Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1([O:8][CH3:9])[CH2:7][CH2:6][NH:5][CH2:4]1.Cl[C:11]1[CH:20]=[C:19]2[C:14]([C:15](=[O:27])[C:16]([C:24]([OH:26])=[O:25])=[CH:17][N:18]2[CH:21]2[CH2:23][CH2:22]2)=[CH:13][C:12]=1[F:28]>>[CH:21]1([N:18]2[C:19]3[C:14](=[CH:13][C:12]([F:28])=[C:11]([N:5]4[CH2:6][CH2:7][C:3]([O:8][CH3:9])([O:2][CH3:1])[CH2:4]4)[CH:20]=3)[C:15](=[O:27])[C:16]([C:24]([OH:26])=[O:25])=[CH:17]2)[CH2:22][CH2:23]1
Reactant: COC1(OC)CCNC1
Reactant: O=C(O)c1cn(C2CC2)c2cc(Cl)c(F)cc2c1=O
Product: COC1(OC)CCN(c2cc3c(cc2F)c(=O)c(C(=O)O)cn3C2CC2)C1

Procedure:
Following procedures similar to Step 5 of Example 1, a 0.186 g (1.4 mmol) sample of 3,3-dimethoxypyrrolidine, from Step 4 of Example 1, was reacted with 0.200 g (0.7 mmol) of 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (preparation described by K. Grohe, et al., DE 3142854, May, 1983) at 60° C. under N2 for 188 hours to yield the title compound, mp 224°-226° C.: MS (DCl) M/Z 377 (M+H); NMR d 1.42 (d, 1H), 1.63 (m, 2H), 3.75 (s, 3H), 3.99 (s, 3H), 4.02 (m, 1H), 4.26 (m, 2H), 4.40 (m, 2H), 7.46 (d, 1H, J=7.5 Hz), 8.13 (d, 1H, J=13.5 Hz), 9.19 (s, 1H). Analysis calculated for C19H21FN2O5 ·0.5 H2O: C, 59.21; H, 5.75; N, 7.27. Found: C, 59.70; H, 5.48; N, 7.13.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([C:6](SC)=[N:7][C:8]([C:12]([F:21])([F:20])[C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][N:14]=3)=[N:9]2)=[CH:4][CH:3]=1.[CH3:24][S:25]([O-:27])=[O:26].[Na+].CN(C)CCN.CS(C)=[O:37]>>[F:20][C:12]([F:21])([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][N:14]=1)[C:8]1[N:7]=[C:6]([OH:37])[C:5]2[C:10](=[CH:11][C:2]([S:25]([CH3:24])(=[O:27])=[O:26])=[CH:3][CH:4]=2)[N:9]=1
Reactant: CSc1nc(C(F)(F)c2ccc(F)cn2)nc2cc(Br)ccc12
Reactant: CS(C)=O
Reactant: CS(=O)[O-]
Agent: CN(C)CCN
Agent: [Na+]
Product: CS(=O)(=O)c1ccc2c(O)nc(C(F)(F)c3ccc(F)cn3)nc2c1
Temperature: 130 °C
Yield: 42 %

Procedure:
To a mixture of 7-bromo-2-(difluoro(5-fluoropyridin-2-yl)methyl)-4-(methylthio)quinazoline from Example 7 step C (400 mg, 1 mmol), copper(I) trifluoromethanesulfonate benzene complex (503 mg, 1 mmol), sodium methanesulfinate (752 mg, 6.26 mmol) and N,N-dimethylethylenediamine (0.039 mL, 0.36 mmol) was added DMSO (15 mL). The reaction vessel was evacuated and flushed with argon (2×). The mixture was then heated in a microwave synthesizer at 130° C. for 10 min. The mixture was filtered and the filtrate was purified by preparative HPLC (Varian diphenyl reverse phase column, eluted with gradient of solvent B=0.05% AcOH/ACN and solvent A=5% ACN/0.05% AcOH/H2O) to afford 2-(difluoro(5-fluoropyridin-2-yl)methyl)-7-(methylsulfonyl)quinazolin-4-ol (155 mg, 42%). 1H NMR (300 MHz, DMSO-d6) δ ppm 7.98-8.13 (m, 3H) 8.19 (s, 1H) 8.40 (d, J=8.29 Hz, 1H) 8.68 (d, J=2.45 Hz, 1H) 13.50 (br s, 1H).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:26][O:27][CH3:28])[C:8]([NH:10][CH:11]2[C:24](=[O:25])[N:13]3[C:14]([C:21]([O-:23])=[O:22])=[C:15]([CH2:18][O:19][CH3:20])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.[Na+].FC(F)(F)C([O-])=O.[C:37]([O:43][CH2:44]I)(=[O:42])[C:38]([CH3:41])([CH3:40])[CH3:39].C(OCC)(=O)C>CC(N(C)C)=O>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:26][O:27][CH3:28])[C:8]([NH:10][CH:11]2[C:24](=[O:25])[N:13]3[C:14]([C:21]([O:23][CH2:44][O:43][C:37](=[O:42])[C:38]([CH3:41])([CH3:40])[CH3:39])=[O:22])=[C:15]([CH2:18][O:19][CH3:20])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: CC(C)(C)C(=O)OCI
Reactant: COCC1=C(C(=O)[O-])N2C(=O)C(NC(=O)C(=NOC)c3csc(N)n3)[C@H]2SC1
Agent: O=C([O-])C(F)(F)F
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: COCC1=C(C(=O)OCOC(=O)C(C)(C)C)N2C(=O)C(NC(=O)C(=NOC)c3csc(N)n3)[C@H]2SC1
Yield: 90.4 %

Procedure:
To a solution of 45 mg of sodium 7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-methoxymethyl-3-cephem-4-carboxylate (prepared from the corresponding trifluoroacetate) in 1 ml of dimethylacetamide were added, at -15° C., 27 mg of iodomethyl pivalate and the mixture was allowed to react for 15 minutes. At the end of this time, 20 ml of ethyl acetate were added to the reaction mixture, and the mixture was washed, in turn, with water, an aqueous solution of potassium bisulphate and an aqueous solution of sodium bicarbonate. The organic phase was separated and concentrated by evaporation under reduced pressure, and the residue was subjected to column chromatography through silica gel eluted with a 3:1 by volume mixture of ethyl acetate and hexane, to give 49 mg of the title compound, whose properties were identical with those of the compound obtained in Example 1.
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[C:9]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)=[N:10][C:11]3[C:16]([N:17]=2)=[CH:15][C:14]([C:18]([O:20]C)=[O:19])=[CH:13][CH:12]=3)[CH2:3]1.CO.[OH-].[Na+]>O>[CH3:1][C:2]1([CH3:29])[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[C:9]([C:22]3[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=3)=[N:10][C:11]3[C:16]([N:17]=2)=[CH:15][C:14]([C:18]([OH:20])=[O:19])=[CH:13][CH:12]=3)[CH2:3]1
Reactant: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(N3CCCC(C)(C)C3)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC1(C)CCCN(c2nc3cc(C(=O)O)ccc3nc2-c2ccc(F)cc2)C1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of methyl 3-(3,3-dimethylpiperidin-1-yl)-2-(4-fluorophenyl)quinoxaline-6-carboxylate (120 mg, 0.31 mmol, 1.00 equiv), methanol (15 mL), sodium hydroxide (61 mg, 1.52 mmol, 4.99 equiv), and water (2 mL). The resulting solution was stirred for 2 h at 50° C. in an oil bath. The resulting mixture was concentrated under vacuum. The resulting solution was diluted with 20 mL of H2O. The pH value of the aqueous solution was adjusted to 4-5 with hydrogen chloride (1 mol/L). The resulting solids were collected by filtration. This resulted in 60 mg (52%) of 3-(3,3-dimethylpiperidin-1-yl)-2-(4-fluorophenyl)quinoxaline-6-carboxylic acid as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[C:6](Cl)=[N:7][C:8]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][CH:16]=2)=[N:9][C:10]=1[N:11]([CH3:13])[CH3:12].C([O-])(=O)C.[K+]>CO.[Pd]>[CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[C:10]([N:11]([CH3:12])[CH3:13])=[N:9][C:8]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=2)=[N:7][CH:6]=1
Reactant: COC(=O)Cc1c(Cl)nc(Cc2ccc([N+](=O)[O-])cc2)nc1N(C)C
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CO
Product: COC(=O)Cc1cnc(Cc2ccc(N)cc2)nc1N(C)C
Reaction time: 15 h
Yield: 97.2 %

Procedure:
A suspension of methyl[4-chloro-6-(dimethylamino)-2-(4-nitrobenzyl)pyrimidin-5-yl]acetate (3.00 g, 8.22 mmol) and potassium acetate (2.42 g, 24.7 mmol) in methanol (30 mL) was treated with 10% Pd/C (1.00 g). The resulting black suspension was stirred under an atmosphere of hydrogen for 15 hours and then filtered over Celite. The residue was rinsed with methanol and the filtrate concentrated to dryness before partitioning between EtOAc and water. The separated organic layer was sequentially washed with saturated NaHCO3 and brine, dried over anhydrous MgSO4, filtered, and concentrated in vacuo. Chromatographic purification (silica gel, 1% MeOH in CHCl3) of the thus obtained crude product then yielded methyl[2-(4-aminobenzyl)-4-(dimethylamino)pyrimidin-5-yl]acetate (2.40 g, 97% yield) as a brown oil.
Reaction SMILES: [CH3:1][P:2]([O-:9])[O:3][CH2:4][CH2:5][CH:6]([CH3:8])[CH3:7].[CH3:10][C:11]([O:13][CH:14]([C:17]#[N:18])[CH:15]=[CH2:16])=[O:12]>>[C:11]([O:13][CH:14]([C:17]#[N:18])[CH2:15][CH2:16][P:2]([CH3:1])(=[O:9])[O:3][CH2:4][CH2:5][CH:6]([CH3:8])[CH3:7])(=[O:12])[CH3:10]
Reactant: C=CC(C#N)OC(C)=O
Reactant: CC(C)CCOP(C)[O-]
Product: CC(=O)OC(C#N)CCP(C)(=O)OCCC(C)C
Temperature: 80 °C
Reaction time: 3 h
Yield: 100.9 %

Procedure:
235.0 g of isopentyl methanephosphonite are heated to 80° C. under nitrogen, and 0.5 g of tert.-butyl perpivalate is added. 63.9 g of acrolein cyanohydrin acetate and 2.5 g of tert.-butyl perpivalate are added drop-wise, with vigorous stirring at 80° C., within 3 hours. After reaction is complete, 155.2 g of 97.5% pure isopentyl methanephosphonite are distilled out under high vacuum. (Recovery: 95%). 141.8 g of isopentyl (3-acetoxy-3-cyanopropyl)methylphosphinate (yield=96.5%; purity=93.6%) are obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]2[CH:16]=[C:17]([C:19]3[N:20]=[CH:21][N:22]([CH2:24][CH2:25][CH3:26])[CH:23]=3)[S:18][C:11]=12)[NH2:5].[F:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[NH:34][C:35](=[O:40])[CH2:36][C:37](O)=[O:38].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([NH:5][C:37](=[O:38])[CH2:36][C:35]([NH:34][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[F:27])=[O:40])[CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]2[CH:16]=[C:17]([C:19]3[N:20]=[CH:21][N:22]([CH2:24][CH2:25][CH3:26])[CH:23]=3)[S:18][C:11]=12
Reactant: O=C(O)CC(=O)Nc1ccccc1F
Reactant: CCCn1cnc(-c2cc3nccc(Oc4ccc(N)cc4F)c3s2)c1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CCCn1cnc(-c2cc3nccc(Oc4ccc(NC(=O)CC(=O)Nc5ccccc5F)cc4F)c3s2)c1
Reaction time: 1 h
Yield: 36.4 %

Procedure:
To a solution of the amino compound 133 (400 mg, 1.08 mmol) in DMF (20 mL), 3-(2-fluorophenylamino)-3-oxopropanoic acid (29) (427 mg, 2.17 mmol), EDC (352 mg, 2.60 mmol) was added HOBT (499 mg, 2.60 mmol). The reaction mixture was allowed to stir for 1 hr. The solution was extracted with EtOAc and the extract was washed with water, aqueous ammonium chloride and brine then dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The residue was purified by flash chromatography (eluents DCM-MeOH, 98:2, 95:5) to afford title compound 130 (215 mg, 36% yield) as a yellow solid. 1H NMR (DMSO-d6). δ (ppm): 10.56 (s, 1H), 10.06 (s, 1H), 8.43 (d, J=5.6 Hz, 1H), 8.10-7.96 (m, 1H), 7.94 (d, J=1.2 Hz, 1H), 7.87 (dd, J=1.6 and 12.8 Hz, 1H), 7.77 (d, J=1.2 Hz, 1H), 7.68 (s, 1H), 7.49 (t, J=8.8 Hz, 1H), 7.42 (dd, J=2.0 and 8.8 Hz, 1H), 7.32-7.25 (m, 1H), 7.22-7.14 (m, 2H), 6.58 (d, J=5.6 Hz, 1H), 3.98 (t, J=7.2 Hz, 2H), 3.62 (s, 2H), 1.78 (sex, J=7.2 Hz, 2H), 0.87 (t, J=7.2 Hz, 3H). MS (m/z): 548.1 (M+H).
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[O:38][CH2:39][CH3:40].[Cl:41][C:42]1[C:43]([C:52]([F:55])([F:54])[F:53])=[N:44][N:45]([CH2:48][C:49](O)=[O:50])[C:46]=1[CH3:47]>>[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]2[CH2:33][CH2:34][N:35]([C:49](=[O:50])[CH2:48][N:45]3[C:46]([CH3:47])=[C:42]([Cl:41])[C:43]([C:52]([F:55])([F:54])[F:53])=[N:44]3)[CH2:36][CH2:37]2)=[CH:28][C:27]=1[O:38][CH2:39][CH3:40]
Reactant: CCOc1cc(N2CCNCC2)ccc1Cl
Reactant: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: CCOc1cc(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-ethoxyphenyl)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) 7.20 (d, 1H), 6.66 (s, 1H), 6.48 (d, 1H), 5.38 (s, 2H), 4.08 (q, 2H), 3.61 (m, 4H), 3.25 (m, 2H), 3.16 (m, 2H), 2.18 (s, 3H), 1.33 (t, 3H) ppm; MS (ES) M+H expected=465.1, found 465.0.
Reaction SMILES: [OH-].[Na+].CN(C)C=[CH:6][C:7]([C:9]1[S:13][C:12]([N:14]=[CH:15]N(C)C)=[N:11][C:10]=1[CH3:19])=O.[NH2:21][C:22]([NH2:24])=[S:23].[CH3:25]I>C(O)C.O>[CH3:6][C:7]1[N:21]=[C:22]([NH2:24])[S:23][C:9]=1[C:10]1[CH:19]=[CH:15][N:14]=[C:12]([S:13][CH3:25])[N:11]=1
Reactant: Cc1nc(N=CN(C)C)sc1C(=O)C=CN(C)C
Reactant: NC(N)=S
Reactant: CI
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CSc1nccc(-c2sc(N)nc2C)n1
Temperature: 25 °C

Procedure:
Powdered sodium hydroxide (1.09 g) is added to a solution of N′-[5-(3-dimethylamino-acryloyl)-4-methyl-thiazol-2-yl]-N,N-dimethyl-formamidine (2.0 g, prepared as described by S. Wang et al J. Med. Chem. 2004, 47, 1662-1675.) and thiourea (0.57 g) in ethanol (25 ml) and the mixture is heated at reflux for 3 hour with stirring. The reaction mixture is cooled to room temperature and water then methyliodide (0.47 ml) is added. After 1 hour at room temperature the ethanol is removed by evaporation and water is added and the pH is adjusted to 7 with 2N aqueous hydrochloric acid. The title compound is then obtained by filtration. ESI-MS: M+H 239 and M−H 237.
Reaction SMILES: S(Cl)([Cl:3])=O.[NH2:5][C@H:6]([C:8]([OH:10])=[O:9])[CH3:7].[CH2:11](O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[Cl-:3].[CH2:11]([O:9][C:8](=[O:10])[C@@H:6]([NH3+:5])[CH3:7])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: OCc1ccccc1
Reactant: C[C@H](N)C(=O)O
Reactant: O=S(Cl)Cl
Product: C[C@H]([NH3+])C(=O)OCc1ccccc1
Product: [Cl-]
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Thionyl chloride (27 mL) was added drop-wise to a solution L-alanine (42) (6.83 g, 76.6 mmol) in benzyl alcohol (120 mL). After stirring at 0° C. for 2 h, the reaction mixture was warmed to room temperature and stirred for a further 24 h and then evaporated to dryness under reduced pressure. Trituration with diethyl ether, followed by filtration and evaporation under reduced pressure, provided the crude product 43 (3.5 g), which was used directly without further purification. LC-MS (M-Cl)+=180
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[CH:8]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:22][CH3:23])[CH:16]=1)[NH:7][CH:6]=[C:5]2[CH:24]=[O:25]>C(Cl)(Cl)Cl.[O-2].[Mn+4].[O-2]>[OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[C:8]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:22][CH3:23])[CH:16]=1)=[N:7][CH:6]=[C:5]2[CH:24]=[O:25]
Reactant: CCOc1cccc(CC2NC=C(C=O)c3cc(O)c(OC)cc32)c1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: CCOc1cccc(Cc2ncc(C=O)c3cc(O)c(OC)cc23)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 91.2 %

Procedure:
To a stirred solution of 6-hydroxy-7-methoxy-1-(3-ethoxy-benzyl)-1,2-dihydro-isoquinoline-4-carbaldehyde (660 mg, 1.95 mmol) in chloroform (30 μL) was addend manganese (IV) oxide (1.99 mg, 19.5 mmol). The reaction mixture was stirred at room temperature for 15 hrs, filtered through a celite® pad, and washed with chloroform. The filtrate was concentrated in vacuo to afford 6-hydroxy-7-methoxy-1-(3-ethoxy-benzyl)-isoquinoline-4-carbaldehyde (600 mg, 89% yield). The crude product was used without further purification.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([NH2:16])=[CH:8][CH:7]=1.[F:17][C:18]1[CH:19]=[C:20]([CH:24]=[C:25]([N:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)[CH:26]=1)[C:21](O)=[O:22].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.C(OCC)(=O)C>[Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([NH:16][C:21](=[O:22])[C:20]2[CH:24]=[C:25]([N:27]3[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]3)[CH:26]=[C:18]([F:17])[CH:19]=2)=[CH:8][CH:7]=1
Reactant: Nc1ccc(OCCCCl)c2ccccc12
Reactant: O=C(O)c1cc(F)cc(N2CCCCC2)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(OCCCCl)c2ccccc12)c1cc(F)cc(N2CCCCC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.8 %

Procedure:
To a solution of 4-(3-chloropropoxy)naphthalen-1-amine (2.85 g, 10.5 mmol) and 3-fluoro-5-piperidin-1-ylbenzoic acid (3.52 g, 15.7 mmol), in DMF (30 ml) is added HBTU (7.1 g, 18.9 mmol), and Hunig's base (6.0 ml, 33.6 mmol). The mixture is stirred overnight at room temperature then diluted with ethyl acetate (200 ml) and washed with water (3×100 ml). The organic layer is dried over Na2SO4 and evaporated. The residue is purified by column chromatography on silica gel to yield N-[4-(3-chloropropoxy)-naphthalen-1-yl]-3-fluoro-5-piperidin-1-yl-benzamide as a white solid (3.0 g, 65%). Mp: 181-182° C. 1H NMR (300 MHz, DMSO-d6) δ 10.25 (s, 1H), 8.26 (m, 1H), 7.87 (m, 1H), 7.55 (m, 2H), 7.46 (s, 1H), 7.43 (d, J=8.1 Hz, 1H), 7.17 (d, J=9.3 Hz, 1H), 7.04 (d, J=8.4 Hz, 1H), 6.97 (d, J=10.5 Hz, 1H), 4.33 (t, J=6.0 Hz, 2H), 3.96(t, J=6.6, Hz, 2H), 3.29 (m, 4H), 2.34 (m, 6H), 1.59 (m, 6H). MS: 441.3 (M+1).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[C:7]([NH:10][C:11]([NH:13][CH2:14][CH2:15]Cl)=[O:12])[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[H-].[Na+].C(OCC)(=O)C>CN(C=O)C.C1COCC1>[S:1]1[C:5]2[CH:6]=[C:7]([N:10]3[CH2:15][CH2:14][NH:13][C:11]3=[O:12])[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: O=C(NCCCl)Nc1ccc2ncsc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C1NCCN1c1ccc2ncsc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.1 %

Procedure:
1-Benzothiazol-6-yl-3-(2-chloro-ethyl)-urea (I-84a: 2.7 g, 10.58 mmol) in dry DMF (80 mL) was added dropwise to a stirred mixture of sodium hydride (0.76 g, 31.74 mmol) in THF (100 mL) over a period of 20 minutes at 0° C. under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 2 hours. The reaction was monitored by TLC (100% ethyl acetate). The reaction mixture was quenched with MeOH (6 mL), concentrated under reduced pressure, followed by the addition of ice. The precipitate was collected and dried under reduced pressure to afford 2.3 g (85.18% yield) of 1-benzothiazol-6-yl-imidazolidin-2-one as the required product.
Reaction SMILES: [CH:1]1([O:6][C:7]2[C:12](B(O)O)=[CH:11][CH:10]=[CH:9][N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Br[C:17]1[CH:22]=[CH:21][C:20]([C:23]2[N:24]=[CH:25][C:26]([NH2:29])=[N:27][CH:28]=2)=[C:19]([F:30])[CH:18]=1>>[CH:1]1([O:6][C:7]2[C:12]([C:17]3[CH:22]=[CH:21][C:20]([C:23]4[N:24]=[CH:25][C:26]([NH2:29])=[N:27][CH:28]=4)=[C:19]([F:30])[CH:18]=3)=[CH:11][CH:10]=[CH:9][N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OB(O)c1cccnc1OC1CCCC1
Reactant: Nc1cnc(-c2ccc(Br)cc2F)cn1
Product: Nc1cnc(-c2ccc(-c3cccnc3OC3CCCC3)cc2F)cn1

Procedure:
The title compound was prepared using methods analogous to those described in Example 369 using (2-(cyclopentyloxy)pyridin-3-yl)boronic acid and 5-(4-bromo-2-fluorophenyl)pyrazin-2-amine in Step B. MS (ESI): mass calcd. for C20H19FN4O, 350.15; m/z found, 351.1 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.62-8.58 (m, 1H), 8.19-8.15 (m, 1H), 8.12 (d, J=1.5, 1H), 8.00-7.90 (m, 1H), 7.69-7.63 (m, 1H), 7.48-7.40 (m, 2H), 6.98-6.92 (m, 1H), 5.59-5.50 (m, 1H), 4.68 (s, 2H), 2.03-1.89 (m, 2H), 1.89-1.70 (m, 4H), 1.71-1.55 (m, 2H).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]([C:24]3[CH:29]=[CH:28][C:27]4[O:30][CH2:31][O:32][C:26]=4[CH:25]=3)[CH:16]2[C:33]([NH2:35])=O)=[CH:11][CH:10]=1>CN(C=O)C>[CH3:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]([C:24]3[CH:29]=[CH:28][C:27]4[O:30][CH2:31][O:32][C:26]=4[CH:25]=3)[CH:16]2[C:33]#[N:35])=[CH:11][CH:10]=1
Reactant: COc1ccc(C2c3ccccc3C(c3ccc4c(c3)OCO4)C2C(N)=O)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Product: COc1ccc(C2c3ccccc3C(c3ccc4c(c3)OCO4)C2C#N)cc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 93.7 %

Procedure:
To ice-cold DMF (1 ml) under an argon atmosphere was added oxalyl chloride (68 ml, 0.78 mmol). After stirring for 5 min at 0° C., a solution of (1RS,2SR,3SR)-1-(4-methoxyphenyl)-3-(3,4-methylenedioxyphenyl)indane2-carboxamide (150 mg, 0.39 mmol) in DMF (2 ml) was added, and stirring was continued for an additional 10 min at 0° C. The reaction mixture was partitioned between EtOAc and 3M HCl. The aqueous phase was extracted with EtOAc, and the combined organic extracts were washed successively with H2O, aqueous NaHCO3, H2O and saturated aqueous NaCl and dried. The solvent was removed in vacuo to afford the title compound as a white solid (135 mg, 94%) which was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][C:8](=O)[CH2:7][CH2:6]2.[NH:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)[CH2:7][CH2:6]2
Reactant: C1CCNC1
Reactant: COc1ccc2c(c1)CCC(=O)C2
Solvent: CO
Product: COc1ccc2c(c1)CCC(N1CCCC1)=C2

Procedure:
A solution of 6-methoxy-3,4-dihydro-1H-naphthalen-2-one (1) (5.64 g, 32 mmol) in methanol (60 mL) was treated with pyrrolidine (3.5 mL, 41.6 mmol) and the resultant mixture was stirred at ambient temperature for 1.5 h. The product precipitated from solution within minutes of the addition of pyrrolidine. The resultant suspension was cooled in an ice bath and the enamine product (2) was collected by filtration as a white solid (5.6 g, 76%). NMR (CDCl3): δ 1.86-1.94 (m, 4 H), 2.46 (t, 2H), 2.80 (t, 2 H), 3.19-3.25 (m, 4 H), 3.77 (s, 3 H), 5.10 (s, 1 H), 6.59-6.65 (m, 2 H) and 6.78 d, 1 H).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]([F:15])([F:14])[CH2:8][N:7]([CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[C:6]=2[N:22]=1.O.C1(C)C(S(O)(=O)=O)=CC=CC=1.[NH2:35][C:36]1[CH:54]=[CH:53][C:39]([C:40]([NH:42][CH:43]2[CH2:48][CH2:47][N:46]([S:49]([CH3:52])(=[O:51])=[O:50])[CH2:45][CH2:44]2)=[O:41])=[CH:38][CH:37]=1.[CH:55]([OH:58])(C)C>>[CH:16]1([N:7]2[CH2:8][C:9]([F:15])([F:14])[C:10](=[O:13])[N:11]([CH3:12])[C:5]3[CH:4]=[N:3][C:2]([NH:35][C:36]4[CH:54]=[CH:53][C:39]([C:40]([NH:42][CH:43]5[CH2:44][CH2:45][N:46]([S:49]([CH3:52])(=[O:51])=[O:50])[CH2:47][CH2:48]5)=[O:41])=[CH:38][C:37]=4[O:58][CH3:55])=[N:22][C:6]2=3)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: CS(=O)(=O)N1CCC(NC(=O)c2ccc(N)cc2)CC1
Reactant: CC(C)O
Reactant: CN1C(=O)C(F)(F)CN(C2CCCCC2)c2nc(Cl)ncc21
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: O
Product: COc1cc(C(=O)NC2CCN(S(C)(=O)=O)CC2)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C

Procedure:
A mixture of 0.101 g (0.31 mmole) 2-chloro-9-cyclohexyl-7,7-difluoro-5-methyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-246), 0.088 g (0.47 mmole) of toluenesulfonic acid monohydrate, 0.10 g (0.31 mmole) of 4-amino-N-(1-methanesulfonyl-piperidin-4-yl)-benzamide and 1 mL of isopropanol was heated in a sealed vessel at 170 degrees in a microwave reactor for 2 hours, cooled and concentrated under reduced pressure. The residue taken up in ethyl acetate and washed successively with 50 mL of saturated aqueous sodium bicarbonate, 50 mL of water, 50 mL of brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was recrystallized from acetonitrile to give 0.110 g of 4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(1-methanesulfonyl-piperidin-4-yl)-3-methoxy-benzamide (I-268).
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:23]=[CH:22][C:6]([C:7]([C:9]2[N:13]([CH3:14])[C:12]([CH2:15][C:16]([O:18]CC)=[O:17])=[CH:11][C:10]=2[CH3:21])=[O:8])=[CH:5][CH:4]=1.C(I)CC>>[CH2:15]([C:12]1[N:13]([CH3:14])[C:9]([C:7](=[O:8])[C:6]2[CH:22]=[CH:23][C:3]([C:2]([F:24])([F:25])[F:1])=[CH:4][CH:5]=2)=[C:10]([CH3:21])[CH:11]=1)[CH3:16].[CH2:12]([CH2:15][C:16]([O-:18])=[O:17])[CH2:11][CH3:10]
Reactant: CCOC(=O)Cc1cc(C)c(C(=O)c2ccc(C(F)(F)F)cc2)n1C
Solvent: CCCI
Product: CCCCC(=O)[O-]
Product: CCc1cc(C)c(C(=O)c2ccc(C(F)(F)F)cc2)n1C

Procedure:
The alkylation procedure of Example 77A is performed upon ethyl 5-(p-trifluoromethylbenzoyl)-1,4-dimethylpyrrole-2-acetate (from Example 89), using an equivalent quantity of n-propyl iodide instead of methyl iodide used in Example 77A to yield ethyl 5-(p-trifluoromethylbenzoyl)-1,4-dimethylpyrrole-2-(α-n-propyl)-acetate.