Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [BH4-].[Li+].[CH3:3][C:4]1[C:9]([C:10]2C=CN=CC=2)=[C:8]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]3[N:31]=[N:32][N:33]([C:35]([C:48]4[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=4)([C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)[C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[N:34]=3)=[CH:20][CH:19]=2)[CH:7]=[C:6]([CH3:54])[N:5]=1.[OH2:55]>O1CCCC1>[OH:55][CH2:10][C:9]1[C:4]([CH3:3])=[N:5][C:6]([CH3:54])=[CH:7][C:8]=1[O:16][CH2:17][C:18]1[CH:19]=[CH:20][C:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[C:30]2[N:31]=[N:32][N:33]([C:35]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)([C:48]3[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=3)[C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[N:34]=2)=[CH:22][CH:23]=1
Reactant: Cc1cc(OCc2ccc(-c3ccccc3-c3nnn(C(c4ccccc4)(c4ccccc4)c4ccccc4)n3)cc2)c(-c2ccncc2)c(C)n1
Reactant: O
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cc(OCc2ccc(-c3ccccc3-c3nnn(C(c4ccccc4)(c4ccccc4)c4ccccc4)n3)cc2)c(CO)c(C)n1
Temperature: 0 °C

Procedure:
Lithium borohydride (66 mg) was added over a period of 10 minutes to a solution of compound A (800 mg) in tetrahydrofuran (THF) (25 ml) stirred at 0° C. under an atmosphere of argon. The solution was then stirred at ambient temperature for 16 hours, cooled to 0° C. and water (100 ml) was added. The mixture was extracted with dichloromethane (2×50 ml) and the extracts were washed with saturated sodium chloride solution (50 ml) and dried (MgSO4). The solvent was removed by evaporation and the residue purified by flash chromatography, eluting with methanol/dichloromethane (1:19 v/v, to give 3-hydroxymethyl-2,6-dimethyl-4-[(2'-(2-triphenylmethyl-2-H-tetrazol-5-yl)biphenyl-4-yl)methoxy]pyridine (B) (246 mg), as a foam; NMR (d6 -DMSO/d4 -acetic acid): 2.55(s,3H), 2.65(s,3H), 4.7(s,2H), 5.4(s,2H), 6.9-7.0(m,6H), 7.2(d,2H), 7.25-7.45(complex m,12 H), 7.45-7.8(complex m,3H), 7.9(dd,1H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C.[NH2:19][C:20]1[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][C:21]=1[N:28]1[CH:32]=[CH:31][CH:30]=[CH:29]1>C(O)C>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]2([NH:19][C:20]3[C:21](=[CH:22][CH:23]=[C:24]([O:26][CH3:27])[CH:25]=3)[N:28]3[CH:29]=[CH:30][CH:31]=[C:32]23)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: COc1ccc(-n2cccc2)c(N)c1
Solvent: CCO
Solvent: CC(=O)O
Product: COc1ccc2c(c1)NC1(CCN(Cc3ccccc3)CC1)c1cccn1-2

Procedure:
510 g (0.027 mole) of 1-benzyl-4-piperidone and 2 ml. of glacial acetic acid are added to a solution of 50 g (0.027 mole) of 1-(2-amino-4-methoxy-phenyl)pyrrole [Example 19(b)] in 80 ml. of absolute ethanol. The solution is refluxed for 43 hours and concentrated to an oil which is washed with water. The oil is recrystallized from isopropanol to give 1'-benzyl-7-methoxy-4,5-dihydrospiro[pyrrolo(1,2-a)quinoxaline-4,4'-piperidine], m.p. 123°-124° C.
Reaction SMILES: O[C:2]1([CH3:13])[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1.[Br:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.FC(F)(F)S(O)(=O)=O.[OH-].[Na+]>>[Br:14][C:15]1[CH:20]=[CH:19][C:18]([C:2]2([CH3:13])[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]2)=[CH:17][CH:16]=1
Reactant: CCOC(=O)N1CCC(C)(O)CC1
Reactant: Brc1ccccc1
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Product: CCOC(=O)N1CCC(C)(c2ccc(Br)cc2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 81.4 %

Procedure:
At 0° C. under N2 atmosphere, to a solution of ethyl 4-hydroxy-4-methylpiperidine-1-carboxylate (283) (2.4 g, 12.8 mmol) in bromobenzene (20.1 g, 128 mmol) was added trifluoromethanesulfonic acid (19.2 g, 128 mmol). The resulting mixture was stirred at RT for 3 hours before being poured onto ice. The mixture was basified with 1N NaOH and extracted with DCM (20 mL×3). The combined organic layers were washed with brine, dried, concentrated in vacuo and subjected to silica flash column using 0 to 20% EtOAc in PE to give ethyl 4-(4-bromophenyl)-4-methylpiperidine-1-carboxylate (284) (3.4 g, 81%) as a light yellow oil.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:9]([N:10]=1)=[CH:8][CH:7]=[C:6]([O:11][C:12]1[CH:13]=[C:14]([NH:19][C:20](=[O:32])[C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]4([C:30]#[N:31])[CH2:29][CH2:28]4)[CH:22]=3)[CH:15]=[CH:16][C:17]=1[CH3:18])[N:5]=2.[CH:33]1([C:36](Cl)=[O:37])[CH2:35][CH2:34]1.C(=O)([O-])O.[Na+]>N1C=CC=CC=1>[C:30]([C:27]1([C:23]2[CH:22]=[C:21]([CH:26]=[CH:25][CH:24]=2)[C:20]([NH:19][C:14]2[CH:15]=[CH:16][C:17]([CH3:18])=[C:12]([O:11][C:6]3[N:5]=[C:4]4[S:3][C:2]([NH:1][C:36]([CH:33]5[CH2:35][CH2:34]5)=[O:37])=[N:10][C:9]4=[CH:8][CH:7]=3)[CH:13]=2)=[O:32])[CH2:29][CH2:28]1)#[N:31]
Reactant: Cc1ccc(NC(=O)c2cccc(C3(C#N)CC3)c2)cc1Oc1ccc2nc(N)sc2n1
Reactant: O=C(Cl)C1CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: Cc1ccc(NC(=O)c2cccc(C3(C#N)CC3)c2)cc1Oc1ccc2nc(NC(=O)C3CC3)sc2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 60.8 %

Procedure:
To a solution of N-{3-[(2-amino[1,3]thiazolo[5,4-b]pyridin-5-yl)oxy]-4-methylphenyl}-3-(1-cyanocyclopropyl)benzamide (200 mg, 0.452 mmol) in pyridine (5 mL) was added cyclopropanecarbonyl chloride (77.8 μL, 1.13 mmol), and the mixture was stirred at room temperature for 30 min. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtrated. The solvent was evaporated under reduced pressure, and the residue was precipitated with tetrahydrofuran to give the title compound (140 mg, 61%) as a white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:13][C:12]([CH3:15])([CH3:14])[CH2:11][CH2:10][C:9]=2[CH:16]=[O:17])=[CH:4][CH:3]=1.[CH3:18][Mg]Cl>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH2:13][C:12]([CH3:14])([CH3:15])[CH2:11][CH2:10][C:9]=2[CH:16]([OH:17])[CH3:18])=[CH:6][CH:7]=1
Reactant: CC1(C)CCC(C=O)=C(c2ccc(Cl)cc2)C1
Reactant: C[Mg]Cl
Solvent: C1CCOC1
Product: CC(O)C1=C(c2ccc(Cl)cc2)CC(C)(C)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a mixture of EXAMPLE 218A (3.52 g) in tetrahydrofuran (30 ml) was slowly added methylmagnesium chloride (3 M in tetrahydrofuran, 7.08 ml) at −78° C. After the addition was completed, the reaction mixture was stirred at 0° C. for 30 minutes and ice-water was added. The resulting mixture was extracted with dichloromethane and the organic layer was dried over Na2SO4 and concentrated. The residue was purified by flash chromatography, eluting with 0-100% dichloromethane in hexane to provide the title compound.
Reaction SMILES: [CH:1]1([N:4]([CH:26]2[CH2:28][CH2:27]2)[C:5]([C:7]2[N:23]([CH2:24][CH3:25])[C:10]3=[N:11][C:12]([NH:19][C:20]([NH2:22])=[S:21])=[C:13]4[N:17]=[CH:16][N:15]([CH3:18])[C:14]4=[C:9]3[CH:8]=2)=[O:6])[CH2:3][CH2:2]1.Br[CH2:30][C:31](=O)[CH2:32][CH3:33]>>[CH:26]1([N:4]([CH:1]2[CH2:2][CH2:3]2)[C:5]([C:7]2[N:23]([CH2:24][CH3:25])[C:10]3=[N:11][C:12]([NH:19][C:20]4[S:21][CH:30]=[C:31]([CH2:32][CH3:33])[N:22]=4)=[C:13]4[N:17]=[CH:16][N:15]([CH3:18])[C:14]4=[C:9]3[CH:8]=2)=[O:6])[CH2:27][CH2:28]1
Reactant: CCn1c(C(=O)N(C2CC2)C2CC2)cc2c3c(ncn3C)c(NC(N)=S)nc21
Reactant: CCC(=O)CBr
Product: CCc1csc(Nc2nc3c(cc(C(=O)N(C4CC4)C4CC4)n3CC)c3c2ncn3C)n1

Procedure:
Prepared from N,N-dicyclopropyl-6-ethyl-1-methyl-4-thioureido-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxamide (example 2B) and 1-bromobutan-2-one using the same procedure as reported for 2.
Reaction SMILES: [CH2:1]([OH:9])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:10]1([CH3:20])[CH:15]=[CH:14][C:13]([S:16](Cl)(=[O:18])=[O:17])=[CH:12][CH:11]=1>N1C=CC=CC=1.C(OCC)(=O)C>[CH3:20][C:10]1[CH:15]=[CH:14][C:13]([S:16]([O:9][CH2:1][CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)(=[O:18])=[O:17])=[CH:12][CH:11]=1
Reactant: OCCc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)OCCc2ccccc2)cc1
Reaction time: 16 h
Yield: 51.2 %

Procedure:
To a stirred solution of phenethyl alcohol (0.50 mL, 4.17 mmol) in pyridine (4 mL) at 0° C. was added p-toluenesulfonyl chloride (0.80 g, 4.18 mmol). The reaction mixture was stirred for 16 h, and then diluted with ethyl acetate (75 mL). The organic solution was washed with 10% aqueous hydrochloric acid (2×25 mL), saturated aqueous sodium bicarbonate (50 mL) and brine (25 mL), then dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified by column chromatography eluting with 0-20% ethyl acetate in hexane to afford the title compound as a light yellow liquid (0.59 g, 51%): 1H NMR (300 MHz, CDCl3) δ 7.69 (d, J=8.3 Hz, 2H), 7.31-7.20 (m, 5H), 7.11 (dd, J=7.4, 1.7 Hz, 2H), 4.21 (t, J=7.1 Hz, 2H), 2.96 (t, J=7.1 Hz, 2H), 2.43 (s, 3H); MS (ES+) m/z 299.2 (M+23).
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][C:5]1[CH:6]=[C:7]([CH:20]=[CH:21][CH:22]=1)[O:8][C:9]1[C:14]([CH2:15][C:16]([O:18][CH3:19])=[O:17])=[CH:13][CH:12]=[CH:11][N:10]=1.[CH:23]([O:25][CH3:26])=O.Cl>CN(C=O)C.O>[OH:3][CH2:4][C:5]1[CH:6]=[C:7]([CH:20]=[CH:21][CH:22]=1)[O:8][C:9]1[C:14](/[C:15](=[CH:23]\[O:25][CH3:26])/[C:16]([O:18][CH3:19])=[O:17])=[CH:13][CH:12]=[CH:11][N:10]=1
Reactant: COC=O
Reactant: COC(=O)Cc1cccnc1Oc1cccc(CO)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CO/C=C(/C(=O)OC)c1cccnc1Oc1cccc(CO)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 15 %

Procedure:
To a stirred suspension of sodium hydride (1.056 g, 50% dispersion in oil, pre-washed with petroleum ether) in dry DMF (15 ml) at 0°-5° C. was added dropwise over 5 minutes a solution containing methyl 2-(3-hydroxymethylphenoxy)pyridin-3-ylacetate (2.0 g) and methyl formate (9 ml) in DMF (effervescence). After the addition was complete, the reaction mixture was allowed to warm to room temperature. After stirring for a further 3 hours, the reaction mixture was carefully poured into water, neutralised with 2N hydrochloric acid and then extracted thoroughly with ether (×6). The combined ether layers were dried, filtered and evaporated to afford a crude residue which was used without further purification. The residue was dissolved in DMF (10 ml) and then treated with potassium carbonate (0.60 g) and dimethyl sulphate (0.64 g). Standard work-up and chromatography on silica gel (eluent petroleum ether-ether, 1:1) afforded (E)-methyl 2-[2-(3-hydroxymethylphenoxy)pyridin-3-yl]-3-methoxypropenoate (0.35 g, 15 %); mass spectrum m/e 315 (M+).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[N:10][C:11](Cl)=[C:12]([F:17])[CH:13]=2)[N:8]([CH:19]2[CH2:21][CH2:20]2)[CH:7]=1)=[O:5])[CH3:2].[C:22]([O:26][C:27]([NH:29][CH2:30][C:31]1[CH:39]=[CH:38][CH:37]=[C:36]2[C:32]=1[CH2:33][NH:34][CH2:35]2)=[O:28])([CH3:25])([CH3:24])[CH3:23].C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[N:10][C:11]([N:34]3[CH2:33][C:32]4[C:36](=[CH:37][CH:38]=[CH:39][C:31]=4[CH2:30][NH:29][C:27]([O:26][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:28])[CH2:35]3)=[C:12]([F:17])[CH:13]=2)[N:8]([CH:19]2[CH2:21][CH2:20]2)[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cn(C2CC2)c2nc(Cl)c(F)cc2c1=O
Reactant: CC(C)(C)OC(=O)NCc1cccc2c1CNC2
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1cn(C2CC2)c2nc(N3Cc4cccc(CNC(=O)OC(C)(C)C)c4C3)c(F)cc2c1=O
Yield: 80 %

Procedure:
A mixture of 310 mg of 1-cyclopropyl-6-fluoro-7- chloro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester, 524 mg of 4-(t-butyloxycarbonylaminomethyl)isoindoline, 0.42 ml of triethylamine, and 5 ml of anhydrous chloroform was heated at 60°-70° C. for 0.5 hours while stirring. The resulting reaction mixture was diluted with 25 ml of chloroform. The mixture was washed with 5% acetic acid and brine in this order, dried over anhydrous sodium sulfate, and condensed. The residue was crystallized by the addition of ethylether. The crystals were collected by filtration and recrystallized from a mixed solvent of chloroform, methanol, and ethanol to obtain 417 mg of 7-[4- (t-butoxycarbonylaminomethyl)-2-isoindolinyl]-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:40])=[N:14][C:15]([CH3:39])=[C:16]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH2:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[CH:28][CH:27]=2)[C:17]=1[N:18]1[CH2:23][CH2:22][C:21]([CH3:25])([CH3:24])[CH2:20][CH2:19]1)[C:7]([O:9]CC)=[O:8])([CH3:4])([CH3:3])[CH3:2].[Li+].[OH-]>CCO.O>[C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:40])=[N:14][C:15]([CH3:39])=[C:16]([C:26]2[CH:27]=[CH:28][C:29]([O:32][CH2:33][CH2:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[CH:30][CH:31]=2)[C:17]=1[N:18]1[CH2:23][CH2:22][C:21]([CH3:25])([CH3:24])[CH2:20][CH2:19]1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc(C)c(-c2ccc(OCCC(C)(C)C)cc2)c1N1CCC(C)(C)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1nc(C)c([C@H](OC(C)(C)C)C(=O)O)c(N2CCC(C)(C)CC2)c1-c1ccc(OCCC(C)(C)C)cc1
Yield: 83.3 %

Procedure:
A mixture of (S)-ethyl 2-(tert-butoxy)-2-(5-(4-(3,3-dimethylbutoxy)phenyl)-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)acetate (0.02 g, 0.036 mmol) and LiOH (8.66 mg, 0.362 mmol) in 9:1 EtOH/H2O (2 mL) was refluxed for 4 h. Then, cooled and purified by prep-HPLC to afford (S)-2-(tert-butoxy)-2-(5-(4-(3,3-dimethylbutoxy)phenyl)-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)acetic acid (0.0158 g, 0.030 mmol, 83% yield) as white solid. 1H NMR (500 MHz, CDCl3) δ 7.12-7.16 (m, 1H), 7.06 (d, J=7.7 Hz, 1H), 6.96-7.00 (m, 2H), 5.92 (br. s., 1H), 4.06-4.15 (m, 2H), 3.46-3.81 (m, 1H), 2.90 (br. s., 1H), 2.69 (br. s., 3H), 2.27-2.42 (m, 1H), 2.25 (s, 3H), 1.95-2.17 (m, 1H), 1.79 (t, J=7.3 Hz, 2H), 1.50-1.64 (m, 1H), 1.27-1.40 (m, 3H), 1.25 (s, 9H), 1.04 (s, 9H), 0.81 (br.s., 6H). LCMS (M+H)=525.3.
Reaction SMILES: [C:1]([C:4]1[N:8]([CH2:9][CH2:10][NH:11]C(=O)OC(C)(C)C)[N:7]=[C:6]([N:19]2[C:23]([CH3:24])=[CH:22][CH:21]=[C:20]2[CH3:25])[CH:5]=1)(=O)[CH3:2].C(O)(C(F)(F)F)=O>ClCCl>[CH3:25][C:20]1[N:19]([C:6]2[CH:5]=[C:4]3[C:1]([CH3:2])=[N:11][CH2:10][CH2:9][N:8]3[N:7]=2)[C:23]([CH3:24])=[CH:22][CH:21]=1
Reactant: CC(=O)c1cc(-n2c(C)ccc2C)nn1CCNC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1=NCCn2nc(-n3c(C)ccc3C)cc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer was charged with 287e (5.40 g, 1.0 eq., 15.6 mmol), CF3COOH (10 mL), and dichloromethane (50 mL). The mixture was stirred at room temperature for 1 h and concentrated under reduced pressure to afford crude 287f, which was used in the next step without further purification. MS-ESI: [M+H]+ 229.1
Reaction SMILES: [C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:8][CH2:9][NH2:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:18][C:19]#[N:20].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.ClCCl>[C:19]([CH2:18][NH:10][CH2:9][CH2:8][CH:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)#[N:20]
Reactant: N#CCBr
Reactant: NCCC(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: ClCCl
Product: N#CCNCCC(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 50 %

Procedure:
A mixture of 2.11 g (10 mmol) 3,3-diphenylpropylamine (Aldrich), (0.54 g, 4.54 mmol) bromoacetonitrile (Aldrich), and 2.5 g potassium carbonate in 5 ml acetonitrile was stirred at room temperature for 16 hours. The reaction mixture was diluted with dichloromethane, washed with water, the solvent evaporated, and the residue chromatographed on silica gel column with 30% ethyl acetate in hexanes to give 1.24 g (yield 50%) N-cyanomethyl-3,3-diphenylpropylamine as an oil which solidified on standing. 1H NMR (CDCl3, 300 MHz) 7.45–7.10 (m, 10 H), 4.05 (t, 1 H), 3.50 (s, 2 H), 2.67 (t, 2 H), 2.23 (dt, 2H); 13C NMR (CDCl3, 75 MHz) 144.25, 128.53, 127.68, 126.33, 117.72, 48.58, 47.13, 37.19, 35.14.
Reaction SMILES: [C:1]1(=[O:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:7](=O)[CH2:8][CH2:9][CH2:10][CH3:11].Cl>[OH-].[Na+].O>[CH:7](=[C:2]1[CH2:3][CH2:4][CH2:5][C:1]1=[O:6])[CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCCC=O
Reactant: O=C1CCCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCCC=C1CCCC1=O
Temperature: 27.5 °C
Reaction time: 2 h
Yield: 68.7 %

Procedure:
A 3-L reaction flask was charged with cyclopentanone (500 g, 6 mol), water (H2O) (500 mL) and sodium hydroxide (NaOH) (10 g, 0.25 mol). Valeraldehyde (430 g, 5 mol) was fed into the reaction flask over 3 hours while the temperature was maintained at 25-30° C. After the feeding was completed, the reaction was aged for 2 hours and neutralized with hydrochloric acid (HCl) (30 g, 0.3 mol) while the temperature was maintained at 25-30° C. The reaction mass was further aged for 2 hours. The organic layer was separated and washed with saturated aqueous sodium bicarbonate (NaHCO3) (200 mL). The obtained crude product was fractionated to provide 2-pentylidene-cyclopentanone (523 g) having a boiling point of 122° C. at 3 mmHg A 1-L zipper autoclave was charged with 2-pentylidine cyclopentanone (523 g) and palladium on carbon (Pd/C) (2 g). The autoclave was purged three times with nitrogen followed by three times with hydrogen. The autoclave agitator was then turned on to 1500 rpm and the pressure was set to 100 psi. The reaction was allowed to exotherm to about 120° C. and maintained at this temperature for 2 hours. The autoclave was cooled to an ambient temperature. The hydrogen was then vented and the autoclave was subsequently purged three times with nitrogen. The Pd/C was removed by filtration through Celite®. The crude product 2-pentyl-cyclopentanone (520 g) was obtained and used in following steps without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=O)[CH:5]=[C:6]([F:8])[CH:7]=1.[CH2:13]([O:17][C:18](=[O:22])[C@H:19]([CH3:21])[NH2:20])[CH:14]([CH3:16])[CH3:15]>>[CH2:13]([O:17][C:18](=[O:22])[C@H:19]([CH3:21])[NH:20][C:10](=[O:12])[CH2:9][C:4]1[CH:5]=[C:6]([F:8])[CH:7]=[C:2]([F:1])[CH:3]=1)[CH:14]([CH3:16])[CH3:15]
Reactant: CC(C)COC(=O)[C@H](C)N
Reactant: O=C(O)Cc1cc(F)cc(F)c1
Product: CC(C)COC(=O)[C@H](C)NC(=O)Cc1cc(F)cc(F)c1

Procedure:
Following General Procedure BI above, and using 3,5-difluorophenylacetic acid (Aldrich) and alanine iso-butyl ester (prepared following General Procedure BJ above), the title compound was prepared. The reaction was monitored by tlc on silica gel and purification was by filtration as described in the general procedure.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][OH:8])[CH2:3][CH2:2]1.F[C:10]1[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][C:11]=1[C:18]([F:21])([F:20])[F:19].C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[OH:8][CH2:7][CH:4]1[CH2:5][CH2:6][N:1]([C:10]2[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][C:11]=2[C:18]([F:19])([F:21])[F:20])[CH2:2][CH2:3]1
Reactant: N#Cc1ccc(F)c(C(F)(F)F)c1
Reactant: OCC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: N#Cc1ccc(N2CCC(CO)CC2)c(C(F)(F)F)c1
Temperature: 100 °C
Reaction time: 4 h
Yield: 79.6 %

Procedure:
To a solution of piperidin-4-ylmethanol (2.19 g) in DMSO (40 mL) were added 4-fluoro-3-(trifluoromethyl)benzonitrile (3.00 g) and potassium carbonate (3.21 g). The reaction mixture was stirred at 100° C. for 4 hr, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (3.59 g).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH:9]2[CH2:14][CH2:13][CH2:12][CH:11]([NH2:15])[CH2:10]2)[CH:5]=[C:4]([I:16])[CH:3]=1.C(N(CC)CC)C.[O:24]=[C:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27](=[O:34])[N:26]1[CH2:35][CH2:36][S:37](Cl)(=[O:39])=[O:38]>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH:9]2[CH2:14][CH2:13][CH2:12][CH:11]([NH:15][S:37]([CH2:36][CH2:35][N:26]3[C:25](=[O:24])[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[C:27]3=[O:34])(=[O:38])=[O:39])[CH2:10]2)[CH:5]=[C:4]([I:16])[CH:3]=1
Reactant: O=C1c2ccccc2C(=O)N1CCS(=O)(=O)Cl
Reactant: NC1CCCC(Nc2cc(I)cc(Cl)n2)C1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1c2ccccc2C(=O)N1CCS(=O)(=O)NC1CCCC(Nc2cc(I)cc(Cl)n2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of Example 145a (280 mg, 0.8 mmol) in CH2Cl2 (10 mL) was added triethylamine (110 mg, 1 mmol) and followed by 2-(1,3-dioxoisoindolin-2-yl)ethanesulfonyl chloride (262 mg, 0.95 mmol). The mixture was stirred at room temperature overnight. The reaction mixture was concentrated and the residue was purified by flash chromophatography (EtOAc/hexanes=1:4) to give the title compound. Yield: 180 mg (32%). MS (DCI/NH3) m/z 589 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:27][CH3:28])=[C:17]([NH:20][C:21](=[O:26])[CH:22]=[CH:23][CH2:24]Br)[CH:18]=3)[N:13]=[CH:12][C:11]=2[C:29]#[N:30])[CH:5]=[CH:6][C:7]=1[F:8].[NH:31]([CH2:36][CH:37]([OH:39])[CH3:38])[CH2:32][CH:33]([OH:35])[CH3:34].C(=O)(O)[O-].[Na+]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:27][CH3:28])=[C:17]([NH:20][C:21](=[O:26])[CH:22]=[CH:23][CH2:24][N:31]([CH2:36][CH:37]([OH:39])[CH3:38])[CH2:32][CH:33]([OH:35])[CH3:34])[CH:18]=3)[N:13]=[CH:12][C:11]=2[C:29]#[N:30])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: COc1cc2ncc(C#N)c(Nc3ccc(F)c(Cl)c3)c2cc1NC(=O)C=CCBr
Reactant: CC(O)CNCC(C)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc2ncc(C#N)c(Nc3ccc(F)c(Cl)c3)c2cc1NC(=O)C=CCN(CC(C)O)CC(C)O
Temperature: 60 °C
Reaction time: 2 h

Procedure:
A mixture of 250 mg (0.51 mmol) of 4-bromo-but-2-enoic acid[4-(3-chloro-4-fluoro-phenylamino)-3-cyano-7-methoxy-quinolin-6-yl]-amide, and 136 mg (1.02 mmol) of 1,1′-iminodi-2-propanol in 2.25 ml dimethylformamide was stirred at room temperature for 3 hr and at 60° C. for 2 hr. After the mixture was cooled, saturated sodium bicarbonate solution was added and the solution was subsequently extracted with ethyl acetate. The extracts were evaporated to an oil, washed with hexane and dried under reduced pressure. Yield 240.1 mg (87%) tan solid: mp 122-125° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[N:3]=1.[CH3:20][O:21][C:22]1[CH:23]=[CH:24][C:25]([CH3:29])=[C:26]([CH:28]=1)[NH2:27]>>[CH3:20][O:21][C:22]1[CH:23]=[CH:24][C:25]([CH3:29])=[C:26]([CH:28]=1)[NH:27][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[N:3]=1
Reactant: Clc1cc(-c2ccccn2)nc(-c2ccccn2)n1
Reactant: COc1ccc(C)c(N)c1
Product: COc1ccc(C)c(Nc2cc(-c3ccccn3)nc(-c3ccccn3)n2)c1

Procedure:
The title compound was prepared from a mixture 4-chloro-2,6-di(2-pyridinyl)pyrimidine (25 mg, 0.093 mmol) and 5-methoxy-2-methylaniline (19 mg, 0.140 mmol) similar to Example 111 and isolated as a white solid (21 mg, 61%). 1H NMR (CDCl3): 8.88-8.86 (m, 1H), 8.71-8.60 (m, 3H), 7.92-7.83 (m, 2H), 7.62 (s, 1H), 7.44-7.34 (m, 2H), 7.22 (d, J=8.4 Hz, 1H), 7.08 (d, J=2.7 Hz, 1H), 7.06 (s, 1H), 6.78 (dd, J=2.4, 8.4 Hz, 1H), 3.82 (s, 3H), 2.52 (s, 3H).