Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:15]([O:17]C)=[O:16])[C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][C:3]=1[CH3:19].CS(O[CH2:25][CH2:26][CH2:27][C:28]1[C:33]([Cl:34])=[CH:32][CH:31]=[CH:30][C:29]=1[Cl:35])(=O)=O>>[C:15]([C:10]1[C:11](=[O:14])[N:12]([CH2:25][CH2:26][CH2:27][C:28]2[C:29]([Cl:35])=[CH:30][CH:31]=[CH:32][C:33]=2[Cl:34])[N:13]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[C:3]([CH3:19])[CH:4]=2)[CH:9]=1)([OH:17])=[O:16]
Reactant: COC(=O)c1cc(-c2ccc(F)c(C)c2)n[nH]c1=O
Reactant: CS(=O)(=O)OCCCc1c(Cl)cccc1Cl
Product: Cc1cc(-c2cc(C(=O)O)c(=O)n(CCCc3c(Cl)cccc3Cl)n2)ccc1F
Yield: 89.8 %

Procedure:
Following the procedure of Example 1(6), 6-(4-fluoro-3-methylphenyl)-4-methoxycarbonyl-2H-pyridazin-3-one and 3-(2, 6-dichlorophenyl)-1-propanol methanesulfonate were reacted. Without purification, the reaction product was reacted further following the procedure of Example 1(7) to yield the title compound as a pale yellow solid (yield: 89.8%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:18](=[CH:19][CH:20]=1)[C:7]1[N:8]([CH3:17])[C:9]3[CH:10]=[C:11]([CH3:16])[CH:12]=[C:13]([CH3:15])[C:14]=3[C:6]=1[CH2:5]2.[Li]CCCC.[CH3:26][Si:27](Cl)([CH3:29])[CH3:28]>CCOCC>[F:1][C:2]1[CH:3]=[C:4]2[C:18]([CH:7]([Si:27]([CH3:29])([CH3:28])[CH3:26])[C:6]3[C:14]4[C:13]([CH3:15])=[CH:12][C:11]([CH3:16])=[CH:10][C:9]=4[N:8]([CH3:17])[C:5]=32)=[CH:19][CH:20]=1
Reactant: C[Si](C)(C)Cl
Reactant: Cc1cc(C)c2c3c(n(C)c2c1)-c1ccc(F)cc1C3
Agent: [Li]CCCC
Solvent: CCOCC
Product: Cc1cc(C)c2c3c(n(C)c2c1)-c1cc(F)ccc1C3[Si](C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78 %

Procedure:
A round bottom flask containing 48b (1.11 g, 4.17 mmol) in dry ether (27 mL) was immersed in a 25° C. water bath. n-BuLi (1.5 M in THF, 3.33 mL, 5.00 mmol) was added via syringe pump over one hour, generating a brown solution. Following addition of base, the reaction mixture was stirred at 25° C. for an additional 30 minutes and then cooled to −78° C. TMSCl (1.11 mL, 8.76 mmol) was added rapidly via syringe and the solution was subsequently warmed to room temperature. The reaction was diluted with ether, filtered, and concentrated in vacuo. Crude product was purified by flash column chromatography (20:1 hexanes-ethyl acetate followed by a second column 40:1 to 26:1 hexanes—ethyl acetate) to yield 49b as an orange solid in 78% yield (1.09 g, 3.24 mmol). 1H NMR (400 MHz, CDCl3): δ 7.57-7.60 (dd, 1H, J=8.4, 5.2 Hz), 7.19-7.22 (dd, 1H, J=9.6, 2.4 Hz), 7.00-7.04 (m, 2H), 6.78 (s, 1H), 4.01 (s, 3H), 3.97 (s, 1H), 2.61 (s, 3H), 2.49 (s, 3H), −0.15 (s, 9H); 13C NMR (150 MHz, CDCl3): δ 159.7 (d, J=289.5 Hz), 152.2 (d, J=10.1 Hz), 142.1, 141.2, 131.17, 129.4, 129.0, 122.7, 121.9, 121.7, 117.2 (d, J=10.5 Hz), 111.7 (d, J=27.9 Hz), 111.6 (d, J=29.7 Hz), 107.0, 38.2, 31.0, 21.8, 20.1, −2.2; 19F NMR (CD3CD, 376 MHz): δ −118.6 (m) FTIR: cm−1 2952, 1583, 1445, 1357, 1248, 1198, 1037, 838. EI-HRMS: Calcd. for C21H24FNSi+ [M]+: 337.1662. found 337.1664.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC(=O)[NH:14][CH:15]1[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][O:23][C:24]2[CH:33]=[N:32][C:31]3[C:26](=[CH:27][C:28]([O:34][CH3:35])=[CH:29][CH:30]=3)[N:25]=2)[CH2:17][CH2:16]1)(C)(C)C>ClCCl>[CH3:35][O:34][C:28]1[CH:27]=[C:26]2[C:31]([N:32]=[CH:33][C:24]([O:23][CH2:22][CH2:21][N:18]3[CH2:17][CH2:16][CH:15]([NH2:14])[CH2:20][CH2:19]3)=[N:25]2)=[CH:30][CH:29]=1
Reactant: COc1ccc2ncc(OCCN3CCC(NC(=O)OC(C)(C)C)CC3)nc2c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc2ncc(OCCN3CCC(N)CC3)nc2c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 102.5 %

Procedure:
Trifluoroacetic acid (580 μL, 7.52 mmol, 15.0 eq) is added at 0° C. to a stirred solution of {1-[2-(7-methoxy-quinoxalin-2-yloxy)-ethyl]-piperidin-4-yl}-carbamic acid tert-butyl ester (206 mg, 0.50 mmol, 1.0 eq) in dichloromethane (20 mL). After 15 hours stirring at room temperature, the reaction mixture is extracted with dichloromethane (3×20 mL) and water (20 mL) and the pH is adjusted to 12 by the addition of a 1N sodium hydroxide aqueous solution. The combined organic layers are dried over sodium sulfate, filtered and concentrated to afford 1-[2-(7-methoxy-quinoxalin-2-yloxy)-ethyl]-piperidin-4-ylamine as an orange oil (155 mg, 99.5% yield).
Reaction SMILES: [CH3:1][N:2]1[C:6]([NH:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][N:19]([CH3:21])[CH3:20])[CH:13]=2)=[N:5][C:4](Cl)=[N:3]1.[NH:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1.[I-].[Na+]>Cl>[CH3:1][N:2]1[C:6]([NH:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][N:19]([CH3:21])[CH3:20])[CH:13]=2)=[N:5][C:4]([N:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)=[N:3]1
Reactant: CN(C)Cc1cccc(OCCCNc2nc(Cl)nn2C)c1
Reactant: C1CCNC1
Agent: Cl
Agent: [I-]
Agent: [Na+]
Product: CN(C)Cc1cccc(OCCCNc2nc(N3CCCC3)nn2C)c1
Yield: 61 %

Procedure:
A mixture of 1-methyl-3-chloro-N5 -[3-[3-[(dimethylamino)methyl]phenoxy]propyl]-1H-1,2,4-triazole-5-amine (0.4 g), pyrrolidine (0.71 g) and sodium iodide (0.3 g) was heated at 180° in an autoclave for 16 hr. The reaction mixture was dissolved in dilute hydrochloric acid, washed with ethyl acetate, basified with sodium hydroxide and extracted with toluene. The toluene extracts were fractionally distilled to give the title compound as a pale yellow oil (0.27 g) b.p. 210° (0.04 mm). TLC silica; ethyl acetate:isopropanol:water:0.88 ammonia 25:15:8:2; Rf 0.6.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([CH2:32][C:33]([N:35]1[CH2:39][C@@H:38]([F:40])[CH2:37][C@H:36]1[C:41]#[N:42])=[O:34])[C:12]12[CH2:19][CH2:18][C:15]([C:20]([O:22]N3C4C=CC=CC=4N=N3)=O)([CH2:16][CH2:17]1)[CH2:14][CH2:13]2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:43]([NH2:51])[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50]>>[CH2:1]([O:8][C:9]([N:11]([CH2:32][C:33]([N:35]1[CH2:39][C@@H:38]([F:40])[CH2:37][C@H:36]1[C:41]#[N:42])=[O:34])[C:12]12[CH2:13][CH2:14][C:15]([C:20]([NH:51][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])=[O:22])([CH2:16][CH2:17]1)[CH2:18][CH2:19]2)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CN(C(=O)OCc1ccccc1)C12CCC(C(=O)On3nnc4ccccc43)(CC1)CC2
Reactant: CCCCCCCCN
Product: CCCCCCCCNC(=O)C12CCC(N(CC(=O)N3C[C@@H](F)C[C@H]3C#N)C(=O)OCc3ccccc3)(CC1)CC2

Procedure:
In a similar manner to Example 4, (2S,4S)-1-[[N-benzyloxycarbonyl-N-[4-(benzotriazol-1-yl)oxycarbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (50.0 mg) and octylamine (15.0 μL) were used to obtain (2S,4S)-1-[[N-benzyloxycarbonyl-N-[4-(N-octylamino)carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (42.4 mg).
Reaction SMILES: C(O[C:4]([C:6]1[CH:14]=[C:13]([OH:15])[C:9]2[CH:10]=[CH:11][O:12][C:8]=2[CH:7]=1)=[O:5])C.[F:16][C:17]1[CH:27]=[C:26](F)[CH:25]=[CH:24][C:18]=1[C:19]([N:21]([CH3:23])[CH3:22])=[O:20].[NH2:29][C:30]1[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][N:31]=1>>[CH3:22][N:21]([CH3:23])[C:19]([C:18]1[CH:24]=[CH:25][C:26]([O:15][C:13]2[C:9]3[CH:10]=[CH:11][O:12][C:8]=3[CH:7]=[C:6]([C:4]([NH:29][C:30]3[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][N:31]=3)=[O:5])[CH:14]=2)=[CH:27][C:17]=1[F:16])=[O:20]
Reactant: CCOC(=O)c1cc(O)c2ccoc2c1
Reactant: CN(C)C(=O)c1ccc(F)cc1F
Reactant: Cc1ccc(N)nc1
Product: Cc1ccc(NC(=O)c2cc(Oc3ccc(C(=O)N(C)C)c(F)c3)c3ccoc3c2)nc1
Reaction time: 4 h

Procedure:
The title compound was prepared in a similar manner as described for Example 341, from ethyl 4-hydroxy-benzofuran-6-carboxylate (8a) (0.26 g, 1.24 mmol), 2,4-difluoro-N,N-dimethylbenzamide (0.287 g, 1.55 mmol), and 2-amino-5-methyl pyridine (0.228 g, 2.11 mmol) (except that amide coupling was carried out at 75° C. for four hours) to give a solid (81 mg, 15% yield) as the expected product. 1H NMR (400 MHz, DMSO-d6) δ 10.84 (s, 1 H) 8.27 (s, 1 H) 8.22-8.23 (m, 1 H) 8.18-8.19 (m, 1 H)) 8.06-8.08 (d, 1 H) 7.67 (m, 1 H) 7.64 (m, 1 H) 7.39-7.44 (t, 1 H) 7.09-7.12 (m, 1 H) 6.95-6.97 (m, 1 H) 6.90 (m, 1 H) 3.00 (s, 3 H) 2.88 (m, 3 H) 2.28 (s, 3 H). LCMS for C24H20FN3O4 m/z 434.10 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH2:13])[C:7](=[CH:11][CH:12]=1)[C:8]([OH:10])=O)([O-:3])=[O:2].Cl.[CH:15](N)=[NH:16]>>[N+:1]([C:4]1[CH:5]=[C:6]2[C:7]([C:8](=[O:10])[NH:16][CH:15]=[N:13]2)=[CH:11][CH:12]=1)([O-:3])=[O:2]
Reactant: N=CN
Reactant: Nc1cc([N+](=O)[O-])ccc1C(=O)O
Agent: Cl
Product: O=c1[nH]cnc2cc([N+](=O)[O-])ccc12
Reaction time: 1 h
Yield: 44.3 %

Procedure:
4-Nitroanthranilic acid (10.0 g, 54.9 mmol) and formamidine hydrochloride (6.63 g, 82.4 mmol) were ground together in a mortar and pestle to produce a fine, intimate mixture. The mixture was placed in a 250 mL round-bottom flask, and spread evenly over the surface. The flask was placed in an oilbath at 200° C. The solid underwent a color change, and a distillate was seen on the side of flask, but did not really melt. After 30 min the flask was removed from the heating bath. 0.3M sodium hydroxide solution (150 mL) was added to the cooled flask, the black solid mass was broken up with a spatula, and stirred for 1 h. The solid was filtered off and washed with water. The filtrate was discarded. The black solid was suspended in dichloromethane/methanol (10:1) and filtered through a plug of silica, eluting with the same solvent until no more product came off. The material was one spot by TLC, plus black baseline material, but was poorly soluble, so a large volume of solvent was needed. The filtrate was evaporated to dryness and the solid residue triturated with a little methanol and filtered to give 7-nitroquinazoline-4-one (4.65 g, 44%).
Reaction SMILES: OO.C(OC(C(F)(F)F)=O)(C(F)(F)F)=[O:4].[CH3:16][N:17]([CH3:35])[CH2:18][CH2:19][NH:20][C:21]1[N:22]=[N+:23]([O-:34])[C:24]2[CH:33]=[C:32]3[C:28]([CH2:29][CH2:30][CH2:31]3)=[CH:27][C:25]=2[N:26]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl.C(Cl)(Cl)Cl.N>[O-:34][N+:23]1[C:24]2[CH:33]=[C:32]3[C:28](=[CH:27][C:25]=2[N+:26]([O-:4])=[C:21]([NH:20][CH2:19][CH2:18][N:17]([CH3:35])[CH3:16])[N:22]=1)[CH2:29][CH2:30][CH2:31]3
Reactant: CN(C)CCNc1nc2cc3c(cc2[n+]([O-])n1)CCC3
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Agent: N
Agent: OO
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CN(C)CCNc1n[n+]([O-])c2cc3c(cc2[n+]1[O-])CCC3
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 54.4 %

Procedure:
H2O2 (70%, 0.54 mL, ca. 10.8 mmol) was added dropwise to a stirred solution of TFAA (1.5 mL, 10.8 mmol) in DCM (10 mL) at 0° C. The solution was stirred at 0° C. for 5 min, warmed to 20° C. for 10 min, then cooled to 0° C. and added to a stirred solution of 1-oxide 22 (294 mg, 1.1 mmol) and TFA (0.17 mL, 2.2 mmol) in CHCl3 (15 mL) at 0° C. The solution was stirred at 20° C. for 6 h, diluted with dilute aqueous NH3 solution (10 mL) and extracted with CHCl3 (4×50 mL). The combined organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-10%) of MeOH/DCM, to give 1,4-dioxide 23 (173 mg, 55%) as a red solid: mp (MeOH/EtOAc) 150-153° C.; 1H NMR δ 8.12 (s, 1H, H-9), 8.10 (s, 1H, H-5), 7.40 (br s, 1H, NH), 3.62-3.67 (m, 2H, CH2N), 3.03-3.13 (m, 4H, H-6, H-8), 2.63 (t, J=6.0 Hz, 2H, CH2N), 2.31 [s, 6H, N(CH3)2], 2.17-2.23 (m, 2H, H-7); 13C NMR δ 155.6, 149.5, 145.8, 138.0, 129.7, 115.7, 111.6, 57.5, 45.2 (2), 38.8, 33.6, 32.4, 25.6; MS m/z 289 (M+, 0.5%), 272 (5), 58 (100); HRMS calcd for C14H19N5O2 (M+) m/z 289.1539, found 289.1536. The hydrochloride salt was crystallised from MeOH/EtOAc. Anal. calcd for C14H20CIN5O2.½CH3OH: C, 49.7; H, 6.8; N, 19.3. Found: C, 49.4; H, 7.0; N, 19.8%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:29]=[CH:28][C:6]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([O:17][C:18]4[C:23]([F:24])=[CH:22][C:21]([NH2:25])=[C:20]([Cl:26])[CH:19]=4)=[C:11]3[C:10](I)=[N:9]2)=[CH:5][CH:4]=1.[NH2:30][CH:31]1[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]1.C([O-])([O-])=O.[K+].[K+].N1CCC[C@H]1C(O)=O>CS(C)=O.C(Cl)Cl.O>[CH3:1][O:2][C:3]1[CH:29]=[CH:28][C:6]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([O:17][C:18]4[CH:19]=[C:20]([Cl:26])[C:21]([NH2:25])=[CH:22][C:23]=4[F:24])=[C:11]3[C:10]([NH:30][CH:31]3[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]3)=[N:9]2)=[CH:5][CH:4]=1
Reactant: CN1CCC(N)CC1
Reactant: COc1ccc(Cn2nc(I)c3c(Oc4cc(Cl)c(N)cc4F)ccnc32)cc1
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: O
Product: COc1ccc(Cn2nc(NC3CCN(C)CC3)c3c(Oc4cc(Cl)c(N)cc4F)ccnc32)cc1
Temperature: 100 °C
Yield: 66.9 %

Procedure:
4-(1-(4-methoxybenzyl)-3-iodo-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-2-chloro-5-fluorobenzenamine (200 mg, 0.38 mmol) was added into a suspension of 4-amino-1-methylpiperidine (131 mg, 1.14 mmol), Cu(I)I (14.5 mg, 0.0762 mmol), K2CO3 (263 mg, 1.91 mmol) and L-proline (17.6 mg, 0.152 mmol) in DMSO (6 mL) and the reaction mixture was heated at 100° C. for 12 hours. The reaction with diluted with CH2Cl2 and water (10 mL) was added. The organic layer was then washed with water (10 mL), brine, dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (5% MeOH in CH2Cl2) to afford the product (130 mg, 66.7% yield) as a brown oil. LRMS (APCI pos) m/e 511.1 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([CH3:23])[C:17]=1[CH3:24].Cl[C:26](Cl)([O:28]C(=O)OC(Cl)(Cl)Cl)Cl.[O:37]1[CH2:42][CH2:41][N:40]([CH2:43][CH2:44][CH:45]([OH:49])[CH2:46][CH2:47][CH3:48])[CH2:39][CH2:38]1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:26](=[O:28])[O:49][CH:45]([CH2:44][CH2:43][N:40]2[CH2:41][CH2:42][O:37][CH2:38][CH2:39]2)[CH2:46][CH2:47][CH3:48])=[C:18]([CH3:23])[C:17]=1[CH3:24]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2nccc(Oc3ccc(N)c(C)c3C)c2cc1OC
Reactant: CCCC(O)CCN1CCOCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CCCC(CCN1CCOCC1)OC(=O)Nc1ccc(Oc2ccnc3cc(OC)c(OC)cc23)c(C)c1C
Yield: 98.9 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,3-dimethylaniline (50 mg) was added to toluene (5 ml), and triethylamine (0.5 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (68 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, 1-morpholino-3-hexanol (43 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, and the extract was washed with water and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (82 mg, yield 90%).
Reaction SMILES: F[C:2]1[C:10]([CH3:11])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.[F:12][C:13]([F:19])([CH:16]([F:18])[F:17])[CH2:14][OH:15]>>[CH3:11][C:10]1[C:2]([O:15][CH2:14][C:13]([F:19])([F:12])[CH:16]([F:18])[F:17])=[N:3][CH:4]=[C:5]([CH:9]=1)[C:6]([OH:8])=[O:7]
Reactant: Cc1cc(C(=O)O)cnc1F
Reactant: OCC(F)(F)C(F)F
Product: Cc1cc(C(=O)O)cnc1OCC(F)(F)C(F)F
Yield: 99 %

Procedure:
The title compound is prepared in >99% yield (3.7 g, white solid) from 6-fluoro-5-methylnicotinic acid (2.0 g, 12.9 mmol) and 2,2,3,3-tetrafluoropropan-1-ol (3.4 g, 25.8 mmol) instead of 2,2,2-trifluoroethanol in a similar manner to Step-1 of Amine-1.
Reaction SMILES: C(N(CC)CC)C.Cl[Si:9]([CH3:12])([CH3:11])[CH3:10].[CH:13]([O:16][C:17]1[C:18]([OH:27])([CH3:26])[C:19](=[O:25])[C:20]=1[O:21][CH:22]([CH3:24])[CH3:23])([CH3:15])[CH3:14]>C(OCC)C>[CH:13]([O:16][C:17]1[C:18]([O:27][Si:9]([CH3:12])([CH3:11])[CH3:10])([CH3:26])[C:19](=[O:25])[C:20]=1[O:21][CH:22]([CH3:23])[CH3:24])([CH3:15])[CH3:14]
Reactant: CC(C)OC1=C(OC(C)C)C(C)(O)C1=O
Reactant: C[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CC(C)OC1=C(OC(C)C)C(C)(O[Si](C)(C)C)C1=O
Reaction time: 18 h
Yield: 94.2 %

Procedure:
Triethylamine (28 mL, 0.20 mol) and chlorotrimethylsilane (13 mL, 0.10 mol) were successively added to a stirred solution of 3,4-diisopropoxy-2-hydroxy-2-methylcyclobut-3-ene-1-one (14.3 g, 0.0667 mol) in diethyl ether (250 mL). The mixture was allowed to stir at ambient temperatures for 18 hrs. The mixture was filtered through SiO2 contained in a sintered glass funnel. The filter cake was washed with additional diethyl ether. The ether was removed to leave 3,4-diisopropoxy-2-trimethylsilyloxy-2-methylcyclobut-3-ene-1-one (18 g, 94% yield) as a clear oil. Trimethylsilyl trifluoromethanesulfonate (150 μL, 0.78 mmol) was added to a stirred solution of the silyl ether (18 g, 0.0628 mol) and 1,2-bis(trimethylsilyloxy)ethane (16.2 mL, 0.066 mmol) in tetrahydrofuran (36 mL). The solution was stirred for 1 hr at 22° C. and additional trimethylsilyl trifluoromethanesulfonate (150 μL) was then added. The solution was stirred for an additional 0.25 hr and was concentrated to dryness The residue was flash chromatographed on SiO2 (200 g) with diethyl etherhexanes (1:1) to afford 2,2-ethylenedioxy-3-isopropoxy-4-methylcyclobut-3-ene-1-one (9 g, 73% yield) as a colorless crystalline solid. A solution of n-Bu4N+CN- (140 mg, 0.52 mmol) in tetrahydrofuran (4 mL) was added dropwise to a stirred solution of the ketal (2.0 g, 0.010 mol) and n-Bu3SnSi(CH3)3 (4.03 g, 0.011 mol) in tetrahydrofuran (60 mL) at 22° C. Stirring was continued for 0.66 hr, and the dark solution was concentrated to dryness. The residue was flash chromatographed on SiO2 (80 g) with hexane and then with diethyl ether-hexane (25:75) to afford the title compound as a yellow oil (4.11 g, 95% yield).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH3:7].[CH2:8]([Br:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH2:16]([N:18]([CH2:27][CH3:28])[C:19]1[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][CH:20]=1)[CH3:17].N1CCCCC1>C(O)(C)C.CO>[Br-:15].[CH2:8]([N+:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]=[CH:23][C:22]1[CH:25]=[CH:26][C:19]([N:18]([CH2:16][CH3:17])[CH2:27][CH3:28])=[CH:20][CH:21]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CCN(CC)c1ccc(C=O)cc1
Reactant: Cc1ccccn1
Reactant: BrCc1ccccc1
Solvent: CO
Solvent: CC(C)O
Solvent: C1CCNCC1
Product: CCN(CC)c1ccc(C=Cc2cccc[n+]2Cc2ccccc2)cc1
Product: [Br-]
Temperature: 100 °C
Yield: 44.4 %

Procedure:
2-Picoline (9.3 g, 0.1 mole) and benzyl bromide (17.1 g, 0.1 mole) were refluxed in isopropanol (50 ml) overnight. The solvent was evaporated giving an oil which was heated at 100° C. for six hours. The resulting crude oil (8.5 g, 0.032 mole) and 4-diethylaminobenzaldehyde (6.0 g, 0.033 mole) were refluxed in methanol (40 ml) in the presence of piperidine (0.2 ml) under nitrogen for three hours. On cooling dark-coloured crystals were obtained which were collected to give 1-benzyl-2-[4-(diethylamino)styryl]pyridinium bromide (6.2 g), melting point 231°-233° C.
Reaction SMILES: C[CH2:2][O:3][CH2:4]C.[OH-].[K+].N(CNC(N)=O)=[O:9].[CH3:15][O:16][C:17]1[CH:25]=[C:24]([O:26][CH:27]2[CH2:32][CH2:31][N:30]([C:33](=[O:35])[CH3:34])[CH2:29][CH2:28]2)[CH:23]=[CH:22][C:18]=1[C:19](Cl)=O>C1COCC1>[CH3:15][O:16][C:17]1[CH:25]=[C:24]([O:26][CH:27]2[CH2:32][CH2:31][N:30]([C:33](=[O:35])[CH3:34])[CH2:29][CH2:28]2)[CH:23]=[CH:22][C:18]=1[CH2:19][C:2]([O:3][CH3:4])=[O:9]
Reactant: COc1cc(OC2CCN(C(C)=O)CC2)ccc1C(=O)Cl
Reactant: CCOCC
Reactant: NC(=O)NCN=O
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COC(=O)Cc1ccc(OC2CCN(C(C)=O)CC2)cc1OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of ether (14 ml) and 40% aqueous potassium hydroxide (4.2 ml) was cooled in ice. N-Nitrosomethylurea (1.4g) was added in portions with gentle swirling over 30 min. The ether layer was decanted and dried over solid potassium hydroxide for 15 min. The ether solution was decanted, then cooled in an ice bath. A solution of 2-methoxy-4-(1-acetyl-4-piperidyloxy)benzoyl chloride (0.58 g, 1.86 mmol) in THF (3 ml) was added dropwise and the mixture was stirred at ambient temperature for 2 hours. Nitrogen was passed through the mixture for 1 hour, and the solution was then concentrated in vacuo. The residue was dissolved in methanol and treated with freshly prepared silver oxide (48 mg), and the mixture was heated at reflux for 30 min. Three additional lots of 100 mg of silver oxide were added with 1 hour reflux following each. The mixture was cooled and filtered, and the filtrate was concentrated in vacuo. The residue was chromatographed on silica gel eluted with 2%, followed by 4% methanol in methylene chloride. The product fractions were combined and evaporated to dryness in vacuo to give methyl 2-methoxy-4-(1-acetyl-4-piperidyloxy)phenylacetate.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[S:10][C:9]([CH:11]=O)=[CH:8][CH:7]=1.[NH2:13][C:14]1[S:15][C:16]([NH2:29])=[C:17]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:18]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20].C(O)(C(F)(F)F)=O>C(O)(C)C>[CH2:22]([O:21][C:19]([C:18]1[C:17]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:16]([N:29]=[CH:11][C:9]2[S:10][C:6]([C:2]3[S:1][CH:5]=[CH:4][CH:3]=3)=[CH:7][CH:8]=2)[S:15][C:14]=1[NH2:13])=[O:20])[CH3:23]
Reactant: O=Cc1ccc(-c2cccs2)s1
Reactant: CCOC(=O)c1c(N)sc(N)c1C(=O)OCC
Solvent: CC(C)O
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1c(N)sc(N=Cc2ccc(-c3cccs3)s2)c1C(=O)OCC

Procedure:
5-(Thiophen-2-yl)thiophene-2-carbaldehyde (40 mg, 0.25 mmol) was added to diethyl 2,5-diaminothiophene-3,4-dicarboxylate (30 mg, 0.25 mmol) in isopropanol and refluxed for five hours after the addition of a catalytic amount of TFA. The solvent was removed and the title product was isolated as a yellow solid after purification by flash chromatography (42 mg, 64%). 1H-NMR (300 MHz, [D] DMSO): δ=8.19 (s, 1H), 7.89 (s, 2H), 7.58 (d, 1H, 3J=5.2 Hz), 7.50 (d, 1H, 3J=3.9 Hz) 7.41 (d, 1H, 3J=3.6 Hz), 7.34 (d, 1H, 3J=3.9 Hz), 7.11 (t, 1H, J=3.6 Hz), 4.25 (q, 2H, 3J=7.1 Hz), 4.12 (q, 2H, 3J=7.2 Hz), 1.31 (t, 3H, 3J=7.2 Hz), 1.19 (t, 3H, 3J=7.0 Hz). 13C-NMR (60 MHz, [D] acetone): δ=165.5, 164.8, 161.7, 146.1, 142.3, 141.9, 137.7, 137.6, 133.5, 133.4, 131.1, 129.2, 126.9, 125.8, 125.3, 61.5, 60.5, 14.8, 14.6. EI-MS: m/z 434.9 ([M]+, 96%).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[C:15]([C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][CH:23]=1)[NH2:20])#[CH:16]>C(O)(C)C>[ClH:1].[C:15]([C:17]1[CH:18]=[C:19]([NH:20][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=3)[N:5]=[CH:4][N:3]=2)[CH:21]=[CH:22][CH:23]=1)#[CH:16]
Reactant: C#Cc1cccc(N)c1
Reactant: O=[N+]([O-])c1ccc2ncnc(Cl)c2c1
Solvent: CC(C)O
Product: C#Cc1cccc(Nc2ncnc3ccc([N+](=O)[O-])cc23)c1
Product: Cl
Temperature: 25 °C

Procedure:
4-Chloro-6-nitroquinazoline (1.06 g,5.00 mmol) and 3-ethynylaniline (1.00 g,5.30 mmol) were refluxed in 10 mL of isopropyl alcohol for 3 hours, cooled and, after 16 hours at room temperature, filtered to afford solid title product which was washed with 10 mL of isopropyl alcohol and dried in vacuo, at 70° C., 1.27 g (78%); mp 255°-256° C.
Reaction SMILES: S([O-])(O[O-])(=O)=[O:2].[K+].[K+].[CH:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][C:10]=1[S:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([Br:26])[CH:21]=1.C(O)C.[OH2:30]>>[CH:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][C:10]=1[S:19]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([Br:26])[CH:21]=1)(=[O:2])=[O:30]
Reactant: O=S(=O)([O-])O[O-]
Reactant: O
Reactant: Brc1cccc(Sc2ccc3ccccc3c2)c1
Agent: [K+]
Solvent: CCO
Product: O=S(=O)(c1cccc(Br)c1)c1ccc2ccccc2c1
Temperature: 0 °C
Reaction time: 5 h
Yield: 82 %

Procedure:
A solution of potassium peroxymonosulphate (17.7 g) in water (30 ml) was added to a mixture of 3-bromophenyl 2-naphthyl sulphide (3 g) and ethanol (30 ml) which had been cooled to 0° C. in an ice-bath. The mixture was stirred at ambient temperature for 18 hours and at 60° C. for 5 hours. The mixture was cooled to ambient temperature and partitioned between chloroform and water. The organic phase was dried (MgSO4) and evaporated to give 3-bromophenyl 2-naphthyl sulphone (2.7 g, 82%) as a solid which was used without further purification.