Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[CH:37]=[CH:36][C:6]([CH2:7][N:8]2[C:12]3[CH:13]=[CH:14][C:15]([O:17][CH2:18][C:19]4[CH:28]=[CH:27][C:26]5[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=5)[N:20]=4)=[CH:16][C:11]=3[N:10]=[C:9]2[CH2:29][C:30]([CH3:35])([CH3:34])[C:31]([OH:33])=[O:32])=[CH:5][CH:4]=1)=[O:2].F[C:39]1(F)CCCN[CH2:40]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].ClCCCl>C(Cl)Cl.O>[CH:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[C:12]3[CH:13]=[CH:14][C:15]([O:17][CH2:18][C:19]4[CH:28]=[CH:27][C:26]5[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=5)[N:20]=4)=[CH:16][C:11]=3[N:10]=[C:9]2[CH2:29][C:30]([CH3:35])([CH3:34])[C:31]([O:33][CH2:39][CH3:40])=[O:32])=[CH:36][CH:37]=1)=[O:2]
Reactant: CC(C)(Cc1nc2cc(OCc3ccc4ccccc4n3)ccc2n1Cc1ccc(C=O)cc1)C(=O)O
Reactant: FC1(F)CCCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: ClCCCl
Solvent: O
Product: CCOC(=O)C(C)(C)Cc1nc2cc(OCc3ccc4ccccc4n3)ccc2n1Cc1ccc(C=O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a 10 mL flask were added 3-(1-(4-formylbenzyl)-5-(quinolin-2-ylmethoxy)-1H-benzo[d]imidazol-2-yl)-2,2-dimethylpropanoic acid (160 mg, 0.31 mmol), 3,3-difluoropiperidine (58 mg, 0.37 mmol), sodium triacetoxyborohydride (130 mg, 0.61 mmol) and DCE (3.0 mL) and was stirred at RT overnight. The mixture was diluted with DCM (5 mL) and poured into water (10 mL) then extracted with DCM (3×10 mL), dried over Na2SO4, and concentrated to dryness. The residue was purified using FCC to provide the title compound. MS (ESI): mass calcd. for C37H40F2N4O3, 626.75; m/z found, 627.2 [M+H]+. 1H NMR (600 MHz, CDCl3) δ 8.17 (d, J=8.5, 1H), 8.09 (d, J=8.5, 1H), 7.80 (t, J=11.1, 1H), 7.72 (ddd, J=13.3, 7.6, 3.9, 2H), 7.55-7.50 (m, 1H), 7.35 (d, J=2.3, 1H), 7.22 (t, J=10.3, 2H), 7.07 (t, J=10.5, 1H), 6.99-6.93 (m, 3H), 5.42 (s, 2H), 5.34 (s, 2H), 4.09 (q, J=7.1, 2H), 3.53 (s, 2H), 3.05 (s, 2H), 2.61-2.53 (m, 2H), 2.40 (dd, J=16.1, 11.1, 2H), 1.90-1.80 (m, 2H), 1.78-1.70 (m, 2H), 1.36 (s, 6H), 1.16 (t, J=7.1, 3H).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7]([C:9]2[S:10][CH:11]=[CH:12][N:13]=2)=[O:8])[CH2:3]1.[C:14]([N:21]1[CH2:24][CH2:23][C:22]1=O)([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].CCN(CC)CC.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>ClCCCl.C(O)(=O)C>[S:10]1[CH:11]=[CH:12][N:13]=[C:9]1[C:7]([N:4]1[CH2:5][CH2:6][C@H:2]([NH:1][CH:23]2[CH2:22][N:21]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:24]2)[CH2:3]1)=[O:8]
Reactant: CC(C)(C)OC(=O)N1CCC1=O
Reactant: N[C@H]1CCN(C(=O)c2nccs2)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC(N[C@H]2CCN(C(=O)c3nccs3)C2)C1
Temperature: 25 °C
Reaction time: 5 h
Yield: 84 %

Procedure:
To a solution of compound 1d (diHCl salt, 2.7 g, 10 mmol) and N-Boc azetidinone 1e (2.4 g, 14 mmol) in 1,2-DCE (50 mL) was added slowly Et3N (20 mmol) followed by acetic acid (3.5 mL). To this mixture was added Na(OAc)3BH (3.39 g, 16 mmol). The reaction was stirred at room temperature for 5 h. To the reaction mixture was added aq. NaHCO3, and the resultant mixture was extracted with CH2Cl2. The organic layer was dried over Na2SO4 and concentrated. Purification by flash column chromatography (silica gel, 80% EtOAc/heptane) gave compound 1f (2.96 g). 1H NMR (300 MHz, CDCl3): δ 7.91 (m, 1H), 7.53 (m, 1H), 4.28 (m, 1H), 4.22-4.11 (m, 2.5H), 3.91 (m, 0.5H), 3.83 (m, 1H), 3.73-3.60 (m, 3.5H), 3.49 (m, 0.5H), 3.41 (m, 1H), 2.11 (m, 1H), 1.89-1.73 (m, 1H), 1.44 (s, 9H).
Reaction SMILES: [F:1][C:2]1([F:20])[CH2:8][O:7][CH2:6][C:5]([NH2:9])=[N:4][C@@:3]21[C:18]1[C:13](=[CH:14][CH:15]=[C:16]([NH2:19])[CH:17]=1)[CH2:12][CH2:11][CH2:10]2.[Cl:21][C:22]1[CH:23]=[CH:24][C:25]([C:28](O)=[O:29])=[N:26][CH:27]=1>>[NH2:9][C:5]1[CH2:6][O:7][CH2:8][C:2]([F:1])([F:20])[C@@:3]2([C:18]3[C:13](=[CH:14][CH:15]=[C:16]([NH:19][C:28](=[O:29])[C:25]4[CH:24]=[CH:23][C:22]([Cl:21])=[CH:27][N:26]=4)[CH:17]=3)[CH2:12][CH2:11][CH2:10]2)[N:4]=1
Reactant: NC1=N[C@@]2(CCCc3ccc(N)cc32)C(F)(F)COC1
Reactant: O=C(O)c1ccc(Cl)cn1
Product: NC1=N[C@@]2(CCCc3ccc(NC(=O)c4ccc(Cl)cn4)cc32)C(F)(F)COC1
Yield: 45 %

Procedure:
The condensation of (R)-6′,6′-difluoro-3,4,6′,7′-tetrahydro-2H,2′H-spiro[naphthalene-1,5′-[1,4]oxazepine]-3′,7-diamine (intermediate C4.1) and 5-chloropicolinic acid yielded the title compound (45% yield) as an off-white solid. MS (ISP): m/z=421.1 [M+H]+.
Reaction SMILES: [C:1]1(=[O:22])[N:5]([CH:6]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:7](O)=[O:8])[C:4](=[O:17])[C:3]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:2]12.O1CCCC1.[OH-].[NH4+:29]>O>[C:1]1(=[O:22])[N:5]([CH:6]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:7]([NH2:29])=[O:8])[C:4](=[O:17])[C:3]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:2]12
Reactant: [NH4+]
Reactant: O=C(O)C(Cc1ccccc1)N1C(=O)c2ccccc2C1=O
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: NC(=O)C(Cc1ccccc1)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 84 %

Procedure:
To a stirred solution of 2-phthalimido-3-phenylpropionic acid (2.95 g, 10.0 mmol) in tetrahydrofuiran (25 mL) are added carbonyldiimridazole (1.62 g, 10.0 mmol) and a few crystals of 4-N,N-dimethylaminopyridine, followed by 15 mL of tetrahydrofuran. The reaction mixture is stirred at room temperature for 45 minutes and 1 mL of concentrated ammonium hydroxide then is added. After 10 minutes, the reaction mixture is diluted with 50 mL water and the resulting slurry is partially concentrated to remove the tetrahydrofuran and filtered. The solid is washed with water and dried in vacuo (60° C., <1 mm) to afford 2.46 g (84%) of 2-phthalimido-3-phenylpropionamide as a white powder: mp 224°-226° C.; 1H NMR (DMSO-d6, 250 MHz) δ 7.79 (s, 4 H, Ar), 7.71 (br s, 1 H, CONH2), 7.32 (br s, 1 H, CONH2), 7.20-7.02 (m, 5H, Ar), 5.06-4.98 (m, 1H), 3.56-3.25 (m, 2H); 13C NMR (DMSO-d6, 250 MHz) d: 169.6, 168.0, 137.1, 134.3, 131.2, 129.5, 128.1, 126.3, 122.9, 54.2, 33.7. Anal. Calculated for C17H14N2O3. Theoretical: C, 69.38; H, 4.79; N, 9.52. Found: C, 69.37; H, 4.73; N, 9.43.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:28][CH2:29]C)[C:5]1[N:9]([CH3:10])[N:8]=[C:7]([C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:27])[O:19][CH2:20][C:21]3C=CC=CC=3)=[CH:13][CH:12]=2)[CH:6]=1)C.[Li]CCCC.[C:36](OC[C@H]1CO1)(=[O:40])CCC.Cl.C(OC)(OC)OC>C1COCC1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.C(N(CC)CC)C.CO>[CH3:1][O:3][CH:4]([O:28][CH3:29])[C:5]1[N:9]([CH3:10])[N:8]=[C:7]([C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:21][C@H:20]([CH2:36][OH:40])[O:19][C:18]3=[O:27])=[CH:13][CH:12]=2)[CH:6]=1
Reactant: CCOC(OCC)c1cc(-c2ccc(NC(=O)OCc3ccccc3)cc2)nn1C
Reactant: CCCC(=O)OC[C@H]1CO1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: Cl
Agent: [Li]CCCC
Solvent: COC(OC)OC
Solvent: CO
Solvent: CCN(CC)CC
Product: COC(OC)c1cc(-c2ccc(N3C[C@H](CO)OC3=O)cc2)nn1C
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 49.5 %

Procedure:
Benzyl 4-[5-(diethoxymethyl)-1-methyl-1H-pyrazol-3-yl]phenylcarbamate (Intermediate 11, 8.29 g, 20.2 mmol), was dissolved in THF (150 ml) and cooled to −70° C. nBuLi (15 ml of a 1.6 M solution in hexanes, 24 mmol) was added dropwise over 10 min. After 25 min at −70° C., (2R)-oxiran-2-ylmethyl butyrate (3.7 ml, 26.2 mmol) was added and the solution was allowed to warm slowly to room temperature over 16 hours. The mixture was poured into 0.25M HCl and extracted with ethyl acetate, the organic layer was washed with saturated NaCl, dried over sodium sulfate and evaporated to give the crude product which was partially hydrolysed to the aldehyde. The crude product was dissolved in 1:1 THF:methanol (12 ml), trimethyl orthoformate (2.6 ml, 24 mmol) and camphorsulfonic acid (100 mg, 0.4 mmol) were added and the solution was warmed at 50° C. for 1 hour. Triethylamine (0.5 ml) was added and the solution was evaporated and purified by chromatography on silica gel, eluting with 60–100% ethyl acetate/hexane, to give the title compound as a white solid (3.47 g).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][OH:5].[H-].[Na+].Cl[C:9]1[CH:10]=[C:11]([CH:32]=[CH:33][N:34]=1)[C:12]([NH:14][C:15]1[S:16][C:17]2[C:23]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)=[CH:22][CH:21]=[C:20]([O:30][CH3:31])[C:18]=2[N:19]=1)=[O:13]>O1CCOCC1.C(OCC)(=O)C>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:9]1[CH:10]=[C:11]([CH:32]=[CH:33][N:34]=1)[C:12]([NH:14][C:15]1[S:16][C:17]2[C:23]([N:24]3[CH2:25][CH2:26][O:27][CH2:28][CH2:29]3)=[CH:22][CH:21]=[C:20]([O:30][CH3:31])[C:18]=2[N:19]=1)=[O:13]
Reactant: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccnc(Cl)c3)nc12
Reactant: COCCO
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COCCOc1cc(C(=O)Nc2nc3c(OC)ccc(N4CCOCC4)c3s2)ccn1
Temperature: 115 °C
Reaction time: 0.17 h
Yield: 50 %

Procedure:
To a stirred solution of 0.058 ml (0.74 mmol) 2-methoxyethanol in 2 ml dioxane at room temperature was added 49 mg (1.24 mmol) sodium hydride (60% dispersion in mineral oil) and stirring continued for 10 minutes. 200 mg (0.49 mmol) 2-chloro-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide was then added and the mixture heated at 115° C. for 16 h. The reaction mixture was then cooled to room temperature, diluted with ethyl acetate, and washed sequentially with 1 M hydrochloric acid and saturated brine. The organic phase was then dried over sodium sulfate and concentrated in vacuo. Flash chromatography (2/1 ethyl acetate/toluene) afforded 109 mg (50%) 2-(2-methoxy-ethoxy)-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide as a yellow crystalline solid. ES-MS m/e (%): 467 (M+Na+, 16), 445 (M+H+, 100).
Reaction SMILES: [C:1]1([C:7]2[CH:11]=[C:10]([NH:12][CH2:13][CH2:14][CH2:15][N:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Br[CH2:25][C:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=[CH:28][CH:27]=1>CN(C=O)C>[C:26]1([CH2:25][N:12]([C:10]2[O:9][N:8]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH:11]=2)[CH2:13][CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=[CH:28][CH:27]=1
Reactant: c1ccc(-c2cc(NCCCN3CCCCC3)on2)cc1
Reactant: BrCc1cccc2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1ccc(-c2cc(N(CCCN3CCCCC3)Cc3cccc4ccccc34)on2)cc1
Reaction time: 0.08 h

Procedure:
To a solution of 3-phenyl-isoxazol-5-yl-(3-piperidin-1-yl-propyl)amine (142.5 mg, 0.0005 m) in DMF (6 ml) was added 25 mg 60% sodium hydride in oil. The reaction foamed and turned yellow. After stirring for 5 minutes, 110.5 mg 1-(bromomethyl)naphthalene in DMF (3 ml) was added. The reaction turned from yellow to brown in color. The DMF was removed under reduced pressure. The oil was flash chromatographed using a 50 mm×6″ silica gel column with methylene chloride 95-methanol 5-ammonium hydroxide 0.5 as the solvent system. The product fractions were collected and concentrated to an oil. Add hexane/ether and remove under reduced pressure (2×s). Ethanol was added followed by 1M HCl in ether (1 ml). Remove the solvent. Add hexane/ether (2×s) to yield “title” as a foam. Dry under high vac. HPLC 95.43% at 215. Mass Spectra cal'd. 425.57; found 426.4. H NMR (CDCl3) 11.95-11.75(br,s,1H), 8.1-7.3(m, 12H), 5.6-5.4(s,1H), 5.2-4.8(s,2H), 3.6-3.4(br,2H)3.35-3.15(br,2H), 2.7-2.5(br, 2H),2.3-2.0(br,6H.)
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[C:5](=[CH:11]OCC)[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].[CH:16]1([NH:21][C:22]2[CH:27]=[C:26]([F:28])[C:25]([F:29])=[C:24]([F:30])[CH:23]=2)[CH2:20][CH2:19][CH2:18][CH2:17]1>>[CH:16]1([N:21]([CH:11]=[C:5]([C:4]([O:3][CH2:1][CH3:2])=[O:15])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[C:22]2[CH:23]=[C:24]([F:30])[C:25]([F:29])=[C:26]([F:28])[CH:27]=2)[CH2:17][CH2:18][CH2:19][CH2:20]1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: Fc1cc(NC2CCCC2)cc(F)c1F
Product: CCOC(=O)C(=CN(c1cc(F)c(F)c(F)c1)C1CCCC1)C(=O)OCC
Temperature: 130 °C
Reaction time: 4 h

Procedure:
3.2 ml of diethyl(ethoxymethylene)malonate was added to 3.3 g of N-cyclopentyl-3,4,5-trifluoroaniline, followed by stirring at 130° C. for 4 hours. By purifying by silica gel column chromatography, 2.2 g of diethyl {[cyclopentyl(3,4,5-trifluorophenyl)amino]methylene}malonate was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH3:12][C:13]1[N:14]=[CH:15][S:16][C:17]=1[CH2:18][CH2:19]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>C1COCC1>[CH3:12][C:13]1[N:14]=[CH:15][S:16][C:17]=1[CH2:18][CH2:19][O:8][C:5]1[CH:6]=[CH:7][C:2]([NH2:1])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: Cc1ncsc1CCO
Reactant: Nc1ccc(O)cc1[N+](=O)[O-]
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1ncsc1CCOc1ccc(N)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 86.2 %

Procedure:
A mixture of 4-amino-3-nitrophenol (386 mg, 2.5 mmol), 2-(4-methyl-1,3-thiazol-5-yl)ethanol (0.299 mL, 2.5 mmol), polymer supported triphenylphosphine (1.25 g, 3 mmol/g, 3.75 mmol), and di-tert-butyl azodicarboxylate (864 mg, 3.75 mmol) in THF (10 mL) was stirred at room temperature for 16 hours. Filtered through Celite and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel with 1:1 hexanes/ethyl acetate to provide 602 mg (86%) of the desired product. MS (DCI) m/e 279 (M+H)+, 1H NMR (300 MHz, DMSO-d6): □ 8.83 (s, 1H), 7.37 (d, J=3.05 Hz, 1H), 7.25 (s, 2H), 7.16 (dd, J=8.99, 2.88 Hz, 1H), 7.01 (s, 1H), 4.10 (t, J=6.27 Hz, 2H), 3.19 (t, J=6.27 Hz, 2H), 2.35 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C@H:8]([C:10]1[CH:15]=[CH:14][C:13]([C@H:16]2[CH2:18][O:17]2)=[CH:12][CH:11]=1)[CH3:9])([CH3:4])([CH3:3])[CH3:2].[C:20]([NH2:24])([CH3:23])([CH3:22])[CH3:21]>C(O)C>[C:20]([NH:24][CH2:18][C@H:16]([C:13]1[CH:14]=[CH:15][C:10]([C@@H:8]([NH:7][C:6](=[O:19])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH3:9])=[CH:11][CH:12]=1)[OH:17])([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)N
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1ccc([C@H]2CO2)cc1
Solvent: CCO
Product: C[C@H](NC(=O)OC(C)(C)C)c1ccc([C@H](O)CNC(C)(C)C)cc1
Temperature: 50 °C
Reaction time: 72 h

Procedure:
4.4 g of the compound [5-4] was dissolved in 40 mL of ethanol, 20 mL of tert-butylamine was added thereto, and the mixture was stirred for 3 days at 50° C. The reaction solution was concentrated, and the resulting residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=100/0-0/100), to obtain 3.1 g of tert-butyl ((1S)-1-{4-[(1S)-2-(tert-butylamino)-1-hydroxyethyl]phenyl}ethyl)carbamate [5-5] (hereinafter, referred to as the compound [5-5]) as a white solid.
Reaction SMILES: [CH2:1]1[N:6]2[CH2:7][N:8]3[CH2:10][N:4]([CH2:5]2)[CH2:3][N:2]1[CH2:9]3.[C:11]([OH:21])(=[O:20])[C@@H:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[OH:13]>C(C(C)=O)C>[CH2:1]1[N:6]2[CH2:7][N:8]3[CH2:10][N:4]([CH2:5]2)[CH2:3][N:2]1[CH2:9]3.[C:11]([O-:21])(=[O:20])[CH:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[OH:13]
Reactant: O=C(O)[C@H](O)c1ccccc1
Agent: C1N2CN3CN1CN(C2)C3
Solvent: CCC(C)=O
Product: O=C([O-])C(O)c1ccccc1
Temperature: 25 °C

Procedure:
To a boiling suspension of 140 ml. of methyl ethyl ketone containing 18.7 g. (0.133 mole) of methenamine is slowly added a hot solution of 20.3 g (0.133 mole) of d-mandelic acid in 50 ml. of methyl ethyl ketone with vigorously stirring. The heat source is removed. The reaction mixture is stirred to room temperature, and then cooled in an ice-water bath. White crystals are collected by filtration, washed with a small amount of methyl ethyl ketone, followed by anhydrous ether, and dried at 50° C. in vacuum for 3 hours to obtain methenamine dextro-mandelate. mp. 133-4° C [c]D21 + 62.0° (C = 3,H2O)
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[C:19]([CH:31]=[CH:32][CH:33]=2)[C:20]([NH:22][C:23]2[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:24]=2[F:30])=[O:21])[CH:5]=[CH:4][N:3]=1.[CH3:34][O:35][C:36]1[CH:42]=[C:41]([N:43]2[CH2:48][CH2:47][N:46]([CH2:49][CH2:50][O:51][CH3:52])[CH2:45][CH2:44]2)[CH:40]=[CH:39][C:37]=1[NH2:38].C1(C)C=CC(S(O)(=O)=O)=CC=1.C(O)C(F)(F)F.N>CO.C(Cl)Cl>[F:30][C:24]1[CH:25]=[CH:26][CH:27]=[C:28]([F:29])[C:23]=1[NH:22][C:20](=[O:21])[C:19]1[CH:31]=[CH:32][CH:33]=[C:17]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]3[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:38][C:37]3[CH:39]=[CH:40][C:41]([N:43]4[CH2:48][CH2:47][N:46]([CH2:49][CH2:50][O:51][CH3:52])[CH2:45][CH2:44]4)=[CH:42][C:36]=3[O:35][CH3:34])[N:7]=2)[CH:18]=1
Reactant: COCCN1CCN(c2ccc(N)c(OC)c2)CC1
Reactant: O=C(Nc1c(F)cccc1F)c1cccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: N
Solvent: OCC(F)(F)F
Solvent: CO
Solvent: ClCCl
Product: COCCN1CCN(c2ccc(Nc3nccc(-c4c(-c5cccc(C(=O)Nc6c(F)cccc6F)c5)nc5ccccn45)n3)c(OC)c2)CC1
Temperature: 100 °C
Yield: 53.6 %

Procedure:
3-[3-(2-Chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)benzamide (Intermediate Example 1) (100 mg, 0.22 mmol), 2-(methyloxy)-4-{4-[2-(methyloxy)ethyl]-1-piperazinyl}aniline (Example 238, step A) (51 mg, 0.194 mmol), and p-toluenesulfonicacid (99 mg, 0.52 mmol) were weighed into a 20 mL vial. 1 mL of trifluoroethanol was added and the mixture was heated to 100° C. for 72 h. 2 mL of 2 N ammonia in MeOH was added. The solvent was rotovaped down. The residue was taken up in 3 mL of DCM. 1 g of silica gel was added. The solvent was rotovaped down and the pre-absorbed solids were purified by flash chromatography to give the title compound (72 mg, 0.104 mmol, 53%). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.24 (s, 1H), 9.40 (s, 1H), 8.47 (s, 1H), 8.33 (s, 1H), 8.20 (d, J=5.50 Hz, 1H), 8.05 (d, J=7.70 Hz, 1H), 7.81 (d, J=8.07 Hz, 1H), 7.72 (d, J=8.80 Hz, 1H), 7.61 (t, J=7.88 Hz, 1H), 7.43-7.49 (m, 1H), 7.35-7.43 (m, 2H), 7.17-7.24 (m, 2H), 6.97 (t, J=6.97 Hz, 1H), 6.67 (d, J=2.20 Hz, 1H), 6.46 (d, J=5.50 Hz, 2H), 3.79 (s, 3H), 3.46 (t, J=5.68 Hz, 2H), 3.24 (s, 3H), 3.09-3.16 (m, 4H), 2.53-2.58 (m, 4H), 2.51 (t, J=5.87 Hz, 2H); MS (ESI): 691 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:15][NH:16][CH3:17].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.CO.C(Cl)Cl.CCOC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([N:16]([CH3:17])[CH3:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: CNC
Reactant: O=C1CCN(c2ccc(Br)cc2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CC(=O)O
Product: CN(C)C1CCN(c2ccc(Br)cc2)CC1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a mixture of 1-(4-bromophenyl)piperidin-4-one (200 mg, 0.79 mmol), dimethylamine (0.80 mL, 1.57 mmol, 2M in THF), and acetic acid (0.20 mL, 3.15 mmol) in DCE (8 mL) was added sodium triacetoxyborohydride (250 mg, 1.18 mmol) at rt. The resulting mixture was stirred at rt for 2.5 h. The reaction was quenched with sat. NaHCO3 solution, extracted with CH2Cl2, dried over MgSO4, filtered, and concentrated to give a yellow oil. The title compound was isolated by silica gel chromatography (EtOAc to MeOH/CH2Cl2, 35:100) as a yellow solid (139 mg, 63%). 1H NMR (400 MHz, CD3OD) δ 7.31 (d, J=9.0 Hz, 2H), 6.88 (d, J=9.0 Hz, 2H), 3.76-3.73 (m, 2H), 2.69 (t, J=12.3 Hz, 2H), 2.53-2.45 (m, 1H), 2.41 (s, 6H), 2.01-1.98 (m, 2H), 1.67-1.57 (m, 2H); MS ESI 283.0 [M+H]+, calcd for [C13H19BrN2+H]+ 283.07.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8](/[CH:9]=[CH:10]/[C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=2)=[CH:7][C:6]([C:20]2[C:21](=[O:26])[NH:22][CH:23]=[CH:24][CH:25]=2)=[CH:5][C:4]=1[C:27]1([CH3:30])[CH2:29][CH2:28]1>CO.CCOC(C)=O.[Pd]>[NH2:17][C:14]1[CH:15]=[CH:16][C:11]([CH2:10][CH2:9][C:8]2[CH:7]=[C:6]([C:20]3[C:21](=[O:26])[NH:22][CH:23]=[CH:24][CH:25]=3)[CH:5]=[C:4]([C:27]3([CH3:30])[CH2:29][CH2:28]3)[C:3]=2[O:2][CH3:1])=[CH:12][CH:13]=1
Reactant: COc1c(/C=C/c2ccc([N+](=O)[O-])cc2)cc(-c2ccc[nH]c2=O)cc1C1(C)CC1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1c(CCc2ccc(N)cc2)cc(-c2ccc[nH]c2=O)cc1C1(C)CC1
Yield: 72.5 %

Procedure:
To a suspension of 136 (0.14 g, 0.35 mmol) in MeOH-EtOAc (2:1, 7.5 mL) was added 10% Pd/C (0.014 g), and the reaction mixture was stirred under a hydrogen atmosphere maintained by a balloon for 16 h. The reaction mixture was filtered through diatomaceous earth and the pad was rinsed successively with EtOAc, MeOH and DCM. The combined filtrates were concentrated under reduced pressure, and the crude residue was purified by SiO2 chromatography eluting with EtOAc/hexane to afford 0.095 g (76%) of 3-[3-[2-(4-amino-phenyl)-ethyl]-4-methoxy-5-(1-methylcyclopropyl)phenyl]-1H-pyridin-2-one (I-99) as a light yellow powder.
Reaction SMILES: [Si]([O:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([N:15]2[CH:19]=[C:18]([C:20]3[CH:25]=[N:24][C:23]([NH:26][CH3:27])=[C:22]4[O:28][C:29](Cl)=[CH:30][C:21]=34)[CH:17]=[N:16]2)[CH2:11][CH2:10]1)(C(C)(C)C)(C)C.CC1(C)C(C)(C)OB([C:40]2[C:48]3[C:43](=[CH:44][N:45]=[CH:46][CH:47]=3)[S:42][CH:41]=2)O1.C(=O)([O-])[O-].[Na+].[Na+].Cl>O1CCOCC1.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>[CH3:27][NH:26][C:23]1[N:24]=[CH:25][C:20]([C:18]2[CH:17]=[N:16][N:15]([C@H:12]3[CH2:11][CH2:10][C@H:9]([OH:8])[CH2:14][CH2:13]3)[CH:19]=2)=[C:21]2[CH:30]=[C:29]([C:40]3[C:48]4[C:43](=[CH:44][N:45]=[CH:46][CH:47]=4)[S:42][CH:41]=3)[O:28][C:22]=12
Reactant: CNc1ncc(-c2cnn([C@H]3CC[C@H](O[Si](C)(C)C(C)(C)C)CC3)c2)c2cc(Cl)oc12
Reactant: CC1(C)OB(c2csc3cnccc23)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CNc1ncc(-c2cnn([C@H]3CC[C@H](O)CC3)c2)c2cc(-c3csc4cnccc34)oc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 4-[1-(trans-4-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl)-1H-pyrazol-4-yl]-2-chloro-N-methylfuro[2,3-c]pyridin-7-amine (44.3 mg, 0.0961 mmol), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thieno[2,3-c]pyridine (33.9 mg, 0.130 mmol), and Pd(PPh3)4 (12.8 mg, 0.0111 mmol) in 1,4-dioxane (0.5 mL) was charged with 1.0 M aqueous sodium carbonate (0.5 mL) and then irradiated in a microwave at 120° C. for 60 min. The reaction mixture was then charged with 4.0 M hydrochloric acid in 1,4-dioxane (0.6 mL) and stirred at rt for 30 min. The suspension was concentrated in vacuo. The residue was partitioned between a mixture of dichloromethane and aqueous sodium bicarbonate and the layers were separated. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. Purification by ISCO chromatography (2 to 10% 7 N ammonia/methanol:dichloromethane) afforded 30.1 mg (69%) of the title compound as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 9.40 (s, 1H), 8.79 (s, 1H), 8.65 (s, 2H), 8.23 (s, 1H), 8.08 (s, 1H), 7.95 (d, J=0.76 Hz, 1H), 7.73 (s, 1H), 6.97 (q, J=4.55 Hz, 1H), 4.70 (d, J=4.55 Hz, 1H), 4.19 (tt, J=3.95, 11.59 Hz, 1H), 3.48-3.59 (m, 1H), 3.02 (d, J=4.80 Hz, 3H), 2.07 (d, J=12.13 Hz, 2H), 1.82-2.01 (m, 4H), 1.31-1.46 (m, 2H); MS (ESI): 446.16 [M+H]+; HPLC tR=2.50 min.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[C:4]([N+:15]([O-])=O)[CH:3]=1.Cl[Sn]Cl>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[C:4]([NH2:15])[CH:3]=1
Reactant: O=[N+]([O-])c1cc(Br)ccc1Oc1ccccc1
Agent: Cl[Sn]Cl
Product: Nc1cc(Br)ccc1Oc1ccccc1
Yield: 99.3 %

Procedure:
The product from Example 124a (6.6 g, 22.5 mmol) was reduced with SnCl2 following the procedure from Example 1f giving the title compound as a brown oil (5.9 g, 100%).