Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]=O.[CH3:9][NH:10][CH3:11].Cl.[C-:13]#[N:14].[K+]>O>[CH3:9][N:10]([CH3:11])[CH:7]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)[C:13]#[N:14]
Reactant: O=Cc1ccccn1
Reactant: [C-]#N
Reactant: CNC
Agent: Cl
Agent: [K+]
Solvent: O
Product: CN(C)C(C#N)c1ccccn1
Reaction time: 8 h

Procedure:
To cold 2-pyridinecarboxaldehyde (21.4 g., 0.2 mole) is added dimethylamine (22.5 g. of a 40% aqueous solution, 0.2 mole) and the solution is neutralized with concentrated hydrochloric acid. To the stirred neutralized solution is added 14.4 g. (0.22 mole) of potassium cyanide. The mixture is stirred overnight, then diluted with water, transferred to a separatory funnel and repeatedly extracted with chloroform. The combined chloroform extracts are washed three times with water, once with brine and dried over magnesium sulfate. The mixture is filtered, the solvent is removed under reduced pressure and methanol is added to the residue. The mixture is allowed to stand at -20°C. for 18 hours, then filtered. The filtrate is concentrated and distilled in vacuo to give 2-dimethylamino-2-(2-pyridyl)acetonitrile.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([S:11][C:12]3[CH:17]=[CH:16][C:15]([C:18]4[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=4)=[CH:14][C:13]=3[C:24]([F:27])([F:26])[F:25])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.OC1CCNC1.[C:34]([N:37]1[CH2:43][CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1)(=[O:36])[CH3:35]>>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([S:11][C:12]3[CH:17]=[CH:16][C:15]([C:18]4[CH:19]=[CH:20][N:21]=[C:22]([N:40]5[CH2:41][CH2:42][CH2:43][N:37]([C:34](=[O:36])[CH3:35])[CH2:38][CH2:39]5)[CH:23]=4)=[CH:14][C:13]=3[C:24]([F:25])([F:26])[F:27])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: CC(=O)N1CCCNCC1
Reactant: FC(F)(F)c1cc(-c2ccncc2)ccc1Sc1ccc2c(c1)OCCO2
Agent: OC1CCNC1
Product: CC(=O)N1CCCN(c2cc(-c3ccc(Sc4ccc5c(c4)OCCO5)c(C(F)(F)F)c3)ccn2)CC1

Procedure:
The title compound was prepared according to the procedures of Example 38E, substituting compound 76 with compound 118 (0.033 g, 0.0779 mmol) and 3-hydroxypyrrolidine with N-acetylhomopiperazine. A yellow solid 133 was obtained (0.021 g, 40%). 1H-NMR (CDCl3, 400 MHz) δ 2.01–2.10 (m, 2H), 2.08 (s, 3H), 3.52–3.60 (m, 2H), 3.76–3.91 (m, 4H), 4.01–4.06 (m, 1H), 4.11–4.16 (m, 1H), 4.28–4.34(m, 4H), 6.85 (s, ⅓H), 6.87 (s, ⅔H), 6.95 (d, J=8.4 Hz, 1H), 6.97 (d, J=6.6 Hz, 1H), 7.05 (dd, J=1.4 Hz, 8.4 Hz, 1H), 7.10 (d, J=2.2 Hz, 1H), 7.11–7.14 (m, 1H), 7.50–7.56 (m, 1H), 7.81 (s, ⅓H), 7.82 (s, ⅔H), 8.26–8.30 (m, 1H);MS (APCI) m/z 530 (M+H)+.
Reaction SMILES: Br[C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([CH2:10][O:11][CH3:12])=[CH:4][C:3]=1[O:13][CH3:14].C([Li])CCC.CCCCCC.C[O:27][B:28]([O:31]C)[O:29]C.Cl>O1CCCC1>[CH3:14][O:13][C:3]1[CH:4]=[C:5]([CH2:10][O:11][CH3:12])[CH:6]=[C:7]([O:8][CH3:9])[C:2]=1[O:27][B:28]([OH:31])[OH:29]
Reactant: COB(OC)OC
Reactant: COCc1cc(OC)c(Br)c(OC)c1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COCc1cc(OC)c(OB(O)O)c(OC)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 66.9 %

Procedure:
To a solution of 2-bromo-1,3-dimethoxy-5-(methoxymethyl)benzene (20.0 g, 76.6 mmol) in tetrahydrofuran (200 mL) which had been cooled in a dry ice-acetone bath was added 1.58M n-butyllithium in hexane (50.9 mL, 80.4 mmol) under a nitrogen stream, and the reaction mixture was stirred for 30 minutes. A solution of trimethoxyborane (8.75 g, 84.2 mmol) in tetrahydrofuran (20 mL) was then added to the reaction mixture, and the reaction temperature was increased to 0° C. while stirring. After adding 1N hydrochloric acid (200 mL) to the reaction mixture, it was stirred for 30 minutes at room temperature. After the reaction terminated, toluene (200 mL) was added to the reaction mixture and the organic layer was separated off, after which the aqueous layer was extracted with toluene (100 mL). The combined organic extracts were washed with water (100 mL) and then concentrated under reduced pressure. The residue was dissolved in tert-butyl methyl ether (75 mL) and the reaction mixture was stirred for 30 minutes, after which heptane (223 mL) was added thereto and the reaction mixture was further stirred for 2 hours. The precipitate was filtered out and washed with a mixed solution of tert-butyl methyl ether and heptane (1:3, 3.75 mL), and then dried at 40° C. for 24 hours to afford 12.4 g of the title compound (71.8% yield).
Reaction SMILES: [CH:1]([NH2:3])=[O:2].C#N.C(#N)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>>[C:1]([NH2:3])(=[O:2])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: NC=O
Reactant: N#Cc1ccccc1
Agent: C#N
Product: NC(=O)c1ccccc1

Procedure:
A solution of formamide (0.5047 g, 11.2 retool), PdBr2 (0.165 g, 0.62 mmol) in 25 mL of benzonitrile was stirred at reflux for 16 hours. At the end of this time, it was found that 0.29 mmol of HCN was produced. Benzamide was also produced.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([N:11]2[C:15]3[CH:16]=[C:17]([C:20]#[N:21])[CH:18]=[CH:19][C:14]=3[N:13]=[CH:12]2)[N:8]=[C:7]2[C:3]=1[NH:4][C:5](=[O:30])[N:6]2[CH:22]([C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1)[CH3:23].Cl.[F:32][C:33]1([F:37])[CH2:36][NH:35][CH2:34]1>>[F:32][C:33]1([F:37])[CH2:36][N:35]([C:2]2[N:10]=[C:9]([N:11]3[C:15]4[CH:16]=[C:17]([C:20]#[N:21])[CH:18]=[CH:19][C:14]=4[N:13]=[CH:12]3)[N:8]=[C:7]3[C:3]=2[NH:4][C:5](=[O:30])[N:6]3[CH:22]([C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)[CH3:23])[CH2:34]1
Reactant: CC(c1cccnc1)n1c(=O)[nH]c2c(Cl)nc(-n3cnc4ccc(C#N)cc43)nc21
Reactant: FC1(F)CNC1
Agent: Cl
Product: CC(c1cccnc1)n1c(=O)[nH]c2c(N3CC(F)(F)C3)nc(-n3cnc4ccc(C#N)cc43)nc21
Yield: 57 %

Procedure:
White semi-solid. 57% yield. Synthesized from 3-(6-chloro-8-oxo-9-(1-(pyridin-3-yl)ethyl)-8,9-dihydro-7H-purin-2-yl)-3H-benzo[d]imidazole-5-carbonitrile (19 mg, 0.046 mmol) and 3,3-difluoroazetidine hydrochloride (3 equiv.) following the general procedure for displacement reactions of 6-chloropurinones with aliphatic amines. 1H NMR (300 MHz, CD3OD) δ, ppm: 9.27 (s, 1H), 9.20-9.00 (br m, 1H), 8.78 (d, 1H), 8.88-8.77 (m, 1H, overlapping with 8.78 ppm), 8.63 (s, 1H), 8.09 (br s, 1H), 7.88 (d, 1H), 7.67 (d, 1H), 6.13 (q, J=7.1 Hz, 1H), 4.78 (t, 4H), 2.16 (d, J=7.1 Hz, 3H); MS (EI) m/z 474.0 (MH)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C@@H:19]3[CH2:24][CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20]3)[CH2:14][CH2:13]2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].FC(F)(F)C(O)=O.ClCCl.C([O-])(O)=O.[Na+]>O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C@@H:19]3[CH2:24][CH2:23][CH2:22][NH:21][CH2:20]3)[CH2:14][CH2:13]2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](CN2CCN(C(=O)Nc3ccc(Cl)c(Cl)c3)CC2)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(Nc1ccc(Cl)c(Cl)c1)N1CCN(C[C@@H]2CCCNC2)CC1
Yield: 67.4 %

Procedure:
tert-Butyl (3S)-3-[(4-{[(3,4-dichlorophenyl)amino]carbonyl}piperazin-1-yl)methyl]piperidine-1-carboxylate (1 g), trifluoroacetic acid (10 ml) and dichloromethane (20 ml) were stirred at room temperature for one hour. The solvent was removed in vacuo to yield a dark brown oil. Water (20 ml) was added to this giving a milky solution and this was then basified to ˜pH 6 by addition of solid NaHCO3. This left a milky solution which was diluted with water (˜50 ml) before extracting with ethyl acetate (3×75 ml). The combined organics were washed with brine (˜100 ml) and separated then dried (MgSO4) before removing solvent in vacuo to yield the title compound (531 mg).
Reaction SMILES: Cl.[CH3:2][CH:3]1[CH2:8][CH2:7][NH:6][CH:5]([C:9]([OH:11])=[O:10])[CH2:4]1.[CH2:12](O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.O.[C:21]1([CH3:31])[CH:26]=[CH:25][C:24]([S:27]([OH:30])(=[O:29])=[O:28])=[CH:23][CH:22]=1.O>C1C=CC=CC=1>[C:21]1([CH3:31])[CH:22]=[CH:23][C:24]([S:27]([OH:30])(=[O:28])=[O:29])=[CH:25][CH:26]=1.[CH3:2][CH:3]1[CH2:8][CH2:7][NH:6][CH:5]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:4]1
Reactant: OCc1ccccc1
Reactant: CC1CCNC(C(=O)O)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: O
Solvent: c1ccccc1
Product: CC1CCNC(C(=O)OCc2ccccc2)C1
Yield: 22 %

Procedure:
A solution of 20 g (0.112 mole) of 4-methyl-2-piperidinecarboxylic acid hydrochloride, 24 g (0.224 mole) of benzyl alcohol and 25.6 g (0.134 mole) of p-toluenesulfonic acid monohydrate in 100 ml of benzene was refluxed for 5 hours with the continuous removal of water through a Dean-Stark water trap. At the end of this period, the solvent was distilled off, and the residue was washed with ether-n-hexane and recrystallized to give 10 g (22%) of benzyl 4-methyl-2-piperidinecarboxylate p-toluenesulfonate, M.P. 160°-163° C.
Reaction SMILES: CSC.B.[Br:5][C:6]1[CH:14]=[CH:13][C:9]([C:10](O)=[O:11])=[C:8]([CH3:15])[CH:7]=1.O>O1CCCC1>[Br:5][C:6]1[CH:14]=[CH:13][C:9]([CH2:10][OH:11])=[C:8]([CH3:15])[CH:7]=1
Reactant: Cc1cc(Br)ccc1C(=O)O
Agent: B
Solvent: C1CCOC1
Solvent: CSC
Solvent: O
Product: Cc1cc(Br)ccc1CO
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.9 %

Procedure:
Borane-dimethyl sulfide complex (2M in THF; 1150 mL, 2.3 mol) is added over 1.5 hours to a solution of 4-bromo-2-methylbenzoic acid (250 g, 1.16 mol) in anhydrous tetrahydrofuran (1500 mL) at 0° C. The reaction is allowed to warm slowly to ambient temperature and stirred overnight. The solution is cooled to −10° C. and water (500 mL) is added very slowly. Further water (5000 mL) is added and the mixture is extracted with ethyl acetate (2×5000 mL). The combined organic layers are washed with saturated aqueous NaCl solution (5000 mL) and dried over Na2SO4. Filtration and concentration under reduced pressure provides the title compound (226 g, 97% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[C:13]([C:19]([NH:21][NH2:22])=O)=[N:14][CH:15]=[C:16]([Cl:18])[CH:17]=2)(=[O:10])=[O:9])=[CH:4][C:3]=1[C:23]([F:26])([F:25])[F:24].[NH2:27][C:28]1[C:32]([CH2:33]O)=[CH:31][NH:30][N:29]=1.N[C:36]1C(C(OCC)=O)=CNN=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[C:13]([C:19]3[N:27]([C:28]4[C:32]([CH3:33])=[CH:31][NH:30][N:29]=4)[CH:36]=[N:22][N:21]=3)=[N:14][CH:15]=[C:16]([Cl:18])[CH:17]=2)(=[O:10])=[O:9])=[CH:4][C:3]=1[C:23]([F:26])([F:25])[F:24]
Reactant: CCOC(=O)c1c[nH]nc1N
Reactant: Nc1n[nH]cc1CO
Reactant: NNC(=O)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1c[nH]nc1-n1cnnc1-c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1

Procedure:
The titled compound was prepared according to general Method B using 4-chloro-N-(2-(hydrazinecarbonyl)-5-chloropyridin-3-yl)-3-(trifluoromethyl)benzenesulfonamide and 3-amino-4-hydroxymethylpyrazole ((MS, 409 [M+H]+, which was generated in situ by reduction of ethyl 3-amino-1H-pyrazole-4-carboxylate using LAH in THF): 1H NMR (400 MHz, CDCl3) δ 8.28 (s, 1H), 8.16 (d, 1H), 8.13 (d, 1H), 7.97 (d, 1H), 7.94 (dd, 1H), 7.56 (d, 1H), 7.42 (d. 1H), 1.65 (s, 3H). MS (ES) [M+H]+ expected 518.0. found 518.0.
Reaction SMILES: C([N:8]1[CH2:13][C@H:12]([CH3:14])[CH2:11][C@H:10]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:9]1)C1C=CC=CC=1>CO.[Pd]>[CH3:14][C@H:12]1[CH2:13][NH:8][CH2:9][C@@H:10]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:11]1
Reactant: C[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CN(Cc2ccccc2)C1
Agent: [Pd]
Solvent: CO
Product: C[C@H]1CNC[C@@H](NC(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
10 wt % Pd on carbon (120 mg, 0.11 mmol) was added to a solution of tert-butyl [(3S,5R)-1-benzyl-5-methylpiperidin-3-yl]carbamate (0.34 g, 1.1 mmol) in MeOH (15.0 mL). The mixture was stirred at room temperature under a hydrogen atmosphere (1 atm.) for 15 h. The reaction was filtered through a pad of diatomaceous earth (eluted with MeOH), and then concentrated under reduced pressure. The resulting crude product was used directly in the next step residue without further purification (0.21 g, 88%). LCMS calc. for C11H23N2O2 (M+H)+: m/z=215.2. found 215.2. 1H NMR (CDCl3, 400 MHz) δ 4.33 (1H, m), 3.46 (1H, m), 3.25 (1H, m), 2.94 (1H, dd, J=3.6 and 12.8 Hz), 2.18-2.02 (3H, m), 1.60 (1H, m), 1.43 (9H, s), 0.85 (3H, d, J=6.8 Hz) ppm.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:20])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[CH:12]=[C:13]([C:15]([O:17][CH3:18])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:19]=1.[F:21][C:22]1[CH:23]=[C:24]([CH:27]=[C:28]([F:30])[CH:29]=1)[CH:25]=[O:26]>>[Br:1][C:2]1[C:3]([F:20])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([CH:25]([C:24]4[CH:23]=[C:22]([F:21])[CH:29]=[C:28]([F:30])[CH:27]=4)[OH:26])=[C:13]([C:15]([O:17][CH3:18])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:19]=1
Reactant: COC(=O)c1cn2c(n1)-c1cc(Br)c(F)cc1OCC2
Reactant: O=Cc1cc(F)cc(F)c1
Product: COC(=O)c1nc2n(c1C(O)c1cc(F)cc(F)c1)CCOc1cc(F)c(Br)cc1-2
Yield: 69 %

Procedure:
Methyl 10-bromo-3-((3,5-difluorophenyl)(hydroxy)methyl)-9-fluoro-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxylate was prepared similarly according to the procedure in Example 9. Methyl 10-bromo-9-fluoro-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxylate was reacted with 3,5-difluorobenzaldehyde to afford 291 mg (69% yield) of the title compound.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[C:31]([C:34]([OH:36])=O)[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].C(=O)=O.C(O)(C)C.CN1CCOCC1.C(OC(Cl)=O)C(C)C.[C:59]1([CH2:65][CH2:66][NH2:67])[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1>O1CCCC1>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[C:18]([C:23]([O:25][C:26]([CH3:27])([CH3:29])[CH3:28])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:15][CH:16]=2)[C:8]2[CH:30]=[C:31]([C:34]([NH:67][CH2:66][CH2:65][C:59]3[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=3)=[O:36])[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: NCCc1ccccc1
Reactant: CCCCc1nc2ccc(C(=O)O)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Agent: CC(C)COC(=O)Cl
Agent: O=C=O
Solvent: CN1CCOCC1
Solvent: CC(C)O
Solvent: C1CCOC1
Product: CCCCc1nc2ccc(C(=O)NCCc3ccccc3)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Temperature: -20 °C

Procedure:
484 mg (1 mmol) of tert.-butyl 4'-[(2-n-butyl-6-carboxy-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate are dissolved in 10 ml of absolute tetrahydrofuran and cooled to -20° C. with stirring and cooling with dry ice/isopropanol. At this temperature 101 mg (1 mmol) of N-methylmorpholine are added. The resulting mixture is then cooled to -30° C. and a solution of 136 mg (1 mmol) of isobutylchloroformate dissolved in 5 ml of absolute tetrahydrofuran is slowly added dropwise. To complete the formation of the mixed anhydride the mixture is stirred for a further hour at -40° C. At -40° C. 134 mg (1.1 mmol) of 2-phenylethylamine dissolved in 2 ml of absolute tetrahydrofuran are slowly added dropwise. Then the mixture is allowed to rise slowly to ambient temperature and stirred for 16 hours at ambient temperature. The solvent is distilled off, the remaining viscous oil is taken up in saturated common salt solution/ethyl acetate and extracted 3 times in all with ethyl acetate. The ethyl acetate phases are dried over sodium sulphate and evaporated down. The viscous oil is dissolved in methylene chloride and purified over a silica gel column (eluant: methylene chloride/ethanol 50:1 and 25:1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[C:12]1[CH:16]=[C:15]([C:17]2[CH:26]=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[C:22]([O:27][CH3:28])[CH:23]=3)[CH:18]=2)[N:14]([C@H:29]([C:31]2[CH:41]=[CH:40][C:34]([C:35]([O:37]CC)=[O:36])=[CH:33][CH:32]=2)[CH3:30])[N:13]=1.[OH-].[Na+]>CO.O1CCOCC1.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[C:12]1[CH:16]=[C:15]([C:17]2[CH:26]=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[C:22]([O:27][CH3:28])[CH:23]=3)[CH:18]=2)[N:14]([C@H:29]([C:31]2[CH:32]=[CH:33][C:34]([C:35]([OH:37])=[O:36])=[CH:40][CH:41]=2)[CH3:30])[N:13]=1
Reactant: CCOC(=O)c1ccc([C@H](C)n2nc(-c3cc(C(F)(F)F)ccc3F)cc2-c2ccc3cc(OC)ccc3c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc2cc(-c3cc(-c4cc(C(F)(F)F)ccc4F)nn3[C@@H](C)c3ccc(C(=O)O)cc3)ccc2c1
Reaction time: 8 h

Procedure:
Ethyl 4-{(1S)-1-[3-[2-fluoro-5-(trifluoromethyl)phenyl]-5-(6-methoxy-2-naphthyl)-1H-pyrazol-1-yl]ethyl}benzoate (2.87 g, 5.11 mmol) was dissolved in MeOH-dioxane (1:2, 60 ml) and treated with NaOH (2.5 g, excess) in water (20 ml). The mixture slowly cleared with stirring, and was left overnight. The reaction mixture was first concentrated to 30 ml, acidified with 2N HCl and extracted with ethyl acetate. The organic layer was washed with brine 2× and dried over Na2SO4. Evaporation of solvent and vacuum drying afforded 4-{(1S)-1-[3-[2-fluoro-5-(trifluoromethyl)phenyl]-5-(6-methoxy-2-naphthyl)-1H-pyrazol-1-yl]ethyl}benzoic acid as colorless dry foam. NMR (500 MHz, CDCl3) δ: 2.00 (d, J=7.0 Hz, 3H); 3.95 (s, 3H); 5.65 (q, J=7.0 Hz, 1H); 6.88 (d, JF-H=4.2 Hz, 1H); 7.17 (d, J=2.5 Hz, 1H); 7.20 (dd, J=2.5 Hz, 8.9 Hz, 1H); 7.26 (t, J=8.6 Hz, 1H); 7.31 (dd, J=1.8 Hz, 8.5 Hz, 1H); 7.32 (d, J=8.4 Hz, 2H); 7.56 (m, 1H); 7.66 (d, J=1.8 Hz, 1H); 7.68 (d, J=8.9 Hz, 1H); 7.77 (d, J=8.5 Hz, 1H); 8.06 (d, J=8.4 Hz, 2H); 8.48 (dd, J=2.9 Hz, 6.9 Hz, 1H). MS C30H22F4N2O3 Cald: 534.16; Obsd (M+1): 535.17.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][C:23]([O:39][CH2:40][CH3:41])=[C:24]([NH:27][C:28](=[O:38])[CH2:29]P(OCC)(OCC)=O)[CH:25]=3)[N:20]=[CH:19][C:18]=2[C:42]#[N:43])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C1(C)C=CC=CC=1.[CH3:61][N:62]1[CH2:67][CH2:66][CH2:65][CH2:64][CH:63]1[CH:68]=O>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][C:23]([O:39][CH2:40][CH3:41])=[C:24]([NH:27][C:28](=[O:38])/[CH:29]=[CH:68]/[CH:63]4[CH2:64][CH2:65][CH2:66][CH2:67][N:62]4[CH3:61])[CH:25]=3)[N:20]=[CH:19][C:18]=2[C:42]#[N:43])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1
Reactant: CN1CCCCC1C=O
Reactant: CCOc1cc2ncc(C#N)c(Nc3ccc(OCc4ccccn4)c(Cl)c3)c2cc1NC(=O)CP(=O)(OCC)OCC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCOc1cc2ncc(C#N)c(Nc3ccc(OCc4ccccn4)c(Cl)c3)c2cc1NC(=O)/C=C/C1CCCCN1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 4.9 %

Procedure:
N-[4-[[3-Chloro-4-(2-pyridylmethoxy)phenyl]amino]-3-cyano-7-ethoxy-6-quinolyl]-2-diethoxyphosphoryl-acetamide 1d (300 mg, 0.48 mmol) was dissolved in 10 mL of tetrahydrofuran in a dry ice bath, followed by dropwise addition of a solution of lithium bis(trimethylsilyl)amide (1 M) in toluene (530 μL, 0.53 mmol). After stirring for 30 minutes, a solution of 1-methylpiperidine-2-carbaldehyde 6b (120 mg, 0.96 mmol) in 5 mL of tetrahydrofuran was added dropwise. The reaction mixture was stirred for another 30 minutes, then warmed up to room temperature and stirred for 12 hours. The reaction mixture was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography with elution system A to obtain the title compound (E)-N-[4-[[3-chloro-4-(2-pyridylmethoxy)phenyl]amino]-3-cyano-7-ethoxy-6-quinolyl]-3-(1-methyl-2-piperidyl)prop-2-enamide 6 (14 mg, yield 4.9%) as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9]3[N:18]([CH3:19])[CH:17]=[CH:16][C:10]3=[N:11][C:12]=2[C@@H:13]([NH2:15])[CH3:14])=[C:5]([CH3:20])[O:4][N:3]=1.[NH2:21][C:22]1[N:27]=[C:26]([NH2:28])[C:25]([C:29]#[N:30])=[C:24](Cl)[N:23]=1.C(N(C(C)C)C(C)C)C>C(#N)C>[NH2:21][C:22]1[N:27]=[C:26]([NH2:28])[C:25]([C:29]#[N:30])=[C:24]([NH:15][C@H:13]([C:12]2[N:11]=[C:10]3[CH:16]=[CH:17][N:18]([CH3:19])[C:9]3=[CH:8][C:7]=2[C:6]2[C:2]([CH3:1])=[N:3][O:4][C:5]=2[CH3:20])[CH3:14])[N:23]=1
Reactant: N#Cc1c(N)nc(N)nc1Cl
Reactant: Cc1noc(C)c1-c1cc2c(ccn2C)nc1[C@H](C)N
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1noc(C)c1-c1cc2c(ccn2C)nc1[C@H](C)Nc1nc(N)nc(N)c1C#N
Temperature: 120 °C
Yield: 56.1 %

Procedure:
(1S)-1-(6-(3,5-Dimethylisoxazol-4-yl)-1-methyl-1H-pyrrolo[3,2-b]pyridin-5-yl)ethanamine (106 mg, 0.393 mmol), 2,4-diamino-6-chloropyrimidine-5-carbonitrile (100 mg, 0.590 mmol), and N-ethyl-N-isopropylpropan-2-amine (0.205 mL, 1.179 mmol) were combined in acetonitrile (6 mL). The reaction mixture was heated in a microwave reactor at 120° C. for 2 hours and then concentrated. The residue was taken up in DMF and purified by preparative HPLC (basic mode) eluting with 35% ACN in water. The fractions containing the desired product were combined and concentrated in vacuo to give the title compound (89 mg, 56%). 1H NMR (500 MHz, CD3OD) δ ppm 1.36 (ddd, J=13.42, 6.59, 1.46 Hz, 3 H), 2.01 (d, J=1.46 Hz, 2 H), 2.15 (d, J=1.95 Hz, 1 H), 2.18-2.21 (m, 1 H), 2.32 (d, J=1.46 Hz, 2 H), 3.86 (d, J=1.46 Hz, 3 H), 5.38-5.49 (m, 1 H), 6.67 (dd, J=2.20, 1.22 Hz, 1H), 7.58 (dd, J=2.93, 1.46 Hz, 1 H), 7.69 (d, J=5.86 Hz, 1 H); ESI-MS m/z [M+H]+ calc'd for C20H21N9O, 404; found 404.
Reaction SMILES: [CH3:1][Sn:2]([CH3:10])([CH3:9])[CH2:3][CH2:4][C:5]([NH:7][NH2:8])=[O:6].[CH:11](=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(O)C>[C:12]1([CH:11]=[N:8][NH:7][C:5](=[O:6])[CH2:4][CH2:3][Sn:2]([CH3:10])([CH3:9])[CH3:1])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=Cc1ccccc1
Reactant: C[Sn](C)(C)CCC(=O)NN
Solvent: CCO
Product: C[Sn](C)(C)CCC(=O)NN=Cc1ccccc1
Yield: 88.5 %

Procedure:
In the manner described in Example 2, 3.0 g (0.012 mole) of 3-trimethylstannylpropionic acid hydrazide was reacted with 1.5 ml (0.015 mole) of benzaldehyde in 2.0 ml of ethanol. Recrystallization of the solid product from 95% ethanol gave 3.6 g of 3-trimethylstannylpropionic acid phenylmethylenehydrazide, Compound 3 of Table I. The infrared spectrum (KBr disc) showed N--H absorptions at 3100 cm-1 and a carbonyl band at 1670 cm-1. The carbon-tin bond gave characteristic absorptions at 770, 540, 520 and 505 cm-1. NMR spectroscopy (CDCl3) showed the following: the singlet at 10.43 delta (1H, N--H); a broadened singlet at 7.87 delta (1H, -N=CHPh); the aromatic protons formed two complex bands, 2H ortho centered at 7.64 delta and 3H meta and para centered at 7.38 delta; a triplet centered at 2.99 delta (2H, COCH2); a triplet centered at 1.11 delta (2H, SnCH2); and a singlet at the 0.14 delta (9H, Sn(CH3)3) flanked by the J(117/119Sn--CH3) doublets.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4]([N+:9]([O-])=O)[CH:3]=1.C(O)(=O)C>[Fe].O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4]([NH2:9])[CH:3]=1
Reactant: O=[N+]([O-])c1cc(Br)ccc1F
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Product: Nc1cc(Br)ccc1F
Yield: 67.4 %

Procedure:
Add 4-bromo-1-fluoro-2-nitrobenzene (19.4 g, 88.2 mmol) and 10 g of fine mesh iron to a solution of acetic acid (75 mL) and water (5 mL) and heat to 105° C. for 4 h or until the 4-bromo-1-fluoro-2-nitrobenzene is completely consumed. Concentrate to remove most of the acetic acid, pour into water and extract with ethyl acetate. Wash the ethyl acetate layers with water, an aqueous saturated solution of sodium chloride, dry (potassium carbonate), filter and concentrate. Purify the residue by silica gel chromatography, eluting with hexanes:ethyl acetate, to give the title compound as an amber oil (11.3 g, 67%).