Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([CH2:9]O)=[CH:7][CH:6]=1.S(Br)([Br:15])=O>O1CCOCC1.CCOCC>[Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([CH2:9][Br:15])=[CH:7][CH:6]=1
Reactant: O=S(Br)Br
Reactant: OCc1ccc(OCCCl)cc1
Solvent: CCOCC
Solvent: C1COCCO1
Product: ClCCOc1ccc(CBr)cc1
Reaction time: 0.08 h
Yield: 58 %

Procedure:
To 4-(2-Chloroethoxy)benzylalcohol CAS No. [111728-87-1] (6.4 g, 34.31 mmol) in dioxane (100 mL) at 0° C. was added slowly thionylbromide (7.13 g, 34.31 mmol). The reaction was run at 0° C. after 5 min. The reaction mixture was diluted with ether (200 mL) and washed with H2O (1×30 mL) then NaHCO3 (2×25 mL), and brine (30 mL). The organic extract was dried over MgSO4 and concentrated. The crude product was purified by silica gel chromatography (15% EtOAc/Hex) to yield 5.0 g (58%) of the desired product. Mp=64-66° C.; 1H NMR (DMSO) 7.37 (d, 2 H, J=8.8 Hz), 6.93 (d, 2 H, J=8.8 Hz), 4.68 (s, 2 H), 4.24 (t, 2 H, J=5.05 Hz), 3.93 (t, 2 H, J=5.27 Hz); MS eI m/z 248 (M+).
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH:7]([CH:17]([OH:19])[CH3:18])[CH2:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:5]=[CH:4][C:3]=1[C:20]([NH2:22])=[O:21].[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH2:33][C:34](Cl)=O)[CH:28]=[CH:29][C:30]=1[O:31][CH3:32]>>[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH:28]=[CH:29][C:30]=1[O:31][CH3:32])[CH2:33][C:34]1[NH:22][C:20](=[O:21])[C:3]2[CH:4]=[N:5][N:6]([CH:7]([CH:17]([OH:19])[CH3:18])[CH2:8][CH2:9][CH2:10][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:2]=2[N:1]=1
Reactant: CC(O)C(CCCc1ccccc1)n1ncc(C(N)=O)c1N
Reactant: COc1ccc(CC(=O)Cl)cc1OC
Product: COc1ccc(Cc2nc3c(cnn3C(CCCc3ccccc3)C(C)O)c(=O)[nH]2)cc1OC

Procedure:
Starting from 400 mg (1.32 mmol) of 5-amino-1-[1-(1-hydroxy-ethyl)-4-phenyl-butyl]-1H-pyrazol-4-carboxamide and 711 mg (3.32 mmol) of 3,4-dimethoxyphenylacetylchloride, the title compound is obtained analogously to the protocol of Example 13.
Reaction SMILES: [CH2:1]([CH:4]1[CH2:9][CH2:8][CH:7]([CH2:10][OH:11])[CH2:6][CH2:5]1)[C:2]#[CH:3].N1C=CC=CC=1.[C:18](OC(=O)C)(=[O:20])[CH3:19]>CN(C=O)C>[C:18]([O:11][CH2:10][CH:7]1[CH2:8][CH2:9][CH:4]([CH2:1][C:2]#[CH:3])[CH2:5][CH2:6]1)(=[O:20])[CH3:19]
Reactant: C#CCC1CCC(CO)CC1
Reactant: CC(=O)OC(C)=O
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: C#CCC1CCC(COC(C)=O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.4 %

Procedure:
To a solution of 960 mg (6.31 mmol) of 86 in 6 mL DMF was added 0.62 mL (7.57 mmol) pyridine and 0.78 mL (8.27 mmol) acetic anhydride. The reaction was allowed to stir overnight at room temperature. After 16 hours, starting material still remained. The reaction mixture was heated at 75° C. for 3 hours. The solvent was removed under reduced pressure to yield a yellow oil which was purified by flash chromatography, on silica gel, eluting with 1:3 ether/petroleum ether to yield 1.12 g (91%) of 87 as an oil. 1H NMR (CDCl3) δ3.87 (d, J=6.2 Hz, 2H), 2.06 (d, J=4.3 Hz, 2H), 2.03 (s, 3H), 1.98-1.93 (m, 1H), 1.92-1.83 (m, 2H), 1.83-1.74 (m, 2H), 1.63-1.36 (m, 2H), 1.12-0.90 (m, 4H); 13C NMR (CDCl3) δ 171.7, 83.7, 69.9, 69.6, 37.4, 37.3, 32.1, 29.7, 26.5, 21.4; APCI m/z (rel intensity) 195 (M+, 30), 153 (M+, 70), 135 (M+, 100).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.[CH3:11][C:12]1[C:13]([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[N:14][CH:15]=[C:16]([CH:19]=1)[C:17]#[N:18]>>[Br:1][C:2]1[N:3]=[CH:4][C:5]([C:6]([N:23]2[CH2:24][CH2:25][N:20]([C:13]3[C:12]([CH3:11])=[CH:19][C:16]([C:17]#[N:18])=[CH:15][N:14]=3)[CH2:21][CH2:22]2)=[O:8])=[CH:9][CH:10]=1
Reactant: O=C(O)c1ccc(Br)nc1
Reactant: Cc1cc(C#N)cnc1N1CCNCC1
Product: Cc1cc(C#N)cnc1N1CCN(C(=O)c2ccc(Br)nc2)CC1
Yield: 74.2 %

Procedure:
By reaction and treatment in the same manner as in Preparation Example 60 and using 6-bromonicotinic acid (500 mg) and 5-methyl-6-piperazin-1-ylnicotinonitrile (501 mg), the title compound (709 mg) was obtained.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[F:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1.C(N(CC)CC)C.FOB(C1C=CC=CC=1)O.Cl>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C.CO.CCOC(C)=O.C(Cl)(Cl)Cl>[F:16][C:17]1[CH:22]=[CH:21][C:20]([O:1][C:2]2[CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:5]=[C:4]([CH:3]=2)[C:12]([O:14][CH3:15])=[O:13])=[CH:19][CH:18]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: COC(=O)c1cc(O)cc(C(=O)OC)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: COC(=O)c1cc(Oc2ccc(F)cc2)cc(C(=O)OC)c1
Temperature: 25 °C
Reaction time: 38 h
Yield: 84.7 %

Procedure:
A mixture of dimethyl 5-hydroxyisophthalate (3.1 g, 14.75 mmol), 4-fluorophenylboronic acid (4.13 g, 29.5 mmol), copper(II) acetate (2.68 g, 14.75 mmol) and triethylamine (4.48 g, 44.2 mmol) in CH2Cl2 (65 mL) was stirred at rt in the open air for 38 h. An additional 1 g of fluorophenylboronic acid was added and the reaction mixture was continued to stir at rt in the open air. After 24 h, an additional 1 g of fluorophenylboronic acid and 300 mg of copper acetate were added to the reaction mixture and it was continued to stir for 6 h in the open air. The mixture was mixed with CHCl3 and aq HCl, the organic layer was separated, washed with aq HCl, aq NaHCO3, dried over MgSO4, concentrated, and the residue was purified by flash column chromatography on SiO2 eluting with Hexane:EtOAc:MeOH/800:200:40 to obtain the desired product (3.8 g, 12.49 mmol, 85% yield) as a white solid. 1H NMR (CDCl3): δ 8.36 (s, 1H), 7.75 (s, 2H), 7.06˜6.96 (m, 4H), 3.89 (s, 6H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]2=[N:14][CH:15]=[CH:16][C:17](B(O)O)=[C:12]2[CH:11]=[N:10]1.[F:21][C:22]1([F:33])[CH2:25][N:24]([C:26]2[C:31](I)=[CH:30][N:29]=[CH:28][N:27]=2)[CH2:23]1.C(O)C.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[F:33][C:22]1([F:21])[CH2:23][N:24]([C:26]2[C:31]([C:17]3[CH:16]=[CH:15][N:14]=[C:13]4[N:9]([C:3]5[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=5[F:1])[N:10]=[CH:11][C:12]=34)=[CH:30][N:29]=[CH:28][N:27]=2)[CH2:25]1
Reactant: OB(O)c1ccnc2c1cnn2-c1ccc(F)cc1F
Reactant: FC1(F)CN(c2ncncc2I)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Solvent: CCO
Product: Fc1ccc(-n2ncc3c(-c4cncnc4N4CC(F)(F)C4)ccnc32)c(F)c1
Temperature: 90 °C
Reaction time: 0.42 h

Procedure:
To a solution of Intermediate 63A (35.7 mg, 0.1 mmol) and Intermediate 102A (44.6 mg, 0.150 mmol) in a mixture of DME (1 mL), ethanol (0.5 mL) and water (0.5 mL) was added Na2CO3 (0.042 g, 0.400 mmol). This suspension was degassed with a stream of N2 for 10 minutes and then tetrakis(triphenylphosphine)palladium(0) (5.78 mg, 5.00 mmol) was added followed by degassing for 10 minutes. The tube was then sealed, heated at 90° C. for 14 hours, and cooled to room temperature. The contents of the tube were diluted with MeOH, filtered, rinsed with MeOH, and concentrated to a brown sludge. The crude material was purified via preparative LC/MS with the following conditions: Column: Waters XBridge C18, 19×250 mm, 5-μm particles; Guard Column: Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 15-100% B over 25 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of Example 103 was 6.0 mg, and its purity was approximately 100%. LC/MS (condition C): ret time=1.52 min, MS (ES): m/z=401.01 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]2[S:13][CH:12]=[C:11]([C:14]([O:16]C)=[O:15])[C:10]=2[O:18][CH2:19][CH2:20][O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[CH:5]=[CH:6][CH:7]=1>[OH-].[Li+].CO.O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]2[S:13][CH:12]=[C:11]([C:14]([OH:16])=[O:15])[C:10]=2[O:18][CH2:19][CH2:20][O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1csc(Cc2cccc(Cl)c2)c1OCCO[Si](C)(C)C(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCCOc1c(C(=O)O)csc1Cc1cccc(Cl)c1
Reaction time: 18 h
Yield: 42.5 %

Procedure:
Methyl 5-[(3-chlorophenyl)methyl]-4-{2-[(1,1-dimethylethyl)dimethylsilyl]oxyethoxy}thiophene-3-carboxylate (10.2 g) was dissolved in a mixture of 1M lithium hydroxide (50 ml), methanol (50 ml) and tetrahydrofuran (150 ml) and stirred for 18 hr. The reaction mixture was concentrated and the residue was partitioned between dichloromethane and 2M hydrochloric acid. The organic layer was collected, dried and filtered. t-Butyl-dimethylsilyl chloride (7 g) and imidazole (3.1 g) were added to the solution and the mixture was stirred for 72 hours. The reaction mixture was concentrated and the residue was dissolved in methanol. Potassium carbonate (5 g) was added to the solution and the suspension was vigorously stirred for 3 minutes, then filtered and concentrated. The residue was dissolved in ethyl acetate, washed with 2M hydrochloric acid, dried, filtered and concentrated. The residue was purified by chromatography, eluting with 10:1:1 isohexane:ethyl acetate:acetic acid, to give the sub-title compound (4.2 g).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10](COCC[Si](C)(C)C)[C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][N:20]([C:23]1[N:28]=[C:27]([C:29]([O:31]C(C)(C)C)=[O:30])[C:26]([CH2:36][CH2:37][CH2:38][O:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)=[CH:25][CH:24]=1)[CH2:19][CH2:18]2)=[O:12].O.Cl>CCO>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][N:20]([C:23]1[N:28]=[C:27]([C:29]([OH:31])=[O:30])[C:26]([CH2:36][CH2:37][CH2:38][O:39][C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=3)=[CH:25][CH:24]=1)[CH2:19][CH2:18]2)=[O:12]
Reactant: CC(C)(C)OC(=O)c1nc(N2CCc3cccc(C(=O)N(COCC[Si](C)(C)C)c4nc5ccccc5s4)c3C2)ccc1CCCOc1ccccc1
Agent: Cl
Solvent: CCO
Solvent: O
Product: O=C(Nc1nc2ccccc2s1)c1cccc2c1CN(c1ccc(CCCOc3ccccc3)c(C(=O)O)n1)CC2
Temperature: 50 °C
Reaction time: 12 h

Procedure:
Compound 121E (55 mg, 0.073 mmol) was dissolved in 1 mL of EtOH. Water (1 mL) was added followed by 1 mL of concentrated HCl. The reaction was stirred at 50° C. for 12 hours. The solids that precipitated were collected by filtration and rinsed with water. The solid was purified by preparative HPLC to give a white solid: 1H NMR (300 MHz, DMSO-d6) δ2.09 (t, 2H), 3.06 (t, 2H), 3.21 (t, 2H), 3.91 (t, 2H), 3.97 (t, 2H), 5.21 (s, 2H), 6.87-6.94 (m, 4H), 7.25-7.42 (m, 5H), 7.46-7.50 (m, 2H), 7.56 (m, 1H), 8.01 (m, 1H); LCMS m/z 565.7 (M+1).
Reaction SMILES: [CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[CH:15]=[CH:14][N:13]=[C:12]([NH:16][CH2:17][C:18]4[CH:32]=[C:31]([F:33])[C:21]5[N:22](C6CCCCO6)[CH:23]=[N:24][C:20]=5[CH:19]=4)[N:11]=3)[CH:5]=2)[CH2:3][CH2:2]1.CC1C=CC(S(O)(=O)=O)=CC=1.O>CO.O>[CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[CH:15]=[CH:14][N:13]=[C:12]([NH:16][CH2:17][C:18]4[CH:32]=[C:31]([F:33])[C:21]5[NH:22][CH:23]=[N:24][C:20]=5[CH:19]=4)[N:11]=3)[CH:5]=2)[CH2:2][CH2:3]1
Reactant: Fc1cc(CNc2nccc(Nc3cc(C4CC4)[nH]n3)n2)cc2ncn(C3CCCCO3)c12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: Fc1cc(CNc2nccc(Nc3cc(C4CC4)[nH]n3)n2)cc2nc[nH]c12

Procedure:
A mixture of 272 (140 mg, 0.31 mmol) and p-TsOH.H2O (59 mg, 0.31 mmol) in MeOH (5 mL) and H2O (1 mL) was heated at reflux for 2 h. The mixture was cooled and concentrated in vacuo. The crude product was purified by preparative HPLC to afford 50 mg (44%) of I-96 as white solid.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6](OC)=[O:7])=[CH:4][C:3]=1[CH2:12][C:13]([F:16])([F:15])[F:14].[H-].[H-].[H-].[H-].[Li+].[Al+3]>O1CCCC1>[Br:1][C:2]1[CH:11]=[CH:10][C:5]([CH2:6][OH:7])=[CH:4][C:3]=1[CH2:12][C:13]([F:14])([F:15])[F:16]
Reactant: COC(=O)c1ccc(Br)c(CC(F)(F)F)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1ccc(Br)c(CC(F)(F)F)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Into a 100-mL round-bottom flask, was placed a solution of methyl 4-bromo-3-(2,2,2-trifluoroethyl)benzoate (900 mg, 3.03 mmol, 1.00 equiv) in tetrahydrofuran (30 mL). This was followed by the addition of LAH (231 mg, 6.09 mmol, 2.00 equiv), in portions at 0° C. The resulting solution was stirred for 2 h at 0° C. The reaction was then quenched by the addition of 5 g of sodium sulfate. 10H2O. The solids were filtered out. The resulting mixture was concentrated under vacuum. This resulted in 800 mg (98%) of [4-bromo-3-(2,2,2-trifluoroethyl)phenyl]methanol as yellow oil.
Reaction SMILES: [F:1][C:2]([F:56])([F:55])[C:3]1[CH:4]=[C:5]([CH:48]=[C:49]([C:51]([F:54])([F:53])[F:52])[CH:50]=1)[CH2:6][N:7]([CH2:20][C:21]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:22]=1[N:31]([CH2:46][CH3:47])[C:32](=[O:45])[NH:33][C@@H:34]([CH2:39][O:40]C(C)(C)C)[C:35]([O:37][CH3:38])=[O:36])[C:8]1[N:13]=[CH:12][C:11]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[CH:10][N:9]=1.C(=O)(O)[O-].[Na+].C(OCC)(=O)C>Cl.O1CCOCC1>[F:54][C:51]([F:52])([F:53])[C:49]1[CH:48]=[C:5]([CH:4]=[C:3]([C:2]([F:55])([F:1])[F:56])[CH:50]=1)[CH2:6][N:7]([CH2:20][C:21]1[CH:26]=[C:25]([C:27]([F:28])([F:29])[F:30])[CH:24]=[CH:23][C:22]=1[N:31]([CH2:46][CH3:47])[C:32](=[O:45])[NH:33][C@@H:34]([CH2:39][OH:40])[C:35]([O:37][CH3:38])=[O:36])[C:8]1[N:13]=[CH:12][C:11]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[CH:10][N:9]=1
Reactant: CCN(C(=O)N[C@@H](COC(C)(C)C)C(=O)OC)c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(N2CCOCC2)cn1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCN(C(=O)N[C@@H](CO)C(=O)OC)c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(N2CCOCC2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.3 %

Procedure:
Methyl (S)-2-[3-(2-{[(3,5-bis-trifluoromethyl-benzyl)-(5-morpholin-4-yl-pyrimidin-2-yl)-amino]-methyl}-4-trifluoromethyl-phenyl)-3-ethyl-ureido]-3-tert-butoxy-propionate (455 mg) is dissolved in a 4N-hydrochloric acid in dioxane (5 ml), and the mixture is stirred at room temperature for 8 hours. To the reaction solution are added a saturated aqueous sodium bicarbonate solution and ethyl acetate, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=1:1→0:1) to give methyl (S)-2-[3-(2-{[(3,5-bis-trifluoromethyl-benzyl)-(5-morpholin-4-yl-pyrimidin-2-yl)-amino]-methyl}-4-trifluoromethyl-phenyl)-3-ethyl-ureido]-3-hydroxy-propionate (285 mg). MS (m/z): 753 [M+H]+
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]1([F:23])[CH:14]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[CH2:13][CH2:12][NH:11][CH2:10]1.Br[CH:25]1[CH2:29][CH2:28][N:27]([C:30]2[CH:35]=[CH:34][C:33]([CH3:36])=[C:32]([F:37])[CH:31]=2)[C:26]1=[O:38].CCN(C(C)C)C(C)C>CN(C=O)C>[F:23][C:9]1([F:8])[CH:14]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[CH2:13][CH2:12][N:11]([CH:25]2[CH2:29][CH2:28][N:27]([C:30]3[CH:35]=[CH:34][C:33]([CH3:36])=[C:32]([F:37])[CH:31]=3)[C:26]2=[O:38])[CH2:10]1
Reactant: Cc1ccc(N2CCC(Br)C2=O)cc1F
Reactant: COc1ccc(C2CCNCC2(F)F)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: COc1ccc(C2CCN(C3CCN(c4ccc(C)c(F)c4)C3=O)CC2(F)F)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 74.1 %

Procedure:
To a solution of 3,3-difluoro-4-(4-methoxyphenyl)piperidine trifluoroacetate (67 mg, 0.2 mmol) in DMF (0.8 mL) was added 3-bromo-1-(3-fluoro-4-methylphenyl)pyrrolidin-2-one (from Example 49, step C, 96 mg, 0.35 mmol) and DIPEA (0.1 mL, 0.6 mmol). The mixture was stirred at rt for 18 h, then raised to 80° C. for 2 h. The mixture was cooled, the solvent was removed under vacuum and the residue was purified via silica gel chromatography, eluting with a gradient from 0 to 100% ethyl acetate in hexanes to yield 62 mg of 3-(3,3-difluoro-4-(4-methoxyphenyl)piperidin-1-yl)-1-(3-fluoro-4-methylphenyl)pyrrolidin-2-one (along with 20 mg of the sideproduct, 1-(3-fluoro-4-methylphenyl)-3-hydroxypyrrolidin-2-one). LCMS (method U) RT 3.755 min, m/z 419.3 (M+H+); 1H NMR (500 MHz, chloroform-d) δ 7.51 (d, J=11.9, 2H), m 7.26-7.26 (3H), m 7.20 (1H), 6.90 (d, J=8.7) 3.82 (s, 3H), 3.65-3.78 (m, 3H), 3.2-3.45 (m, 3H), 2.87-3.00 (m, 1H), 2.72-2.85 (m, 0.4H), 2.65 (t, 0.5H), 2.37-2.48 (m, 1H), 2.27 (s, 3H), 2.1-2.25 (m, 2H), 1.87-1.95 (m, 1H). Chiral HPLC (method A-2) revealed that the chirality present in the starting material for step A had been lost.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[C:5]([OH:9])=[C:4]([Cl:10])[CH:3]=1.C(=O)=O.CC(C)=O.C[Si](Cl)(C)C.C([O:25][B:26](OCC)[O:27]CC)C>C1COCC1>[Cl:10][C:4]1[CH:3]=[C:2]([B:26]([OH:27])[OH:25])[CH:7]=[C:6]([F:8])[C:5]=1[OH:9]
Reactant: Oc1c(F)cc(Br)cc1Cl
Reactant: CCOB(OCC)OCC
Agent: C[Si](C)(C)Cl
Agent: O=C=O
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: OB(O)c1cc(F)c(O)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
4-Bromo-2-chloro-6-fluoro-phenol (0.500 g, 2.21 mmol) is dissolved in dry THF, the reaction mixture is cooled to −78° C. (dry-ice/acetone bath) and 2.5M n-butylithium (1.06 ml, 2.66 mmol) is slowly added drop wise with stirring for 5 minutes. TMSCl (0.298 ml, 2.33 mmol) is added drop wise maintaining the temperature below −70° C. and the reaction mixture is stirred for 30 minutes. Boric acid triethyl ester is then added (0.385 ml, 2.26 mmol) followed by the second addition of n-butylitlium (1.06 ml, 2.66 mmol) maintaining the temperature below −65° C. The reaction mixture is stirred at −70° C. for 30 minutes then quenched with 5M HCl (5 ml) and allowed to warm to room temperature with stirring for 30 minutes. The reaction mixture is diluted with water and EtOAc and the organic portion is washed with 5M NaOH. The aqueous layer is acidified with 5M HCl and extracted with EtOAc, this organic portion is washed with brine, dried over MgSO4 and concentrated in vacuo to afford the title compound as an off white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][C:3]=1[C:4]([NH:6][C:7]1[C:8](Cl)=[N:9][CH:10]=[CH:11][CH:12]=1)=[O:5].Cl>S1(CCCC1)(=O)=O.C(OCC)(=O)C>[CH3:18][C:15]1[CH:16]=[CH:17][C:2]2[NH:1][C:8]3[N:9]=[CH:10][CH:11]=[CH:12][C:7]=3[NH:6][C:4](=[O:5])[C:3]=2[CH:14]=1
Reactant: Cc1ccc(N)c(C(=O)Nc2cccnc2Cl)c1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O=S1(=O)CCCC1
Product: Cc1ccc2c(c1)C(=O)Nc1cccnc1N2
Temperature: 220 °C
Yield: 70.2 %

Procedure:
A solution of 2-amino-N-(2-chloropyridin-3-yl)-5-methylbenzamide (2.515 g, 9.61 mmol) in sulfolane (15 mL) was treated with hydrogen chloride (0.25 mL, 1.0 mmol; 4N in dioxane). The reaction mixture was heated to 220° C. under microwave conditions for 8 minutes. The reaction mixture was then diluted with ethyl acetate (75 mL) and washed with water (5×50 mL). The organic layer (aqueous emulsion) was concentrated to give an aqueous slurry which was filtered and washed with water (50 mL). The product was dried under high vacuum at 60° C. to afford 8-methyl-5H-benzo[e]pyrido[3,2-b][1,4]diazepin-6(11H)-one (1.52 g) that was used without further purification. LCMS [M+H]: 226.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:20])[C:10]2[CH:15]=[CH:14][C:13](F)=[C:12]([N+:17]([O-:19])=[O:18])[CH:11]=2)=[CH:4][CH:3]=1.[CH3:21][N:22]([CH3:26])[CH2:23][CH2:24][NH2:25].C([O-])(O)=O.[Na+]>CCO>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:20])[C:10]2[CH:15]=[CH:14][C:13]([NH:25][CH2:24][CH2:23][N:22]([CH3:26])[CH3:21])=[C:12]([N+:17]([O-:19])=[O:18])[CH:11]=2)=[CH:4][CH:3]=1
Reactant: CN(C)CCN
Reactant: O=C(Nc1ccc(Br)cc1)c1ccc(F)c([N+](=O)[O-])c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CN(C)CCNc1ccc(C(=O)Nc2ccc(Br)cc2)cc1[N+](=O)[O-]
Temperature: 50 °C
Yield: 116.5 %

Procedure:
A mixture of N-(4-bromophenyl)-4-fluoro-3-nitrobenzamide (400 mg; 1.18 mmol) and 2-dimethylamino ethylamine (208 mg; 2.36 mmol) in EtOH (5 mL) was stirred over night at 50° C. The mixture was then poured into aqueous NaHCO3 and extracted with EtOAc. The organic layers were dried over Na2SO4, filtered and concentrated. Recrystallization from EtOAc/petroleum ether gave the crude sub-title compound (560 mg).
Reaction SMILES: [N+:1]([CH2:4][CH:5]([C:12]1[O:13][C:14]2[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=2[CH:16]=1)[CH2:6][C:7](OCC)=[O:8])([O-])=O.[H][H]>C(O)C.[Ni]>[O:13]1[C:14]2[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=2[CH:16]=[C:12]1[CH:5]1[CH2:4][NH:1][C:7](=[O:8])[CH2:6]1
Reactant: [H][H]
Reactant: CCOC(=O)CC(C[N+](=O)[O-])c1cc2ccccc2o1
Agent: [Ni]
Solvent: CCO
Product: O=C1CC(c2cc3ccccc3o2)CN1
Temperature: 100 °C
Reaction time: 7 h

Procedure:
Ester (IV) (81.5 g; 0.297 mole) obtained in b) is dissolved in 500 ml ethanol and hydrogenated at ordinary pressure at 55° C., in the presence of 10 g Raney Nickel. The hydrogen required for the reaction (14.8 l) is taken up within 7 hours. After filtration of the catalyst and evaporation of the ethanol, the oily residue is heated at 100° C. under the vacuum of a water pump, for 2 hours. On trituration with isopropyl ether, the product crystallizes. M.P. (inst.)=142° C. Weight: 47.9 g (80%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[O:9][CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.Br[CH:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)=[CH:4][C:3]=1[O:9][CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: BrC1CCCC1
Reactant: Oc1ccc(Br)c(OCCN2CCCCC2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Brc1ccc(OC2CCCC2)cc1OCCN1CCCCC1

Procedure:
4-Bromo-3-(2-{piperidin-1-yl}ethoxy)phenol (1.5 g), bromocyclopentane (0.59 ml) and anhydrous potassium carbonate (1.04 g) were stirred and heated at 80° C. in dimethylformamide for 18 h. The mixture was partitioned between ethyl acetate (100 ml) and water (70 ml). The aqueous was extracted further with ethyl acetate (100 ml) and the combined organics were washed with 2N sodium hydroxide solution (50 ml), water (50 ml), brine (50 ml), dried (MgSO4) and evaporated to give the product as an oil (1.5 g).
Reaction SMILES: [CH:1]1([NH:7][C:8](=[O:33])[C:9]2[CH:14]=[C:13]([CH2:15][C:16]3[C:17](=[O:28])[C:18]([O:26][CH3:27])=[C:19]([O:24][CH3:25])[C:20](=[O:23])[C:21]=3[CH3:22])[CH:12]=[CH:11][C:10]=2[O:29]C(=O)C)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])O.[Na+]>CO.O>[CH:1]1([NH:7][C:8](=[O:33])[C:9]2[CH:14]=[C:13]([CH2:15][C:16]3[C:17](=[O:28])[C:18]([O:26][CH3:27])=[C:19]([O:24][CH3:25])[C:20](=[O:23])[C:21]=3[CH3:22])[CH:12]=[CH:11][C:10]=2[OH:29])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)NC3CCCCC3)c2)=C(C)C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC1=C(OC)C(=O)C(Cc2ccc(O)c(C(=O)NC3CCCCC3)c2)=C(C)C1=O
Yield: 54.9 %

Procedure:
N-Cyclohexyl-5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzamide (0.070 g, 0.154 mmol) was dissolved in methanol (3 ml) and after adding thereto an aqueous saturated sodium hydrogencarbonate solution (1.5 ml), the solution was stirred at room temperature for 3 hours. After the completion of reaction, the reaction solution was diluted with water and then extracted with ethyl acetate. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was recrystallized from ether to obtain the titled compound (0.035 g, 0.0846 mmol, 55%).