Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[S:13][C:12]([C:14]([O:16][CH3:17])=[O:15])=[CH:11][C:10]=1[C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=1.Br[CH2:26][CH2:27][CH2:28][O:29][CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][O:31]1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>CCOCC>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[S:13][C:12]([C:14]([O:16][CH3:17])=[O:15])=[CH:11][C:10]=1[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:26][CH2:27][CH2:28][O:29][CH:30]2[CH2:35][CH2:34][CH2:33][CH2:32][O:31]2)=[CH:20][CH:19]=1
Reactant: BrCCCOC1CCCCO1
Reactant: COC(=O)c1cc(-c2ccc(O)cc2)c(-c2ccc(F)cc2Cl)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COC(=O)c1cc(-c2ccc(OCCCOC3CCCCO3)cc2)c(-c2ccc(F)cc2Cl)s1
Temperature: 60 °C
Yield: 92.8 %

Procedure:
4.8 g of the compound obtained in stage 16E), 3.6 g of 2-(3-bromopropoxy)tetrahydro-2H-pyran and 2.2 g of potassium carbonate are added to 30 ml of DMF and then the mixture is heated at 60° C. for 7 hours. It is poured onto ice-cold water, extraction is carried out with ether and the extract is dried and concentrated to dryness. After purifying by chromatography on silica (heptane and then heptane/AcOEt: 90/10), 6.2 g of the expected compound are obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[N:5][C:6]([O:19][CH3:20])=[CH:7][C:8]=1[C:9]1[N:17]2[C:12]([CH:13]=[N:14][C:15](O)=[N:16]2)=[CH:11][CH:10]=1.C1C=CC(N(S(C(F)(F)F)(=O)=O)S(C(F)(F)F)(=O)=O)=CC=1.C(N(CC)C(C)C)(C)C.CN(C)C=O.[NH2:56][C:57]1[CH:62]=[CH:61][C:60]([CH:63]2[CH2:68][CH2:67][N:66]([CH2:69][C:70]([NH2:72])=[O:71])[CH2:65][CH2:64]2)=[CH:59][CH:58]=1>>[CH3:1][O:2][C:3]1[N:4]=[N:5][C:6]([O:19][CH3:20])=[CH:7][C:8]=1[C:9]1[N:17]2[C:12]([CH:13]=[N:14][C:15]([NH:56][C:57]3[CH:62]=[CH:61][C:60]([CH:63]4[CH2:64][CH2:65][N:66]([CH2:69][C:70]([NH2:72])=[O:71])[CH2:67][CH2:68]4)=[CH:59][CH:58]=3)=[N:16]2)=[CH:11][CH:10]=1
Reactant: NC(=O)CN1CCC(c2ccc(N)cc2)CC1
Reactant: COc1cc(-c2ccc3cnc(O)nn23)c(OC)nn1
Agent: O=S(=O)(N(c1ccccc1)S(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(-c2ccc3cnc(Nc4ccc(C5CCN(CC(N)=O)CC5)cc4)nn23)c(OC)nn1
Yield: 15.4 %

Procedure:
7-(3,6-Dimethoxy-pyridazin-4-yl)-pyrrolo[2,1-f][1,2,4]triazin-2-ol (70 mg, 0.2 mmol), N-Phenylbis(trifluoromethanesulphonimide) (95.1 mg, 0.266 mmol), N,N-Diisopropylethylamine (0.126 mL, 0.726 mmol), and N,N-Dimethylformamide (2 mL, 30 mmol) and stir at room temperature for half an hour. Add 2-[4-(4-Amino-phenyl)-piperidin-1-yl]-acetamide (90.3 mg, 0.387 mmol) and stir at 60° C. overnight. An LCMS showed product. The reaction was concentrated, DMSO added, filtered and placed onto the Gilson for purification. The most pure fractions were collected, free based with saturated sodium bicarbonate, extracted with DCM, filtered and concentrated to give 2-(4-{4-[7-(3,6-Dimethoxy-pyridazin-4-yl)-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino]-phenyl}-piperidin-1-yl)-acetamide as a yellow solid (15 mg, 10%). MP 249-251° C. LCMS (E/I+) 489 (M+H). NMR 1H (DMSO-d6)-9.56 (s, 1H), 9.1 (s, 1H), 8.27 (s, 1H), 7.60 (d, 2H, J=8.30 Hz), 7.40 (d, 2H, J=4.82 Hz), 7.21 (bs, 1H), 7.18 (d, 1H, J=8.42 Hz), 7.13 (bs, 1H), 6.97 (d, 1H, J=4.87 Hz), 4.06 (s, 3H), 4.04 (s, 3H), 2.87-2.96 (m, 4H), 2.40-2.48 (m, 1H), 2.14-2.25 (m, 2H), 1.70-1.78 (m, 4H).
Reaction SMILES: [CH:1]1[N:2]=[C:3]([CH2:10][C:11]([OH:13])=[O:12])[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.[C:14]12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>CO>[CH3:14][O:12][C:11](=[O:13])[CH2:10][C:3]1[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]2=[CH:1][N:2]=1
Reactant: O=C(O)Cc1ncc2ccccn12
Reactant: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: CO
Product: COC(=O)Cc1ncc2ccccn12
Temperature: 25 °C

Procedure:
A suspension of imidazo[1,5-a]pyridin-3-ylacetic acid (Ellanovalabs, 2 g, 11.35 mmol) and camphorsulfonic acid (2.9 g, 12.49 mmol) in MeOH (120 mL) was refluxed for 4 h. Then allowed to cool to RT and concentrated under reduced pressure. The crude residue was diluted in CH2Cl2 and the organic layer was washed with a saturated aqueous solution of NaHCO3. The organics were dried (Na2SO4), filtered and concentrated. The material thus obtained was used in the next step without further purification: TLC, Rf (CH2Cl2/MeOH 9:1)=0.55; MS (UPLC/MS): 191.1 [M+H]+; tR (HPLC conditions f): 0.4 min.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:3][CH2:2]1.N1C=CC=CC=1.[C:21](OC(=O)C)(=[O:23])[CH3:22]>ClCCl>[C:21]([N:1]1[CH2:2][CH2:3][CH:4]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:13])[CH3:12])[CH2:5][CH2:6]1)(=[O:23])[CH3:22]
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)N1CCC(NC(=O)OC(C)(C)C)CC1
Reaction time: 3 h

Procedure:
To a suspension of O-tert-butyl N-(piperidin-4-yl)carbamate (4.0 g) in dichloromethane (40 ml) were added pyridine (1.94 ml), dichloromethane (40 ml), acetic anhydride (20.8 ml) and then N,N-dimethylaminopyridine (0.1 g) at ambient temperature. After stirring for 3 hours, the mixture was washed with 0.1N hydrochloric acid, water, and brine. After drying with magnesium sulfate, the solvents were removed under reduced pressure. After rinse with diisopropyl ether, O-tert-butyl N-(1-acetylpiperidin-4-yl)carbamate (4.01 g) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([OH:24])=O)=[CH:20][CH:19]=3)=[CH:17][C:9]1=2.[NH2:32][CH2:33][C:34]1[CH:39]=[CH:38][C:37]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=[CH:36][CH:35]=1>>[C:37]1([C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)[CH:36]=[CH:35][C:34]([CH2:33][NH:32][C:22](=[O:24])[C:21]2[CH:25]=[CH:26][C:18]([C:16]3[CH:15]=[N:14][C:10]4[NH:11][CH2:12][CH2:13][N:8]([CH2:7][C:6]5[CH:27]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=5[C:28]([F:31])([F:29])[F:30])[C:9]=4[CH:17]=3)=[CH:19][CH:20]=2)=[CH:39][CH:38]=1
Reactant: NCc1ccc(-c2ccccc2)cc1
Reactant: O=C(O)c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1
Product: O=C(NCc1ccc(-c2ccccc2)cc1)c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1

Procedure:
4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 4-(aminomethyl)biphenyl as in General Procedure 10 to give the title compound. LCMS: m/z=613.00 (M+H+); retention time=1.07 minutes.
Reaction SMILES: O(P(O[C:18]1[C@H:19]([CH3:42])[C@H:20]2[C@@H:37]([C@H:38]([OH:40])[CH3:39])[C:36](=[O:41])[N:21]2[C:22]=1[C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=1)=[O:24])(OC1C=CC=CC=1)=O)C1C=CC=CC=1.[SH:43][C@@H:44]1[CH2:48][N:47]([C:49]([O:51][CH2:52][C:53]2[CH:58]=[CH:57][C:56]([N+:59]([O-:61])=[O:60])=[CH:55][CH:54]=2)=[O:50])[C@H:46]([CH:62]2[CH2:66][NH:65][C:64](=[O:67])[CH2:63]2)[CH2:45]1>>[OH:40][C@@H:38]([C@H:37]1[C:36](=[O:41])[N:21]2[C:22]([C:23]([O:25][CH2:26][C:27]3[CH:28]=[CH:29][C:30]([N+:33]([O-:35])=[O:34])=[CH:31][CH:32]=3)=[O:24])=[C:18]([S:43][C@@H:44]3[CH2:48][N:47]([C:49]([O:51][CH2:52][C:53]4[CH:58]=[CH:57][C:56]([N+:59]([O-:61])=[O:60])=[CH:55][CH:54]=4)=[O:50])[C@H:46]([CH:62]4[CH2:66][NH:65][C:64](=[O:67])[CH2:63]4)[CH2:45]3)[C@H:19]([CH3:42])[C@H:20]12)[CH3:39]
Reactant: O=C1CC([C@@H]2C[C@H](S)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)CN1
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(OP(=O)(Oc3ccccc3)Oc3ccccc3)[C@H](C)[C@@H]12
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](C4CNC(=O)C4)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)[C@H](C)[C@H]12
Yield: 83.7 %

Procedure:
The same procedure as in Example 1-1 was carried out by using p-nitrobenzyl (1R,5S,6S)-2-diphenoxyphosphoryloxy-6-[(R)-1-hydroxyethyl]-1-methyl-1-carbapen- 2-em-3-carboxylate (10.61 g, 17 mmol) and (2S,4S)-4-mercapto-N-(p-nitrobenzyloxycarbonyl)-2-(2-pyrrolidon-4-yl)pyrrolidine diastereomer B (5.92 g, 16.2 mmol, compound of Reference Example 19-4) to obtain p-nitrobenzyl (1R,5S,6S)-6-[(R)-1-hydroxyethyl]-1-methyl-2-[(2S,4S)-N-(p-nitrobenzyloxycarbonyl)-2-(2-pyrrolidon-4-yl)pyrrolidin-4-ylthio]-1-carbapen-2-em-3-carboxylate diastereomer B (9.9 g, yield: 83.7%).
Reaction SMILES: [CH:1]1([S:7]([CH2:10][CH2:11][C:12]([OH:14])=[O:13])(=[O:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH:15]S(O)(=O)=O.OO>C(Cl)Cl>[CH:1]1([S:7]([CH2:10][CH2:11][C:12]([O:14][OH:15])=[O:13])(=[O:9])=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(O)CCS(=O)(=O)C1CCCCC1
Reactant: O=S(=O)(O)O
Agent: OO
Solvent: ClCCl
Product: O=C(CCS(=O)(=O)C1CCCCC1)OO
Temperature: 25 °C
Yield: 61 %

Procedure:
To a 150 mL beaker equipped with a support clamp, ice bath, alcohol thermometer, mechanical stirrer, and dropping funnel were charged 22.03 g (0.1 mole) of powdered 3-(cyclohexylsulfonyl)propionic acid and 29.8 mL of 82 wt. % aqueous H2SO4. After a few minutes mixing at ambient temperature, a uniform slurry was obtained. To the dropping funnel was charged a solution prepared by adding 33.3 mL of 95.5% H2SO4 to 17.0 mL of 50% H2O2 (0.3 mole, 3 fold excess) with stirring and cooling to maintain ≤30° C., with final cooling to 25° C. With agitation, the mixture in the dropping funnel was added to the beaker over a 10 minute period, the temperature rising to 27° C. The ice bath was not applied because the heat evolution was so small. The mixture was agitated for another 130 minutes, the temperature gradually declining to 26.5° C. Most of the solids dissolved. The mixture was then contacted with ten 25-30 mL portions of methylene chloride at ambient temperature in an effort to recover the product by direct extraction into the methylene chloride. The combined extracts were washed with pH 5 phosphate buffer solution, then washed with water, partially evaporated, mixed with a weighed amount of boric acid, and dried. The weight and active oxygen analysis of this product showed that only 3.57 g of the organic product had been recovered by extraction (~15% of theory) and that its activity was 91.1% of that for the pure peracid. The crude reaction product remaining after methylene chloride extraction was mixed with 100 mL of cold pH 5 buffer with agitation and ice cooling, resulting in immediate formation of a large amount of white solids. The slurry was filtered at 15°-20° C. and the solids were washed on the filter with two 100 mL portions of cold buffer followed by 100 mL cold water. The resulting product was mixed with boric acid and dried and then blended uniformly with most of the product recovered by extraction. The resulting final product weighed about 30 g and had an active oxygen content of 3.27% (boric acid content roughly 47%). The calculated active yield was 61% of theory. (Equipment, analysis, and yield calculation were as described in Example 3.)
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([NH:11][CH2:12][CH2:13][OH:14])[CH:8]=[C:7]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([C:23]([F:26])([F:25])[F:24])[CH:16]=2)[N:6]=1)(=O)=O.[C-:27]#[N:28].[Na+]>CS(C)=O>[OH:14][CH2:13][CH2:12][NH:11][C:9]1[CH:8]=[C:7]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([C:23]([F:26])([F:25])[F:24])[CH:16]=2)[N:6]=[C:5]([C:27]#[N:28])[N:10]=1
Reactant: COc1ccc(-c2cc(NCCO)nc(S(C)(=O)=O)n2)cc1C(F)(F)F
Reactant: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1ccc(-c2cc(NCCO)nc(C#N)n2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 48 h
Yield: 71.5 %

Procedure:
2-[2-Methanesulfonyl-6-(4-methoxy-3-trifluoromethyl-phenyl)-pyrimidin-4-ylamino]-ethanol (0.68 g) was dissolved in DMSO (10 ml) and sodium cyanide (0.17 g) was added. The mixture was stirred at RT for 48 hours. Mixture was partitioned between ethyl acetate (100 ml) and water (100 ml). Organics were dried and evaporated then flash chromatographed over silica (DCM-2% methanol in DCM) to afford 420 mg of 4-(2-Hydroxy-ethylamino)-6-(4-methoxy-3-trifluoromethyl-phenyl)-pyrimidine-2-carbonitrile as a white solid.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21]O)=[CH:17][N:16]=1.C1(C)C=CC=CC=1.S(Cl)([Cl:32])=O>O>[Cl:32][CH2:21][C:18]1[CH:19]=[CH:20][C:15]([O:14][CH2:13][C:3]2[N:4]=[C:5]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[O:6][C:2]=2[CH3:1])=[N:16][CH:17]=1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CO)cn1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(CCl)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.3 %

Procedure:
To a mixture of 2-(5-methyl-2-phenyl-4-oxazolylmethoxy)pyridine-5-methanol (12.2 g) and toluene (200 ml) was added thionyl chloride (5.39 g), and the mixture was stirred at room temperature for 1 hr. Iced water was added to the reaction mixture, and after neutralization with saturated aqueous sodium hydrogencarbonate, the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to give crystals (11.7 g, yield 90%) of 5-chloromethyl-2-(5-methyl-2-phenyl-4-oxazolylmethoxy)pyridine from a fraction eluted with ethyl acetate-hexane (1:3, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 86-87° C.
Reaction SMILES: [NH:1]1[CH2:7][C:5](=[O:6])[NH:4][C:2]1=[S:3].[OH:8][C:9]1[CH:10]=[C:11]([CH:14]=[C:15]([N+:18]([O-:20])=[O:19])[C:16]=1[OH:17])[CH:12]=O.N1CCCCC1>C(O)(=O)C>[OH:8][C:9]1[CH:10]=[C:11]([CH:12]=[C:7]2[C:5](=[O:6])[NH:4][C:2](=[S:3])[NH:1]2)[CH:14]=[C:15]([N+:18]([O-:20])=[O:19])[C:16]=1[OH:17]
Reactant: O=Cc1cc(O)c(O)c([N+](=O)[O-])c1
Reactant: O=C1CNC(=S)N1
Solvent: C1CCNCC1
Solvent: CC(=O)O
Product: O=C1NC(=S)NC1=Cc1cc(O)c(O)c([N+](=O)[O-])c1
Temperature: 100 °C

Procedure:
A solution containing 2.9 g (0.025 mol) of 2-thiohydantoin, 4.6 g (0.025 mol) of 3,4-dihydroxy-5-nitrobenzaldehyde and 0.25 ml of piperidine in 50 ml of acetic acid was heated for 7-8 h at 100° C. The crystalls were filtered and washed with 2-propanol. Yield 5.0 g (71%), mp>350° C. (decom.).
Reaction SMILES: [C:1]([NH:9][C:10](=[N:13]C(OCCCC)=O)[S:11][CH3:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(OC)C=CC=CC=1.C(O)(C(F)(F)F)=O>>[C:1]([NH:9][C:10](=[NH:13])[S:11][CH3:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCOC(=O)N=C(NC(=O)c1ccccc1)SC
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: CSC(=N)NC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 128.7 %

Procedure:
To a mixture of 78b (160 mg, 0.54 mmol) and anisole (0.1 mL) was added TFA (1.0 mL). The resulting mixture was stirred for 30 min at room temperature, evaporated to dryness and put on vacuum line for 2 hours, and triturated with anhydrous Et2O to give 135 mg of 79b as a semi-solid. This crude product was used directly in the next step without further purification. 1HNMR (300 MHz, CD3OD): δ2.74 (3H, m); 7.55 (2H, t, J=7.8 Hz); 7.69 (1H, t, J=7.5 Hz); 8.02 (2H, d, J=7.5 Hz) ppm. IR (NaCl, film): 3226, 2936, 1695, 1680, 1540, 1188 cm-1.
Reaction SMILES: [Br:1]Br.[CH:3]([NH:5][CH:6]1[CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][C:7]1=[O:16])=[O:4].C([O-])(=O)C.[Na+].O>C(O)(=O)C>[CH:3]([NH:5][CH:6]1[CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([Br:1])[CH:13]=2)[NH:8][C:7]1=[O:16])=[O:4]
Reactant: O=CNC1Cc2ccccc2NC1=O
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=CNC1Cc2cc(Br)ccc2NC1=O
Reaction time: 1 h
Yield: 66.1 %

Procedure:
Bromine (16.0 g, 0.1 mol) was added to a stirred solution of 3-(formylamino)-3,4-dihydro-2(1H)quinolinone (19.0 g, 0.1 mol) and anhydrous sodium acetate (12.7 g, 0.2 mol) in acetic acid (500 mL). After 1 hour, water (1.5 L) was added and the precipitate was filtered off and air dried to give 17.8 g of 3-(formylamino)-6-bromo-3,4-dihydro-2(1H)quinolinone, mp 275°-282° C. (dec). This was dissolved in trifluoracetic acid (300 mL) and sodium nitrate (9.0 g) was added to the stirred solution. After 1 hour, water was added and the precipitate was filtered off and air dried to give 18.2 g of 3-(formylamino)-6-bromo-3,4-dihydro-8-nitro-2(1H)quinolinone, mp 232°-235° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][C:20](Cl)=[N:21][C:22]([N:23]4[CH2:29][CH:28]5[O:30][CH:25]([CH2:26][CH2:27]5)[CH2:24]4)=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:32][C:33]1[CH:38]=[CH:37][C:36]([OH:39])=[CH:35][CH:34]=1>C(O)CO.CS(C)=O>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][C:20]([NH:32][C:33]4[CH:38]=[CH:37][C:36]([OH:39])=[CH:35][CH:34]=4)=[N:21][C:22]([N:23]4[CH2:29][CH:28]5[O:30][CH:25]([CH2:26][CH2:27]5)[CH2:24]4)=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccc(O)cc1
Reactant: Clc1nc(N2CC3CCC(C2)O3)c2cnn(C3CCN(Cc4ccccc4)CC3)c2n1
Solvent: CS(C)=O
Solvent: OCCO
Product: Oc1ccc(Nc2nc(N3CC4CCC(C3)O4)c3cnn(C4CCN(Cc5ccccc5)CC4)c3n2)cc1
Yield: 28.4 %

Procedure:
50 mg (0.11 mmol) of 1-(1-benzylpiperidin-4-yl)-6-chloro-4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1H-pyrazolo[3,4-d]pyrimidine was dissolved in 1 mL ethylene glycol. 0.24 mmol (26.2 mg) 4-aminophenol was added and the mixture was heated under microwave irradiation to 220 C (15 min). The mixture was diluted with 1 mL DMSO and purified by HPLC (TFA buffers) to give 16 mg of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][N:5]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]3[NH:13][CH:14]=[CH:15][C:8]=23)[CH:6]=1.CN(C)C=O.[H-].[Na+].[CH3:23][Si:24]([CH3:31])([CH3:30])[CH2:25][CH2:26][O:27][CH2:28]Cl>>[Br:1][C:2]1[CH:3]=[N:4][N:5]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]3[N:13]([CH2:28][O:27][CH2:26][CH2:25][Si:24]([CH3:31])([CH3:30])[CH3:23])[CH:14]=[CH:15][C:8]=23)[CH:6]=1
Reactant: Brc1cnn(-c2ccnc3[nH]ccc23)c1
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1ccc2c(-n3cc(Br)cn3)ccnc21
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
A solution of 4-(4-bromo-1H-pyrazol-1-yl)-1H-pyrrolo[2,3-b]pyridine (1.1 g, 0.0042 mol) in N,N-dimethylformamide (20.0 mL, 0.258 mol) was cooled to 0° C. Sodium hydride (160.0 mg, 0.006667 mol) (60% in oil) was added and the mixture stirred for 10 min. [β-(Trimethylsilyl)ethoxy]methyl chloride (1.4 mL, 0.0079 mol) was added and stirred for 20 min at 0° C. The reaction was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over MgSO4 and concentrated to give the crude material. The product was purified by FCC on silica gel (EtOAc/Hexanes, 1/10) to give 4-(4-bromo-1H-pyrazol-1-yl)-1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridine as a solid product, LC/MS (M+H)+: 393, 395, 1H NMR (CDCl3) δ 8.47 (d, 1H, J=7.0), 8.27 (s, 1H), 7.88 (s, 1H), 7.52 (d, 1H, J=4.5), 7.39 (d, 1H, J=7.0), 7.069 (d, 1H, J=4.5), 5.80 (s, 2H), 3.6 (t, 2H), 1.95 (t, 2H), 0.0 (s, 9H).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].Cl[CH2:8][CH2:9][C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:11].[CH3:18][CH:19]([CH3:35])[C:20]([NH:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH:24]=1)=[O:21]>>[CH3:18][CH:19]([CH3:35])[C:20]([NH:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH:29]2[CH2:34][CH2:33][N:32]([CH2:8][CH2:9][C:10](=[O:11])[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:31][CH2:30]2)[CH:24]=1)=[O:21]
Reactant: O=C(CCCl)c1ccccc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCC(=O)c3ccccc3)CC2)c1

Procedure:
Procedure K (KI) and Scheme E (K2CO3) using 3-chloro-1-phenyl-1-propanone and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 379.2 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]1[C:7](=[O:8])[CH:6]=[CH:5][C:4]([CH3:10])([CH3:9])[C:3]1=[O:11].C1C=CC=CC=1.[CH2:18](O)[CH:19]([CH3:21])[CH3:20].CC1C=CC(S(O)(=O)=O)=CC=1>O>[CH3:1][C:2]1[C:3](=[O:11])[C:4]([CH3:10])([CH3:9])[CH2:5][CH2:6][C:7]=1[O:8][CH2:18][CH:19]([CH3:21])[CH3:20]
Reactant: CC1C(=O)C=CC(C)(C)C1=O
Reactant: CC(C)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: CC1=C(OCC(C)C)CCC(C)(C)C1=O
Temperature: 25 °C

Procedure:
The compound 2,6,6-trimethylcyclohexen-1,3-dione (43.6 g) was added to a mixture of benzene (250 ml), isobutanol (50 ml) and PTSA (500 mg) and heated under reflux for 3 hr in conjunction with a Dean and Stark water separator. The reaction was then cooled to room temperature, washed with aqueous sodium carbonate solution and brine and taken to dryness "in vacuo". Distillation of residue through a 6 inch vacuum jacketed vigreaux column yielded pure 2,6,6-trimethyl-3-isobutoxycyclohex-2-en-1 one (54.6 g) bp 104°-107°.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[C:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)=[C:6]([CH3:20])[N:5]=[CH:4][N:3]=1.C(N(CC)CC)C.Cl[CH2:29][C:30]1[O:34][C:33]([C:35]([O:37][CH2:38][CH3:39])=[O:36])=[CH:32][CH:31]=1>ClCCl>[CH3:20][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:1][CH2:29][C:30]2[O:34][C:33]([C:35]([O:37][CH2:38][CH3:39])=[O:36])=[CH:32][CH:31]=2)[C:7]=1[C:8]#[C:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]([F:19])([F:17])[F:18])=[CH:14][CH:15]=1
Reactant: Cc1ncnc(N)c1C#Cc1ccc(C(F)(F)F)cc1
Reactant: CCOC(=O)c1ccc(CCl)o1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(CNc2ncnc(C)c2C#Cc2ccc(C(F)(F)F)cc2)o1
Reaction time: 72 h

Procedure:
A mixture of 4-amino-6-methyl-5-{[4-(trifluoromethyl)phenyl]ethynyl}pyrimidine (2 g), triethylamine (0.76 g), ethyl 5-chloromethyl-2-furancarboxylate (1.4 g) and dichloromethane (60 ml) was heated to reflux while stirring for 72 hours. The mixture thus obtained was concentrated under reduced pressure. After the resultant residue was washed with water added thereto, an organic phase was dried over anhydrous sodium sulfate and then evaporated. The evaporation residue was purified by column chromatography to obtain a target substance (0.5 g). The target substance was subjected to e.g., proton nuclear magnetic resonance spectrometry (1H-NMR) and mass spectrometry (MS) and confirmed as the titled compound. Furthermore, MS measurement result is shown.
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:36])[NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:13]=[C:14]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][C@@H:30]3[CH3:35])[C:15]3[CH2:21]C[N:19]([C:22]([O:24][C:25]([CH3:28])(C)C)=[O:23])[CH2:18][C:16]=3[N:17]=2)=[CH:8][CH:7]=1)[CH3:2].ClC1N=C(N2CCOC[C@@H]2C)C2CN(C(OCC)=O)CC=2N=1.[F:59]C1C=C(C=CC=1B1OC(C)(C)C(C)(C)O1)N>>[CH2:25]([O:24][C:22]([N:19]1[CH2:21][C:15]2[C:14]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][C@@H:30]3[CH3:35])=[N:13][C:12]([C:9]3[CH:8]=[CH:7][C:6]([NH:5][C:4]([NH:3][CH2:1][CH3:2])=[O:36])=[CH:11][C:10]=3[F:59])=[N:17][C:16]=2[CH2:18]1)=[O:23])[CH3:28]
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCN(C(=O)OC(C)(C)C)C3)cc1
Reactant: CC1(C)OB(c2ccc(N)cc2F)OC1(C)C
Agent: CCOC(=O)N1Cc2nc(Cl)nc(N3CCOC[C@@H]3C)c2C1
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CN(C(=O)OCC)C3)c(F)c1
Yield: 44 %

Procedure:
Step 1 Method as described for intermediate 5 using (S)-ethyl 2-chloro-4-(3-methylmorpholino)-5H-pyrrolo[3,4-d]pyrimidine-6(7H)-carboxylate (intermediate 11) and 3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline as starting materials. The mixture was filtered through a celite 545 pre-packed cartridge (2.5 g), washed with MeOH and solvent removed in vacuo. The residue was purified by prep HPLC (high pH) yielding the title compound (54.7 mg, 0.13 mmol, 44%).