Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:23][C:24]2[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[C:26]([O:32][CH3:33])[CH:25]=2)[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11](Br)=[CH:10][CH:9]=2)=[O:4].[H][H]>CO.[C].[Pd]>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:23][C:24]2[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[C:26]([O:32][CH3:33])[CH:25]=2)[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:4]
Reactant: COC(=O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1cc(OC)cc(OC)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1c(-c2ccccc2)c2ccccc2c(=O)n1Cc1cc(OC)cc(OC)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 87.4 %

Procedure:
To a solution of 6-bromo-2-(3,5-dimethoxybenzyl)-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester (153 mg) in methanol (5 ml) was added palladium carbon (10%, 15 mg), and hydrogen gas was filled. The mixture was stirred at room temperature for 15 hrs. and filtered through celite. The solvent was evaporated under reduced pressure, and the obtained residue was recrystallized from methanol to give the title compound (113 mg, 88%).
Reaction SMILES: [C:1]([N:3]=[C:4]([N:12]1[CH2:17][CH2:16][C:15]([CH2:24][CH2:25][N:26]2[CH:31]3[CH2:32][CH2:33][CH:27]2[CH2:28][CH:29]([N:34]2[C:38]4[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=4[N:36]=[C:35]2[CH3:43])[CH2:30]3)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:14][CH2:13]1)[O:5][C:6]1C=CC=CC=1)#[N:2].C[O-].[Na+].[Na]>C1COCC1.CO>[C:1]([N:3]=[C:4]([N:12]1[CH2:13][CH2:14][C:15]([CH2:24][CH2:25][N:26]2[CH:31]3[CH2:32][CH2:33][CH:27]2[CH2:28][CH:29]([N:34]2[C:38]4[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=4[N:36]=[C:35]2[CH3:43])[CH2:30]3)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:16][CH2:17]1)[O:5][CH3:6])#[N:2]
Reactant: Cc1nc2ccccc2n1C1CC2CCC(C1)N2CCC1(c2ccccc2)CCN(C(=NC#N)Oc2ccccc2)CC1
Agent: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=NC#N)N1CCC(CCN2C3CCC2CC(n2c(C)nc4ccccc42)C3)(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.1 %

Procedure:
To a stirred solution of phenyl N-cyano-4-{2-[3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidine-1-carboximidoate 6 (35 mg, 0.06 mmol) in THF (1 mL) was added sodium methoxide in methanol (100 μL, ˜0.8 M, freshly made from methanol and sodium). The resulting mixture was stirred at ambient temperature for 30 minutes before evaporation of the solvent. The crude product was then purified by flash chromatography on silical gel, eluting with a gradient of 0-15% methanol in ethyl acetate to afford methyl N-cyano-4-{2-[3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidine-1-carboximidoate as amorphous solid (21.8 mg, 72%). 1H NMR (300 MHz, CDCl3) δ 7.69-7.66 (m, 1H), 7.42-7.37 (m, 2H), 7.32-7.24 (m, 4H), 7.21-7.13 (m, 2H), 4.64 (br, 1H), 4.19-4.07 (br, 2H), 3.92 (s, 3H), 3.40-3.27 (m, 4H), 2.59 (s, 3H), 2.35-2.30 (m, 4H), 1.97-1.83 (m, 10H), 1.66-1.63 (m, 2H). HRMS m/z (M+H)+ calcd 511.3185; obsd 511.3211.
Reaction SMILES: [C:1]([O:5][CH:6]([C:11]1[C:12]([C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[O:27][CH2:26][CH2:25][CH2:24]3)=[C:13]2[CH:20]=[CH:19][NH:18][C:14]2=[N:15][C:16]=1[CH3:17])[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].[F:31][C:32]1[CH:39]=[CH:38][CH:37]=[CH:36][C:33]=1[CH2:34]Br>>[C:1]([O:5][CH:6]([C:11]1[C:12]([C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[O:27][CH2:26][CH2:25][CH2:24]3)=[C:13]2[CH:20]=[CH:19][N:18]([CH2:34][C:33]3[CH:36]=[CH:37][CH:38]=[CH:39][C:32]=3[F:31])[C:14]2=[N:15][C:16]=1[CH3:17])[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: Fc1ccccc1CBr
Reactant: COC(=O)C(OC(C)(C)C)c1c(C)nc2[nH]ccc2c1-c1ccc2c(c1)CCCO2
Product: Cc1nc2c(ccn2Cc2ccccc2F)c(-c2ccc3c(c2)CCCO3)c1C(OC(C)(C)C)C(=O)O

Procedure:
The title compound was prepared in a manner similar to that described in Example 27, Step H from methyl 2-(tert-butoxy)-2-(4-(chroman-6-yl)-6-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)acetate and 2-fluorobenzyl bromide. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.50-7.42 (m, 1 H), 7.28-7.17 (m, 3 H), 7.15-7.06 (m, 3 H), 6.93 (dd, J=5.1, 8.4 Hz, 1 H), 6.27 (dd, J=3.5, 11.7 Hz, 1 H), 5.67-5.51 (m, 3 H), 4.32-4.25 (m, 2 H), 2.98-2.81 (m, 2 H), 2.76 (s, 3 H), 2.13-2.06 (m, 2 H), 1.02-0.91 (s, 9 H); LC/MS (m/z) ES+=503.51 (M+1).
Reaction SMILES: C1(S([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[C:12]([CH2:19][C:20]3[CH:21]=[CH:22][C:23]([NH:26][CH2:27][C:28]4[C:33]([F:34])=[CH:32][CH:31]=[CH:30][C:29]=4[Cl:35])=[N:24][CH:25]=3)=[CH:11]2)(=O)=O)C=CC=CC=1.CO.[OH-].[K+]>C(O)(=O)C>[Cl:35][C:29]1[CH:30]=[CH:31][CH:32]=[C:33]([F:34])[C:28]=1[CH2:27][NH:26][C:23]1[CH:22]=[CH:21][C:20]([CH2:19][C:12]2[C:13]3[C:14](=[N:15][CH:16]=[CH:17][CH:18]=3)[NH:10][CH:11]=2)=[CH:25][N:24]=1
Reactant: O=S(=O)(c1ccccc1)n1cc(Cc2ccc(NCc3c(F)cccc3Cl)nc2)c2cccnc21
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Product: Fc1cccc(Cl)c1CNc1ccc(Cc2c[nH]c3ncccc23)cn1
Temperature: 80 °C

Procedure:
[5-(1-Benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(2-chloro-6-fluoro-benzyl)-amine 617 was combined with methanol:potassium hydroxide (1M) (1:1, 0.5 mL). The mixture was heated at 80° C. for 2 hours. Acetic acid (0.1 mL) was added and the solvents removed under reduced pressure. The remaining residue was dissolved in dimethylsulfoxide (0.4 mL) and purified by reverse phase HPLC on a Phenomenex column (50 mm×10 mm ID) eluting with 0.1% trifluoroacetic acid in water and 20-100% acetonitrile with 0.1% trifluoroacetic acid over 16 minutes at a flow rate of 6 mL/minute to provide the desired compound P-0210. MS (ESI) [M+H+]+=367.1.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.Br[CH2:11][CH2:12][CH2:13][CH2:14][Cl:15]>>[Cl:15][CH2:14][CH2:13][CH2:12][CH2:11][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: ClCCCCBr
Reactant: c1ccc2[nH]ccc2c1
Product: ClCCCCn1ccc2ccccc21

Procedure:
Prepared by Procedure AH, and Scheme P using 1H-indole and 1-bromo-4-chlorobutane: 1NMR (400 MHz, CDCl3) δ 7.72–7.02 (m, 5H), 6.49 (d, 1H, J=2.8 Hz), 4.13 (t, 2H, J=6.8 Hz), 3.48 (t, 2H, J=6.8 Hz), 2.06–1.92 (m, 2H), 1.80–1.70 (m, 2H).
Reaction SMILES: [OH:1][C:2]([CH3:16])([CH3:15])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[N:9]=[N:10][C:11](Cl)=[CH:12][CH:13]=1)=[O:7].[N:17]1([C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:31]([F:34])([F:33])[F:32])=[O:24])[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>>[OH:1][C:2]([CH3:16])([CH3:15])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[N:9]=[N:10][C:11]([N:20]2[CH2:21][CH2:22][N:17]([C:23](=[O:24])[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]([F:34])([F:32])[F:33])[CH2:18][CH2:19]2)=[CH:12][CH:13]=1)=[O:7]
Reactant: CC(C)(O)CCNC(=O)c1ccc(Cl)nn1
Reactant: O=C(c1ccccc1C(F)(F)F)N1CCNCC1
Product: CC(C)(O)CCNC(=O)c1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1

Procedure:
Following the procedure of Example 15, making variations only as required to use 6-chloropyridazine-3-carboxylic acid (3-hydroxy-3-methylbutyl)amide in place of 6-chloropyridazine-3-carboxylic acid (2-cyclopropyl-2-hydroxyethyl)amide to react with piperazin-1-yl-(2-trifluoromethylphenyl)methanone, the title compound was obtained as a white powder (46.4% yield). 1H NMR (500 MHz, CDCl3) δ 8.30, 8.05, 7.75, 7.65, 7.57, 7.37, 6.98, 4.06, 3.88, 3.81-3.69, 3.64, 3.40-3.32, 1.80, 1.64, 1.30. MS (ES+) m/z 466 (M+1).
Reaction SMILES: S(O)(O)(=O)=O.N[C:7]1[S:8][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:10][N:11]=1.[BrH:18].N([O-])=O.[Na+]>C(Cl)Cl.O>[Br:18][C:7]1[S:8][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:10][N:11]=1
Reactant: Br
Reactant: Nc1nnc(-c2ccccc2)s1
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: Brc1nnc(-c2ccccc2)s1
Temperature: 5 °C
Reaction time: 0.25 h
Yield: 74 %

Procedure:
A mixture of 2-amino-5-phenyl-1,3,4-thiadiazole sulfate (Aldrich, 2.5 g, 9.08 mmol) and 48% aqueous HBr (10 mL) was cooled to 5° C. and a solution of NaNO2 (0.69 g, 9.99 mmol) H2O (10 mL) was added dropwise at a rate so the internal temperature is maintained at approximately 5° C. The mixture was stirred for 15 min after the addition, then CuBr (0.69 g, 4.8 mmol) was added portion-wise so as to maintain the temperature at approximately 5° C. After the addition was complete, the mixture was allowed to warm to ambient temperature and stirred for 16 h. The mixture was diluted with 20 mL CH2Cl2 and 10 mL H2O. The organic layer was separated and concentrated under reduced pressure to provide the title compound (1.63 g, 6.76 mmol, 74% yield). MS (DCl/NH3) m/z 241, 243 (M+H)+.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[C:6]([CH2:11][C:12]([OH:14])=O)[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.[CH3:15][C:16]1[N:17]=[C:18]([C:21]2[S:22][CH:23]=[CH:24][C:25]=2[NH2:26])[S:19][CH:20]=1>>[CH:1]1[C:10]2[C:5](=[C:6]([CH2:11][C:12]([NH:26][C:25]3[CH:24]=[CH:23][S:22][C:21]=3[C:18]3[S:19][CH:20]=[C:16]([CH3:15])[N:17]=3)=[O:14])[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1
Reactant: Cc1csc(-c2sccc2N)n1
Reactant: O=C(O)Cc1cccc2cnccc12
Product: Cc1csc(-c2sccc2NC(=O)Cc2cccc3cnccc23)n1

Procedure:
2-(Isoquinolin-5-yl)-N-(2-(4-methylthiazol-2-yl)thiophen-3-yl)acetamide was prepared from 2-(isoquinolin-5-yl)acetic acid (63 mg, 0.341 mmol) and 2-(4-methylthiazol-2-yl)thiophen-3-amine (67 mg, 0.341 mmol) according to protocol A. Retention time (min)=3.130, method [7], MS (ESI) 366.0 (M+H); 1H NMR (300 MHz, CDCl3) δ 11.55 (s, 1H), 9.64 (s, 1H), 8.60 (d, J=6.8 Hz, 1H), 8.39 (d, J=6.6 Hz, 1H), 8.20 (d, J=8.4 Hz, 1H), 8.05-8.08 (m, 2H), 7.88-7.91 (m, 1H), 7.24 (d, J=5.5 Hz, 1H), 6.74 (s, 1H), 4.31 (s, 2H), 2.45 (s, 3H).
Reaction SMILES: [NH2:1][C@@H:2]1[C:8](=[O:9])[N:7]([CH2:10][CH2:11][O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:6]2[CH:20]=[CH:21][CH:22]=[CH:23][C:5]=2[C:4]2[CH:24]=[CH:25][CH:26]=[CH:27][C:3]1=2.[CH2:28]([O:30][C:31](=[O:38])[C:32]([F:37])([CH3:36])[C:33](O)=[O:34])[CH3:29]>>[CH2:28]([O:30][C:31](=[O:38])[C:32]([F:37])([CH3:36])[C:33]([NH:1][C@@H:2]1[C:8](=[O:9])[N:7]([CH2:10][CH2:11][O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:6]2[CH:20]=[CH:21][CH:22]=[CH:23][C:5]=2[C:4]2[CH:24]=[CH:25][CH:26]=[CH:27][C:3]1=2)=[O:34])[CH3:29]
Reactant: N[C@@H]1C(=O)N(CCOCc2ccccc2)c2ccccc2-c2ccccc21
Reactant: CCOC(=O)C(C)(F)C(=O)O
Product: CCOC(=O)C(C)(F)C(=O)N[C@@H]1C(=O)N(CCOCc2ccccc2)c2ccccc2-c2ccccc21

Procedure:
Using (S)-7-amino-5-(2-benzyloxy-ethyl)-5H,7H-dibenzo[b,d]azepin-6-one and 2-fluoro-2-methyl-malonic acid monoethyl ester, the title compound was prepared in the same manner as described for example 1c. Colorless oil (>98%). MS: m/e=505(M+H+).
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3][OH:4].[H-].[Na+].Cl[C:10]1[C:15]([C:16]#[N:17])=[C:14]([N:18]2[CH2:23][CH2:22][CH:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:20][CH2:19]2)[N:13]=[C:12]([S:30][CH3:31])[N:11]=1>O1CCCC1>[CH3:31][S:30][C:12]1[N:13]=[C:14]([N:18]2[CH2:19][CH2:20][CH:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:22][CH2:23]2)[C:15]([C:16]#[N:17])=[C:10]([O:4][CH2:3][C:2]([F:6])([F:5])[F:1])[N:11]=1
Reactant: OCC(F)(F)F
Reactant: CSc1nc(Cl)c(C#N)c(N2CCC(c3ccccc3)CC2)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CSc1nc(OCC(F)(F)F)c(C#N)c(N2CCC(c3ccccc3)CC2)n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 63.6 %

Procedure:
A solution of 56 mg (0.55 mmol) of 2,2,2-trifluoroethanol in 5 ml of tetrahydrofurane was cooled to 0° C. and treated under an argon atmosphere with 23 mg (0.52 mmol) of sodium hydride (55% dispersion in oil). The mixture was kept at 0° C. during 10 min, then a solution of 200 mg (0.58 mmol) of 4-chloro-2-methylsulfanyl-6-(4-phenyl-piperidin-1-yl)-pyrimidine-5-carbonitrile in 5 ml of tetrahydrofurane was added and, thereupon, the mixture was warmed to room temperature and stirring continued during 36 hours. For the working-up, the reaction mixture was evaporated and the residue obtained was directly chromatographed on silica gel using a 9:1 mixture of hexane and ethyl acetate as the eluent yielding 142 mg (0.35 mmol, 60% of theory) of the 2-methylsulfanyl-4-(4-phenyl-piperidin-1-yl)-6-(2,2,2-trifluoro-ethoxy)-pyrimidine-5-carbonitrile as an amorphous, white solid; MS: [M+H]+=409.
Reaction SMILES: [C:1]([CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][CH3:14])[CH:11]=2)[N:6](C(OC(C)(C)C)=O)[CH:5]=1)#[N:2].[H-].[Na+].[F:24][C:25]1[N:30]=[CH:29][C:28]([CH:31]=O)=[CH:27][CH:26]=1.C(OCC)C>C1COCC1>[F:24][C:25]1[N:30]=[CH:29][C:28](/[CH:31]=[C:3](/[C:4]2[C:12]3[C:7](=[CH:8][CH:9]=[C:10]([O:13][CH3:14])[CH:11]=3)[NH:6][CH:5]=2)\[C:1]#[N:2])=[CH:27][CH:26]=1
Reactant: COc1ccc2c(c1)c(CC#N)cn2C(=O)OC(C)(C)C
Reactant: O=Cc1ccc(F)nc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1ccc2[nH]cc(/C(C#N)=C/c3ccc(F)nc3)c2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl 3-(cyanomethyl)-5-methoxy-1H-indol-1-carboxylate (719 mg, 2.51 mmol, 1.0 eq.) in anhydrous THF (30 mL) was added, under an argon atmosphere, NaH (106 mg, 80%, 3.52 mmol, 1.4 eq.). The mixture was stirred at room temperature for 2 hours, and then cooled to 0° C. before the addition of 6-fluoro-pyridine-3-carbaldehyde (440 mg, 3.52 mmol, 1.4 eq.) in anhydrous THF (6 mL). The reaction apparatus was protected from light and the mixture was stirred at 0° C. for 4 hours, and then quenched with a saturated aqueous ammonium chloride solution. The mixture was stirred again at room temperature for 4 hours and extracted with ethyl acetate. The organic layer was washed with brine and dried over MgSO4. The solvent was removed under reduced pressure, and the residue purified by silica gel flash-column chromatography (eluent: CH2Cl2/EtOH, 98:2) to afford, after trituration with diethyl ether, the compound (28) as a yellow powder (45 mg, 6%). IR νmax (cm-1): 2215 (νCN); 1H NMR (DMSO, 300 MHz): δ (ppm): 3.84 (3H, s, 5′-methoxy), 6.91 (1H, dd, J6′-7′=8.9 Hz, J6′-4′=2.1 Hz, H6′), 7.36 (1H, dd, J5″-4″=8.5 Hz, J5″-F=2.1 Hz, H5″), 7.41 (1H, d, J7′-6′=8.9 Hz, H7′), 7.49 (1H, d, J4′-6′=2.4 Hz, H4′), 7.76 (1H, s, H3), 7.78 (1H, s, H2′), 8.52 (1H, td, J5″-4″=J5″-F=10.1 Hz, J4″-2″=1.8 Hz, H4″), 8.67 (1H, d, J2″-4″=1.8 Hz, H2″), 11.66 (1H, s, indolic H); 13C NMR (DMSO, 75.5 MHz): δ (ppm): 55.6 (5′-methoxy), 102.0 (C4′), 108.2 (C2), 109.7 (1C, d, 2JC—F=37 Hz, C5″), 110.0 (C3′), 112.4 (C6′), 113.2 (C7′), 118.0 (C1), 124.0 (C3a′), 127.7 (C2′), 129.5 (1C, d, 4JC—F=4 Hz, C3″), 130.7 (C3), 132.3 (C7a′), 140.7 (1C, d, 3JC—F=8 Hz, C4″), 148.2 (1C, d, 3JC—F=15 Hz, C2″), 154.6 (C5′), 162.6 (1C, d, 1JC—F=237 Hz, C6″); ESI: 294.1 ([M+H]+), 316.1 ([M+Na]+), 348.1 ([M+Na+MeOH]+); HRESI-MS: m/z 294.1052 (calcd for C17H13N3OF, 294.1043).
Reaction SMILES: Br[CH2:2][CH2:3][N:4]1[C:8](=[O:9])[C:7]2=[CH:10][CH:11]=[CH:12][CH:13]=[C:6]2[C:5]1=[O:14].[CH3:15][N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1>>[CH3:15][N:16]1[CH2:21][CH2:20][N:19]([CH2:2][CH2:3][N:4]2[C:8](=[O:9])[C:7]3=[CH:10][CH:11]=[CH:12][CH:13]=[C:6]3[C:5]2=[O:14])[CH2:18][CH2:17]1
Reactant: CN1CCNCC1
Reactant: O=C1c2ccccc2C(=O)N1CCBr
Product: CN1CCN(CCN2C(=O)c3ccccc3C2=O)CC1

Procedure:
The title compound was synthesized by using N-(2-bromoethyl)phthalimide and 1-methylpiperazine according to the same process as in Preparation Example 2.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[F-:13].[K+]>CN(C)C=O>[F:13][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11]
Reactant: O=Cc1ccc(Cl)c([N+](=O)[O-])c1
Reactant: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1ccc(F)c([N+](=O)[O-])c1
Reaction time: 3 h

Procedure:
18.6 g (0.1 mol) of 4-chloro-3-nitrobenzaldehyde and 6.4 g (0.11 mol) of potassium fluoride in 50 ml of dimethylformamide are stirred at 160° C. After 3 hours, 4-chloro-3-nitrobenzaldehyde is no longer detectable in the reaction mixture, according to gas chromatography. Instead, 4-fluoro-3-nitrobenzaldehyde has formed quantitatively.
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4].C(O)(=O)C.[O:13]1[CH2:18][CH2:17][CH:16]([CH:19]=O)[CH2:15][CH2:14]1.S([O-])([O-])(=O)=O.[Na+].[Na+].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C>ClCCCl>[O:13]1[CH2:18][CH2:17][CH:16]([CH2:19][N:1]2[CH2:8][CH2:7][CH2:6][C@H:2]2[C:3]([OH:5])=[O:4])[CH2:15][CH2:14]1
Reactant: O=CC1CCOCC1
Reactant: O=C(O)[C@@H]1CCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: O=C(O)[C@@H]1CCCN1CC1CCOCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of L-proline (1 g; 8.686 mmol) in 1,2-dichloroethane (10 mL)/acetic acid (1.98 mL; 33.007 mmol)) is added tetrahydro-pyran-4-carbaldehyde (0.991 g; 8.686 mmol) and sodium sulfate (˜10 equivalents). After 45 minutes of agitation on an orbital shaker, MP-triacetoxyborohydride resin (4.272 g; 10.423 mmol) is added. The mixture is agitated at room temperature overnight and filtered, washing resin with methylene chloride. The combined filtrate is washed with aqueous saturated sodium bicarbonate solution and brine, dried (Na2SO4), filtered and concentrated in vacuo. Excess acetic acid is removed by successive azeotropic distillation with toluene on the rotary evaporator. Title compound is afforded by this method. ESI m/z 214 [M+H]+
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:40])[CH2:9][CH2:10][CH2:11][N:12]2[CH2:39][CH2:38][C:15]3([N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH2:18][N:17]([CH2:26][C:27]4[CH:28]=[C:29]([CH:34]=[CH:35][CH:36]=4)[C:30]([O:32]C)=[O:31])[C:16]3=[O:37])[CH2:14][CH2:13]2)=[CH:4][CH:3]=1.[OH-].[Li+].CO>O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:40])[CH2:9][CH2:10][CH2:11][N:12]2[CH2:39][CH2:38][C:15]3([N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH2:18][N:17]([CH2:26][C:27]4[CH:28]=[C:29]([CH:34]=[CH:35][CH:36]=4)[C:30]([OH:32])=[O:31])[C:16]3=[O:37])[CH2:14][CH2:13]2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1cccc(CN2CN(c3ccccc3)C3(CCN(CCCC(=O)c4ccc(F)cc4)CC3)C2=O)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1cccc(CN2CN(c3ccccc3)C3(CCN(CCCC(=O)c4ccc(F)cc4)CC3)C2=O)c1
Temperature: 35 °C
Reaction time: 24 h
Yield: 22.8 %

Procedure:
A solution of methyl 3-((8-(4-(4-fluorophenyl)-4-oxobutyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate (450 mg, 0.828 mmol, 1 equiv) and lithium hydroxide (34.7 mg, 1.656 mmol, 2.0 equiv) in a 3:1 mixture of methanol and water (5 ml t/v) was stirred at 35° C. for 24 hrs. The reaction was concentrated in vacuo and purified using preparatory high performance liquid chromatography. The combined pure fractions were lyophilized to afford the acetate salt of the title compound as a white solid (100 mg, 25%); 1H NMR (400 MHz, DMSO-d6): δ 1.59 (d, 2H, J=13.6 Hz), 1.84 (t, 2H, J=7.2 and 6.8 Hz); 2.45-2.46 (m, 4H); 2.72-2.78 (m, 4H); 3.05 (t, 2H, J=6.8 and 7.2 Hz); 4.57 (s, 2H); 4.60 (s, 2H); 6.72-6.78 (m, 3H); 7.12-7.16 (m, 2H); 7.32-7.36 (m, 2H); 7.47-7.53 (m, 2H); 7.86-7.88 (m, 2H); 8.04-8.08 (m, 2H); 10.82 (s, 1H); 12.9 (bs, 1H); MS for C31H32FN3O4 m/z 529.99 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([O:22][CH2:23][CH2:24][C:25]([O:27]CC)=O)[C@@H:9]2[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]2)[CH:5]=[CH:6][CH:7]=1.[CH3:30][NH2:31]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([C@H:8]([O:22][CH2:23][CH2:24][C:25]([NH:31][CH3:30])=[O:27])[C@@H:9]2[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CCOC(c1cccc(Cl)c1)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Reactant: CN
Solvent: CO
Product: CNC(=O)CCO[C@@H](c1cccc(Cl)c1)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 41 %

Procedure:
(3R)-tert-butyl 3-((3-chlorophenyl)(3-ethoxy-3-oxopropoxy)methyl)piperidine-1-carboxylate (2.0 g, 4.71 mmol) was dissolved in a solution CH3NH2 in CH3OH ((180 mL) and stirred overnight at rt. After the reaction was complete by HPLC analysis, the solvent was removed in vacuo. The residue was purified by preparative HPLC and afforded the desired isomerically pure product (R)-tert-butyl 3-((R)-(3-chlorophenyl)(3-(methylamino)-3-oxopropoxy)methyl)piperidine-1-carboxylate (0.80 g, 1.95 mmol, 41% yield). MS (E/Z): 411 (M+H+).
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([C:11]([OH:14])([CH3:13])[CH3:12])=[N:10][C:5]2=[N:4][CH:3]=1.[F:15][C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][C:17]=1[C:25]1[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=1>>[F:15][C:16]1[CH:21]=[CH:20][C:19]([C:2]2[N:6]3[CH:7]=[CH:8][C:9]([C:11]([OH:14])([CH3:13])[CH3:12])=[N:10][C:5]3=[N:4][CH:3]=2)=[CH:18][C:17]=1[C:25]1[CH:26]=[CH:27][N:28]=[CH:29][CH:30]=1
Reactant: CC(C)(O)c1ccn2c(Br)cnc2n1
Reactant: OB(O)c1ccc(F)c(-c2ccncc2)c1
Product: CC(C)(O)c1ccn2c(-c3ccc(F)c(-c4ccncc4)c3)cnc2n1
Yield: 58 %

Procedure:
2-(3-Bromoimidazo[1,2-α]pyrimidin-7-yl)propan-2-ol was coupled with 4-fluoro-3-(pyridin-4-yl)benzeneboronic acid as described in Example 1 to give 2-[3-(4-fluoro-3-(pyridin-4-yl)phenyl)imidazo[1,2-α]pyrimidin-7-yl]propan-2-ol as a white solid (240 mg, 58%). Bis-hydrochloride salt (from ethyl acetate/ethanol): δH (360 MHz, DMSO) 1.56 (6H, s), 7.77 (1H, dd, J 11 and 9), 7.85 (1H, d, J 7), 7.94-7.98 (1H, m), 8.12-8.15 (3H, m), 8.55 (1H, s), 8.95 (2H, d, J 6), 9.38 (1H, d, J 7); m/z (ES+) 349 (M++H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])[C:5]2=[CH:14]OC.[NH2:17][CH2:18][CH2:19][CH2:20][CH2:21][OH:22]>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]\[NH:17][CH2:18][CH2:19][CH2:20][CH2:21][OH:22]
Reactant: NCCCCO
Reactant: COC=C1C(=O)NC(=O)c2ccc(Br)cc21
Solvent: CN(C)C=O
Product: O=C1NC(=O)c2ccc(Br)cc2/C1=C/NCCCCO
Temperature: 0 °C
Yield: 64.6 %

Procedure:
6-Bromo-4-methoxymethylene-4H-isoquinoline-1,3-dione (250 mg, 0.89 mmol), and 4-amino-butan-1-ol (79 mg, 0.89 mmol) in N,N-dimethylformamide (DMF) (5 mL) is stirred at 25° C. for 3 days. A precipitate formed. The reaction mixture is cooled to 0° C. The precipitate is filtered and dried in vacuo to give 195 mg (64.5%) of the title compound as a tan powder. HRMS (ESI) m/z calcd for C14H15BrN2O3 (M+H)+1 339.03389. found: 339.03308.
Reaction SMILES: [CH3:1]Br.[Mg].[Br:4][C:5]1[C:6]([CH3:17])=[C:7]2[C:12](=[C:13]([CH3:15])[CH:14]=1)[S:11][CH2:10][CH2:9][C:8]2=[O:16].Cl>O1CCCC1>[Br:4][C:5]1[C:6]([CH3:17])=[C:7]2[C:12](=[C:13]([CH3:15])[CH:14]=1)[S:11][CH2:10][CH2:9][C:8]2([CH3:1])[OH:16]
Reactant: Cc1cc(Br)c(C)c2c1SCCC2=O
Reactant: CBr
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Product: Cc1cc(Br)c(C)c2c1SCCC2(C)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 99 %

Procedure:
A 300-ml three-necked flask was charged with 55 ml (55 mmol, 3 equivalents) of a 1 M solution of magnesium methyl bromide (MeMgBr) and 100 ml of tetrahydrofuran (THF), and the mixture was cooled with ice under nitrogen current. To this mixture was dropwise added a solution of 5.0 g (18.4 mmol) of 6-bromo-5,8-dimethylthiochroman-4-one in 15 ml of THF, and the mixture was stirred at room temperature for 3 hours and then refluxed for 2 hours. To the reaction mixture was added 5% HCl, and the mixture was extracted with ethyl acetate. The resultant organic layer was washed with a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate, and the solvent was distilled off to give 5.2 g (yield 99%) of 6-bromo-4,5,8-trimethylthiochroman-4-ol.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[O:7][C:6](=[O:8])[NH:5][C:4]2[CH:9]=[CH:10][C:11](B(O)O)=[CH:12][C:3]1=2.Br[C:18]1[CH:22]=[C:21]([CH:23]([O:27][CH2:28][CH3:29])[O:24][CH2:25][CH3:26])[O:20][CH:19]=1>O>[CH2:28]([O:27][CH:23]([O:24][CH2:25][CH3:26])[C:21]1[O:20][CH:19]=[C:18]([C:11]2[CH:10]=[CH:9][C:4]3[NH:5][C:6](=[O:8])[O:7][C:2]([CH3:16])([CH3:1])[C:3]=3[CH:12]=2)[CH:22]=1)[CH3:29]
Reactant: CCOC(OCC)c1cc(Br)co1
Reactant: CC1(C)OC(=O)Nc2ccc(B(O)O)cc21
Solvent: O
Product: CCOC(OCC)c1cc(-c2ccc3c(c2)C(C)(C)OC(=O)N3)co1

Procedure:
Prepared according to procedure B from 4,4-dimethyl 2 oxo-1,4-dihydro 2H-benzo[d][1,3]oxazin-6-boronic acid and 3-bromo-5-Diethoxymethyl furan. A brown gum: 1H NMR (DMSO-d6) δ 10.2 (s, 1H), 8.12 (s, 1H), 7.54-7.49 (m, 2H), 6.93-6.88 (m, 2H), 5.56 (s, 1H), 3.60-3.38 (m, 4H), 1.67 (s, 6H), 1.2-1.14 (m, 6H). MS (ESI) m/z 344 [M−H]−. Anal. Calcd. For C19H23NO5.1/2 H2O: C, 64.39; H, 6.77; N, 3.95. Found C, 64.90; H, 6.79; N, 3.78.