Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:11]1[CH2:15][CH2:14][C:13]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([CH2:16][CH2:17]OS(C)(=O)=O)[CH2:12]1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[CH2:29]([O:31][CH2:32][CH2:33][N:34]1[C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=2[N:36]=[C:35]1[NH:43][CH:44]1[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]1)[CH3:30].C(N(CC)C(C)C)(C)C>C(#N)C>[C:1]([N:11]1[CH2:15][CH2:14][C:13]([CH2:16][CH2:17][N:47]2[CH2:46][CH2:45][CH:44]([NH:43][C:35]3[N:34]([CH2:33][CH2:32][O:31][CH2:29][CH3:30])[C:38]4[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=4[N:36]=3)[CH2:49][CH2:48]2)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:12]1)([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2]
Reactant: CS(=O)(=O)OCCC1(c2ccccc2)CCN(C(=O)OCc2ccccc2)C1
Reactant: CCOCCn1c(NC2CCNCC2)nc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCOCCn1c(NC2CCN(CCC3(c4ccccc4)CCN(C(=O)OCc4ccccc4)C3)CC2)nc2ccccc21
Reaction time: 18 h

Procedure:
Combine 1-carbobenzyloxy-3-phenyl-3-(2-methanesulfonyloxyethyl)pyrrolidine (10.2 g, 25.3 mmol), (1.34 g, 2.5 mmol), (1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)(piperidin-4-yl)amine (30.4 mmol), and N,N-diisopropylethylamine (18 mL, 101 mmol) in acetonitrile (300 mL). Heat to reflux. After 18 hours, evaporate in vacuo to give a residue. Chromatograph the residue on silica gel to give 1-carbobenzyloxy-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl-amino)piperidin-1-yl)ethyl)-3-phenylpyrrolidine.
Reaction SMILES: [CH3:1][C:2](=[N:4][OH:5])[CH3:3].[CH3:6][S:7]([O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH:17]1[O:21][N:20]=[C:19]([C:22]2[N:23]=[C:24]([CH:27]3[CH2:32][CH2:31][N:30]([C:33](=[O:36])[CH2:34]Cl)[CH2:29][CH2:28]3)[S:25][CH:26]=2)[CH2:18]1)(=[O:9])=[O:8].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[CH3:6][S:7]([O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH:17]1[O:21][N:20]=[C:19]([C:22]2[N:23]=[C:24]([CH:27]3[CH2:32][CH2:31][N:30]([C:33](=[O:36])[CH2:34][O:5][N:4]=[C:2]([CH3:3])[CH3:1])[CH2:29][CH2:28]3)[S:25][CH:26]=2)[CH2:18]1)(=[O:9])=[O:8]
Reactant: CS(=O)(=O)Oc1ccccc1C1CC(c2csc(C3CCN(C(=O)CCl)CC3)n2)=NO1
Reactant: CC(C)=NO
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)=NOCC(=O)N1CCC(c2nc(C3=NOC(c4ccccc4OS(C)(=O)=O)C3)cs2)CC1
Reaction time: 2 h
Yield: 9.3 %

Procedure:
To a solution of acetone oxime (9.3 mg) in N,N-dimethylformamide (0.28 ml) at room temperature was added 3 Å molecular sieve, and the mixture was stirred at this temperature for 2 hours. Thereafter, 2-(3-{2-[1-(chloroacetyl)piperidin-4-yl]-1,3-thiazol-4-yl}-4,5-dihydro-1,2-oxazol-5-yl)phenyl methanesulphonate (50 mg) and caesium carbonate (64 mg) were added thereto, and the mixture was stirred at room temperature for 18 hours. Subsequently, the mixture was filtered and extracted twice with ethyl acetate. The combined organic phases were dried over magnesium sulphate and concentrated. Purification by column chromatography gave 2-{3-[2-(1-{[(propan-2-ylideneamino)oxy]acetyl}piperidin-4-yl)-1,3-thiazol-4-yl]-4,5-dihydro-1,2-oxazol-5-yl}phenyl methanesulphonate (5 mg, 10%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=1)[C:5]([O:7][CH3:8])=[O:6].[CH:12]1([C:15](Cl)=[O:16])[CH2:14][CH2:13]1>>[CH:12]1([C:15]([NH:1][C:2]2[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=2)[C:5]([O:7][CH3:8])=[O:6])=[O:16])[CH2:14][CH2:13]1
Reactant: COC(=O)c1ccnc(N)c1
Reactant: O=C(Cl)C1CC1
Product: COC(=O)c1ccnc(NC(=O)C2CC2)c1
Yield: 92 %

Procedure:
The title compound is prepared in 92% yield (1.60 g, a yellow solid) from methyl 2-aminoisonicotinate (1.20 g, 7.89 mmol) and cyclopropanecarbonyl chloride by the similar manner in Step-1 of Carboxylic acid-1.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)=[CH:28][C:27]=1[CH3:38].[Cl:39][C:40]1[C:41]([C:50]([F:53])([F:52])[F:51])=[N:42][N:43]([CH2:46][C:47](O)=[O:48])[C:44]=1[CH3:45]>>[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]2[CH2:37][CH2:36][N:35]([C:47](=[O:48])[CH2:46][N:43]3[C:44]([CH3:45])=[C:40]([Cl:39])[C:41]([C:50]([F:53])([F:52])[F:51])=[N:42]3)[CH2:34][CH2:33]2)=[CH:28][C:27]=1[CH3:38]
Reactant: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)O
Reactant: Cc1cc(N2CCNCC2)ccc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: Cc1cc(N2CCN(C(=O)Cn3nc(C(F)(F)F)c(Cl)c3C)CC2)ccc1Cl

Procedure:
Title compound was prepared following the HATU mediated coupling protocol P, wherein 1-(4-Chloro-3-methylphenyl)-piperazine and (4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid were used as the coupling components, to give the product as a solid: 1H NMR (DMSO-d6, 400 MHz) 7.25 (d, 1H), 7.05 (s,1H), 6.90 (d, 1H), 5.38 (s, 2H), 3.64 (m, 4H), 3.27 (m, 2H), 3.17 (m, 2H), 2.26 (s, 3H), 2.19 (s, 3H) ppm; MS (ES) M+H expected=435.1, found=435.0.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH2:13][N:14]3C(=O)C4=CC=CC=C4C3=O)=[CH:11][N:10]=[C:9]2[CH2:25][N:26]([CH3:28])[CH3:27])=[C:4]([C:29]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=2)=O)[CH:3]=1.O.NN>C(O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[N:8]3[C:9]([CH2:25][N:26]([CH3:28])[CH3:27])=[N:10][CH:11]=[C:12]3[CH2:13][N:14]=[C:29]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=3)[C:4]=2[CH:3]=1
Reactant: CN(C)Cc1ncc(CN2C(=O)c3ccccc3C2=O)n1-c1ccc(Br)cc1C(=O)c1ccccn1
Agent: NN
Solvent: CCO
Solvent: O
Product: CN(C)Cc1ncc2n1-c1ccc(Br)cc1C(c1ccccn1)=NC2

Procedure:
In the manner given in Example 4, N-[[1-[4-bromo2-(2-pyridylcarbonyl)phenyl]-2-[(dimethylamino)methyl]-imidazol-5-yl]methyl]phthalimide in ethanol is heated with hydrazine hydrate to give 8-bromo-6-(2-pyridyl)-1-[(dimethylamino)methyl]-4H-imidazo[1,5-a][1,4]benzodiazepine.
Reaction SMILES: C(N(CC)C(C)C)(C)C.Cl.[NH2:11][C@@H:12]([CH2:16][C:17]1[CH:22]=[C:21]([I:23])[CH:20]=[CH:19][C:18]=1[O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:13]([OH:15])=[O:14].[CH2:32]([O:39][C:40](N1C(=O)CCC1=O)=[O:41])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>CN(C=O)C>[CH2:32]([O:39][C:40]([NH:11][C@@H:12]([CH2:16][C:17]1[CH:22]=[C:21]([I:23])[CH:20]=[CH:19][C:18]=1[O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:13]([OH:15])=[O:14])=[O:41])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: O=C1CCC(=O)N1C(=O)OCc1ccccc1
Reactant: N[C@@H](Cc1cc(I)ccc1OCc1ccccc1)C(=O)O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(N[C@@H](Cc1cc(I)ccc1OCc1ccccc1)C(=O)O)OCc1ccccc1
Reaction time: 8 h

Procedure:
9.25 ml (53.09 mol) of N,N-diisopropylethylamine are added to a solution of 10.46 g (24.13 mmol) of 2(S)-amino-3-(2-benzyloxy-5-iodophenyl)propionic acid hydrochloride (Example 9A) in DMF. 6.615 g (26.54 mmol) of N-(benzyloxycarbonyl)succinimide (Z-OSuc) are added thereto. The resulting solution is stirred overnight and then concentrated on a rotary evaporator in vacuo. The residue is taken up in dichloromethane and extracted twice each with a 0.1N hydrochloric acid solution and a saturated aqueous sodium chloride solution. The organic phase is dried, filtered and concentrated. The mixture is purified by column chromatography on silica gel (mobile phase: cyclohexane/diethyl ether 9:1 to 8:2).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1.[H-].[Na+].[CH3:15][O:16][C:17](=O)[O:18]C.Cl>C1COCC1>[CH3:1][O:2][C:3](=[O:12])[CH:4]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1)[C:17]([O:16][CH3:15])=[O:18]
Reactant: COC(=O)Cc1ccc(Cl)cc1
Reactant: COC(=O)OC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)C(C(=O)OC)c1ccc(Cl)cc1
Reaction time: 0.67 h

Procedure:
At 35° C. a solution of 4-chlorophenylacetic acid methyl ester (52 g) in THF (170 ml) was carefully added over a period of 70 min to a suspension of NaH (15.6 g) in dry THF (550 ml). Stirring was continued for 40 min without heating and the temperature dropped to 290C. The evolution of gas had stopped before dimethylcarbonate (94.8 ml) was added dropwise while the temperature of the mixture was maintained at 25–28° C. After the evolution of gas had ceased, the mixture was diluted with THF (200 ml) and stirring was continued for 72 h at rt. The mixture was carefully acidified with aq. HCl before bulk of the THF was removed in vacuo. The residue was dissolved in diethyl ether (1200 ml), washed three times with 1 N aq. HCl and once with brine, dried over MgSO4 and evaporated. The residue formed was collected, washed with diethyl ether and dried to give 2-(4-chloro-phenyl)-malonic acid dimethyl ester (42 g) as white crystals.
Reaction SMILES: [F-].[CH2:2]([N+](CCCC)(CCCC)CCCC)[CH2:3]CC.[CH2:19]([CH:26]1[N:31]([CH3:32])[C:30](=[O:33])[CH:29]([CH:34](C#C[Si](C)(C)C)[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[N:28]([CH3:47])[C:27]1=[O:48])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[NH4+].[Cl-]>C1COCC1>[CH2:19]([CH:26]1[N:31]([CH3:32])[C:30](=[O:33])[CH:29]([CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=2[C:2]#[CH:3])[N:28]([CH3:47])[C:27]1=[O:48])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Reactant: CN1C(=O)C(C(C#C[Si](C)(C)C)c2ccccc2)N(C)C(=O)C1Cc1ccccc1
Agent: [Cl-]
Agent: [F-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C#Cc1ccccc1CC1C(=O)N(C)C(Cc2ccccc2)C(=O)N1C
Reaction time: 1 h
Yield: 65.6 %

Procedure:
At 0° C., tetrabutylammonium fluoride (1 mM in THF, 0.5 ml, 0.5 mmol) was added dropwise to 3-benzyl-1,4-dimethyl-6-(2-trimethylsilanylethynylbenzyl)piperazine-2,5-dione (140 mg, 0.22 mmol) in THF (abs., 5 ml). The mixture was stirred at this temperature for 1 h. After addition of NH4Cl solution (saturated, aq.), the mixture was extracted with ethyl acetate and the organic phases were dried and concentrated. Purification by column chromatography gave 50 mg (65%) of the target compound as a yellow oil.
Reaction SMILES: [C:1]1(/[C:7](/[C:17]2[CH:22]=[CH:21][C:20]([CH:23]=[CH:24][C:25](O)=[O:26])=[CH:19][CH:18]=2)=[C:8](/[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)\[CH2:9][CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:28][C:29]([F:41])([F:40])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[S:36]([NH2:39])(=[O:38])=[O:37]>>[C:1]1([C:7]([C:17]2[CH:22]=[CH:21][C:20]([CH:23]=[CH:24][C:25]([NH:39][S:36]([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=3[C:29]([F:28])([F:40])[F:41])(=[O:38])=[O:37])=[O:26])=[CH:19][CH:18]=2)=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:9][CH3:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC/C(=C(\c1ccccc1)c1ccc(C=CC(=O)O)cc1)c1ccccc1
Reactant: NS(=O)(=O)c1ccccc1C(F)(F)F
Product: CCC(=C(c1ccccc1)c1ccc(C=CC(=O)NS(=O)(=O)c2ccccc2C(F)(F)F)cc1)c1ccccc1

Procedure:
Prepared by coupling 1a and 2-(trifluoromethyl)-benzenesulfonamide (Synlett, 1997, 375) in accordance with Procedure 1, Method B described hereinabove. Yield (14%); 1H NMR (d6-DMSO) δ 12.49 (br s, 1H), 7.98–7.90 (m, 3H), 7.39–7.08 (m, 13H), 6.85 (d, J=8.0 Hz, 2H), 6.47 (d, J=15.7 Hz, 1H), 2.36 (q, J=7.3 Hz, 2H), 0.82 (t, J=7.3 Hz, 3H); APcI m/z: 562 (M+H+).
Reaction SMILES: [N:1]1([S:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]#[CH:16])=[CH:11][CH:10]=2)(=[O:8])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.C([Li])CCC.[F:22][C:23]([F:28])([F:27])[C:24](=[O:26])[CH3:25]>O1CCCC1>[F:22][C:23]([F:28])([F:27])[C:24]([OH:26])([CH3:25])[C:16]#[C:15][C:12]1[CH:13]=[CH:14][C:9]([S:6]([N:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)(=[O:7])=[O:8])=[CH:10][CH:11]=1
Reactant: CC(=O)C(F)(F)F
Reactant: C#Cc1ccc(S(=O)(=O)N2CCCC2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(O)(C#Cc1ccc(S(=O)(=O)N2CCCC2)cc1)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a solution of the 4-(1-pyrrolidinylsulfonyl)phenylacetylene (1.3 g) in anhydrous tetrahydrofuran (60 mL) cooled to -78° C. under a nitrogen atmosphere was added n-butyllithium (2.43 mL of a 2.5M solution in hexanes, 6.09 mmol). The anion was generated over a ten minute period at -78° C. To the anion was added a cooled (0° C.) solution of trifluoroacetone (644 mL) in anhydrous tetrahydrrofuran (10 mL) over a 20 second period. The reaction was stirred at -78° C. for five minutes before the ice bath was removed. After an additional five minutes, the reaction was quenched with 2N HCl (50 mL). The product was extracted into diethyl ether. The combined organic extracts were dried, filtered, and evaporated under reduced pressure. The crude product was purified by chromatography (1:3 acetone: hexanes) followed by recrystallization (1:1 diethyl ether:hexanes) to yield the title compound as a white solid (1.38 g); mp 167.8°-168.7° C.; MS: m/z=348(M+1); NMR (CDCl3): 1.74 (s,3), 1.71-1.78 (m,4), 3.15 (s,1), 3.21-3.26.(m,4), 7.56-7.59 (m,2), 7.77-7.80 (m,2). Analysis for C15H16F3NO3S: Calculated: C, 51.87; H, 4.64; N, 4.03; Found: C, 51.80; H, 4.67; N, 3.88.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:18]=1)[C:13]([O:15]C)=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Li+]>CO.O1CCCC1>[CH2:1]([O:8][C:9]([NH:11][CH:12]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:18]=1)[C:13]([OH:15])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)C(NC(=O)OCc1ccccc1)c1cccc(OCc2ccccc2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(NC(C(=O)O)c1cccc(OCc2ccccc2)c1)OCc1ccccc1
Yield: 67.2 %

Procedure:
A solution of methyl 2-(benzyloxycarbonylamino)-2-(3-benzyloxyphenyl)acetate (640 mg, 1.75 mmol) and aqueous lithium hydroxide (1 N, 3.50 mL, 3.50 mmol) in methanol (5 mL) and tetrahydrofuran (5 mL) was stirred at room temperature for one hour. The mixture was concentrated in vacuo and the residue diluted with dichloromethane (30 mL) and acidified to pH 0.5 with 2 N HCl. The aqueous phase was re-extracted with dichloromethane (2×50 mL). The combined organic fractions were dried over a hydrophobic frit and the solvent was removed in vacuo to give the title compound as a light brown oil (460 mg, 67%). This was used in the next step without further purification.
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]3[C:18]([O:25][CH3:26])=[N:19][C:20]([O:23][CH3:24])=[N:21][CH:22]=3)[CH:12]=2)[CH:10]=1)=[O:5].Br[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[O:35][CH3:36]>>[CH3:24][O:23][C:20]1[N:19]=[C:18]([O:25][CH3:26])[C:17]([C:13]2[CH:12]=[C:11]([N:9]3[CH:10]=[C:6]([C:4]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[O:35][CH3:36])=[O:5])[N:7]=[CH:8]3)[CH:16]=[CH:15][CH:14]=2)=[CH:22][N:21]=1
Reactant: COc1ccccc1Br
Reactant: COc1ncc(-c2cccc(-n3cnc(C(=O)N(C)OC)c3)c2)c(OC)n1
Product: COc1ncc(-c2cccc(-n3cnc(C(=O)c4ccccc4OC)c3)c2)c(OC)n1

Procedure:
This compound is prepared by method C using compound 12m and 2-bromoanisole
Reaction SMILES: CS([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[O:13][C:14]([CH2:42]C)=[C:15]([CH2:17][O:18][C:19]3[CH:24]=[CH:23][C:22]([CH2:25][O:26][C:27]4[C:31]([CH:32]=[O:33])=[CH:30][N:29]([C:34]5[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=5)[N:28]=4)=[CH:21][C:20]=3[O:40][CH3:41])[N:16]=2)[CH:7]=1)(=O)=O.O1CCCC1.[OH-].[Na+].Cl>C(O)C>[OH:5][C:6]1[CH:7]=[C:8]([C:12]2[O:13][C:14]([CH3:42])=[C:15]([CH2:17][O:18][C:19]3[CH:24]=[CH:23][C:22]([CH2:25][O:26][C:27]4[C:31]([CH:32]=[O:33])=[CH:30][N:29]([C:34]5[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=5)[N:28]=4)=[CH:21][C:20]=3[O:40][CH3:41])[N:16]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: CCc1oc(-c2cccc(OS(C)(=O)=O)c2)nc1COc1ccc(COc2nn(-c3ccccc3)cc2C=O)cc1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1cc(COc2nn(-c3ccccc3)cc2C=O)ccc1OCc1nc(-c2cccc(O)c2)oc1C
Temperature: 60 °C
Reaction time: 1 h
Yield: 59 %

Procedure:
To a mixture of 3-{4-[(4-{[(4-formyl-1-phenyl-1H-pyrazol-3-yl)oxy]methyl}-2-methoxyphenoxy)methyl]-5-ethyl-1,3-oxazol-2-yl}phenyl methanesulfonate (0.20 g), tetrahydrofuran (2 mL) and ethanol (2 mL) was added 1N aqueous sodium hydroxide solution (2 mL), and the mixture was stirred at 60° C. for 1 hr. To the reaction mixture was added dilute hydrochloric acid to acidify the solution, and the precipitated crystals were collected by filtration to give 3-[(4-{[2-(3-hydroxyphenyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-phenyl-1H-pyrazole-4-carbaldehyde as colorless crystals (0.10 g, yield 59%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 193-194° C.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([OH:14])=[C:10]([Br:13])[CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[O:15]1[C:19]2([CH2:24][CH2:23][C:22]([CH2:25]O)=[CH:21][CH2:20]2)[O:18][CH2:17][CH2:16]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1.C(OCC)(=O)C>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([O:14][CH2:25][C:22]3[CH2:23][CH2:24][C:19]4([O:15][CH2:16][CH2:17][O:18]4)[CH2:20][CH:21]=3)=[C:10]([Br:13])[CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCc2cc(O)c(Br)cc21
Reactant: OCC1=CCC2(CC1)OCCO2
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(=O)N1CCc2cc(OCC3=CCC4(CC3)OCCO4)c(Br)cc21
Reaction time: 1 h
Yield: 180.6 %

Procedure:
1-Acetyl-6-bromo-2,3-dihydro-1H-indol-5-ol (Tetrahedron 1973, 29, 1115) (1.10 g, 4.3 mmol), 1,4-dioxaspiro[4,5]dec-7-ene-8-methanol (D11, 0.88 g, 5.2 mmol) and triphenylphosphine (1.36 g, 5.2 mmol) were stirred under Ar in dry THF (50 ml) as diethyl azodicarboxylate (0.82 ml, 5.2 mmol) was added dropwise. The mixture was stirred for 1 h, diluted with ethyl acetate (100 ml), washed with brine, dried (Na2SO4) and evaporated to give a dark oil. Chromatography on silica gel, eluting with 0-5% methanol/dichloromethane, gave the title compound (3.17 g) contaminated by substantial amounts of triphenylphosphine and diethyl azodicarboxylate-derived residues (NMR).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[C:15](=O)[CH2:14][CH2:13][CH2:12]3)[CH:5]=[CH:4][N:3]=[CH:2]1.[C:20]([CH2:23][O:24][NH2:25])([OH:22])=[O:21].Cl>N1C=CC=CC=1.O>[N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[C:15](=[N:25][O:24][CH2:23][C:20]([OH:22])=[O:21])[CH2:14][CH2:13][CH2:12]3)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=C1CCCc2cc(OCCn3ccnc3)ccc21
Reactant: NOCC(=O)O
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: O=C(O)CON=C1CCCc2cc(OCCn3ccnc3)ccc21
Yield: 43.6 %

Procedure:
A solution of 1.0 g (3.9 mmol) of 6-[2-(1H-1-imidazolyl)ethoxy]-1,2,3,4-tetrahydro-1-naphthalenone in 10 mL of pyridine was treated with 1.02 g (9.3 mmol) of carboxymethoxyamine×0.5 HCl and the solution heated at reflux for 2 days. The solution was diluted with H2O and extracted with EtOAc. On standing, the aqueous phase deposited a solid which was collected and dried. There was obtained 0.56 g (43% yield) of the product as a white solid, mp 193-195° C. The structure was confirmed by NMR and mass spectroscopy. MS m/z 330 (M+H+).
Reaction SMILES: C(O)(C(F)(F)F)=O.[Cl:8][C:9]1[C:10]([F:46])=[C:11]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][C:22]([O:44][CH3:45])=[C:23]([O:26][C@H:27]4[CH2:32][CH2:31][N:30](C(OC(C)(C)C)=O)[C@H:29]([C:40]([NH:42][CH3:43])=[O:41])[CH2:28]4)[CH:24]=3)[N:19]=[CH:18][N:17]=2)[CH:12]=[CH:13][CH:14]=1>C(Cl)Cl>[Cl:8][C:9]1[C:10]([F:46])=[C:11]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][C:22]([O:44][CH3:45])=[C:23]([O:26][C@H:27]4[CH2:32][CH2:31][NH:30][C@H:29]([C:40]([NH:42][CH3:43])=[O:41])[CH2:28]4)[CH:24]=3)[N:19]=[CH:18][N:17]=2)[CH:12]=[CH:13][CH:14]=1
Reactant: CNC(=O)[C@@H]1C[C@@H](Oc2cc3c(Nc4cccc(Cl)c4F)ncnc3cc2OC)CCN1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNC(=O)[C@@H]1C[C@@H](Oc2cc3c(Nc4cccc(Cl)c4F)ncnc3cc2OC)CCN1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.2 %

Procedure:
TFA (15 ml) was added over a period of 5 minutes to a stirred solution of tert-butyl (2S,4S)-4-({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}oxy)-2-[(methylamino)carbonyl]piperidine-1-carboxylate (4.1 g, 7.31 mmol) in DCM (15 ml) at 0° C. The reaction mixture was allowed to warm to room temperature and stirred for 1 hour after which time, the reaction was complete. The reaction mixture was concentrated to dryness, azeotroped twice with toluene to give (2S,4S)-4-({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}oxy)-N-methylpiperidine-2-carboxamide (3.0 g, 89%) the crude residue was used without further purification; Mass Spectrum: (M+H)+ 460.1.
Reaction SMILES: [SH:1][C:2]1[N:6]([CH2:7][CH2:8][CH2:9][CH3:10])[CH:5]=[N:4][N:3]=1.[OH-].[Na+].[CH3:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19]Cl)=[CH:17][CH:16]=1>CO>[CH3:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19][S:1][C:2]2[N:6]([CH2:7][CH2:8][CH2:9][CH3:10])[CH:5]=[N:4][N:3]=2)=[CH:17][CH:16]=1
Reactant: COc1ccc(CCl)cc1
Reactant: CCCCn1cnnc1S
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCn1cnnc1SCc1ccc(OC)cc1

Procedure:
To a mixture of 10 g. (0.064 mole) of 3-mercapto-4-n-butyl-1,2,4-triazole and 2.6 g. (0.064 mole) of sodium hydroxide in 200 ml. of methanol was added 9.9 g. (0.064 mole) of p-methoxybenzyl chloride. The reaction mixture was heated at reflux about 20 hours. The solvent was evaporated off, the residue washed with water, dried and distilled. There was obtained 17.8 g. of yellow liquid distilling at 190°-205° C. at 0.03 mm. Nuclear magnetic resonance and ultraviolet spectra indicated this to be approximately an equal mixture of 3-(4-methoxybenzylmercapto)-4-n-butyl-1,2,4-triazole and 4-n-butyl-2-(4-methoxybenzyl)-1,2,4-triazoline-3-thione.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:10]([NH2:12])=[O:11])[CH2:3][C:4]1[CH:9]=[N:8][CH:7]=[CH:6][CH:5]=1.Cl>C(Cl)Cl.O1CCOCC1>[NH2:1][C@H:2]([C:10]([NH2:12])=[O:11])[CH2:3][C:4]1[CH:9]=[N:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cccnc1)C(N)=O
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: NC(=O)[C@@H](N)Cc1cccnc1

Procedure:
Suspend Boc-(L)-Pal-NH2 (0.98 g) in methylene chloride (15 mL) with light heating and add a solution of hydrochloric acid (4M, 10 mL) in dioxane. After 30 minutes evaporate methylene chloride and dioxane. Dissolve the solid in methanol, precipitate by addition of ether and filtrate to give H-(L)-Pal-NH2. 2HCl (0.86 g, 98%).
Reaction SMILES: [N:1]1[C:11]2[C:10]3[S:12][C:13]([C:15]4[CH:16]=[CH:17][C:18]([C:21]#[N:22])=[N:19][CH:20]=4)=[CH:14][C:9]=3[CH2:8][CH2:7][O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1>C(O)(=O)C.O1CCCC1.[Pd]>[N:1]1[C:11]2[C:10]3[S:12][C:13]([C:15]4[CH:16]=[CH:17][C:18]([CH2:21][NH2:22])=[N:19][CH:20]=4)=[CH:14][C:9]=3[CH2:8][CH2:7][O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: N#Cc1ccc(-c2cc3c(s2)-c2ncccc2OCC3)cn1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: NCc1ccc(-c2cc3c(s2)-c2ncccc2OCC3)cn1

Procedure:
A solution of 25 mg (0.082 mmol) of 5-(6,7-dihydropyrido[3,2-b]thieno[2,3-d]oxepin-9-yl)pyridin-2-nitrile in 3 ml of acetic acid and 3 ml of tetrahydrofuran was subjected to hydrogenation over 40 mg of 5% palladium on charcoal for 4 hours. The catalyst was filtered off, the mother liquor was concentrated in vacuum. The residue was triturated with ethyl ether afforded a precipitate which was collected and dried in vacuum to give 319. Yield 24 mg (79%). MS: (ESI+) 310.0. 1H NMR (400 MHz, DMSO) δ 8.82 (s, 1H), 8.25 (dd, J=4.4, 1.1, 1H), 8.06 (dd, J=8.1, 1.9, 1H), 7.50 (d, J=9.9, 2H), 7.42 (dd, J=8.1, 1.1, 1H), 7.23 (dd, J=8.1, 4.5, 1H), 4.35 (t, J=4.6, 1H), 3.86 (s, 2H), 3.24 (t, J=4.6, 2H).