Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][C:14]=3[C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:21])=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:28][CH3:29].Br[CH2:31][CH2:32][CH2:33][Cl:34].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:34][CH2:33][CH2:32][CH2:31][O:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][C:14]=3[C:20]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)=[O:21])=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:28][CH3:29]
Reactant: ClCCCBr
Reactant: COc1cc2c(Oc3ccc(C)cc3C(=O)c3ccccc3)ccnc2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc(C)cc3C(=O)c3ccccc3)ccnc2cc1OCCCCl
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.6 %

Procedure:
{2-[(7-Hydroxy-6-methoxy-4-quinolyl)oxy]-5-methylphenyl}-(phenyl)methanone (200 mg), 1-bromo-3-chloropropane (245 mg), and potassium carbonate (358 mg) were suspended in N,N-dimethylformamide (5 ml), and the suspension was stirred at room temperature overnight. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using acetone-hexane to give the title compound (210 mg, yield 87%).
Reaction SMILES: [C:1]([OH:7])(=[O:6])[CH2:2][C:3](O)=O.[CH:8](=O)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]C.N1CCCCC1.Cl>N1C=CC=CC=1>[C:1]([OH:7])(=[O:6])/[CH:2]=[CH:3]/[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH3:8]
Reactant: O=C(O)CC(=O)O
Reactant: CCCCCCCCCCCC=O
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: CCCCCCCCCCC/C=C/C(=O)O
Temperature: 35 °C
Yield: 65.6 %

Procedure:
To a dry flask containing malonic acid (56.5 g) and pyridine (132 ml) was added dodecanal (100 g) dropwise to maintain the internal temperature under 35° C. under nitrogen atmosphere while stirring. After the addition, piperidine (4 ml) was added. The reaction mixture was then heated to 55° C. for 1 hr and 90° C. for 3 hrs. The mixture was cooled to room temperature and poured into ice-water (˜1 L). After the addition of 400 ml 6M HCl, the mixture was extracted with ethyl acetate (2 L). The ethyl acetate phase was washed with DI water twice. The solvent was removed under vacuum. The crude product was crystallized from hexane. The pure product was obtained as a white solid (80.5 g, 65.6% yield). Proton NMR(CDCl3) δ 0.88 (t, 3H), 1.26 (m, 16H), 1.45 (m, 2H), 2.22 (m, 2H), 5.82 (td, 1H), 7.09 (td, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)(=O)=O)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([NH:26][C:27]([C:29]4[CH:33]=[CH:32][S:31][CH:30]=4)=[O:28])[CH:22]=[CH:23][C:24]=3[CH3:25])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:38].[CH3:39][C:40]1([CH3:49])[CH2:45][CH:44]([NH2:46])[CH2:43][C:42]([CH3:48])([CH3:47])[NH:41]1>C(#N)C>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:46][CH:44]3[CH2:45][C:40]([CH3:49])([CH3:39])[NH:41][C:42]([CH3:48])([CH3:47])[CH2:43]3)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([NH:26][C:27]([C:29]4[CH:33]=[CH:32][S:31][CH:30]=4)=[O:28])[CH:22]=[CH:23][C:24]=3[CH3:25])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:38]
Reactant: Cc1ccc(NC(=O)c2ccsc2)cc1-c1nc(S(C)(=O)=O)nc2c1ccc(=O)n2-c1c(F)cccc1F
Reactant: CC1(C)CC(N)CC(C)(C)N1
Solvent: CC#N
Product: Cc1ccc(NC(=O)c2ccsc2)cc1-c1nc(NC2CC(C)(C)NC(C)(C)C2)nc2c1ccc(=O)n2-c1c(F)cccc1F
Yield: 16 %

Procedure:
The title compound was prepared from N-{3-[8-(2,6-difluorophenyl)-2-(methylsulfonyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methylphenyl}-3-thiophenecarboxamide and 2,2,6,6-tetramethyl-4-piperidinamine according to General Procedure for Sulfoxide/Sulfone Displacement, described above. The concentrated reaction mixture was slurried with acetonitrile and filtered. The solid was recrystallized from methanol/water to afford the desired product as a crystalline solid (0.2 g, 16%). HPLC indicated >99% pure: LC-MS m/z 629 (M+H)+, 1.86 min (ret time).
Reaction SMILES: [I:1]Cl.[N:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:14]([C:15]3[CH:27]=[CH:26][C:25]4[C:24]5[C:19](=[CH:20][C:21]([Si](C)(C)C)=[CH:22][CH:23]=5)[C:18]([CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])([CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[C:17]=4[CH:16]=3)=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1>CO.ClCCl>[N:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:14]([C:15]3[CH:27]=[CH:26][C:25]4[C:24]5[C:19](=[CH:20][C:21]([I:1])=[CH:22][CH:23]=5)[C:18]([CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])([CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[C:17]=4[CH:16]=3)=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1
Reactant: CCCCCCCCC1(CCCCCCCC)c2cc(-c3ccccc3-c3ccncc3)ccc2-c2ccc([Si](C)(C)C)cc21
Reactant: ClI
Solvent: ClCCl
Solvent: CO
Product: CCCCCCCCC1(CCCCCCCC)c2cc(I)ccc2-c2ccc(-c3ccccc3-c3ccncc3)cc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
1.5 ml of an 1.0 M ICl solution in MeOH was slowly added to a solution of 500 mg (0.813 mmol) of 2-(6-p-pyridyl-phenyl)-7-trimethylsilyl-9,9-dioctylfluorene in 5 mL of dichloromethane. The resulting darkred solution was stirred for 2 h at room temperature after which the reaction mixture was quenched with a large excess of a Na2S2O3 in water. The mixture was extracted with water, and the organic fraction was dried using MgSO4 and the solvents were removed under reduced pressure. The product was purified using flash column chromatography (dichloromethane: Rf: 0.36). 450 mg (85%) product was obtained as a highly blue fluorescent, colourless solid material. 1H NMR (250 MHz, CDCl3): δ=8.73 (d, 3J=4.7 Hz, 1H; CH—N), 8.12 (d, 3J=8.5 Hz, 2H; CH—C—C(CH)—N), 7.80-7.73 (mp, 4H, ArH), 7.68 (s, 2H, ArH), 7.65 (d, 3J=5.0 Hz, 2H; CH—CH—N), 7.60 (s, 2H; ArH), 7.48 (d, 1H; 3J=8.4 Hz; ArH), 2.05-1.94 (mp, 4H; CH2—C), 1.05-1.25 (mp, 20H, CH2), 0.81 (t, 3J=6.6 Hz, 6H; CH3), 0.70 (br m, 4H, CH2). 13C{1H} NMR (500 MHz, CDCl3): δ=157.0 (CN), 153.4, 150.9 (C—C—CH2), 149.8 (CH—N), 142.0, 140.4, 140.0, 139.6, 138.2 (ArC), 136.8 (CH—CH—CH—N), 135.9, 132.1 (C—CI), 127.5, 127.3, 126.1, 122.1, 121.5, 121.3, 120.4, 120.1 (CH), 92.6 (CI), 55.5 (C—CH2), 40.2 (C—CH2), 31.7, 29.9, 29.2, 29.1 (CH2), 23.7 (C—CH2—CH2), 22.6 (CH3—CH2), 14.1 (CH3). Exact Mass (IE) m/z: 669.2825 [M]+ (calcd. 669.2832) fractions: 543.6 (m; [M-I]+), 318.4 (m; [M-(C8H17)—I]+). C40H48IN: calcd. C, 71.74; H, 7.22; N, 2.09. found C, 72.34; H, 7.20; N, 2.12.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][S:8][CH:9]([CH3:13])[C:10]([O-:12])=[O:11])=[CH:3][CH:2]=1.[Na+].[CH2:15](O)[CH3:16]>>[N:1]1[CH:6]=[CH:5][C:4]([CH2:7][S:8][CH:9]([CH3:13])[C:10]([O:12][CH2:15][CH3:16])=[O:11])=[CH:3][CH:2]=1
Reactant: CC(SCc1ccncc1)C(=O)[O-]
Reactant: CCO
Agent: [Na+]
Product: CCOC(=O)C(C)SCc1ccncc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Crude sodium 2-(4-pyridylmethylthio)propionate (approximately 7 g.) was taken up in 100 ml. of absolute ethanol and approximately 5 cc. of 3 A molecular sieves were added. Dry hydrogen chloride was bubbled into the reaction mixture, which was refluxed for 75 minutes, while continuing to saturate with hydrogen chloride during the initial 15 minutes. The mixture was cooled to room temperature and allowed to stir overnight (approximately 16 hours). The mixture was filtered through diatomaceous earth and concentrated to a semi-solid mixture. The esterification step was repeated on this mixture, except saturation with hydrogen chloride was continued during 1 hour of reflux and refluxing was continued overnight. The reaction mixture was cooled to room temperaure, filtered through diatomaceous earth and evaporated to an oil. The oil was extracted with chloroform, leaving filterable salts behind, and the chloroform stripped to yield ethyl 2-(4-picolylthio)propionate (waxy solid; ir (KBr) 3.0, 3.5, 5.75, 6.15, 6.30, 6.70, 8.6, 12.25μ; m.s.: m/e calcd: 225, found: 225, 152, 124, 102, 92, 45).
Reaction SMILES: [F:1][CH:2]([F:10])[C:3]1[CH:8]=[CH:7][N:6]=[C:5](O)[N:4]=1.O.P(Cl)(Cl)([Cl:14])=O>C(Cl)Cl>[Cl:14][C:5]1[N:4]=[C:3]([CH:2]([F:10])[F:1])[CH:8]=[CH:7][N:6]=1
Reactant: Oc1nccc(C(F)F)n1
Reactant: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: O
Product: FC(F)c1ccnc(Cl)n1
Temperature: 85 °C

Procedure:
4-(difluoromethyl)pyrimidin-2-ol was diluted with phosphorus oxychloride (80 mL) then heated at 85° C. for 3 hours with periodic venting of the reaction mixture. The mixture was cooled to rt, diluted with DCM (500 mL) and poured into water (˜1 L) cooled in an ice bath at such a rate the exotherm was maintained at ˜30° C. The mixture was transferred to a separatory funnel and the layers were separated. The aqueous layer was extracted with DCM (2×500 mL) and the organics were combined and dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to afford 2-chloro-4-(difluoromethyl) as a light yellow oil. MS ESI calcd. for C5H4ClF2N2 [M+H]+ 165. found 165. 1H NMR δ ppm DMSO-d6): 8.18 (1H, d, J=6.25 Hz), 6.63 (1H, t, J=54.22 Hz). 6.57 (2H, d, J=6.26 Hz).
Reaction SMILES: [P:1]([O:8][CH2:9][CH3:10])([O:5]CC)[O:2][CH2:3][CH3:4].[CH3:11][O:12][CH:13](OC)[C:14]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[C:16]([Cl:22])[CH:15]=1.B(F)(F)F.CCOCC>C(Cl)Cl>[CH3:11][O:12][CH:13]([C:14]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[C:16]([Cl:22])[CH:15]=1)[P:1]([O:2][CH2:3][CH3:4])(=[O:5])[O:8][CH2:9][CH3:10]
Reactant: CCOP(OCC)OCC
Reactant: COc1cc(Cl)cc(C(OC)OC)c1
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: CCOP(=O)(OCC)C(OC)c1cc(Cl)cc(OC)c1
Yield: 77 %

Procedure:
Triethyl phosphite (3.2 ml, 19 mmol) was added dropwise to a solution of acetal 7 (4.0 g, 18.5 mmol), boron trifluoride etherate (2.3 ml, 19 mmol) and CH2Cl2 (20 ml) at 0° C. After slowly warming the reaction to room temperature (30 min), the solution was partitioned with dilute NaHCO3, dried over Na2SO4, evaporated and purified on silica gel (40%-100% EtOAc/hexanes) to give 4.6 g (77.5%) of phosphonate 8 as a light yellow oil.
Reaction SMILES: Br[C:2]1[C:3]2[CH:4]=[CH:5][C:6]([N:43]=2)=[C:7]([C:34]2[C:39]([CH3:40])=[CH:38][C:37]([CH3:41])=[CH:36][C:35]=2[CH3:42])[C:8]2[NH:12][C:11]([CH:13]=[C:14]3[N:33]=[C:17]([C:18]([C:24]4[C:29]([CH3:30])=[CH:28][C:27]([CH3:31])=[CH:26][C:25]=4[CH3:32])=[C:19]4[NH:23][C:22]=1[CH:21]=[CH:20]4)[CH:16]=[CH:15]3)=[CH:10][CH:9]=2.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[C:52]([NH:55][C:56]1[CH:61]=[CH:60][C:59](B(O)O)=[CH:58][CH:57]=1)(=[O:54])[CH3:53]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1COCC1>[C:52]([NH:55][C:56]1[CH:61]=[CH:60][C:59]([C:2]2[C:3]3[CH:4]=[CH:5][C:6]([N:43]=3)=[C:7]([C:34]3[C:35]([CH3:42])=[CH:36][C:37]([CH3:41])=[CH:38][C:39]=3[CH3:40])[C:8]3[NH:12][C:11]([CH:13]=[C:14]4[N:33]=[C:17]([C:18]([C:24]5[C:25]([CH3:32])=[CH:26][C:27]([CH3:31])=[CH:28][C:29]=5[CH3:30])=[C:19]5[NH:23][C:22]=2[CH:21]=[CH:20]5)[CH:16]=[CH:15]4)=[CH:10][CH:9]=3)=[CH:58][CH:57]=1)(=[O:54])[CH3:53]
Reactant: Cc1cc(C)c(-c2c3nc(c(Br)c4ccc([nH]4)c(-c4c(C)cc(C)cc4C)c4nc(cc5ccc2[nH]5)C=C4)C=C3)c(C)c1
Reactant: CC(=O)Nc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc(-c2c3nc(c(-c4c(C)cc(C)cc4C)c4ccc(cc5nc(c(-c6c(C)cc(C)cc6C)c6ccc2[nH]6)C=C5)[nH]4)C=C3)cc1
Reaction time: 0.17 h
Yield: 73 %

Procedure:
To a flask was added 157 mg (0.250 mmol) of 10-bromo-5,15-bis(2,4,6-trimethylphenyl)porphyrin, (6), 1.06 g (5.00 mmol) of potassium phosphate tribasic, 314 mg (1.76 mmol) of 4-acetamidophenylboronic acid (supplied by Acros), and 70 mL of THF. The suspension was flushed with argon for 10 min, and then 39 mg (0.025 mmol) of tetrakis(triphenylphosphine)palladium(0) was added and the argon flushing procedure continued for an additional 10 min. The reaction mixture was then warmed to reflux under an argon atmosphere for 48 h. The solvent was evaporated at reduced pressure, the residue was redissolved in dichloromethane and washed with water, the organic phase was dried over sodium sulfate, and the solvent was once again evaporated at reduced pressure. The crude product was chromatographed on silica gel (dichloromethane/1% acetone) to give 124 mg (73% yield) of the desired porphyrin. 1H NMR (300 MHz) δ−2.89 (2H, s, N—H), 1.84 (12H, s, Ar—CH3), 2.33 (3H, s, acetyl-CH3), 2.67 (6H, s, Ar—CH3), 7.29 (4H, s, Ar—H), 7.47 (1H, s, N—H), 7.85 (2H, d, J=8 Hz, Ar—H), 8.15 (2H, d, J=8 Hz, Ar—H), 8.72 (2H, d, J=5 Hz, β-H), 8.82 (4H, d, J=5 Hz, β-H), 9.26 (2H, d, J=5 Hz, β-H), 10.11 (1H, s, meso-H); MALDI-TOF-MS m/z calcd for C46H41N5O1 679.33, obsd 679.33.
Reaction SMILES: [CH3:1][CH:2]([CH2:7][CH2:8][CH2:9][CH:10]([CH3:17])[CH2:11][CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])[CH2:3][C:4]([OH:6])=O.FC(F)(F)C(OC(=O)C(F)(F)F)=O.[O:31]1[CH:35]=[CH:34][CH:33]=[C:32]1[CH:36]=[C:37]([CH3:43])[C:38]([O:40][CH2:41][CH3:42])=[O:39].C(=O)([O-])[O-].[Na+].[Na+]>Cl(O)(=O)(=O)=O.CCOCC>[CH3:43][C:37](=[CH:36][C:32]1[O:31][C:35]([C:4](=[O:6])[CH2:3][CH:2]([CH3:1])[CH2:7][CH2:8][CH2:9][CH:10]([CH3:17])[CH2:11][CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])=[CH:34][CH:33]=1)[C:38]([O:40][CH2:41][CH3:42])=[O:39]
Reactant: CC(C)CCCC(C)CCCC(C)CC(=O)O
Reactant: CCOC(=O)C(C)=Cc1ccco1
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CCOCC
Product: CCOC(=O)C(C)=Cc1ccc(C(=O)CC(C)CCCC(C)CCCC(C)C)o1
Temperature: 0 °C

Procedure:
A mixture of 24.2 g (0.1 mole) of 3,7,11-trimethyldodecanoic acid and 21.0 g (0.1 mole) of trifluoroacetic anhydride is stirred at reflux for 1/2 hour. The mixture is cooled and 18.0 g (0.1 mole) of ethyl 3-(2-furanyl)-2-methylpropenoate is added. The mixture is cooled to about 0° C. and 5 drops of 70% perchloric acid is added. The mixture is stirred at 0° C. for 2 hours, then diluted with anhydrous ether and treated with saturated aqueous sodium carbonate solution until basic. The layers are separated and the ether layer washed with water, brine and evaporated to dryness. The residue is distilled at reduced pressure to give ethyl 2-methyl-3-[5-(1-oxo-3,-7,11-trimethyldodecyl)-2-furanyl]-2-propenoate.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13].[F:17][C:18]([F:27])([F:26])C1C=CC(N)=CC=1>>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:18]([F:27])([F:26])[F:17])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: CCOC(=O)c1cnc2ccccc2c1O
Product: CCOC(=O)c1cnc2ccc(C(F)(F)F)cc2c1O

Procedure:
The title compound was prepared following the procedure described in Step 1 for the synthesis of 2a using 4-trifluoromethylaniline instead of aniline. 1H NMR (DMSO-d6) δ (ppm): 1.26 (3H, t, J=7.14 Hz), 4.22 (2H, q, J=7.14 Hz), 7.80 (1H, d, J=9.34 Hz), 8.00 (m), 8.39 (1H, s), 8.64 (1H, s). m/z 286.5 (MH+).
Reaction SMILES: C([Li])(C)(C)C.[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][CH:22]3[C:31]4[C:26](=[C:27](Br)[CH:28]=[CH:29][CH:30]=4)[CH2:25][CH2:24][O:23]3)[CH2:16][CH2:15]2)=[CH:10][CH:9]=1.C[Si]([N:37]=[C:38]=[O:39])(C)C>C1COCC1.O1CCOCC1>[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][CH:22]3[C:31]4[C:26](=[C:27]([C:38]([NH2:37])=[O:39])[CH:28]=[CH:29][CH:30]=4)[CH2:25][CH2:24][O:23]3)[CH2:16][CH2:15]2)=[CH:10][CH:9]=1
Reactant: COc1ccc(N2CCN(CCC3OCCc4c(Br)cccc43)CC2)cc1
Reactant: C[Si](C)(C)N=C=O
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: COc1ccc(N2CCN(CCC3OCCc4c(C(N)=O)cccc43)CC2)cc1
Reaction time: 0.25 h

Procedure:
A mixture of t-butyl lithium (2 eqs, 1.7 M in hexane) in THF (2 ml/mmol bromide) is cooled to -78° for 10 minutes before adding the 1-(4-methoxyphenyl)-4-[2-(5-bromoisochroman-1-yl)ethyl]piperazine (LXXIV, EXAMPLE 100) in THF (4 ml/mmol) dropwise over 10 minutes. A freshly distilled solution of trimethylsilylisocyanate (1.5 eqs) is added via syringe as a solution in dioxane (4 volume equivalents) at once. After 15 minutes, the cooling bath is removed and the mixture allowed to warm to 20-25°. The reaction mixture is quenched with ammonium chloride, the organics are removed under reduced pressure, and the aqueous residue is extracted two times with methylene chloride, dried over sodium sulfate, filtered and concentrated. The crude material is purified by flash chromatography on silica gel. In this manner, 1-(4-methoxyphenyl)-4-[2-(5-bromoisochroman-1-yl)ethyl]piperazine (LXXIV, EXAMPLE 100, 345 mg) is converted to the corresponding amide, the title compound, mp 185-186°.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5](=[O:7])[CH:4](P(OCC)(=O)OCC)[NH:3]1.[N+:16]([C:19]1[CH:26]=[CH:25][C:24]([N:27]2[CH2:32][CH2:31][CH:30]([C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH2:29][CH2:28]2)=[CH:23][C:20]=1[CH:21]=O)([O-:18])=[O:17]>>[O:1]=[C:2]1[NH:6][C:5](=[O:7])[C:4](=[CH:21][C:20]2[CH:23]=[C:24]([N:27]3[CH2:32][CH2:31][CH:30]([C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH2:29][CH2:28]3)[CH:25]=[CH:26][C:19]=2[N+:16]([O-:18])=[O:17])[NH:3]1
Reactant: CCOC(=O)C1CCN(c2ccc([N+](=O)[O-])c(C=O)c2)CC1
Reactant: CCOP(=O)(OCC)C1NC(=O)NC1=O
Product: CCOC(=O)C1CCN(c2ccc([N+](=O)[O-])c(C=C3NC(=O)NC3=O)c2)CC1

Procedure:
Prepared from diethyl 2,4-dioxoimidazolidine-5-phosphonate and 2-nitro-5-(4-ethoxycarbonyl-1-piperidinyl)benzaldehyde analogous to the procedure of Example (2-1), m.p. 221°-223° C., crystallized from MeOH.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[N:11]1([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1>C(#N)C>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([N:14]2[CH2:13][CH2:12][N:11]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:16][CH2:15]2)=[N:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(Br)nc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCN(c2ccc([N+](=O)[O-])cn2)CC1
Yield: 54.1 %

Procedure:
A mixture of 2-bromo-5-nitropyridine (5.0 g, 24.6 mmol), tert-butyl piperazine-1-carboxylate (13.8 g, 74.2 mmol), acetonitrile (150 mL) was stirred at reflux for 2.5 h. After the reaction was completed, the solvent was removed under reduced pressure to afford 197a as a yellow solid (4.1 g, 54%). MS-ESI: [M+H]+ 309.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][C:13]=1[CH3:14])[C:7]([O:9][CH3:10])=[O:8])(=[O:3])[CH3:2].[Br:15]Br>C(Cl)(Cl)Cl>[Br:15][CH2:2][C:1]([C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][C:13]=1[CH3:14])[C:7]([O:9][CH3:10])=[O:8])=[O:3]
Reactant: COC(=O)c1ccc(C)c(C(C)=O)c1
Reactant: BrBr
Solvent: ClC(Cl)Cl
Product: COC(=O)c1ccc(C)c(C(=O)CBr)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Into a 50-mL round-bottom flask, which was purged and maintained with an inert atmosphere of nitrogen, was placed a solution of methyl 3-acetyl-4-methylbenzoate (compound 27.1, 200 mg, 1.04 mmol) in chloroform (4 mL). Bromine (53 μL, 1.04 mmol) was added drop-wise and the solution was stirred for 2 h at room temperature, then concentrated under reduced pressure. Obtained 300 mg (crude) of the title compound as a brown solid.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:10]([CH3:11])=[CH:9][C:8]([O:12][CH2:13][CH3:14])=[CH:7][C:6]=1[CH3:15])=O.[NH2:16][C:17]([NH2:19])=[S:18]>CCO>[CH2:13]([O:12][C:8]1[CH:9]=[C:10]([CH3:11])[C:5]([C:3]2[N:16]=[C:17]([NH2:19])[S:18][CH:2]=2)=[C:6]([CH3:15])[CH:7]=1)[CH3:14]
Reactant: NC(N)=S
Reactant: CCOc1cc(C)c(C(=O)CBr)c(C)c1
Solvent: CCO
Product: CCOc1cc(C)c(-c2csc(N)n2)c(C)c1
Yield: 71.9 %

Procedure:
A mixture of 2-bromo-1-(4-ethoxy-2,6-dimethylphenyl)ethanone (6.35 g, 23.4 mmol) and thiourea (1.78 g, 23.4 mmol) in 95% EtOH (33.5 mL) was heated at reflux for 60 min. The solution was concentrated and added with water (50 mL) and saturated aqueous Na2CO3 (5.0 mL). The resultant precipitate was filtered and recrystallized in toluene (30 mL). The solids were filtered and dried under vacuum to give 4-(4-ethoxy-2,6-dimethylphenyl)thiazol-2-amine (4.18 g) as white solids in 72% yield: 1H NMR (500 MHz, DMSO-d6) δ 6.84 (s, 2 H), 6.60 (s, 2 H), 6.27(s, 1 H), 3.99 (q, J=6.5 Hz, 2 H), 2.06 (s, 6 H), 1.31 (t, J=6.95 Hz, 3 H).
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([CH2:9][C:10]#[CH:11])[CH2:5][CH2:4]1)[CH3:2].[F:12][C:13]1[CH:14]=[C:15]([CH:17]=[CH:18][C:19]=1[O:20][C:21]1[CH:26]=[CH:25][N:24]=[C:23]2[CH:27]=[C:28](I)[S:29][C:22]=12)[NH2:16]>>[CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([CH2:9][C:10]#[C:11][C:28]2[S:29][C:22]3[C:23](=[N:24][CH:25]=[CH:26][C:21]=3[O:20][C:19]3[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][C:13]=3[F:12])[CH:27]=2)[CH2:5][CH2:4]1)[CH3:2]
Reactant: C#CCN1CCN(CC)CC1
Reactant: Nc1ccc(Oc2ccnc3cc(I)sc23)c(F)c1
Product: CCN1CCN(CC#Cc2cc3nccc(Oc4ccc(N)cc4F)c3s2)CC1
Temperature: 50 °C
Yield: 45 %

Procedure:
Prepared from 1-ethyl-4-(prop -2-ynyl)piperazine (59 mg, 0.39 mmol) and 3-fluoro-4-(2-iodothieno[3,2-b]pyridin-7-yloxy)benzenamine (Example 6, Step A; 100 mg, 0.26 mmol) according to the procedure described for Example 6, Step B, except the reaction was heated at 50° C. for 7 hours. The crude was purified by preparative TLC [5% MeOH (containing 7N NH3) in CH2Cl2]. The product was obtained as a waxy solid (48 mg, 40%). 1H NMR (400 MHz, CDCl3) δ 8.47 (d, J=6 Hz, 1H), 7.58 (s, 1H), 7.03 (t, J=9 Hz, 1H), 6.53 (m, 2H), 6.47 (m, 1H), 3.86 (br s, 2H), 3.60 (s, 2H), 2.45-2.74 (m, 8H), 2.46 (q, J=7 Hz, 2H), 1.11 (t, J=7 Hz, 3H).
Reaction SMILES: [Br:1][C:2]1([C:10]2[CH:29]=[CH:28][C:13]([CH2:14][N:15]3[C:19]4=[N:20][CH:21]=[CH:22][C:23]([CH3:24])=[C:18]4[N:17]=[C:16]3[S:25][CH2:26][CH3:27])=[CH:12][CH:11]=2)[CH2:6][C:5]([C:7]#[N:8])=[CH:4][N:3]1[CH3:9].C[Sn]([N:34]=[N+:35]=[N-:36])(C)C>C1(C)C(C)=CC=CC=1>[Br:1][C:2]1([C:10]2[CH:29]=[CH:28][C:13]([CH2:14][N:15]3[C:19]4=[N:20][CH:21]=[CH:22][C:23]([CH3:24])=[C:18]4[N:17]=[C:16]3[S:25][CH2:26][CH3:27])=[CH:12][CH:11]=2)[CH2:6][C:5]([C:7]2[NH:36][N:35]=[N:34][N:8]=2)=[CH:4][N:3]1[CH3:9]
Reactant: C[Sn](C)(C)N=[N+]=[N-]
Reactant: CCSc1nc2c(C)ccnc2n1Cc1ccc(C2(Br)CC(C#N)=CN2C)cc1
Solvent: Cc1ccccc1C
Product: CCSc1nc2c(C)ccnc2n1Cc1ccc(C2(Br)CC(c3nnn[nH]3)=CN2C)cc1
Reaction time: 36 h
Yield: 48.7 %

Procedure:
To a stirred solution of 3-[4-(2-bromo-4-cyano-1-methyl-2-pyrrolyl)benzyl]-2-ethylthio-7-methyl-3H-imidazo[4,5-b]pyridine (1.30 g) in xylene (15 ml) was added trimethyltin azide (1.72 g) at 125° C., stirred at the same temperature for 36 hours under nitrogen atmosphere, and the mixture was evaporated in vacuo. The residue was diluted with methanol and conc. hydrochloric acid (1 ml) was added therein. The mixture was stirred for 1 hour at ambient temperature. The mixture was concentrated in vacuo. The residue was diluted with methanol and adjusted to pH4 with aqueous 1N sodium hydroxide. The organic layer was separated, and evaporated in vacuo. The residue was purified by flash column chromatography on silica gel (elution by dichloromethane/methanol=15/1) and by preparative thin layer chromatography (elution by dichloromethane/methanol=8/1) to yield 3-[4-[2-bromo-1-methyl-4-(1H-tetrazol-5yl)-2-pyrrolyl]benzyl-2-ethylthio-7-methyl-3H-imidazo[4,5-b]pyridine (691 mg) as a colorless amorphous solid.