Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][O:10][CH3:11])=[CH:4][CH:3]=1.[Li]CCCC.[B:17](OC)([O:20]C)[O:18]C.Cl>C1COCC1>[CH3:11][O:10][CH2:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([B:17]([OH:20])[OH:18])=[CH:3][CH:4]=1
Reactant: COCCc1ccc(Br)cc1
Reactant: COB(OC)OC
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COCCc1ccc(B(O)O)cc1
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
To a solution of 1-bromo-4-(2-methoxyethyl)benzene (1 g, 4.6 mmole) in THF (15 mL) at −78° C. was added dropwise BuLi (2.5M in hexane) (2.4 mL, 6 mmole). After stirring at −78° C. for 20 min, trimethyl borate (0.62 g, 6 mmole) was added to the mixture at −78° C. The mixture was slowly warmed to room temperature and stirred at room temperature for 1 h. 2N HCl was added to the reaction mixture and stirred for 2 h. The mixture was extracted with ether, washed with water, dried over MgSO4, and filtered. Hexane was added to the ether solution. Solid was precipitated and collected by filtration. The solid was used in the next step without purification. MS (ESI) m/z: Calc: 180.0 (M+). Found: 181.3 (M++1).
Reaction SMILES: Cl.[C:2]([C:5]1[CH:12]=[CH:11][C:8]([CH2:9][NH2:10])=[CH:7][CH:6]=1)(=[O:4])[CH3:3].C(N(CC)CC)C.[CH3:20][C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1>ClCCl>[C:2]([C:5]1[CH:12]=[CH:11][C:8]([CH2:9][NH:10][S:27]([C:24]2[CH:25]=[CH:26][C:21]([CH3:20])=[CH:22][CH:23]=2)(=[O:29])=[O:28])=[CH:7][CH:6]=1)(=[O:4])[CH3:3]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(=O)c1ccc(CN)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)c1ccc(CNS(=O)(=O)c2ccc(C)cc2)cc1
Temperature: 4 °C
Reaction time: 0.25 h

Procedure:
To a stirred suspension under argon of 4-acetylbenzylamine hydrochloride (700 mg) in dichloromethane (20 ml) was added triethylamine (1.15 ml) and stirring continued for 15 minutes. The mixture was cooled to 4° C., then 4-methylphenylsulphonyl chloride (790 mg) in dichloromethane (5 ml) added dropwise over 30 minutes. The reaction mixture was stirred for 18 hours at ambient temperature, then diluted with further dichloromethane (50 ml), washed with water, dried (MgSO4) and evaporated. Trituration of the residue gave N-([4-acetylphenyl]methyl)4-methylphenylsulphonamide (A), 1.02 g., as an off-white solid: m.p. 125°-128° C.; NMR (d6DMSO) δ8.13(1H,t), 7.86(2H,d), 7.68(2H,d), 7.37(4H,dd), 4.03(2H,d), 2.55(3H,s), 2.39(3H,s); m/e304(M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[O:5][CH2:6][CH2:7][N:8]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]1=[O:18].[O:22]1[CH:24]([CH:25]([CH3:27])[CH3:26])[CH2:23]1>>[OH:22][CH:24]([CH:25]([CH3:27])[CH3:26])[CH2:23][O:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[O:5][CH2:6][CH2:7][N:8]1[C:9](=[O:18])[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:16]1=[O:17]
Reactant: O=C1c2ccccc2C(=O)N1CCOc1cccc(O)c1
Reactant: CC(C)C1CO1
Product: CC(C)C(O)COc1cccc(OCCN2C(=O)c3ccccc3C2=O)c1

Procedure:
Alkylation reaction of phenol 24 with 1,2-epoxy-3-methylbutane gave 2-(2-(3-(2-hydroxy-3-methylbutoxy)phenoxy)ethyl)isoindoline-1,3-dione as yellow oil. Yield (1.0 g, 76%): 1H NMR (400 MHz, CDCl3) δ 8.01-8.03 (m, 1H), 7.47-7.55 (m, 3H), 7.13-7.17 (m, 1H), 6.49-6.54 (m, 3H), 4.12 (t, J=5.6 Hz, 2H), 3.98-4.02 (m, 1H), 3.82-3.88 (m, 3H), 3.68-3.73 (m, 1H), 1.82-1.88 (m, 1H), 1.01 (d, J=6.8 Hz, 3H), 0.91 (d, J=6.8 Hz, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:15]=[CH:14][C:6]2[O:7][CH2:8][C:9]([CH3:13])([CH3:12])[CH2:10][O:11][C:5]=2[CH:4]=1)#[CH:2].I[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1>>[CH3:24][O:23][C:20]1[CH:21]=[CH:22][C:17]([C:2]#[C:1][C:3]2[CH:15]=[CH:14][C:6]3[O:7][CH2:8][C:9]([CH3:12])([CH3:13])[CH2:10][O:11][C:5]=3[CH:4]=2)=[CH:18][CH:19]=1
Reactant: C#Cc1ccc2c(c1)OCC(C)(C)CO2
Reactant: COc1ccc(I)cc1
Product: COc1ccc(C#Cc2ccc3c(c2)OCC(C)(C)CO3)cc1

Procedure:
The title compound is prepared in analogy to example 1 from 7-ethynyl-3,3-dimethyl-3,4-dihydro-2H-benzo[b][1,4]dioxepine (6) (example 1d) and 1-iodo-4-methoxy-benzene. MS (ESI) 308.2 (M•)+.
Reaction SMILES: [NH3:1].[F:2][C:3]1[C:8]2[N:9]([CH3:13])[C:10](=[O:12])[O:11][C:7]=2[CH:6]=[C:5]([N:14]2[CH2:18][C@H:17]([C:19](OC)=[O:20])[O:16][C:15]2=[O:23])[CH:4]=1>CO>[F:2][C:3]1[C:8]2[N:9]([CH3:13])[C:10](=[O:12])[O:11][C:7]=2[CH:6]=[C:5]([N:14]2[CH2:18][C@H:17]([C:19]([NH2:1])=[O:20])[O:16][C:15]2=[O:23])[CH:4]=1
Reactant: COC(=O)[C@H]1CN(c2cc(F)c3c(c2)oc(=O)n3C)C(=O)O1
Reactant: N
Solvent: CO
Product: Cn1c(=O)oc2cc(N3C[C@H](C(N)=O)OC3=O)cc(F)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 55 %

Procedure:
A solution of ammonia in methanol (2M, 5 ml) is added to solid methyl (5R)-3-(4-fluoro-3-methyl-2-oxo-2,3-dihydro-6-benzoxazolyl)-2-oxo-1,3-oxazolidine-5-carboxylate (Step 9, 0.250 g, 0.806 mmol) and the suspension stirred overnight at room temperature. The reaction mixture is concentrated under reduced pressure and the residue purified by PTLC (10% methanol/dichloromethane) to give product as a white solid (0.13 g, 55%); MS for C12H10FN3O5 m/z 296 (M+H)+; 1H NMR (DMSO-d6, 300 Mhz) δ 7.87 (br s, 1H), 7.63 (br s, 1H), 7.50 (d, 1H), 7.42 (dd, 1H), 5.03 (dd, 1H), 4.26 (t, 1H), 4.01 (dd, 1H), 3.42 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10]([CH:12]=C)=[N:9][C:8]([C@@H:14]([NH:16][C:17]1[N:25]=[CH:24][N:23]=[C:22]3[C:18]=1[N:19]=[CH:20][N:21]3[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=1)[CH3:15])=[CH:7]2.I([O-])(=O)(=O)=[O:36].[Na+]>O1CCOCC1.O.[Os](=O)(=O)(=O)=O>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10]([CH:12]=[O:36])=[N:9][C:8]([C@@H:14]([NH:16][C:17]1[N:25]=[CH:24][N:23]=[C:22]3[C:18]=1[N:19]=[CH:20][N:21]3[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=1)[CH3:15])=[CH:7]2
Reactant: C=Cc1nc([C@H](C)Nc2ncnc3c2ncn3Cc2ccc(OC)cc2)cc2cccc(Cl)c12
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(Cn2cnc3c(N[C@@H](C)c4cc5cccc(Cl)c5c(C=O)n4)ncnc32)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred mixture of (S)—N-(1-(8-chloro-1-vinylisoquinolin-3-yl)ethyl)-9-(4-methoxybenzyl)-9H-purin-6-amine 2 (3.6 g, 7.6 mmol, 1 eq) in a mixture of 1,4-dioxane (40 mL) and H2O (40 mL) at RT, osmium tetraoxide (5 mg) was added and the resulting mixture was stirred at RT for 30 min. To this mixture, sodium periodate (3.3 g, 15.2 mmol, 2 eq) was added and the resulting mixture was stirred at RT overnight. The reaction mixture was filtered through silica gel (10 g). The filtrate was extracted with DCM (3×60 mL), washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was purified by flash column chromatography on silica gel (1-5% MeOH-DCM) to afford the product, (S)-8-chloro-3-(1-((9-(4-methoxybenzyl)-9H-purin-6-yl)amino)ethyl)isoquinoline-1-carbaldehyde 5.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[C:7]3[C:12](=[CH:13][C:4]=2[N:3]=[C:2]1[SH:14])[CH:11]=[CH:10][CH:9]=[CH:8]3.[OH-].[Na+].Cl.Cl[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1>O>[N:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[CH2:19][S:14][C:2]1[NH:3][C:4]2[CH:13]=[C:12]3[C:7](=[CH:6][C:5]=2[N:1]=1)[CH:8]=[CH:9][CH:10]=[CH:11]3
Reactant: ClCc1ccccn1
Reactant: Sc1nc2cc3ccccc3cc2[nH]1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: c1ccc(CSc2nc3cc4ccccc4cc3[nH]2)nc1

Procedure:
10.1 g of 1H-naphth[2,3-d]imidazole-2-thiol are suspended in 100 ml of alcohol in a 250 ml volume sulphonating flask equipped with a stirrer, thermometer, cooler and dropping funnel. A solution of 4.0 g of sodium hydroxide in 50 ml of water was then added dropwise, and a clear solution formed. The solution was then heated to boiling, 8.2 g of 2-chloromethyl-pyridine-hydrochloride were added, and the resulting mixture was boiled under reflux overnight. The reaction mixture was then concentrated by evaporation, the residue was taken up in 600 ml of ethyl acetate and 200 ml of water, and the ethyl acetate phase was washed twice with 200 ml of water, dried over sodium sulphate, and concentrated by evaporation in vacuo. The residue was recrystallised once from ethyl acetate/petroleum ether and provided 2-[(2-pyridylmethyl)thio]-1H-naphth[2,3-d]imidazole having a melting point of 165°-167°; the hydrochloride melts at 230°-231°.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([F:30])[C:5]([F:29])=[C:6]([C@:8]23[CH2:16][O:15][C@H:14]([C:17]([F:20])([F:19])[F:18])[C@H:13]2[CH2:12][S:11][C:10]([NH:21]C(=O)OC(C)(C)C)=[N:9]3)[CH:7]=1.[F:31][CH2:32][C:33]1[N:34]=[CH:35][C:36]([C:39](O)=[O:40])=[N:37][CH:38]=1>>[NH2:21][C:10]1[S:11][CH2:12][C@@H:13]2[C@@H:14]([C:17]([F:19])([F:18])[F:20])[O:15][CH2:16][C@:8]2([C:6]2[CH:7]=[C:2]([NH:1][C:39]([C:36]3[CH:35]=[N:34][C:33]([CH2:32][F:31])=[CH:38][N:37]=3)=[O:40])[CH:3]=[C:4]([F:30])[C:5]=2[F:29])[N:9]=1
Reactant: CC(C)(C)OC(=O)NC1=N[C@@]2(c3cc(N)cc(F)c3F)CO[C@H](C(F)(F)F)[C@H]2CS1
Reactant: O=C(O)c1cnc(CF)cn1
Product: NC1=N[C@@]2(c3cc(NC(=O)c4cnc(CF)cn4)cc(F)c3F)CO[C@H](C(F)(F)F)[C@H]2CS1

Procedure:
Synthesized from tert-butyl [(4aS,5S,7aS)-7a-(5-amino-2,3-difluorophenyl)-5-trifluoromethyl-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-yl]carbamate and 5-(fluoromethyl)pyrazine-2-carboxylic acid according to the general procedure. 1H NMR (400 MHz, CDCl3) δ ppm 2.89 (dd, J=13.6, 3.8 Hz, 1 H), 3.19 (dd, J=13.6, 3.0 Hz, 1 H), 3.43 (dd, J=7.5, 3.4 Hz, 1 H), 3.86-3.99 (m, 1 H), 4.39-4.67 (m, 3 H), 4.74 (quin, J=7.1 Hz, 1 H), 5.76 (d, J=45.5 Hz, 2 H), 8.10 (ddd, J=11.4, 6.8, 2.8 Hz, 1 H), 8.77 (s, 1 H), 9.46 (s, 1H), 9.69 (s, 1 H)
Reaction SMILES: C[N:2]([CH3:21])[CH:3]=[C:4]([C:10](=O)[C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].NC(C(N)=O)[C:24]([NH2:26])=[O:25]>CC(O)=O>[NH2:26][C:24]([C:21]1[NH:2][CH:3]=[C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:10]=1[C:11]1[CH:12]=[CH:13][C:14]([N+:17]([O-:19])=[O:18])=[CH:15][CH:16]=1)=[O:25]
Reactant: NC(=O)C(N)C(N)=O
Reactant: CCOC(=O)C(=CN(C)C)C(=O)c1ccc([N+](=O)[O-])cc1
Solvent: CC(=O)O
Product: CCOC(=O)c1c[nH]c(C(N)=O)c1-c1ccc([N+](=O)[O-])cc1
Temperature: 80 °C
Yield: 83.7 %

Procedure:
A 3 L round bottomed flask was charged with ethyl 3-(dimethylamino)-2-(4-nitrobenzoyl)acrylate (63.59 g, 217.5 mmol) and 2-aminomalonamide (33.12 g, 282.8 mmol) and AcOH (800 mL). The reaction mixture was heated to 80° C. over night. The starting material appeared consumed by TLC. The AcOH was removed under reduced pressure and TFA (400 mL) was added. The mixture was heated over night at 60° C. The reaction was cooled to room temperature and the TFA was removed under reduced pressure. The orange oil was washed with saturated aqueous NaHCO3 (1 L) and solid NaHCO3 was added until the solution was neutral. The solids were filtered and placed in a 1 L erlenmeyer flask. The solids were washed with H2O (3×1 L) and the water was decanted off through the filter. On the last washing the solids were poured onto the filter and allowed to air dry. The solids were once again removed from the filter and washed with Et2O (4×500 mL). The Et2O was decanted off through the filter and on the final washing the solids were transferred to the filter. An addition portion of Et2O (200 mL) was used to wash the flask and the filter cake. The product was dried in a vacuum oven at 40° C. over P2O5 for 4 h affording ethyl 5-(aminocarbonyl)-4-(4-nitrophenyl)-1H-pyrrole-3-carboxylate as a tan solid (55.2 g, 182 mmol, 83.7%). 1H-NMR (DMSO-d6) δ 12.33 (br s, 1H), 8.19-8.15 (m, 2H), 7.57 (d, J=3.6 Hz, 1H), 7.53-7.49 (m, 2H), 7.29 (br s, 1H), 6.41 (br s, 1H), 3.99 (q, J=7.2 Hz, 2H), 1.03 (t, J=7.2 Hz, 3H); LCMS RT=2.79 min; MS {M+H]+=304.2.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=2[CH2:9]Cl)=[CH:4][CH:3]=1.[C-:17]#[N:18].[Na+]>CS(C)=O>[F:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=2[CH2:9][C:17]#[N:18])=[CH:4][CH:3]=1
Reactant: Fc1ccc(Oc2ccccc2CCl)cc1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Product: N#CCc1ccccc1Oc1ccc(F)cc1
Temperature: 0 °C
Reaction time: 26 h

Procedure:
12.0 g of 2-(4-fluorophenoxy)benzyl chloride are added portionwise over a 30 minute span to a mixture of 2.9 g of sodium cyanide in 120 ml of dimethylsulfoxide. After total addition, the reaction mixture is stirred for 26 hours before being poured onto 150-200 ml of crushed ice. The mixture is extracted four times with 70 ml portions of ether and the combined ether extracts are successively washed four times with 50 ml portions of water, washed once with 25 ml of saturated sodium chloride solution and dried, providing a clear oil. The oil is distilled at 128.5° C. and 0.1 mm to provide 2-(4-fluorophenoxy)benzyl cyanide.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH:14]([CH3:16])[CH3:15])[C:9]=2/[CH:17]=[CH:18]/[CH2:19][OH:20])=[CH:4][CH:3]=1.[CH3:21][O:22][C:23](=[O:33])[C:24]([C:26]1[CH:31]=[CH:30][C:29](O)=[CH:28][CH:27]=1)=[O:25].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[CH3:21][O:22][C:23](=[O:33])[C:24](=[O:25])[C:26]1[CH:27]=[CH:28][C:29]([O:20][CH2:19]/[CH:18]=[CH:17]/[C:9]2[C:10]([CH:14]([CH3:16])[CH3:15])=[CH:11][CH:12]=[CH:13][C:8]=2[C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[CH:30][CH:31]=1
Reactant: COC(=O)C(=O)c1ccc(O)cc1
Reactant: CC(C)c1cccc(-c2ccc(F)cc2)c1/C=C/CO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)C(=O)c1ccc(OC/C=C/c2c(-c3ccc(F)cc3)cccc2C(C)C)cc1
Yield: 59.3 %

Procedure:
As in Example 15, (E)-3-[4'-fluoro-3-(1-methylethyl)[1,1'-biphenyl]-2-yl]-2-propen-1-ol (0.58 g) was reacted with 4-hydroxyphenylglyoxylic acid methyl ester (0.387 g) in the presence of diethyl azoclicarboxylate (0.448 g) and triphenylphosphine (0.68 g) in tetrahydrofuran (25 mL). The usual work up afforded 1.3 g of a crude mixture that was purified by flash chromatography over silica gel (130 g; ethyl acetate-hexane; 3:7) to furnish 0.55 g of (E)-4-[3-[4'-fluoro-3-(1-methylethyl)[1,1'-biphenyl]-2-yl]-2-propenyloxy]-alpha-oxobenzeneacetic acid methyl ester as a oil.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]2[C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[S:12][C:3]=12.C(OCCO)C.[Br:23][C:24]1[CH:25]=[C:26]([CH:28]=[CH:29][CH:30]=1)[NH2:27].Cl.N1C=CC=CC=1>>[Br:23][C:24]1[CH:25]=[C:26]([NH:27][C:2]2[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]3[C:10]4[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=4[S:12][C:3]=23)[CH:28]=[CH:29][CH:30]=1
Reactant: Nc1cccc(Br)c1
Reactant: N#Cc1cnc2c(sc3ccccc32)c1Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOCCO
Product: N#Cc1cnc2c(sc3ccccc32)c1Nc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 58 %

Procedure:
A solution of 150 mg (0.61 mmol) of 4-chlorobenzo[4,5]thieno[3,2-b]pyridine-3-carbonitrile in 3 mL of 2-ethoxyethanol containing 80 mg (0.74 mmol) of 3-bromoaniline and 71 mg of pyridine hydrochloride is heated at reflux temperature for 4 hours, then allowed to stir at room temperature for 3 days. The reaction mixture is partitioned between ethyl acetate and saturated sodium bicarbonate and the organic layer is dried over magnesium sulfate, filtered and concentrated in vacuo. Diethyl ether is added to the residue and the resultant solid is collected by filtration to give 139 mg (58%) of a white solid, mp 240–242° C.
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[CH:8]=[CH:9][C:10]([CH3:38])=[C:11]([N:13]3[C:22](=[O:23])[C:21]4[C:16](=[CH:17][CH:18]=[C:19]([O:24][CH:25]5[CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27][CH2:26]5)[CH:20]=4)[N:15]=[CH:14]3)[CH:12]=2)=[O:6])[CH2:3][CH2:2]1.CO>Cl.O1CCOCC1>[CH:1]1([NH:4][C:5](=[O:6])[C:7]2[CH:8]=[CH:9][C:10]([CH3:38])=[C:11]([N:13]3[C:22](=[O:23])[C:21]4[C:16](=[CH:17][CH:18]=[C:19]([O:24][CH:25]5[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]5)[CH:20]=4)[N:15]=[CH:14]3)[CH:12]=2)[CH2:2][CH2:3]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-n1cnc2ccc(OC3CCN(C(=O)OC(C)(C)C)CC3)cc2c1=O
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1cnc2ccc(OC3CCNCC3)cc2c1=O
Yield: 96.7 %

Procedure:
tert-Butyl 4-[(3-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-4-oxo-3,4-dihydroquinazolin-6-yl)oxy]piperidine-1-carboxylate (3.42 g) was stirred in 4N HCl in dioxane (20 ml) and methanol (3 ml) at room temperature for 18 hours and then concentrated. The residue was purified by column chromatography on an ion exchange column (isolute SCX-2 column from International Sorbent Technology Limited, Henoed, Mid-Glamorgan, UK) washing with methanol initially and then eluting with a 99:1 mixture of methanol and aqueous ammonia solution to give N-cyclopropyl-4-methyl-3-[4-oxo-6-(piperidin-4-yloxy)quinazolin-3(4H)-yl]benzamide (2.67 g) as a light brown solid; NMR Spectrum: (DMSOd6) 0.54 (m, 2H), 0.69 (m, 2H), 1.50 (m, 2H), 1.95 (m, 2H), 2.15 (s, 3H), 2.60 (m, 2H), 2.85 (m, 1H), 2.95 (m, 2H), 4.59 (m, 1H), 7.51 (d, 1H), 7.52 (d, 1H), 7.59 (s, 1H), 7.71 (d, 1H), 7.82 (s, 1H), 7.90 (d, 1H), 8.18 (s, 1H), 8.42 (d, 1H); Mass Spectrum: M+H+ 419.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:11]/[O:12][C:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])([CH3:15])[CH3:14])/[C:8]([OH:10])=[O:9])[N:6]=1.C(N(CC)CC)C.[C:30]1([C:36]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)Cl)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C(Cl)Cl>[C:19]([O:18][C:16]([C:13]([O:12]/[N:11]=[C:7](/[C:5]1[N:6]=[C:2]([NH:1][C:36]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)([C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=2)[C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)[S:3][CH:4]=1)\[C:8]([OH:10])=[O:9])([CH3:14])[CH3:15])=[O:17])([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)OC(=O)C(C)(C)O/N=C(\C(=O)O)c1csc(N)n1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)C(C)(C)O/N=C(\C(=O)O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 22.5 °C
Reaction time: 6 h

Procedure:
To a suspension of (Z)-2-(2-aminothiazol-4-yl)-2-(2-tert-butoxycarbonylprop-2-oxyimino) acetic acid (monoblocked acid) (100 g) prepared as in Example 1 in methylene chloride (1.74 lt) is added triethylamine (33.76 g) slowly at 5-10° to obtain a clear solution. Add triphenylchloromethane (118.5 g) at 5-10° and then mass temperature is raised to 36-38°. The resulting reaction mixture is stirred for 6 hours. It is then cooled to 20-25° and washed with DM water. The organic layer is concentrated and toluene is added to the residue. The resulting slurry is cooled to 20-25° C., the product is filtered, washed with toluene and dried under reduced pressure at 40-45° C. Yield 171 g (98.5% of theory), water <0.2% w/w, assay 96-97% w/w, methylene chloride 2-2.5% w/w and toluene 1-2% w/w.
Reaction SMILES: O[Li].O.[CH:4]1[C:9]([C:10]2[CH:11]=[CH:12][C:13]([F:17])=[CH:14][C:15]=2[F:16])=[CH:8][C:7]([C:18]([OH:20])=[O:19])=[C:6]([OH:21])[CH:5]=1.[CH2:22]1COCC1.Cl>CO.O>[F:16][C:15]1[CH:14]=[C:13]([F:17])[CH:12]=[CH:11][C:10]=1[C:9]1[CH:4]=[CH:5][C:6]([O:21][CH3:22])=[C:7]([C:18]([OH:20])=[O:19])[CH:8]=1
Reactant: O=C(O)c1cc(-c2ccc(F)cc2F)ccc1O
Reactant: C1CCOC1
Agent: Cl
Agent: [Li]O
Solvent: CO
Solvent: O
Product: COc1ccc(-c2ccc(F)cc2F)cc1C(=O)O
Yield: 93 %

Procedure:
LiOH.H2O (60 mg, 1.43 mmol) was added to a solution of fully methylated diflunisal (140 mg, 0.50 mmol) in MeOH:THF:H2O (4.5 mL 1:1:1), and stirred at rt for 4 h. Upon completion, the reaction was acidified with 30% HCl, extracted with ethyl acetate (3×5 mL), dried over MgSO4 and concentrated in vacuo. The residue was purified by flash chromatography (2:1 ethyl acetate:hexane, 1% acetic acid) to afford 33 (122 mg, 93%) as a white solid. 1H NMR (CDCl3, 400 MHz) δ 10.77 (br s, 1H), 8.31 (dd, 1H, J=2.5, 0.9 Hz), 7.75 (dt, 1H, J=8.6, 2.1 Hz), 7.41 (dt, 1H, J=8.9, 6.6 Hz), 7.15 (d, 1H, J=8.8 Hz), 6.94 (m, 1H), 4.13 (s, 3H). 13C NMR (CDCl3, 100 MHz) δ 177.7, 161.4, 158.2, 135.7, 133.9, 131.4, 129.0, 123.5, 118.1, 112.2, 112.0, 104.6, 56.9. HRESIMS calculated for C14H10F2O3 (M−H) 263.0520, found 263.0514. Normal phase HPLC retention time: 21.6 min. Reverse phase HPLC retention time: 11.9 min. >99% pure.
Reaction SMILES: CN([CH:4]=[C:5]1[C:10](=[O:11])[CH2:9][CH2:8][CH2:7][C:6]1=O)C.C([O-])(=O)C.[Na+].[C:18]([S:21][CH3:22])(=[NH:20])[NH2:19]>CN(C=O)C.ClCCl>[CH3:22][S:21][C:18]1[N:19]=[CH:4][C:5]2[C:10](=[O:11])[CH2:9][CH2:8][CH2:7][C:6]=2[N:20]=1
Reactant: CSC(=N)N
Reactant: CN(C)C=C1C(=O)CCCC1=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CSc1ncc2c(n1)CCCC2=O
Temperature: 100 °C
Yield: 88.8 %

Procedure:
To a solution of 2-((dimethylamino)methylene)cyclohexane-1,3-dione (0.5 g, 2.9 mmol) in DMF (2 mL) was added sodium acetate (0.39 g, 4.7 mmol) and methyl carbamimidothioate (0.9 g, 3.5 mmol). The reaction mixture was heated at 100° C. for 5 hours. On completion of the reaction, the reaction mixture was diluted with dichloromethane (30 mL). The organic layer was separated and washed with water (2×30 mL). The solvent was then removed under reduced pressure and the residue dissolved in EtOAc (50 mL) and washed with water (2×30 mL). The organic layer was dried using sodium sulfate and concentrated under reduced pressure to give the desired product (0.5 g, 86%) as a solid. 1H NMR (CDCl3, 400 MHz): δ 8.94 (s, 1H), 3.01 (t, J=6 Hz, 2H), 2.64 (t, J=6.0 Hz, 2H), 2.58 (s, 3H), 2.14 (quintet, J=6.2 Hz, 2H); LCSM [M+H]: 195.
Reaction SMILES: I/[CH:2]=[CH:3]/[CH:4]([O:10][C:11]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].C1(C)C=CC=CC=1.C([Li:41])CCC>CCCCCC>[C:12]1([C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[O:10][CH:4]([CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])/[CH:3]=[CH:2]/[Li:41])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CCCCCC(/C=C/I)OC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: [Li]CCCC
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: [Li]/C=C/C(CCCCC)OC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: -40 °C

Procedure:
To a solution of 4.96 g. of 1-iodo-3-triphenylmethoxy-trans-1-octene (Example 730) in 10 ml. of toluene cooled to -78° C. is added under an inert atmosphere 1 molar equivalent of n-butyllithium dissolved in hexane. The reaction mixture is allowed to warm to -40° C. and is then maintained at that temperature for 1 hour to yield a hydrocarbon solution of 3-triphenylmethoxy-trans-1-octenyllithium.
Reaction SMILES: C(OC([CH2:8][NH:9][CH2:10][C:11]1[CH:12]=[C:13]([C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24]3[CH:34]=[CH:33][CH:32]=[CH:31][C:25]=3[C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:19][CH:18]=2)[CH:14]=[CH:15][CH:16]=1)=O)(C)(C)C>ClCCl.FC(F)(F)C(O)=O>[CH3:8][NH:9][CH2:10][C:11]1[CH:12]=[C:13]([C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24]3[CH:34]=[CH:33][CH:32]=[CH:31][C:25]=3[C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:19][CH:18]=2)[CH:14]=[CH:15][CH:16]=1
Reactant: CCOC(=O)c1ccccc1Oc1ccc(-c2cccc(CNCC(=O)OC(C)(C)C)c2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)c1ccccc1Oc1ccc(-c2cccc(CNC)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
3.1 g (6.7 mmol) of ethyl 2-{3′-[(tert-butoxycarbonylmethylamino)methyl]biphenyl-4-yloxy}benzoate are placed in 50 ml of dichloromethane and 2.6 ml of trifluoroacetic acid. After stirring at room temperature for 8 hours, the reaction medium is concentrated, placed in water, brought to pH 8 with aqueous 1N sodium hydroxide solution and extracted with ethyl acetate. The organic phase is dried over sodium sulfate, filtered and concentrated under vacuum. 2.3 g of ethyl 2-(3′-methylaminomethylbiphenyl-4-yloxy)benzoate are obtained in the form of an orange-colored oil, in a yield of 95%.