Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:12])[CH:10]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[OH:19])[N:3]=1.[NH:20]1[CH2:25][CH2:24][CH:23]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:22][CH2:21]1.C(N(CC)CC)C>C(Cl)Cl>[F:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[C:4]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[OH:19])[N:3]=[C:2]2[N:20]1[CH2:21][CH2:22][CH:23]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:31])([CH3:30])[CH3:32])[CH2:24][CH2:25]1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: Oc1ccccc1-c1nc(Cl)c2cc(F)ccc2n1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC1CCN(c2nc(-c3ccccc3O)nc3ccc(F)cc23)CC1
Reaction time: 3 h

Procedure:
To a stirred solution of 2-(4-chloro-6-fluoroquinazolin-2-yl)phenol (0.20 g, 0.73 mmol) in CH2Cl2 (5 mL) was added dropwise a solution of tert-butyl piperidin-4-ylcarbamate (0.19 g, 0.95 mmol) and triethylamine (203 μL, 147 mg, 1.46 mmol) in CH2Cl2. The reaction was stirred for 3 h and then quenched with water. The aqueous layer was extracted with CH2Cl2. The combined organic layers were dried over MgSO4, filtered, and concentrated to obtain tert-butyl 1-(6-fluoro-2-(2-hydroxyphenyl)quinazolin-4-yl)piperidin-4-ylcarbamate. The residue was dissolved in 10 mL CH2Cl2 and 3 mL TFA. The reaction was stirred for 2 hours and neutralized with a 1.0 M aqueous NaOH solution. The mixture was partitioned between H2O/CH2Cl2 and separated, and the aqueous layer was extracted with CH2Cl2. The combined organic layers were dried over MgSO4, filtered, and concentrated to obtain 2-(4-(4-aminopiperidin-1-yl)-6-fluoroquinazolin-2-yl)phenol. LC/MS: m/z 339.3 (M+H)+ at 1.87 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].[F:19][CH:20]([F:29])[C:21]1[CH:22]=[C:23]([CH:25]=[CH:26][C:27]=1[F:28])[NH2:24].Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1.CN(C)C=O>[F:29][CH:20]([F:19])[C:21]1[CH:22]=[C:23]([NH:24][C:15](=[O:17])[CH2:14][C:9]2[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]3[CH2:2][CH2:3][O:4][CH2:5][CH2:6]3)[N:8]=2)[CH:25]=[CH:26][C:27]=1[F:28]
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Reactant: Nc1ccc(F)c(C(F)F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)Nc1ccc(F)c(C(F)F)c1
Yield: 71.1 %

Procedure:
The product is prepared according to the procedure described in example 5, using 250 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate, 1.1 g of 3-(difluoromethyl)-4-fluoroaniline (stage 2) and 300 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride in a mixture of 2 ml of pyridine and 2 ml of N,N-dimethylformamide. 260 mg of N-[3-(difluoromethyl)-4-fluorophenyl]-2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetamide are obtained in the form of a white solid, the characteristics of which are the following:
Reaction SMILES: [C:1]([C:3](=[CH:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]2[N:16]=[C:17]3[C:23]([C:24](=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:22][N:21](COCC[Si](C)(C)C)[C:18]3=[N:19][CH:20]=2)=[CH:10][CH:9]=1)[C:4]([NH2:6])=[O:5])#[N:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:1]([C:3](=[CH:7][C:8]1[CH:9]=[CH:10][C:11]([NH:14][C:15]2[N:16]=[C:17]3[C:23]([C:24](=[O:29])[C:25]([CH3:27])([CH3:26])[CH3:28])=[CH:22][NH:21][C:18]3=[N:19][CH:20]=2)=[CH:12][CH:13]=1)[C:4]([NH2:6])=[O:5])#[N:2]
Reactant: CC(C)(C)C(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Nc3ccc(C=C(C#N)C(N)=O)cc3)nc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)C(=O)c1c[nH]c2ncc(Nc3ccc(C=C(C#N)C(N)=O)cc3)nc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 25.7 %

Procedure:
To a 25 ml one necked round bottom flask 2-cyano-3-(4-(7-pivaloyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-2-ylamino)phenyl)acrylamide (0.1 g, 0.0002 mole) was taken in CH2Cl2 (10 ml). To this reaction mixture TFA (2.0 ml) was added dropwise at 0° C. After completion of the addition, the reaction mixture was warmed up to RT and then stirred for 16 hr. After completion of the reaction, CH2Cl2 was distilled out and the pH was adjusted to 8 to 9 using saturated NaHCO3 solution at 5° C. The reaction mixture was stirred for 15 min, solid was filtered, washed with n-pentane and dried. In a 25 ml RBF, dried solid was taken in ethanol and NaOAc. 3H2O (0.27 g, 0.002 mole) was added at RT. The reaction mixture was stirred for 20 hr at RT, diluted with ethyl acetate and distilled out under vacuum. To the resultant residual solid water was added, the mixture was stirred for 15 min, filtered, wash with water and n-pentane was added. The product was filtered and dried under vacuum to yield 20 mg of 2-cyano-3-(4-(7-pivaloyl-5H-pyrrolo[2,3-b]pyrazin-2-ylamino)phenyl)acrylamide.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:17]2[CH2:18][CH2:19][CH:9]1[C:10]1[C:11]([OH:28])=[C:12]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH:13]=[CH:14][C:15]=1[CH2:16]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].S(OC)(O[CH3:33])(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+].O1CCOCC1>O>[C:1]([O:5][C:6]([N:8]1[CH:17]2[CH2:18][CH2:19][CH:9]1[C:10]1[C:11]([O:28][CH3:33])=[C:12]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH:13]=[CH:14][C:15]=1[CH2:16]2)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1ccc2c(c1O)C1CCC(C2)N1C(=O)OC(C)(C)C
Reactant: COS(=O)(=O)OC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: COc1c(NC(=O)OC(C)(C)C)ccc2c1C1CCC(C2)N1C(=O)OC(C)(C)C

Procedure:
4-tert-Butoxycarbonylamino-3-hydroxy-12-aza-tricyclo[7.2.1.0*2,7*]dodeca-2(7),3,5-triene-12-carboxylic acid tert-butyl ester (260 mg, 0.67 mmol), dimethyl sulfate (0.13 mL, 1.3 mmol), cesium carbonate (430 mg, 1.3 mmol) and dioxane (3 mL) were stirred together at 90° C. for 20 h. The reaction mixture was then diluted with water (5 mL), extracted with CH2Cl2 (2×5 mL), dried over MgSO4, filtered and concentrated. The resulting residue was purified with silica gel chromatography (0-50% EtOAc in hexanes) to obtain 4-tert-Butoxycarbonylamino-3-methoxy-12-aza-tricyclo[7.2.1.0*2,7*]dodeca-2(7),3,5-triene-12-carboxylic acid tert-butyl ester as a yellow, foamy residue (198 mg, 74%). 1HNMR (400 MHz, CDCl3) δ 7.6 (s, 1H), 7.4 (d, 1H, J=8.0 Hz), 7.1 (d, 1H, J=8.0 Hz), 4.5 (m, 1H), 4.1 (m, 1H), 3.3 (s, 3H), 3.1 (dd, 1H, J=14.4, 4.8 Hz), 2.9 (dd, 1H, J=14.5, 5.0 Hz), 2.7 (dd, 1H, J=17.9, 7.8 Hz), 2.6 (dd, 1H, J=18.4, 10.4 Hz), 2.2 (m, 1H), 1.5-1.4 (m, 19H); MS (m/e) 349 (M-C4H7).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[CH2:10][CH2:11][N:12]([CH3:23])[CH2:13][C:14]=3[C:15]3[NH:20][C:19](=[O:21])[C:18](=O)[C:16]=3[CH:17]=2)=[CH:4][CH:3]=1.Cl.[NH2:25][OH:26]>C(O)C>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[CH2:10][CH2:11][N:12]([CH3:23])[CH2:13][C:14]=3[C:15]3[NH:20][C:19](=[O:21])[C:18](=[N:25][OH:26])[C:16]=3[CH:17]=2)=[CH:4][CH:3]=1
Reactant: NO
Reactant: CN1CCc2c(-c3ccc(Cl)cc3)cc3c(c2C1)NC(=O)C3=O
Agent: Cl
Solvent: CCO
Product: CN1CCc2c(-c3ccc(Cl)cc3)cc3c(c2C1)NC(=O)C3=NO
Reaction time: 0.25 h

Procedure:
A mixture of 5-(4-chlorophenyl)-8-methyl-6,7,8,9-tetrahydro-1-H-pyrrolo[3.2-h]isoquinoline-2,3-dione (0.50 g, 1.53 mmol), hydroxylamine hydrochloride (0.5 g, 7.2 mmol) and ethanol (5 ml, 96%) was stirred at room-temperature for 15 minutes. The colour shifted from yellow to red and the product precipitated. The product was filtered and 0.44 g (76%) was isolated. Mp decomp. 300-305° C.
Reaction SMILES: [Br:1]Br.[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:12]=1[O:13][CH3:14])[CH:8]=[O:9].S([O-])([O-])(=O)=S.[Na+].[Na+].C(=O)(O)[O-].[Na+]>C(O)(=O)C>[Br:1][C:10]1[C:7]([CH:8]=[O:9])=[CH:6][C:5]([O:4][CH3:3])=[C:12]([O:13][CH3:14])[CH:11]=1
Reactant: BrBr
Reactant: COc1ccc(C=O)cc1OC
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1cc(Br)c(C=O)cc1OC
Reaction time: 3 h
Yield: 56.4 %

Procedure:
A solution of bromine (0.96 g) in acetic acid (10 ml) was dropped into a solution of 3,4-dimethoxybenzaldehyde (1.0 g) in acetic acid (4 ml) and the mixture was stirred for three hours. Sodium thiosulfate was added to the reaction mixture, then sodium bicarbonate was added thereto and the mixture was filtered. The crude crystals collected by the filtration were recrystallized from chloroform-ether to give the title compound (0.83 g, 56%). The peaks of this compound in 1H-NMR (400 MHz, CDCl3) were as follows.
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[Cl:16][C:17]1[CH:18]=[C:19]([N:24]=[C:25]=[S:26])[CH:20]=[CH:21][C:22]=1[Cl:23].C1(C)C=CC=CC=1>CCOCC>[CH2:9]([O:8][C:7]1[C:2]([NH:1][C:25]([NH:24][C:19]2[CH:20]=[CH:21][C:22]([Cl:23])=[C:17]([Cl:16])[CH:18]=2)=[S:26])=[N:3][CH:4]=[CH:5][CH:6]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: S=C=Nc1ccc(Cl)c(Cl)c1
Reactant: Nc1ncccc1OCc1ccccc1
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: S=C(Nc1ccc(Cl)c(Cl)c1)Nc1ncccc1OCc1ccccc1

Procedure:
A mixture of 2-amino-3-benzyloxypyridine (2.14 g, 0.011 mol), 3,4-dichlorophenyl isothiocyanate (2.62 g, 0.013 mol) and toluene (10 ml) was refluxed for 3.5 hours, then cooled and treated with ether to induce crystallisation of the product. Yield 3.64 g (84%), m.p. 144°-146 ° C.
Reaction SMILES: [C:1]([C:3]1[CH:12]=[C:11]([NH:13][CH2:14][C:15]([O:17]C(C)(C)C)=[O:16])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:22]([F:25])([F:24])[F:23])[CH:9]=2)[N:4]=1)#[N:2]>ClCCl.C(O)(C(F)(F)F)=O>[C:1]([C:3]1[CH:12]=[C:11]([NH:13][CH2:14][C:15]([OH:17])=[O:16])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:22]([F:25])([F:24])[F:23])[CH:9]=2)[N:4]=1)#[N:2]
Reactant: CC(C)(C)OC(=O)CNc1cc(C#N)nc2ccc(C(F)(F)F)cc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cc(NCC(=O)O)c2cc(C(F)(F)F)ccc2n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a 25 mL vial, was placed a solution of tert-butyl 2-(2-cyano-6-(trifluoromethyl)quinolin-4-ylamino)acetate (as prepared in the previous step, 80 mg, 0.23 mmol, 1.00 equiv) in dichloromethane (10 mL) and CF3COOH (2 mL). The reaction mixture was stirred overnight at room temperature. The resulting mixture was concentrated under vacuum. The title compound was obtained as a white solid
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.Cl.[NH2:19][CH:20]([C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1)[C:21]([O:23][CH2:24][CH3:25])=[O:22]>CO.C(Cl)(Cl)Cl>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:19][CH:20]([C:26]2[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=2)[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[O:17])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Reactant: CCOC(=O)C(N)c1ccc(F)cc1
Agent: Cl
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C(NC(=O)[C@H](C)NC(=O)Cc1cc(F)cc(F)c1)c1ccc(F)cc1

Procedure:
Following General Procedure C and using N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and ethyl 2-amino-2-(4-fluorophenyl)acetate hydrochloride (prepared from 4-fluorophenylglycine (Fluka) and ethanol using General Procedure H), the title compound was prepared as a solid (mp=169-183° C.). The reaction was monitored by tlc (Rf=0.3 in 4% MeOH/CHCl3) and the product was purified by silica gel chromatography using 4% MeOH/CHCl3 as the eluent, followed by recrystallization from 1-chlorobutane/acetonitrile.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]([N:12]2[CH2:16][CH2:15][C@@H:14]([NH:17]C(=O)OC(C)(C)C)[CH2:13]2)[C:9]2[C:4](=[CH:5][C:6]([CH3:25])=[CH:7][CH:8]=2)[N:3]=1.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[N:11]=[C:10]([N:12]2[CH2:16][CH2:15][C@@H:14]([NH2:17])[CH2:13]2)[C:9]2[C:4](=[CH:5][C:6]([CH3:25])=[CH:7][CH:8]=2)[N:3]=1
Reactant: Cc1ccc2c(N3CC[C@@H](NC(=O)OC(C)(C)C)C3)nc(Cl)nc2c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc2c(N3CC[C@@H](N)C3)nc(Cl)nc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.6 %

Procedure:
To a solution of (R)-tert-butyl 1-(2-chloro-7-methylquinazolin-4-yl)pyrrolidin-3-ylcarbamate (1.17 g, 3.22 mmol) in 50 mL of dichloromethane was added 10 mL of trifluoroacetic acid in portions. The reaction was stirred at RT for 1 hour. The solvent was evaporated, and the residue was dissolved in 20 mL of dichloromethane, cooled to 0° C., and quenched with 1 M NaOH until basic. After partitioning between CH2Cl2 and H2O, the mixture was separated and the aqueous layer was twice extracted with CH2Cl2. The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. Purification via silica gel chromatography using 0%-10% EtOAc in DCM gave (R)-1-(2-chloro-7-methylquinazolin-4-yl)pyrrolidin-3-amine (800 mg, 94% yield). LC/MS: m/z 262.9 (M+H)+ at 0.79 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[C:5]([O:11][CH3:12])[CH:4]=1.[Cl:13][S:14](O)(=[O:16])=[O:15].P(Cl)(Cl)(Cl)=O>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:11][CH3:12])[C:6]([O:9][CH3:10])=[CH:7][C:8]=1[S:14]([Cl:13])(=[O:16])=[O:15]
Reactant: O=S(=O)(O)Cl
Reactant: COc1ccc(OC)c(OC)c1
Solvent: ClC(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: COc1cc(OC)c(S(=O)(=O)Cl)cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 11.4 %

Procedure:
To a solution of 10.0 g of 1,3,4-trimethoxy benzene in CHCl3 (100 ml) was added dropwise 6.90 g of chlorosulfonic acid over 10 minutes under ice cooling. After stirring at room temperature for two hours, the solution was poured into ice water and the resulting mixture was extracted with CHCl3. The aqueous layer was filtered with celite, the filtrate was neutralized with an aqueous solution of 2 mol/L KOH (pH=9), and the solvent was evaporated under reduced pressure to obtain 7.81 g. Phosphorus oxychloride (30 ml) was added to the obtained residue and the reaction mixture was stirred at an external temperature of 100° C. for one hour. The solution was poured into ice water and the resulting mixture was extracted with Et2O; the organic layer was washed with water and with saturated brine and then dried over MgSO4; the drying agent was separated by filtration, and then the solvent was evaporated under reduced pressure. The obtained residue was purified by column chromatography (silicagel 60N; mobile phase: EtOAc/n-hexane=1/10 to 1/2; v/v) to obtain 1.80 g of the title compound.
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][CH2:8][CH:7]([CH2:11][N:12]3[CH2:17][CH:16]=[C:15]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH2:14][CH2:13]3)[CH2:6]2)[O:4]CC1>CC(C)=O.Cl>[C:18]1([C:15]2[CH2:16][CH2:17][N:12]([CH2:11][CH:7]3[CH2:8][CH2:9][CH2:10][C:5](=[O:4])[CH2:6]3)[CH2:13][CH:14]=2)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: C1=C(c2ccccc2)CCN(CC2CCCC3(C2)OCCO3)C1
Agent: Cl
Solvent: CC(C)=O
Product: O=C1CCCC(CN2CC=C(c3ccccc3)CC2)C1
Yield: 88.7 %

Procedure:
A solution of 1-(1,4-dioxaspiro[4.5]dec-7-ylmethyl)-1,2,3,6-tetrahydro-4-phenylpyridine (Step C) (90.4 g) in 500 mL of acetone and 500 mL of 10% aqueous hydrochloric acid solution is refluxed, under nitrogen, for 3 hours. The solvent is evaporated in vacuo and partitioned into ethyl acetate/dilute ammonium hydroxide solution. The organic extract is dried over magnesium sulfate and concentrated, leaving the title compound (68.9 g) as a light pink solid; mp 56°-59° C. Mass spectrum (MS) electron ionization (EI) 269 (m, 41%), 172 (100%).
Reaction SMILES: FC(F)(F)C(O)=O.C(O[N:13]([C:17]1[CH:21]=[CH:20][S:19][C:18]=1[CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])C(=O)[O-])(C)(C)C>ClCCl>[CH3:26][Si:24]([CH3:25])([CH3:27])[CH2:23][CH2:22][C:18]1[S:19][CH:20]=[CH:21][C:17]=1[NH2:13]
Reactant: CC(C)(C)ON(C(=O)[O-])c1ccsc1CC[Si](C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[Si](C)(C)CCc1sccc1N
Temperature: 25 °C
Reaction time: 3 h
Yield: 64.7 %

Procedure:
5 ml of trifluoroacetic acid are added to a solution consisting of 2.8 g (9.3 mmol) of tert-butoxy[2-(2-trimethylsilanylethyl)thiophen-3-yl]carbamate (IX-1) in 50 ml of dichloromethane. The reaction solution is stirred at room temperature for 3 h and then concentrated under reduced pressure. Column chromatography (gradiant cyclohexane/ethyl acetate 4:1 to 1:1) gives 1.2 g (65% of theory) of 2-(2-trimethylsilanylethyl)thiophen-3-ylamine [log P (pH 2.3)=1.78].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]([CH2:17][C:18]([OH:20])=[O:19])[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH3:26]O>>[CH3:26][O:19][C:18](=[O:20])[CH2:17][N:16]1[C:11]2=[N:12][CH:13]=[CH:14][CH:15]=[C:10]2[N:9]=[C:8]1[C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: O=C(O)Cn1c(-c2ccc(Cl)cc2)nc2cccnc21
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)Cn1c(-c2ccc(Cl)cc2)nc2cccnc21
Reaction time: 12 h
Yield: 56 %

Procedure:
A solution of 2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (3.1 g, 0.1011 mole), methanol (100 ml) and concentrated sulfuric acid (3 ml) was refluxed overnight under a Dean-Stark trap. Another 2 ml of concentrated sulfuric acid and methanol (50 ml) was added and reflux continued for 12 hr. The methanol was evaporated, water (50 ml) was added, and sodium bicarbonate (solid) added until basic. The mixture was extracted with ethyl acetate (3×25 ml). The combined ethyl acetate extracts were washed with water (25 ml), dried over sodium sulfate, and concentrated in vacuo. The residue (2.5 g) was combined with a sample obtained previously and recrystallized from isopropyl ether-isopropyl alcohol to give 3.0 g (56%) of white needles, mp 198°-200° C.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][S:5](=[O:8])(=[O:7])[NH:4][CH2:3]1.Br[C:10]1[CH:15]=[CH:14][C:13]([C:16]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[C:29]([CH3:30])=[CH:28][C:27]([CH3:31])=[CH:26][N:25]=3)[CH2:20][CH2:19]2)=[O:17])=[C:12]([F:32])[CH:11]=1>>[CH3:30][C:29]1[C:24]([N:21]2[CH2:22][CH2:23][N:18]([C:16]([C:13]3[CH:14]=[CH:15][C:10]([N:4]4[CH2:3][C@H:2]([CH3:1])[CH2:6][S:5]4(=[O:8])=[O:7])=[CH:11][C:12]=3[F:32])=[O:17])[CH2:19][CH2:20]2)=[N:25][CH:26]=[C:27]([CH3:31])[CH:28]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3F)CC2)c(C)c1
Reactant: C[C@H]1CNS(=O)(=O)C1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4C[C@H](C)CS4(=O)=O)cc3F)CC2)c(C)c1
Yield: 17.6 %

Procedure:
Using (S)-4-methylisothiazolidine 1,1-dioxide (150 mg) described in Preparation Example 4 and (4-bromo-2-fluorophenyl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (219 mg) described in Preparation Example 114 and by the reaction and treatment in the same manner as in Example 4, the title compound (44 mg) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]3[CH:18]=[C:19]([C:23](O)=[O:24])[O:20][C:21]=3[CH3:22])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.Cl.CN(C)CCCN=C=NCC.[C:38]1([S:44]([NH2:47])(=[O:46])=[O:45])[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>ClCCl.CN(C1C=CN=CC=1)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]3[CH:18]=[C:19]([C:23]([NH:47][S:44]([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)(=[O:46])=[O:45])=[O:24])[O:20][C:21]=3[CH3:22])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2ccc(OCc3cc(C(=O)O)oc3C)cc2)cc1
Reactant: NS(=O)(=O)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: COc1ccc(-c2ccc(OCc3cc(C(=O)NS(=O)(=O)c4ccccc4)oc3C)cc2)cc1
Yield: 8.5 %

Procedure:
A stirred solution of 4-(4′-methoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carboxylic acid (4) (250 mg) in dichloromethane (50 mL) was treated with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (142 mg), 4-(N,N-dimethylamino)pyridine (2 mg) and benzenesulfonamide (232 mg). After 16 hours the reaction mixture was concentrated in vacuo, the residue dissolved in ethyl acetate (200 mL) and washed successively with water (20 mL), 1.0 M hydrochloric acid (20 mL), saturated sodium hydrogen carbonate solution (20 mL), brine (20 mL), dried and concentrated in vacuo. The crude product was purified by HPLC to afford compound 5 as a white solid (30 mg). LC/MS System D: Rt=5.45 mins, m/z (ES−)=476 (M− for C26H23NO6S).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH:15]1[CH2:17][O:16]1)[N:9]=[CH:8][CH:7]=[C:6]2[O:18][C:19]1[C:20]([C:27]2[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][N:28]=2)=[N:21][C:22]([CH3:26])=[C:23]([CH3:25])[CH:24]=1.FC(F)(F)C(O)=[O:37].[OH-].[Na+].O>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH:15]([OH:37])[CH2:17][OH:16])[N:9]=[CH:8][CH:7]=[C:6]2[O:18][C:19]1[C:20]([C:27]2[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][N:28]=2)=[N:21][C:22]([CH3:26])=[C:23]([CH3:25])[CH:24]=1
Reactant: COc1cc2c(Oc3cc(C)c(C)nc3-c3ccc(C)cn3)ccnc2cc1OCC1CO1
Reactant: O=C(O)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: COc1cc2c(Oc3cc(C)c(C)nc3-c3ccc(C)cn3)ccnc2cc1OCC(O)CO
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 63 %

Procedure:
3-(6-Methoxy-7-oxiranylmethoxy-quinolin-4-yloxy)-5,6,5′-trimethyl-[2,2′]bipyridine (compound 457) (54 mg) was dissolved in methylene chloride (2 ml) to prepare a solution which was then brought to 0° C. Trifluoroacetic acid (1 ml) was added thereto, and the mixture was stirred at 0° C. for 30 min and then at room temperature for 5 hr. The reaction solution was brought to 0° C., was stirred and was made alkaline by the addition of a 10% aqueous sodium hydroxide solution. Water was added to the reaction solution, the mixture was extracted with chloroform, and the chloroform layer was then washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (35 mg, yield 63%).
Reaction SMILES: [Br:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]([CH2:18][CH:19]([O:22][CH3:23])[O:20][CH3:21])[S:8]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.BrC1C=CC(CNCC(OC)OC)=CC=1[Cl:41]>>[Br:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]([CH2:18][CH:19]([O:20][CH3:21])[O:22][CH3:23])[S:8]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)(=[O:10])=[O:9])=[CH:4][C:3]=1[Cl:41]
Reactant: COC(CNCc1ccc(Br)c(Cl)c1)OC
Reactant: COC(CN(Cc1ccc(Br)cc1)S(=O)(=O)c1ccc(C)cc1)OC
Product: COC(CN(Cc1ccc(Br)c(Cl)c1)S(=O)(=O)c1ccc(C)cc1)OC

Procedure:
The title compound was prepared by the protocol described for N-(4-Bromo-benzyl)-N-(2,2-dimethoxy-ethyl)-4-methyl-benzenesulfonamide (2), starting from (4-Bromo-3-chloro-benzyl)-(2,2-dimethoxy-ethyl)-amine (7). Rt=1.93 min (Method C). Detected mass: 430.3/432.3 (M−OMe−).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([N:7]=[C:8]=[O:9])[CH:2]=1.[Cl:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][CH2:15][CH2:14]2>>[Cl:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[N:16]([C:8](=[O:9])[NH:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)[CH2:15][CH2:14]2
Reactant: Clc1ccc2c(c1)CCN2
Reactant: O=C=Nc1cccnc1
Product: O=C(Nc1cccnc1)N1CCc2cc(Cl)ccc21

Procedure:
The title compound was prepared as in the method of (Example 2) from 3-pyridylisocyanate and 5-chloroindoline (D35) to give (E18) (1.4 g, 82%) m.p. 204°-5° C.
Reaction SMILES: [CH:1]1[S:2][CH:3]=[C:4]2[C:10]=1[C:9](=[O:11])[NH:8][C:7]1[CH:12]=[CH:13][CH:14]=[CH:15][C:6]=1[NH:5]2.[C:16](Cl)(=[O:19])[CH2:17][CH3:18]>C1C=CC=CC=1>[C:16]([N:5]1[C:6]2[CH:15]=[CH:14][CH:13]=[CH:12][C:7]=2[NH:8][C:9](=[O:11])[C:10]2=[CH:1][S:2][CH:3]=[C:4]12)(=[O:19])[CH2:17][CH3:18]
Reactant: O=C1Nc2ccccc2Nc2cscc21
Reactant: CCC(=O)Cl
Solvent: c1ccccc1
Product: CCC(=O)N1c2ccccc2NC(=O)c2cscc21
Reaction time: 8 h

Procedure:
A reaction mixture comprising 9.9 g. of 4,9-dihydro-10H-thieno[3,4-b][1,5]benzodiazepin-10-one and 4.7 g. (4.4 ml.) of propionyl chloride in 100 ml. of benzene is refluxed for 3 hours and allowed to stand overnight. The precipitate is collected, washed with benzene and dried. A 3 g. portion of this solid is heated to boiling in 125 ml. of ethyl acetate, filtered and the filtrate is cooled. The solid is collected, washed with hexane and dried giving the desired product, mp. 222°-224° C.