Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]([C:11]2[C:19]3[C:15](=[N:16][O:17][N:18]=3)[CH:14]=[CH:13][CH:12]=2)[C:9]([C:20]([O:22][CH:23]([CH3:25])[CH3:24])=[O:21])=[C:8]([CH3:26])[NH:7][N:6]=1)=[O:4].[OH-].[K+].[CH3:29]I>CS(C)=O>[CH3:1][O:2][C:3]([C:5]1[CH:10]([C:11]2[C:19]3[C:15](=[N:16][O:17][N:18]=3)[CH:14]=[CH:13][CH:12]=2)[C:9]([C:20]([O:22][CH:23]([CH3:24])[CH3:25])=[O:21])=[C:8]([CH3:26])[N:7]([CH3:29])[N:6]=1)=[O:4]
Reactant: COC(=O)C1=NNC(C)=C(C(=O)OC(C)C)C1c1cccc2nonc12
Reactant: CI
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: COC(=O)C1=NN(C)C(C)=C(C(=O)OC(C)C)C1c1cccc2nonc12
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To the solution of 3.2 g of 4-(2,1,3-benzoxadiazol-4-yl)-1,4-dihydro-5-isopropoxycarbonyl-6-methyl-3-pyridazine carboxylic acid methylester (I R4 =H, R3 =CH3, R1 =CH3, R2 =isopropyl) in 60 ml of dimethyl sulphoxide are added 2.0 g of powdered potassium hydroxide, and then 1.1 ml of methyl iodide are dropwise added. The mixture is stirred for 45 minutes at room temperature, and is then poured into 120 ml of ice water and extracted with methylene chloride. The product obtained after drying the methylene chloride solution over magnesium sulphate and evaporating under vacuum is purified by chromatography on silica gel. After elution with methylene chloride - ether mixtures and subsequent crystallization from ether - petroleum ether, the pure substance is obtained with a m.p. of 107° .
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH2:9][CH2:8][N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:6]1)=[O:4].[CH3:18][Si](C)(C)N[Si](C)(C)C.[Na].IC>C1COCC1>[CH3:1][O:2][C:3]([C:5]1([CH3:18])[CH2:10][CH2:9][CH2:8][N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:6]1)=[O:4]
Reactant: C[Si](C)(C)N[Si](C)(C)C
Reactant: COC(=O)C1CCCN(C(=O)OC(C)(C)C)C1
Agent: [Na]
Solvent: C1CCOC1
Solvent: CI
Product: COC(=O)C1(C)CCCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.8 %

Procedure:
To a −78 ° C. stirred solution of Intermediate 53 (2.22 g, 9.13 mmol) in dry THF (30 ml) was added NaHMDS (sodium hexamethyldisilazane) (1.0 M in THF, 10.03 mmol) dropwise. The reaction was stirred at this temperature for 30 minutes and then iodomethane (0.682 ml, 10.95 mmol) was added dropwise. The reaction was allowed to warm to room temperature overnight with good stirring. The reaction was cooled and then quenched with saturated NH4Cl. The layers were separated and the aqueous layer was extracted three times with 20 ml of EtOAc and the organic extracts were combined. The organic phase was dried over Na2SO4, filtered and concentrated under reduced pressure. The oil was purified by silica chromatography using hexanes/EtOAc (0→15%) to yield 2.25 g (95.8%) of 3-methyl-piperidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester (Intermediate 54). 1H NMR (400 MHz, CDCl3) δ ppm 1.0 (s, 3H), 1.3 (s, 9H), 1.4 (m, 2H), 1.9 (m, 2H), 3.0 (d, J=13.2 Hz, 1H), 3.1 (m, 1H), 3.3 (m, 1H), 3.5 (s, 3H), 3.7 (d, J=13.4 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](=[O:11])[CH3:10])=[CH:4][CH:3]=1.[BrH:12].BrBr.CC(C)=O>C(O)(=O)C>[Br:12][CH2:10][C:9](=[O:11])[CH2:8][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1
Reactant: Br
Reactant: CC(=O)Cc1ccc(Cl)cc1
Agent: BrBr
Solvent: CC(=O)O
Solvent: CC(C)=O
Product: O=C(CBr)Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 69.3 %

Procedure:
To a solution of 1-(4-chlorophenyl)propan-2-one (25.0 g, 148 mmol) in acetic acid (37.9 mL) was added 48% aqueous HBr (19.0 mL, 168 mmol). A solution of bromine (16.3 mL, 316 mmol) in acetic acid (63.2 mL) was then added over 10 minutes and the resulting solution was stirred for 4 hours at room temperature. Acetone (190 mL) was added and the resulting solution was stirred at room temperature for 3 days. The reaction was concentrated in vacuo and the residue was taken up in DCM (300 mL) and brine (100 mL). The layers were separated and the aqueous layer was extracted with DCM (100 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (ethyl acetate/hexanes=0/100→15/85) to give 25.4 grams of the title compound as a dark gray solid (69% yield). 1H NMR (400 MHz, CDCl3) δ: 7.34-7.31 (m, 2H), 7.18-7.15 (m, 2H), 3.94 (s, 2H), 3.91 (2, 2H).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][O:11][CH2:12][CH:13]2[CH2:15][O:14]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N-:16]=[N+:17]=[N-:18].[Na+].C(OC)=O.CO>O>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][O:11][CH2:12][CH:13]([OH:14])[CH2:15][N:16]=[N+:17]=[N-:18])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [N-]=[N+]=[N-]
Reactant: c1ccc(CCCCOCC2CO2)cc1
Agent: [Na+]
Solvent: O
Solvent: COC=O
Solvent: CO
Product: [N-]=[N+]=NCC(O)COCCCCc1ccccc1
Yield: 99.7 %

Procedure:
A procedure similar to that described in Preparation 12 was repeated, except that 3.70 g of 4-phenylbutoxymethyloxirane (prepared as described in Preparation 58), 5.83 g of sodium azide, 37 ml of methyl formate and 135 ml of an 8:1 by volume mixture of methanol and water were used, to give 4.46 g of the title compound as a colorless oil having an Rf value of 0.67 (on silica gel thin layer chromatography, using a 2:1 by volume mixture of hexane and ethyl acetate as the developing solvent).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[CH:11]=[C:12]([C:16]([N:18]=[S@:19]([CH2:27][C:28](OCC)=[O:29])([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:20])=[O:17])[CH:13]=[N:14][CH:15]=2)[CH:5]=[CH:6][CH:7]=1.Cl.[NH2:34][CH2:35][C:36]([NH2:38])=[O:37]>>[NH2:38][C:36](=[O:37])[CH2:35][NH:34][C:28](=[O:29])[CH2:27][S:19](=[O:20])([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[N:18][C:16](=[O:17])[C:12]1[CH:11]=[C:10]([C:9]#[C:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([OH:1])[CH:3]=2)[CH:15]=[N:14][CH:13]=1
Reactant: CCOC(=O)C[S@@](=O)(=NC(=O)c1cncc(C#Cc2cccc(O)c2)c1)c1ccccc1
Reactant: NCC(N)=O
Agent: Cl
Product: NC(=O)CNC(=O)CS(=O)(=NC(=O)c1cncc(C#Cc2cccc(O)c2)c1)c1ccccc1
Yield: 49.4 %

Procedure:
In a manner similar to that described for Example 471, (S)-Ethyl [N-({5-[(3-hydroxyphenyl)ethynyl]pyridin-3-yl}carbonyl)-S-phenylsulfonimidoyl]acetate (75 mg, 0.17 mmol) and glycinamide hydrochloride (95 mg, 0.84 mmol) were reacted to give the title compound as colorless oil (40 mg, 50%).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[C:9](=O)[CH2:8][S:7][CH2:6]1)=[O:4].[NH2:11]O.N>>[NH2:11][C:9]1[C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][S:7][CH:8]=1
Reactant: NO
Reactant: COC(=O)C1CSCC1=O
Agent: N
Product: COC(=O)c1cscc1N

Procedure:
Diazotization of methyl 4-aminothiophene-3-carboxylate with sodium nitrite followed by treatment with dimethylamine provides methyl 4-[(dimethylamino)diazenyl]thiophene-3-carboxylate. Treatment of the ester with ammonia gave the required 4-[dimethylamino)diazenyl]thiophene-3-carboxamide (compd. No. 13). The methyl 4-aminothiophene-3-carboxylate is produced using known procedures in the prior art (33, 34, 35). Thus addition of methyl acrylate to methyl thioglycolate provided methyl 3-[(methoxycarbonyl)methylthio]propanoate in quantitative yield, which on cyclization in presence of sodium methoxide gave methyl 4-oxo-2,3,5-trihydrothiophene-3-carboxylate. Treatment of methyl 4-oxo-2,3,5-trihydrothiophene-3-carboxylate with hydroxylamine followed by basification with ammonia gave methyl 4-aminothiophene-3-carboxylate.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][C:13]([CH:17]([N:19]=[N+]=[N-])[CH3:18])([F:16])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>CO.[Ni]>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][C:13]([CH:17]([NH2:19])[CH3:18])([F:16])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [H][H]
Reactant: CC(N=[N+]=[N-])C1(F)CCN(C(=O)OCc2ccccc2)C1
Agent: [Ni]
Solvent: CO
Product: CC(N)C1(F)CCN(C(=O)OCc2ccccc2)C1
Yield: 90.1 %

Procedure:
A solution of 3-(1-azidoethyl)-3-fluoropyrrolidine-1-carboxylic acid benzyl ester (Example A16, 0.16 g, 0.5 mmol) in methanol (10 mL) is treated with Raney nickel (100 mg, wet weight) and shaken in a hydrogen atmosphere at room temperature and at 55 psi for 17 hours. The catalyst is removed by filtration through Celite, and the solvent is removed in vacuo to afford the title compound (0.12 g). 1H NMR (200 MHz, CDCl3): δ 7.30 (s, 5H), 5.12 (s, 2H), 3.84–3.22 (m, 5H), 2.23–1.79 (m, 4H), 1.20 (d, 3H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:18]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:20]=1)[NH2:17]>>[CH3:12][O:13][C:14]1[CH:15]=[C:16]([NH:17][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH2:8][C:9]([OH:11])=[O:10])[CH:18]=[C:19]([C:21]([F:22])([F:24])[F:23])[CH:20]=1
Reactant: COc1cc(N)cc(C(F)(F)F)c1
Reactant: O=C(O)Cc1ccccc1Br
Product: COc1cc(Nc2ccccc2CC(=O)O)cc(C(F)(F)F)c1

Procedure:
In the manner described in example 3, 2-bromophenylacetic acid is condensed with 3-methoxy-5-(trifluoromethyl)aniline to yield 2-[(3-methoxy-5-(trifluoromethyl)phenyl)amino]phenylacetic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([OH:16])=O)=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[F:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH2:25][NH2:26]>>[Cl:20][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:26][CH2:25][C:24]2[CH:27]=[CH:28][CH:29]=[C:22]([F:21])[CH:23]=2)=[O:16])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: NCc1cccc(F)c1
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Product: O=C(NCc1cccc(F)c1)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1

Procedure:
Prepared according to the procedure described for example 44 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carboxylic acid (35 mg, 0.1 mmol) and 3-fluorobenzylamine (14.0 mg, 0.12 mmol). The title compound was obtained as a solid (22.5 mg, 49% yield). MS m/z: 457.96, 459.96 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH3:9].[CH3:10][C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1.[F-].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:10][C:11]1[CH:16]=[CH:15][C:14]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[O:8][CH3:9])=[CH:13][CH:12]=1
Reactant: Cc1ccc(B(O)O)cc1
Reactant: COc1ccccc1Cl
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [Cs+]
Solvent: C1COCCO1
Product: COc1ccccc1-c1ccc(C)cc1
Reaction time: 24 h
Yield: 83.2 %

Procedure:
The general procedure from Example 12 was followed using 2-chloroanisole (143 mg, 1.0 mmol) and 4-MeC6H4B(OH)2 (204 mg, 1.5 mmol) with Pd2(dba)3 (13.3 mg, 0.0145 mmol) and (Me3C)2PH(O) from Experiment 2 (9.6 mg, 0.058 mmol) and CsF (456 mg, 3.0 mmol) in 4.0 mL of 1,4-dioxane. After 24 h, the reaction mixture was chromatographed with 5% ethyl acetate/hexane to give 165 mg (83% yield) of 2-(4-methylphenyl)anisole. It was >95% pure by 1H NMR and GC/MS. 1H NMR (500 MHz, CDCl3): δ 7.32 (d, J=8.06 Hz, 2H), 7.18 (m, 2H), 7.10 (d, J=7.88 Hz, 2H), 6.92-6.84 (m, 2H), 3.67 (s, 3H), 2.28 (s, 3H) ppm. 13C NMR (125 MHz, CDCl3): δ 156.5, 136.5, 135.6, 130.7, 129.4, 128.7, 128.3, 120.8, 111.2, 55.5, 21.1 ppm.
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][C:8]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]3[S:17][CH:18]=[C:19]([C:21](O)=[O:22])[N:20]=3)[CH2:12][CH2:11]2)=[O:9])[N:5]=[C:4]([C:24]([F:27])([F:26])[F:25])[CH:3]=1.C(Cl)(=O)C([Cl:31])=O>ClCCl.CN(C)C=O>[CH3:1][C:2]1[N:6]([CH2:7][C:8]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]3[S:17][CH:18]=[C:19]([C:21]([Cl:31])=[O:22])[N:20]=3)[CH2:12][CH2:11]2)=[O:9])[N:5]=[C:4]([C:24]([F:27])([F:26])[F:25])[CH:3]=1
Reactant: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(c2nc(C(=O)O)cs2)CC1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(c2nc(C(=O)Cl)cs2)CC1
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 99.6 %

Procedure:
A solution of 2-[1-[[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl]-4-piperidinyl]-4-thiazolecarboxylic acid (2.55 g, 5.87 mmol) (i.e. the product of Example 19, Step C) in 100 mL of dichloromethane was cooled to −10° C. and added 1 drop of N,N-dimethylformamide. The reaction mixture was treated with a dropwise addition of a solution of oxalyl chloride (0.60 mL, 6.8 mmol) in 10 mL of dichloromethane. The reaction mixture was stirred at −10° C. for 30 minutes, allowed to warm to room temperature and stirred an additional 16 h. The resulting homogeneous mixture was evaporated in vacuo and the residue placed under high vacuum for several hours to give 2.46 g of the title compound as a light yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:10][CH2:11][CH2:12][C:13]([OH:15])=O)[CH:6]=[CH:7][C:8]=1[CH3:9].FC(F)(F)C(OC(=O)C(F)(F)F)=O>C(Cl)Cl.CCOCC>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:6](=[CH:7][C:8]=1[CH3:9])[C:13](=[O:15])[CH2:12][CH2:11][CH2:10]2
Reactant: COc1cc(CCCC(=O)O)ccc1C
Solvent: ClCCl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CCOCC
Product: COc1cc2c(cc1C)C(=O)CCC2
Temperature: 0 °C
Reaction time: 1 h
Yield: 54.5 %

Procedure:
A solution of 5.6 g (26.9 mmol) of 4-(3-methoxy-4-methylphenyl)butanoic acid in 100 mL of CH2Cl2 was cooled in ice and treated dropwise with 25 mL of trifluoroacetic anhydride. After stirring at 0° C. for 1 hour, the solution was diluted with Et2O and washed twice with 5% NaOH, then with saturated NaCl. Drying over MgSO4 and removal of the solvent under reduced pressure left the crude product. Chromatography on silica gel, eluting with CH2Cl2 gave 2.79 g (54.7% yield) of the product as a white solid, mp 104-107° C. The structure was confirmed by NMR and mass spectroscopy. MS m/z 191 (M+H+).
Reaction SMILES: C([O:3][C:4](=[O:21])[CH:5]([NH:18]C=O)/[C:6](/[CH3:17])=[CH:7]/[CH2:8][P:9]([O:14]CC)([O:11]CC)=[O:10])C>Cl>[NH2:18][CH:5](/[C:6](/[CH3:17])=[CH:7]/[CH2:8][P:9]([OH:14])([OH:11])=[O:10])[C:4]([OH:21])=[O:3]
Reactant: CCOC(=O)C(NC=O)/C(C)=C/CP(=O)(OCC)OCC
Agent: Cl
Product: C/C(=C\CP(=O)(O)O)C(N)C(=O)O

Procedure:
6.3 g of E-2-formylamino-3-methyl-5-diethylphosphono-3-pentenoic acid ethyl ester are heated for 30 hours at 100°-100° under nitrogen in 400 ml of 4.35 N hydrochloric acid. Working up as in Example 11 yields E-2-amino-3-methyl-5-phosphono-3-pentenoic acid in the form of a white powder, m.p. 168°, 1H-NMR (D2O): 1.50 (d, 3H, CH3); 2.4 (m, 2H, CH2); 4.30 (s, 1H, C(2)-H); 5.60 (m, 1H, C(4)-H).
Reaction SMILES: [S:1]1[C:5]2[C:6]3[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][C:7]=3[O:8][CH2:9][CH2:10][C:4]=2[CH:3]=[CH:2]1.C1C(=O)N([Br:24])C(=O)C1>CN(C=O)C.CCOC(C)=O>[Br:24][C:2]1[S:1][C:5]2[C:6]3[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][C:7]=3[O:8][CH2:9][CH2:10][C:4]=2[CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: N#Cc1ccc2c(c1)OCCc1ccsc1-2
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N#Cc1ccc2c(c1)OCCc1cc(Br)sc1-2
Yield: 62.2 %

Procedure:
A solution of 4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-8-carbonitrile (240 mg, 1.05 mmol) in 3 ml of DMF was treated with NBS (206 mg, 1.16 mmol) at room temperature for 15 hours. The reaction mixture was diluted with a large volume of EtOAc and the organic was washed with water and saline and concentrated in vacuo to a solid. This residue was filtered onto celite and purified by MPLC on a 14 gram silica column, eluting with 20-80% EtOAc/heptanes to give 200 mg (62%) of 2-bromo-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-8-carbonitrile as a white powder in high purity as determined by LC/MS.
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:19])[NH:5][C:6](=[O:18])[NH:7][C:8]=1[S:9][C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[CH:11]=1)[CH3:2].[F:20][C:21]([F:35])([F:34])[C:22]1[CH:23]=[C:24]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[CH2:25]Br>>[F:20][C:21]([F:34])([F:35])[C:22]1[CH:23]=[C:24]([CH:27]=[C:28]([C:30]([F:33])([F:31])[F:32])[CH:29]=1)[CH2:25][N:7]1[C:8]([S:9][C:10]2[CH:11]=[C:12]([CH3:17])[CH:13]=[C:14]([CH3:16])[CH:15]=2)=[C:3]([CH2:1][CH3:2])[C:4](=[O:19])[NH:5][C:6]1=[O:18]
Reactant: CCc1c(Sc2cc(C)cc(C)c2)[nH]c(=O)[nH]c1=O
Reactant: FC(F)(F)c1cc(CBr)cc(C(F)(F)F)c1
Product: CCc1c(Sc2cc(C)cc(C)c2)n(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c(=O)[nH]c1=O
Yield: 45 %

Procedure:
5-Ethyl-6-(3,5-dimethylphenyl)thio-2,4-pyrimidinedione and 3,5-bis(trifluoromethyl)benzyl bromide were reacted by the same way with the example 1 to obtain the titled compound (226 mg, yield: 45.0%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:14])([CH3:13])[C:9]([O:11]C)=[O:10])=[CH:4][C:3]=1[O:15][CH3:16]>CO.[OH-].[Na+].O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:14])([CH3:13])[C:9]([OH:11])=[O:10])=[CH:4][C:3]=1[O:15][CH3:16]
Reactant: COC(=O)C(C)(C)c1ccc(F)c(OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1cc(C(C)(C)C(=O)O)ccc1F
Temperature: 25 °C
Yield: 69.4 %

Procedure:
A solution of methyl 2-(4-fluoro-3-methoxyphenyl)-2-methylpropanoate (146 g) in MeOH (2 L) and 25% NaOH in H2O (590 mL) was heated at reflux for 5 h. The reaction mixture was then allowed to cool to room temperature and concentrated at reduced pressure. The residue was dissolved in H2O (2 L) and washed with ether (500 mL). The aqueous layer was acidified cautiously with conc HCl to pH 2. The resulting mixture was extracted with DCM (3 L), and combined extracts were dried over MgSO4, and concentrated at reduced pressure to give 2-(4-fluoro-3-methoxyphenyl)-2-methylpropanoic acid (95 g, 84% over 2 steps). 1H NMR (400 MHz, CDCl3): δ 7.06-7.00 (m, 2H), 6.93 (m, 1H), 3.90 (s, 3H), 3.86 (s, 2H), 1.60 (s, 6H).
Reaction SMILES: [H-].[Na+].[CH2:3]([N:6]([CH2:22][CH2:23][CH3:24])[CH:7]1[CH2:15][C:14]2[C:9](=[CH:10][C:11]([O:19][CH2:20][CH3:21])=[C:12]([C:16]([NH2:18])=[O:17])[CH:13]=2)[CH2:8]1)[CH2:4][CH3:5].Br[CH2:26][CH2:27][F:28]>CCCCCC.CN(C=O)C>[CH2:22]([N:6]([CH2:3][CH2:4][CH3:5])[CH:7]1[CH2:15][C:14]2[C:9](=[CH:10][C:11]([O:19][CH2:20][CH3:21])=[C:12]([C:16]([NH:18][CH2:26][CH2:27][F:28])=[O:17])[CH:13]=2)[CH2:8]1)[CH2:23][CH3:24]
Reactant: FCCBr
Reactant: CCCN(CCC)C1Cc2cc(OCC)c(C(N)=O)cc2C1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: CCCN(CCC)C1Cc2cc(OCC)c(C(=O)NCCF)cc2C1
Reaction time: 0.5 h

Procedure:
Sodium hydride (0.05 g, 1.2 mmol) was washed with hexane under nitrogen and suspended in DMF (5 mL). 2-(Dipropylamino)-6-ethoxy-2,3-dihydro-1H-indene-5-carboxamide (81, 0.15 g, 0.5 mmol) in DMF (5 mL) was added dropwise at 0-5° C. over 30 min and the mixture stirred 30 min. 1-Bromo-2-fluoroethane (0.26 g, 2 mmol) in DMF (5 mL) was added and the resulting mixture was stirred 3 h. The reaction was quenched with saturated NaHCO3 and extracted with EtOAc. The organic layer is washed with water, brine, dried (MgSO4), filtered and concentrated to give crude product. Chromatographic purification yielded pure product 85 as an oil that was converted into the HCl salt and crystallized from EtOAc/hexane/MeOH to give a white solid (m.p. 158-159° C.).
Reaction SMILES: [OH:1][C:2]1[C:7]([CH2:8][CH:9]=[C:10]([CH3:12])[CH3:11])=[C:6]([OH:13])[C:5]([CH2:14][CH:15]=[C:16]([CH3:18])[CH3:17])=[C:4](O)[C:3]=1[C:20](=[O:23])[CH2:21][CH3:22].C(=O)([O-])[O-].[K+].[K+].[F:30][C:31]1[CH:32]=[C:33]([CH:37]=[CH:38][C:39]=1[Cl:40])[C:34](Cl)=[O:35]>CCCC[N+](CCCC)(CCCC)CCCC.[Br-].C1(C)C=CC=CC=1>[F:30][C:31]1[CH:32]=[C:33]([C:34]2[O:35][C:4]3[C:5]([CH2:14][CH:15]=[C:16]([CH3:18])[CH3:17])=[C:6]([OH:13])[C:7]([CH2:8][CH:9]=[C:10]([CH3:12])[CH3:11])=[C:2]([OH:1])[C:3]=3[C:20](=[O:23])[C:21]=2[CH3:22])[CH:37]=[CH:38][C:39]=1[Cl:40]
Reactant: CCC(=O)c1c(O)c(CC=C(C)C)c(O)c(CC=C(C)C)c1O
Reactant: O=C(Cl)c1ccc(Cl)c(F)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: Cc1ccccc1
Product: CC(C)=CCc1c(O)c(CC=C(C)C)c2oc(-c3ccc(Cl)c(F)c3)c(C)c(=O)c2c1O
Temperature: 25 °C
Yield: 1.9 %

Procedure:
Under nitrogen atmosphere, 1-[2,4,6-trihydroxy-3,5-di(3-methyl-2-buten-1-yl)phenyl]propan-1-one (300 mg, 0.943 mmol), anhydrous potassium carbonate powder (817 mg, 5.91 mmol), TBAB (tetrabutyl ammonium bromide, 477 mg, 1.47 mmol) and 3-fluoro-4-chlorobenzoyl chloride (380 mg, 1.97 mmol) were dissolved in toluene (30 mL), and refluxed for 6 hours. After cooling, toluene was removed, and then water (20 mL) was added. The aqueous solution was extracted with ethyl acetate. The combined organic phase was washed with water and saturated brine, and dried over anhydrous sodium sulfate. A brown residue was obtained after removal of solvent. The residue was dissolved in a 5% potassium carbonate aqueous solution and heated to reflux for 2 hr. After cooling to ambient temperature, the mixture was acidified to pH 6 with 1N HCl solution, and extracted with dichloromethane three times. The combined organic phase was dried over anhydrous sodium sulfate, and the solvent was removed. The crude product was purified by silica gel column chromatography (eluent:ethyl acetate/petroleum ether, 1:50) and recrystallized in ethanol to give the desired compound (8 mg, yield 1.9%). 1H NMR (400 MHz, CDCl3): δ=13.10 (s, 1H), 7.56 (d, 1H, J=7.6 Hz), 7.43 (dd, 1H, J1=9.6 Hz, J2=1.6 Hz), 7.37 (d, 1H, J=1.6 Hz), 6.35 (s, 1H), 5.28-5.17 (m, 2H), 3.47 (d, 2H, J=7.2 Hz), 3.44 (d, 2H, J=7.2 Hz), 2.14 (s, 3H), 1.84 (s, 3H), 1.77 (s, 3H), 1.73 (s, 3H), 1.72 (s, 3H); LC-MS (ESI) m/z 457.9 [M+H]+.
Reaction SMILES: [C:1]1([C:11]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=O)=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[NH2:22][OH:23].Cl>C(N(CC)CC)C>[OH:23][NH:22][C:19](=[O:21])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:11]([C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1)=[O:12]
Reactant: NO
Reactant: O=C(O)CCCCCCC(=O)c1cccc2ccccc12
Agent: Cl
Solvent: CCN(CC)CC
Product: O=C(CCCCCCC(=O)c1cccc2ccccc12)NO
Yield: 58 %

Procedure:
Following the procedure described in Example 14, step 3, but substituting carboxylic acid 50f for 37 and using 1.1 equivalent of NH2OH.HCl and triethylamine each, the title compound was obtained as light yellow solid in 58% yield: 1H NMR (300 MHz, CD3OD/CDCl3=5/1) δ 8.50 (d, J=8.1 Hz, 1H), 7.40-7.90 (m, 6H), 2.93(t, J=7.5 Hz, 2H), 2.12 (m, 2H), 1.69 (m, 2H), 1.59 (m, 2H), 1.30 (m, 4H); 13C NMR (75.4 MHz, CD3OD/CDCl3=5/1) δ 24.27, 25.08, 28.63(2), 32.65, 41.88, 124.29, 125.53, 126.27, 127.33, 127.70, 128.30, 129.91, 132.32, 133.77, 135.91, 171.87, 205.28.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Mg].[CH2:9]([Cl:18])[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:11].[Cl-].[NH4+]>[Na].C(OCC)C>[C:2]1([C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)([OH:11])[CH2:9][Cl:18])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1ccccc1
Reactant: O=C(CCl)c1ccccc1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Product: OC(CCl)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 60 %

Procedure:
Bromobenzene (0.2 mol, 31.4 g) in sodium dry diethyl ether (200 ml) was added dropwise to magnesium (0.22 gram atoms, 5.3 g). After all the magnesium had reacted, phenacyl chloride (0.1 mol, 15.5 g) in diethyl ether (100 ml) was added dropwise and the solution stirred at room temperature for 1 hour. The reaction mixture was poured into saturated ammonium chloride solution, washed with water (3×150 ml), and dried (Na2SO4). Removal of the ether gave a pale yellow oil which solidified on standing. Recrystallisation from petroleum ether (60°-80°) gave 1,1-diphenyl-2-chloro-ethan-1-ol (60%) as a white crystalline solid, m.p. 56°-57°.
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[C:4](C1C=CC=CC=1)=O.[C:16](#[N:18])[CH3:17]>>[CH3:17][C:16]1[N:18]=[CH:4][C:3]2[C:2](=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:1]=1
Reactant: CC#N
Reactant: Nc1ccccc1C(=O)c1ccccc1
Product: Cc1ncc2ccccc2n1

Procedure:
In this method, 2-aminobenzophenone derivative (IV) is reacted with acetonitrile to yield 2-methylquinazoline derivative (IX), which is then brominated to 2-bromomethylquinazoline derivative (II-4). The reaction of compound (IV) and acetonitrile is carried out in the same manner as method D. Bromination of compound (IX) is carried out in the same manner as the bromination of compound (VII) by method C.