Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][NH2:11])=[CH:6][CH:5]=1.[CH3:12][C:13]([CH3:20])([CH3:19])[C:14](=O)[CH2:15][C:16]#[N:17].CCO.C([O-])([O-])=O.[Na+].[Na+]>CCOCC.CC(O)=O>[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:16]([NH2:17])=[CH:15][C:14]([C:13]([CH3:20])([CH3:19])[CH3:12])=[N:11]2)=[CH:6][CH:5]=1
Reactant: COc1ccc(NN)cc1
Reactant: CC(C)(C)C(=O)CC#N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Solvent: CCOCC
Product: COc1ccc(-n2nc(C(C)(C)C)cc2N)cc1

Procedure:
A mixture of 4-methoxyphenylhydrazine hydrochloride (3.5 g), 4,4-dimethyl-3-oxopentanenitrile (2.5 g), EtOH (30 mL), and AcOH (1 mL) was heated at the reflux temperature for 3 h, cooled to room temp., and poured into a mixture of Et2O (100 mL) and a 10% Na2CO3 solution (100 mL). The organic layer was washed with a saturated NaCl solution, dried (MgSO4) and concentrated under reduced pressure. The solid residue was washed with pentane to afford the desired pyrazole as a pale brown solid. (4.25 g): 1H-NMR (DMSO-d6) δ 1.18 (s, 9H); 3.78 (s, 3H); 5.02 (br s, 2H); 5.34 (s, 1H); 6.99 (d, J=8 Hz, 2H); 7.42 (d, J=8 Hz, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([C:22]2[S:23][CH:24]=[CH:25][C:26]=2Br)=[N:15][NH:16][CH2:17][C:18]([F:21])([F:20])[F:19])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>COC(O)C.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:22]3[S:23][CH:24]=[CH:25][C:26]=3[N:16]([CH2:17][C:18]([F:21])([F:20])[F:19])[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=NNCC(F)(F)F)c2sccc2Br)CC1
Agent: COC(C)O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(c2nn(CC(F)(F)F)c3ccsc23)CC1
Temperature: 75 °C
Yield: 104.7 %

Procedure:
4-{(3-Bromo-thiophen-2-yl)-[(2,2,2-trifluoro-ethyl)-hydrazono]-methyl}-piperidine-1-carboxylic acid tert-butyl ester (2.34 g, 4.98 mmol) was mixed with Cul (50 mg), CsCO3 (1.9 g, 1.2 eq) in methoxyethanol (25 mL). The mixture was heated to 75° C. for 1 hour. The mixture was then diluted with EtOAc and filtered. The filtrate was evaporated and the residue was purified via chromatography (eluted with 0-10% MeOH in DCM) yielding 2.03 g (>95%) of the desired product.
Reaction SMILES: [CH2:1]([O:3][C@H:4]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:5][C:6]1[CH:16]=[CH:15][C:9]([O:10][CH2:11][C:12]([OH:14])=O)=[CH:8][CH:7]=1)[CH3:2].[C:22]([C:26]1[CH:41]=[CH:40][C:29]([CH2:30][NH:31][CH2:32][C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=2)=[CH:28][CH:27]=1)([CH3:25])([CH3:24])[CH3:23].C(N(CC)C(C)C)(C)C.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>C(Cl)Cl>[C:22]([C:26]1[CH:41]=[CH:40][C:29]([CH2:30][N:31]([CH2:32][C:33]2[CH:34]=[CH:35][C:36]([Cl:39])=[CH:37][CH:38]=2)[C:12](=[O:14])[CH2:11][O:10][C:9]2[CH:8]=[CH:7][C:6]([CH2:5][C@H:4]([O:3][CH2:1][CH3:2])[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:16][CH:15]=2)=[CH:28][CH:27]=1)([CH3:25])([CH3:23])[CH3:24]
Reactant: CCOC(=O)[C@H](Cc1ccc(OCC(=O)O)cc1)OCC
Reactant: CC(C)(C)c1ccc(CNCc2ccc(Cl)cc2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)[C@H](Cc1ccc(OCC(=O)N(Cc2ccc(Cl)cc2)Cc2ccc(C(C)(C)C)cc2)cc1)OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 27 %

Procedure:
To a solution of {4-[(2S)-2,3-diethoxy-3-oxopropyl]phenoxy}acetic acid (0.889 g, 3.00 mmol) in methylene chloride (30 mL) were added N-(4-tert-butylbenzyl)-N-(4-chlorobenzyl)amine (1.04 g, 3.60 mmol), N,N-diisopropylethylamine (1.20 mL, 6.9 mmol) and O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (1.01 g, 3.15 mmol) and the reaction mixture was stirred at room temperature overnight. The resulting solution was diluted with methylene chloride (220 mL) and the organic phase was washed with 2 M HCl (3×50 mL), saturated aqueous NaHCO3 (2×50 mL), and brine (50 mL), dried over Na2SO4, and concentrated in vacuo. Twice repeated purification on prepacked columns of silica gel (Isolute® SPE Column, 50 g/150 mL) with methanol (0-2% gradient) in methylene chloride as the eluent and collection of pure fractions yielded 0.459 g (27%) of a whitish oil.
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:14]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:13]=[C:12]1[C:28]1[CH:33]=[CH:32][C:31]([O:34]C)=[CH:30][CH:29]=1)([OH:3])=[O:2].B(Br)(Br)Br.O>ClCCl>[C:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:14]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:13]=[C:12]1[C:28]1[CH:29]=[CH:30][C:31]([OH:34])=[CH:32][CH:33]=1)([OH:3])=[O:2]
Reactant: COc1ccc(-c2nc(-c3ccccc3)c(-c3ccccc3)n2CCCCCCCC(=O)O)cc1
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: O=C(O)CCCCCCCn1c(-c2ccc(O)cc2)nc(-c2ccccc2)c1-c1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 20.2 %

Procedure:
1-(7-Carboxyheptyl)-2-(4-methoxyphenyl)-4,5-diphenyl-imidazole (2.5 g) was added, in portions over 40 minutes, to a solution of boron tribromide (2.17 ml) in anhydrous dichloromethane (40 ml). The reaction was stirred at room temperature for 5 h, cooled and water (50 ml) was carefully added. The organic layer was removed and the aqueous layer was washed with dichloromethane (3×75 ml). The organic extracts were combined, dried over anhydrous magnesium sulphate and evaporated to dryness in vacuo. Column chromatography on silica gel eluted with a dichloro-methane:methanol gradient and recrystallisation from ethanol/water and acetonitrile gave 1-(7-carboxy-heptyl)-2-(4-hydroxyphenyl)-4,5-diphenyl-imidazole (0.49 g, 20%) as a white solid, m.p. 171°-172°. Further material was obtained from the mother liquors (0.79 g, 33%) m.p. 167°. Found C: 76.85; H, 6.65; N, 6.20%; C29H30N2O3 requires: C, 76.63; H, 6.65; N, 6.16%;
Reaction SMILES: [C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:8]2[CH:17]=[CH:18][C:19]([S:21](Cl)(=[O:23])=[O:22])=[CH:20][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:25]1[CH2:30][CH2:29][CH2:28][C@H:27]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:26]1.CCN(C(C)C)C(C)C>ClCCCl>[C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:8]2[CH:17]=[CH:18][C:19]([S:21]([N:25]3[CH2:30][CH2:29][CH2:28][C@H:27]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:26]3)(=[O:23])=[O:22])=[CH:20][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)[C@H]1CCCNC1
Reactant: CC(C)(C)c1nc2cc(S(=O)(=O)Cl)ccc2n1CC1CCOCC1
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)[C@H]1CCCN(S(=O)(=O)c2ccc3c(c2)nc(C(C)(C)C)n3CC2CCOCC2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A suspension of 2-tert-butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazole-5-sulfonyl chloride (300 mg, 0.80 mmol) in DCE (5 mL) was slowly added to a solution of ethyl (3S)-piperidine-3-carboxylate (140 mg, 0.88 mmol) and DIPEA (1.4 mL, 8.0 mmol) in DCE (25 mL). The reaction mixture was stirred overnight at ambient temperature and the solvent was concentrated. The product was purified by MPLC on silica gel using 60-90% EtOAc/heptane as eluent to provide the title compound as white solid. Yield: 276 mg (69%). 1H NMR (400 MHz, CDCl3) δ 1.26 (t, J=7.13 Hz, 3 H), 1.33 (td, J=12.21, 3.32 Hz, 1 H), 1.50-1.57 (m, 3 H), 1.59 (s, 9 H), 1.62-1.73 (m, 2 H), 1.73-1.83 (m, 1 H), 1.91-2.01 (m, 1 H), 2.30 (td, J=11.43, 2.93 Hz, 2 H), 2.44 (t, J=11.13 Hz, 1 H), 2.58-2.69 (m, 1 H), 3.28-3.40 (m, 2 H), 3.65-3.74 (m, 1 H), 3.91 (dd, J=11.43, 3.81 Hz, 1 H), 4.01 (dd, J=11.33, 2.93 Hz, 2 H), 4.13 (q, J=7.23 Hz, 2H), 4.25 (d, J=7.42 Hz, 2 H), 7.43 (d, J=8.59 Hz, 1 H), 7.64 (dd, J=8.59, 1.76 Hz, 1 H), 8.19 (d, J=1.76 Hz, 1 H). MS (ESI) (M+H)+=492.0.
Reaction SMILES: [H-].[Na+].[NH2:3][C@@H:4]([CH:7]([CH3:9])[CH3:8])[CH2:5][OH:6].Cl[CH2:11][C:12](OCC)=[O:13]>C1(C)C=CC=CC=1>[CH:7]([C@@H:4]1[NH:3][C:12](=[O:13])[CH2:11][O:6][CH2:5]1)([CH3:9])[CH3:8]
Reactant: CCOC(=O)CCl
Reactant: CC(C)[C@H](N)CO
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(C)[C@H]1COCC(=O)N1
Temperature: 25 °C
Yield: 67.2 %

Procedure:
To an ice-cold, stirred suspension of sodium hydride (2.59 g, 64.8 mmol) in toluene (90 mL) was added dropwise a solution of (S)-2-amino-3-methylbutan-1-ol (3 g, 29.1 mmol) in toluene (60 mL). The reaction was then warmed to room temperature and a solution of ethyl chloroacetate (3.56 g, 29.1 mmol) in toluene (16 mL) was added dropwise. The resulting mixture was heated to reflux for 20 h under nitrogen and then concentrated under vacuum. The residue was purified by flash chromatography to afford 2.8 g of product (MS: (M+H)=144.3).
Reaction SMILES: [CH:1]1([O:5][C:6]2[CH:11]=[CH:10][C:9]([NH:12]C(C3C=C(CCCOCCOCCOCCOCCC(OC(C)(C)C)=O)C=CC=3)=O)=[C:8]([C:43]3[CH:48]=[C:47]([C:49](=[O:61])[NH:50][C@@H:51]4[C:60]5[C:55](=[CH:56][CH:57]=[CH:58][CH:59]=5)[CH2:54][CH2:53][CH2:52]4)[CH:46]=[CH:45][N:44]=3)[CH:7]=2)[CH2:4][CH2:3][CH2:2]1.[CH2:62]([C:89]1[CH:90]=[C:91]([CH:95]=[CH:96][CH:97]=1)[C:92]([OH:94])=O)[O:63][CH2:64][CH2:65][O:66][CH2:67][CH2:68][O:69][CH2:70][CH2:71][O:72][CH2:73][CH2:74][O:75][CH2:76][CH2:77][O:78][CH2:79][CH2:80][O:81][CH2:82][CH2:83][O:84][CH2:85][CH2:86][O:87][CH3:88]>>[CH2:62]([C:89]1[CH:90]=[C:91]([CH:95]=[CH:96][CH:97]=1)[C:92]([NH:12][C:9]1[CH:10]=[CH:11][C:6]([O:5][CH:1]2[CH2:4][CH2:3][CH2:2]2)=[CH:7][C:8]=1[C:43]1[CH:48]=[C:47]([CH:46]=[CH:45][N:44]=1)[C:49]([NH:50][C@@H:51]1[C:60]2[C:55](=[CH:56][CH:57]=[CH:58][CH:59]=2)[CH2:54][CH2:53][CH2:52]1)=[O:61])=[O:94])[O:63][CH2:64][CH2:65][O:66][CH2:67][CH2:68][O:69][CH2:70][CH2:71][O:72][CH2:73][CH2:74][O:75][CH2:76][CH2:77][O:78][CH2:79][CH2:80][O:81][CH2:82][CH2:83][O:84][CH2:85][CH2:86][O:87][CH3:88]
Reactant: CC(C)(C)OC(=O)CCOCCOCCOCCOCCCc1cccc(C(=O)Nc2ccc(OC3CCC3)cc2-c2cc(C(=O)N[C@H]3CCCc4ccccc43)ccn2)c1
Reactant: COCCOCCOCCOCCOCCOCCOCCOCCOCc1cccc(C(=O)O)c1
Product: COCCOCCOCCOCCOCCOCCOCCOCCOCc1cccc(C(=O)Nc2ccc(OC3CCC3)cc2-c2cc(C(=O)N[C@H]3CCCc4ccccc43)ccn2)c1

Procedure:
This compound was prepared according to the procedure described for the synthesis of (S)-tert-butyl 16-(3-((4-cyclobutoxy-2-(4-((1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)pyridin-2-yl)phenyl)carbamoyl)phenyl)-4,7,10,13-tetraoxahexadecan-1-oate Example 284, using intermediate 3-(2,5,8,11,14,17,20,23,26-nonaoxaheptacosyl)benzoic acid in place of 3-(2,2-dimethyl-4-oxo-3,7,10,13,16-pentaoxanonadecan-19-yl)benzoic acid. MS (ES, m/z): 914.6 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[C:21]3[C:22]4=[C:23]5[C:18](=[CH:19][CH:20]=3)[CH:17]=[CH:16][CH:15]=[C:14]5[CH:13]=[CH:12][C:11]4=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:24][C:25]1([CH3:59])[C:49]2[C:29]([CH:30]=[C:31]3[CH:48]=[C:47]4[C:34]([C:35]5[C:40]([C:41]6[C:46]4=[CH:45][CH:44]=[CH:43][CH:42]=6)=[CH:39][CH:38]=[CH:37][CH:36]=5)=[CH:33][C:32]3=2)=[CH:28][C:27](B2OC(C)(C)C(C)(C)O2)=[CH:26]1.C([O-])([O-])=O.[Na+].[Na+].CCO>CO.C1(C)C=CC=CC=1>[CH3:59][C:25]1([CH3:24])[C:49]2[C:29]([CH:30]=[C:31]3[C:32]=2[CH:33]=[C:34]2[C:47]([C:46]4[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=4[C:40]4[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=42)=[CH:48]3)=[CH:28][C:27]([C:6]2[CH:7]=[CH:2][CH:3]=[C:4]([C:8]3[C:21]4[C:22]5=[C:23]6[C:18](=[CH:19][CH:20]=4)[CH:17]=[CH:16][CH:15]=[C:14]6[CH:13]=[CH:12][C:11]5=[CH:10][CH:9]=3)[CH:5]=2)=[CH:26]1
Reactant: Brc1cccc(-c2ccc3ccc4cccc5ccc2c3c45)c1
Reactant: CC1(C)C=C(B2OC(C)(C)C(C)(C)O2)C=C2C=c3cc4c5ccccc5c5ccccc5c4cc3=C21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC1(C)C=C(c2cccc(-c3ccc4ccc5cccc6ccc3c4c56)c2)C=C2C=c3cc4c5ccccc5c5ccccc5c4cc3=C21
Temperature: 90 °C
Yield: 57 %

Procedure:
A mixture of 5 g (14 mmol) of 1-(3-bromophenyl)pyrene, 7.53 g (16 mmol) of 2-(10,10-dimethyl-10H-indeno[1,2-b]triphenylen-12-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane, 0.16 g (0.14 mmol) of tetrakis(triphenyl phosphine)palladium, 11 ml of 2M Na2CO3, 30 ml of EtOH and 65 ml toluene was degassed and placed under nitrogen, and then heated at 90° C. for 4 h. After finishing the reaction, the mixture was allowed to cool to room temperature. Than 500 ml MeOH was added, while stirring and the precipitated product was filtered off with suction to give 4.95 g (yield 57%) of yellow product which was recrystallized from toluene. MS(m/z, FAB+): 620.1; 1H NMR (CDCl3, 400 MHz): chemical shift (ppm) 9.05 (s, 1H), 8.46˜8.41 (m, 2H), 8.40 (s, 1H), 8.06˜7.84 (m, 9H), 7.74 (d, J=8.00 Hz, 1H), 7.69˜7.59 (m, 4H), 7.54˜7.39 (m, 5H), 7.31˜7.16 (m, 3H), 1.82 (s, 6H).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][N:6]2[C:8](=[O:20])[C@@H:9]([NH:10][C:11](=[O:19])[CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C@H:5]2[S:4][CH2:3]1.O1CCCC1.Cl>C(Cl)Cl>[O:1]=[C:2]1[CH2:7][N:6]2[C:8](=[O:20])[C@@H:9]([NH:10][C:11](=[O:19])[CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C@H:5]2[S:4][CH2:3]1
Reactant: O=C(Cc1ccccc1)N[C@@H]1C(=O)N2C[C@@H](O)CS[C@H]12
Agent: Cl
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=C1CS[C@@H]2[C@H](NC(=O)Cc3ccccc3)C(=O)N2C1
Reaction time: 1 h

Procedure:
A solution of (3R,6R,7R)-3-hydroxy-7-phenylacetamidocepham (0.5 g., 1.72 mmole) in anhydrous acid-free methylene chloride (15 ml.) containing anhydrous tetrahydrofuran (3 ml.) was treated with a solution of chromium trioxide/pyridine complex (1.3 g., 3 equivalents) in methylene chloride 30 ml.) at 21° for 1 hour. The reaction mixture was poured into excess dilute hydrochloric acid. After separation, the organic phase was washed with water, dried, and evaporated to an oil. Trituration with ethyl acetate and ether gave the title compound (0.095 g., 19% m.p. 174° to 177° (cap.) νmax. (bromoform, Unicam) 3430 (NH), 1770 (β-lactam), 1735 (ketone), 1678 and 1515 cm.- 1 (amide).
Reaction SMILES: [OH:1][N:2]=[C:3](Cl)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Cl:11][C:12]1[C:21]2[N:22]=[C:23]([CH2:28][O:29][CH2:30][CH3:31])[N:24]([CH2:25][C:26]#[CH:27])[C:20]=2[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N:13]=1.C(N(CC)CC)C>ClCCl>[Cl:11][C:12]1[C:21]2[N:22]=[C:23]([CH2:28][O:29][CH2:30][CH3:31])[N:24]([CH2:25][C:26]3[O:1][N:2]=[C:3]([C:4]4[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=4)[CH:27]=3)[C:20]=2[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N:13]=1
Reactant: C#CCn1c(COCC)nc2c(Cl)nc3ccccc3c21
Reactant: ON=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOCc1nc2c(Cl)nc3ccccc3c2n1Cc1cc(-c2ccccc2)no1
Temperature: 25 °C

Procedure:
N-Hydroxybenzenecarboximidoyl chloride (prepared as described in Part A of Example 2, 1.72 g, 10.5 mmol) was added to a solution of 4-chloro-2-(ethoxymethyl)-1-prop-2-ynyl-1H-imidazo[4,5-c]quinoline (3.00 g, 10.0 mmol) and triethylamine (1.70 mL, 12.0 mmol) in dichloromethane (40 mL). The solution was heated at reflux under a nitrogen atmosphere for 3.5 hours and additional N-hydroxybenzenecarboximidoyl chloride (0.1 g) was added. The solution was heated at reflux for one hour more, then was allowed to cool to room temperature and was diluted with dichloromethane. The solution was transferred to a separatory funnel and was washed with water and brine, dried over sodium sulfate, filtered, and concentrated. The crude product was purified by flash chromatography (silica gel, gradient elution from 4:1 to 3:2 hexanes/ethyl acetate) to provide pure 4-chloro-2-(ethoxymethyl)-1-[(3-phenylisoxazol-5-yl)methyl]-1H-imidazo[4,5-c]quinoline (1.48 g).
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([C@H:11]([NH:16][C:17]([C:19]2[C:27]3[C:22](=[N:23][CH:24]=[C:25](Br)[N:26]=3)[N:21](COCC[Si](C)(C)C)[CH:20]=2)=[O:18])[C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1)#[N:2].C(C1CCN(C(=O)[C@H](NC(C2C3C(=NC=C(Br)N=3)N(COCC[Si](C)(C)C)C=2)=O)C2CC2)CC1)#N.C([Sn](CCCC)(CCCC)[C:77]1[CH:82]=[C:81]([C:83]([F:86])([F:85])[F:84])[CH:80]=[CH:79][N:78]=1)CCC.C(C1C=CN=C([Sn](CCCC)(CCCC)CCCC)C=1)(C)(C)C>>[C:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([C@H:11]([NH:16][C:17]([C:19]2[C:27]3[C:22](=[N:23][CH:24]=[C:25]([C:77]4[CH:82]=[C:81]([C:83]([F:86])([F:85])[F:84])[CH:80]=[CH:79][N:78]=4)[N:26]=3)[NH:21][CH:20]=2)=[O:18])[C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1)#[N:2]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc(C(F)(F)F)ccn1
Reactant: CC(C)(C)[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12)C(=O)N1CCC(C#N)CC1
Agent: CCCC[Sn](CCCC)(CCCC)c1cc(C(C)(C)C)ccn1
Agent: C[Si](C)(C)CCOCn1cc(C(=O)N[C@@H](C(=O)N2CCC(C#N)CC2)C2CC2)c2nc(Br)cnc21
Product: CC(C)(C)[C@@H](NC(=O)c1c[nH]c2ncc(-c3cc(C(F)(F)F)ccn3)nc12)C(=O)N1CCC(C#N)CC1

Procedure:
Prepared according to the procedure outlined in Example 111, steps 4-5 substituting 2-bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-1-(4-cyano-piperidine-1-carbonyl)-2,2-dimethyl-propyl]-amide for 2-bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(4-cyano-piperidin-1-yl)-1-cyclopropyl-2-oxo-ethyl]-amide and 2-tributylstannanyl-4-trifluoromethyl-pyridine for 4-tert-butyl-2-(tributylstannyl)pyridine. MS: (M+H)+=514.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]([OH:11])=[O:10])=[N:6][C:7]=1Cl.[OH-].[K+].[O:14]1[CH2:18][CH2:17][CH2:16][CH:15]1[CH2:19][OH:20].[OH-].[Na+]>CS(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]([OH:11])=[O:10])=[N:6][C:7]=1[O:20][CH2:19][CH:15]1[CH2:16][CH2:17][CH2:18][O:14]1
Reactant: OCC1CCCO1
Reactant: O=C(O)c1ccc(Br)c(Cl)n1
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: O=C(O)c1ccc(Br)c(OCC2CCCO2)n1
Temperature: 0 °C
Reaction time: 24 h
Yield: 99.4 %

Procedure:
5-Bromo-6-chloropicolinic acid (200 mg, 846 μmol; CAN 959958-25-9) and powdered potassium hydroxide (190 mg, 3.38 mmol) were combined with DMSO (1.93 mL) to give a colorless solution which was stirred for 15 min at ambient temperature before tetrahydro-2-furanmethanol (130 mg, 123 μl, 1.27 mmol, CAN 97-99-4) was added, and stirring continued for 1 day at ambient temperature. The reaction mixture was poured into a mixture of ice-water and 1 M NaOH, and extracted with t-butylmethyl ether (2×25 mL) and washed with ice-water/brine. The water phases were combined acidified with ice/1 N HCl and extracted with isopropyl acetate (2×30 mL). The organic layers were washed with ice-water/brine (2×30 mL), dried with Na2SO4 and concentrated in vacuo to give the title compound (254 mg, 99%) as light brown oil; MS (ESI): 301.8 [M−H]−.
Reaction SMILES: Br[C:2]1[N:11]=[C:10]([C:12]2[NH:16][C:15]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)=[N:14][N:13]=2)[C:9]([OH:25])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[NH:26]1[CH2:31][CH2:30][NH:29][CH2:28][C:27]1=[O:32].O>CN1CCCC1=O>[F:24][C:21]1[CH:22]=[CH:23][C:18]([CH2:17][C:15]2[NH:16][C:12]([C:10]3[C:9]([OH:25])=[C:8]4[C:3]([CH:4]=[CH:5][CH:6]=[N:7]4)=[C:2]([N:29]4[CH2:30][CH2:31][NH:26][C:27](=[O:32])[CH2:28]4)[N:11]=3)=[N:13][N:14]=2)=[CH:19][CH:20]=1
Reactant: Oc1c(-c2nnc(Cc3ccc(F)cc3)[nH]2)nc(Br)c2cccnc12
Reactant: O=C1CNCCN1
Solvent: CN1CCCC1=O
Solvent: O
Product: O=C1CN(c2nc(-c3nnc(Cc4ccc(F)cc4)[nH]3)c(O)c3ncccc23)CCN1
Yield: 55.6 %

Procedure:
A solution of 5-bromo-7-[5-(4-fluorobenzyl)-4H-1,2,4-triazol-3-yl)-1,6-naphthyridin-8-ol (10 mg, 0.03 mmol) and piperazin-2-one (60 mg, 0.60 mmol) in 1-methylpyrrolidin-2-one (2 mL) was heated at 150° C. for 18 hours. The resultant solution was cooled to room temperature and water was added. The solids which formed were removed by filtration and further purified by prep HPLC to give 4-{7-[5-(4-Fluorobenzyl)-4H-1,2,4-triazol-3-yl]-8-hydroxy-1,6-naphthyridin-5-yl}piperazin-2-one (7 mg, 67%) as a white solid. 1H NMR (CD3OD/CDCl3): δ 9.03 (d, J=4.4 Hz, 1 H), 8.48 (d, J=8.4 Hz, 1 H), 7.64 (dd, J=8.4, 4.4 Hz, 1 H), 7.32 (dd, J=8.4, 5.6Hz, 2 H), 6.97 (t, J=8.4Hz, 2 H). 4.13 (s, 2 H), 4.10 (5,2 H), 3.60 (m, 2 H), 3.42 (m, 2 H); 19F NMR (CD3OD/CDCl3): δ −117.93; MS m/z 420 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[C:9](=[O:14])[CH2:10]S(C)=O.[C:15]([C:17]1[CH:26]=[CH:25][C:20]([CH:21]=[CH:22][CH:23]=O)=[CH:19][CH:18]=1)#[N:16].COC1C2OC(C=CC3C=CC(C#N)=CC=3)=CC(=O)C=2C=CC=1>>[CH3:8][C:5]1[CH:6]=[CH:7][C:2]2[O:1][C:23]([CH:22]=[CH:21][C:20]3[CH:19]=[CH:18][C:17]([C:15]#[N:16])=[CH:26][CH:25]=3)=[CH:10][C:9](=[O:14])[C:3]=2[CH:4]=1
Reactant: N#Cc1ccc(C=CC=O)cc1
Reactant: Cc1ccc(O)c(C(=O)CS(C)=O)c1
Agent: COc1cccc2c(=O)cc(C=Cc3ccc(C#N)cc3)oc12
Product: Cc1ccc2oc(C=Cc3ccc(C#N)cc3)cc(=O)c2c1

Procedure:
This was prepared by reacting 6.36 g of 2'-hydroxy-5'-methyl-2-(methylsulfinyl)acetophenone with 6.36 g of p-cyanocinnamaldehyde in analogous fashion to 4-[2-(8-methoxy-4-oxo-4H-1-benzopyran-2-yl)ethenyl]benzonitrile. The material was recrystallized from toluene, mp 249°-51°; yield 3.5g (41%) λ max mμ (ε) 219 (19,300); 278 (13,500), 339 (41,000); ν max 825 (m), 980 (m), 1235 (m), 1580 (m), 1630 (m), 1670 (s), 2240 (m) cm-1.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=[C:13]([C:21]4[CH:22]=[C:23]([CH:29]=[CH:30][CH:31]=4)[O:24][CH2:25][C:26]([OH:28])=O)[N:12]=3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl.[O:75]1[CH2:80][CH2:79][CH:78]([NH2:81])[CH2:77][CH2:76]1>C(Cl)Cl.CN(C=O)C>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=[C:13]([C:21]4[CH:22]=[C:23]([CH:29]=[CH:30][CH:31]=4)[O:24][CH2:25][C:26]([NH:81][CH:78]4[CH2:79][CH2:80][O:75][CH2:76][CH2:77]4)=[O:28])[N:12]=3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: NC1CCOCC1
Reactant: O=C(O)COc1cccc(-c2nc(Nc3ccc4[nH]ncc4c3)c3ccccc3n2)c1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(COc1cccc(-c2nc(Nc3ccc4[nH]ncc4c3)c3ccccc3n2)c1)NC1CCOCC1
Reaction time: 0.5 h

Procedure:
A suspension of 2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)acetic acid (70 mg, 0.14 mmol), PyBOP® (40 mg, 0.077 mmol), DIEA (24 μL, 0.14 mmol) in dry CH2Cl2:DMF (2:0.1 mL) was stirred at RT for 15 minutes. To this solution of activated acid was added tetrahydro-2H-pyran-4-amine hydrochloride (13 mg, 0.091 mmol). After 30 minutes, 1.0 equivalent of DIEA and 0.55 equivalents of PyBOP® were added. After stirring the solution for 15 minutes, 0.65 equivalents of tetrahydro-2H-pyran-4-amine hydrochloride were added and the mixture was stirred for an additional 30 minutes. The solvent was removed in vacuo and the crude product was purified using prep HPLC (15-40—90 mins) to afford 2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)-N-(tetrahydro-2H-pyran-4-yl)acetamide. (32 mg, 0.065 mmol, 46%)
Reaction SMILES: [CH:1]1([O:7][C:8]2[CH:15]=[CH:14][C:11]([CH2:12][OH:13])=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>C(Cl)Cl>[CH:1]1([O:7][C:8]2[CH:9]=[CH:10][C:11]([CH:12]=[O:13])=[CH:14][CH:15]=2)[CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1
Reactant: OCc1ccc(OC2C=CCCC2)cc1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: O=Cc1ccc(OC2C=CCCC2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 77.6 %

Procedure:
The alcohol resulting from Example 37A (4.24 g, 20.7 mmol) was dissolved in 250 mL of methylene chloride under an atmosphere of dry nitrogen. Pyridinium chlorochromate (5.62 g, 26.1 mmol) was added over 5 minutes. After stirring at ambient temperature 72 hours, the mixture was filtered through Celite® and concentrated in vacuo. Flash chromatography on silica gel eluting with 10% ethyl acetate in hexane afforded 3.25 g (77%) of the title compound.