Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(NCCO)C=CC=CC=1.[CH2:11]([O:13][C@@H:14]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:21][CH:20]=1)[C:15]([OH:17])=[O:16])[CH3:12].O.S(=O)(=O)(O)O>C1(C)C=CC=CC=1>[CH2:11]([O:13][CH:14]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:21][CH:20]=1)[C:15]([OH:17])=[O:16])[CH3:12]
Reactant: CCO[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)O
Agent: O=S(=O)(O)O
Agent: OCCNc1ccccc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(Cc1ccc(OCc2ccccc2)cc1)C(=O)O
Temperature: 12.5 °C
Reaction time: 0.12 h

Procedure:
A mixture of (S)-2-ethoxy-3-(4-benzyloxyphenyl)propanoic acid α-methyl benzyl amino salt of the formula (12) or (S)-2-ethoxy-3-(4-benzyloxyphenyl) propanoic acid phenyl glycinol salt of the formula (18), (6.7 g) water (70 ml) and toluene (35 ml) was taken in a reaction flask and stirred for 5-10 min. The reaction mass was cooled to 10-15° C. and 25% cold sulfuric acid was added slowly to adjust pH of the reaction mass to 2. Aqueous and organic layers were separated. Aqueous layer was extracted with toluene (35 ml). The combined toluene layers were washed with water (20 ml) and evaporated to yield (S) 2-ethoxy-3-(4-benzyloxyphenyl)propanoic acid the formula (9b) (4 g).
Reaction SMILES: [C:1]1([NH:11][C:12](=[O:17])[O:13][CH2:14][CH2:15][NH2:16])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.Cl[CH2:26][CH2:27][S:28](Cl)(=[O:30])=[O:29]>C(Cl)(Cl)Cl>[C:1]1([NH:11][C:12](=[O:17])[O:13][CH2:14][CH2:15][NH:16][S:28]([CH:27]=[CH2:26])(=[O:30])=[O:29])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: NCCOC(=O)Nc1cccc2ccccc12
Reactant: O=S(=O)(Cl)CCCl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: C=CS(=O)(=O)NCCOC(=O)Nc1cccc2ccccc12

Procedure:
To a solution of 2-aminoethyl N-(1-naphthyl)carbamate [2.30 g(10.0 mmol.)] and triethylamine [1.53 ml(11.0 mmol.)] in chloroform(20 ml) was added, while stirring under ice-cooling, 2-chloroethanesulfonyl chloride [1.06 ml(10.0 mmol.)]. The mixture was stirred for 30 minutes under ice-cooling. The reaction mixture was washed with a 1N aqueous solution of sodium hydroxide, and dried, followed by distilling off the solvent under reduced pressure. The residue was subjected to a silica gel colum chromatography, eluting with hexane-ethyl acetate(1:1) to obtain the compound(270) [1.50 g(46.9%)] as a yellow oily product.
Reaction SMILES: [N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:26](O)=[O:27])[CH2:10]2)=[O:8])[CH2:6][CH2:5][S:4][CH2:3][CH2:2]1.CN(C(O[N:37]1N=N[C:39]2[CH:40]=[CH:41]C=[N:43][C:38]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.ON=C(C1CC1)N>CN(C)C=O>[CH:39]1([C:38]2[N:43]=[C:26]([CH:11]3[CH2:12][CH:13]([C:15]4[CH:20]=[CH:19][C:18]([O:21][C:22]([F:24])([F:25])[F:23])=[CH:17][CH:16]=4)[CH2:14][N:9]([C:7]([N:1]4[CH2:2][CH2:3][S:4][CH2:5][CH2:6]4)=[O:8])[CH2:10]3)[O:27][N:37]=2)[CH2:41][CH2:40]1
Reactant: O=C(O)C1CC(c2ccc(OC(F)(F)F)cc2)CN(C(=O)N2CCSCC2)C1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: NC(=NO)C1CC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(N1CCSCC1)N1CC(c2ccc(OC(F)(F)F)cc2)CC(c2nc(C3CC3)no2)C1
Temperature: 120 °C
Reaction time: 0.5 h

Procedure:
Alternative Synthesis: 600 mg (1.43 mmol) of the compound from Example 25A in dimethylformamide (29.0 ml) were admixed at RT with 654 mg (1.72 mmol) of HATU and 0.55 ml (498 mg, 3.16 mmol) of N,N-diisopropylethylamine, and the mixture was stirred for 30 min. Subsequently, 158 mg (1.58 mmol) of N′-hydroxycyclopropanecarboximidamide were added and the mixture was stirred at RT overnight. The reaction solution was heated to 120° C. and stirred at this temperature for 1 h. The reaction solution was subsequently purified directly by means of preparative HPLC. Yield: 315 mg (45% of theory)
Reaction SMILES: [NH2:1][C@@H:2]1[C@@H:6]([C:7]([OH:9])=[O:8])[O:5][C@@H:4]([N:10]2[CH:18]=[N:17][C:16]3[C:11]2=[N:12][CH:13]=[N:14][C:15]=3[NH:19][C:20](=[O:27])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C@@H:3]1[OH:28].[CH2:29]([O:36][C:37]([NH:39][C@H:40]([C:56](O)=[O:57])[CH2:41][C:42]1[CH:47]=[CH:46][C:45]([O:48][CH2:49][C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)=[CH:44][CH:43]=1)=[O:38])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[C:20]([NH:19][C:15]1[N:14]=[CH:13][N:12]=[C:11]2[C:16]=1[N:17]=[CH:18][N:10]2[C@@H:4]1[O:5][C@H:6]([C:7]([OH:9])=[O:8])[C@@H:2]([NH:1][C:56](=[O:57])[C@H:40]([CH2:41][C:42]2[CH:43]=[CH:44][C:45]([O:48][CH2:49][C:50]3[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=3)=[CH:46][CH:47]=2)[NH:39][C:37]([O:36][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:38])[C@H:3]1[OH:28])(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(N[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)O)OCc1ccccc1
Reactant: N[C@H]1[C@@H](O)[C@H](n2cnc3c(NC(=O)c4ccccc4)ncnc32)O[C@@H]1C(=O)O
Product: O=C(N[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)N[C@H]1[C@@H](O)[C@H](n2cnc3c(NC(=O)c4ccccc4)ncnc32)O[C@@H]1C(=O)O)OCc1ccccc1
Yield: 52.3 %

Procedure:
1-(6-Benzoylamino-9H-purin-9-yl)-3-(N-benzyloxycarbonyl-O-benzyl-L-tyrosylamino)-1,3-dideoxy-β-D-ribofuranuronic acid (210 mg) was prepared by reacting 1-(6-benzoylamino-9H-purin-9-yl)-1,3-dideoxy-3-amino-β-D-ribofuranuronic acid (200 mg) prepared in Example 1 with N-hydroxysuccinimide ester of N-benzyloxycarbonyl-O-benzyl-L-tyrosine (260 mg) according to a similar manner to that of Example 5, mp. 150°-155° C.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1.[O:12]1[CH2:16][CH2:15][NH:14][C:13]1=[O:17]>>[CH3:9][O:8][C:6](=[O:7])[C:5]1[CH:10]=[CH:11][C:2]([N:14]2[CH2:15][CH2:16][O:12][C:13]2=[O:17])=[N:3][CH:4]=1
Reactant: COC(=O)c1ccc(Br)nc1
Reactant: O=C1NCCO1
Product: COC(=O)c1ccc(N2CCOC2=O)nc1
Yield: 78.8 %

Procedure:
By reaction and treatment in the same manner as in Preparation Example 12 and using methyl 6-bromonicotinate (1 g) and oxazolidin-2-one (474 mg), the title compound (810 mg) was obtained.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[CH:21]=2)([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:10](=[O:27])[CH2:9]1)=O)(C)(C)C.[ClH:28]>C(OCC)(=O)C>[ClH:28].[O:27]=[C:10]1[C:11]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[CH:21]=2)([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:12][CH2:13][NH:8][CH2:9]1
Reactant: CCOC(=O)C1(Cc2cccc(C)c2)CCN(C(=O)OC(C)(C)C)CC1=O
Agent: Cl
Solvent: CCOC(C)=O
Product: CCOC(=O)C1(Cc2cccc(C)c2)CCNCC1=O

Procedure:
To a cold (0° C.) solution of ethyl N-tert-butoxycarbonyl-3-oxo-4-(3-methylbenzyl)piperidine-4-carboxylate (1.55 g, 4.13 mmol) in ethyl acetate (75 mL), a stream of anhydrous hydrogen chloride gas was bubbled for 20 min. The resultant mixture was stirred at 0° C. for 1 h, purged with argon for 10 min., and concentrated under vacuum to provide the title compound as white solid.
Reaction SMILES: [CH2:1]([N:8]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:9]1[N:10]=[CH:11][CH:12]=[C:13]2[CH:17]=[C:16]([C:18]([OH:20])=O)[NH:15][C:14]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:28][CH2:29][C:30]1[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=1.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>O.CN(C)C=O>[CH2:21]([N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:9]1[N:10]=[CH:11][CH:12]=[C:13]2[CH:17]=[C:16]([C:18]([NH:28][CH2:29][C:30]3[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=3)=[O:20])[NH:15][C:14]=12)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: NCc1ccncc1
Reactant: O=C(O)c1cc2ccnc(N(Cc3ccccc3)Cc3ccccc3)c2[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NCc1ccncc1)c1cc2ccnc(N(Cc3ccccc3)Cc3ccccc3)c2[nH]1
Temperature: 25 °C
Reaction time: 18 h
Yield: 84.3 %

Procedure:
A mixture of 7-(dibenzylamino)-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid (Reference Example 4) (398 mg, 1.11 mmol), 4-(aminomethyl)pyridine (169 mg, 1.56 mmol), 1-ethyl-3-dimethylaminopropylcarbodiimide (EDCI) (299 mg, 1.56 mmol), 1-hydroxybenzotriazole (HOBt) (211 mg, 1.56 mol) and N,N-dimethylformamide (5 mL) was stirred at room temperature for 18 h. The mixture was diluted with water and extracted with ethyl acetate. The organic extract was washed with aqueous sodium hydrogen carbonate, dried over sodium sulfate, and concentrated in vacuo. The residue was purified by column chromatography (silica gel, 0:10 to 1:10 methanol/ethyl acetate). Recrystallization from hexanes/ethyl acetate gave 7-(dibenzylamino)-N-(4-pyridinylmethyl)-1H-pyrrolo[2,3-c]pyridine-2-carboxamide (419 mg, 84%) as colorless crystals: Rf 0.20 (silica gel, ethyl acetate); mp 119-120° C.; 1H NMR (300 MHz, CDCl3) δ4.62 (2H, d, J=6.0 Hz), 4.90 (4H, s), 6.40-6.52 (1H, m), 6.75 (1H, s), 7.01 (1H, d, J=5.6 Hz), 7.21 (2H, d, J=5.9 Hz), 7.25-7.38 (10H, m), 7.91 (1H, d, J=5.6 Hz), 8.57 (2H, d, J=5.9 Hz), 8.98 (1H, br s); ESI MS m/z 448 [C28H25N5O+H]+; HPLC (Method A) >99% (AUC), tR=15.7 min.
Reaction SMILES: [CH2:1]([C:3]12[CH2:31][CH2:30][C:25]3(OCC[O:26]3)[CH2:24][CH:4]1[CH2:5][CH2:6][O:7][C:8]1[C:9]2=[CH:10][C:11]2[CH:12]=[N:13][N:14]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([CH3:23])[CH:18]=3)[C:15]=2[CH:16]=1)[CH3:2].CC1C=CC(S(O)(=O)=O)=CC=1>CC(C)=O>[CH2:1]([C@:3]12[CH2:31][CH2:30][C:25](=[O:26])[CH2:24][C@H:4]1[CH2:5][CH2:6][O:7][C:8]1[C:9]2=[CH:10][C:11]2[CH:12]=[N:13][N:14]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([CH3:23])[CH:18]=3)[C:15]=2[CH:16]=1)[CH3:2]
Reactant: CCC12CCC3(CC1CCOc1cc4c(cnn4-c4ccnc(C)c4)cc12)OCCO3
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Product: CC[C@]12CCC(=O)C[C@H]1CCOc1cc3c(cnn3-c3ccnc(C)c3)cc12
Reaction time: 1 h
Yield: 100.4 %

Procedure:
A 100 mL round-bottom flask equipped with air cooled reflux condenser and nitrogen inlet adapter was charged with rac-(4aR,12bS)-12b-ethyl-9-(2-methylpyridin-4-yl)-1,2,4,4a,5,6,9,12b-octahydrospiro[benzo[4,5]oxepino[3,2-f]indazole-3,2′-[1,3]dioxolane] (91, R1=2-methylpyridin-4-yl, R2=Ethyl) (1.11 g, 2.65 mmol) and pTSA (0.654 g, 3.44 mmol) in acetone (26.5 mL) and the reaction mixture was heated at about reflux in a heating block for about 16 h, after which additional acetone (26.5 mL) was added and heating continued for 1 h. The reaction mixture was allowed to cool and then was quenched by careful addition of sat. aq. NaHCO3 (25 mL). The mixture was concentrated under reduced pressure and the remainder was partitioned against EtOAc (50 mL). After separating the layers, the aqueous phase was extracted with EtOAc (2×25 mL). The combined organic phases were washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give (4aR,12bS)-12b-ethyl-9-(2-methylpyridin-4-yl)-4,4a,5,6,9,12b-hexahydro-1H-benzo[4,5]oxepino[3,2-f]indazol-3(2H)-one (92, R1=2-methylpyridin-4-yl, R2=Ethyl) (1.00 g, 2.66 mmol, 101% yield), which was used without further purification. LC/MS, method 3, Rt=2.13 min, MS m/z 376 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 8.60 (d, J=5.9 Hz, 1H), 8.25 (s, 1H), 7.95-7.75 (m, 2H), 7.72 (s, 1H), 7.61 (s, 1H), 4.45-4.36 (m, 1H), 3.88-3.71 (m, 1H), 2.93-2.54 (m, 6H), 2.51-2.29 (m, 3H), 2.23-2.06 (m, 1H), 1.96-1.83 (m, 1H), 1.72-1.42 (m, 2H), 0.68 (s, 1H), (t, J=7.5 Hz, 3H).
Reaction SMILES: [CH2:1]([CH:8]1[O:12][C:11](=[O:13])[N:10]([CH2:14][CH2:15][C:16](=[O:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B.[Na].O>C(O)C>[CH2:1]([CH:8]1[O:12][C:11](=[O:13])[N:10]([CH2:14][CH2:15][CH:16]([OH:23])[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CCN1CC(Cc2ccccc2)OC1=O)c1ccccc1
Agent: B
Agent: [Na]
Solvent: O
Solvent: CCO
Product: O=C1OC(Cc2ccccc2)CN1CCC(O)c1ccccc1
Yield: 99.6 %

Procedure:
5-Benzyl-3-(3-oxo-3-phenylpropyl)-1,3-oxazolidin-2-one (0.31 g, 1 mmol) prepared in the above (1) was dissolved in 3 ml of ethanol. To the solution, sodium boron hydride (80 mg, 2 mmol) was added under stirring while chilling with ice. After the resulting solution was stirred to cause reaction at room temperature for 30 minutes, water was added. The obtained solution was extracted with ethyl acetate. The organic portion was sequentially washed with water and saturated aqueous sodium chloride, and then dried over anhydrous sodium sulfate. The solvent was then removed by distillation under reduced pressure to obtain 0.31 g of the titled compound as a colorless oil (yield: 100%).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]([OH:8])=[O:7])=[CH:2]1.C([N-]C(C)C)(C)C.[Li+].[CH3:17][CH:18]([CH3:22])[CH2:19][CH:20]=[O:21].Cl>O1CCCC1.O>[OH:21][CH:20]([C:2]1[O:1][CH:5]=[CH:4][C:3]=1[C:6]([OH:8])=[O:7])[CH2:19][CH:18]([CH3:22])[CH3:17]
Reactant: CC(C)CC=O
Reactant: O=C(O)c1ccoc1
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)CC(O)c1occc1C(=O)O
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
3-Furoic acid (2.85 g) was dissolved in tetrahydrofuran (50 ml) and cooled to −78° C. A solution of lithium diisopropylamide (56 mmol) in tetrahydrofuran (100 ml) was added dropwise and the mixture was stirred for 15 minutes. A solution of 3-methylbutanal (3.0 ml) in tetrahydrofuran (15 ml) was added dropwise. The reaction mixture was stirred at −78° C. for 1 h and then allowed to warm to ambient temperature. The mixture was poured into water, the aqueous phase was acidified with 2M hydrochloric acid and the mixture was extracted twice with ethyl acetate. The organic phases were washed with brine, dried, filtered and evaporated. Chromatography, eluting with dichloromethane:ethyl acetate:acetic acid (160:40:1), gave the sub-title compound (2.75 g).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:17]=[CH:18][CH:19]=1)[O:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)([OH:3])=[O:2].[NH2:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>>[C:1]([C:4]1[CH:5]=[C:6]([CH:17]=[CH:18][CH:19]=1)[O:7][C:8]1[CH:9]=[CH:10][C:11]([N+:14]([O-:16])=[O:15])=[CH:12][CH:13]=1)([OH:3])=[O:2].[N:23]1([CH2:22][CH2:21][NH:20][C:1]([C:4]2[CH:5]=[C:6]([CH:17]=[CH:18][CH:19]=2)[O:7][C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=2)=[O:3])[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1
Reactant: NCCN1CCOCC1
Agent: O=C(O)c1cccc(Oc2ccc([N+](=O)[O-])cc2)c1
Product: O=C(NCCN1CCOCC1)c1cccc(Oc2ccc([N+](=O)[O-])cc2)c1

Procedure:
Entry 61: 4-(3-Carboxyphenoxy)-1-nitrobenzene was synthesized according to Method A13, Step 2. 4-(3-Carboxyphenoxy)-1-nitrobenzene was coupled with 4-(2-aminoethyl)morpholine according to Method A13, Step 3 to give 4-(3-(N-(2-morpholinylethyl) carbamoyl)phenoxy)-1-nitrobenzene. According to Method A13 Step 4, 4-(3-(N-(2-morpholinylethyl)carbamoyl)phenoxy)-1-nitrobenzene was reduced to 4-(3-(N-(2-morpholinylethyl) carbamoyl)phenoxy)aniline. According to Method C1a, 4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(3-(N-(2-morpholinylethyl) carbamoyl)phenoxy)aniline to afford the urea.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[C:5]2[N:11]=[C:10]([CH2:12][NH:13][C:14](=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16])[CH:9]=[CH:8][C:6]=2[N:7]=1.[Si]([N:33]1[C:41]2[C:36](=[C:37](B3OC(C)(C)C(C)(C)O3)[C:38]([F:42])=[CH:39][CH:40]=2)[CH:35]=[CH:34]1)(C(C)(C)C)(C)C>>[F:42][C:38]1[C:37]([C:2]2[N:3]=[C:4]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[C:5]3[N:11]=[C:10]([CH2:12][NH:13][C:14](=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16])[CH:9]=[CH:8][C:6]=3[N:7]=2)=[C:36]2[C:41](=[CH:40][CH:39]=1)[NH:33][CH:34]=[CH:35]2
Reactant: CC1(C)OB(c2c(F)ccc3c2ccn3[Si](C)(C)C(C)(C)C)OC1(C)C
Reactant: CC(C)(C)C(=O)NCc1ccc2nc(Cl)nc(N3CCOCC3)c2n1
Product: CC(C)(C)C(=O)NCc1ccc2nc(-c3c(F)ccc4[nH]ccc34)nc(N3CCOCC3)c2n1

Procedure:
N-((2-chloro-4-morpholinopyrido[3,2-d]pyrimidin-6-yl)methyl)pivalamide (0.13 g) was reacted with 1-(tert-butyldimethylsilyl)-5-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole via General Procedure A to produce 44 mg of 145 following reverse phase HPLC purification. MS (Q1) 463.2 (M)+
Reaction SMILES: [F:1][C:2]([F:18])([CH:8](I)[C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].C([SnH](CCCC)CCCC)CCC.N(C(C)(C)C#N)=NC(C)(C)C#N>C1(C)C=CC=CC=1>[F:1][C:2]([F:18])([CH2:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCOC(=O)C(F)(F)C(I)c1ccc(OC)cc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CCCC[SnH](CCCC)CCCC
Solvent: Cc1ccccc1
Product: CCOC(=O)C(F)(F)Cc1ccc(OC)cc1
Yield: 76.4 %

Procedure:
A solution of ethyl 2,2-difluoro-3-iodo-3-(4-methoxyphenyl)-propionate (5.24 g, 14.2 mmol) in toluene (125 ml) was treated with tributyltin hydride (28.9 g, 0.10 mol) and a few crystals of 2,2′-azobisisobutyronitrile. The resulting solution was then irradiated for 15 minutes at 25° C. with a sun lamp. The solvent was then evaporated in vacuo and the residue was partitioned between acetonitrile and pentane. The acetonitrile fraction was concentrated and chromatographed on silica gel (elution hexane-ethyl acetate, 85:15) to give 2.65 g (76%) of the title material as an oil: bp 90-95° C./0.1 torr (air bath temperature).
Reaction SMILES: Cl[C:2]1[C:11]2[CH:10]=[C:9]3[N:12]=[CH:13][N:14]([CH2:15][CH2:16][N:17]4[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)[C:8]3=[CH:7][C:6]=2[N:5]=[CH:4][C:3]=1[C:23]#[N:24].[Cl:25][C:26]1[C:32]([O:33][CH3:34])=[CH:31][C:29]([NH2:30])=[C:28]([CH3:35])[CH:27]=1.Cl.N1C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>C(OCCO)C.O>[Cl:25][C:26]1[C:32]([O:33][CH3:34])=[CH:31][C:29]([NH:30][C:2]2[C:11]3[CH:10]=[C:9]4[N:12]=[CH:13][N:14]([CH2:15][CH2:16][N:17]5[CH2:18][CH2:19][O:20][CH2:21][CH2:22]5)[C:8]4=[CH:7][C:6]=3[N:5]=[CH:4][C:3]=2[C:23]#[N:24])=[C:28]([CH3:35])[CH:27]=1
Reactant: N#Cc1cnc2cc3c(cc2c1Cl)ncn3CCN1CCOCC1
Reactant: COc1cc(N)c(C)cc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CCOCCO
Solvent: O
Product: COc1cc(Nc2c(C#N)cnc3cc4c(cc23)ncn4CCN2CCOCC2)c(C)cc1Cl
Yield: 69.9 %

Procedure:
A mixture of 86.5 mg (0.25 mmol) of 8-chloro-3-[2-(4-morpholinyl)ethyl]-3H-imidazo[4,5-g]quinoline-7-carbonitrile, 67.2 mg (0.39 mmol) of 4-chloro-5-methoxy-2-methyl aniline and 28.9 mg (0.25 mmol) of pyridine hydrochloride in 3 mL of 2-ethoxyethanol is heated at 130–135° C. for 11 hours. After cooling, the mixture is diluted with water and neutralized with 2 equivalents of sodium carbonate, and then extracted with ethyl acetate. The separated organic layer is washed with brine and dried over sodium sulfate. Removal of the solvent yields a residue which is purified on preparative TLC (developing solvent: 1:9 methanol/methylene chloride), giving 83.3 mg (69.9%) of the product as a beige solid, mp 246–248° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]([O:14]CC)=[O:13])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[CH2:17]([O:20][C:21]1[C:26]([C:27]([CH3:30])([CH3:29])[CH3:28])=[CH:25][C:24]([C:31]([CH3:34])([CH3:33])[CH3:32])=[CH:23][C:22]=1B(O)O)[CH2:18][CH3:19]>>[C:27]([C:26]1[C:21]([O:20][CH2:17][CH2:18][CH3:19])=[C:22]([C:2]2[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[C:4]([CH:10]=[CH:11][C:12]([OH:14])=[O:13])[CH:3]=2)[CH:23]=[C:24]([C:31]([CH3:34])([CH3:33])[CH3:32])[CH:25]=1)([CH3:30])([CH3:28])[CH3:29]
Reactant: CCCOc1c(B(O)O)cc(C(C)(C)C)cc1C(C)(C)C
Reactant: CCOC(=O)C=Cc1ccc(OC)c(Br)c1
Product: CCCOc1c(-c2cc(C=CC(=O)O)ccc2OC)cc(C(C)(C)C)cc1C(C)(C)C
Yield: 80.8 %

Procedure:
In a manner similar to that of Example 1(c), by reaction of 1.0 g (3.5 mmol) of ethyl 3-(3-bromo-4-methoxyphenyl)acrylate obtained in Example 13(d) with 1.54 g (5.26 mmol) of 2-propyloxy-3,5-di-tert-butylphenylboronic acid obtained in Example 39(b), 1.20 g (76%) of the expected compound was obtained in the form of a white powder having a melting point of 107°-109° C.
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]([CH3:6])[CH3:5].C([N:10]1[C:18]2[CH:17]=[CH:16][N:15]=[CH:14][C:13]=2[NH:12][C:11]1=[O:19])(C)=C>>[CH3:5][CH:4]([CH3:6])[CH2:3][CH2:2][N:12]1[C:13]2[CH:14]=[N:15][CH:16]=[CH:17][C:18]=2[NH:10][C:11]1=[O:19]
Reactant: CC(C)CCBr
Reactant: C=C(C)n1c(=O)[nH]c2cnccc21
Product: CC(C)CCn1c(=O)[nH]c2ccncc21

Procedure:
The title compound was prepared according to the procedure described in the literature (Meth-Cohn, O.; Smith, D. I. J.C.S. Perkin Trans. 1, 1982, 261-270.; Vernin G. et al. J. Heterocyclic Chem. 1981, 18, 85-89.) from 1-bromo-3-methylbutane and 1-isopropenyl-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one (Israel, M.; Jones, L. C. J. Heterocyclic Chem. 1971, 8, 797.
Reaction SMILES: NC1C=CC=CC=1.[CH3:8][N:9]([CH3:24])[S:10]([C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][C:14]=1[C:20]([F:23])([F:22])[F:21])(=[O:12])=[O:11].C(N(CC)CC)C.[CH3:32][C:33]1([C:36](Cl)=[O:37])[CH2:35][CH2:34]1>O1CCCC1>[CH3:8][N:9]([CH3:24])[S:10]([C:13]1[CH:19]=[CH:18][C:16]([NH:17][C:36]([C:33]2([CH3:32])[CH2:35][CH2:34]2)=[O:37])=[CH:15][C:14]=1[C:20]([F:21])([F:23])[F:22])(=[O:11])=[O:12]
Reactant: CN(C)S(=O)(=O)c1ccc(N)cc1C(F)(F)F
Reactant: CC1(C(=O)Cl)CC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: Nc1ccccc1
Product: CN(C)S(=O)(=O)c1ccc(NC(=O)C2(C)CC2)cc1C(F)(F)F
Temperature: 0 °C
Yield: 86 %

Procedure:
To a solution of 6.7 g (0.025 mole) of the aniline prepared as in (c) above and 2.5 g of triethylamine in 50 ml of tetrahydrofuran was added dropwise 3.0 g (0.025 mole) of 1-methylcyclopropanecarboxylic chloride. The mixture was refluxed for one hour, poured into ice water, filtered and recrystallized from methanol to give 7.5 g (86%) of product as a white crystalline solid; m.p. 153°-156° C.
Reaction SMILES: [ClH:1].C([N:9]1[CH2:14][CH2:13][C@@H:12]2[C:15]3[C:16]([O:22][CH3:23])=[CH:17][CH:18]=[CH:19][C:20]=3[CH2:21][C@@H:11]2[CH2:10]1)C1C=CC=CC=1>CO.[Pd]>[ClH:1].[CH3:23][O:22][C:16]1[C:15]2[C@@H:12]3[C@@H:11]([CH2:10][NH:9][CH2:14][CH2:13]3)[CH2:21][C:20]=2[CH:19]=[CH:18][CH:17]=1
Reactant: COc1cccc2c1[C@H]1CCN(Cc3ccccc3)C[C@H]1C2
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: COc1cccc2c1[C@H]1CCNC[C@H]1C2
Yield: 82.6 %

Procedure:
The product from Example 41 (1.80 g) was combined with 0.90 g 20% Pd/C in 100 ml methanol and evaporated to yield 1.08 g of the desired product as a white solid, mp: 140°-3° C. NMR (d6DMSO) δ 1.70 (m, 1H), 2.02 (m, 1H), 2.60 (m, 1H), 2.78-3.30 (m, 7H), 3.77 (s, 3H), 6.80 (d, 1H), 6.84 (d, 1H), 7.15 (t, 1H).
Reaction SMILES: [Cl:1][CH:2]([CH2:6][C:7]1[CH:12]=[C:11]([N:13]2[C:17](=[O:18])[N:16]([CH:19]([F:21])[F:20])[C:15]([CH3:22])=[N:14]2)[C:10]([Cl:23])=[CH:9][C:8]=1[Cl:24])[C:3]([OH:5])=O.[Cl:25][C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][CH:27]=1.O.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1>[Cl:1][CH:2]([CH2:6][C:7]1[CH:12]=[C:11]([N:13]2[C:17](=[O:18])[N:16]([CH:19]([F:20])[F:21])[C:15]([CH3:22])=[N:14]2)[C:10]([Cl:23])=[CH:9][C:8]=1[Cl:24])[C:3]([NH:30][C:29]1[CH:31]=[CH:32][C:26]([Cl:25])=[CH:27][CH:28]=1)=[O:5]
Reactant: Cc1nn(-c2cc(CC(Cl)C(=O)O)c(Cl)cc2Cl)c(=O)n1C(F)F
Reactant: Nc1ccc(Cl)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: C1CCOC1
Product: Cc1nn(-c2cc(CC(Cl)C(=O)Nc3ccc(Cl)cc3)c(Cl)cc2Cl)c(=O)n1C(F)F
Temperature: 25 °C
Reaction time: 18 h
Yield: 42.2 %

Procedure:
A stirred solution of 0.50 g (0.0013 mole) of 2-chloro-3-[2,4-dichloro-5-(4-difluoromethyl-4,5-dihydro-3-methyl-5-oxo-1H-1,2,4-triazol-1-yl)phenyl]propionic acid (Compound 2), 0.16 g (0.0013 mole) of 4-chloroaniline, 0.17 g (0.0013 mole) of 1-hydroxybenzotriazole hydrate, and 0.18 g (0.0014 mole) of N,N-diisopropylethylamine in approximately 15 mL of tetrahydrofuran was cooled to 0° C. To this cold reaction mixture was added 0.26 g (0.0013 mole) of 1,3-dicyclohexylcarbodiimide. After complete addition, the reaction mixture was allowed to warm to room temperature and was stirred for approximately 18 hours. The reaction mixture was filtered. The filtrate was diluted with carbon tetrachloride and was washed in succession with a 1N hydrochloric acid solution, an aqueous 10% sodium hydroxide solution, water, and an aqueous saturated sodium chloride solution. The organic phase was dried over anhydrous magnesium sulfate, filtered, and the filtrate evaporated under reduced pressure to give 0.28 g of 2-chloro-3-[2,4-dichloro-5-(4-difluoromethyl-4,5-dihydro-3-methyl-5-oxo-1H-1,2,4-triazol-1-yl)phenyl]-N-(4-chlorophenyl)propionamide as an oil, Compound A23 of Table 1A.