Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([O:26][C:27]([F:30])([F:29])[F:28])[CH:23]=[CH:22][C:21]=3[NH:31][CH2:32][CH3:33])[C@H:14]2[CH3:34])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH3:37][C:38]1([CH3:49])[CH2:43][O:42][CH:41]([CH2:44][CH2:45][CH2:46][CH:47]=O)[O:40][CH2:39]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClC(Cl)C.CCOC(C)=O>[F:36][C:2]([F:1])([F:35])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([O:26][C:27]([F:28])([F:29])[F:30])[CH:23]=[CH:22][C:21]=3[N:31]([CH2:47][CH2:46][CH2:45][CH2:44][CH:41]3[O:40][CH2:39][C:38]([CH3:37])([CH3:49])[CH2:43][O:42]3)[CH2:32][CH3:33])[C@H:14]2[CH3:34])[CH:6]=[C:7]([C:9]([F:11])([F:10])[F:12])[CH:8]=1
Reactant: CC1(C)COC(CCCC=O)OC1
Reactant: CCNc1ccc(OC(F)(F)F)cc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(Cl)Cl
Product: CCN(CCCCC1OCC(C)(C)CO1)c1ccc(OC(F)(F)F)cc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-(ethylamino)-5-(trifluoromethoxy)benzyl]-4-methyl-1,3-oxazolidin-2-one (68.2 mg, 0.129 mmol) in dichloroethane (2 mL) was added 4-(5,5-dimethyl-1,3-dioxan-2-yl)butanal (119 mg, 0.643 mmol) and NaBH(OAc)3 (136 mg, 0.643 mmol). The reaction was stirred at room temperature for 72 hours and then diluted with EtOAc (30 mL), quenched with saturated NH4Cl solution (10 mL), and washed with water and brine (10 mL each). The organic layer was dried over Na2SO4, filtered, and concentrated. Purification of the residue by flash chromatography on silica gel (0 to 25% EtOAc/hexanes) afforded (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-[[4-(5,5-dimethyl-1,3-dioxan-2-yl)butyl](ethyl)amino]-5-(trifluoromethoxy)benzyl]-4-methyl-1,3-oxazolidin-2-one. Rf=0.62 (25% EtOAc/hexanes). LCMS=701.3 (M+1)+. 1H NMR (CDCl3, 500 MHz) δ7.97 (s, 1H), 7.85 (s, 2H), 7.23-7.19 (m, 3H), 5.79 (d, J=8.1 Hz, 1H), 4.79 (d, J=16.0 Hz, 1H), 4.62 (d, J=16.0 Hz, 1H), 4.43 (t, J=4.9 Hz, 1H), 4.11-4.01 (m, 1H), 3.61 (d, J=1.1 Hz, 2H), 3.44 (d, J=10.8 Hz, 2H), 3.06-3.00 (m, 4H), 1.71-1.41 (m, 6H), 1.12 (s, 3H), 1.05-1.01 (t, J=7.0 Hz, 3H), 0.77 (s, 3H), 0.74 (d, J=6.6 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:16]2[C:24]3[C:19](=[C:20]([OH:27])[CH:21]=[C:22]([C:25]#[N:26])[CH:23]=3)[CH:18]=[CH:17]2)[CH:5]=[CH:6][C:7]=1[O:8]CC1C=CC=CC=1>C(O)C.C(OCC)(=O)C.[Pd]>[F:1][C:2]1[CH:3]=[C:4]([N:16]2[C:24]3[C:19](=[C:20]([OH:27])[CH:21]=[C:22]([C:25]#[N:26])[CH:23]=3)[CH:18]=[CH:17]2)[CH:5]=[CH:6][C:7]=1[OH:8]
Reactant: N#Cc1cc(O)c2ccn(-c3ccc(OCc4ccccc4)c(F)c3)c2c1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: N#Cc1cc(O)c2ccn(-c3ccc(O)c(F)c3)c2c1
Yield: 73.3 %

Procedure:
A solution of 1-{3-fluoro-4-[(phenylmethyl)oxy]phenyl}-4-hydroxy-1H-indole-6-carbonitrile (D14) (320 mg, 0.89 mmol) in ethanol (25 mL) and ethyl acetate (5 mL) was hydrogenated in an H-cube over a 10% palladium on charcoal catalyst. The resulting solution was concentrated and the product purified by silica gel chromatography eluting with 2-60% ethyl acetate in hexane to yield the title compound (E8), (175 mg).
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:22]1[N:23]=[C:24]([NH2:27])[S:25][CH:26]=1)[C:5]([NH:7][CH:8]1[C:20](=[O:21])[N:10]2[C:11]([C:17](O)=[O:18])=[C:12]([CH2:15][OH:16])[CH2:13][S:14][C@H:9]12)=[O:6].Cl>CC(C)=O.O>[CH3:1][O:2][N:3]=[C:4]([C:22]1[N:23]=[C:24]([NH2:27])[S:25][CH:26]=1)[C:5]([NH:7][CH:8]1[CH:9]2[S:14][CH2:13][C:12]3[CH2:15][O:16][C:17](=[O:18])[C:11]=3[N:10]2[C:20]1=[O:21])=[O:6]
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CO)CS[C@H]12)c1csc(N)n1
Agent: Cl
Solvent: O
Solvent: CC(C)=O
Product: CON=C(C(=O)NC1C(=O)N2C3=C(COC3=O)CSC12)c1csc(N)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 80.2 %

Procedure:
A solution of 7-[2-methoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetamido]-3-hydroxymethyl-3-cephem-4-carboxylic acid (syn isomer) (0.3 g) in a mixture of acetone (3 ml) and water (1.5 ml) was adjusted to pH 2 with 6N hydrochloric acid and stirred for 4 hours at ambient temperature. After the acetone was distilled off, to the residue was added water (1 ml). The mixture was adjusted to pH 7 with a saturated aqueous solution of sodium bicarbonate and ice-cooled for 1 hour. Precipitating crystals were collected by filtration, washed with water and dried to give 6-[2-methoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetamido]-5a,6-dihydro-3H,7H-azeto[2,1-b]furo[3,4-d][1,3]-thiazine-1,7(4H)-dione (syn isomer) (0.23 g), mp 210° to 215° C. (dec.).
Reaction SMILES: C([NH:8][C:9](=[O:24])[C:10]1[C:15](C2C=CC=CC=2C)=[CH:14][C:13](Cl)=[N:12][CH:11]=1)C1C=CC=CC=1.[CH3:25][N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>C(OCC)(=O)C>[CH3:25][N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.[C:30]1([CH3:31])[CH:9]=[CH:10][CH:15]=[CH:14][C:13]=1[N:12]1[CH:13]=[CH:14][CH:15]=[C:10]([C:9]([NH2:8])=[O:24])[CH2:11]1
Reactant: Cc1ccccc1-c1cc(Cl)ncc1C(=O)NCc1ccccc1
Agent: CN1CCNCC1
Solvent: CCOC(C)=O
Product: Cc1ccccc1N1C=CC=C(C(N)=O)C1
Reaction time: 2 h

Procedure:
A solution of 2.5 g (7.4 mMol) N-benzyl-6-chloro-4-o-tolyl-nicotinamide and 3.3 ml (29.7 mMol) N-methyl-piperazine in 25 ml ethyl acetate was heated to 80° C. for 18 hours. After adding 1.65 ml (14.8 mMol) N-methyl-piperazine, the reaction mixture was further heated 2 hours at 80° C., and after a new addition of 1.65 ml (14.8 mMol) N-methyl-piperazine 6 hours at 85° C. It was then concentrated under reduced pressure and the residue was filtered on silica gel (eluent: CH2Cl2/MeOH 5:1) to yield 2.21 g (74%) N-benzyl-6-(4-methyl-piperazin-1-o-tolyl-nicotinamide as a yellow resin.
Reaction SMILES: [Br-].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[S:22]1[CH:26]=[CH:25][N:24]=[C:23]1[C:27]1[CH:35]=[CH:34][CH:33]=[C:32]2[C:28]=1[CH:29]=[CH:30][NH:31]2.[OH2:36]>CC(O)(C)C.C(O)C.C(O)(=O)C.[Zn]>[S:22]1[CH:26]=[CH:25][N:24]=[C:23]1[C:27]1[CH:35]=[CH:34][CH:33]=[C:32]2[C:28]=1[CH2:29][C:30](=[O:36])[NH:31]2
Reactant: O
Reactant: c1cc(-c2nccs2)c2cc[nH]c2c1
Agent: [Br-]
Agent: [Zn]
Agent: c1cc[nH+]cc1
Solvent: CC(C)(C)O
Solvent: CC(=O)O
Solvent: CCO
Product: O=C1Cc2c(cccc2-c2nccs2)N1
Reaction time: 1.5 h

Procedure:
Pyridinium tribromide (90% (Aldrich), 1.9 g, 5.34 mmol) was added portion-wise over 10 minutes to a suspension of 4-thiazol-2-yl-1H-indole (360 mg, 1.78 mmol) in 2-methyl-2-propanol (15 mL), ethanol (9 mL) and acetic acid (5 mL). The mixture was stirred at room temperature for 2 hours after which acetic acid (18 mL), water (1 mL) and zinc dust (1.5 g, 23.14 mmol) were added. Stirring was continued for 1.5 hours. Residual zinc dust was removed by filtration and washed with methanol. The filtrate was concentrated and the syrupy residue was stirred in water (50 mL) overnight. The solid which formed was filtered, washed with water to remove the zinc and pyridine salts and dried under high vacuum to give 4-thiazol-2-yl-1,3-dihydroindol-2-one.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([CH:14](O)[CH2:15]C=C)=[C:12]([CH:19]([CH3:21])[CH3:20])[N:11]=[C:10]([N:22]([CH3:27])[S:23]([CH3:26])(=[O:25])=[O:24])[N:9]=2)=[CH:4][CH:3]=1.CSC.[C:31](=[O:34])([O-])[O-].[K+].[K+].C(=O)(O)[O-].[Na+]>CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([CH:14]=[CH:15][CH:31]=[O:34])=[C:12]([CH:19]([CH3:21])[CH3:20])[N:11]=[C:10]([N:22]([CH3:27])[S:23]([CH3:26])(=[O:25])=[O:24])[N:9]=2)=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: C=CCC(O)c1c(-c2ccc(F)cc2)nc(N(C)S(C)(=O)=O)nc1C(C)C
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CSC
Solvent: CO
Product: CC(C)c1nc(N(C)S(C)(=O)=O)nc(-c2ccc(F)cc2)c1C=CC=O
Reaction time: 2 h
Yield: 96.1 %

Procedure:
N-[4-(4-fluorophenyl)-5-(1-hydroxybut-3-enyl)-6-isopropyl-pyrimidin-2-yl]-N-methylmethanesulfonamide (4 g, 10.2 mmol) is diluted in 102 mL methanol. O3 gas is bubbled through the solution at −15° C. to −10° C. for 60 min. Reaction solution is bubbled through with Argon for 2 min to remove the excess of O3. Dimethylsulfide (1.5 ml, 20.3 mmol) is added to the solution, maintaining stirring for 2 hours. To the reaction mixture, potassium carbonate (2.8 g, 20.3 mmol) is added at room temperature. The progress of the reaction is monitored by TLC. Upon completion of the reaction, 150 ml sodium bicarbonate (aq.) is added and methanol is distilled off under reduced pressure. The residue is extracted with ethyl acetate (2×300 mL) and washed with DM water (100 mL) and brine (150 mL). The organic solvent is distilled off under reduced pressure to give 3.7 g (95%) of N-(4-(4-fluorophenyl)-6-isopropyl-5-(3-oxoprop-1-enyl)pyrimidin-2-yl)-N-methyl-methanesulfonamide The product is recrystallized from 20% ethylacetate:cyclohexane at 0° C. to 5° C. to afford 2.4 g (67%) of N-(4-(4-fluorophenyl)-6-isopropyl-5-(3-oxoprop-1-enyl)pyrimidin-2-yl)-N-methyl-methanesulfonamide as an oily white-yellow solid.
Reaction SMILES: Cl(O)(=O)(=O)=O.COC1C=CC(C[N:13](CC2C=CC(OC)=CC=2)[C:14]2[C:23]3[CH:22]=[N:21][C:20]([NH:24][CH:25]4[CH2:30][CH2:29][CH:28]([OH:31])[CH2:27][CH2:26]4)=[N:19][C:18]=3[N:17]([CH:32]3[CH2:36][CH2:35][CH2:34][CH2:33]3)[C:16](=[O:37])[CH:15]=2)=CC=1>C(Cl)Cl.C([O-])(O)=O.[Na+]>[NH2:13][C:14]1[C:23]2[CH:22]=[N:21][C:20]([NH:24][C@H:25]3[CH2:26][CH2:27][C@H:28]([OH:31])[CH2:29][CH2:30]3)=[N:19][C:18]=2[N:17]([CH:32]2[CH2:36][CH2:35][CH2:34][CH2:33]2)[C:16](=[O:37])[CH:15]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2cc(=O)n(C3CCCC3)c3nc(NC4CCC(O)CC4)ncc23)cc1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: ClCCl
Product: Nc1cc(=O)n(C2CCCC2)c2nc(N[C@H]3CC[C@H](O)CC3)ncc12
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Perchloric acid (0.1 mL) was slowly added at RT to a solution of 5-[bis-(4-methoxy-benzyl)-amino]-8-cyclopentyl-2-(4-hydroxy-cyclohexylamino)-8H-pyrido[2,3-d]pyrimidin-7-one (51 mg, 0.087 mmol) in DCM (0.9 mL) and the resulting mixture was stirred at RT for 20 min. The reaction mixture was then diluted with DCM and NaHCO3 (sat'd aq) was slowly added. The organic layer was washed 4 times with NaHCO3 (sat'd aq). The combined aqueous layers were extracted 3 times with DCM and once with a mixture of chloroform and isopropanol. The combined organic extracts were dried over Na2SO4, filtered and evaporated under reduced pressure. The crude residue was purified by preparative TLC (DCM/MeOH 90/10) to afford 31.9 mg of trans-5-amino-8-cyclopentyl-2-(4-hydroxy-cyclohexylamino)-8H-pyrido[2,3-d]pyrimidin-7-one as a yellow solid. MS=344 [M+H]+; MP=246.5-248.0° C.
Reaction SMILES: [F:1][C:2]1[C:3]([NH2:10])=[CH:4][C:5]([NH2:9])=[C:6]([CH3:8])[CH:7]=1.[C:11]1([S:17](Cl)(=[O:19])=[O:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>N1C=CC=CC=1>[F:1][C:2]1[C:3]([NH:10][S:17]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)(=[O:19])=[O:18])=[CH:4][C:5]([NH:9][S:17]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)(=[O:19])=[O:18])=[C:6]([CH3:8])[CH:7]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Cc1cc(F)c(N)cc1N
Solvent: c1ccncc1
Product: Cc1cc(F)c(NS(=O)(=O)c2ccccc2)cc1NS(=O)(=O)c1ccccc1
Temperature: 120 °C
Reaction time: 1 h
Yield: 41 %

Procedure:
8 g 5-fluoro-2,4-diaminotoluene from Step 2 are dissolved in 250 ml pyridine, mixed with 7.9 ml benzenesulfonyl chloride, and stirred for 1 hour at 120° C. After cooling, the reaction preparation is poured over ice. The obtained precipitate is washed with water, dried in vacuum over phosphorus pentoxide, and recrystallized from methanol. 3.9 g (41% of theory) 5-fluoro-2,4-bis[(N-benzenesulfonyl)amino]toluene are obtained which melts at 146° C.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[N:5]=[C:6]([NH:11][C:12]3[CH:13]=[C:14]([NH:19][C:20](=[O:32])[C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([C:30]#[N:31])([CH3:29])[CH3:28])[CH:22]=4)[CH:15]=[CH:16][C:17]=3[CH3:18])[N:7]=[CH:8][C:9]=2[N:10]=1.[CH3:33][N:34]1[CH:38]=[CH:37][C:36]([C:39](O)=[O:40])=[N:35]1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(=O)([O-])O.[Na+]>N1C=CC=CC=1>[C:30]([C:27]([C:23]1[CH:22]=[C:21]([C:20]([NH:19][C:14]2[CH:15]=[CH:16][C:17]([CH3:18])=[C:12]([NH:11][C:6]3[N:7]=[CH:8][C:9]4[N:10]=[C:2]([NH:1][C:39]([C:36]5[CH:37]=[CH:38][N:34]([CH3:33])[N:35]=5)=[O:40])[S:3][C:4]=4[N:5]=3)[CH:13]=2)=[O:32])[CH:26]=[CH:25][CH:24]=1)([CH3:29])[CH3:28])#[N:31]
Reactant: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1Nc1ncc2nc(N)sc2n1
Reactant: Cn1ccc(C(=O)O)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: c1ccncc1
Product: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1Nc1ncc2nc(NC(=O)c3ccn(C)n3)sc2n1
Temperature: 90 °C
Reaction time: 17 h
Yield: 40.3 %

Procedure:
To a solution of N-{3-[(2-amino[1,3]thiazolo[5,4-d]pyrimidin-5-yl)amino]-4-methylphenyl}-3-(1-cyano-1-methylethyl)benzamide (80 mg, 180 μmol) produced in Example D25(iii) in pyridine (3 mL) were added 1-methyl-1H-pyrazole-3-carboxylic acid (45 mg, 360 μmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (205 mg, 540 μmol), and the mixture was stirred at 90° C. for 17 hr. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution (15 mL), and the mixture was extracted with ethyl acetate (20 mL, 5 mL). The combined organic layer was washed with saturated brine (5 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (ethyl acetate/methanol=100/0→92/8), and the fractions containing the object product were concentrated under reduced pressure. The obtained residue was recrystallized from ethyl acetate to give the title compound (40 mg, 40%) as pale-yellow crystals.
Reaction SMILES: [C:1]([NH:6][C:7]1[CH:8]=[C:9]([CH:15]=[CH:16][C:17]=1[N+:18]([O-:20])=[O:19])[C:10]([O:12][CH2:13][CH3:14])=[O:11])(=[O:5])[CH2:2][CH2:3][CH3:4].[H-].[Na+].[CH:23](I)([CH3:25])[CH3:24].Cl>CN(C)C=O.C(OCC)(=O)C>[N+:18]([C:17]1[CH:16]=[CH:15][C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:8][C:7]=1[NH:6][C:1](=[O:5])[CH2:2][CH2:3][CH2:4][CH:23]([CH3:25])[CH3:24])([O-:20])=[O:19]
Reactant: CCCC(=O)Nc1cc(C(=O)OCC)ccc1[N+](=O)[O-]
Reactant: CC(C)I
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc([N+](=O)[O-])c(NC(=O)CCCC(C)C)c1
Reaction time: 0.5 h
Yield: 11.3 %

Procedure:
A solution of 2.00 g of ethyl 3-butyrylamino-4-nitrobenzoate in 10 ml of N,N-dimethylformamide was added dropwise to a slurry of 0.428 g of 60% sodium hydride and 10 ml of N,N-dimethylformamide at room temperature, and the mixture was stirred for 30 minutes. A solution of 1.46 g of isopropyl iodide in 10 ml of N,N-dimethylformamide was then added dropwise thereto, and the mixture was stirred at 100° C. for 5 days. The reaction solution was poured into a mixed solution of 80 g of dilute hydrochloric acid and 80 g of ethyl acetate for separation. The resulting organic layer was washed with 50 g of water, and was then concentrated under reduced pressure. The residue was purified through silica-gel column chromatography (eluent: a mixture of hexane and ethyl acetate at a ratio of 4:1) to obtain 0.260 g of crude ethyl 4-nitro-3-(N-i-propylbutyrylamino)benzoate. Subsequently, 3 ml of ethanol and 2 ml of acetic acid were added to 0.260 g of ethyl 4-nitro-3-(N-i-propylbutyrylamino)benzoate at room temperature, and 0.519 g of reduced iron were further added thereto. The mixture was heat-refluxed for 4 hours. The solid material was removed using a filtration aid, and the filtrate was concentrated. The residue were added 30 ml of ethyl acetate and 30 ml of dilute hydrochloric acid for separation. The organic layer was washed with 30 ml of water, and was then concentrated under reduced pressure. The residue was purified through preparative thin-layer silica-gel chromatography (developing eluent: a mixture of hexane and ethyl acetate at a ratio of 1:1) to give 0.06 g of ethyl 4-amino-3-(N-i-propylbutyrylamino)benzoate.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[S:12]([CH3:15])(=[O:14])=[O:13].[F:16][C:17]1[CH:22]=[C:21](B2OC(C)(C)C(C)(C)O2)[CH:20]=[CH:19][C:18]=1[C:32]1[CH:33]=[N:34][C:35]([NH2:38])=[N:36][CH:37]=1>>[F:16][C:17]1[CH:22]=[C:21]([C:2]2[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=2[S:12]([CH3:15])(=[O:14])=[O:13])[CH:20]=[CH:19][C:18]=1[C:32]1[CH:37]=[N:36][C:35]([NH2:38])=[N:34][CH:33]=1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)nc3)c(F)c2)OC1(C)C
Reactant: CS(=O)(=O)c1cc(C(F)(F)F)ccc1Br
Product: CS(=O)(=O)c1cc(C(F)(F)F)ccc1-c1ccc(-c2cnc(N)nc2)c(F)c1

Procedure:
The title compound was prepared in a manner similar to that described in Example 88 using 1-bromo-2-(methylsulfonyl)-4-(trifluoromethyl)benzene and 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amine. MS (ESI): mass calcd. for C18H13F4N3O2S, 411.07; m/z found, 412.0 [M+H]+. 1H NMR (500 MHz, CD3OD) δ 8.61-8.51 (d, J=1.4, 2H), 8.44 (s, 1H), 8.11-8.05 (d, J=7.5, 1H), 7.72-7.66 (d, J=8.0, 1H), 7.66-7.59 (m, 1H), 7.45-7.35 (m, 2H), 2.89 (s, 3H).
Reaction SMILES: [CH:1]1[C:14]2[C:13](=[O:15])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Cl.Cl[CH2:20][CH2:21][N:22]([CH3:24])[CH3:23]>CN(C)C=O>[CH3:23][N:22]([CH3:24])[CH2:21][CH2:20][N:6]1[C:5]2[C:14](=[CH:1][CH:2]=[CH:3][CH:4]=2)[C:13](=[O:15])[C:12]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]1=2
Reactant: O=c1c2ccccc2[nH]c2ccccc12
Reactant: CN(C)CCCl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)CCn1c2ccccc2c(=O)c2ccccc21
Reaction time: 0.5 h

Procedure:
A mixture of 3.9 g of acridanone, 1.0 g of sodium hydride and 80 ml of dimethylformamide is stirred for 0.5 hours, then treated with 2.9 g of 1-chloro-2-dimethylaminoethane hydrochloride, stirred at 60° for 18 hours and evaporated. The residue is extracted with methylene chloride. The extract is washed with water, dried over sodium sulfate and evaporated. By crystallization from isopropyl ether there is obtained 10-[2-(dimethylamino)ethyl]-9-acridanone of melting point 145°-146°.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:22])[N:7]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][C:15]=3[F:21])[C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28].O>CN(C)C=O>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:22])[N:7]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][C:15]=3[F:21])[C:8](=[O:12])[N:9]2[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:4][CH:3]=1
Reactant: O=c1[nH]c2cc(Br)ccc2c(=O)n1Cc1ccc(Br)cc1F
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1c(=O)n(Cc2ccc(Br)cc2F)c(=O)c2ccc(Br)cc21
Temperature: 0 °C

Procedure:
To a solution of 7-bromo-3-(4-bromo-2-fluorobenzyl)-1,2,3,4-tetrahydro-2,4-dioxoquinazoline (2.80 g) in N,N-dimethylformamide (56 ml) was added sodium hydride (60% in mineral oil, 334 mg) with stirring at 0° C. under an atmosphere of nitrogen and the mixture was stirred at room temperature for 1 hour. To this mixture was added ethyl bromoacetate (0.85 ml) dropwise and the mixture was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure to give a residue, which was poured into water and extracted with ethyl acetate. The extract was washed with water and dried. Removal of the solvent followed by recrystallization from isopropyl either gave ethyl 2-[7-bromo-3-(4-bromo-2-fluorobenzyl)-1,2,3,4-tetrahydro-2,4-dioxoquinazolin-1-yl]acetate (3.11 g).
Reaction SMILES: [F:1][C:2]1([F:6])[CH2:5][NH:4][CH2:3]1.[Cl:7][C:8]1[CH:9]=[N:10][N:11]([C:13]2([C:16]3[NH:33][C:19]4=[N:20][C:21]([N:24]5[CH2:29][CH2:28][CH2:27][C@@H:26]([C:30](O)=[O:31])[CH2:25]5)=[CH:22][CH:23]=[C:18]4[N:17]=3)[CH2:15][CH2:14]2)[CH:12]=1.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>ClCCl>[Cl:7][C:8]1[CH:9]=[N:10][N:11]([C:13]2([C:16]3[NH:33][C:19]4=[N:20][C:21]([N:24]5[CH2:29][CH2:28][CH2:27][C@@H:26]([C:30]([N:4]6[CH2:5][C:2]([F:6])([F:1])[CH2:3]6)=[O:31])[CH2:25]5)=[CH:22][CH:23]=[C:18]4[N:17]=3)[CH2:15][CH2:14]2)[CH:12]=1
Reactant: O=C(O)[C@@H]1CCCN(c2ccc3nc(C4(n5cc(Cl)cn5)CC4)[nH]c3n2)C1
Reactant: FC1(F)CNC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C([C@@H]1CCCN(c2ccc3nc(C4(n5cc(Cl)cn5)CC4)[nH]c3n2)C1)N1CC(F)(F)C1
Reaction time: 2 h
Yield: 43.3 %

Procedure:
3,3-Difluoroazetidine (33 mg, 0.2 mmol) was added to a mixture of (R)-1-(2-(1-(4-chloro-1H-pyrazol-1-yl)cyclopropyl)-3H-imidazo[4,5-b]pyridin-5-yl)piperidine-3-carboxylic acid (100 mg, 0.25 mmol), diisopropylethylamine (0.1 mL, 0.77 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′,-tetramethyluronium hexafluorophosphate (HATU) (118 mg, 0.31 mmol) in anhydrous dichloromethane (5 mL) at room temperature. The reaction mixture was stirred for 2 h, then partitioned between dichloromethane and water. The organics were dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified via preparative TLC to afford the title compound (40 mg, 43% yield). MS (ES+) (M+H) 462.2; LCMS retention time 2.163 minutes (Method N1). 1H NMR (300 MHz, CDCl3) δ 1.17-1.39 (m, 1H), 1.71-2.24 (m, 7H), 2.35-2.58 (m, 1H), 2.83-3.13 (m, 2H), 4.04-4.78 (m, 6H), 6.63 (d, 1H), 7.62 (s, 2H), 7.69-7.80 (m, 1H), 9.15 (br s, 1H).
Reaction SMILES: CN(CC(O)C)CC(O)C.C(N(CCO)CCO)C.C(C(CN(C)C)(CO)CO)C.[C:31]([N:36]([CH2:41][CH:42]([OH:44])[CH3:43])[CH2:37][CH:38]([OH:40])[CH3:39])([CH2:34]C)([CH3:33])[CH3:32].C1(N(CCO)CCO)CCCCC1>>[C:31]([N:36]([CH2:37][CH:38]([OH:40])[CH3:39])[CH2:41][CH:42]([OH:44])[CH3:43])([CH3:33])([CH3:34])[CH3:32]
Reactant: CCC(C)(C)N(CC(C)O)CC(C)O
Agent: CC(O)CN(C)CC(C)O
Agent: CCC(CO)(CO)CN(C)C
Agent: CCN(CCO)CCO
Product: CC(O)CN(CC(C)O)C(C)(C)C

Procedure:
4-methyl-4-azaheptane-2,6-diol; 3-ethyl-3-azapentane-1,5-diol; 2-ethyl-2-dimethylamino methyl-propane-1,3-diol; 4-tertiary-pentyl-4-azaheptane-2,6-diol; 3-cyclohexyl-3-azapentane-1,5-diol, 3-tert-butylmethyl-3-azapentandiol-1,5, 3-tert.-pentyl-3-aza-pentandiol-1,
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][NH:23][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[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1
Reactant: Oc1ccccc1-c1nc(Cl)c2cc(F)ccc2n1
Reactant: C1CNCCN1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Oc1ccccc1-c1nc(N2CCNCC2)c2cc(F)ccc2n1
Reaction time: 1 h
Yield: 67.8 %

Procedure:
To a stirring solution of 2-(4-chloro-6-fluoroquinazolin-2-yl)phenol (500 mg, 1.82 mmol) in CH2Cl2 (20 mL) at 0° C., under an N2 atmosphere was rapidly added a solution of piperazine (0.263 g, 7.28 mmol) and triethylamine (0.35 mL, 2.55 mmol) in CH2Cl2. The mixture was stirred for 1 h and then quenched with H2O, extracted twice with CH2Cl2, dried over Na2SO4, filtered, and concentrated. Purification via silica gel chromatography using 0-5% MeOH in CH2Cl2 gave 2-(6-fluoro-4-(piperazin-1-yl)quinazolin-2-yl)phenol (400 mg, 68%). LC/MS: m/z 325.5 (M+H)+ at 2.12 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)). 1H NMR (400 MHz, DMSO-d6) δ 8.42 (m, 1H), 7.97 (m, 1H), 7.78 (m, 2H), 7.39 (m, 1H), 6.95 (m, 2H), 3.83 (t, J=4.9 Hz, 4H), 2.92 (t, J=4.9 Hz, 4H) ppm.