Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:12]2[NH:11][C:10]3[CH:9]=[C:8](I)[C:7]4[C:16](=[O:20])[NH:17][C:18](=[O:19])[C:6]=4[C:5]=3[C:4]=2[CH:3]=1.[CH:21]([C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][CH:28]=1)=[O:22]>>[OH:1][C:2]1[CH:14]=[CH:13][C:12]2[NH:11][C:10]3[CH:9]=[C:8]([C:27]4[CH:28]=[C:23]([CH:24]=[CH:25][CH:26]=4)[CH:21]=[O:22])[C:7]4[C:16](=[O:20])[NH:17][C:18](=[O:19])[C:6]=4[C:5]=3[C:4]=2[CH:3]=1
Reactant: O=C1NC(=O)c2c1c(I)cc1[nH]c3ccc(O)cc3c21
Reactant: O=Cc1cccc(B(O)O)c1
Product: O=Cc1cccc(-c2cc3[nH]c4ccc(O)cc4c3c3c2C(=O)NC3=O)c1
Yield: 69 %

Procedure:
The reaction of 9-hydroxy-4-iodopyrrolo[3,4-c]carbazole-1,3(2H,6H)-dione, prepared as in example 7, with 3-formylbenzeneboronic acid according to the procedure described in example 8 gave 3-(9-Hydroxy-1,3-dioxo-1,2,3,6-tetrahydropyrrolo[3,4-c]carbazol-4-yl)benzaldehyde (507) (I; Ar=3-formylphenyl) in a 69% yield; mp (THF/CH2Cl2/pentane) 280–286° C. (dec). 1H NMR [(CD3)2SO] δ 11.82 (br s, 1H), 11.07 (br s, 1H), 10.11 (s, 1H), 9.27 (br s, 1H), 8.35 (d, J=2.4 Hz, 1H), 8.14 (t, J=1.4 Hz, 1H), 7.97 (m, 2H), 7.70 (t, J=7.7 Hz, 2H), 7.65 (s, 1H), 7.46 (d, J=8.7 Hz, 1H), 7.08 (dd, J=8.7, 2.5 Hz, 1H). FABMS found [M+H]+: 357.0857. C21H13N2O4 requires 357.0875.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:8])[CH2:6][NH2:7])[CH3:3].[S:9]([Cl:13])(Cl)(=[O:11])=[O:10].[CH3:14]C#N>>[CH2:2]([O:4][C:5](=[O:8])[CH:6]([NH:7][S:9]([Cl:13])(=[O:11])=[O:10])[CH3:14])[CH3:3]
Reactant: O=S(=O)(Cl)Cl
Reactant: CC#N
Reactant: CCOC(=O)CN
Agent: Cl
Product: CCOC(=O)C(C)NS(=O)(=O)Cl
Temperature: 65 °C
Reaction time: 20 h

Procedure:
Glycine ethyl ester hydrochloride (1 eq.) was dissolved in CH3CN and placed in an ice bath. Sulfuryl chloride (3 eq.) was added slowly (20 min). The reaction mixture was stirred at room temperature for 15 min and at 65° C. for 20 h. The solvent was evaporated and the residue was dried under high vacuum to yield Chlorosulfonylamino-propionic acid ethyl ester. The crude sulfamoyl chloride was used in the next step without further purification.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]2[CH:19]=[C:18](F)[CH:17]=[CH:16][C:12]=2[C:13]([OH:15])=[O:14])[N:7]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[CH3:27])[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[Li][N:29]([CH3:31])[CH3:30]>C1COCC1>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]2[CH:19]=[C:18]([N:29]([CH3:31])[CH3:30])[CH:17]=[CH:16][C:12]=2[C:13]([OH:15])=[O:14])[N:7]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[CH3:27])[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccccc1-n1nc(C(C)(C)C)cc1Nc1cc(F)ccc1C(=O)O
Reactant: [Li]N(C)C
Solvent: C1CCOC1
Product: Cc1ccccc1-n1nc(C(C)(C)C)cc1Nc1cc(N(C)C)ccc1C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 15 %

Procedure:
To a solution of 2-{[3-tert-butyl-1-(2-methylphenyl)-1H-pyrazol-5-yl]amino}-4-fluorobenzoic acid (Example 248, 35 mg, 0.09 mmol) in THF (1 mL) at −40° C. was added LiNMe2 (0.19 mL, 1 M in hexanes) under nitrogen. The mixture was then stirred at this temperature for 30 min, and then gradually warmed to rt over a 4 h period. The pH of the solution was adjusted to pH 5, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The crude was purified by HPLC using gradient elution from 10 to 80% acetonitrile in water to afford 5.7 mg (15%) of the title compound. 1H NMR (300 MHz, CD2Cl2) δ 9.55 (s, 1H), 7.73 (d, 1H), 7.22-7.35 (m, 4H), 6.44 (d, 1H), 6.18 (dd, 1H), 6.15 (s, 1H), 3.00 (s, 6H), 2.04 (s, 3H), 1.32 (s, 9H). ES-MS m/z 393.2 (MH30 ); HPLC RT (min) 2.84.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:11][CH2:12][O:13][CH3:14])=[C:4]([OH:10])[C:5]([O:8][CH3:9])=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH:22]([F:24])[F:23]>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([O:10][CH:22]([F:24])[F:23])[C:3]=1[O:11][CH2:12][O:13][CH3:14]
Reactant: FC(F)Cl
Reactant: COCOc1c(Br)ccc(OC)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCOc1c(Br)ccc(OC)c1OC(F)F
Temperature: -45 °C
Yield: 30 %

Procedure:
To a stirring solution of 3-bromo-6-methoxy-2-(methoxymethoxy)phenol (700 mg, 2.64 mmol) in dimethylformamide (15 mL) was added potassium carbonate (729 mg, 5.28 mmol), cooled to −45° C. and chlorodifluoromethane gas was passed for 10 min and the resultant reaction mixture was heated to 80° C. for 2 h. The reaction mixture was quenched with ice-cold water and extracted with ethyl acetate (3×). The combined ethyl acetate layers were dried over sodium sulphate and concentrated under reduced pressure. Purification of the residue by flash column chromatography (silica gel, 0-5% ethyl acetate in pet ether) afforded 1-Bromo-3-(difluoromethoxy)-4-methoxy-2-(methoxymethoxy)benzene as a liquid (250 mg, 30%).
Reaction SMILES: O.NN.[Cl:4][C:5]1[CH:6]=[C:7]([C:17](=O)[C:18]([OH:20])=[O:19])[CH:8]=[CH:9][C:10]=1[S:11][CH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1.[OH-].[K+].O>C(OCC)C>[Cl:4][C:5]1[CH:6]=[C:7]([CH2:17][C:18]([OH:20])=[O:19])[CH:8]=[CH:9][C:10]=1[S:11][CH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: O=C(O)C(=O)c1ccc(SC2CCCC2)c(Cl)c1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Product: O=C(O)Cc1ccc(SC2CCCC2)c(Cl)c1
Temperature: -78 °C

Procedure:
Hydrazine hydrate (10 equiv.) is placed in a three neck flask fitted with an overhead mechanical stirrer and a reflux condenser and cooled in a dry ice acetone bath at −78° C. After the solution reached −50° C. the bath is removed and (3-chloro-4-cyclopentylsulfanyl-phenyl)-oxo-acetic acid (15.00 mmol) is added in one portion. It is then heated in an oil bath to 80° C. After the reaction is at 80° C. it is treated with potassium hydroxide (0.60 equiv.) and stirred vigorously. When the reaction returns to 80° C. a second portion of potassium hydroxide (0.60 equiv.) is added and allowed to cool back to 80° C. This cycle is repeated two more times adding potassium hydroxide (0.60 equiv.) each time. The reaction is then heated at 100° C. for 16 h. It is then cooled to 25° C. and water (3 mL) added to the reaction. It was then transferred to a separatory funnel and another portion of water (3 mL) is added and diethyl ether (10 mL). The layers are separated and the aqueous layer separated into a flask. The organic layer is then extracted with water (5 mL) and this aqueous layer combined with the first. To the aqueous layer is then added heptane (5 mL) and stirred vigorously. This solution is cooled to 0° C. in an ice bath and is treated dropwise with concentrated hydrochloric acid (˜7 mL) over 30 min until the aqueous layer is at pH=2 keeping the temperature of the solution below 50° C. during the addition process. It is then allowed to cool to 25° C. and stirred for 3 h. It is then filtered to remove the solids and the solids are washed with 1N aqueous hydrochloric acid (1.5 mL), water (2×1.5 mL), heptane (5 mL) and 1:1 heptane:diethyl ether (5 mL) and the solid is then dried in a vacuum oven to afford (3-chloro-4-cyclopentylsulfanyl-phenyl)-acetic acid.
Reaction SMILES: N1[C:5]([C:6]2[CH:7]=[C:8]3[C:13](=[CH:14][CH:15]=2)[N:12]=[CH:11][NH:10][C:9]3=[O:16])=[N:4][N:3]=N1.[C:17](OC(=O)C)(=[O:19])[CH3:18]>>[CH3:18][C:17]1[O:19][C:5]([C:6]2[CH:7]=[C:8]3[C:13](=[CH:14][CH:15]=2)[N:12]=[CH:11][NH:10][C:9]3=[O:16])=[N:4][N:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: O=c1[nH]cnc2ccc(-c3nnn[nH]3)cc12
Product: Cc1nnc(-c2ccc3nc[nH]c(=O)c3c2)o1

Procedure:
6-(1,2,3,4-Tetrazol-5-yl)-quinazolin-4-one (3.31 g) was treated with acetic anhydride (115 ml) at reflux under N2 for 1 hour. The anhydride was removed in vacuo, the residue absorbed onto silica and purified by chromatography to give the title compound as a white solid (3.47 g). The analytical data was consistent with that given earlier.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[C:9]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:8]=[C:7]([F:15])[CH:6]=1.[CH:16]1([NH2:21])[CH2:20][CH2:19][CH2:18][CH2:17]1>C(O)C>[F:15][C:7]1[CH:6]=[C:5]([CH:10]=[C:9]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:8]=1)[O:4][CH2:3][CH2:2][NH:21][CH:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: CS(=O)(=O)c1cc(F)cc(OCCBr)c1
Reactant: NC1CCCC1
Solvent: CCO
Product: CS(=O)(=O)c1cc(F)cc(OCCNC2CCCC2)c1
Yield: 87.5 %

Procedure:
Preparation according to Example 1 but performed in one portion: 1-(2-bromoethoxy)-3-fluoro-5-methylsulfonyl-benzene (0.5 g, 1.68 mmol) and cyclopentylamine (1.34 ml, 13.46 mmol) in ethanol (5 ml). Purification by flash column chromatography (ethyl acetate/methanol, 100:0 to 85:15) gave the title compound (443 mg, 87.4%). The amine was converted to the hydrochloric acid salt and re-crystallized from methanol/diethyl ether: M.p. 207.5° C. MS m/z (relative intensity, 70 eV) 301(M+, 2), 272 (7), 99 (24), 98 (bp), 70 (7).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[H-].[Na+].Cl[CH2:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1>CN(C)C=O.C1(C)C=CC=CC=1>[CH3:11][O:10][C:8]1[CH:7]=[CH:6][C:3]([CH:4]=[O:5])=[C:2]([O:1][CH2:15][CH2:16][CH2:17][N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[CH:9]=1
Reactant: COc1ccc(C=O)c(O)c1
Reactant: ClCCCN1CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: COc1ccc(C=O)c(OCCCN2CCOCC2)c1
Yield: 65.8 %

Procedure:
2-Hydroxy-4-methoxybenzaldehyde (25 g) in 125 ml of dimethylformamide is treated first with 8.2 g of 50% sodium hydride, then with 36 g of N-(3-chloropropyl)morpholine dissolved in 65 ml of toluene, following the procedure described in Example 1A, yielding 30.2 g of the title compound, boiling point 190°-195° C. at 0.1-0.2 mm of Hg.
Reaction SMILES: Cl[C:2]([F:7])([F:6])[C:3]([O-])=O.[Na+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:28]([C@H:33]1[CH2:38][CH2:37][C@H:36]([C@H:39]2[CH2:44][CH2:43][C@H:42]([C:45](=O)C)[CH2:41][CH2:40]2)[CH2:35][CH2:34]1)[CH2:29][CH2:30][CH2:31][CH3:32].CCCCCCC>CN(C=O)C>[F:6][C:2]([F:7])=[CH:3][CH2:45][C@H:42]1[CH2:43][CH2:44][C@H:39]([C@H:36]2[CH2:37][CH2:38][C@H:33]([CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH2:34][CH2:35]2)[CH2:40][CH2:41]1
Reactant: O=C([O-])C(F)(F)Cl
Reactant: CCCCC[C@H]1CC[C@H]([C@H]2CC[C@H](C(C)=O)CC2)CC1
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCCCCCC
Product: CCCCC[C@H]1CC[C@H]([C@H]2CC[C@H](CC=C(F)F)CC2)CC1
Temperature: 80 °C

Procedure:
A nitrogen-purged 1-L three-neck flask equipped with a stirrer, a thermometer and a dropping funnel was charged with 16.4 g (107.7 mmol) of sodium chlorodifluoroacetate, 28.3 g (107.7 mmol) of triphenylphosphine and 200 ml of DMF, and the mixture was heated up to 80° C. while stirring. A solution of 15.0 g (53.9 mmol) of 1-(trans-4-(trans-4-pentylcyclohexyl)-cyclohexyl)acetaldehyde dissolved in 100 ml of DMF was added dropwise at 80 to 110° C., and the solution was stirred at 100° C. for 2 hours. The reaction mixture was transferred into a 2-L beaker, and 500 ml of heptane was added thereto. Insoluble materials were separated by filtration by means of a glass filter, and 300 ml of water was added thereto. The separated heptane layer was washed twice with 300 ml of water and dried over anhydrous magnesium sulfate. The solvent was distilled of under reduced pressure, and then the concentrated residue was purified by means of a silica gel column chromatography with heptane as a developing solvent to obtain 14.1 g of 1,1-difluoro-3-(trans-4-(trans-4-pentylcyclohexyl)cyclohexyl)-1-propene.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:8]2[N:9]=[C:10]([CH3:19])[N:11]([CH2:12][CH2:13][CH2:14][NH:15]C(=O)C)[C:7]=2[C:6]([CH3:20])=[C:5]([CH3:21])[N:4]=1>C(O)C>[NH2:15][CH2:14][CH2:13][CH2:12][N:11]1[C:7]2[C:6]([CH3:20])=[C:5]([CH3:21])[N:4]=[C:3]([NH2:2])[C:8]=2[N:9]=[C:10]1[CH3:19]
Reactant: CC(=O)NCCCn1c(C)nc2c(N)nc(C)c(C)c21
Agent: Cl
Solvent: CCO
Product: Cc1nc(N)c2nc(C)n(CCCN)c2c1C
Temperature: 25 °C
Reaction time: 48 h
Yield: 62.3 %

Procedure:
Concentrated hydrochloric acid (5 mL) was slowly added to a solution of N-[3-(4-amino-2,6,7-trimethyl-1H-imidazo[4,5-c]pyridin-1-yl)propyl]acetamide (15.94 g, 57.9 mmol) in absolute ethanol (100 mL). A precipitate formed immediately and the mixture thickened. Ethanol (50 mL) was added followed by the addition of concentrated hydrochloric acid (119.5 mL). The reaction mixture was heated at reflux for 2 days. The solvents were removed under reduced pressure. Water (250 mL) was added to the residue, solid potassium carbonate was added until the pH reached 7 at which time chloroform (250 mL) was added. Sodium carbonate addition was resumed until the pH reached 10, then 50% sodium hydroxide was added until the pH reached 14. The mixture was diluted with additional chloroform (500 mL) and then stirred at ambient temperature for 2 days. The organic layer was separated, dried with magnesium sulfate and then concentrated under reduced pressure. The residue was recrystallized from acetonitrile to provide 8.42 g of 1-(3-aminopropyl)-2,6,7-trimethyl-1H-imidazo[4,5-c]pyridin-4-amine as an off-white crystalline solid, m.p. 191.5-191.9° C. Analysis: Calculated for C12H19N5.0.25 H2O: % C, 60.61; % H, 8.26; % N, 29.45; Found: % C, 60.50; % H, 8.28; % N, 29.57.
Reaction SMILES: [C:1]([O:5][CH2:6][CH2:7][CH2:8][CH3:9])(=[O:4])[CH2:2][OH:3].[H-].[Na+].[Cl:12][C:13]1[CH:29]=[CH:28][CH:27]=[CH:26][C:14]=1[CH2:15][N:16]1[CH2:22][CH2:21][C:20]([CH:23]=O)=[C:19](Cl)[CH2:18][CH2:17]1>O1CCOCC1>[Cl:12][C:13]1[CH:29]=[CH:28][CH:27]=[CH:26][C:14]=1[CH2:15][N:16]1[CH2:22][CH2:21][C:20]2[CH:23]=[C:2]([C:1]([O:5][CH2:6][CH2:7][CH2:8][CH3:9])=[O:4])[O:3][C:19]=2[CH2:18][CH2:17]1
Reactant: O=CC1=C(Cl)CCN(Cc2ccccc2Cl)CC1
Reactant: CCCCOC(=O)CO
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCCCOC(=O)c1cc2c(o1)CCN(Cc1ccccc1Cl)CC2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2.0 gm (0.015 mol) of butyl glycolate were slowly added dropwise, while vigorously stirring, to a suspension of 0.72 gm (0.015 mol) of 50% sodium hydride in 10 ml of absolute dioxane at room temperature while dry nitrogen was introduced. The temperature of the intensely foaming reaction mixture was kept below 30° C. by cooling with ice-cold water, as needed. After 11/2 hours of stirring at room temperature, a solution of 2.84 gm (0.010 mol) of 1-(2-chlorobenzyl)-4-chloro-5-formyl-2,3,6,7-tetrahydro-1H-azepine in 20 ml of absolute dioxane was added dropwise, whereupon the temperature of the reaction mixture rose from 20° C. to about 33° C. Then, the mixture was stirred for two hours at room temperature, poured into about 150 ml of ice-cold water, and the aqueous mixture was extracted three times with ethyl acetate. The combined organic phases were extracted with water three times, dried over sodium sulfate and concentrated by evaporation. The residue was purified by column chromatography on silicagel, using chloroform/ethyl acetate (93:7) as eluant.
Reaction SMILES: [I:1][C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N+:11]([O-])=O>C(O)C.O>[I:1][C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH2:11]
Reactant: O=[N+]([O-])c1ccccc1Oc1ccccc1I
Solvent: CCO
Solvent: O
Product: Nc1ccccc1Oc1ccccc1I
Yield: 98 %

Procedure:
A solution of 1-(2-iodophenoxy)-2-nitrobenzene (9.60 g, 28.1 mmol) and SnCl.2H2O (13.0 g, 56.0 mmol) in ethanol (25 mL) and water (5 mL) was refluxed until no starting material remained (˜1 h). The ethanol was removed in vacuo and the aq layer was basified to pH>10 and extracted with CH2Cl2 (4×10 mL). The combined organic layers were dried over Na2SO4, and the solvent was removed to give a crude 2-(2-Iodophenoxy)benzenamine (8.57 g, 98%), which was used for the next step without purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:17])([C:13]([F:16])([F:15])[F:14])[C:9]([F:12])([F:11])[F:10])=[CH:4][C:3]=1[SH:18].Br[CH2:20][C:21](OCC)=[O:22].N1C=CC=CC=1>C(O)CO>[F:16][C:13]([F:14])([F:15])[C:8]([C:5]1[CH:6]=[CH:7][C:2]2[NH:1][C:21](=[O:22])[CH2:20][S:18][C:3]=2[CH:4]=1)([OH:17])[C:9]([F:10])([F:11])[F:12]
Reactant: CCOC(=O)CBr
Reactant: Nc1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1S
Solvent: OCCO
Solvent: c1ccncc1
Product: O=C1CSc2cc(C(O)(C(F)(F)F)C(F)(F)F)ccc2N1
Temperature: 0 °C
Yield: 52.8 %

Procedure:
To 140 ml. of ethylene glycol is added 24 gm (0.08 mole) of 4-amino-3-mercapto[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]-benzene, 14 gm. (0.08 mole) ethyl bromoacetate, and 6.4 gm. (0.08 mole) of pyridine. The solution is stirred and heated at 105°-110° for 8 hours. At the end of this period the solution is cooled and poured into 800 ml of ice-water. The resultant precipitate is filtered. The precipitate is air dried and recrystallized from ethyl acetate/hexane to give 14 gm of 7-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)-ethyl]-2H-1,4-benzothiazin-3(4H)-one, m.p. 230°-232°.
Reaction SMILES: [CH:1]1([CH2:6][CH2:7][C:8](Cl)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:11]1([CH2:17][C@H:18]2[CH2:22][O:21][C:20](=[O:23])[NH:19]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH:1]1([CH2:6][CH2:7][C:8]([N:19]2[C@@H:18]([CH2:17][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH2:22][O:21][C:20]2=[O:23])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C1N[C@@H](Cc2ccccc2)CO1
Reactant: O=C(Cl)CCC1CCCC1
Product: O=C(CCC1CCCC1)N1C(=O)OC[C@@H]1Cc1ccccc1
Yield: 96.6 %

Procedure:
Following the procedure described in Example 45, 6.4 g of cyclopentane propionyl chloride and 7.1 g of (S)-4-phenylmethyl-2-oxazolidinone yielded 11.6 g of (S)-3-[3-cyclopentyl-1-oxopropyl]-4-(phenylmethyl)-2-oxazolidinone. [α]D25 =+99.61°
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[CH:13][N:12]=[C:11]([O:15][C:16]3[CH:25]=[C:24]4[C:19]([CH:20]=[C:21]([CH:26]=[O:27])[CH:22]=[N:23]4)=[CH:18][CH:17]=3)[CH:10]=2)=[CH:5][CH:4]=1.[CH3:30][Mg]Br.[NH4+].[Cl-]>C1COCC1>[F:29][C:2]([F:1])([F:28])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[CH:13][N:12]=[C:11]([O:15][C:16]3[CH:25]=[C:24]4[C:19]([CH:20]=[C:21]([CH:26]([OH:27])[CH3:30])[CH:22]=[N:23]4)=[CH:18][CH:17]=3)[CH:10]=2)=[CH:5][CH:4]=1
Reactant: O=Cc1cnc2cc(Oc3cc(-c4ccc(C(F)(F)F)cc4)ncn3)ccc2c1
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(O)c1cnc2cc(Oc3cc(-c4ccc(C(F)(F)F)cc4)ncn3)ccc2c1
Temperature: -78 °C
Reaction time: 0.08 h

Procedure:
A solution of 7-{6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yloxy}quinoline-3-carbaldehyde, (Example 60b), (220 mg, 0.56 mmol) in anhydrous THF (10 mL) was magnetically stirred under N2 in a −78° C. bath while methylmagnesium bromide (0.22 mL, 0.66 mmol, 3.0 M in Et2O, Aldrich) was added quickly. The reaction mixture was stirred at −78° C. for 5 min, then treated with satd NH4Cl (5 mL). The bath was removed and the mixture was stirred for 5 min, then diluted with EtOAc (60 mL) and washed with satd NH4Cl (20 mL), water (20 mL), satd NaHCO3 (20 mL), satd NaCl (20 mL), dried over Na2SO4, filtered and concentrated in vacuum. Purification by silica gel chromatography (gradient: 60–85% EtOAc in hexanes) provided the title compound as an off-white solid. Mp: 156–157° C. MS (ESI, pos. ion.) m/z: 412 (M+1). Anal. Calcd for C22H16F3N3O2: C, 64.23; H, 3.92; N, 10.21; F, 13.85. Found: C, 63.99; H, 4.05; N, 10.01; F, 13.63.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:33])=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:31][CH3:32])=[C:16]([CH2:19][N:20]([CH3:30])[C:21]4([C:27]([NH2:29])=[O:28])[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]4)[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.[CH2:34]=O>>[Cl:1][C:2]1[C:3]([F:33])=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:31][CH3:32])=[C:16]([CH2:19][N:20]([CH3:30])[C:21]4([C:27]([NH2:29])=[O:28])[CH2:26][CH2:25][N:24]([CH3:34])[CH2:23][CH2:22]4)[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: C=O
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1CN(C)C1(C(N)=O)CCNCC1
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1CN(C)C1(C(N)=O)CCN(C)CC1

Procedure:
4-[({4-[(3-Chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)(methyl)amino]piperidine-4-carboxamide (Example 16) was reacted with paraformaldehyde using an analogous method to that described for the equivalent step in Example 11 to give 4-[({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)(methyl)amino]-1-methylpiperidine-4-carboxamide; 1H NMR Spectrum: (DMSO d6) 1.80 (m, 2H); 2.03-2.17 (m, 10H); 2.66 (m, 2H); 3.64 (s, 2H); 3.95 (s, 3H); 7.08 (s, 1H); 7.17 (m, 2H); 7.30 (t, 1H); 7.51 (m, 1H); 7.57 (m, 1H); 8.34 (s, 1H); 8.42 (s, 1H); 9.68 (s, 1H). Mass Spectrum: (M+H)+ 487.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([C:17]1[N:18]=[C:19]([CH2:48][CH3:49])[N:20]([C:39]2[CH:40]=[CH:41][C:42]3[O:46][CH2:45][CH2:44][C:43]=3[CH:47]=2)[C:21](=[O:38])[C:22]=1[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[C:31]([C:36]#[N:37])=[CH:32][CH:33]=[CH:34][CH:35]=2)=[CH:26][CH:25]=1)[CH2:14][CH2:15][CH3:16]>C(OCC)(=O)C>[CH2:13]([C:17]1[N:18]=[C:19]([CH2:48][CH3:49])[N:20]([C:39]2[CH:40]=[CH:41][C:42]3[O:46][CH2:45][CH2:44][C:43]=3[CH:47]=2)[C:21](=[O:38])[C:22]=1[CH2:23][C:24]1[CH:25]=[CH:26][C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:36]2[NH:3][C:4](=[O:7])[O:5][N:37]=2)=[CH:28][CH:29]=1)[CH2:14][CH2:15][CH3:16]
Reactant: [NH3+]O
Reactant: CCCCc1nc(CC)n(-c2ccc3c(c2)CCO3)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCCCc1nc(CC)n(-c2ccc3c(c2)CCO3)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 74.4 %

Procedure:
A mixture of hydroxylammonium chloride (9.4 g), sodium hydrogen carbonate (13.6 g) and dimethyl sulfoxide (60 mL) was stirred at 50° C. for 30 min, 4′-{[4-butyl-1-(2,3-dihydro-1-benzofuran-5-yl)-2-ethyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (5.4 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (60 mL), N,N′-carbonyldiimidazole (3.3 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (3.0 mL) were added, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography and recrystallized from dichloromethane and diisopropyl ether to give the title compound (4.5 g, 75%) as a colorless solid.
Reaction SMILES: [N:1]#[C:2]Br.[NH2:4][C:5]1[CH:24]=[CH:23][C:22]([C:25](=[O:32])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:21][C:6]=1[CH2:7][NH:8][CH2:9][CH2:10][C:11]([N:13]([CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[CH3:14])=[O:12]>CO>[NH2:1][C:2]1[N:8]([CH2:9][CH2:10][C:11]([N:13]([CH:15]2[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]2)[CH3:14])=[O:12])[CH2:7][C:6]2[C:5](=[CH:24][CH:23]=[C:22]([C:25](=[O:32])[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:21]=2)[N:4]=1
Reactant: CN(C(=O)CCNCc1cc(C(=O)c2ccccc2)ccc1N)C1CCCCC1
Reactant: N#CBr
Solvent: CO
Product: CN(C(=O)CCN1Cc2cc(C(=O)c3ccccc3)ccc2N=C1N)C1CCCCC1
Temperature: 25 °C

Procedure:
Cyanogen bromide (0.011 mol) was added to a solution of 3-(2-amino-5-benzoyl-benzylamino)-N-cyclohexyl-N-methyl-propionamide (0.01 mol) in methanol (200 mL), stirred at room temperature. The reaction solution was stirred over a weekend at room temperature, then stirred and refluxed for an additional 5 h. The solvent was evaporated to yield a residue. The residue was crystallized from ethyl acetate (100 mLI). The resulting precipitate was filtered off and dried. The product fraction was recrystallized from 2-propanol (50 mL). The crystals were filtered off and dried to yield the title compound as a residue.