Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([S:52]([CH2:55][CH3:56])(=[O:54])=[O:53])=[C:6]([CH2:8][N:9]([CH3:51])[C:10]([CH:12]([NH:24][C:25]2[CH:26]=[C:27]3[C:32](=[CH:33][CH:34]=2)[C:31]([N:35]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[N:30][CH:29]=[C:28]3[F:50])[C:13]2[CH:18]=[CH:17][C:16]([C@@H:19]([CH3:22])[CH2:20][OH:21])=[C:15]([CH3:23])[CH:14]=2)=[O:11])[CH:7]=1.[C:57](Cl)(Cl)=[O:58]>C(#N)C.ClCCl>[C:38]([O:37][C:36]([N:35]([C:31]1[C:32]2[C:27](=[CH:26][C:25]([NH:24][C@H:12]3[C:10](=[O:11])[N:9]([CH3:51])[CH2:8][C:6]4[CH:7]=[C:2]([CH:3]=[CH:4][C:5]=4[S:52]([CH2:55][CH3:56])(=[O:54])=[O:53])[NH:1][C:57](=[O:58])[O:21][CH2:20][C@H:19]([CH3:22])[C:16]4[CH:17]=[CH:18][C:13]3=[CH:14][C:15]=4[CH3:23])=[CH:34][CH:33]=2)[C:28]([F:50])=[CH:29][N:30]=1)[C:43](=[O:44])[O:45][C:46]([CH3:47])([CH3:48])[CH3:49])=[O:42])([CH3:41])([CH3:39])[CH3:40]
Reactant: CCS(=O)(=O)c1ccc(N)cc1CN(C)C(=O)C(Nc1ccc2c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)ncc(F)c2c1)c1ccc([C@@H](C)CO)c(C)c1
Reactant: O=C(Cl)Cl
Solvent: CC#N
Solvent: ClCCl
Product: CCS(=O)(=O)c1ccc2cc1CN(C)C(=O)[C@H](Nc1ccc3c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)ncc(F)c3c1)c1ccc(c(C)c1)[C@@H](C)COC(=O)N2
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 31.9 %

Procedure:
To a solution of 3D (303 mg, 0.382 mmol) in acetonitrile (7 mL) and dichloromethane (4 mL) at 0° C., was added phosgene solution (20% in toluene) (0.241 mL, 0.458 mmol) dropwise. The mixture was stirred at 0° C. for 40 min, then at rt for 10 min while extra phosgene was removed by bubbling Ar. The resulting solution was added dropwise via syringe pump into a solution of TEA (0.426 mL, 3.05 mmol) in dichloromethane (120 mL) at rt over 3.0 h. The solution was stirred at rt for additional 45 min. Solvent was removed and the crude was purified by prep HPLC to give a mixture of diastereoisomer (237 mg). The diastereoisomers were separated by chiral HPLC ((R,R)-Whelk-01 250×21.1 mm column) to give 3E (100 mg, 63.9% yield). MS (ESI) m/z: 820 [M+1]+; 1H NMR (400 MHz, chloroform-d) δ ppm 1.29-1.41 (m, 24H) 2.21 (s, 3H) 3.18-3.33 (m, 2H) 3.33-3.39 (m, 3H) 3.38-3.48 (m, 1H) 3.95 (dd, J=10.77, 4.17 Hz, 1H) 4.28 (d, J=17.58 Hz, 1H) 4.67 (t, J=11.21 Hz, 1H) 5.43 (d, J=5.71 Hz, 1H) 5.65 (d, J=17.58 Hz, 1H) 6.39-6.48 (m, 2H) 6.63 (s, 1H) 6.76 (d, J=8.35 Hz, 1H) 6.85 (s, 1H) 7.03 (d, J=9.23 Hz, 1H) 7.08 (s, 1H) 7.50 (d, J=7.91 Hz, 1H) 7.56-7.65 (m, 2H) 7.85 (d, J=8.35 Hz, 1H) 8.05 (s, 1H). 19F NMR (376 MHz, chloroform-d) δ ppm −141.30 (br. s., 1F).
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:3]=1[C:4]([C:6]1[C:11]([F:12])=[CH:10][CH:9]=[CH:8][C:7]=1[F:13])=O.O.[NH2:20][NH2:21]>C(O)COCCO>[NH2:1][C:2]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:3]=1[C:4](=[N:20][NH2:21])[C:6]1[C:11]([F:12])=[CH:10][CH:9]=[CH:8][C:7]=1[F:13]
Reactant: Nc1ccc(Cl)cc1C(=O)c1c(F)cccc1F
Reactant: NN
Solvent: OCCOCCO
Solvent: O
Product: NN=C(c1cc(Cl)ccc1N)c1c(F)cccc1F

Procedure:
In the manner given in Preparation 1, 2-amino-5-chloro-2',6'-difluorobenzophenone is refluxed with hydrazine hydrate in diethylene glycol to give 2-amino-5-chloro-2',6'-difluorobenzophenone hydrazone.
Reaction SMILES: [CH2:1]([Si:4]1(C2C=CC=CC=2)[CH2:9][CH2:8][CH:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[C:20]([F:22])[C:19]([OH:23])=[C:18]([F:24])[CH:17]=3)=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)[CH2:2][CH3:3].[F:31][C@@H:32]([CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[CH2:33]O>>[CH2:1]([Si@H:4]1[CH2:9][CH2:8][C@H:7]([C:10]2[CH:11]=[CH:12][C:13]([C:16]3[CH:21]=[C:20]([F:22])[C:19]([O:23][CH2:33][C@H:32]([F:31])[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])=[C:18]([F:24])[CH:17]=3)=[CH:14][CH:15]=2)[CH2:6][CH2:5]1)[CH2:2][CH3:3]
Reactant: CCC[Si]1(c2ccccc2)CCC(c2ccc(-c3cc(F)c(O)c(F)c3)cc2)CC1
Reactant: CCCCCC[C@H](F)CO
Product: CCCCCC[C@@H](F)COc1c(F)cc(-c2ccc([C@H]3CC[Si@H](CCC)CC3)cc2)cc1F

Procedure:
The general procedure of Example 1 was repeated using 4-(4-(4-n-propyl-4-phenyl-4-silacyclohexyl)phenyl) -2,6-difluorophenol and (S)-2-fluoro-1-octanol, thereby obtaining the intended compound.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1/[CH:11]=[CH:12]/[C:13]1[S:14][CH:15]=[C:16]([C:18]([O-:20])=[O:19])[N:17]=1.[OH-].[Na+]>C(O)C.O>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1/[CH:11]=[CH:12]/[C:13]1[S:14][CH:15]=[C:16]([C:18]([OH:20])=[O:19])[N:17]=1
Reactant: O=C([O-])c1csc(/C=C/c2ccc3ccccc3n2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1csc(/C=C/c2ccc3ccccc3n2)n1
Temperature: 0 °C

Procedure:
2-[(E)-2-(2-Quinolinyl)ethenyl]-1,3-thiazole-4-carboxylate (0.137 g, 0.44 mmol; see step (vi) above) was suspended in ethanol (2 mL), NaOH (0.052 g, 1.32 mmol) in water (5 mL) was added and the solution was then refluxed for 2 h. The reaction was then hot-filtered and then cooled to 0° C., whereupon dilute HCl was added dropwise until the title compound precipitated as a yellow solid (0.103 g, 83%).
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6]2[CH:11]=[CH:10][C:9]([C@@H:12]([NH:14][C:15](=[O:17])[CH3:16])[CH3:13])=[CH:8][CH:7]=2)[CH2:3]1.[F:18][C:19]1[CH:24]=[C:23](F)[CH:22]=[CH:21][N:20]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[F:18][C:19]1[CH:24]=[C:23]([O:1][CH:2]2[CH2:3][N:4]([C:6]3[CH:7]=[CH:8][C:9]([C@@H:12]([NH:14][C:15](=[O:17])[CH3:16])[CH3:13])=[CH:10][CH:11]=3)[CH2:5]2)[CH:22]=[CH:21][N:20]=1
Reactant: Fc1ccnc(F)c1
Reactant: CC(=O)N[C@@H](C)c1ccc(N2CC(O)C2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)N[C@@H](C)c1ccc(N2CC(Oc3ccnc(F)c3)C2)cc1
Temperature: 80 °C
Reaction time: 12 h

Procedure:
1.0 g (4.3 mmol) (S)—N-{1-[4-(3-Hydroxy-azetidin-1-yl)-phenyl]-ethyl}-acetamide (V.1), 0.6 g (5.2 mmol) 2,4-difluoropyridine and 2.0 g (6.2 mmol) cesium carbonate are combined in 40 mL DMF and the mixture is stirred for 12 h at 80° C. Water is added and the mixture is extracted twice with ethylacetate. After concentration in vacuo the residue is purified by chromatography (silica; ethylacetate) to yield the desired product.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([N:10]2[CH2:15][CH2:14][CH:13]([N:16]3[CH2:21][CH2:20][CH:19]([N:22]4[C:26]5[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=5[NH:24][C:23]4=[O:31])[CH2:18][CH2:17]3)[CH2:12][CH2:11]2)=[O:9])[CH:5]=[N:4][CH:3]=1.[N-:32]=[N+:33]=[N-:34].[Na+]>CN(C)C=O>[N:32]([C:2]1[N:7]=[C:6]([C:8]([N:10]2[CH2:15][CH2:14][CH:13]([N:16]3[CH2:21][CH2:20][CH:19]([N:22]4[C:26]5[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=5[NH:24][C:23]4=[O:31])[CH2:18][CH2:17]3)[CH2:12][CH2:11]2)=[O:9])[CH:5]=[N:4][CH:3]=1)=[N+:33]=[N-:34]
Reactant: O=C(c1cncc(Cl)n1)N1CCC(N2CCC(n3c(=O)[nH]c4ccccc43)CC2)CC1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=Nc1cncc(C(=O)N2CCC(N3CCC(n4c(=O)[nH]c5ccccc54)CC3)CC2)n1
Reaction time: 24 h
Yield: 105.1 %

Procedure:
A mixture of 0.15 g of 1,3-dihydro-1-{1-[1-(6-chloro-2-pyrazinecarbonyl)piperidin-4-yl]piperidin-4-yl}-2H-benzimidazol-2-one, 0.26 g of sodium azide and 5 mL of anhydrous N,N-dimethylformamide was stirred for 24 h, then concentrated to dryness under reduced pressure. The residue was partitioned between 50 mL of chloroform and 5 mL of saturated sodium carbonate and the organic extracts dried over MgSO4. Removal of solvents under reduced pressure and drying under vacuum gave 0.16 g of crude 1,3-dihydro-1-{1-[1-(6-azido-2-pyrazinecarbonyl)piperidin-4-yl]piperidin-4-yl}-2H-benzimidazol-2-one.
Reaction SMILES: [I:1]I.N1C=CN=C1.[C:8]([O:12][C:13](=[O:38])[NH:14][C@H:15]([C:19]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[O:20][SiH2:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:16][CH2:17]O)([CH3:11])([CH3:10])[CH3:9]>ClCCl>[C:8]([O:12][C:13](=[O:38])[NH:14][C@H:15]([C:19]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[O:20][SiH2:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:16][CH2:17][I:1])([CH3:11])([CH3:10])[CH3:9]
Reactant: II
Reactant: CC(C)(C)OC(=O)N[C@@H](CCO)C(O[SiH2]C(C)(C)C)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](CCI)C(O[SiH2]C(C)(C)C)(c1ccccc1)c1ccccc1
Reaction time: 0.25 h

Procedure:
A suspension of polystyrene resin-bound triphenylphosphine (2.33 g, 3 mmol/g in dry dichloromethane (25 ml) is treated with iodine (1.56 g, 6.16 mmol) and stirred for 15 minutes under argon. Imidazole (0.477 g, 7.0 mmol) is added and the reaction mixture stirred at room temperature for a further 15 minutes. The reaction mixture is then treated with a solution of [(S)-1-(tert-butyl-diphenyl-silanyloxymethyl)-3-hydroxy-propyl]carbamic acid tert-butyl ester (1.24 g, 2.8 mmol) in dichloromethane (5 ml). The reaction mixture is refluxed for 2 hours under argon, then filtered through a Celite™ filter pad, washing with dichloromethane. The filtrate is washed with 5% aqueous sodium thiosulphate solution and water, dried over MgSO4 and evaporated. The crude product is purified by flash silica chromatography (elution with 1:99 methanol/dichloromethane) to afford [(S)-1-(tert-butyl-diphenyl-silanyloxymethyl)-3-iodo-propyl]-carbamic acid tert-butyl ester. [M-BOC] 453.9.
Reaction SMILES: [CH3:1][C:2]1([N:15]2[CH2:20][CH2:19][C:18](=O)[CH2:17][CH2:16]2)[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[C@@H:22]1([NH2:29])[CH2:27][CH2:26][CH2:25][CH2:24][C@H:23]1[NH2:28].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClCCl>[NH2:28][C@@H:23]1[CH2:24][CH2:25][CH2:26][CH2:27][C@H:22]1[NH:29][CH:18]1[CH2:19][CH2:20][N:15]([C:2]2([CH3:1])[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]2)[CH2:16][CH2:17]1
Reactant: N[C@@H]1CCCC[C@H]1N
Reactant: CC(C)(C)OC(=O)N1CCC(C)(N2CCC(=O)CC2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(C)(N2CCC(N[C@@H]3CCCC[C@H]3N)CC2)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of tert-butyl 4-methyl-4-(4-oxo-1-piperidyl)piperidine-1-carboxylate (2.0 g, 6.76 mmol) and (1R,2R)-cyclohexane-1,2-diamine (1.55 g, 13.5 mmol) in dichloromethane (60 mL) was added sodium triacetoxyborohydride (2.12 g, 10.0 mmol) and stirred at room temperature for 12 h. Saturated NaHCO3 (40 mL) was added, the phases were separated and the aqueous phase was extracted with dichloromethane (2×60 mL). The combined organic phases were washed with brine, dried over Na2SO4, and concentrated in vacuo. The crude product was used for the next step without further purification.
Reaction SMILES: [CH3:1][NH:2][C:3]([O:5][N:6]=[C:7]([S:9][CH3:10])[CH3:8])=[O:4].[CH3:11][O:12][CH2:13][CH2:14][N:15]([CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21])[S:16]Cl.C(N(CC)CC)C.S(=O)(=O)(O)O>ClC(Cl)C>[CH3:1][N:2]([S:16][N:15]([CH2:14][CH2:13][O:12][CH3:11])[CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21])[C:3]([O:5][N:6]=[C:7]([S:9][CH3:10])[CH3:8])=[O:4]
Reactant: CNC(=O)ON=C(C)SC
Reactant: COCCN(CCC(=O)OC)SCl
Agent: O=S(=O)(O)O
Solvent: CC(Cl)Cl
Solvent: CCN(CC)CC
Product: COCCN(CCC(=O)OC)SN(C)C(=O)ON=C(C)SC
Yield: 87.8 %

Procedure:
A 14.6 g (0.09 mole) quantity of S-methyl N-[(methylcarbamoyl)oxy]thioacetimidate was poured into 100 ml of a dichloroethane solution containing 22.75 g (0.1 mole) of N-methoxyethyl-N-methoxycarbonylethylaminosulfenyl-chloride. The mixture was agitated by a stirred and 18 g (0.18 mole) of triethylamine was added dropwise at less than 5° C. over a period of 30 minutes. Thereafter the mixture was agitated at the same temperature for 1 hour. A 5% aqueous solution of sulfuric acid was added to the mixture until a pH of 6 was achieved. The dichloroethane solution was washed with a 5% aqueous solution of sodium hydrogencarbonate and with an aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated at reduced pressure, giving 31 g of a yellow brown oily product in a yield of 87.8%.
Reaction SMILES: [OH:1][C:2]1[C:9]([O:10][CH3:11])=[CH:8][C:7]([O:12][CH3:13])=[CH:6][C:3]=1[CH:4]=[O:5].C([O-])([O-])=O.[K+].[K+].[CH2:20]([O:22][CH:23]([O:26][CH2:27][CH3:28])[CH2:24]Br)[CH3:21]>CN(C=O)C>[CH2:20]([O:22][CH:23]([O:26][CH2:27][CH3:28])[CH2:24][O:1][C:2]1[C:9]([O:10][CH3:11])=[CH:8][C:7]([O:12][CH3:13])=[CH:6][C:3]=1[CH:4]=[O:5])[CH3:21]
Reactant: CCOC(CBr)OCC
Reactant: COc1cc(C=O)c(O)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(COc1c(C=O)cc(OC)cc1OC)OCC
Yield: 67 %

Procedure:
To a stirred suspension containing 2 (1.1 g, 6.0 mmol) and K2CO3 (1.0 g, 7.2 mmol) in DMF (100 mL), bromoacetaldehyde diethyl acetal (0.93 mL, 6.0 mmol) was added dropwise. The mixture was refluxed for 4 h. After cooling, the precipitate was filtered off and the solvent was evaporated in vacuo. The crude residue was adsorbed on silica gel and purified by flash chromatography, eluting with hexane/EtOAc (4:1) to give 3 (1.2 g, 67%) as a clear oil. 1H NMR (500 MHz, CDCl3): δ: 10.50 (1H, s, CHO), 6.88 (1H, d, J4,6=2.9 Hz, H-6), 6.74 (1H, d, J4,6=2.9 Hz, H-4), 4.83 (1H, t, J4,6=5.3 Hz, CH), 4.14 (2H, d, J4,6=5.3 Hz, CH2), 3.88 (3H, s, OMe), 3.83 (3H, s, OMe), 3.77-3.71) (2H, m, CH2CH3), 3.63-3.58 (2H, m, CH2CH3), 1.24 (6H, t, J=7.1 Hz, 2×CH3).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=[O:6].[CH3:12][O:13][C:14]([C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1)=[O:15].C(=O)([O-])[O-].[Cs+].[Cs+]>COCCOC.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>[CH3:12][O:13][C:14]([C:16]1[CH:21]=[CH:20][C:19]([C:2]2[C:10]([CH3:11])=[CH:9][CH:8]=[C:4]([C:5]([OH:7])=[O:6])[CH:3]=2)=[CH:18][CH:17]=1)=[O:15]
Reactant: Cc1ccc(C(=O)O)cc1I
Reactant: COC(=O)c1ccc(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=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Product: COC(=O)c1ccc(-c2cc(C(=O)O)ccc2C)cc1
Yield: 25.3 %

Procedure:
3-Iodo-4-methylbenzoic acid (8.7 g, 33.3 mmol), (4-methoxycarbonylphenyl)boronic acid (6.0 g, 33.3 mmol), caesium carbonate (1 0.8 g, 33.3 mmol) and tetrakis(triphenylphosphine)palladium (1.92 g, 1.∂mmol) in DME (120 ml) were heated at 90° C. for 6 h. The cooled reaction mixture was filtered and the residue washed with DME. The combined filtrate and washings were absorbed onto silica and chromatographed on a silica flash column eluting with DCM/ethanol/ammonia (40:8:1 then 30:8:1). The product fractions were reduced to dryness under vacuum to give 4′-(methoxycarbonyl)-6-methyl-1,1′-biphenyl-3-carboxylic acid (2.28 g, 25%). LCMS: retention time 3.22 min, [M−H]−269.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH:9]1[CH2:18][C:17]2[N:16]=[CH:15][CH:14]=[C:13]([CH3:19])[C:12]=2[C:11](=O)[CH2:10]1.[C:21]([NH:24][NH2:25])([NH2:23])=[NH:22].Cl.Cl>C(O)C>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH:9]1[CH2:18][C:17]2[N:16]=[CH:15][CH:14]=[C:13]([CH3:19])[C:12]=2[C:11](=[N:25][NH:24][C:21]([NH2:23])=[NH:22])[CH2:10]1
Reactant: Cc1ccnc2c1C(=O)CC(c1c(Cl)cccc1Cl)C2
Reactant: N=C(N)NN
Agent: Cl
Solvent: CCO
Product: Cc1ccnc2c1C(=NNC(=N)N)CC(c1c(Cl)cccc1Cl)C2
Yield: 175.1 %

Procedure:
A mixture of 7-(2,6-dichlorophenyl)-4-methyl-5,6,7,8-tetrahydroquinolin-5-one (171 mg), aminoguanidine hydrochloride (67 mg) and concentrated hydrochloric acid (0.1 ml) in ethanol (3 ml) was refluxed for 2 hours. The reaction solution was concentrated under reduced pressure, and precipitated crystals were recrystallized form ethanol to give 7-(2,6-dichlorophenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline hydrochloride (Compound 63) (195 mg) as colorless crystals.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[C:16](=[O:34])[N:17]([CH2:30][CH:31]3[CH2:33][CH2:32]3)[N:18]=[C:19]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([F:29])[CH:22]=3)[CH:20]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(=O)([O-])[O-].[K+].[K+]>O>[CH:31]1([CH2:30][N:17]2[C:16](=[O:34])[C:15]([CH2:14][N:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)=[CH:20][C:19]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([F:29])[CH:22]=3)=[N:18]2)[CH2:33][CH2:32]1
Reactant: COc1ccc(-c2cc(CN3CCN(C(=O)OC(C)(C)C)CC3)c(=O)n(CC3CC3)n2)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: COc1ccc(-c2cc(CN3CCNCC3)c(=O)n(CC3CC3)n2)cc1F
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 68.6 %

Procedure:
4-(4-tert-Butoxycarbonyl-1-piperazinyl)methyl-2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazine-3-one (220 mg, 0.47 mmol) was dissolved in ice-cold trifluoroacetic acid (2 mL), and at the same temperature, the mixture was stirred for 15 minutes. Water (10 mL) was added to the reaction mixture. The mixture was alkalinized with potassium carbonate and extracted twice with chloroform (20 mL). The extracts were washed with brine (20 mL) and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was recrystallized from chloroform-hexane to yield the title compound as pale yellow prisms (120 mg, 69.2%).
Reaction SMILES: C(O)(=O)/C=C\C(O)=O.[CH3:9][N:10]([CH2:12][C:13]1[O:17][C:16]([CH2:18][S:19][C:20](=N)N)=[CH:15][CH:14]=1)[CH3:11].ClC[CH2:25][NH:26][C:27]([NH:32][CH3:33])=[CH:28][N+:29]([O-:31])=[O:30].C(=O)([O-])[O-].[K+].[K+]>O.O1CCCC1>[CH3:11][N:10]([CH2:12][C:13]1[O:17][C:16]([CH2:18][S:19][CH2:20][CH2:25][NH:26][C:27]([NH:32][CH3:33])=[CH:28][N+:29]([O-:31])=[O:30])=[CH:15][CH:14]=1)[CH3:9]
Reactant: CNC(=C[N+](=O)[O-])NCCCl
Reactant: CN(C)Cc1ccc(CSC(=N)N)o1
Agent: O=C(O)/C=C\C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CNC(=C[N+](=O)[O-])NCCSCc1ccc(CN(C)C)o1
Temperature: 25 °C
Reaction time: 120 h
Yield: 19 %

Procedure:
A mixture of 1-[[[5-[(dimethylamino)methyl]-2-furanyl]-methyl]thio]methanimidamide maleate (1:2) (2.23 g), N-(2-chloroethyl)-N'-methyl-2-nitro-1,1-ethenediamine (0.9 g) and potassium carbonate (3.46 g) in water (10 ml) and tetrahydrofuran (10 ml) was stirred under nitrogen at room temperature for 5 days. The suspension was evaporated in vacuo; the residue suspended in water (50 ml) and extracted with ether (2×40 ml). The aqueous fraction was evaporated in vacuo and magnesium sulphate and tetrahhydrofuran (100 ml) added. After 18 hours, the mixture was filtered and the filtrate evaporated to give a semi-solid which was chromatographed (silica/methanol). The appropriate eluate was evaporated in vacuo to give the title compound (0.3 g), which had an n.m.r. identical to that of the product according to Example 1 above.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]2[CH:13]=[CH:14][C:15]([N+:18]([O-])=O)=[C:16]([CH3:17])[C:11]=2[N:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OCC)(=O)C.C([O-])=O.[NH4+]>CO.[Pd]>[NH2:18][C:15]1[CH:14]=[CH:13][C:12]2[N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH:9]=[N:10][C:11]=2[C:16]=1[CH3:17]
Reactant: Cc1c([N+](=O)[O-])ccc2c1ncn2C(=O)OC(C)(C)C
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1c(N)ccc2c1ncn2C(=O)OC(C)(C)C
Temperature: 50 °C
Reaction time: 2 h

Procedure:
To a solution of 1-tert-butoxycarbonyl-4-methyl-5-nitrobenzimidazole (8 g) in methanol (40 mL)/ethyl acetate (400 mL) is added palladium-on-carbon (Pd/C) (10%, 0.5 g) and ammonium formate (7.27g). The mixture is stirred at 50° C for 2 hours, then filtered on Celite, with methanol wash of the solids. The filtrate is rotary evaporated and the residue partitioned between water and ethyl acetate. The organic layer is washed with saturated ammonium chloride, dried over magnesium sulfate, filtered and rotary evaporated to afford pure 5-amino-1-tert-butoxycarbonyl-4-methylbenzimidazole as an off-white solid.
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]([F:24])([F:23])[F:22])[CH:15]=2)[N:8]=1)=O.[NH:26]([C:28]1[CH:29]=[C:30]([NH:34][C:35](=[O:37])[CH3:36])[CH:31]=[CH:32][CH:33]=1)N>>[O:13]=[C:12]1[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]([F:24])([F:23])[F:22])[CH:15]=2)[N:8]=[C:7]1[C:5]1[N:26]([C:28]2[CH:29]=[C:30]([NH:34][C:35](=[O:37])[CH3:36])[CH:31]=[CH:32][CH:33]=2)[N:2]=[CH:3][CH:4]=1
Reactant: CC(=O)Nc1cccc(NN)c1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(OC(F)(F)F)c2)ccc1=O
Product: CC(=O)Nc1cccc(-n2nccc2-c2nn(-c3cccc(OC(F)(F)F)c3)ccc2=O)c1

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(3-trifluoromethoxy-phenyl)-1H-pyridazin-4-one (A-6) and N-(3-hydrazino-phenyl)-acetamide according to the method described for example 91. MS: M=456.2 (M+H)+
Reaction SMILES: [CH3:1][C:2]1([C:7]2([CH2:10][CH2:11]OS(C3C=CC(C)=CC=3)(=O)=O)[CH2:9][CH2:8]2)[O:6][CH2:5][CH2:4][O:3]1.[C:23]1([SH:29])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CN(C)C=O>[CH3:1][C:2]1([C:7]2([CH2:10][CH2:11][S:29][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:8][CH2:9]2)[O:3][CH2:4][CH2:5][O:6]1
Reactant: Cc1ccc(S(=O)(=O)OCCC2(C3(C)OCCO3)CC2)cc1
Reactant: Sc1ccccc1
Solvent: CN(C)C=O
Product: CC1(C2(CCSc3ccccc3)CC2)OCCO1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
590 mg of 10 is dissolved in 2 ml of dimethylformamide (DMF) and added under nitrogen to a mixture of 300 mg of potassium-t-butylate and 0.27 ml of thiophenol in 5 ml of DMF. It is stirred for 1 hour at room temperature and then quenched with sodium chloride solution. It is extracted with ethyl acetate, washed with sodium bicarbonate solution and sodium chloride solution, dried on sodium sulfate, concentrated by evaporation, and the residue is chromatographed on silica gel with ethyl acetate/hexane, whereby 630 mg of title compound 11 accumulates as a yellowish oil.
Reaction SMILES: Cl.[C:2]([O:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[CH2:16][CH:15]([NH2:20])[CH2:14]2)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:22]1[C:23]2[C:30]([CH3:31])=[CH:29][S:28][C:24]=2[N:25]=[CH:26][N:27]=1.C(N(CC)CC)C>C(O)C>[C:2]([O:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[CH2:16][CH:15]([NH:20][C:22]1[C:23]3[C:30]([CH3:31])=[CH:29][S:28][C:24]=3[N:25]=[CH:26][N:27]=1)[CH2:14]2)(=[O:9])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: Cc1csc2ncnc(Cl)c12
Reactant: NC1Cc2ccc(OC(=O)c3ccccc3)cc2C1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1csc2ncnc(NC3Cc4ccc(OC(=O)c5ccccc5)cc4C3)c12
Yield: 48.6 %

Procedure:
Using 5-benzoyloxy-2-aminoindan hydrochloride (67 mg, 0.35 mmol), 4-chloro-5-methylthieno[2,3-d]pyrimidine (68 mg, 0.37 mmol), triethylamine (0.52 ml, 3.7 mmol), and ethanol (6 ml), a similar procedure to b) in Production Example 208 was carried out. The product obtained was purified by silica gel chromatography (hexane:ethyl acetate=2:1) to obtain the title compound (70 mg, 0.17 mmol) having the following physical properties:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([OH:12])=[O:11].S(=O)(=O)(O)O.[CH3:18]O>>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([O:12][CH3:18])=[O:11]
Reactant: O=C(O)c1cc2ccccc2[nH]1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc2ccccc2[nH]1
Temperature: 25 °C
Yield: 77 %

Procedure:
Indole-2-carboxylic acid (47.0 g, 292 mmol) was dissolved in 200 ml of methanol. To this solution was added 6 ml of concentrated sulfuric acid. The resulting mixture was heated to reflux and maintained at this temperature for about 16 hours. The reaction mixture was then cooled to room temperature and the solids were removed by filtration and then washed with 200 ml of methanol. The crystals were dried in a vacuum oven, yielding 39.5 grams (77%) of the desired title product as white needles. Analytical data obtained was consistent with the proposed title structure.