Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH:3]([CH:7]1[C:11]([Cl:12])=[C:10](Cl)C(=O)O1)[C:4]([NH2:6])=[O:5])#[N:2].Cl.[NH2:16][CH2:17][C:18]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=1[NH:25][C:26](=[O:29])[CH2:27][CH3:28].C(N(C(C)C)CC)(C)C>C(O)C>[ClH:12].[Cl:12][C:11]1[CH:7]=[C:3]([C:4]([NH2:6])=[O:5])[C:1](=[NH:2])[N:16]([CH2:17][C:18]2[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=2[NH:25][C:26](=[O:29])[CH2:27][CH3:28])[CH:10]=1
Reactant: N#CC(C(N)=O)C1OC(=O)C(Cl)=C1Cl
Reactant: CCC(=O)Nc1ccc(Cl)cc1CN
Agent: Cl
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CCC(=O)Nc1ccc(Cl)cc1Cn1cc(Cl)cc(C(N)=O)c1=N
Yield: 6.2 %

Procedure:
(Step 3) A solution of 2-cyano-2-(3,4-dichloro-5-oxo-2,5-dihydrofuran-2-yl)acetamide (1.88 g), N-[2-(aminomethyl)-4-chlorophenyl]propanamide hydrochloride obtained in Step 2 (1.99 g) and diisopropylethylamine (4.1 ml) in ethanol (15 ml) was stirred overnight at 70° C. The reaction solvent was evaporated under reduced pressure, the residue was dissolved in ethyl acetate and 1N sodium hydroxide, and the solution was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and filtered. The solvent was evaporated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate:hexane=7:3→1:0). The obtained residue was further purified by HPLC. The obtained residue was extracted with ethyl acetate and saturated sodium hydrogen carbonate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and filtered. The solvent was evaporated under reduced pressure. The residue was dissolved in ethanol, and 4N hydrogen chloride-ethyl acetate solution was added. The precipitated crystals were collected by filtration, and recrystallized from ethanol and ethyl acetate to give the title compound (100 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:15]([O:17]C)=[O:16])[C:7](=[CH:13][CH:14]=1)[CH2:8][C:9]([O:11][CH3:12])=[O:10])([O-:3])=[O:2].[H-].[Na+].[Br:21][C:22]1[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=1[CH:24]=O>C1COCC1>[Br:21][C:22]1[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=1[CH:24]=[C:8]([C:7]1[CH:13]=[CH:14][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][C:6]=1[C:15]([OH:17])=[O:16])[C:9]([O:11][CH3:12])=[O:10]
Reactant: COC(=O)Cc1ccc([N+](=O)[O-])cc1C(=O)OC
Reactant: O=Cc1ccccc1Br
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)C(=Cc1ccccc1Br)c1ccc([N+](=O)[O-])cc1C(=O)O
Temperature: 0 °C
Yield: 70.1 %

Procedure:
Dimethyl 4-nitrohomophthalate (Ghosh, C. K.; Mukherjee, K. K. J. Ind. Chem. Soc. 1976, 53, 662) (5 g, 0.02 tool) in THF (20 mL) was added to a suspension of sodium hydride (0.85 g of 60% disp., 0.021 mol) in THF (30 mL) with stirring at 0° C. under nitrogen. The resulting solution was stirred for 5-10 min and 2-bromobenzaldehyde (2.3 mL, 0.02 mol) was added in one portion. The cooling bath was removed after 10 min and the reaction was stirred at room temperature until the mixture solidified. The solid was dissolved in water and extracted with dichloromethane (2×). The aqueous phase was acidified and reextracted 3× with fresh portions of dichloromethane. The latter extracts were combined, washed with water and brine, dried over anhydrous magnesium sulfate, filtered, and evaporated. The residue crystallized on standing to give 5.62 g (70%) of off-white product: 1H NMR (300 MHz, CDCl3) δ 3.90 (3H, s), 6.66 (1H, d), 7.09 (1H, t), 7.16-7.23 (3H, m), 7.69 (1H, d), 7.86 (1H, s), 8.24 (1H, dd), 8.68 (1H, d); MS m/e 423-425 (M+NH4+).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:30]=[CH:29][C:6]([C:7]([NH:9][C:10]2[CH:15]=[C:14]([C:16]3[S:17][CH:18]=[CH:19][CH:20]=3)[CH:13]=[CH:12][C:11]=2[NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:8])=[CH:5][CH:4]=1.CCN(C(C)C)C(C)C.[Cl:40][CH2:41][O:42][C:43](Cl)=[O:44]>ClCCl>[C:24]([O:23][C:22]([NH:21][C:11]1[CH:12]=[CH:13][C:14]([C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)=[CH:15][C:10]=1[NH:9][C:7]([C:6]1[CH:29]=[CH:30][C:3]([CH2:2][NH:1][C:43](=[O:44])[O:42][CH2:41][Cl:40])=[CH:4][CH:5]=1)=[O:8])=[O:28])([CH3:25])([CH3:26])[CH3:27]
Reactant: O=C(Cl)OCCl
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2cccs2)cc1NC(=O)c1ccc(CN)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)Nc1ccc(-c2cccs2)cc1NC(=O)c1ccc(CNC(=O)OCCl)cc1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
tert-butyl [2-{[4-(aminomethyl)benzoyl]amino}-4-(2-thienyl)phenyl]carbamate (2.0 g, 4.72 mmol) was suspended in dichloromethane (50 ml). Hunig's Base (1 ml, 5.73 mmol) was added. The solution was cooled to 0° C. Chlorocarbonic acid chloromethyl ester (0.5 ml, 5.68 mmol) was added slowly. The reaction was stirred for approximately 1-2 h. The mixture, while cold, was diluted with dichloromethane and washed with saturated aqueous sodium bicarbonate. The aqueous layer was extracted three times with dichloromethane. The combined organic layers were dried over Na2SO4, filtered, and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with EtOAc/hexane. MS: calc'd 417 (MH+-Boc), exp 417 (MH+-Boc).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([Cl:9])[C:4]=1[I:10].[C-:11]#[N:12].[K+]>CCO.O>[Cl:9][C:5]1[C:4]([I:10])=[C:3]([CH2:2][C:11]#[N:12])[CH:8]=[CH:7][CH:6]=1
Reactant: [C-]#N
Reactant: Clc1cccc(CBr)c1I
Agent: [K+]
Solvent: CCO
Solvent: O
Product: N#CCc1cccc(Cl)c1I
Temperature: 25 °C
Yield: 54.9 %

Procedure:
A mixture of 1-(bromomethyl)-3-chloro-2-iodobenzene (7 g, 21 mmol) in 100 mL EtOH was treated with a solution of potassium cyanide (2 mL, 42 mmol) in 20 mL water. The mixture was refluxed for 2.5 hours. The mixture was cooled to room temperature and concentrated. The residue was diluted with 200 mL EtOAc, washed with water (2×50 mL), saturated NaCl (50 mL), dried over anhydrous sodium sulfate and concentrated. The crude product was purified by column chromatography (20% EtOAc/hexane) to give 3.2 g pale yellow solid. MS m/e: (M+H)+ 278.
Reaction SMILES: [Br:1][C:2]([Br:5])(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:25]([C:30]1[CH:31]=[N:32][C:33]([C:36]2[CH:43]=[CH:42][C:39]([CH:40]=O)=[CH:38][CH:37]=2)=[N:34][CH:35]=1)[CH2:26][CH2:27][CH2:28][CH3:29].CCCCCC>C(Cl)Cl>[Br:1][C:2]([Br:5])=[CH:40][C:39]1[CH:38]=[CH:37][C:36]([C:33]2[N:32]=[CH:31][C:30]([CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[CH:35][N:34]=2)=[CH:43][CH:42]=1
Reactant: CCCCCc1cnc(-c2ccc(C=O)cc2)nc1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCCCCC
Product: CCCCCc1cnc(-c2ccc(C=C(Br)Br)cc2)nc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 80.5 %

Procedure:
A solution of 5.44 g of tetrabromomethane in 80 ml of methylene chloride was placed at 0° C. under argon gasification in a sulphonation flask equipped with a mechanical stirrer and treated within 10 minutes with a solution of 8.6 g of triphenylphosphine in 20 ml of methylene chloride. After completion of the addition, the clear orange solution was stirred at 0° C. for a further 5 minutes and then a solution of 2.08 g of p-(5-pentyl-2-pyrimidinyl)benzaldehyde in 15 ml of methylene chloride was added dropwise within 5 minutes. The mixture was subsequently stirred at 0° C. for a further 30 minutes, then the flask content was poured into 700 ml of hexane and the precipitate which thereby separated was filtered off (rinsing with hexane). The concentrated filtrate was digested with 200 ml of hexane, left to stand at 0° C. for 18 hours, filtered (rinsing with hexane) and the filtrate was concentrated. Low-pressure chromatography (0.5 bar) of the residue (3.7 g) on silica gel with 3% ethyl acetate/petroleum ether gave 2.70 g (80%) of 2-[p-(2,2-dibromovinyl)phenyl]-5-pentylpyrimidine as colourless crystals (purity 94.5%); m.p. 74° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][C:13]([N:15]([CH2:24][CH:25](OC)OC)[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C(S(O)(=O)=O)=CC=CC=1>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]([N:11]1[CH:25]=[CH:24][N:15]([CH2:16][C:17]2[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=2)[C:13](=[O:14])[CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(CN(Cc1ccc(F)cc1)C(=O)CNC(=O)OCc1ccccc1)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: Cc1ccccc1
Solvent: O
Product: O=C1CN(C(=O)OCc2ccccc2)C=CN1Cc1ccc(F)cc1
Temperature: 25 °C

Procedure:
A solution of N2-benzyloxycarbonyl-N1-(2,2-dimethoxyethyl)-N1-(4-fluorobenzyl)glycinamide (61.5 g, 152 mmol) and p-toluenesulfonic acid monohydrate (3 g) in toluene (450 mL) was stirred at 75° C. for 5 days. Each day an additional 3 g of toluenesulfonic acid was added. The resultant reaction mixture was cooled to room temperature and filtered through a pad of Celite. The filtrate was concentrated under vacuum, and the residue dissolved in dichloromethane. The organic solution was washed successively with saturated aqueous sodium bicarbonate, brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residual solid was subjected to column chromatography on silica gel eluted first with dichloromethane and then 5% ethyl acetate in dichloromethane. Appropriate fractions were collected and concentrated under vacuum. Residual ethyl acetate and dichloromethane was removed by co-evaporation with toluene 3 times for subsequent hydrogenation. The residue was triturated with hexane, and filtered to provide the cyclization product as an off-white solid.
Reaction SMILES: [CH:1]1([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[N:21]([C:22]4[CH:30]=[CH:29][C:25]([CH2:26][CH2:27][NH2:28])=[CH:24][CH:23]=4)[C:16]4=[N:17][CH:18]=[CH:19][CH:20]=[C:15]4[N:14]=3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([Si]([O:48][C:49]1[CH:54]=[CH:53][C:52]([O:55][CH2:56][CH:57]2[CH2:59][O:58]2)=[CH:51][CH:50]=1)(C1C=CC=CC=1)C1C=CC=CC=1)(C)(C)C>C(Cl)(Cl)Cl.CO>[CH:1]1([C:7]2[CH:8]=[CH:9][C:10]([C:13]3[N:21]([C:22]4[CH:30]=[CH:29][C:25]([CH2:26][CH2:27][NH:28][CH2:59][C@H:57]([OH:58])[CH2:56][O:55][C:52]5[CH:53]=[CH:54][C:49]([OH:48])=[CH:50][CH:51]=5)=[CH:24][CH:23]=4)[C:16]4=[N:17][CH:18]=[CH:19][CH:20]=[C:15]4[N:14]=3)=[CH:11][CH:12]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: NCCc1ccc(-n2c(-c3ccc(C4CCCCC4)cc3)nc3cccnc32)cc1
Reactant: CC(C)(C)[Si](Oc1ccc(OCC2CO2)cc1)(c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: Oc1ccc(OC[C@@H](O)CNCCc2ccc(-n3c(-c4ccc(C5CCCCC5)cc4)nc4cccnc43)cc2)cc1
Yield: 42.6 %

Procedure:
4-[2-(4-Cyclohexylphenyl)-3H-imidazo[4,5-b]pyridin-3-yl]phenethylamine (0.37 g, 0.93 mmol) was reacted with tert-butyl-(4-oxiranylmethoxy-phenoxy)-diphenyl-silane (0.377 g, 0.93 mmol) according to Procedure G (eluant: 20:1 going to 5:1 chloroform-methanol) to give the title compound (0.317 g, 0.396 mmol).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]2[N:7]=[C:8]([SH:10])[NH:9][C:5]=2[CH:4]=1.[CH3:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20]Br)=[CH:16][CH:15]=1.C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]2[NH:7][C:8]([S:10][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)=[N:9][C:5]=2[CH:4]=1
Reactant: COc1ccc2nc(S)[nH]c2c1
Reactant: Cc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2[nH]c(SCc3ccc(C)cc3)nc2c1
Reaction time: 24 h

Procedure:
To a mixture of 5-methoxy-2-mercaptobenzimidazole (1.673 g, 9.285 mmol) and p-xylyl bromide (1.718 g, 9.285 mmol) in DMF (33.5 mL) at 0° C., Cs2CO3 (4.53 g, 13.93 mmol) was added and the suspension was stirred for 24 h while being allow to warm from 0° C. to rt. Distilled water (150 mL) was added with vigorous stirring. The murky white suspension turned into a clearer solution with white granules. After being stirred for 20 min at rt, the mixture was filtered and the residue was rinsed with water (3×20 mL) and hexanes (3×20 mL). The crude product was >95% pure by 1H NMR analysis and was not further purified. The yield was 2.437 g, 92%. 1H NMR (500 MHz, CDCl3): δ 2.25 (s, 3H), 3.76/3.78 (app d*, 3H), 4.38/4.42 (app d*, 2H), 6.74-7.17 (m, 6H), 7.52 (d, 1H, J=7.5 Hz), 8.87 (brs, 1H); 13C NMR (125 MHz, CDCl3): δ 21.30, 37.39, 37.63, 55.89, 55.96, 94.15, 101.18, 110.39, 111.10, 112.45, 119.07, 128.98, 129.58, 133.94, 156.61. *The apparent doublets may arise from the 1,3-proton shift between the nitrogen atoms in the heterocycle.
Reaction SMILES: Cl[C:2]1[N:30]=[CH:29][C:5]2[N:6]=[C:7]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH:19]4[CH2:24][CH2:23][N:22]([CH:25]5[CH2:28][CH2:27][CH2:26]5)[CH2:21][CH2:20]4)=[CH:14][CH:13]=3)[N:8]([CH3:11])[C:9](=[O:10])[C:4]=2[CH:3]=1.C(N(CC)CC)C.[H][H]>C(OCC)(=O)C.[C].[Pd]>[CH:25]1([N:22]2[CH2:21][CH2:20][CH:19]([O:18][C:15]3[CH:16]=[CH:17][C:12]([C:7]4[N:8]([CH3:11])[C:9](=[O:10])[C:4]5[CH:3]=[CH:2][N:30]=[CH:29][C:5]=5[N:6]=4)=[CH:13][CH:14]=3)[CH2:24][CH2:23]2)[CH2:26][CH2:27][CH2:28]1
Reactant: Cn1c(-c2ccc(OC3CCN(C4CCC4)CC3)cc2)nc2cnc(Cl)cc2c1=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Cn1c(-c2ccc(OC3CCN(C4CCC4)CC3)cc2)nc2cnccc2c1=O
Yield: 14.9 %

Procedure:
6-Chloro-2-{4-[(1-cyclobutylpiperidin-4-yl)oxy]phenyl}-3-methylpyrido[3,4-d]pyrimidin-4(3H)-one (40.8 mg, 0.096 mmol) produced in Example 30 and triethylamine (77 μL, 0.48 mmol) were dissolved in ethyl acetate (0.5 mL), and 10% palladium-carbon (10 mg) was added thereto and stirred in a hydrogen atmosphere at room temperature for 1 hour. The reaction solution was filtered through Celite, then the Celite was washed with ethyl acetate, and the mother liquid was concentrated. The residue was purified through silica gel thin-layer chromatography (chloroform/methanol=9/1) to obtain the entitled compound (5.6 mg, 15%) as a pale yellow solid. The resulting compound was recrystallized from ethanol-water to give a colorless solid (m.p. 147.0-148.0° C.).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C:13]([C:14](O)=[O:15])=[CH:12][N:11]([CH3:17])[C:10](=[O:18])[NH:9]2)=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:22])=O>CN(C=O)C.ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C:13]([C:14]([Cl:22])=[O:15])=[CH:12][N:11]([CH3:17])[C:10](=[O:18])[NH:9]2)=[CH:4][CH:3]=1
Reactant: CN1C=C(C(=O)O)[C@H](c2ccc(F)cc2)NC1=O
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CN1C=C(C(=O)Cl)[C@H](c2ccc(F)cc2)NC1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 10 mL dichloromethane and 1 drop of DMF was added 150 mg of (S)-4-(4-fluoro-phenyl)-1-methyl-2-oxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid. To this mixture was added 70 μl oxalyl chloride. When the bubbling stopped another drop of oxalyl chloride was added but as no bubbling was observed the solution was stirred at room temperature for 30 minutes after which the solvent was removed in vacuo to afford crude (S)-4-(4-fluoro-phenyl)-1-methyl-2-oxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid chloride (not shown in Scheme H). This acid chloride was taken up in propionitrile and added to a solution of 125 mg 5-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-4-chloro-2-methyl-phenylamine, 3 ml propionitrile, and 0.1 ml di-iso-propylethylamine. The solution was stirred at room temperature for 18 hours, then diluted with ethyl acetate and aqueous pH 2 buffer. The layers were separated and the organic layer dried over Na2SO4, filtered and the solvent removed in vacuo to give (S)-4-(4-fluoro-phenyl)-1-methyl-2-oxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid{5-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-4-chloro-2-methyl-phenyl}-amide, which was used directly in the next step without further purification.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.CSC.[CH3:12][C:13]([CH2:17][CH2:18][CH:19]=[C:20]([CH3:28])[CH2:21][CH2:22][CH:23]=[C:24]([CH3:27])[CH2:25][CH3:26])=[CH:14]CO>ClCCl>[Cl:1][CH2:26][CH:25]=[C:24]([CH3:27])[CH2:23][CH2:22][CH:21]=[C:20]([CH3:28])[CH2:19][CH2:18][CH:17]=[C:13]([CH3:14])[CH3:12]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCC(C)=CCCC(C)=CCCC(C)=CCO
Solvent: CSC
Solvent: ClCCl
Product: CC(C)=CCCC(C)=CCCC(C)=CCCl
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 84.8 %

Procedure:
(Note all temperatures indicated are for the contents of the reaction flask) To a stirred solution of 299 mg (2.24 mmol) of N-chlorosuccinimide in 15 mL of dichloromethane at -30° C. under argon was added 0.18 mL (2.45 mmol) of distilled dimethyl sulfide over 5 minutes. After 10 minutes at -30° C., the reaction was allowed to warm to 0° C. for 10 minutes, followed by cooling to -40° C. A solution of 441.4 mg (1.99 mmol) of 3,7,11-trimethyl-2,6,10-tridecatrien-1-ol in 5 mL of dichloromethane was added dropwise over 10 minutes. The reaction was allowed to warm gradually to 0° C. over 1 hour, and then maintained at 0° C. for 1 hour. After quenching with cold water, the mixture was extracted with hexane and the hexane extract was washed with cold water and cold brine, dried (MgSO4) and evaporated to afford 483 mg of a crude product. Rapid flash chromatography on 20 g of Merck 9385 silica gel eluted with 3:97 ethyl acetate:petroleum ether provided 406.5 mg (85%) of a colorless liquid. 13C NMR indicated that this material contained a trace (3%) impurity.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7](Cl)=[O:8])=[CH:4][CH:3]=1.[CH3:10][N:11]([CH3:29])[CH:12]1[CH2:16][CH2:15][N:14]([C:17]2[C:25]3[S:24][C:23]([NH2:26])=[N:22][C:21]=3[C:20]([O:27][CH3:28])=[CH:19][CH:18]=2)[CH2:13]1>>[CH3:10][N:11]([CH3:29])[CH:12]1[CH2:16][CH2:15][N:14]([C:17]2[C:25]3[S:24][C:23]([NH:26][C:7]([C:5]4[S:6][C:2]([CH3:1])=[CH:3][CH:4]=4)=[O:8])=[N:22][C:21]=3[C:20]([O:27][CH3:28])=[CH:19][CH:18]=2)[CH2:13]1
Reactant: COc1ccc(N2CCC(N(C)C)C2)c2sc(N)nc12
Reactant: Cc1ccc(C(=O)Cl)s1
Product: COc1ccc(N2CCC(N(C)C)C2)c2sc(NC(=O)c3ccc(C)s3)nc12

Procedure:
Using 5-methyl-thiophene-2-carbonyl chloride and 7-(3-dimethylamino-pyrrolidin-1-yl)-4-methoxy-benzothiazol-2-yl-amine the title compound was prepared using the general method of example 1 as yellow solid (90%), MS: m/e=417 (M+H+).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][OH:9].[H][H]>>[NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][CH2:8][OH:9]
Reactant: [H][H]
Reactant: OCCc1ccccn1
Product: OCCC1CCCCN1

Procedure:
Low pressure hydrogenations were carried out by charging 250 mL of solvent, 246 g of 2-pyridineethanol, and catalyst into a pressure vessel capable of agitation, agitating the resulting mixture and pressurizing the vessel and its contents to 500 psi with hydrogen. Under constant hydrogen pressure and continued agitation, the reaction mixture was heated to 150° C. until hydrogen uptake ceased. The pressure vessel and its contents were cooled, vented and the catalyst removed with vacuum filtration. Upon distillation of the filtrate, 2-piperidineethanol was obtained and analyzed on two separate gc columns (6′ CW 20M 160° C. and 15M DB-1 80° C.→220° C.@ 16° C./m capillary column) to provide product yield and composition of the distillate. The results are provided in Table I.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:14]=[CH:13][C:7]([C:8]([O:10]CC)=O)=[CH:6][CH:5]=1)[CH3:2].[O-]CC.[Na+].[C:19](#[N:21])[CH3:20]>C1(C)C=CC=CC=1.O>[CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7]([C:8]([CH2:20][C:19]#[N:21])=[O:10])=[CH:13][CH:14]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(OCC)cc1
Reactant: CC#N
Agent: CC[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CCOc1ccc(C(=O)CC#N)cc1
Reaction time: 26 h
Yield: 45 %

Procedure:
Ethyl 4-ethoxybenzoate (45.3 mL, 250 mmole) was added to a suspension of sodium ethoxide (17.0 g, 250 mmole) and acetonitrile (16 mL, 300 mmole) in dry toluene (100 mL) and the mixture was mechanically stirred at 106°-110° for 26 hours. The reaction was then cooled and diluted with water (400 mL). After most of the solid had dissolved, the solution was washed with ethyl ether (2×200 mL) and then acidified with concentrated HCl (approximately 20 mL) to pH of about 5. The copious off-white precipitate was collected by suction filtration and air dried. Crystallization from 95% ethanol (350 mL) provided 21.3 g. of the subtitled compound as white needles, sufficiently pure for further transformation (yield: 45%). 1H NMR (CDCl3, δ) 7.85 (d, 2H, J=8 Hz, o-phenyl), 6.95 (d, 2H, J=8 Hz, m-phenyl), 4.1 (q, 2H, J= 7 Hz, OCH2), 4.0 (s, 2H, CH2CN), 1.45 (t, 3H, CH3).
Reaction SMILES: [N+:1]([C:4]1[NH:8][C:7](C(OC)=O)=[CH:6][C:5]=1C1C2C(=CC=CC=2)N=CC=1)([O-])=O.CO.CO[C:27]1[CH:32]=CC(C(C=O)C=O)=C[CH:28]=1>[Pd].CC(O)=O>[N:1]1[C:4]2[N:8]([CH:7]=[CH:6][CH:5]=2)[CH:28]=[CH:27][CH:32]=1
Reactant: COc1ccc(C(C=O)C=O)cc1
Reactant: COC(=O)c1cc(-c2ccnc3ccccc23)c([N+](=O)[O-])[nH]1
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: c1cnc2cccn2c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 253.9 %

Procedure:
A mixture of methyl 5-nitro-4-quinolin-4-yl-1H-pyrrole-2-carboxylate (23, 90 mg, 0.3 mmol), Pd/C (5%, 45 mg), and MeOH (15 mL) was stirred under argon for 5 min, then under hydrogen for 40 min before removal of the catalyst by filtration through celite. To the orange color filtrate was added 2-(4-methoxyphenyl)malondialdehyde (54 mg, 0.3 mmol) followed by AcOH (2 mL). The resulting reaction mixture was stirred overnight at 82° C., then cooled to rt, quenched with sat. NaHCO3, and extracted with ethyl acetate and CH2Cl2. The combined organic layers were dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography on silica gel using CH2Cl2/MeOH (90:10) to give 25 as a yellow solid (90 mg, 73%). 1H NMR (DMSO-d6, 500 MHz) δ 9.80 (d, J=3.0 Hz, 1H), 8.97 (d, J=5.0 Hz, 1H), 8.87 (d, J=3.0 Hz, 1H), 8.10 (m, 1H), 8.04 (s, 1H), 7.80 (m, 1H), 7.75 (d, J=5.0 Hz, 1H), 7.75 (d, J=8.5 Hz, 2H), 7.61 (m, 1H), 7.15 (d, J=8.5 Hz, 2H), 3.94 (s, 3H), 3.84 (s, 3H); nip 230-231° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]([O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])=[O:15])=[CH:4][CH:3]=1.[Br:23]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:23][CH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]([O:16][CH2:17][CH2:18][Si:19]([CH3:21])([CH3:20])[CH3:22])=[O:15])=[CH:6][CH:7]=1
Reactant: Cc1ccc(-c2ccccc2C(=O)OCC[Si](C)(C)C)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: C[Si](C)(C)CCOC(=O)c1ccccc1-c1ccc(CBr)cc1

Procedure:
312 mg of 4-methyl-2'-(trimethylsilylethoxycarbonyl)biphenyl, 178 mg of N-bromosuccinimide, 5 mg of azoisobutyronitrile and 15 ml of carbon tetrachloride are heated to reflux for one hour. After cooling, the mixture is evaporated. Flash chromatography (ethyl acetate/hexane 95:5) yields 4-bromomethyl-2'-(trimethylsilylethoxycarbonyl)biphenyl as a slightly yellowish oil. 1H-NMR (CFCl3): 0 ppm (s, 9 H), 0.7 ppm (t, 2 H), 4.5 ppm (s, 2 H), 7.1-8 ppm aromatics.
Reaction SMILES: [SH:1][C:2]1[S:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[CH:8]=2)[N:3]=1.[O-]Cl.[Na+].[OH-].[NH4+:18]>[OH-].[Na+].O>[Cl:13][C:9]1[CH:8]=[C:7]([C:4]2[N:3]=[C:2]([S:1][NH2:18])[S:6][N:5]=2)[CH:12]=[CH:11][CH:10]=1
Reactant: [NH4+]
Reactant: Sc1nc(-c2cccc(Cl)c2)ns1
Agent: [Na+]
Agent: [O-]Cl
Agent: [OH-]
Solvent: O
Product: NSc1nc(-c2cccc(Cl)c2)ns1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 41 g of 5-mercapto-3-(3-chlorophenyl)-1,2,4-thiadiazole in 602 ml of 5% sodium hydroxide and a solution prepared by diluting 378 ml of 5.25% NaOCl to 602 ml with water were added dropwise simultaneously to 1634 ml of ammonium hydroxide solution while maintaining the mixture at 0° C. with a salt/ice bath. The resulting mixture was stirred for 30 minutes and the solids were collected, washed with water and dried under vacuum (with P2O5) to give 5.4 g of solid, m.p.>150° dec.