Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH:6]([CH3:7])[CH:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[NH:4][C:3]1=[O:14].CCN(C(C)C)C(C)C.[C:24](Cl)(=[O:27])[CH:25]=[CH2:26]>C(Cl)Cl.Cl[Cu]>[C:24]([N:4]1[CH:5]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:6]([CH3:7])[N:2]([CH3:1])[C:3]1=[O:14])(=[O:27])[CH:25]=[CH2:26]
Reactant: CC1C(c2ccccc2)NC(=O)N1C
Reactant: C=CC(=O)Cl
Agent: Cl[Cu]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CC(=O)N1C(=O)N(C)C(C)C1c1ccccc1
Temperature: 25 °C
Yield: 78 %

Procedure:
To a solution of (4 S, 5 R)1,5-dimethyl-4-phenyl-2-imidazolidinone (45.0 g, 237 mmole) and (i-Pr)2NEt (62 mL, 355 mmole) in CH2Cl2 (1200 mL) was added CuCl (50 mg, 0.51 mmole) then acryloyl chloride (29 mL, 355 mmole), and the mixture was heated to reflux. After 2 hr the mixture was cooled to RT, washed with H2O (3×400 mL), dried over MgSO4, and concentrated. The resulting solid was triturated with Et2O (300 mL) and collected by filtration to give the title compound (45.15 g, 78%): 1H NMR (300 MHz, CDCl3) δ 7.72 (dd, J=17.0, 10.5 Hz, 1 H), 7.20-7.38 (m, 3 H), 7.10-7.20 (m, 2 H), 6.40 (dd, J=17.0, 2.1 Hz, 1 H), 5.77 (dd, J=10.4, 2.0 Hz, 1 H), 5.36 (d, J=8.5 Hz, 1 H), 3.85-4.00 (m, 1 H), 2.85 (s, 3 H), 0.82 (d, J=6.6 Hz, 3 H); MS (ES) m/e 245 (M+H)+.
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][C:7]([B:10]2[O:14][C:13]([CH3:16])([CH3:15])[C:12]([CH3:18])([CH3:17])[O:11]2)=[CH:6][CH:5]=1)=[C:2]=[O:3].[N:19]1[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][CH:20]=1.C(N(CC)CC)C>C1COCC1>[N:19]1[CH:24]=[CH:23][C:22]([NH:25][C:2]([NH:1][C:4]2[CH:9]=[CH:8][C:7]([B:10]3[O:14][C:13]([CH3:16])([CH3:15])[C:12]([CH3:18])([CH3:17])[O:11]3)=[CH:6][CH:5]=2)=[O:3])=[CH:21][CH:20]=1
Reactant: Nc1ccncc1
Reactant: CC1(C)OB(c2ccc(N=C=O)cc2)OC1(C)C
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC1(C)OB(c2ccc(NC(=O)Nc3ccncc3)cc2)OC1(C)C

Procedure:
2-(4-isocyanatophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1 g, 4.1 mmol) was dissolved in dry THF and stirred with pyridin-4-amine (460 mg, 4.9 mmol) and triethlyamine (1.13 ml, 8.2 mmol) at 60° C. for 3 hours. The mixture was cooled and then purified by flash chromatography (0-100% EtOAc in Petroleum ether 40-60, followed by 0-10% MeOH in EtOAc) to afford the title compound. (875 mg, 63%) uPLC (method D), (M+H+) 340, Rt=0.89 mins
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]([N:8]1[C:14](=[O:15])[CH2:13][CH2:12][N:11]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=2)[CH2:10][CH2:9]1)[CH2:5][CH:6]=O.Cl.[CH3:27][C@@H:28]1[CH2:33][NH:32][CH2:31][C@@H:30]([OH:34])[CH2:29]1>>[OH:34][C@H:30]1[CH2:29][C@H:28]([CH3:27])[CH2:33][N:32]([CH2:6][CH2:5][C@H:4]([N:8]2[C:14](=[O:15])[CH2:13][CH2:12][N:11]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:23])[F:24])[CH:17]=3)[CH2:10][CH2:9]2)[CH2:3][O:2][CH3:1])[CH2:31]1
Reactant: COC[C@H](CC=O)N1CCN(c2cccc(C(F)(F)F)c2)CCC1=O
Reactant: C[C@@H]1CNC[C@@H](O)C1
Agent: Cl
Product: COC[C@H](CCN1C[C@@H](C)C[C@H](O)C1)N1CCN(c2cccc(C(F)(F)F)c2)CCC1=O
Yield: 63 %

Procedure:
In analogy to the procedure described in example 1K, (S)-4-methoxy-3-[7-oxo-4-(3-trifluoromethyl-phenyl)-[1,4]diazepan-1-yl]-butyraldehyde (example 23D) and (3S,5S)-5-methyl-piperidin-3-ol hydrochloride (intermediate 4) gave the title compound in 63% yield as light yellow gum. MS: 458.3 (MH+).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([C:19]2[O:20][CH:21]=[CH:22][CH:23]=2)[C:5]2[CH:10]=[CH:9][N:8]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[F:18])[C:6]=2[N:7]=1.[CH2:24]([NH2:35])[C:25]1[CH:34]=[CH:33][C:30]([O:31][CH3:32])=[C:27]([O:28][CH3:29])[CH:26]=1>CN1CCCC1=O>[CH3:29][O:28][C:27]1[CH:26]=[C:25]([CH:34]=[CH:33][C:30]=1[O:31][CH3:32])[CH2:24][NH:35][C:2]1[N:3]=[C:4]([C:19]2[O:20][CH:21]=[CH:22][CH:23]=2)[C:5]2[CH:10]=[CH:9][N:8]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[F:18])[C:6]=2[N:7]=1
Reactant: Fc1ccccc1Cn1ccc2c(-c3ccco3)nc(Cl)nc21
Reactant: COc1ccc(CN)cc1OC
Solvent: CN1CCCC1=O
Product: COc1ccc(CNc2nc(-c3ccco3)c3ccn(Cc4ccccc4F)c3n2)cc1OC
Temperature: 100 °C
Yield: 88.4 %

Procedure:
A solution of 2-chloro-7-(2-fluorobenzyl)-4-(2-furyl)-7H-pyrrolo[2,3-d]pyrimidine (254 mg, 0.78 mmol) in N-methylpyrrolidone (2 mL) was treated with veratrylamine (0.25 mL, 1.66 mmol), heated to 100° C. for 16 h and purified by chromatography (Heptane:EtOAc, 4:1) to give the title compound (316 mg, 88%) as a cream solid.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[O:7][N:6]=[C:5]([C:8]2[S:12][C:11]([C:13]([OH:15])=O)=[CH:10][CH:9]=2)[C:4]=1[CH3:16].Cl.[F:20][C:21]([F:29])([F:28])[CH:22]1[CH2:27][CH2:26][CH2:25][NH:24][CH2:23]1>>[CH3:16][C:4]1[C:5]([C:8]2[S:12][C:11]([C:13]([N:24]3[CH2:25][CH2:26][CH2:27][CH:22]([C:21]([F:29])([F:28])[F:20])[CH2:23]3)=[O:15])=[CH:10][CH:9]=2)=[N:6][O:7][C:3]=1[C:2]([F:1])([F:18])[F:17]
Reactant: Cc1c(-c2ccc(C(=O)O)s2)noc1C(F)(F)F
Reactant: FC(F)(F)C1CCCNC1
Agent: Cl
Product: Cc1c(-c2ccc(C(=O)N3CCCC(C(F)(F)F)C3)s2)noc1C(F)(F)F

Procedure:
Prepared from 5-(5-Trifluoromethyl-4-methyl-isoxazol-3-yl)-thiophene-2-carboxylic acid and (±)-3-trifluoromethylpiperidine hydrochloride by the method described in Example 41. Colorless solid (123 mg, 82%). 1H NMR (CDCl3) 1.53-1.76 (m, br, 2H), 1.84-1.95 (m, br, 1H), 2.10-2.22 (m, br, 1H), 2.31-2.43 (m, br, 4H), 2.92-3.16 (m, br, 2H), 4.28-4.45 (m, br, 1H), 4.54-4.72 (m, br, 1H), 7.34 (d, J=4.0, 1H), 7.47 (d, J=4.0, 1H). 13C NMR 7.7, 23.5, 24.2, 40.5 (q, J=27), 44.0 (br), 46.3 (br), 114.5 (q, J=2), 118.5 (q, J=271), 126.1 (q, J=283), 127.8, 129.1, 131.4, 139.3, 155.0 (q, J=41), 157.6, 162.8. 19F NMR −72.8, −63.2. LC/MS 6.99 min, [M+1]+ 413.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH:12]2[CH2:14][CH2:15][CH:9]1[C@@H:10]([OH:16])[CH2:11]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[N+]1([O-])CCOCC1>C(#N)C.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[CH2:1]([N:8]1[CH2:13][CH:12]2[CH2:14][CH2:15][CH:9]1[C:10](=[O:16])[CH2:11]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O[C@H]1CC2CCC1N(Cc1ccccc1)C2
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: CC#N
Product: O=C1CC2CCC1N(Cc1ccccc1)C2
Yield: 80.8 %

Procedure:
To a vigorously stirring suspension of (6S)—N-benzyl-2-azabicyclo[2.2.2]octan-6-ol (1.5 g, 6.9 mmol, Maybridge) and activated 4 Å MS (1.0 g) in acetonitrile (70 mL) at 23° C. was sequentially added 4-methylmorpholine-N-oxide (1.2 g, 10 mmol) and tetrapropylammonium perruthenate (240 mg, 0.69 mmol). After stirring the resulting black suspension for 30 min, the mixture was concentrated in vacuo, and the resulting residue was purified by flash chromatography (20-50% ethyl acetate in hexanes) to provide N-benzyl-2-azabicyclo[2.2.2]octan-6-one as an orange oil (1.2 g, 81%). MS (AP CI) 216 (M+H).
Reaction SMILES: C(N(CC)CC)C.[F:8][C:9]([F:18])([F:17])[C:10]1[CH:11]=[N:12][C:13](=[O:16])[NH:14][CH:15]=1.Cl[CH2:20][O:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=1>ClCCl>[Cl:29][C:26]1[CH:27]=[CH:28][C:23]([CH2:22][O:21][CH2:20][N:12]2[CH:11]=[C:10]([C:9]([F:17])([F:8])[F:18])[CH:15]=[N:14][C:13]2=[O:16])=[CH:24][CH:25]=1
Reactant: O=c1ncc(C(F)(F)F)c[nH]1
Reactant: ClCOCc1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=c1ncc(C(F)(F)F)cn1COCc1ccc(Cl)cc1
Temperature: 40 °C
Reaction time: 3 h
Yield: 91 %

Procedure:
Triethylamine (1 mmol) was added to a mixture of 5-trifluoromethyl pyrimidin-2-one (see Preparation 11 of European Patent Publication Ser. No. 0 056 319) (1 mmol) in dichloromethane (10 ml) and the solution stirred for 5 minutes before 4-chlorobenzyl chloromethyl ether (see Preparation 5a and 5b) (1 mmol) in dichloromethane (2 ml) was added. The mixture was stirred at room temperature overnight and at 40° C. for 3 hours before the solvent was distilled off and the residue triturated with water. The product was extracted into chloroform, dried (MgSO4) and evaporated. The residue was washed with ether and dried; yield 91%, m.p. 120° C. 1H NMR (CDCl3): δ4.64 (CH2Ph), 5.38 (NCH2), 7.24 (Ph), 8.11 (H-4, J 3 Hz), 8.74 (H-6, J 3 Hz). IR (KBr): 1680 cm-1 (CO).
Reaction SMILES: [H-].[Na+].[CH3:3][CH:4]([C@H:6]1[CH2:10][N:9]([C:11]2[CH:12]=[N:13][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:15][CH:16]=2)[C:8](=[O:21])[NH:7]1)[CH3:5].Br[CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25].C(=O)([O-])O.[Na+]>CN(C=O)C.O>[O:21]=[C:8]1[N:9]([C:11]2[CH:12]=[N:13][C:14]([C:17]([F:19])([F:18])[F:20])=[CH:15][CH:16]=2)[CH2:10][C@H:6]([CH:4]([CH3:3])[CH3:5])[N:7]1[CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25]
Reactant: CC(C)[C@H]1CN(c2ccc(C(F)(F)F)nc2)C(=O)N1
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)[C@H]1CN(c2ccc(C(F)(F)F)nc2)C(=O)N1CC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Sodium hydride (0.53 g) was added to a solution of (4S)-4-(propan-2-yl)-1-[6-(trifluoromethyl)pyridin-3-yl]imidazolidin-2-one (5.6 g) in DMF (20 mL), and the mixture was stirred at room temperature for 10 min. Thereafter, tert-butyl bromoacetate (2.0 mL) was added portionwise thereto, and the mixture was stirred at room temperature for 2 hr. Water and saturated aqueous sodium hydrogen carbonate solution were added thereto, and the mixture was extracted with chloroform. The organic layer was separated out by phase-separation cartridge (Biotage, Isolute Phase Separator) and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel cartridge, hexane/ethyl acetate) to afford tert-butyl {(5S)-2-oxo-5-(propan-2-yl)-3-[6-(trifluoromethyl)pyridin-3-yl]imidazolidin-1-yl}acetate (802 mg).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:12]=[CH:11][C:7]([CH2:8][CH2:9][OH:10])=[CH:6][CH:5]=1.C1([O:19][C:20](=O)[NH:21][C:22]2[CH:27]=[CH:26][C:25]([S:28]([CH:31]([CH3:33])[CH3:32])(=[O:30])=[O:29])=[C:24]([CH2:34][N:35]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH3:36])[CH:23]=2)C=CC=CC=1>C1COCC1.O>[Br:3][C:4]1[CH:12]=[CH:11][C:7]([CH2:8][CH2:9][O:10][C:20](=[O:19])[NH:21][C:22]2[CH:27]=[CH:26][C:25]([S:28]([CH:31]([CH3:32])[CH3:33])(=[O:29])=[O:30])=[C:24]([CH2:34][N:35]([C:37]([O:39][C:40]([CH3:41])([CH3:43])[CH3:42])=[O:38])[CH3:36])[CH:23]=2)=[CH:6][CH:5]=1
Reactant: CC(C)S(=O)(=O)c1ccc(NC(=O)Oc2ccccc2)cc1CN(C)C(=O)OC(C)(C)C
Reactant: OCCc1ccc(Br)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)S(=O)(=O)c1ccc(NC(=O)OCCc2ccc(Br)cc2)cc1CN(C)C(=O)OC(C)(C)C
Temperature: -40 °C
Reaction time: 3 h

Procedure:
Sodium hydride (60% in oil, 60 mg, 1.5 mmol) was added portionwise to a solution of 4-bromophenethyl alcohol (0.718 g, 3.57) in THF (6 mL) at 0° C. The reaction mixture was cooled to −40° C., and a solution of 16G (0.550 g, 1.19 mmol) in THF (5 mL) was added slowly dropwise. The reaction mixture was slowly warmed to 0° C., and then stirred for 3 h at 0° C. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried (MgSO4) and concentrated in vacuo. The residue was purified by silica gel chromatography (gradient from 0 to 50% ethyl acetate in hexanes) to give 16H (0.503 g, 74%) as a white solid.
Reaction SMILES: [CH2:1](Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:9][C:10]1[CH:23]=[CH:22][C:21]2[S:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][C:18]=3[S:24](=[O:29])(=[O:28])[N:25]([CH3:27])[CH3:26])[NH:13][C:12]=2[CH:11]=1>>[CH2:1]([O:9][C:10]1[CH:23]=[CH:22][C:21]2[S:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][C:18]=3[S:24](=[O:29])(=[O:28])[N:25]([CH3:26])[CH3:27])[NH:13][C:12]=2[CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)S(=O)(=O)c1cccc2c1Sc1ccc(O)cc1N2
Reactant: ClCc1ccccc1
Product: CN(C)S(=O)(=O)c1cccc2c1Sc1ccc(OCc3ccccc3)cc1N2
Yield: 27 %

Procedure:
2-Benzyloxy-6-dimethylsulphamoylphenothiazine (m.p. 192°-194°C.; 69.0 g.) is prepared by reacting benzyl chloride (106.0 g.) with 2-hydroxy-6-dimethylsulphamoylphenothiazine (200 g.).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8]3=[C:9]([CH2:11][CH2:12][N:7]3[C@H:6]3[CH2:13][CH2:14][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:16][C@@H:5]23)[CH:10]=1.[Cl:24][C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[C:29]([Cl:31])[CH:30]=1>>[Cl:24][C:25]1[CH:26]=[C:27]([C:2]2[CH:3]=[C:4]3[C:8]4=[C:9]([CH2:11][CH2:12][N:7]4[C@H:6]4[CH2:13][CH2:14][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:16][C@@H:5]34)[CH:10]=2)[CH:28]=[C:29]([Cl:31])[CH:30]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]2[C@@H](C1)c1cc(Br)cc3c1N2CC3
Reactant: OB(O)c1cc(Cl)cc(Cl)c1
Product: CC(C)(C)OC(=O)N1CC[C@H]2[C@@H](C1)c1cc(-c3cc(Cl)cc(Cl)c3)cc3c1N2CC3

Procedure:
The title compound was prepared by the method of Example 89 step C from tert-butyl(6aS,10aR)-2-bromo-4,5,7,8,10,10a-hexahydropyrido[4,3-b]pyrrolo[3,2,1-hi]indole-9(6aH)carboxylate (189 mg, 0.5 mmol) and 3,5-dichlorophenylboronic acid (191 mg, 1.0 mmol) to afford after chromatographic purification the title compound (85 mg, 38%). 1H NMR (CDCl3, 300 MHz) δ 7.35 (s, 2H), 7.21–7.23 (m, 1H), 7.13 (s, 1H), 7.10 (s, 1H), 3.82–4.22 (m, 2H), 3.65–3.75 (m, 1H), 2.84–3.52 (m, 7H), 1.80–1.90 (m, 2H), 1.49 (s, 9H) ppm. MS-ApCI: 445 [M+H+].
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[I:12][C:13]1[C:14]([O:23][CH3:24])=[N:15][C:16]([S:21][CH3:22])=[C:17]([CH:20]=1)[C:18]#[N:19].C(OCC)(=O)C>ClCCl>[I:12][C:13]1[C:14]([O:23][CH3:24])=[N:15][C:16]([S:21]([CH3:22])=[O:9])=[C:17]([CH:20]=1)[C:18]#[N:19]
Reactant: COc1nc(SC)c(C#N)cc1I
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COc1nc(S(C)=O)c(C#N)cc1I
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.8 %

Procedure:
1.42 g (1.1 eq) of 70% 3-chloroperbenzoic acid is added to a solution of 1.6 g (5.23 mmol) of 5-iodo-6-methoxy-2-(methylthio)nicotinonitrile in 20 ml of dichloromethane. The reaction medium is stirred at room temperature for 1 hour. Ethyl acetate is added and the organic phase is washed with saturated sodium bicarbonate solution, dried on magnesium sulfate, filtered and evaporated to yield 1.63 g (97%) of 5-iodo-6-methoxy-2-(methylsulfinyl)nicotinonitrile in the form of a white powder which may also contain 5-iodo-6-methoxy-2-(methylsulfonyl)nicotinonitrile in small proportions (<20%). If necessary, the mixture is used as-is in the following steps.
Reaction SMILES: [C:1]([C:9]1[C:10]([NH:15][C:16](=[O:19])[CH2:17][Cl:18])=[CH:11][NH:12][C:13]=1[CH3:14])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20]([O-])([O-])=O.[K+].[K+].COS(OC)(=O)=O>CC(=O)CC>[C:1]([C:9]1[C:10]([NH:15][C:16](=[O:19])[CH2:17][Cl:18])=[CH:11][N:12]([CH3:20])[C:13]=1[CH3:14])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1[nH]cc(NC(=O)CCl)c1C(=O)c1ccccc1
Agent: [K+]
Solvent: CCC(C)=O
Solvent: COS(=O)(=O)OC
Product: Cc1c(C(=O)c2ccccc2)c(NC(=O)CCl)cn1C
Temperature: 25 °C

Procedure:
N-(4-benzoyl-5-methyl(1H)-pyrrol-3-yl)2-chloroacetamide (0.019 mole) was dissolved in butan-2-one (60 ml) and K2CO3 (4.5 g) and dimethylsulphate (0.037 mole) were added to the obtained solution. The reaction mixture was maintained at the reflux temperature for 5 hours and at room temperature overnight. An inert atmosphere was maintained throughout the process. The inorganic salts were filtered and the clear solution was evaporated under vacuum to yield a residue which upon crystallization from methanol gave the compound of the title.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([Cl:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:13][N:14]1[CH2:19][CH2:18][N:17](C)[CH2:16][CH2:15]1.C([O-])(O)=O.[Na+].O>O1CCOCC1>[Cl:12][C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]([N:17]2[CH2:18][CH2:19][N:14]([CH3:13])[CH2:15][CH2:16]2)[N:11]=1
Reactant: CN1CCN(C)CC1
Reactant: Clc1nc(Cl)c2ccccc2n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CN1CCN(c2nc(Cl)c3ccccc3n2)CC1
Temperature: 150 °C
Yield: 51.3 %

Procedure:
2,4-Dichloroquinazoline (2.00 g, 10.1 mmol, prepared as described in Prasad, M., et al. Org. Process Res. Dev. 2004, 8, 330-340) was slurried in 1,4-dioxane (20.0 mL). 1,4-Dimethylpiperazine (1.44 mL, 10.6 mmol) was added. The mixture was heated in a CEM microwave at about 150° C. for about 5 min. The material was poured into saturated aqueous NaHCO3/water (1:1, 150 mL). The mixture was extracted with EtOAc (5×100 mL). 20 g of silica gel was added to the combined organics and the volatiles were removed under reduced pressure. The resulting solid was purified by silica gel chromatography eluting with a gradient of 2-10% MeOH/DCM to afford 4-chloro-2-(4-methylpiperazin-1-yl)quinazoline (1.36 g, 52%): LC/MS (Table 1, Method n) Rt=0.51 min; MS m/z 263 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[C:6]([NH2:14])=[N:7][N:8]2[CH:13]=[CH:12][CH:11]=[N:10][C:9]=12)([CH3:4])([CH3:3])[CH3:2].[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[C:17]=1[CH2:23][C:24](O)=[O:25]>>[C:1]([C:5]1[C:6]([NH:14][C:24](=[O:25])[CH2:23][C:17]2[C:16]([Cl:15])=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:22])=[N:7][N:8]2[CH:13]=[CH:12][CH:11]=[N:10][C:9]=12)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1c(N)nn2cccnc12
Reactant: O=C(O)Cc1c(Cl)cccc1Cl
Product: CC(C)(C)c1c(NC(=O)Cc2c(Cl)cccc2Cl)nn2cccnc12

Procedure:
The product from Example 105B and 2-(2,6-dichlorophenyl)acetic acid were processed using the method analogous to that described in Example 137 to afford the title compound. 1H NMR (400 MHz, DMSO-d6/Deuterium Oxide) δ ppm 8.89 (d, J=6.4 Hz, 1H), 8.49 (d, J=2.0 Hz, 1H), 7.46-7.52 (m, 2H), 7.35 (dd, J=7.9 Hz, 1H), 7.01 (dd, J=6.6, 3.9 Hz, 1H), 4.05-4.09 (bs, 2H), 1.48 (s, 9H); MS (ESI) m/z 377, 379 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:26]=[CH:25][C:6]([C:7]([NH:9][C:10]2[C:11]([NH:16][C:17]([CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=[O:18])=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:8])=[CH:5][CH:4]=1.[OH:27][C:28]1[CH:35]=[CH:34][C:31]([CH:32]=O)=[CH:30][CH:29]=1.C([BH3-])#N.[Na+].Cl>C(O)(=O)C.CO>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:9][C:10]2[C:11]([NH:16][C:17]([CH:19]3[CH2:20][CH2:21][N:22]([CH2:32][C:31]4[CH:34]=[CH:35][C:28]([OH:27])=[CH:29][CH:30]=4)[CH2:23][CH2:24]3)=[O:18])=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:8])=[CH:25][CH:26]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: COc1ccc(C(=O)Nc2ccccc2NC(=O)C2CCNCC2)cc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COc1ccc(C(=O)Nc2ccccc2NC(=O)C2CCN(Cc3ccc(O)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of N1-(4-methoxybenzoyl)-N2-(piperidin-4-ylcarbonyl)-1,2-benzenediamine (15 mg, 0.045 mmol), in 10-20% acetic acid in anhydrous methanol (0.20 mL)was added p-hydroxybenzaldehyde (16 mg, 0.14 mmol) and a freshly prepared solution of sodium cyanoborohydride (4.0 mg, 0.060 †mmol) in anhydrous methanol (0.24 mL). The mixture was shaken at room temperature for 14-18 h and then loaded onto an ion exchange resin (SCX, Varian). Elution with methanol (4 column volumes) followed by 2 N ammonia in methanol (2 column volumes) and concentration of the appropriate fractions provided the crude product. After drying the sample under vacuum for 12-20 h, the residue was dissolved in methanol and treated with hydrochloric acid (1-2 eq). The mixture was then concentrated in vacuo to give the title compound as the hydrochloride salt.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5](/[CH:9]=[C:10](\[C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])/[C:11]([O:13][CH3:14])=[O:12])=[CH:4][C:3]=1[CH3:25].ClCCl.[H][H]>CO>[NH2:1][C:2]1[C:3]([CH3:25])=[CH:4][C:5]([CH2:9][C@@H:10]([C:15]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[O:16])[C:11]([O:13][CH3:14])=[O:12])=[CH:6][C:7]=1[CH3:8]
Reactant: [H][H]
Reactant: COC(=O)/C(=C/c1cc(C)c(N)c(C)c1)C(=O)OCc1ccccc1
Solvent: ClCCl
Solvent: CO
Product: COC(=O)[C@@H](Cc1cc(C)c(N)c(C)c1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A flame-dried 2 L Parr hydrogenation bottle was charged with (Z)-methyl 3-(4-amino-3,5-dimethylphenyl)-2-(benzyloxycarbonyl)acrylate (84.5 g, 239 mmoles), dichloromethane (300 mL), and methanol (300 mL). The bottle was swirled so that a light brown suspension was formed. The mixture was degassed using a flow of nitrogen for 30 min. To this was quickly added (−)-1,2-bis((2R,5R)-2,5-diethylphospholano)-benzene(cyclooctadiene) rhodium (I) tetrafluoroborate ([(2R,5R)-Et-DuPhosRh]BF4) (2.11 g, 3.20 mmoles). The bottle was immediately attached to a Parr Hydrogenator. After 5 cycles of hydrogen (60 psi) and vacuum, the bottle was pressurized to 65 psi and the suspension was agitated at room temperature for 16 h. The reaction had become homogeneous. The reaction mixture was concentrated, and the resulting residue purified by flash chromatography (silica gel, 1:9 ethyl acetate/dichloromethane) to give 82.9 g (98%). 1H-NMR (DMSO-d6) δ 2.04 (s, 6H), 2.65 (dd, J=13.4, 9.8 Hz, 1H), 2.82 (dd, J=13.7, 5.2Hz, 1H), 3.62 (s, 3H), 4.15-4.10 (m, 1H), 4.41 (s, 2H), 5.00 (s, 2H), 6.68 (s, 2H), 7.37-7.28 (m, 5H), 7.70 (d, J=7.9 Hz, 1H); 13C-NMR (DMSO-d6) δ 17.7, 35.9, 51.7, 56.1, 65.3, 120.4, 124.0, 127.5, 127.7, 128.2, 128.3, 136.9, 142.6, 155.9, 172.5.
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]1[CH2:8][CH2:7][NH:6][C:5]1=[O:9].[F:10][C:11]1[CH:25]=[CH:24][C:14]2[C:15]([CH:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)=[N:16][O:17][C:13]=2[CH:12]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(C(C)=O)C(C)C>[F:10][C:11]1[CH:25]=[CH:24][C:14]2[C:15]([CH:18]3[CH2:19][CH2:20][N:21]([CH2:2][CH2:3][N:4]4[CH2:8][CH2:7][NH:6][C:5]4=[O:9])[CH2:22][CH2:23]3)=[N:16][O:17][C:13]=2[CH:12]=1
Reactant: O=C1NCCN1CCCl
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(=O)CC(C)C
Product: O=C1NCCN1CCN1CCC(c2noc3cc(F)ccc23)CC1
Yield: 61.9 %

Procedure:
21.4 g (0.144 mol) of 1-(2-chloroethyl)imidazolidin-2-one, 23.6 g (0.107 mol) of 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine, 92.9 g (0.67 mol) of potassium carbonate, 2.6 g of potassium iodide and 524 ml of methyl isobutyl ketone are placed in a three-necked flask. Refluxing is carried out for one night, and then the reaction mixture is concentrated and taken up in a mixture of water/ethyl acetate. Decanting is carried out, and the organic phase is washed several times with water and then extracted with a normal solution of hydrochloric acid. The acidic phase is then rendered basic with sodium hydroxide solution and extracted with methylene chloride. Drying is carried out over MgSO4. After evaporation, the residue is recrystallised from 80 ml of acetonitrile to yield 22 g of a solid that corresponds to the expected product. M.p.=137°-141° C. (Yield=46%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:17]2[CH2:21][C@H:20]([CH2:22][NH:23][C:24](=O)[CH3:25])[O:19][C:18]2=[O:27])[CH:5]=[CH:6][C:7]=1[CH:8]1[CH2:13][CH2:12][S:11](=[O:15])(=[O:14])[N:10]([CH3:16])[CH2:9]1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:37])=CC=1>O1CCOCC1>[F:1][C:2]1[CH:3]=[C:4]([N:17]2[CH2:21][C@H:20]([CH2:22][NH:23][C:24](=[S:37])[CH3:25])[O:19][C:18]2=[O:27])[CH:5]=[CH:6][C:7]=1[CH:8]1[CH2:13][CH2:12][S:11](=[O:15])(=[O:14])[N:10]([CH3:16])[CH2:9]1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(C3CCS(=O)(=O)N(C)C3)c(F)c2)C(=O)O1
Solvent: C1COCCO1
Product: CC(=S)NC[C@H]1CN(c2ccc(C3CCS(=O)(=O)N(C)C3)c(F)c2)C(=O)O1
Temperature: 100 °C
Yield: 85.7 %

Procedure:
N-[[(5S)-3-[3-fluoro-4-(tetrahydro-2-methyl-1,1-dioxido-2H-1,2-thiazin4-yl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide (100 mg, 0.25 mmol) and Lawesson's Reagent (122 mg, 0.30 mmol) were dissolved in dioxane (10 mL) under nitrogen. The reaction is heated to 100° C. for 20 minutes then cooled to ambient and evaporated. The residue is partitioned between ethyl acetate (150 mL) and water (50 mL). The organic phase is washed 3 times with water (50 mL) and brine (50 mL), then dried over MgSO4, filtered and evaporated to a nearly colorless glass. The product is purified by radial chromatography over silica gel, eluting with 0-10% methanol-methylene chloride to give a white solid foam (89 mg, 85%). MP=95-98° C., decomposes.