acrylamide (Procedure 2L, Example 157) (8.6 g, 0.014 mmol) and DIEA (7.5 μl, 0.043 mmol) were stirred in DCM (1.0 ml) at room temperature under nitrogen atmosphere. A solution of acetyl chloride (1.0 μl, 0.016 mmol) in DCM (11 ul) was added and the reaction mixture was stirred at room temperature for 2 hours. The solvent was evaporated and the resulting material was dissolved in 400 ul of DMSO. The DMSO solution was diluted with 1.0 ml of MeOH and purified by prep-HPLC (water/ACN in formic acid condition) to afford the title compound (1.4 mg, yield: 15%). 1H-NMR (400 MHz, MeOH-d4) δ 2.16 (s, 3H) 3.65-3.80 (m, 4H) 3.94 (s, 6H) 5.76 (dd, 1H) 6.15 (s, 1H) 6.28-6.49 (m, 2H) 6.78-6.82 (m, 1H) 6.95 (dd, 2.89 Hz, 1H) 7.28-7.38 (m, 2H) 8.31 (d, 1H) 8.58 (br. s., 1H); ESI-MS: 643 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[NH:18][C:17]([CH3:22])=[CH:16]4)=[N:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:23][CH3:24].Br[CH2:26][CH2:27][CH2:28][Cl:29].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Cl:29][CH2:28][CH2:27][CH2:26][O:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[NH:18][C:17]([CH3:22])=[CH:16]4)=[N:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:23][CH3:24]
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3)ncnc2cc1O
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3)ncnc2cc1OCCCCl
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.4 %

Procedure:
A suspension of 7-hydroxy-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline (321 mg, 1 mmol), (prepared as described in Example 49), 1-bromo-3-chloropropane (120 μl, 1.2 mmol) and potassium carbonate (359 mg, 2.6 mmol) in DMF (5 ml) was stirred at ambient temperature overnight. After addition of water, the precipitate was collected by filtration, washed with water and dried over phosphorus pentoxide at 60° C. to give 7-(3-chloropropoxy)-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline (280 mg, 70%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][C@@H:9]1[CH:14]([CH3:16])[CH3:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Cl[C:20]1[O:21][C:22]2[C:23](=[C:25]([C:29]([O:31][CH3:32])=[O:30])[CH:26]=[CH:27][CH:28]=2)[N:24]=1>COCCOC>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:20]2[O:21][C:22]3[C:23](=[C:25]([C:29]([O:31][CH3:32])=[O:30])[CH:26]=[CH:27][CH:28]=3)[N:24]=2)[CH2:10][C@@H:9]1[CH:14]([CH3:16])[CH3:15])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)c1cccc2oc(Cl)nc12
Reactant: CC(C)[C@H]1CNCCN1C(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: COC(=O)c1cccc2oc(N3CCN(C(=O)OC(C)(C)C)[C@@H](C(C)C)C3)nc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 39.5 %

Procedure:
To a solution of 1-tert-butyloxycarbonyl-(S)-2-isopropylpiperazine (384 mg, 1.7 mmol) in DME (10 mL) was added NaH (70 mg of 60% suspension in mineral oil, 1.6 mmol) and the mixture was stirred for 1 h at room temperature. Methyl 2-chlorobenzoxazole-4-carboxylate (368 mg, 1.6 mmol) was added to the reaction mixture and suspension formed was stirred at room temperature for 17 h. The reaction mixture was quenched with CH3OH (10 mL), silica gel (15 mL) was added, and solvent removed under reduced pressure. The mixture was purified by column chromatography (silica gel, 0 to 80% EtOAc in CH2Cl2) to afford methyl 2-(4-(tert-butoxycarbonyl)-(S)-3-isopropylpiperazin-1-yl)benzoxazole-4-carboxylate (255 mg, 39%) as a white foam. 1H NMR and MS consistent.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1.Cl[CH2:16][CH2:17][CH:18]([OH:27])[CH2:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(=O)([O-])[O-].[Na+].[Na+].C(O)(C)C>C(O)CCC>[O:20]([CH2:19][CH:18]([OH:27])[CH2:17][CH2:16][N:12]1[CH2:13][CH2:14][N:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[CH2:10][CH2:11]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: OC(CCCl)COc1ccccc1
Reactant: COc1ccc(N2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCCCO
Solvent: CC(C)O
Product: COc1ccc(N2CCN(CCC(O)COc3ccccc3)CC2)cc1

Procedure:
This compound was prepared according to the procedure of Example 78. A mixture of 4.8 g (0.025 mole) of 1-(4-methoxyphenyl)piperazine, 5.0 g (0.025 mole) of 4-chloro-1-phenoxy-2-butanol and 8.0 g (0.075 mole) of anhydrous sodium carbonate in 100 ml of 1-butanol gave 6.4 g (72%) of tan towder., m.p. 95°-97° C. Recrystallizing solvent used was isopropyl alcohol.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7](Br)[CH:8]=2)[CH:3]=1.[CH3:13][C:14]1([CH3:27])[CH2:23][CH2:22][C:21]([CH3:25])([CH3:24])[C:20]2[CH:19]=[C:18](Br)[CH:17]=[CH:16][C:15]1=2>>[CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:18]3[CH:17]=[CH:16][C:15]4[C:14]([CH3:27])([CH3:13])[CH2:23][CH2:22][C:21]([CH3:25])([CH3:24])[C:20]=4[CH:19]=3)[CH:8]=2)[CH:3]=1
Reactant: CC1(C)CCC(C)(C)c2cc(Br)ccc21
Reactant: Cc1ccc2cc(Br)ccc2c1
Product: Cc1ccc2cc(-c3ccc4c(c3)C(C)(C)CCC4(C)C)ccc2c1
Yield: 72.5 %

Procedure:
In accordance with the same procedures as in Example 1, part (b), starting with 2-methyl-6-bromonaphthalene (2.21 g, 10 mmoles) and 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-bromonaphthalene (3.20 g, 12 mmoles), there is obtained after column chromatography (9 hexane, 1 dichloromethane) 2-methyl-6-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)naphthalene (2.38 g, 72%) having a melting point of 173°-175° C.
Reaction SMILES: C[O-].[Na+].[CH:4](OCC)=[O:5].[C:9]1([C:17]([CH2:19][C:20]2[CH:27]=[CH:26][C:23]([O:24][CH3:25])=[CH:22][CH:21]=2)=[O:18])[CH:16]=[CH:15][C:12]([O:13][CH3:14])=[CH:11][CH:10]=1.O1CCCC1>C(O)C>[CH:4]([CH:19]([C:20]1[CH:21]=[CH:22][C:23]([O:24][CH3:25])=[CH:26][CH:27]=1)[C:17](=[O:18])[C:9]1[CH:10]=[CH:11][C:12]([O:13][CH3:14])=[CH:15][CH:16]=1)=[O:5]
Reactant: CCOC=O
Reactant: COc1ccc(CC(=O)c2ccc(OC)cc2)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1ccc(C(=O)C(C=O)c2ccc(OC)cc2)cc1
Reaction time: 1 h

Procedure:
A solution of sodium methoxide (11.9 g, 0.22 mole) in 80 ml ethanol was cooled in an ice bath and treated with ethyl formate (20 ml, 0.24 mole). A solution of desoxyanisoin (51.2 g, 0.2 mole) in 275 ml warm tetrahydrofuran was then added while maintaining the reaction temperature below 5°. The reaction mixture was stirred for 1 hour at 0° and then stirred overnight at room temperature.