Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([Br:8])[C:6]=1[Br:7].C([Li])CCC.CN([CH:17]=[O:18])C>C(OCC)C>[Br:7][C:6]1[C:5]([Br:8])=[CH:4][S:3][C:2]=1[CH:17]=[O:18]
Reactant: CN(C)C=O
Reactant: Brc1csc(Br)c1Br
Agent: [Li]CCCC
Solvent: CCOCC
Product: O=Cc1scc(Br)c1Br
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 50.9 %

Procedure:
A solution of 2,3,4-tribromothiophene (2.56 g, 0.0080 mol) in 20 mL of diethyl ether was cooled to -78° C. and then n-butyllithium (5.0 mL, 1.6M) in hexanes was added slowly from an addition funnel. When the addition was complete, the reaction mixture was stirred for 15 minutes. Then DMF (0.88 g, 1.2 mol) was added in one portion. The reaction mixture was gradually warmed to room temperature and was left to stir overnight. The reaction was quenched with aqueous ammonium chloride solution and extracted twice with diethyl ether. The organic extracts were combined, washed with two small portions of water and then brine and dried (MgSO4). The solution was filtered and concentrated, and the residue was purified on flash silica gel with 2.5% diethyl ether-hexanes to provide 1.1 g of 3,4-dibromothiophene-2-carboxaldehyde as an off-white solid. The above sequence was repeated as above except that the n-butyllithium was cooled to -78° C. and then was added to the thiophene solution by cannulation. The reaction mixture was stirred for 2 h before DMF was added. The reaction was worked up as before and the crude product was recrystallized from ether to give 0.9 g of product. A third preparation was also done. A solution of 2,3,4-tribromothiophene (4.8 g, 0.015 mol) in 20 mL of diethyl ether was cooled to -78° C. and then n-butyllithium (10.0 mL, 1.6M) was added slowly from an addition funnel. When the addition was complete, the reaction mixture was stirred for 15 minutes. Then DMF (1.82 g, 0.025 mol) was added in one portion. The reaction mixture was gradually warmed to room temperature, and was left to stir overnight. The reaction was quenched with aqueous ammonium chloride solution and extracted twice with diethyl ether. The organic extracts were combined, washed with two small portions of water and then brine and dried (MgSO4). The solution was filtered and concentrated, and the residue was purified on flash silica gel with 2.5% diethyl ether-hexanes. The product was combined with the previous batches of 3,4-dibromothiophene-2-carboxaldehyde and recrystallized from diethylether to give 3.7 g of 3,4-dibromothiophene-2-carboxaldehyde, A8, whose NMR in CDCl3 supported the desired product structure. ##STR48##
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:30]=[CH:31][C:32]=1[CH3:33])[CH2:5][O:6][C:7]([C:9]1[CH:10]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[N+:27]([O-:29])=[O:28])[C:11]([C:17]([O:19]C)=O)=C(C)[NH:13][C:14]=1[CH3:15])=[O:8]>C(O)C>[CH3:5][O:6][C:7]([CH2:9][C:17](/[CH:11]=[CH:10]/[C:21]1[C:22]([N+:27]([O-:29])=[O:28])=[CH:23][CH:24]=[CH:25][CH:26]=1)=[O:19])=[O:8].[Cl:1][C:2]1[CH:3]=[C:4]([CH:30]=[CH:31][C:32]=1[CH3:33])[CH2:5][O:6][C:7](=[O:8])/[CH:9]=[C:14](\[NH2:13])/[CH3:15]
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OCc2ccc(C)c(Cl)c2)C1c1ccccc1[N+](=O)[O-]
Solvent: CCO
Product: C/C(N)=C/C(=O)OCc1ccc(C)c(Cl)c1
Product: COC(=O)CC(=O)/C=C/c1ccccc1[N+](=O)[O-]

Procedure:
Analogously to Example 1 heating a solution of 75 mmols of 2'-nitrobenzylideneacetoacetic acid methyl ester and 75 mmols of β-aminocrotonic acid 3-chloro-4-methylbenzyl ester in 120 ml of ethanol gave 2,6-dimethyl-3-methoxycarbonyl-4-(2'-nitrophenyl)-1,4-dihydropyridine-5-carboxylic acid 3-chloro-4-methylbenzyl ester of melting point 132° C (from ethanol).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[C:8]([CH2:10][C:11]([NH:13][CH:14]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[N:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[CH2:15][CH2:16][CH3:17])=[O:12])[CH:7]=[CH:6][C:5]=1[CH2:30][CH2:31][C:32]([O:34]CC)=[O:33])[CH3:2]>C(Cl)(Cl)Cl.CO>[CH2:1]([O:3][C:4]1[CH:9]=[C:8]([CH2:10][C:11]([NH:13][CH:14]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[N:24]2[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]2)[CH2:15][CH2:16][CH3:17])=[O:12])[CH:7]=[CH:6][C:5]=1[CH2:30][CH2:31][C:32]([OH:34])=[O:33])[CH3:2]
Reactant: CCCC(NC(=O)Cc1ccc(CCC(=O)OCC)c(OCC)c1)c1ccccc1N1CCCCC1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CCCC(NC(=O)Cc1ccc(CCC(=O)O)c(OCC)c1)c1ccccc1N1CCCCC1

Procedure:
Prepared analogously to Example 33 by alkaline saponification of ethyl 3-[2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-phenyl]-propionate and subsequent purification by column chromatography (chloroform/methanol=9/1).
Reaction SMILES: [CH3:1][N:2]([C:10]1[CH:18]=[C:17]2[C:13]([C:14]([CH:27]=[CH:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[N:15][N:16]2COCC[Si](C)(C)C)=[CH:12][CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([NH2:9])[CH:4]=1.N1C=CC=CC=1.[CH3:41][C:42](OC(C)=O)=[O:43].C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl.CN(C1C=CN=CC=1)C.CCOC(C)=O.C(Cl)Cl.CCOC(C)=O>[CH3:1][N:2]([C:10]1[CH:18]=[C:17]2[C:13]([C:14]([CH:27]=[CH:28][C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)=[N:15][NH:16]2)=[CH:12][CH:11]=1)[C:3]1[CH:4]=[C:5]([NH:9][C:42](=[O:43])[CH3:41])[CH:6]=[CH:7][CH:8]=1
Reactant: CN(c1cccc(N)c1)c1ccc2c(C=Cc3ccccc3)nn(COCC[Si](C)(C)C)c2c1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(=O)Nc1cccc(N(C)c2ccc3c(C=Cc4ccccc4)n[nH]c3c2)c1
Temperature: 23 °C
Reaction time: 1 h
Yield: 22 %

Procedure:
N-Methyl-N-{3-styryl-1-[2-(trimethyl-silanyl)-ethoxymethyl]-1H-indazol-6-yl}-benzene-1,3-diamine, prepared in Example 11 (34 mg, 0.041 mmol) was suspended in CH2Cl2 (0.5 mL) at 23° C. under an atmosphere of argon. Pyridine (81 μl, 1.0 mmol), Ac2O (94 μl, 1.0 mmol) and DMAP (cat.) were added. The reaction became homogeneous immediately. After 1 h, TLC analysis (CH2Cl2:EtOAc 4:1) indicated no starting material. The reaction was quenched with saturated NaHCO3(aq) (2 mL) then diluted with EtOAc (15 mL) and the organic phase was washed with brine (3 mL), decanted and concentrated under reduced pressure to an oil. The oil was suspended in MeOH (2 mL) and K2CO3 (83 mg, 0.6 mmol) was added. The resulting mixture was stirred at 23° C. under an atmosphere of argon. After 1 h, the reaction was diluted with EtOAc (15 mL) and the organic phase was washed with brine (3 mL), decanted and concentrated under reduced pressure. The crude material was purified by semi-prep HPLC to give N-{3-[methyl-(3-styryl-1H-indazol-6-yl)-amino]-phenyl}-acetamide (8.4 mg, 22%). 1H NMR (300 MHz, CDCl3) δ 7.86 (d, 1H, J=8.68 Hz), 7.58 (d, 1H, J=7.17 Hz), 7.16–7.45 (m, 7H), 7.15 (d, 1H, J=8.29 Hz), 6.98 (m, 1H), 6.95 (d, 1H, J=1.92 Hz), 6.8 (dd, 1H, J=1.16, 8.05 Hz), 3.37 (s, 3H), 2.14 (s, 3H). LCMS (ESI) [M+H]/z Calc'd 383. Found 383. Anal. Calc'd: C, 75.37; H, 5.80; N, 14.65. Found: C, 73.53; H, 6.01; N, 13.73.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:14]([OH:16])=O)[CH2:3][C:4](=[O:13])[O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.O[N:25]1[C:29]2C=CC=[CH:33][C:28]=2N=N1.[NH:34]1[CH2:55][CH2:54][CH2:53][C@H:35]1[C:36]([NH:38][C@H:39]([C:50]([OH:52])=[O:51])[C@@H:40]([CH3:49])[O:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)=[O:37].[ClH:56].C([NH-])CC.C(N(C(C)C)CC)(C)C.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl.Cl.O1CCOCC1>[NH2:1][C@H:2]([C:14]([N:34]1[CH2:55][CH2:54][CH2:53][C@H:35]1[C:36]([NH:38][C@H:39]([C:50]([OH:52])=[O:51])[C@@H:40]([CH3:49])[O:41][CH2:42][C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1)=[O:37])=[O:16])[CH2:3][C:4](=[O:13])[O:5][CH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1.[ClH:56].[CH2:29]([NH-:25])[CH2:28][CH3:33]
Reactant: C[C@@H](OCc1ccccc1)[C@H](NC(=O)[C@@H]1CCCN1)C(=O)O
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)OCc1ccccc1)C(=O)O
Reactant: On1nnc2ccccc21
Agent: CCC[NH-]
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: C[C@@H](OCc1ccccc1)[C@H](NC(=O)[C@@H]1CCCN1C(=O)[C@@H](N)CC(=O)OCc1ccccc1)C(=O)O
Temperature: 0 °C
Reaction time: 5 h

Procedure:
Commercially available Boc-L-Asp(OBn)-OH (1 g) was mixed with 1-hydroxybenzotriazole (500 mg), the title compound from Step 1 (1 g) and diisopropylethylamine (736 mg) in methylene chloride (20 mL), and the solution was cooled to 0° C. To this was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (710 mg) in one portion. After allowing the reaction mixture to stir at 0° C. for 5 hours, the organic solution was washed sequentially with water, 1 N hydrochloric acid, 5% sodium bicarbonate, then dried (magnesium sulfate), filtered and evaporated to obtain an oily residue. This residue was taken up in 4 M hydrogen chloride in dioxane solution (50 mL) and allowed to stand at room temperature for 30 minutes. The solvent was then evaporated and the product triturated with ether. The resulting white solid was collected a filter plate to yield the title compound. 1H NMR (400 MHz): consistent with proposed structure.
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][C:12]([O:17][CH3:18])=[C:11]([O:19][CH3:20])[CH:10]=2)([O:3][CH2:4][CH3:5])=[O:2].[Br:21][C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][CH:28]=1)[NH2:25].N1C=CC=CC=1>C(O)C>[Br:21][C:22]1[CH:23]=[C:24]([NH:25][C:15]2[C:14]3[C:9](=[CH:10][C:11]([O:19][CH3:20])=[C:12]([O:17][CH3:18])[CH:13]=3)[N:8]=[CH:7][C:6]=2[C:1]([O:3][CH2:4][CH3:5])=[O:2])[CH:26]=[CH:27][CH:28]=1
Reactant: CCOC(=O)c1cnc2cc(OC)c(OC)cc2c1Cl
Reactant: Nc1cccc(Br)c1
Solvent: CCO
Solvent: c1ccncc1
Product: CCOC(=O)c1cnc2cc(OC)c(OC)cc2c1Nc1cccc(Br)c1

Procedure:
A mixture of 14.8 g of 3-carbethoxy-4-chloro-6,7-dimethoxylquinoline, 9.46 g of 3-bromoaniline, 4.05 ml of pyridine, and 150 ml of ethanol was refluxed for 30 min, evaporated to remove ethanol, and partitioned with dichloromethane-aq sodium bicarbonate. The organic layer was washed with water, dried, and concentrated. The residue was recrystallized from ethanol to give a white solid, mp 155-158° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][CH2:10][CH2:11][O:12][CH3:13])[NH2:5].N1C=CC=CC=1.Cl[C:21]([O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:22]>CC(C)=O>[F:1][C:2]1[CH:3]=[C:4]([NH:5][C:21](=[O:22])[O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][CH2:11][O:12][CH3:13]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: COCCOc1ccc(N)cc1F
Solvent: c1ccncc1
Solvent: CC(C)=O
Product: COCCOc1ccc(NC(=O)Oc2ccccc2)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.9 %

Procedure:
To a stirred solution of 3-fluoro-4-(2-methoxyethoxy)aniline (2.0 g, 10.8 mmol, 1.0 eq) in acetone (50 mL) was added pyridine (2.5 mL, 32.4 mol, 3.0 eq.) and phenyl chloroformate (1.36 mL, 10.8 mmol, 1.0 eq.) at 0° C. and stirred at RT for 1 h. The solvent was evaporated, the residue diluted with EtOAc (50 mL), washed with water (100 mL), brine (20 mL) and evaporated again. The resulting residue was purified by column chromatography using EtOAc/PE (1:4) as eluent to yield phenyl 3-fluoro-4-(2-methoxyethoxy)phenylcarbamate (2.7 g, 76.8%) as a white solid (TLC system: EtOAc/PE (3:7), Rf: 0.5).
Reaction SMILES: [F:1][C:2]1[C:7](I)=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:9][Si:10]([C:13]#[CH:14])([CH3:12])[CH3:11]>C1COCC1.C(N(CC)CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:1][C:2]1[C:7]([C:14]#[C:13][Si:10]([CH3:12])([CH3:11])[CH3:9])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: C#C[Si](C)(C)C
Reactant: Fc1ncccc1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1cccnc1F
Reaction time: 4 h
Yield: 94.6 %

Procedure:
A mixture of 2-fluoro-3-iodopyridine (5 g), trimethylsilylacetylene (2.86 g) copper(I) iodide (0.015 g) and bis(triphenylphosphine)palladium dichloride (0.06 g) in a mixture of THF (20 mL) and triethylamine (30 mL) was stirred under argon for 4 hours. The solvents were evaporated and the residue was taken up in water/ethyl acetate. The organic phase was separated, dried and evaporated. Distillation of the residue gave 2-fluoro-3-(trimethylsilylethynyl)pyridine as an oil (4.10 g).
Reaction SMILES: ClC1C(OCC#C)=CC(N2C(C#N)=C(C#N)N(CCC)C2=O)=C(F)C=1.[Cl:26][C:27]1[C:32]([N+:33]([O-])=O)=[CH:31][C:30]([N:36]2[C:40]([C:41]#[N:42])=[C:39]([C:43]#[N:44])[N:38]([CH:45]([F:47])[F:46])[C:37]2=[O:48])=[C:29]([F:49])[CH:28]=1.C(N(CC)CC)C.[CH3:57][S:58](Cl)(=[O:60])=[O:59].Cl>ClCCl>[Cl:26][C:27]1[C:32]([N:33]([S:58]([CH3:57])(=[O:60])=[O:59])[S:58]([CH3:57])(=[O:60])=[O:59])=[CH:31][C:30]([N:36]2[C:40]([C:41]#[N:42])=[C:39]([C:43]#[N:44])[N:38]([CH:45]([F:47])[F:46])[C:37]2=[O:48])=[C:29]([F:49])[CH:28]=1
Reactant: N#Cc1c(C#N)n(C(F)F)c(=O)n1-c1cc([N+](=O)[O-])c(Cl)cc1F
Reactant: CS(=O)(=O)Cl
Agent: C#CCOc1cc(-n2c(C#N)c(C#N)n(CCC)c2=O)c(F)cc1Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N(c1cc(-n2c(C#N)c(C#N)n(C(F)F)c2=O)c(F)cc1Cl)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 98.4 %

Procedure:
The product of Example 77, 1-(4-chloro-2-fluoro-5-nitrophenyl)-4,5-dicyano-3-difluoromethyl-1,3-dihydro-2H-imidazol-2-one, (0.7 g, 2.1 mmol) was dissolved in dichloromethane and treated sequentially at 0° C. with triethylamine (0.56 g, 5.5 mmol) and methanesulphonyl chloride (0.56 g, 5 mmol). The solution was allowed to stir 16 hours at ambient temperature, then poured onto 10 mL of 1N hydrochloric acid solution. The organic layer was separated, washed with brine, and dried and concentrated via standard techniques to furnish 1 g of 1-(4-chloro-2-fluoro-5-bis(methanesulphonyl) amino-phenyl)-4,5-dicyano-3-difluoromethyl-1,3 -dihydro-2H-imidazol-2-one (VI) (M.S. M+ 483).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:10][C:11]1[C:16]2[CH2:17][CH2:18][O:19][C:15]=2[C:14]([C:20]([NH:22][C@H:23]2[CH2:28][CH2:27][N:26]([CH2:29][CH2:30][CH2:31][CH2:32][NH2:33])[CH2:25][C@H:24]2[O:34][CH3:35])=[O:21])=[CH:13][C:12]=1[Cl:36].C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[OH2:19].[NH2:10][C:11]1[C:16]2[CH2:17][CH2:18][O:19][C:15]=2[C:14]([C:20]([NH:22][C@H:23]2[CH2:28][CH2:27][N:26]([CH2:29][CH2:30][CH2:31][CH2:32][NH:33][C:2]3[C:7]([C:8]#[N:9])=[CH:6][CH:5]=[CH:4][N:3]=3)[CH2:25][C@H:24]2[O:34][CH3:35])=[O:21])=[CH:13][C:12]=1[Cl:36].[NH2:10][C:11]1[C:16]2[CH2:17][CH2:18][O:19][C:15]=2[C:14]([C:20]([NH:22][C@H:23]2[CH2:28][CH2:27][N:26]([CH2:29][CH2:30][CH2:31][CH2:32][NH:33][C:2]3[C:7]([C:8]#[N:9])=[CH:6][CH:5]=[CH:4][N:3]=3)[CH2:25][C@H:24]2[O:34][CH3:35])=[O:21])=[CH:13][C:12]=1[Cl:36]
Reactant: CO[C@@H]1CN(CCCCN)CC[C@@H]1NC(=O)c1cc(Cl)c(N)c2c1OCC2
Reactant: N#Cc1cccnc1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CO[C@@H]1CN(CCCCNc2ncccc2C#N)CC[C@@H]1NC(=O)c1cc(Cl)c(N)c2c1OCC2
Product: O
Temperature: 70 °C
Reaction time: 20 h
Yield: 35.4 %

Procedure:
A mixture of 1.4 parts of 2-chloro-3-pyridinecarbonitrile, 3.2 parts of cis-4-amino-N-[1-(4-aminobutyl)-3-methoxy -4-piperidinyl]-5-chloro-2,3-dihydro-7-benzofurancarboxamide, 65.8 parts of N,N-dimethylformamide and 1.3 parts of sodium carbonate was stirred for 20 hours at 70° C. The solvent was evaporated and the residue was dissolved in trichloromethane. The organic layer was washed with water, dried, filtered and evaporated. The residue was purified by column chromatography (silica gel; CHCl3 /CH3OH(NH3)98:2). The eluent of the desired fraction was evaporated and the residue was crystallized from 2,2'-oxybispropane. The product was dried in vacuo at 60° C., yielding 1.44 parts (35.4%) of cis-4-amino-5-chloro-N-[1-[4-[(3-cyano-2-pyridinyl)-amino]butyl]-3-methoxy-4-piperidinyl]-2,3-dihydro-7-benzofurancarboxamide hemihydrate; mp. 129.7° C. (comp. 6).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)[N:5]=[CH:4][N:3]=1.O.[NH2:16][NH2:17]>>[CH3:14][N:11]1[CH2:12][CH2:13][N:8]([C:6]2[N:5]=[CH:4][N:3]=[C:2]([NH:16][NH2:17])[CH:7]=2)[CH2:9][CH2:10]1
Reactant: CN1CCN(c2cc(Cl)ncn2)CC1
Reactant: NN
Solvent: O
Product: CN1CCN(c2cc(NN)ncn2)CC1

Procedure:
4-Chloro-6-(4-methyl-piperazin-1-yl)-pyrimidine, (200 mg, 0.94 mmol), and hydrazine hydrate, (200 μl, 4 mmol), were heated to 180° for 6 min in a Personal Chemistry Microwave. The solvent was evaporated affording [6-(4-Methyl-piperazin-1-yl)-pyrimidin-4-yl]-hydrazine as yellow brown crystals which were used without further purification.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[SH:6].[C:7]1(=[O:13])[O:12][CH2:11][CH2:10][CH2:9][CH2:8]1>>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6][CH2:11][CH2:10][CH2:9][CH2:8][C:7]([OH:13])=[O:12]
Reactant: Sc1cccs1
Reactant: O=C1CCCCO1
Product: O=C(O)CCCCSc1cccs1

Procedure:
Method in which thiophene-2-thiol is reacted with δ-valerolactone to obtain 5-(2-thienylsulfanyl)valeric acid represented by Chemical Formula [4].
Reaction SMILES: CN(C=O)C.[F:6][C:7]1[CH:8]=[C:9]([CH:13]=[C:14]([F:17])[C:15]=1[F:16])[C:10]([OH:12])=[O:11].[CH2:18](Br)[C:19]#[CH:20].C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C>[F:6][C:7]1[CH:8]=[C:9]([CH:13]=[C:14]([F:17])[C:15]=1[F:16])[C:10]([O:12][CH2:20][C:19]#[CH:18])=[O:11]
Reactant: O=C(O)c1cc(F)c(F)c(F)c1
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C#CCOC(=O)c1cc(F)c(F)c(F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.7 %

Procedure:
To 50 ml of DMF were added 5.0 g of 3,4,5-trifluorobenzoic acid, 4.0 g of propargyl bromide and 4.7 g of potassium carbonate and the mixture obtained was stirred at room temperature for 30 minutes and then heated with stirring at 80° C. for 1 hour. Then, ethyl acetate was added to the reaction mixture and the mixture was filtered through Celite. Water and dilute hydrochloric acid were added to the filtrate in order and it was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure to obtain 6.0 g of 2-propynyl 3,4,5-trifluorobenzoate represented by the formula:
Reaction SMILES: Cl[C:2]1[N:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH3:11][NH:12][NH2:13].O>C1COCC1>[Cl:10][C:8]1[CH:7]=[CH:6][C:3]2[C:2](=[N:13][N:12]([CH3:11])[CH:4]=2)[N:9]=1
Reactant: O=Cc1ccc(Cl)nc1Cl
Reactant: CNN
Solvent: C1CCOC1
Solvent: O
Product: Cn1cc2ccc(Cl)nc2n1
Temperature: 120 °C
Reaction time: 16 h
Yield: 66.5 %

Procedure:
To a solution of 2,6-dichloronicotinaldehyde (600 mg, 3.41 mmol) in THF (5 mL) was added CH3NHNH2 (480 mg, 4.1 mmol) in a seal tube at 26° C. The mixture was stirred for 16 h at 120° C. until the reaction was complete. The mixture was then treated with water (20 ml) and extracted with ethyl acetate (3×20 ml) and the combined organic layers washed with brine (20 ml), dried over Na2SO4 and concentrated to get the crude material, which was purified by column chromatography to yield the desired compound as a yellow solid (380 mg, 72.4%) (420 mg, Yield 75%).
Reaction SMILES: [CH2:1]1[O:9][C:8]2[C:3](=[CH:4][C:5]([C:15](=O)[C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-:24])=[O:23])[CH:17]=3)=[C:6]([CH2:10][C:11](OC)=[O:12])[CH:7]=2)[O:2]1.O.[NH2:27][NH2:28].C(O)C>C(O)(=O)C>[CH2:1]1[O:2][C:3]2=[CH:4][C:5]3[C:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-:24])=[O:23])[CH:17]=4)=[N:28][NH:27][C:11](=[O:12])[CH2:10][C:6]=3[CH:7]=[C:8]2[O:9]1
Reactant: NN
Reactant: COC(=O)Cc1cc2c(cc1C(=O)c1cccc([N+](=O)[O-])c1)OCO2
Solvent: CCO
Solvent: O
Solvent: CC(=O)O
Product: O=C1Cc2cc3c(cc2C(c2cccc([N+](=O)[O-])c2)=NN1)OCO3

Procedure:
The title compound was prepared from methyl 4,5-methylenedioxy-2-(3-nitrobenzoyl)phenylacetate (500 mg, 1.46 mmol), hydrazine hydrate (350 μL, 6.20 mmol), and acetic acid (50 μL) in ethanol (15 mL) as a yellow solid (30 mg, 0.092 mmol, 6%), mp: 251°-253° C. 1H NMR (CDCl3) 8.52 (s, 1H), 8.46 (s, 1H), 8.31 (d, J=8.2, 1H), 7.99 (d, J=8.2, 1H), 7.62 (t, J=8.2, 1H), 6.87 (s, 1H), 6.57 (s, 1H), 6.06 (s, 2H), 3.49 (s, 2H). Anal. Calcd. for C16H11N3O5 : C, 59.08; H, 3.41; N, 12.92. Found: C, 58.95; 11, 3.29; N, 12.15.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[CH2:11][C:12]1[NH:13][CH2:14][NH:15][CH:16]=1.C([O-])(O)=O.[Na+].C1C=CC(OC(Cl)=[S:30])=CC=1>C1COCC1.O>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[CH2:11][C:12]1[NH:13][C:14](=[S:30])[NH:15][CH:16]=1
Reactant: S=C(Cl)Oc1ccccc1
Reactant: Clc1cccc2c1ccn2CC1=CNCN1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: S=c1[nH]cc(Cn2ccc3c(Cl)cccc32)[nH]1
Reaction time: 4 h
Yield: 50 %

Procedure:
4-(4-Chloro-indol-1-ylmethyl)-1,3-dihydro-imidazole (Intermediate A4) (0.5 mmol) in THF (3 mL) and water (3 mL) was treated with NaHCO3 (5 mmol) at rt for 20 m. Phenyl chlorothionoformate (1.3 mmol) was added and stirring was continued for 4 h. The mixture was diluted with water (15 mL) and extracted with ether (3×25 mL). The organic portions were combined, dried over MgSO4, filtered and the solvent was removed under vacuum. The residue was dissolved in MeOH (4 mL) and treated with NEt3 (0.35 mL) for 18 h at rt. The solvent was evaporated and the product was washed on a glass frit with 50% CH2Cl2:hexanes to give a solid 4-(4-chloro-indol-1-ylmethyl)-1,3-dihydro-imidazole-2-thione (Compound 1) (˜50%)
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:22])[C:12]3[CH:19]=[C:18]([CH2:20]O)[S:17][C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1.N1C(C)=CC(C)=CC=1C.CS(Cl)(=O)=O.[CH3:39][NH:40][CH2:41][CH:42]([OH:49])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>CN(C=O)C.CN(C1C=CN=CC=1)C.O>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:22])[C:12]3[CH:19]=[C:18]([CH2:20][N:40]([CH2:41][CH:42]([OH:49])[C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)[CH3:39])[S:17][C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: CNCC(O)c1ccccc1
Reactant: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CO)sc21
Agent: CN(C)c1ccncc1
Agent: CS(=O)(=O)Cl
Solvent: O
Solvent: Cc1cc(C)nc(C)c1
Solvent: CN(C)C=O
Product: CN(Cc1cc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(C)c2s1)CC(O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.6 %

Procedure:
To solution of N-(4-chlorobenzyl)-2-(hydroxymethyl)-7-methyl-4-oxo-4,7-dihydrothieno[2,3-b]pyridine-5-carboxamide (0.300 g) from Example No. 35 in DMF (17 mL) are added DMAP (16 mg), 2,4,6-collidine (0.27 mL), and methanesulfonyl chloride (0.16 mL). The reaction mixture is stirred at room temperature for 1 h and then α-(methylaminomethyl)benzyl alcohol (1.26 g) is added. The mixture is stirred at room temperature for 18 h and is then poured into water (50 mL). The resulting off-white solid is filtered off and purified by column chromatography (CH2Cl2/methanol, 99/1; 97/3) to yield 0.261 g (63%) of the title compound as a pale yellow solid.
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:10](=[O:11])[N:9]2[C@@H:5]1[S:6][C:7]([C@H:18]1[CH2:22][CH2:21][CH2:20][O:19]1)=[C:8]2[C:12]([O:14]CC=C)=[O:13])[CH3:3].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Na].C(C(CCCC)C([O-])=O)C.O>C(Cl)Cl.CC(C)=O>[CH3:3][C@@H:2]([OH:1])[C@H:4]1[C:10](=[O:11])[N:9]2[C:8]([C:12]([OH:14])=[O:13])=[C:7]([C@@H:18]3[O:19][CH2:20][CH2:21][CH2:22]3)[S:6][C@H:5]12
Reactant: C=CCOC(=O)C1=C([C@H]2CCCO2)S[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Agent: CCCCC(CC)C(=O)[O-]
Agent: [Na]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC(C)=O
Solvent: ClCCl
Solvent: O
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)O)=C([C@H]3CCCO3)S[C@H]12
Temperature: 10 °C
Reaction time: 1.5 h

Procedure:
Allyl (5R,6S)-6-[(1R)-1-hydroxyethyl]-7-oxo-3-[(2R)-tetrahydrofuran-2-yl]-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (72 g, 0.221 mol) was dissolved in methylene chloride (950 ml). The solution was cooled to 10° C. and triphenyl phosphine (2.0 g, 0.0076 mol), sodium-2-ethylhexanoate (39.71 g, 0.239 mol) and tetrakis triphenylphosphine palladium (0) (2.0 g) were added together at 10° C. The reaction mixture was stirred for 1-2 hours at 10-15° C. After the completion of reaction, water (50 ml) was added to the reaction mixture. The reaction mixture was stirred for 15 minutes, followed by the addition of acetone (332.5 ml) and the reaction mixture was cooled to 0° C. The solid so separated from the reaction mixture was filtered, washed with acetone and dried under reduced pressure to obtain the title compound.