Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]([C:14]3[O:15][CH:16]=[C:17]([CH2:19][NH:20][C:21](=[O:32])[C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[C:28]([F:31])([F:30])[F:29])[N:18]=3)[CH:9]=[CH:10][C:11]=2[O:12][CH3:13])[CH2:3][CH2:2]1.[H-].[Na+].[CH3:35]I.O>CN(C)C=O.C(OCC)(=O)C>[CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]([C:14]3[O:15][CH:16]=[C:17]([CH2:19][N:20]([CH3:35])[C:21](=[O:32])[C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[C:28]([F:31])([F:29])[F:30])[N:18]=3)[CH:9]=[CH:10][C:11]=2[O:12][CH3:13])[CH2:3][CH2:2]1
Reactant: CI
Reactant: COc1ccc(-c2nc(CNC(=O)c3ccccc3C(F)(F)F)co2)cc1OCC1CC1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(-c2nc(CN(C)C(=O)c3ccccc3C(F)(F)F)co2)cc1OCC1CC1

Procedure:
N-[2-(3-cyclopropylmethoxy-4-methoxyphenyl)oxazol-4-ylmethyl]-2-trifluoromethylbenzamide obtained in Example 25 was dissolved in 1 ml of dimethylformamide. A 30 mg quantity of sodium hydride was added thereto with ice-cooling and stirring, and the mixture was stirred for 30 minutes. A 30 mg quantity of methyl iodide was added thereto, and the reaction mixture was stirred at room temperature for 2 hours. Water and ethyl acetate were then added thereto, and extraction was performed. The organic layer was washed with water twice and concentrated by removing the solvent under reduced pressure. The residue was purified by silica gel chromatography (n-hexane:ethyl acetate=3:1) to give 35 mg of colorless oily N-[2-(3-cyclopropylmethoxy-4-methoxyphenyl)oxazol-4-ylmethyl]-N-methyl-2-trifluoromethylbenzamide.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5](Cl)=[O:6].[CH3:8][O:9][C:10](=[O:19])[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([NH2:18])[CH:12]=1.CCN(CC)CC>C(Cl)Cl>[CH3:8][O:9][C:10](=[O:19])[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([NH:18][C:5](=[O:6])[CH2:4][CH2:3][CH2:2][Cl:1])[CH:12]=1
Reactant: O=C(Cl)CCCCl
Reactant: COC(=O)c1ccc(Cl)c(N)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1ccc(Cl)c(NC(=O)CCCCl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.4 %

Procedure:
4-Chlorobutyryl chloride (2.82 g, 20 mmol, 2.0 equiv) in CH2Cl2 (5 ml) was added over 2 min to a stirred solution of 3-amino-4-chloro-benzoic acid methyl ester (D27c) (1.66 g, 10 mmol, 1 equiv) and NEt3 (2.22 g, 22 mmol, 2.2 equiv) in CH2Cl2 (40 ml). The resulting mixture was stirred for 1 h at room temperature then washed with 2N aqueous HCl solution, dried over MgSO4 and concentrated in vacuo. The residue was triturated with CH2Cl2 to give 4-chloro-3-(4-chloro-butanoylamino)-benzoic acid methyl ester (D28c) (1.81 g, 48%) as a pale pink solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH2:9][CH:10]2[CH2:12][CH2:11]2)[CH:5]=[C:4]([CH2:13][O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[N:3]=1.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][C:28]=1[N:29]1[CH:33]=[C:32]([CH3:34])[N:31]=[CH:30]1)[NH2:25].C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1>C(OC(=O)C)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O1CCOCC1>[CH:10]1([CH2:9][O:8][C:6]2[CH:5]=[C:4]([CH2:13][O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[N:3]=[C:2]([NH:25][C:24]3[CH:26]=[CH:27][C:28]([N:29]4[CH:33]=[C:32]([CH3:34])[N:31]=[CH:30]4)=[C:22]([O:21][CH3:20])[CH:23]=3)[N:7]=2)[CH2:12][CH2:11]1
Reactant: COc1cc(N)ccc1-n1cnc(C)c1
Reactant: FC(F)(F)COCc1cc(OCC2CC2)nc(Cl)n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COc1cc(Nc2nc(COCC(F)(F)F)cc(OCC3CC3)n2)ccc1-n1cnc(C)c1
Temperature: 100 °C

Procedure:
2-Chloro-4-(cyclopropylmethoxy)-6-[(2,2,2-trifluoroethoxy)methyl]pyrimidine (55 mg, 0.19 mmol), 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)aniline (45 mg, 0.22 mmol, cesium carbonate (124 mg, 0.38 mmol) and 2-(dicyclohexylphosphino)biphenyl (10 mg, 0.029 mmol) were added to dioxane (3 mL) in a microwave tube. Palladium (II) acetate (6.4 mg, 0.029 mmol) was added. The tube was vacuum-backfilled with nitrogen and sealed. The mixture was heated in a microwave reactor at 100° C. for 2 hours and then diluted with ethylacetate, washed with water, brine, dried over Mg2SO4 and the solvent was removed under reduced pressure. The residue was purified by chromatography on silica gel, eluting with mixtures of 0% to 5% methanol in ethyl acetate. The product was further purified by chromatography on a reverse phase column, eluting with mixtures of 0% to 100% methanol in water containing 5% trifluoroacetic acid to afford the title compound as a solid, 40 mg (45%). MS (ESI+) m/z 464 [M+H]+. 1H NMR (300 MHz, CDCl3) δ ppm 0.34-0.37 (m, 2H), 0.64-0.70 (m, 2H), 1.20-1.40 (m, 1H), 2.30 (s, 3H), 3.86 (s, 3H), 3.97 (q, 2H), 4.20 (d, 2H), 4.59 (s, 2H), 6.41 (s, 1H), 6.87 (s, 1H), 7.00 (d, 1H), 7.08 (s, 1H), 7.16 (d, 1H), 7.64 (s, 1H), 7.74 (s, 1H).
Reaction SMILES: C[O:2][C:3]1[C:4]([CH3:12])=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2.B(Br)(Br)Br.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH3:12][C:4]1[C:3]([OH:2])=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[CH:7][NH:8]2
Reactant: COc1ccc2[nH]ccc2c1C
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1c(O)ccc2[nH]ccc12
Temperature: 0 °C

Procedure:
5-Methoxy-4-methyl-1H-indole (10 g, 62.0 mmol) is dissolved in DCM (400 mL) and cooled to 0° C. BBr3 (155 mL, 155 mmol) is added dropwise over 1 hour and the black mixture is allowed to warm to room temperature overnight (17 hours). The reaction is poured over a mixture of ice and sodium bicarbonate (aq) solution and extracted with ethyl acetate (1.5 L) and concentrated to a black oil. The oil is absorbed onto silica and separated via FCC (0-50% ethyl acetate:heptanes) to obtain the title compound as a solid. MS (ESI) m/z 148.23 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]([O:11][C:12](=[O:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:9]([O:20][C:21](=[O:28])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:8]=[C:7]([CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:6]=1)=[O:4].[Br:36]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[C:10]([O:11][C:12](=[O:19])[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[C:9]([O:20][C:21](=[O:28])[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:8]=[C:7]([CH:29]([Br:36])[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:6]=1)=[O:4]
Reactant: COC(=O)c1nc(Cc2ccccc2)nc(OC(=O)c2ccccc2)c1OC(=O)c1ccccc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1nc(C(Br)c2ccccc2)nc(OC(=O)c2ccccc2)c1OC(=O)c1ccccc1

Procedure:
A solution of methyl-5,6-bis(benzoyloxy)-2-benzylpyrimidine-4-carboxylate (B-6) (1.0 eq.) in carbon tetrachloride was heated up to 90° C. under nitrogen; N-bromosuccinimide (1.0 eq.) and benzoyl peroxide (0.1 eq.) were added as dry powder and mixture was refluxed for 3 h. After cooling, succinimide was removed by filtration and the filtrate was concentrated and purified by flash column chromatography (SiO2, 85/15 v/v petroleum ether/ethyl acetate as eluent) to give the title product (B-7).
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=3)[N:14]=2)[CH:7]=[CH:6][C:5]=1Br.[CH:25]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1B(O)O)=[O:26]>>[Cl:22][C:17]1[CH:16]=[C:15]([C:13]2[N:14]=[C:10]([C:8]3[CH:9]=[C:4]([C:3]([OH:2])=[O:24])[C:5]([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=4[CH:25]=[O:26])=[CH:6][CH:7]=3)[S:11][CH:12]=2)[CH:20]=[CH:19][C:18]=1[Cl:21]
Reactant: COC(=O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1Br
Reactant: O=Cc1ccccc1B(O)O
Product: O=Cc1ccccc1-c1ccc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)cc1C(=O)O
Yield: 49.5 %

Procedure:
Using the conditions of General Procedure B for Suzuki Coupling and Hydrolysis in Parallel Mode, 2-bromo-5-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-benzoic acid methyl ester (which may be prepared as described for Intermediate 6; 89 mg, 0.2 mmol) was reacted with 2-formylphenylboronic acid (available from Frontier Scientific, Inc.; 60 mg, 0.4 mmol). The resulting ester was hydrolyzed and the acid was purified to give 4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-2′-formyl-biphenyl-2-carboxylic acid (45 mg, 49%). 1H NMR (400 MHz, DMSO-d6) δ 13.11 (br s, 1H), 9.80 (br s, 1H), 8.54 (s, 1H), 8.49 (s, 1H), 8.34 (s, 1H), 8.27 (d, J=7.8 Hz, 1H), 8.10 (d, J=8.5 Hz, 1H), 7.93 (d, J=7.5 Hz, 1H), 7.78 (d, J=8.5 Hz, 1H), 7.73 (t, J=7.2 Hz, 1H), 7.61 (t, J=7.3 Hz, 1H), 7.51 (d, J=7.8 Hz, 1H), 7.36 (d, J=7.5 Hz, 1H).
Reaction SMILES: [CH2:1]([C:7]1[CH:11]=[CH:10][S:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[Cl:12][C:13]([F:17])=[C:14](F)[F:15]>>[Cl:12][C:13]([F:17])=[C:14]([C:10]1[S:9][CH:8]=[C:7]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[CH:11]=1)[F:15]
Reactant: FC(F)=C(F)Cl
Reactant: CCCCCCc1ccsc1
Product: CCCCCCc1csc(C(F)=C(F)Cl)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 3-hexylthiophene (30 g, 0179 mol) in anhydrous petrol (40-60 C., 100 ml) was cooled to −10 C. and diisopropylamine (freshly distilled, 18.1 g, 0179 mol) and tetramethylethylenediamine (TMEDA) (33 g, 028 mol) were added. N-BuLi (1.6M in hexanes, 113 ml, 0.18 mol) was added dropwise over 30 min at −10 C. The solution was warmed to 0 C. over 1 h, and then added via cannula to a solution of chlorotrifluorethylene at −78 C. The reaction was warmed to RT over 2 h and stirred for a further 16 h. The reaction was quenched with sat, ammonium chloride and extracted with THF (3×50 ml). The combined organics were washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure to afford a yellow oil (47 g). High vacuum distillation through a packed column with a reflux ratio head (0.1 mbar, 70-71 C.) afforded 13.0 g of product. Purity (HPLC) >99%. MS (EI) 264 (d, M+). 19F NMR revealed the expected signals, 1H and 13C NMR were complicated by the presence of cis/trans isomers.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][CH2:11][O:12][CH3:13])=[C:4]([N+:14]([O-])=O)[CH:3]=1>C(O)C.N1C=CC=CC=1.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][CH2:11][O:12][CH3:13])=[C:4]([NH2:14])[CH:3]=1
Reactant: COCCCOc1ccc(Cl)cc1[N+](=O)[O-]
Solvent: CCO
Solvent: c1ccncc1
Solvent: O
Product: COCCCOc1ccc(Cl)cc1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.9 %

Procedure:
Stannous chloride (1.04 g, 5.49 mmol) was added to a solution of 4-chloro-1-(3-methoxy-propoxy)-2-nitro-benzene (0.448 g, 1.82 mmol) in a mixture of ethanol and ethyl acetate (1/1, 20 mL) and the resulting mixture was stirred at room temperature overnight. More stannous chloride (0.76 g, 4 mmol) was added and the reaction mixture was stirred for 1 day. The resulting mixture was partitioned between an aqueous solution of sodium bicarbonate (5%) and ethyl acetate, the aqueous solution was separated and extracted twice with ethyl acetate, the combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The yellow oily residue was purified by flash chromatography (hexane/EtOAc, 80/20 to 60/40) to give 0.29 g (74% yield) of 5-chloro-2-(3-methoxy-propoxy)-phenylamine as a yellow oil.
Reaction SMILES: [Li].CC1CCC(O)C/C/1=C/C=C1\CCCC2(C)C(C(/C=C/C(C(C)C)C)C)CCC\12.[CH3:31][Si:32]([CH3:35])([CH3:34])Cl.[N:36]1[CH:41]=[C:40]([C@@H:42]2[CH2:47][CH2:46][CH2:45][N:43]2[CH3:44])[CH:39]=[CH:38][CH:37]=1>C1COCC1>[CH3:44][N:43]1[CH2:45][CH2:46][CH2:47][CH:42]1[C:40]1[CH:39]([Si:32]([CH3:35])([CH3:34])[CH3:31])[CH:38]=[CH:37][N:36]([Si:32]([CH3:35])([CH3:34])[CH3:31])[CH:41]=1
Reactant: CN1CCC[C@H]1c1cccnc1
Reactant: C[Si](C)(C)Cl
Agent: CC1CCC(O)C/C1=C/C=C1\CCCC2(C)C1CCC2C(C)/C=C/C(C)C(C)C
Agent: [Li]
Solvent: C1CCOC1
Product: CN1CCCC1C1=CN([Si](C)(C)C)C=CC1[Si](C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 70.6 %

Procedure:
To a suspension of lithium powder (0.42 g, 60 mmol) in freshly distilled THF (20 mmol) cooled at−10° C. was added freshly distilled trimethylchlorosilane (7.6 mL, 60 mmol). A solution of (S)-nicotine (3.2 mL, 20 mmol) in THF (20 mL) was injected dropwise over 20 min. The reaction mixture was stirred at 0° C. for 1 h. The precipitate formed was decanted over 2 h and the liquid portion was canulated into a 2 neck flask mounted with a distillation apparatus under Ar. After removal of the THF by distillation at atmospheric pressure, the product was distilled under vacuum (1.5 mm Hg, bp=130-135° C.) to give 71% (4.36 g) of 3-(1-methylpyrrolidin-2-yl)-1,4-bis-trimethylsilanyl-1,4-dihydropyridine i as a yellow oil (95% pure by NMR). 1H NMR (400 MHz, CDCl3): 67 8.24 (s, 1 H), 5.78-5.72 (m, 1 H), 4.37-4.29 (m, 1 H), 3.06-2.93 (m, 1 H), 2.4-1.4 (m, 10 H), 0.08 (s, 9 H), −0.05 (s, 9 H). 13C NMR (100 MHz, CDCl3) δ 127.49, 126.41, 121.14, 102.08, 101.00, 66.67, 57.21, 41.05, 32.52, 26.41, 21.84, −0.83, −0.90, −2.43, −2.64. HRMS Calcd for C16H32N2Si2: 309.2182 [M+H]+. Found: 309.2166 [M+H]+.
Reaction SMILES: C[O:2][C:3](=[O:30])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)=[CH:16][CH:15]=2)=[CH:8][C:7]=1[CH3:29].[K+].[Br-]>>[Cl:28][C:25]1[CH:24]=[CH:23][C:22]([CH2:21][O:20][C:17]2[CH:16]=[CH:15][C:14]([CH2:13][S:12][C:9]3[CH:10]=[CH:11][C:6]([O:5][CH2:4][C:3]([OH:30])=[O:2])=[C:7]([CH3:29])[CH:8]=3)=[CH:19][CH:18]=2)=[CH:27][CH:26]=1
Reactant: COC(=O)COc1ccc(SCc2ccc(OCc3ccc(Cl)cc3)cc2)cc1C
Agent: [Br-]
Agent: [K+]
Product: Cc1cc(SCc2ccc(OCc3ccc(Cl)cc3)cc2)ccc1OCC(=O)O

Procedure:
The title compound was prepared in the manner analogous to Example 1 using 58A. mp 164° C.; IR (KBr) cm−1: 3062, 1727, 1612, 1493, 1226, 1193; 400 MHz 1H NMR (DMSO-d6): δ 12.99 (br(s), 1H), 7.36-7.44 (m, 4H), 7.01-7.17 (m, 4H), 6.81-6.89 (m, 2H), 6.69 (d, 1H, J=8.5 Hz), 5.01 (s, 2H), 4.61 (s, 2H), 4.00 (s, 2H), 2.08 (s, 3H); MS m/z 427 (M−1). Anal. Calc'd for C23H21ClO4S: C, 64.40; H, 4.93. found: C, 64.43; H, 4.81.
Reaction SMILES: [CH:1]1([C:5]2[N:6]=[C:7](/[CH:10]=[CH:11]/[C:12]3[CH:13]=[C:14]([NH:18][C:19](=[O:30])[CH2:20][C:21]4[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=4[C:23]([OH:25])=[O:24])[CH:15]=[CH:16][CH:17]=3)[S:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[OH:31][CH2:32][C:33]([CH2:37][OH:38])([CH2:35][OH:36])[NH2:34]>C(O)C>[OH:31][CH2:32][C:33]([CH2:37][OH:38])([CH2:35][OH:36])[NH2:34].[CH:1]1([C:5]2[N:6]=[C:7]([CH:10]=[CH:11][C:12]3[CH:13]=[C:14]([NH:18][C:19](=[O:30])[CH2:20][C:21]4[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=4[C:23]([OH:25])=[O:24])[CH:15]=[CH:16][CH:17]=3)[S:8][CH:9]=2)[CH2:2][CH2:3][CH2:4]1
Reactant: O=C(Cc1ccccc1C(=O)O)Nc1cccc(/C=C/c2nc(C3CCC3)cs2)c1
Agent: NC(CO)(CO)CO
Solvent: CCO
Product: O=C(Cc1ccccc1C(=O)O)Nc1cccc(C=Cc2nc(C3CCC3)cs2)c1

Procedure:
A mixture of 0.418 g of (E)-2-[2-[3-[2-[4-(cyclobutyl)-2-thiazolyl]ethenyl]phenylamino]-2-oxoethyl]benzoic acid and 0.1214 g of tris-(hydroxymethyl)-amino-methane were solubilized in 10 ml of ethyl alcohol with warming on a steam bath until all the solids had solubilized. After cooling the reaction mixture was condensed in vacuo at 40° C. to constant weight to yield E)-2-[2-[3-[2-[4-(cyclobutyl)-2-thiazolyl]ethenyl]phenylamino]-2-oxoethyl]benzoic acid tris-(hydroxymethyl)-amino-methane salt as a white solid.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=[CH:9][C:8]=1[NH2:17].Cl.N1C=C[CH:22]=[CH:21][CH:20]=1>>[Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=[C:20]1[CH2:21][CH3:22]
Reactant: Nc1cnc2ccccc2c1NCCCCCl
Reactant: c1ccncc1
Agent: Cl
Product: CCc1nc2cnc3ccccc3c2n1CCCCCl
Yield: 734.5 %

Procedure:
Using the general method of Example 1 Part D, N4-(4-chlorobutyl)quinoline-3,4-diamine (˜35.75 mmol) was cyclized using triethyl orthopropioniate (7.56 g, 42.9 mmol) in the presence of pyridine hydrochloride (0.41 g). The crude product was purified by chromatography (silica gel eluting with 95/5 dichloromethane/methanol) to provide 7.5 g of 1-(4chlorobutyl)-2-ethyl-1H-imidazo[4,5-c]quinoline as a white powder.
Reaction SMILES: Br[C:2]1[C:7]2[N:8]([CH3:11])[CH:9]=[N:10][C:6]=2[C:5]([O:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=2[F:20])=[C:4]([C:21]2[C:22]3[CH:31]=[N:30][N:29]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37])[C:23]=3[C:24](=[O:28])[N:25]([CH3:27])[CH:26]=2)[CH:3]=1.[CH3:40][C:41]1(C)C(C)(C)OB(C=C)O1.ClCCl.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1.O>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:20][C:14]1[CH:15]=[C:16]([F:19])[CH:17]=[CH:18][C:13]=1[O:12][C:5]1[C:6]2[N:10]=[CH:9][N:8]([CH3:11])[C:7]=2[C:2]([CH:40]=[CH2:41])=[CH:3][C:4]=1[C:21]1[C:22]2[CH:31]=[N:30][N:29]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37])[C:23]=2[C:24](=[O:28])[N:25]([CH3:27])[CH:26]=1
Reactant: Cn1cc(-c2cc(Br)c3c(ncn3C)c2Oc2ccc(F)cc2F)c2cnn(COCC[Si](C)(C)C)c2c1=O
Reactant: C=CB1OC(C)(C)C(C)(C)O1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: ClCCl
Solvent: C1COCCO1
Product: C=Cc1cc(-c2cn(C)c(=O)c3c2cnn3COCC[Si](C)(C)C)c(Oc2ccc(F)cc2F)c2ncn(C)c12
Temperature: 80 °C
Reaction time: 2 h
Yield: 85.4 %

Procedure:
A mixture of 4-[7-bromo-4-(2,4-difluorophenoxy)-1-methyl-1H-benzimidazol-5-yl]-6-methyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1,6-dihydro-7H-pyrazolo[3,4-c]pyridin-7-one (0.0990 g, 0.160 mmol), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (0.0408 mL, 0.241 mmol), [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (1:1) (0.0131 g, 0.0160 mmol) and potassium carbonate (0.0555 g, 0.401 mmol) in 1,4-dioxane (1.0 mL, 12.8 mmol) and water (0.580 mL, 32.2 mmol) was degassed with nitrogen for 10 min, warmed to 80° C. and stirred at 80° C. for 2 h. The reaction mixture was diluted with water and ethyl acetate. Layers were separated and the organic layer was washed with brine, dried with sodium sulfate, filtered, and concentrated in vacuo to give a crude residue. Purification by flash column chromatography (100% hexanes to 100% EtOAc [EtOAc contained 5% MeOH]) gave the desired product (77 mg, 85%) as a white foam. LCMS calculated for C29H32F2N5O3Si (M+H)+: m/z=564.2. found: 564.1.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.C1(C)C=CC=CC=1.CC(=NOC[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[C:39](=[N:44][O:45][CH3:46])[C:40](OC)=[O:41])C1C=CC=C(C(F)(F)F)C=1.ClCCl>CO>[CH3:46][O:45][N:44]=[C:39]([C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:33]=1)[CH:40]=[O:41]
Reactant: CON=C(C(=O)OC)c1ccccc1CON=C(C)c1cccc(C(F)(F)F)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Solvent: CO
Solvent: Cc1ccccc1
Product: CON=C(C=O)c1ccccc1
Reaction time: 3 h
Yield: 109.6 %

Procedure:
1M diisobutylaluminum hydride/toluene solution (11 ml, 16.5 mmol) was added dropwise to a mixture of methyl 2-[(α-methyl-3-trifluoromethylbenzylidene)aminooxymethyl]-α-methoxyiminophenylacetate (4.83 g, 11.8 mmol) and dichloromethane (47 ml) at −65° C. or lower over 4 minutes, and the mixture was stirred at −78° C. to room temperature for 3 hours. Methanol (7 ml) was added to the reaction mixture, and the mixture was stirred at room temperature for 1 hour. The precipitated insoluble materials were removed, and the remaining mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate/n-hexane) to give 2-[(α-methyl-3-trifluoromethylbenzylidene)aminooxymethyl]-(α-methoxyiminophenylacetaldehyde (2.11 g, 47.3%) as a colorless oil.
Reaction SMILES: [C:1]([CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:4])[CH2:2][CH3:3].[CH2:11]([O:13][C:14]([CH:16](C(=O)C)[CH2:17][C:18]#[C:19][CH2:20][CH2:21]CC(OC)=O)=[O:15])[CH3:12].BrCCCCCCC(OCC)=O>>[C:1]([CH:5]([CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][C:14]([O:13][CH2:11][CH3:12])=[O:15])[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:4])[CH2:2][CH3:3]
Reactant: CCOC(=O)CC(=O)CC
Reactant: CCOC(=O)C(CC#CCCCC(=O)OC)C(C)=O
Agent: CCOC(=O)CCCCCCBr
Product: CCOC(=O)CCCCCCC(C(=O)CC)C(=O)OCC

Procedure:
The synthesis of this compound is carried out by the procedure of Example 4, Step A, except that an equivalent quantity of ethyl propionylacetate is substituted for the ethyl acetoacetate of Example 4, Step A, and an equivalent quantity of ethyl 7-bromoheptanoate is substituted for the methyl 7-bromo-5-heptynoate of Example 4, Step A. The product, a viscous oil, is used in the next step directly without distillation.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=O)[CH:5]=[CH:6][C:7]=1[Cl:8].C(Cl)(=O)C(Cl)=O.[NH2:19][C:20](=[N:26]O)[C:21]([O:23][CH2:24][CH3:25])=[O:22].C(N(CC)C(C)C)(C)C>ClCCl.N1C=CC=CC=1.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[Cl:8])[CH2:9][C:10]1[O:12][N:26]=[C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[N:19]=1
Reactant: O=C(O)Cc1ccc(Cl)c(Cl)c1
Reactant: CCOC(=O)C(N)=NO
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)c1noc(Cc2ccc(Cl)c(Cl)c2)n1
Yield: 17.6 %

Procedure:
This compound was prepared according to general method 2 with (step I) 2-(3,4-dichlorophenyl)acetic acid (0.775 g; 3.78 mmol) and oxalyl chloride (0.352 mL; 4.16 mmol) in dichloromethane (8 mL) with few drops of DMF and (step II) ethyl 2-amino-2-(hydroxyimino)acetate (0.500 g; 3.78 mmol) and N,N diisopropylethylamine (1.05 mL; 6.06 mmol) in dichloromethane (10 mL) and (step III) pyridine (18 mL). The crude material was purified by flash chromatography on silica (eluent 20 to 100% ethyl acetate in heptane) to yield 0.2004 g (18%) of ethyl 5-(3,4-dichlorobenzyl)-1,2,4-oxadiazole-3-carboxylate as a white solid.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][N:29]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[CH:10][CH:9]=1)=[O:6].[O:30]1[C:34]2([CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)[O:33][CH2:32][CH2:31]1>>[O:30]1[C:34]2([CH2:39][CH2:38][N:37]([C:2]3[CH:3]=[C:4]([CH:27]=[CH:28][N:29]=3)[C:5]([NH:7][C:8]3[C:17]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[C:11]([O:18][CH2:19][CH2:20][N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)=[CH:10][CH:9]=3)=[O:6])[CH2:36][CH2:35]2)[O:33][CH2:32][CH2:31]1
Reactant: O=C(Nc1ccc(OCCN2CCOCC2)c2ccccc12)c1ccnc(Cl)c1
Reactant: C1CC2(CCN1)OCCO2
Product: O=C(Nc1ccc(OCCN2CCOCC2)c2ccccc12)c1ccnc(N2CCC3(CC2)OCCO3)c1

Procedure:
Compound is formed by reacting 2-chloro-N-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-1-yl]-isonicotinamide and 1,4-dioxa-8-aza-spiro[4.5]decane under conditions described in general procedure A. 1H NMR (300 MHz, DMSO-d6) δ 10.29 (s, 1H), 8.29 (d, 1H), 8.20 (m, 1H), 7.88 (m, 1H), 7.59 (m, 2H), 7.42 (d, 2H), 7.19 (d, 1H), 7.01 (d, 1H), 4.31 (t, 2H), 3.95 (s, 4H), 3.75 (m, 4H), 3.61 (m, 4H), 2.88 (t, 2H), 2.60 (m, 4H), 2.66 (m, 4H). MS: 519.3 (M+1).
Reaction SMILES: [CH3:1]I.[H-].[Na+].[Br:5][C:6]1[N:7]=[C:8]([C:15]([C:17]2[CH:18]=[CH:19][C:20]3[NH:25][C:24](=[O:26])[O:23][C:22](=[O:27])[C:21]=3[CH:28]=2)=[O:16])[N:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=12>CN(C=O)C>[Br:5][C:6]1[N:7]=[C:8]([C:15]([C:17]2[CH:18]=[CH:19][C:20]3[N:25]([CH3:1])[C:24](=[O:26])[O:23][C:22](=[O:27])[C:21]=3[CH:28]=2)=[O:16])[N:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=12
Reactant: O=C(c1ccc2[nH]c(=O)oc(=O)c2c1)c1nc(Br)c2ccccn12
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(=O)oc(=O)c2cc(C(=O)c3nc(Br)c4ccccn34)ccc21
Temperature: 0 °C
Reaction time: 3 h
Yield: 99.1 %

Procedure:
808 mg (5.7 mmol) of methyl iodide and 164 mg (3.42 mmol) of 50% sodium hydride are added, at ambient temperature under an inert atmosphere, to 1.1 g (2.85 mmol) of 6-[(1-bromoimidazo[1,5-a]pyridin-3-yl)carbonyl]-2H-3,1-benzoxazine-2,4(1H)-dione in 20 ml of DMF. After stirring for 3 hours, the reaction medium is poured into 200 ml of ice-cold water. The precipitate is filtered off, rinsed with water, and then dried under reduced pressure for 18 hours at 40° C. 1.13 g of a yellow solid are obtained.