Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Cl[CH2:15][CH2:16][NH:17][C:18](=[O:22])[O:19][CH2:20][CH3:21].C(N(CC)CC)C>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:15][CH2:16][NH:17][C:18](=[O:22])[O:19][CH2:20][CH3:21])[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)NCCCl
Reactant: Brc1ccc(N2CCNCC2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)NCCN1CCN(c2ccc(Br)cc2)CC1
Temperature: 130 °C
Reaction time: 2 h
Yield: 67.1 %

Procedure:
A mixture of 1-(4-bromophenyl)piperazine (0.018 mol) and ethyl (2-chloroethyl)-carbamate (0.036 mol) was stirred for 2 hours at 130° C. Triethylamine (3 ml) was added and the mixture was stirred for 15 minutes at 130° C. The reaction mixture was cooled to room temperature, CH2Cl2 was added and the resulting mixture was washed with water. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2 /CH3OH 95/5). The pure fractions were collected and the solvent was evaporated, yielding 4.3 g (67.2%) of ethyl [2-[4-(4-bromophenyl)-1-piperazinyl]-ethyl]carbamate (interm. 1).
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[N+](=CP(=O)([O-])OC)=[N-].[CH3:15][O:16][C:17]1[CH:29]=[CH:28][C:20]([O:21][C@H:22]2[CH2:25][C@H:24]([CH:26]=O)[CH2:23]2)=[CH:19][CH:18]=1.CCCCCC.C(OCC)(=O)C>C1COCC1>[CH3:15][O:16][C:17]1[CH:29]=[CH:28][C:20]([O:21][C@H:22]2[CH2:25][C@H:24]([C:26]#[CH:1])[CH2:23]2)=[CH:19][CH:18]=1
Reactant: COc1ccc(O[C@H]2C[C@H](C=O)C2)cc1
Reactant: CC(C)(C)[O-]
Agent: COP(=O)([O-])C=[N+]=[N-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C#C[C@H]1C[C@H](Oc2ccc(OC)cc2)C1
Temperature: -78 °C
Reaction time: 3 h
Yield: 54.7 %

Procedure:
A slurry of potassium tert-butoxide (7.85 g, 70 mmol) in THF (50 ml) was cooled to -78° C. under argon atmosphere. To this was added a solution of methyl (diazomethyl)phosphonate (J. Org. Chem. 1979, 44, 4997) (12.5 g, 70 mmol) in THF (100 ml), followed after 0.5 h by a solution of trans-3-(4-methoxyphenoxy)cyclobutanecarbaldehyde (12.1 g, 58.7 mmol) in THF (100 ml) at the same temperature. The resulting solution was stirred at -78° C. for 3 h and then maintained at room temperature for another 8 h. The reaction was quenched with water (300 ml) and the aqueous mixture was extracted with ethyl acetate. The combined organic extracts were washed with brine (200 ml), dried (MgSO4) and concentrated in vacuo to give yellow solids. Silica-gel column chromatography of the solids {SiO2, 800 g; hexane/ethyl acetate (9/1)} of the solids afforded 6.49 g (55%) of {trans-3-(4-methoxyphenoxy)cyclobutyl }ethyne as white solids: 1H NMR δ6.84-6.70 (m, 4H), 4.92-4.82 (m, 1H), 3.76 (s, 3H), 3.20-3.03 (m, 1H), 2.64-2.40 (m, 4H), 2.19 (s, 1H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[C:4]=1[F:25])#[N:2].[CH3:26][N:27]([CH3:34])[C@H:28]1[CH2:33][CH2:32][CH2:31][NH:30][CH2:29]1>>[CH3:26][N:27]([CH3:34])[C@H:28]1[CH2:33][CH2:32][CH2:31][N:30]([C:19]([C:18]2[CH:22]=[CH:23][C:15]([N:12]3[C:13]([OH:14])=[C:9]([C:6]4[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[C:4]([F:25])[C:5]=4[CH3:24])[CH:10]=[N:11]3)=[N:16][CH:17]=2)=[O:21])[CH2:29]1
Reactant: CN(C)[C@H]1CCCNC1
Reactant: Cc1c(-c2cnn(-c3ccc(C(=O)O)cn3)c2O)ccc(C#N)c1F
Product: Cc1c(-c2cnn(-c3ccc(C(=O)N4CCC[C@H](N(C)C)C4)cn3)c2O)ccc(C#N)c1F

Procedure:
The title compound was prepared in a manner similar to Example 301 using 6-(4-(4-cyano-3-fluoro-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and (S)—N,N-dimethylpiperidin-3-amine. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.54 (d, J=11.12 Hz, 1 H) 1.78 (m, J=16.20 Hz, 2 H) 2.12 (d, J=10.86 Hz, 1 H) 2.33 (d, J=2.27 Hz, 3 H) 2.67-2.94 (m, 6 H) 3.13-4.79 (m, 5 H) 7.48-7.70 (m, 1 H) 7.70-7.80 (m, 1 H) 7.98-8.34 (m, 2 H) 8.57 (m, J=1.50 Hz, 2 H) 9.44-10.31 (m, 1 H). ESI-MS m/z [M+H]+ 449.3.
Reaction SMILES: [NH2:1][C:2]1[C:9]([O:10][CH3:11])=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[O:12][CH3:13].[C:14](OC(=O)C)(=[O:16])C>C(O)=O>[CH3:13][O:12][C:3]1[CH:4]=[C:5]([CH:6]=[O:7])[CH:8]=[C:9]([O:10][CH3:11])[C:2]=1[NH:1][CH:14]=[O:16]
Reactant: CC(=O)OC(C)=O
Reactant: COc1cc(C=O)cc(OC)c1N
Solvent: O=CO
Product: COc1cc(C=O)cc(OC)c1NC=O
Temperature: 10 °C
Reaction time: 2 h

Procedure:
A solution (cooled to 10° C.) of 18.1 g. of 4-amino-3,5-dimethoxy-benzaldehyde in 210 ml. of 98% formic acid was treated dropwise with 70 ml. of acetic anhydride with stirring and the temperature was maintained below 15° C. The solution was then stirred for 2 hours at room temperature, treated with 80 ml. of water and evaporated to dryness under vacuum. The residue was washed with water, recrystallized from alcohol and there was obtained 2',6'-dimethoxy-4'-formyl-formanilide having a melting point of 159°-160° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:4]=1[CH2:5][N:6]1[C:16](=[O:17])[C:15]2[N:18]3[C:8](=[C:9]([C:19]4[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][CH:20]=4)[N:10]=[C:11]3[CH:12]=[CH:13][CH:14]=2)[CH2:7]1.[NH:33](C)[CH3:34].Cl.[BH3-]C#N.[Na+]>ClCCCl>[CH3:1][O:2][C:3]1[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:4]=1[CH2:5][N:6]1[C:16](=[O:17])[C:15]2[N:18]3[C:8](=[C:9]([C:19]4[CH:20]=[CH:21][C:22]([CH2:23][NH:33][CH3:34])=[CH:25][CH:26]=4)[N:10]=[C:11]3[CH:12]=[CH:13][CH:14]=2)[CH2:7]1
Reactant: CNC
Reactant: COc1ccc(CN2Cc3c(-c4ccc(C=O)cc4)nc4cccc(n34)C2=O)c(OC)c1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClCCCl
Product: CNCc1ccc(-c2nc3cccc4n3c2CN(Cc2ccc(OC)cc2OC)C4=O)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of (B3) in DCE (0.1 M) was added Me2NH.HCl (8 eq.) and Ti(iPrO)4 (2.0 eq.) and the mixture stirred at RT for 12 h. To this solution, NaBH3CN (1.1 eq.) was added and stirring was continued for 12 h. The reaction mixture was quenched by the addition of sat. aq. NaHCO3, then, the aqueous phase was separated and extracted several times with DCM. The combined organic extracts were washed with brine and dried (Na2SO4). Evaporation of the solvent gave a residue of 4-(2,4-dimethoxybenzyl)-2-{4-[(methylamino)methyl]phenyl}-3,4-dihydro-5H-1,4,8b-triazaacenaphthylen-5-one which was used in the next step without further purification. MS (ES+) C26H26N4O3 requires: 442, found: 443 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]([NH:9][C:10]2[CH:14]=[C:13]([CH3:15])[NH:12][N:11]=2)=[CH:5][C:4]([C:16]2[C:21]([CH:22]=[O:23])=[C:20]([N:24]3[CH2:36][CH2:35][N:27]4[C:28]5[CH2:29][CH2:30][CH2:31][CH2:32][C:33]=5[CH:34]=[C:26]4[C:25]3=[O:37])[N:19]=[CH:18][CH:17]=2)=[CH:3]1.O.[Li+].[OH-]>C1COCC1>[OH:23][CH2:22][C:21]1[C:20]([N:24]2[CH2:36][CH2:35][N:27]3[C:28]4[CH2:29][CH2:30][CH2:31][CH2:32][C:33]=4[CH:34]=[C:26]3[C:25]2=[O:37])=[N:19][CH:18]=[CH:17][C:16]=1[C:4]1[CH:5]=[C:6]([NH:9][C:10]2[CH:14]=[C:13]([CH3:15])[NH:12][N:11]=2)[C:7](=[O:8])[N:2]([CH3:1])[CH:3]=1
Reactant: Cc1cc(Nc2cc(-c3ccnc(N4CCn5c(cc6c5CCCC6)C4=O)c3C=O)cn(C)c2=O)n[nH]1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(Nc2cc(-c3ccnc(N4CCn5c(cc6c5CCCC6)C4=O)c3CO)cn(C)c2=O)n[nH]1
Yield: 0 %

Procedure:
A 100-mL single-neck round-bottomed flask was charged with 115b (190 mg, 0.35 mol) in THF/iPA/H2O (5 mL/5 mL/2 mL) and LiOH (85 mg, 3.5 mmol) while stirring. This mixture was stirred at 50° C. for 0.5 h. Then 20 mL H2O was added and the mixture was extracted with EA (30 mL×3). The combined organic layer was dried over Na2SO4 and concentrated to give a yellow solid, which was further purified by reverse-phase prep-HPLC to afford 115 as a white solid (48 mg, 30% yield). LCMS: [M+H]+ 500. 1H NMR (500 MHz, CDCl3) δ 8.44 (d, J=6.0, 1H), 7.95 (s, 1H), 7.69 (s, 1H), 7.44 (s, 1H), 7.30 (d, J=6.0, 2H), 6.87 (s, 1H), 5.74 (s, 1H), 4.59-3.86 (m, 7H), 3.69 (s, 3H), 2.57-2.56 (m, 4H), 2.25 (s, 3H) 1.88-1.77 (m, 4H)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=1)[C:6]([C:19]([OH:21])=O)=[CH:5]2.S(Cl)(Cl)=O.[NH3:26]>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=1)[C:6]([C:19]([NH2:26])=[O:21])=[CH:5]2
Reactant: N
Reactant: O=C(O)c1cc2cc(F)ccc2n1Cc1cccc(F)c1
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: NC(=O)c1cc2cc(F)ccc2n1Cc1cccc(F)c1
Reaction time: 2 h

Procedure:
To a suspension, stirred at 20° C., of 2 g (6.96 mmol) of 5-fluoro-1-[(3-fluorophenyl)-methyl]-1H-indole-2-carboxylic acid, prepared in step 1.1, in 80 mL of dry toluene are added 5.08 mL (69.62 mmol) of thionyl chloride. The reaction mixture is stirred for 2 hours at reflux and is then concentrated under reduced pressure. The resulting product is taken up in 10 mL of dichloromethane, and this solution is poured dropwise into a solution of 9.12 mL (69.62 mmol) of 30% aqueous ammonia. The reaction mixture is stirred for 14 hours at 20° C. After this time, a solid is collected by filtration, and is triturated in 50 mL of diisopropyl ether. After filtering off and drying under reduced pressure, 0.58 g of the expected product is collected.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[Br:8][C:9]1[CH:14]=[CH:13][C:12](B(O)O)=[CH:11][CH:10]=1.ClC1C=CC([N+]([O-])=O)=CC=1O>>[Br:8][C:9]1[CH:14]=[CH:13][C:12]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)=[CH:11][CH:10]=1
Reactant: OB(O)c1ccc(Br)cc1
Reactant: Brc1ccccn1
Agent: O=[N+]([O-])c1ccc(Cl)c(O)c1
Product: Brc1ccc(-c2ccccn2)cc1

Procedure:
The title compound was prepared from 2-bromopyridine (3 g) and 4bromophenylboronic acid (3.8 g) by the method described in Description 15 as a pale yellow solid (4.4 g, 98%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([NH:11][C:12]1[CH:26]=[CH:25][C:15]([CH2:16][NH:17]C(=O)OC(C)(C)C)=[CH:14][CH:13]=1)=[O:10]>C(Cl)Cl>[NH2:17][CH2:16][C:15]1[CH:14]=[CH:13][C:12]([NH:11][C:9]([NH:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[CH3:1])=[O:10])=[CH:26][CH:25]=1
Reactant: Cc1ccccc1NC(=O)Nc1ccc(CNC(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Product: Cc1ccccc1NC(=O)Nc1ccc(CN)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl 4-({[(2-methylphenyl)amino]carbonyl}amino)benzylcarbamate (2.00 g, 5.63 mmol) in CH2Cl2 (120 mL) TFA (36 mL) was added at 0° C. and stirred for 2 h at r.t.. The reaction mixture was evaporated and the product was collected (2.72 g, TFA salt). M.p. 142–143° C.; TLC (PE/EtOAc 3/2) Rf 0.14; 1H NMR (400 MHz, D6-DMSO) δ 2.24 (s, 3H); 3.97 (q, J=5 Hz, 2H); 6.96 (mc, 1H); 7.13–7.19 (m, 2); 7.36 (mc, 2H); 7.51 (mc, 2H); 7.81 (mc, 2H); 8.06 (s, 1H); 8.08 (s, 3H); 9.23 (s, 1H).
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([O:5][CH2:6]1)[CH2:3][NH:2]2.[N:8]1[O:9][N:10]=[C:11]2[CH:16]=[C:15]([C:17](Cl)=[O:18])[CH:14]=[CH:13][C:12]=12>>[N:8]1[O:9][N:10]=[C:11]2[CH:16]=[C:15]([C:17]([N:2]3[CH2:3][CH:4]4[CH2:7][CH:1]3[CH2:6][O:5]4)=[O:18])[CH:14]=[CH:13][C:12]=12
Reactant: O=C(Cl)c1ccc2nonc2c1
Reactant: C1OC2CNC1C2
Product: O=C(c1ccc2nonc2c1)N1CC2CC1CO2

Procedure:
The title compound was prepared from 2-aza-5-oxabicyclo[2.2.1]heptane and [2,1,3]-benzoxadiazole-5-carbonylchloride as described for Example 7: mp=102-104° C., LC-MS, MH+=246; 1H NMR (300 MHz, CDCl3) δ 7.98-7.90 (m, 2H), 7.58 (dd, J=1.2 and 9.3 Hz, 1H), 5.08 and 4.78 (s, total 1H), 4.66 and 4.47 (s, total 1H), 4.05 (m, 1H), 3.89 (m, 1H), 3.73-3.63 (m, 1H), 3.52 (s, 1H), 2.06-1.95 ppm (m, 2H).
Reaction SMILES: [OH:1][N:2]=[C:3]([C:5]1[C:9]([NH:10][CH2:11][CH2:12][NH:13][S:14]([CH3:17])(=[O:16])=[O:15])=[N:8][O:7][N:6]=1)[NH2:4].[Cl:18][C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][C:25]=1[F:26])N>>[Cl:18][C:19]1[CH:20]=[C:21]([NH:4][C:3]([C:5]2[C:9]([NH:10][CH2:11][CH2:12][NH:13][S:14]([CH3:17])(=[O:16])=[O:15])=[N:8][O:7][N:6]=2)=[N:2][OH:1])[CH:23]=[CH:24][C:25]=1[F:26]
Reactant: Nc1ccc(F)c(Cl)c1
Reactant: CS(=O)(=O)NCCNc1nonc1C(N)=NO
Product: CS(=O)(=O)NCCNc1nonc1C(=NO)Nc1ccc(F)c(Cl)c1

Procedure:
The title compound was prepared according to the procedure of Example 17 step E, using N′-hydroxy-4-({2-[(methylsulfonyl)amino]ethyl}amino)-1,2,5-oxadiazole-3-carboximidamide and 3-chloro-4-fluoroaniline [Aldrich, product #228583] as the starting materials. LCMS for C12H15ClFN6O4S (M+H)+: m/z=393.0. 1H NMR (400 MHz, DMSO-d6): δ 11.50 (s, 1H), 8.91 (s, 1H), 7.19 (m, 2H), 6.96 (dd, J=6.7, 2.5 Hz, 1H), 6.71 (m, 1H), 6.26 (t, J=6.4 Hz, 1H), 3.32 (m, 2H), 3.13 (q, J=5.8 Hz, 2H), 2.89 (s, 3H).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1.[N-:13]=[N+]=[N-].[Na+].CS(O)(=O)=O.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[O:1]=[C:2]1[NH:13][CH2:7][CH2:6][CH:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1
Reactant: [N-]=[N+]=[N-]
Reactant: CCOC(=O)C1CCC(=O)CC1
Agent: CS(=O)(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C1CCNC(=O)CC1
Temperature: 10 °C
Yield: 70 %

Procedure:
In a 250 ml three necked flask fitted with reflux condenser, magnetic stirrer and dropping funnel under inert atmosphere, 5.6 ml (5.98 g, 34 mmoles, 1 eq) of ethyl 4-oxocyclohexanecarboxylate 27 were dissolved in 50 ml of CHCl3. 6.65 g (102 mmole, 3 eq) of sodium azide were added, followed by 22.1 ml (32.8 g, 341 mmoles, 10 eq) of methanesulfonic acid dissolved in 20 ml of over 30 min. The mixture was heated to reflux for 1 hour and cooled down to 10° C. 200 ml of saturated sodium bicarbonate solution were added, the mixture decanted and the aqueous phase extracted with 3×150 ml of CHCl3, the combined organic phases were dried over magnesium sulfate, filtered and concentrated to dryness. The residue was purified by PrepLC (800 g SiO2, CH2Cl2/MeOH, 97/3) to give 5.1 g of crude compound. It was crystallised from 40 ml of diethylether to give 4.41 g of pure ester 28, 70% yield.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1)[CH2:5][C:6]([OH:8])=O.[NH2:17][C:18](=[N:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[S:19][CH3:20].CCN=C=NCCCN(C)C.Cl.C(N(CC)CC)C>CN(C1C=CN=CC=1)C.ClCCl>[CH3:1][O:2][N:3]=[C:4]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1)[CH2:5][C:6]([NH:17][C:18](=[N:21][C:22](=[O:28])[O:23][C:24]([CH3:26])([CH3:25])[CH3:27])[S:19][CH3:20])=[O:8]
Reactant: CON=C(CC(=O)O)c1ccc(OC)cc1
Reactant: CSC(N)=NC(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON=C(CC(=O)NC(=NC(=O)OC(C)(C)C)SC)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 88.6 %

Procedure:
A mixture of 3-(methoxyimino)-3-(4-methoxyphenyl)propanoic acid (223 mg), tert-butyl amino(methylthio)methylenecarbamate (190 mg), EDAC.HCl (384 mg), DMAP (122 mg) and triethylamine (0.56 mL) in dichloromethane (3 mL) was stirred at room temperature for 12 h. The crude reaction mixture was purified directly by preparative TLC eluting with 35% ethyl acetate/75% hexanes to give the title compound as a yellowish oil (350 mg). HPLC retention time: 2.42 min (method A). MS (ESI) (M+Na)+ 418.18.
Reaction SMILES: [CH:1]([C:3]1[Se:7][C:6]([C:8]([O:10]C)=[O:9])=[CH:5][CH:4]=1)=[O:2].[OH-:12].[Na+].Cl>O.[N+]([O-])([O-])=O.[Ag+]>[Se:7]1[C:6]([C:8]([OH:10])=[O:9])=[CH:5][CH:4]=[C:3]1[C:1]([OH:2])=[O:12]
Reactant: COC(=O)c1ccc(C=O)[se]1
Reactant: [OH-]
Agent: [Ag+]
Agent: Cl
Agent: O=[N+]([O-])[O-]
Solvent: O
Product: O=C(O)c1ccc(C(=O)O)[se]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.3 %

Procedure:
A solution of silver nitrate (6.26 g, 36.86 mmol) in water (10 mL) was added to methyl 5-formylselenophene-2-carboxylate (4.0 g, 18.43 mmol) at 0° C. for 5 min. Then a solution of sodium hydroxide (3.05 g, 76.34 mmol) in water (10 mL) was added to the reaction mixture at the same temperature for 5 min and stirred the mixture at room temperature (rt) for 1 h. The cooled reaction mixture was poured into ice cooled water and acidified with dil. HCl. The solution was extracted with ethyl acetate (3×100 mL) and the combined organic layer was washed with water, brine and dried over sodium sulfate. The solution was filtered and evaporated the solvent to give the product as off-white color solid (3.2 g, 80%), mp 293-295° C. 1H NMR (400 MHz, DMSO-d6): δ 13.48 (2H, br s, 2×—COOH), 7.82 (2H, s, H-3,4); LC-MS (negative ion mode): m/z 219, 217 (M−H)−.
Reaction SMILES: [S:1]([Cl:5])(Cl)(=[O:3])=[O:2].CN(C=O)C.[CH3:11][O:12][CH2:13][CH2:14][C:15]1[S:16][CH:17]=[CH:18][C:19]=1[CH3:20]>>[CH3:11][O:12][CH2:13][CH2:14][C:15]1[S:16][C:17]([S:1]([Cl:5])(=[O:3])=[O:2])=[CH:18][C:19]=1[CH3:20]
Reactant: O=S(=O)(Cl)Cl
Reactant: COCCc1sccc1C
Solvent: CN(C)C=O
Product: COCCc1sc(S(=O)(=O)Cl)cc1C
Temperature: 100 °C
Reaction time: 0.25 h

Procedure:
Sulfuryl chloride (0.26 g, 1.9 mmol) was added dropwise to a stirred solution of dry DMF (0.14 ml, 1.9 mmol) at 0° C. under an argon atmosphere resulting in the formation of a white solid. After 15 min, 2-(2-methoxy-ethyl)-3-methyl-thiophene (250 mg, 1.6 mmol) was added and the mixture was warmed to 100° C. and the melt was further stirred for 45 min. Crushed ice was added and the reaction mixture was extracted with ethyl acetate (2×) and the combined organic extracts were washed with water, brine, dried (magnesium sulfate. dihydrate), filtered and concentrated under reduced pressure. The crude solid was purified over silica gel (ethyl acetate/n-heptane): light yellow oil, 220 mg, GC-MS (EI): M=254.
Reaction SMILES: [NH2:1][C@H:2]([CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[C:3]([NH2:5])=[O:4].N1C=CN=C1.[C:21]([Si:25]([CH3:28])([CH3:27])Cl)([CH3:24])([CH3:23])[CH3:22]>C1COCC1>[NH2:1][C@H:2]([CH2:6][CH2:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][Si:25]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:28])[CH3:27])=[CH:13][CH:14]=1)[C:3]([NH2:5])=[O:4]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: NC(=O)[C@H](N)CCCc1ccc(O)cc1
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)Oc1ccc(CCC[C@@H](N)C(N)=O)cc1
Temperature: 70 °C

Procedure:
To a stirred solution of (R)-2-Amino-5-(4-hydroxy-phenyl)-pentanoic acid amide (5 g, 24.01 mmol) in THF (250 ml) is added imidazole (4.90 g, 72 mmol), followed by tert-butyldimethylchlorosilane (3.98 g, 26.4 mmol). The resulting solution is heated at 70° C. for 4 hours and then allowed to cool to room temperature. Dilution with Et2O (200 ml) washing with water (2×100 ml) and brine (100 ml), drying MgSO4, and concentration in vacuo yields (R)-2-Amino-5-[4-(tert-butyl-dimethyl-silanyloxy)-phenyl]-pentanoic acid amide; [M+H]+ 323
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([NH:9][NH2:10])=[CH:7][C:6]([CH3:11])=[C:5]([C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]([F:22])([F:21])[F:20])=[CH:14][C:13]=2[O:23][CH3:24])[N:4]=1>CCO>[CH2:7]([C:6]1[CH:5]=[C:12]([CH2:13][CH3:14])[N:9]([C:8]2[C:3]([O:2][CH3:1])=[N:4][C:5]([C:12]3[CH:17]=[CH:16][C:15]([O:18][C:19]([F:21])([F:22])[F:20])=[CH:14][C:13]=3[O:23][CH3:24])=[C:6]([CH3:11])[CH:7]=2)[N:10]=1)[CH3:8]
Reactant: COc1cc(OC(F)(F)F)ccc1-c1nc(OC)c(NN)cc1C
Solvent: CCO
Product: CCc1cc(CC)n(-c2cc(C)c(-c3ccc(OC(F)(F)F)cc3OC)nc2OC)n1

Procedure:
Preparation of 3-(3,5-Diethyl-pyrazol-1-yl)-2-methoxy-6-(2-methoxy-4-trifluoromethoxy-phenyl)-5-methyl-pyridine 3,5-heptane dione (0.32 ml, 2.33 mmol) is added to a solution of [2-methoxy-6-(2-methoxy-4-trifluoromethoxy-phenyl)-5-methyl-pyridin-3-yl]-hydrazine (0.8 g, 2.33 mmol) in EtOH (15 ml) at room temperature. The mixture is refluxed for 15 hours. The solvent is removed under reduced pressure and the residue is purified by flash column chromatography to obtain 3-(3,5-Diethyl-pyrazol-1-yl)-2-methoxy-6-(2-methoxy-4-trifluoromethoxy-phenyl)-5-methyl-pyridine (Compound 4). Rf(hexane/EtOAc=9:1)=0.18, MS m/z 436.4 (M+H).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:12][C:13]3[CH:21]=[C:20]4[C:16]([CH:17]=[CH:18][NH:19]4)=[CH:15][CH:14]=3)=[N:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:22][CH3:23].O[CH2:25][CH2:26][C:27]1[S:31][CH:30]=[N:29][C:28]=1[CH3:32]>>[CH3:23][O:22][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:2]=1[O:1][CH2:25][CH2:26][C:27]1[S:31][CH:30]=[N:29][C:28]=1[CH3:32])[N:9]=[CH:8][N:7]=[C:6]2[NH:12][C:13]1[CH:21]=[C:20]2[C:16]([CH:17]=[CH:18][NH:19]2)=[CH:15][CH:14]=1
Reactant: COc1cc2c(Nc3ccc4cc[nH]c4c3)ncnc2cc1O
Reactant: Cc1ncsc1CCO
Product: COc1cc2c(Nc3ccc4cc[nH]c4c3)ncnc2cc1OCCc1scnc1C
Yield: 34 %

Procedure:
Using an analogous procedure to that described in Example 201, 7-hydroxy-4-(indol-6-ylamino)-6-methoxyquinazoline (98 mg, 0.32 mmol), (prepared as described for the starting material in Example 217), was reacted with 5-(2-hydroxyethyl)-4-methylthiazole (69 mg, 0.48 mmol) to give 6-methoxy-4-(indol-6-ylamino)-7-(2-(4-methylthiazol-5-yl)ethoxy)quinazoline (47 mg, 34%).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]([CH2:9][C:10]([OH:12])=[O:11])[CH:6]=[CH:7][CH:8]=1.[CH3:15]O>CCOC(C)=O>[CH3:15][O:11][C:10](=[O:12])[CH2:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:13])([F:14])[F:1])[CH:4]=1
Reactant: CO
Reactant: O=C(O)Cc1cccc(C(F)(F)F)c1
Solvent: CCOC(C)=O
Product: COC(=O)Cc1cccc(C(F)(F)F)c1
Temperature: 25 °C
Yield: 89 %

Procedure:
Into a solution of 3-trifluoromethylphenylacetic acid (20.0 g. 98 mmol) in MeOH (100 mL), cooled in an ice-water bath, was bubbled HCl (g) for 15 min. The mixture was allowed to warm to room temperature and was then concentrated in vacuo to furnish a clear, yellow-green liquid which was diluted with EtOAc (0.25L) and washed with saturated aqueous NaHCO3 (2×0.25L), brine (0.25L), and dried (Na2SO4). Concentration in vacuo provided the crude ester which was purified by chromatography on a column of silica gel(230-400 mesh, 600 g, 70 mm o.d., ethyl acetate-hexanes 10:90, 400 mL fractions) using the flash technique. Fractions 6-9 provided 19.08 g (89%) of methyl-3-trifluoromethylphenylacetate as a clear colorless liquid.
Reaction SMILES: C(O[C@@H:5]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[C@H:6]1OC(=O)C)(=O)C.[C:17]([O:20][C:21]1([C:37](=[O:39])[CH3:38])[CH2:30][C:29]2[C:28](=[O:31])[CH:27]=[CH:26][C:25](=[O:32])[C:24]=2[C:23]2([S:36][CH2:35][CH2:34][S:33]2)[CH2:22]1)(=[O:19])[CH3:18]>C1(C)C(C)=CC=CC=1>[C:17]([O:20][C:21]1([C:37](=[O:39])[CH3:38])[CH2:30][C:29]2[C:28](=[O:31])[C:27]3[C:26](=[CH:6][C:7]4[C:8]([CH:5]=3)=[CH:9][CH:10]=[CH:11][CH:12]=4)[C:25](=[O:32])[C:24]=2[C:23]2([S:36][CH2:35][CH2:34][S:33]2)[CH2:22]1)(=[O:19])[CH3:18]
Reactant: CC(=O)O[C@@H]1c2ccccc2[C@H]1OC(C)=O
Reactant: CC(=O)OC1(C(C)=O)CC2=C(C(=O)C=CC2=O)C2(C1)SCCS2
Solvent: Cc1ccccc1C
Product: CC(=O)OC1(C(C)=O)CC2=C(C(=O)c3cc4ccccc4cc3C2=O)C2(C1)SCCS2
Yield: 81.8 %

Procedure:
A mixture of 0.825 g (0.00375 mol) of trans-1,2-diacetoxy-1,2-dihydrobenzocyclobutene and 1.20 g (0.0034 mol) of rac-3'-acetoxy-3'-acetyl-1',2',3',4',5',8'-hexahydro-5',8'-dioxospiro[1,3-dithiolane-2,1'-naphthalene] [prepared as described in Example 5(A)] in 65 ml of xylene was stirred and heated under reflux under an atmosphere of nitrogen for 16 hours. The solution was evaporated to dryness and the residue was stirred with 20 ml of diethyl ether and filtered to give 1.259 g (82%) of rac-3'-acetoxy-3'-acetyl-1',2',3',4',5',12'-hexahydro-5',12'-dioxospiro[1,3-dithiolane-2,1'-naphthacene] in the form of a bright yellow solid of melting point 239°-241° C.