Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]3[O:13][C:14]4[CH:20]=[C:19]([OH:21])[CH:18]=[CH:17][C:15]=4[N:16]=3)=[CH:8][C:7]=2[F:22])[CH2:3][CH2:2]1.O[CH2:24][C@@H:25]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH3:26].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(C)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]3[O:13][C:14]4[CH:20]=[C:19]([O:21][CH2:26][C@@H:25]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:31])([CH3:33])[CH3:32])[CH3:24])[CH:18]=[CH:17][C:15]=4[N:16]=3)=[CH:8][C:7]=2[F:22])[CH2:2][CH2:3]1
Reactant: Oc1ccc2nc(-c3ccc(OCC4CC4)c(F)c3)oc2c1
Reactant: C[C@@H](CO)NC(=O)OC(C)(C)C
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: C[C@@H](COc1ccc2nc(-c3ccc(OCC4CC4)c(F)c3)oc2c1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 48.8 %

Procedure:
To a solution of 2-(4-(cyclopropylmethoxy)-3-fluorophenyl)-1,3-benzoxazol-6-ol (1.00 g), tert-butyl ((2S)-1-hydroxypropan-2-yl)carbamate (0.878 g) and triphenylphosphine (1.32 g) in THF (10 mL) was added dropwise diisopropyl azodicarboxylate toluene solution (1.9 M, 2.64 mL), and the mixture was stirred at room temperature for 16 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (NH, hexane/ethyl acetate) to give the title compound (0.744 g). 1H NMR (300 MHz, CDCl3) δ 0.35-0.45 (2H, m), 0.63-0.76 (2H, m), 1.29-1.39 (4H, m), 1.46 (9H, s), 3.91-4.02 (4H, m), 4.04-4.18 (1H, m), 4.70-4.85 (1H, m), 6.95 (1H, dd, J=8.7, 2.3 Hz), 7.04 (1H, t, J=8.3 Hz), 7.10 (1H, d, J=2.3 Hz), 7.60 (1H, d, J=8.7 Hz), 7.84-8.01 (2H, m).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].C(=O)([O-])[O-].[Na+].[Na+].Br[CH2:19][CH2:20][CH2:21][NH:22][C:23]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(OCC)C>C(Cl)(Cl)Cl.CCCCCC>[C:23]([NH:22][CH2:21][CH2:20][CH2:19][NH:1][CH2:2][CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:8])([CH3:10])[CH3:9])([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: BrCCCNC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Product: CC(C)(C)OC(=O)NCCNCCCNC(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 48.9 %

Procedure:
To a solution of tert-butyl 2-aminoethylcarbamate (481 mg) in dehydrated chloroform (3 ml) were added sodium carbonate (212 mg) and (3-bromopropyl)tritylamine (694 mg), and the mixture was stirred under reflux for 3.5 hours. To the reaction mixture were added diethyl ether and hexane, and the solution was washed with water. The mixture was extracted with 5% aqueous citric acid solution, and the aqueous layer was washed with diethyl ether. The aqueous solution was then made alkaline with sodium hydrogencarbonate followed by extraction with diethyl ether. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give tert-butyl 2-{[3-(tritylamino)propyl]amino}ethylcarbamate (410 mg) as a viscous oil.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[O:12][CH3:13].[Cl:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19](Cl)=[O:20]>C1COCC1>[Cl:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([NH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[O:12][CH3:13])=[O:20]
Reactant: O=C(Cl)CCCCCl
Reactant: COC(=O)c1ccc(N)c(OC)c1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(NC(=O)CCCCCl)c(OC)c1

Procedure:
Prepared analogously to Example 6a from methyl 4-amino-3-methoxy-benzoate and 5-chloro-pentanoic acid chloride in THF with TEA.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=O)=[CH:4][C:3]=1[CH3:17].[C:18]1(=O)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>C1COCC1.[Ti](Cl)(Cl)(Cl)Cl.[Zn]>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[CH:4][C:3]=1[CH3:17]
Reactant: Cc1cc(C(=O)c2ccc(O)cc2)ccc1Br
Reactant: O=C1CCCCC1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [Zn]
Solvent: C1CCOC1
Product: Cc1cc(C(=C2CCCCC2)c2ccc(O)cc2)ccc1Br
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84.7 %

Procedure:
Titanium tetrachloride (2.70 mL, 24.5 mmol) was added dropwise to a suspension of zinc powder (3.24 g, 49.5 mmol) in anhydrous THF (60 mL) at RT. After refluxing for 1 h, a mixture of 66 (1.78 g, 6.11 mmol) and cyclohexanone (1.80 g, 18.3 mmol) dissolved in THF (20 mL) was added dropwise. Refluxing was continued for 30 min. The reaction mixture was cooled to RT and filtered through Celite. Water (250 mL) was added and the mixture was extracted with Et2O (3×100 mL). The combined ethereal extracts were washed with water (200 mL), brine (200 mL), and dried over MgSO4. Concentration followed by flash chromatography (20:1 to 5:1 hexanes:EtOAc) afforded 1.85 g (85%) of 67 as an orange solid. 1H NMR (400 MHz, CDCl3): δ 1.58 (m, 6H), 2.20 (m, 4H), 2.32 (s, 3H), 5.95 (br s, 1H), 6.73 (d, J=8.4 Hz, 2H), 6.79 (dd, J=8.1 Hz, 2.0 Hz, 1H), 6.95 (m, 3H), 7.40 (d, J=8.1 Hz, 1H).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[N:6]=[C:5]2[CH:17]=[O:18].[N:19]1[CH:24]=[CH:23][CH:22]=[C:21](B(O)O)[CH:20]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.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>[N:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[N:7]([CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)[N:6]=[C:5]3[CH:17]=[O:18])[CH:20]=1
Reactant: O=Cc1nn(C2CCCCO2)c2ccc(I)cc12
Reactant: OB(O)c1cccnc1
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: O
Solvent: C1COCCO1
Product: O=Cc1nn(C2CCCCO2)c2ccc(-c3cccnc3)cc12
Temperature: 95 °C
Yield: 47 %

Procedure:
5-Iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carbaldehyde (CXIV) (1.53 g, 4.30 mmol), pyridine-3-boronic acid (CXXXI) (0.58 g, 4.73 mmol), and potassium phosphate tribasic (1.37 g, 6.45 mmol) was dissolved in 1,4-dioxane (43.0 mL) and water (9.0 mL). Tetrakis(triphenylphosphine)palladium(0) (0.50 g, 0.4301 mmol) was added, and the reaction was heated to 95° C. for 2.5 h. The solvent was removed, and the residue was partitioned between EtOAc and water. The organic phase was separated and washed sequentially with water and brine. The material was dried (MgSO4), concentrated, and purified by flash chromatography using a 40 g Thomson normal phase silica gel cartridge (100% hexanes→1:1 EtOAc:hexanes) to afford 5-(pyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carbaldehyde (CXXXII) (0.62 g, 2.02 mmol, 47% yield) as a tan amorphous solid. 1H NMR (DMSO-d6) δ ppm 10.23 (s, 1H), 8.95 (d, J=2.3 Hz, 1H), 8.61 (dd, J=4.8, 1.5 Hz, 1H), 8.39 (d, J=0.98 Hz, 1H), 8.17-8.14 (m, 1H), 8.06 (d, J=8.8 Hz, 1H), 7.95-7.93 (m, 1H), 7.64-7.60 (m, 1H), 6.13 (dd, J=9.4, 2.4 Hz, 1H), 3.93-3.90 (m, 1H), 3.86-3.81 (m, 1H), 2.45-2.41 (m, 1H), 2.11-2.07 (m, 2H), 1.82-1.78 (m, 1H), 1.66-1.62 (m, 2H); ESIMS found for C13H17N3O2 m/z 308 (M+H).
Reaction SMILES: [CH3:1][C:2]([CH3:35])([CH3:34])[CH2:3][N:4]([CH3:33])[C:5]1[N:10]=[C:9]([NH:11][C:12]2[CH:13]=[C:14]([CH:21]=[CH:22][C:23]=2[CH3:24])[C:15]([NH:17][O:18][CH2:19][CH3:20])=[O:16])[CH:8]=[C:7]([N:25]2[CH2:31][CH2:30][CH2:29][N:28]([CH3:32])[CH2:27][CH2:26]2)[N:6]=1.[C-:36]#[N:37].[Na+].BrBr>C(=O)(O)[O-].[Na+].C(Cl)Cl.O>[C:36]([C:8]1[C:9]([NH:11][C:12]2[CH:13]=[C:14]([CH:21]=[CH:22][C:23]=2[CH3:24])[C:15]([NH:17][O:18][CH2:19][CH3:20])=[O:16])=[N:10][C:5]([N:4]([CH2:3][C:2]([CH3:34])([CH3:1])[CH3:35])[CH3:33])=[N:6][C:7]=1[N:25]1[CH2:31][CH2:30][CH2:29][N:28]([CH3:32])[CH2:27][CH2:26]1)#[N:37]
Reactant: [C-]#N
Reactant: CCONC(=O)c1ccc(C)c(Nc2cc(N3CCCN(C)CC3)nc(N(C)CC(C)(C)C)n2)c1
Agent: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CCONC(=O)c1ccc(C)c(Nc2nc(N(C)CC(C)(C)C)nc(N3CCCN(C)CC3)c2C#N)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred mixture of 3-[2-[(2,2-dimethyl-propyl)-methyl-amino]-6-(4-methyl-[1,4]diazepan-1-yl)-pyrimidin-4-ylamino]-N-ethoxy-4-methyl-benzamide (50 mg, 0.1 mmol) and sodium cyanide (0.044 g, 0.89 mmol) in sat. aq. sodium bicarbonate (1 mL) and methylene chloride (3 mL) was added at room temp bromine (0.045 mL, 0.87 mmol). The resulting mixture was continued stirring for 16 h at room temp. The reaction mixture was diluted with water and extracted with methylene chloride (2×15 mL). The combined organic layer was dried (sodium sulfate), filtered and concentrated under reduced pressure, and the product was purified by HPLC. C27H40N8O2 MS m/e=509 (M+H).
Reaction SMILES: [Cl-].[CH2:2]([C:5]1[S:9][CH:8]2[N:10]([CH2:13][C:14]3[CH:19]=[CH:18][C:17](F)=[CH:16][CH:15]=3)[CH:11]=[CH:12][N+:7]2([CH2:21][CH3:22])[C:6]=1[CH2:23][CH3:24])CC.[Br-].C1(C2[N+]3C=CN(CC4C=CC=CC=4OC)C=3SC=2)C=CC=CC=1.[Cl-].COC1C=C(C=C(OC)C=1)CC1[N+]2C=CN(CC3C=CC=CC=3)C=2SC=1.[Br-].CC1[N+]2C=CN(CC3C=CC(C4C=CC=CC=4)=CC=3)C=2SC=1.[Br-].CC1C=C(C)C=CC=1CC1[N+]2C=C(C)N(CC3C=CC([Cl:120])=CC=3)C=2SC=1.[Br-].ClC1C=CC(C2[N+]3C=CN(CC#C)C=3SC=2)=CC=1.[Cl-].CC1C=C(C)C=CC=1C1[N+]2C=C(C3C=CC(C)=CC=3C)N(CC3C=CC=CC=3)C=2SC=1.[Cl-].FC1C=CC(C[N+]2C=CN3C4CCCCC=4SC=23)=CC=1.[Br-].C([N+]1C=CN2C3CCCCC=3SC=12)C#C>>[Cl-:120].[CH3:2][C:5]1[S:9][CH:8]2[N:10]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:11]=[CH:12][N+:7]2([CH2:21][CH3:22])[C:6]=1[CH2:23][CH3:24]
Reactant: CCCC1=C(CC)[N+]2(CC)C=CN(Cc3ccc(F)cc3)C2S1
Reactant: Cc1ccc(Cc2csc3n(Cc4ccc(Cl)cc4)c(C)c[n+]23)c(C)c1
Agent: C#CC[n+]1ccn2c3c(sc21)CCCC3
Agent: C#CCn1cc[n+]2c(-c3ccc(Cl)cc3)csc12
Agent: COc1cc(Cc2csc3n(Cc4ccccc4)cc[n+]23)cc(OC)c1
Product: CCC1=C(C)SC2N(Cc3ccccc3)C=C[N+]12CC

Procedure:
2-n-propyl-3,4-diethyl-7-(p-fluorobenzyl)imidazo[2,1-b]thiazolium chloride, 2-i-propyl-7-(p-fluorobenzyl)imidazo[2,1b]thiazolium chloride; 3-phenyl-7-(o-methoxybenzyl)imidazo[2,1-b]thiazolium bromide; 3-adamantyl-6-phenyl-7-(m-trifluorobenzyl)imidazo[2,1-b]thiazolium bromide; 3-(3,5-dimethoxybenzyl)-7-benzylimidazo[2,1-b]thiazolium chloride, 3-methyl-7-(p-phenylbenzyl)imidazo[2,1-b]thiazolium bromide; 3-(2,4-dimethylbenzyl)-6-methyl-7-(p-chlorobenzyl)imidazo[2,1-b]thiazolium bromide; 3-(p-chlorophenyl)-7-propargylimidazo[2,1-b]thiazolium bromide; 3,6-bis(2,4-dimethylphenyl)-7-benzylimidazo[2,1-b]thiazolium chloride; 1-(p-fluorobenzyl-5,6,7,8-tetrahydroimidazo[2,1-b]benzthiazolium chloride and 1-propargyl-5,6,7,8-tetrahydroimidazo[2,1-b]benzthiazolium bromide.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][N:9]2[C:21]3[CH2:20][CH:19]([CH3:22])[CH2:18][C:17](=[O:23])[C:16]=3[C:15]3[C:10]2=[CH:11][CH:12]=[CH:13][C:14]=3[C:24]([O:26][CH3:27])=[O:25])[CH:5]=[CH:6][CH:7]=1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([CH2:8][N:9]2[C:21]3[CH:20]=[C:19]([CH3:22])[CH:18]=[C:17]([OH:23])[C:16]=3[C:15]3[C:10]2=[CH:11][CH:12]=[CH:13][C:14]=3[C:24]([O:26][CH3:27])=[O:25])[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1cccc2c1c1c(n2Cc2cccc(F)c2)CC(C)CC1=O
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: Cc1ccccc1
Product: COC(=O)c1cccc2c1c1c(O)cc(C)cc1n2Cc1cccc(F)c1
Yield: 24.2 %

Procedure:
A solution of the 9-[(3-fluorophenyl)methyl]-5-carbomethoxy-2-methyl-1,2-dihydrocarbazol-4(3H)-one (1.37 g; 3.75 mM) and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (0.94 g, 4.13 mM) in 38 mL of toluene was stirred between 80-90° C. for 3 hours. The mixture was purified by column chromatography on silica gel (elution with methylene chloride) to afford 0.33 g (24%) of 9-[(3-fluorophenyl)methyl]-2-methyl-4-hydroxy-5-carbomethoxy carbazole. 1H NMR (CDCl3) δ10.45 (s, 1H), 8.0 (d, J=8 Hz, 1H), 7.55 (d, J=8 Hz, 1H), 7.4 (dd, J=8 and 8 Hz, 1H), 7.3 (m, 2H), 6.95 (m, 1H), 6.85 (d, J=8 Hz, 1H), 6.75 (m, 1H), 6.65 (s, 1H), 5.5 (s, 2H), 4.1 (s, 3H), 2.45 (s, 3H). MS (ES) m/e 332, 364.
Reaction SMILES: [NH2:1][CH:2]=[C:3]([C:8]1[N:9]([CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[CH:10]=[CH:11][C:12]=1[C:13](OC)=[O:14])[C:4]([O:6][CH3:7])=[O:5].CC(C)([O-])C.[Na+].O>CN(C=O)C>[CH:17]1([N:9]2[C:8]3[C:3]([C:4]([O:6][CH3:7])=[O:5])=[CH:2][NH:1][C:13](=[O:14])[C:12]=3[CH:11]=[CH:10]2)[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: COC(=O)C(=CN)c1c(C(=O)OC)ccn1C1CCCC1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1c[nH]c(=O)c2ccn(C3CCCC3)c12
Temperature: 160 °C
Reaction time: 1 h
Yield: 43 %

Procedure:
To a solution of methyl 2-(1-amino-3-methoxy-3-oxoprop-1-en-2-yl)-1-cyclopentyl-1H-pyrrole-3-carboxylate (20.45 g) in DMF (205 mL) was added sodium tert-butoxide (6.72 g), and the mixture was stirred at 160° C. for 1 hr. The reaction mixture was allowed to be cooled to room temperature, water was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was washed with ethyl acetate and hexane to give the title compound (7.83 g).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].C(Cl)Cl.[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([S:16]([CH:19]([C:28]2[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:29]=2[F:35])[C:20]2[C:25]([F:26])=[CH:24][N:23]=[C:22]([NH2:27])[CH:21]=2)(=[O:18])=[O:17])=[CH:12][CH:11]=1.N1C=CC=CC=1>CCCCCC.C(OCC)(=O)C>[Cl:9][C:10]1[CH:11]=[CH:12][C:13]([S:16]([CH:19]([C:28]2[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:29]=2[F:35])[C:20]2[C:25]([F:26])=[CH:24][N:23]=[C:22]([NH:27][S:2]([CH3:1])(=[O:4])=[O:3])[CH:21]=2)(=[O:17])=[O:18])=[CH:14][CH:15]=1
Reactant: CS(=O)(=O)Cl
Reactant: Nc1cc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)c(F)cn1
Solvent: CCCCCC
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CS(=O)(=O)Nc1cc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)c(F)cn1
Temperature: 25 °C
Reaction time: 7 h
Yield: 84 %

Procedure:
Under ice cooling, methanesulfonyl chloride (12 μl, 0.157 mmol) was added to a methylene chloride (5 ml) solution of [4-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]-5-fluoropyridin-2-yl]amine (54 mg, 0.131 mmol) and pyridine (16 μl, 0.197 mmol). The resulting mixture was stirred at room temperature for 7 hours, followed by the addition of pyridine (16 μl, 0.197 mmol) and methanesulfonyl chloride (12 μl, 0.157 mmol). After the reaction mixture was stirred at room temperature for 17 hours, pyridine (16 μl, 0.197 mmol) and methanesulfonyl chloride (12 μl, 0.157 mmol) were added thereto. The resulting mixture was stirred at room temperature for 2 hours and then, pyridine (16 μl, 0.197 mmol) and methanesulfonyl chloride (12 μl, 0.157 mmol) were added thereto. After the resulting mixture was stirred at room temperature for 21 hours, pyridine (16 μl, 0.197 mmol) and methanesulfonyl chloride (12 μl, 0.157 mmol) were added thereto. The resulting mixture was stirred at room temperature for 2 hour and then, concentrated under reduced pressure. To the residue thus obtained was added ethyl acetate. The resulting mixture was washed with a saturated aqueous solution of sodium bicarbonate, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue thus obtained was subjected to flash silica gel column chromatography. The fraction obtained from the hexane:ethyl acetate (=2:1) eluate was concentrated under reduced pressure to give the title compound (54 mg, 0.110 mmol, 84%) as a white solid. The resulting white solid was washed with hexane-ether, and collected by filtration to afford the title compound as a white powder.
Reaction SMILES: [CH3:1][NH:2][C:3]([CH:5]1[C:10]2[CH:11]=[C:12]([C:15]#[N:16])[CH:13]=[CH:14][C:9]=2[O:8][C:7]([CH3:18])([CH3:17])[CH:6]1O)=[S:4].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:1][NH:2][C:3]([C:5]1[C:10]2[CH:11]=[C:12]([C:15]#[N:16])[CH:13]=[CH:14][C:9]=2[O:8][C:7]([CH3:18])([CH3:17])[CH:6]=1)=[S:4]
Reactant: CNC(=S)C1c2cc(C#N)ccc2OC(C)(C)C1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CNC(=S)C1=CC(C)(C)Oc2ccc(C#N)cc21

Procedure:
A mixture of 0.44 g of N-methyl-6-cyano-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-4-carbothioamide, 0.07 g of p-toluenesulfonic acid monohydrate, and 30 ml of toluene was heated at reflux for 10 hours. The solvent was removed by distillation, and the residue was purified by silica gel column chromatography (developing solution: CH2Cl2) to obtain 0.18 g of-N-methyl-6-cyano-2,2-dimethyl-2H-1-benzopyran-4-carbothioamide represented by formula shown below.
Reaction SMILES: C([O:8][C:9]([CH:11]1[CH2:14][CH:13]([CH2:15][OH:16])[N:12]1CC1C=CC=CC=1)=[O:10])C1C=CC=CC=1.O.[H][H]>CO.[OH-].[OH-].[Pd+2]>[OH:16][CH2:15][CH:13]1[NH:12][CH:11]([C:9]([OH:10])=[O:8])[CH2:14]1
Reactant: O=C(OCc1ccccc1)C1CC(CO)N1Cc1ccccc1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)C1CC(CO)N1

Procedure:
179 mg (0.575 mmol) of N-benzyl-4-(hydroxymethyl)azetidine-2-carboxylic acid benzyl ester and 60 mg of 20% Pd(OH)2 /C (containing 31% of water) in 30 ml of methanol are hydrogenated in a Parr shaker under 4 atm of hydrogen for 3.5 h. The catalyst is filtered off through a double paper filter and washed with methanol, the solution evaporated, and the residue chromatographed on silica gel (isopropanol/water/conc. NH3 14:5:1) to yield, after evaporation and drying i.v., 53.6 mg (71%) of 4-(hydroxymethyl)azetidine-2-carboxylic acid as a colorless solid. 1H NMR (D2O): δ 4.71 (t, 1H, J=9), 4.56 (m, 1H), 3.80 (m, 2H), 2.81 (dt, 1H, J=12 (d), 9.5 (t)), 2.43 (dt, 1H, J=12.5 (d), 8.5 (t)). IR (nujol): 3239, 3146, 2589, 2438, 1620, 1565, 1410, 1327, 1302, 1188, 1099, 1038, 999, 885, 828, 758, 725 cm-1.
Reaction SMILES: [C:1]([NH:3][C:4]([NH:7][CH2:8][CH2:9][S:10][CH2:11][C:12](=O)[CH:13]([NH:15][CH:16]=O)[CH3:14])=[N:5][CH3:6])#[N:2].C([O-])=O.[NH4+].C([O-])([O-])OC.O.O.O.O.P([O-])([O-])(O)=O.[NH4+].[Na+].C([NH2:41])=O>>[C:1]([NH:3][C:4]([NH:5][CH3:6])=[N:7][CH2:8][CH2:9][S:10][CH2:11][C:12]1[N:41]=[CH:16][NH:15][C:13]=1[CH3:14])#[N:2]
Reactant: CN=C(NC#N)NCCSCC(=O)C(C)NC=O
Reactant: NC=O
Agent: COC([O-])[O-]
Agent: O=C[O-]
Agent: O=P([O-])([O-])O
Solvent: O
Product: CNC(=NCCSCc1nc[nH]c1C)NC#N
Temperature: 100 °C
Reaction time: 2 h
Yield: 87 %

Procedure:
To 136 mg of N-cyano-N'-[2-(3-formylamino-2-oxobutylthio)ethyl]-N"-methylguanidine, 320 mg of amonium formate, 0.6 ml of methyl orthoformate and 209 mg of sodium ammonium hydrogenphosphate tetrahydrate was added 2.5 ml of formamide, and the mixture was stirred at 100° C. for 2 hours. The reaction mixture was cooled and insoluble substances were removed, and the solvent was removed under reduced pressure and the obtained residue was refined by silica gel column chromatography (eluting solvent: chloroform/ethanol=5/1) and recrystallized from isopropanol/ether (60/40) to obtain 100 mg of intended Cimetidine (the yield was 87%).
Reaction SMILES: Br[CH2:2][C:3]([CH2:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1)=[O:4].[C:15]1(=[O:25])[NH:19][C:18](=[O:20])[C:17]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:16]12.[K]>C1(C)C=CC=CC=1>[C:15]1(=[O:25])[N:19]([CH2:2][C:3]([CH2:5][C:6]2[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=2)=[O:4])[C:18](=[O:20])[C:17]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:16]12
Reactant: O=C(CBr)Cc1ccc([N+](=O)[O-])cc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: Cc1ccccc1
Product: O=C(Cc1ccc([N+](=O)[O-])cc1)CN1C(=O)c2ccccc2C1=O
Reaction time: 4 h

Procedure:
A mixture of 1-bromo-3-(4-nitrophenyl)acetone and potassium phthalimide (7.2 g.) in toluene (100 ml.) was heated under reflux with stirring for 4 hours. The mixture was filtered, the filtrate evaporated. The residue was purified by chromatography on silica gel using CH2Cl2 as eluant to give 1-phthalimido-3-(4-nitrophenyl)acetone, m.p. 184°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.C[O:13]C(OC)N(C)C>CN(C=O)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[O:13])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1
Reactant: Cc1ccc(Cl)cc1[N+](=O)[O-]
Reactant: COC(OC)N(C)C
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1ccc(Cl)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 4-chloro-2-nitrotoluene (514.8 mg, 3.000 mmol) and dimethylformamide dimethylacetal (1.200 ml, 1074 mg, 9.000 mmol) in DMF (1.2 ml) was heated at 135° C. in a sealed tube for 15 h. The reaction mixture was cooled to rt and added dropwise to a 20° C. solution of NaIO4 (1926 mg, 9.000 mmol) in water (6.18 ml) and DMF (3.09 ml). After 3 h, the mixture was treated with water (20 ml) and extracted with EtOAc (3×15 ml). The extracts were washed with water (3×15 ml) and brine (15 ml), and dried over MgSO4. After the solid was filtered off and the solvent was removed in vacuo, a brown solid of 4-chloro-2-nitrobenzaldehyde was obtained (J. Org. Chem. 2003, 68, 4104-4107). 1H NMR (CDCl3, 400 MHz) δ 7.74-7.78 (m, 1H), 7.94-7.96 (m, 1H), 8.11-8.12 (m, 1H), 10.39 (s, 1H).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([Cl:13])[C:3]=1[Cl:14].[F:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH2:19][NH2:20].CCN(C(C)C)C(C)C>C(C#N)(C)=O>[Cl:14][C:3]1[C:4]([Cl:13])=[N:5][CH:6]=[C:7]([C:2]=1[NH:20][CH2:19][C:18]1[CH:21]=[CH:22][CH:23]=[C:16]([F:15])[CH:17]=1)[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)c1cnc(Cl)c(Cl)c1Cl
Reactant: NCc1cccc(F)c1
Agent: CC(=O)C#N
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cnc(Cl)c(Cl)c1NCc1cccc(F)c1
Temperature: 50 °C
Reaction time: 5 h
Yield: 97.1 %

Procedure:
To a solution of ethyl 4,5,6-trichloronicotinate (200 mg, 0.78 mmol) in AcCN (1.5 mL) was added 3-fluorobenzylamine (0.108 mL, 0.94 mmol) and DIPEA (0.167 mL, 0.94 mmol). The mixture was stirred at room temperature for 5 h them at 50° C. until the reaction is over. The solution was cooled and concentrated, the resulting residue was diluted with water, the solid was then collected by filtration to give ethyl 5,6-dichloro-4-(3-fluorobenzylamino)nicotinate (260 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[N:12]=[CH:11][CH:10]=[C:9]2[O:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=1)([O-])=O.[NH4+].[Cl-]>CCO.O.[Fe]>[F:24][C:21]([F:22])([F:23])[C:17]1[CH:16]=[C:15]([CH:20]=[CH:19][CH:18]=1)[O:14][C:9]1[C:8]2[C:13](=[C:4]([NH2:1])[CH:5]=[CH:6][CH:7]=2)[N:12]=[CH:11][CH:10]=1
Reactant: O=[N+]([O-])c1cccc2c(Oc3cccc(C(F)(F)F)c3)ccnc12
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Nc1cccc2c(Oc3cccc(C(F)(F)F)c3)ccnc12
Temperature: 25 °C
Yield: 82.2 %

Procedure:
To a suspension of 8-nitro-4-(3-(trifluoromethyl)phenoxy)quinoline (200 mg, 0.60 mmol) and iron powder (267 mg, 4.77 mmol) in EtOH (3 mL) was added a solution of NH4Cl (312 mg, 5.89 mmol) in water (2 mL) and the reaction mixture was heated at reflux for 2 h. Then the reaction mixture was cooled to rt and filtered. The filtrate was concentrated and the concentrate was dissolved in CHCl3. The organic layer was washed with an aq. saturated solution of NaHCO3 and brine. The organic layer was separated, dried, filtered and concentrated to afford 150 mg of the title product. 1H NMR (300 MHz, DMSO d6): δ 8.58 (d, J=4.8 Hz, 1H), 7.77-7.65 (m, 3H), 7.55 (d, J=7.8 Hz, 1H), 7.32 (m, 2H), 6.64 (m, 1H), 6.71 (d, J=4.8 Hz, 1H), 6.00 (br s, 2H); MS (m/z): 305.22 (M+H)+.