Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][C:16]([NH:18][CH:19]([CH2:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[O:17])[C:11](=[O:34])[CH2:10]2)=[CH:5][CH:4]=1)#[N:2].[NH:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1>>[NH:2]=[C:1]([N:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1)[C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][C:16]([NH:18][CH:19]([CH2:26][CH2:27][C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[O:17])[C:11](=[O:34])[CH2:10]2)=[CH:5][CH:4]=1
Reactant: C1COCCN1
Reactant: CCOC(=O)CC(CCc1ccccc1)NC(=O)CN1CCN(c2ccc(C#N)cc2)CC1=O
Product: CCOC(=O)CC(CCc1ccccc1)NC(=O)CN1CCN(c2ccc(C(=N)N3CCOCC3)cc2)CC1=O

Procedure:
Starting material: intermediate B7 and morpholine.
Reaction SMILES: [I:1][C:2]1[CH:7]=[N:6][NH:5][C:4](=[O:8])[CH:3]=1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.[O:26]1[CH:31]=[CH:30][CH2:29][CH2:28][CH2:27]1>O1CCCC1>[I:1][C:2]1[CH:7]=[N:6][N:5]([CH:27]2[CH2:28][CH2:29][CH2:30][CH2:31][O:26]2)[C:4](=[O:8])[CH:3]=1
Reactant: O=c1cc(I)cn[nH]1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: C1CCOC1
Product: O=c1cc(I)cnn1C1CCCCO1
Yield: 98 %

Procedure:
A solution of 5-iodo-2H-pyridazin-3-one (66 g, 0.30 mol) in tetrahydrofuran (500 mL) was treated with pyridinium para-toluene sulfonate (14.3 g, 0.057 mol) and 3,4-dihydro-2H-pyran (52 mL). The reaction mixture was stirred at reflux for 5 h. At this time, the reaction was treated with another aliquot of 3,4-dihydro-2H-pyran (32.5 mL). The solution was stirred at reflux overnight. At this time, the solution was concentrated in vacuo. Chromatography (ethyl acetate/petroleum ether=1/2) afforded 5-iodo-2-(tetrahydro-pyran-2-yl)-2H-pyridazin-3-one (89 g, 98%).
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]#[C:4][C:5]([F:8])([F:7])[F:6].[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([C:18](=[N:20][OH:21])[CH3:19])=[CH:14][CH:13]=1.CO.CC(C)([O-])C.[K+]>O>[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([C:18](=[N:20][OH:21])[CH3:19])=[C:16]([C:4]([C:5]([F:8])([F:7])[F:6])=[CH:3][C:2]([F:10])([F:9])[F:1])[CH:17]=1
Reactant: FC(F)(F)C#CC(F)(F)F
Reactant: CC(=NO)c1ccc(Cl)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CC(=NO)c1ccc(Cl)cc1C(=CC(F)(F)F)C(F)(F)F

Procedure:
Hexafluoro-2-butyne is slowly bubbled through a 55°-60° C. solution of p-chloroacetophenone oxime (17.0 g, 0.10 mol), methanol (80 mL) and potassium tert-butoxide (1.12 g, 0.01 mol) over a 5 hour period. The solvent is removed in vacuo to obtain a liquid which is poured into water and extracted with ether. The combined organic extracts are washed sequentially with water and brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give an oil. The oil is chromatographed using silica gel and eluted with 1% ethylacetate in methylene chloride to 5% ethyl acetate in methylene chloride to give p-chloro-0-[1,2-bis(trifluoromethyl)vinyl]acetophenone oxime, vinyl-(Z) as a yellow liquid (21.5 g, 65%) and 2-(p-chlorophenyl)-4,5-trans-bis(trifluoromethyl)-1-pyrrolin-5-ol as a white solid (2.35 g, mp 152.5°-153° C., 7%).
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([NH:10][C@H:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][C:15]([OH:21])=[CH:16][CH:17]=2)[CH2:12]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].Br[CH2:23][C:24]([NH2:26])=[O:25].O>CN(C=O)C>[C:3]([O:7][C:8]([NH:10][C@H:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][C:15]([O:21][CH2:23][C:24]([NH2:26])=[O:25])=[CH:16][CH:17]=2)[CH2:12]1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: NC(=O)CBr
Reactant: CC(C)(C)OC(=O)N[C@H]1CCc2ccc(O)cc2C1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H]1CCc2ccc(OCC(N)=O)cc2C1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
0.16 g of 60% NaH (0.004 mole) and 3.5 ml of anhydrous DMF were stirred at ambient temperature in a stream of nitrogen and 1 g (0.0038 mole) of (2S)-2-tert-butoxycarbonylamino-7-hydroxy-tetralin in 9 ml of anhydrous DMF and 0.52 g (0.0038 mole) of 2-bromoacetamide in 2.5 ml of anhydrous DMF were added. It was stirred at ambient temperature for 6 hours then the mixture was poured into water. The precipitated product was filtered and the product of the heading was then obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([OH:13])=[C:8]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:7]([CH3:20])=[CH:6]2.[H-].[Na+].F[C:24]1[CH:31]=[CH:30][C:27]([CH:28]=[O:29])=[CH:26][C:25]=1[C:32]([F:35])([F:34])[F:33]>CN(C=O)C>[CH3:20][C:7]1[C:8]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[C:9]([O:13][C:24]2[CH:31]=[CH:30][C:27]([CH:28]=[O:29])=[CH:26][C:25]=2[C:32]([F:33])([F:35])[F:34])[C:10]2[C:5]([CH:6]=1)=[CH:4][C:3]([O:2][CH3:1])=[CH:12][CH:11]=2
Reactant: O=Cc1ccc(F)c(C(F)(F)F)c1
Reactant: COc1ccc2c(O)c(-c3ccccc3)c(C)cc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2c(Oc3ccc(C=O)cc3C(F)(F)F)c(-c3ccccc3)c(C)cc2c1
Temperature: 0 °C
Yield: 61.1 %

Procedure:
Compound 7 (215 mg, 0.81 mmol, 1 equiv) was dissolved in DMF (5 mL) and cooled to 0° C. under N2. Sodium hydride, 60% dispersion (36 mg, 0.89 mmol, 1.1 equiv), followed by 4-fluoro-3-(trifluoromethyl)benzaldehyde (311 mg, 1.62 mmol, 2 equiv) were added and the entire reaction mixture was heated to 70° C. for 3 days. The mixture was then partitioned between EtOAc (50 mL) and H2O (50 mL). The organic layer was washed with saturated aqueous NaCl (100 mL), dried over Na2SO4, filtered and concentrated to dryness. The residue was purified by silica gel flash column chromatography (10% EtOAc in hexanes) to provide compound 33 (216 mg, 61%) as a clear oil. 1HNMR (400 MHz, DMSO-d6): δ 9.84 (s, 1H), 8.10 (m, 1H), 7.87 (m, 1H), 7.81 (s, 1H), 7.48-7.13 (m, 8H), 6.64 (m, 1H), 3.88 (s, 3H), 2.22 (s, 3H). MS m/z 437.4 (M+H)+.
Reaction SMILES: C([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][C:14]=2[CH:17]=[CH2:18])[CH2:9]1)C1C=CC=CC=1.ClC(OC(Cl)C)=O>ClCCCl>[CH:17]([C:14]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:15]=1[CH2:16][NH:8][CH2:9]2)=[CH2:18]
Reactant: C=Cc1cccc2c1CN(Cc1ccccc1)C2
Agent: CC(Cl)OC(=O)Cl
Solvent: ClCCCl
Product: C=Cc1cccc2c1CNC2
Temperature: 25 °C
Yield: 71 %

Procedure:
A solution of 2-benzyl-4-vinylisoindoline (58 mmol) in 1,2-dichloroethane (150 mL) was placed in a 1 L round bottom flask under nitrogen. To this was attached an addition funnel containing a solution of 1-chloroethyl chloroformate (7.51 mL, 69.6 mmol) in 1,2-dichloroethane. The reaction flask was cooled in an ice bath and the contents of the addition funnel were added dropwise over 20 min keeping the internal reaction temperature<5° C. After the addition was complete the reaction flask was allowed to warm to room temperature then heated to reflux for 45 min. The contents of the reaction flask were cooled to room temperature then the solvent removed by evaporation. Methanol (200 mL) was added and the contents of the reaction flask were heated to reflux for 30 min. The reaction flask was cooled and the solvent removed by evaporation. Water (200 mL) was added and the resulting mixture washed with ethyl acetate (2×250 mL). The aqueous layer was made basic with 2N sodium hydroxide then extracted with methylene chloride (4×250 mL). The combined organic extracts were dried with anhydrous sodium sulfate, filtered and the filtrate evaporated. The remaining residue was subjected to flash column chromatography eluting with methylene chloride/methanol/ammonium hydroxide 97/3/0.3 to 95/5/0.5. Evaporation of fractions gave the title compound as a brown oil, 6.00 g (41.4 mmol, 71% yield for two steps). LRMS (ESI) m/z 146 [(M+H)+; calcd for C10H12N: 146].
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[C:14]2[C:9](=[N:10][CH:11]=[N:12][C:13]=2[NH:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)=[C:18]([Cl:30])[CH:17]=2)[NH:8][N:7]=1.[NH:31]1[CH2:35][CH2:34][CH2:33][C@@H:32]1[CH2:36][OH:37]>>[Cl:30][C:18]1[CH:17]=[C:16]([NH:15][C:13]2[N:12]=[CH:11][N:10]=[C:9]3[NH:8][N:7]=[C:6]([O:5][CH2:4][CH2:3][CH2:2][N:31]4[CH2:35][CH2:34][CH2:33][C@@H:32]4[CH2:36][OH:37])[C:14]=23)[CH:21]=[CH:20][C:19]=1[O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1
Reactant: ClCCCOc1n[nH]c2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Reactant: OC[C@H]1CCCN1
Product: OC[C@H]1CCCN1CCCOc1n[nH]c2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Yield: 14 %

Procedure:
The procedure described in Example 23 was repeated using 3-(3-chloropropoxy)-N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine and (R)-2-pyrrolidinemethanol to give the title compound in 14% yield; NMR Spectrum (DMSO+TFA): 1.77-1.81 (m, 1H), 1.89-1.93 (m, 1H), 1.99-2.04 (m, 1H), 2.09-2.14 (m, 1H), 2.25 (br s, 2H), 3.14-3.19 (m, 1H), 3.26 (br s, 1H), 3.58-3.65 (m, 4H), 3.76-3.79 (m, 1H), 4.48 (br s, 2H), 5.62 (s, 2H), 7.45 (d, 1H), 7.56 (d, 1H), 7.80 (s, 1H), 7.98 (t, 1H), 8.12 (d, 1H), 8.40 (s, 1H), 8.55 (t, 1H), 8.98 (d, 1H); Mass Spectrum: 510 (MH+).
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].C[N:12]([CH2:20][CH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)[C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16].CCN(C(C)C)C(C)C>CCO>[CH3:7][N:6]1[C:2]([N:24]2[CH2:25][CH2:26][CH:21]([CH2:20][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:17])([CH3:16])[CH3:18])[CH2:22][CH2:23]2)=[C:3]([N+:8]([O-:10])=[O:9])[CH:4]=[N:5]1
Reactant: CN(CC1CCNCC1)C(=O)OC(C)(C)C
Reactant: Cn1ncc([N+](=O)[O-])c1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: Cn1ncc([N+](=O)[O-])c1N1CCC(CNC(=O)OC(C)(C)C)CC1
Yield: 81.4 %

Procedure:
A solution of 5-chloro-1-methyl-4-nitro-1H-pyrazole from Example 1 (0.2 g, 1.23 mmol), tert-butyl methyl(piperidin-4-ylmethyl)carbamate (0.29 g, 1.36 mmol) and DIPEA (1 mL, 5.7 mmol) in EtOH (3 mL) was heated at 130° C. in a microwave for 2 hr. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (40% EtOAc/isohexane) to give tert-butyl (1-(1-methyl-4-nitro-1H-pyrazol-5-yl)piperidin-4-yl)methylcarbamate as a yellow oil (0.34 g, 80%). To a solution of this oil (0.15 mg, 0.44 mmol) in DMF (5 mL) cooled to 0° C. was added sodium hydride (27 mg, 0.66 mmol, 60% in mineral oil) and the mixture was stirred at 0° C. for 15 min. Iodomethane (0.03 mL, 0.53 mmol) was added and the mixture was stirred at 0° C. for 30 min. Additional sodium hydride (14 mg, 0.33 mmol) and iodomethane (0.02 mL, 0.78 mmol) were added, the reaction mixture was allowed to warm to 10° C. and stirred for 1 hr. Water (10 mL) was added and the mixture was extracted with EtOAc (60 mL). The organic layer was washed with water (7×10 mL), washed with brine (10 mL), separated, dried over MgSO4 and the solvent removed under reduced pressure. Purification of the residue by silica gel column chromatography (30% EtOAc/isohexane) afforded tert-butyl methyl((1-(1-methyl-4-nitro-1H-pyrazol-5-yl)piperidin-4-yl)methyl)carbamate as a yellow oil (148 mg, 95%). 1H NMR (400 MHz, CDCl3) δ 8.01 (s, 1H), 3.74 (s, 3H), 3.38-3.26 (m, 2H), 3.25-3.15 (m, 2H), 3.12-2.95 (m, 2H), 2.89 (s, 3H), 1.90-1.71 (m, 3H), 1.60-1.32 (m, 2H), 1.47 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH2:8])[N:3]=1.[CH3:9][C:10](=O)[CH2:11][C:12](=O)[CH3:13].S(=O)(=O)(O)O.[OH-].[Na+]>O.C(O)(=O)C>[NH2:8][C:4]1[N:3]=[C:2]2[C:7]([C:10]([CH3:9])=[CH:11][C:12]([CH3:13])=[N:1]2)=[CH:6][CH:5]=1
Reactant: CC(=O)CC(C)=O
Reactant: Nc1cccc(N)n1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: Cc1cc(C)c2ccc(N)nc2n1
Reaction time: 24 h

Procedure:
2,6-Diaminopyridine (43.6 g., 0.4 mole), 40.0 g (0.4 mole) of 2,4-pentanedione, 200 ml. of glacial acetic acid and 5 ml. of 96% sulfuric acid were mixed, then refluxed with stirring for 24 hours. The cold solution was added slowly with good stirring and ice bath cooling to 160 g of sodium hydroxide in enough water to make 600 ml. The brown solid, which crystallized, was filtered after the solution had been cooled overnight at 5°, washed twice with cold water and dried, 25.3 g., m.p. 125°-200°. This crude material was dissolved in 130 ml. of boiling 95% ethanol and the solution chilled overnight at -15°, 19.5 g. (28%), m.p. 215°-220°. This material was suitable for the following experiment.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([NH2:8])=[NH:7].[CH2:12]([O:14][C:15](=[O:24])[C:16](=[CH:20]N(C)C)[C:17](=O)[CH3:18])[CH3:13]>CCO>[CH2:12]([O:14][C:15]([C:16]1[C:17]([CH3:18])=[N:7][C:6]([C:5]2[CH:9]=[CH:10][CH:11]=[C:3]([F:2])[CH:4]=2)=[N:8][CH:20]=1)=[O:24])[CH3:13]
Reactant: CCOC(=O)C(=CN(C)C)C(C)=O
Reactant: N=C(N)c1cccc(F)c1
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1cnc(-c2cccc(F)c2)nc1C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 94 %

Procedure:
Na° (0.66 g, 28.6 mmol) is added to anhydrous EtOH (100 mL) and stirred at room temperature for 15 min. 3-Fluorobenzamidine hydrochloride (4.87 g, 27.8 mmol) is added and the solution is stirred for 15 min. 2-Dimethylaminomethylene-3-oxo-butyric acid ethyl ester (5.3 g, 28.6 mmol,) is added and the reaction mixture is heated at reflux under N2 for 1 hours. The reaction is cooled to room temperature and concentrated in vacuo. The residue is dissolved in EtOAc (300 mL), washed with brine (2×100 mL), dried (Na2SO4), filtered, and concentrated to afford 2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid ethyl ester (6.8 g, 99%). MS: 261 (M+H); 1H NMR (300 MHz, CDCl3): δ 1.43 (t, J=7.0 Hz, 3H), 2.92 (s, 3H), 4.42 (q, J=7.0 Hz, 2H), 7.24 (m, 1H), 7.45 (m, 1H), 8.27 (m, 1H), 8.37 (m, 1H), 9.21 (s, 1H).
Reaction SMILES: [CH2:1]([C:4]1[C:5](=[O:11])[NH:6][C:7](=[O:10])[NH:8][CH:9]=1)[CH:2]=[CH2:3]>CCO>[CH:1](/[C:4]1[C:5](=[O:11])[NH:6][C:7](=[O:10])[NH:8][CH:9]=1)=[CH:2]\[CH3:3]
Reactant: C=CCc1c[nH]c(=O)[nH]c1=O
Solvent: CCO
Product: C/C=C/c1c[nH]c(=O)[nH]c1=O

Procedure:
To a solution of 5-allyluracil (80 mg; 0.5 mmol) in 95% aq. EtOH (50 ml) was added (Ph3P)3RhCl (90 mg; 0.1 mmol) and the mixture heated under reflux for 3 days. The solvent was evaporated and the product isolated by flash chromatography on SiO2 eluted with 5% MeOH-CH2Cl2. Yield 56 mg 70%; 200 MHz 1H-NMR DMSO-d6, δ:11.0 (br s, 1H, NH); 7.42 (s, 1H, 6-H); 6.35-6.55 (qq, 1H =CH--Me); 5.95-6.1 (dd, 1H, --CH=); 1.74 (dd, 3H, CH3).
Reaction SMILES: [CH2:1]([N:3]([CH2:18][CH3:19])[CH2:4][CH2:5][NH:6][C:7]([C:9]1[C:13]([CH3:14])=[C:12]([CH:15]=O)[NH:11][C:10]=1[CH3:17])=[O:8])[CH3:2].[F:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[NH:26][C:25](=[O:30])[CH2:24]2.N1CCCC1>CO>[CH3:2][CH2:1][N:3]([CH2:4][CH2:5][NH:6][C:7]([C:9]1[C:13]([CH3:14])=[C:12](/[CH:15]=[C:24]2/[C:23]3[CH:22]=[C:21]([F:20])[CH:29]=[CH:28][C:27]=3[NH:26][C:25]/2=[O:30])[NH:11][C:10]=1[CH3:17])=[O:8])[CH2:18][CH3:19]
Reactant: O=C1Cc2cc(F)ccc2N1
Reactant: CCN(CC)CCNC(=O)c1c(C)[nH]c(C=O)c1C
Solvent: C1CCNC1
Solvent: CO
Product: CCN(CC)CCNC(=O)c1c(C)[nH]c(/C=C2\C(=O)Nc3ccc(F)cc32)c1C

Procedure:
5-Formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl)-amide (10.0 g 0.037 moles) and 5-Fluoro-1,3-dihydro-indol-2-one (5.41 g; 0.0358 moles) in methanol were reacted in presence of catalytic amount of pyrrolidine (0.16 mL) as base at reflux temperature for 2-8 hours. The resultant Sunitinib base was triturated in methanol at reflux temperature for 1-2 hours and isolated at 25-30° C. and dried at 60° C. for 5-20 hours to get Sunitinib base (I) as orange crystalline solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:13]=[C:14]4[C:20]([C:21]([OH:23])=O)=[CH:19][N:18]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.[NH2:32][CH:33]([CH2:36][OH:37])[CH2:34][OH:35].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[OH:35][CH2:34][CH:33]([NH:32][C:21]([C:20]1[C:14]2[C:15](=[N:16][CH:17]=[C:12]([C:6]3[C:5]4[C:9](=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=4)[N:8]([CH3:11])[N:7]=3)[N:13]=2)[N:18]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:29])[CH3:30])[CH:19]=1)=[O:23])[CH2:36][OH:37]
Reactant: NC(CO)CO
Reactant: Cn1nc(-c2cnc3c(n2)c(C(=O)O)cn3COCC[Si](C)(C)C)c2ccc(Cl)cc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cn1nc(-c2cnc3c(n2)c(C(=O)NC(CO)CO)cn3COCC[Si](C)(C)C)c2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.2 %

Procedure:
A 25 mL round-bottomed flask was charged with 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (0.20 g, 0.44 mmol), 2-aminopropane-1,3-diol (119 mg, 1.31 mmol), HBTU (331 mg, 0.87 mmol), and HOBT (134 mg, 0.87 mmol). Then added DMF (1 mL) followed by N,N-diisopropylethylamine (0.31 mL, 1.75 mmol). The yellow reaction mixture was stirred at room temperature overnight then quenched with water and extracted with EtOAc (30 mL). The organic layer was washed once with saturated NaHCO3 and water. The combined aqueous layers were back extracted with EtOAc (25 mL). The combined organic layers was dried over sodium sulfate, filtered and concentrated. The residue was purified by chromatography over SiO2 with EtOAc/hexanes (gradient: 0-100% EtOAc) to afford 157 mg (68%) of 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (2-hydroxy-1-hydroxymethyl-ethyl)-amide as a white solid. MS: [M+Na]+=552.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:33])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]2[C:7]=1[C:8](=[O:32])[C:9]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]3[CH:31]=[CH:30][CH:29]=[N:28]3)=[CH:23][CH:22]=1)=[C:10]([CH:17]([CH3:19])[CH3:18])[NH:11]2.Cl[CH:35]([F:37])[F:36]>>[CH3:1][O:2][C:3](=[O:33])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]2[C:7]=1[C:8]([O:32][CH:35]([F:37])[F:36])=[C:9]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]3[CH:31]=[CH:30][CH:29]=[N:28]3)=[CH:23][CH:22]=1)[C:10]([CH:17]([CH3:19])[CH3:18])=[N:11]2
Reactant: COC(=O)COc1ccc(Cl)c2[nH]c(C(C)C)c(Cc3ccc(-n4cccn4)cc3)c(=O)c12
Reactant: FC(F)Cl
Product: COC(=O)COc1ccc(Cl)c2nc(C(C)C)c(Cc3ccc(-n4cccn4)cc3)c(OC(F)F)c12

Procedure:
The title compound was prepared by the method of Preparation 10c using [8-chloro-2-isopropyl-4-oxo-3-(4-pyrazol-1-ylbenzyl)-1,4-dihydroquinolin-5-yloxy]acetic acid methyl ester and chlorodifluoromethane.
Reaction SMILES: [SH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([N+:12]([O-:14])=[O:13])=[C:5]2[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.Cl[CH:22]([F:24])[F:23]>[OH-].[Na+].O1CCOCC1.O>[F:23][CH:22]([F:24])[S:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([N+:12]([O-:14])=[O:13])=[C:5]2[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=[N+]([O-])c1cnc2ccc(S)cc2c1-c1ccccc1
Reactant: FC(F)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=[N+]([O-])c1cnc2ccc(SC(F)F)cc2c1-c1ccccc1

Procedure:
6-Mercapto-3-nitro-4-phenylquinoline (1.00 g) was dissolved in a mixture of 2N-sodium hydroxide (20 ml) and dioxane (20 ml), and into the solution was introduced chlorodifluoromethane gas for 2 hrs. at 75°-80° C. The reaction mixture was diluted with water and extracted with chloroform. The extract was washed with aqueous 2N-sodium hydroxide solution and water, dried over anhydrous magnesium sulfate, and distilled to remove the solvent. The residue was recrystallized from isopropyl ether to give 6-difluoromethylthio-3-nitro-4-phenylquinoline as yellow prisms. Yield 948 mg (80.5%). m.p. 101°-103° C.
Reaction SMILES: [O:1]1[C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:4]=2[C:3]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2Br)=[N:2]1.C([Li])CCC.C[CH2:23][O:24]CC>CCCCCC>[O:1]1[C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:4]=2[C:3]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH:23]=[O:24])=[N:2]1
Reactant: CCOCC
Reactant: Brc1ccccc1-c1noc2c1CCCC2
Agent: [Li]CCCC
Solvent: CCCCCC
Product: O=Cc1ccccc1-c1noc2c1CCCC2
Temperature: -20 °C
Reaction time: 0.08 h

Procedure:
To a solution of 4.1 g of 2-(4,5,6,7-tetrahydro-1,2-benzisoxazol-3-yl)-bromobenzene in 100 ml of ether at a temperature of -40° C. was added 11 ml of a 1.5M solution of butyllithium in hexane with magnetic stirring. The reaction was warmed to -20° C. and held at this temperature for 5 minutes. The lithio species was quenched by the addition of 1.3 ml of N,N-dimethylformamide. To the reaction was added 100 ml of saturated ammonium chloride and the solution was extracted with two 200 ml portions of ether. The combined organic layers were dried over sodium sulfate and evaporated to yield 3.5 g of 2-(4,5,6,7-tetrahydro-1,2-benzisoxazol-3-yl)-benzaldehyde, GC-M.S. (E.I.) (M/Z): 226 [M-H]+.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O=[CH:16][CH2:17][CH2:18][C:19]1[CH:34]=[CH:33][C:22]([O:23][C:24]2[CH:32]=[CH:31][C:27]([C:28]([NH2:30])=[O:29])=[CH:26][N:25]=2)=[CH:21][CH:20]=1.[NH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.[OH-].[Na+]>ClCCCl>[C:36]1([NH:35][CH2:16][CH2:17][CH2:18][C:19]2[CH:34]=[CH:33][C:22]([O:23][C:24]3[CH:32]=[CH:31][C:27]([C:28]([NH2:30])=[O:29])=[CH:26][N:25]=3)=[CH:21][CH:20]=2)[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: Nc1ccccc1
Reactant: NC(=O)c1ccc(Oc2ccc(CCC=O)cc2)nc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCCl
Product: NC(=O)c1ccc(Oc2ccc(CCCNc3ccccc3)cc2)nc1
Yield: 8.2 %

Procedure:
Add sodium triacetoxyborohydride (0.1633 g, 0.7705 mmol) to a stirred solution of 6-[4-(3-oxo-propyl)-phenoxy]-nicotinamide (0.1341 g, 0.4962 mmol), aniline (0.047 mL, 0.5158 mmol), and 1,2-dichloroethane (7 mL). Stir the reaction for 18 h at room temperature under nitrogen. Pour the reaction mixture into 1 N sodium hydroxide (50 mL), extract with dichloromethane (3× 50 mL), dry the dichloromethane extracts over magnesium sulfate, filter, and concentrate on a rotary evaporator to give the crude product. The crude product is purified by flash chromatography on silica gel eluting with 0.6% concentrated ammonium hydroxide/6% ethanol/chloroform to yield 0.0142 g (8%) of 6-[4-(3-phenylamino-propyl)-phenoxy]-nicotinamide: mass spectrum (ion spray): m/z=348.1 (M+1); 1H NMR (CDCl3): 8.58 (d, 1H), 8.16 (dd, 1H), 7.26-7.1 (m, 7H), 7.10-7.04 (m, 2H), 6.97-6.94 (m, 1H), 6.79-6.51 (m, 2H), 3.19 (t, 2H), 2.76 (t, 2H), 2.04-1.97 (m, 3H).
Reaction SMILES: [CH2:1]([N:6]1[C:14]2[N:13]=[CH:12][NH:11][C:10]=2[C:9](=[O:15])[NH:8]/[C:7]/1=[N:16]\[NH2:17])[CH2:2][CH2:3][CH2:4][CH3:5].[F:18][C:19]([F:24])([F:23])[C:20](O)=O>>[CH2:1]([N:6]1[C:14]2[N:13]=[CH:12][NH:11][C:10]=2[C:9](=[O:15])[N:8]2[C:20]([C:19]([F:24])([F:23])[F:18])=[N:17][N:16]=[C:7]12)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCn1/c(=N/N)[nH]c(=O)c2[nH]cnc21
Reactant: O=C(O)C(F)(F)F
Product: CCCCCn1c2nc[nH]c2c(=O)n2c(C(F)(F)F)nnc12
Yield: 60.2 %

Procedure:
The mixture of (2E)-3-pentyl-3,7-dihydro-1H-purine-2,6-dione 2-hydrazone (200 mg, 0.85 mmol) in trifluoroacetic acid (10 mL) was refluxed overnight. The reaction mixture was concentrated and purified by preparative LCMS to yield the desired product (160 mg, 60.2%). LCMS calculated for C12H14F3N6O(M+H): 315.1; found 315.0.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([CH:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[O:12])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[CH:19]1([CH2:22][CH2:23][C:24](O)=[O:25])[CH2:21][CH2:20]1>>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([NH:10][C:11]([CH:13]2[CH2:18][CH2:17][N:16]([C:24](=[O:25])[CH2:23][CH2:22][CH:19]3[CH2:21][CH2:20]3)[CH2:15][CH2:14]2)=[O:12])=[CH:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1ccc(NC(=O)C2CCNCC2)cc1
Reactant: O=C(O)CCC1CC1
Product: CC(C)c1ccc(NC(=O)C2CCN(C(=O)CCC3CC3)CC2)cc1

Procedure:
This material was prepared in analogy to example 8 step C) from piperidine-4-carboxylic acid (4-isopropyl-phenyl)-amide (0.123 g), 3-cyclopropylpropionic acid (0.057 g) as white solid (0.124 g). MS (ESI): 343.17 (MH+).