Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]([CH:26]3[CH2:31][CH2:30][C:29]([F:33])([F:32])[CH2:28][CH2:27]3)[CH2:14][O:15][C:16]3[C:23]([CH3:24])=[CH:22][C:19]([C:20]#[N:21])=[CH:18][C:17]=3[CH3:25])[C:11]3[CH:34]=[C:35]([F:39])[C:36]([F:38])=[CH:37][C:10]=3[N:9]=2)=[CH:4][CH:3]=1.Cl.C(N(CC)CC)C.[N-:48]=[N+:49]=[N-:50].[Na+].Cl>CC1C=CC=CC=1C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]([CH:26]3[CH2:27][CH2:28][C:29]([F:33])([F:32])[CH2:30][CH2:31]3)[CH2:14][O:15][C:16]3[C:23]([CH3:24])=[CH:22][C:19]([C:20]4[NH:50][N:49]=[N:48][N:21]=4)=[CH:18][C:17]=3[CH3:25])[C:11]3[CH:34]=[C:35]([F:39])[C:36]([F:38])=[CH:37][C:10]=3[N:9]=2)=[CH:4][CH:3]=1
Reactant: Cc1cc(C#N)cc(C)c1OCC(C1CCC(F)(F)CC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)c(F)cc21
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1C
Product: Cc1cc(-c2nnn[nH]2)cc(C)c1OCC(C1CCC(F)(F)CC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)c(F)cc21
Temperature: 150 °C
Reaction time: 72 h

Procedure:
To a solution of 0.16 g (0.29 mmol) 4-[2-[2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-2-(4,4-difluoro-cyclohexyl)-ethoxy]-3,5-dimethyl-benzonitrile in 4 ml o-xylene were added 0.198 g (1.44 mmol) triethylamine hydrochloride and 0.094 g (1.45 mmol) sodium azide and heated for 21 h at 150° C. (oil bath temperature). Another 0.198 g (1.44 mmol) triethylamine hydrochloride and 0.094 g (1.45 mmol) sodium azide were added and the reaction mixture was heated for another 4 h and after cooling down to room temperature stirred 3 days. The reaction was then poured onto 1M aqueous hydrochloric acid solution, the phases were separated and the aqueous phase extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and evaporated. The solid was suspended in acetonitrile, filtered, washed with acetonitrile and dried under high vacuum. White solid (77%). MS (Turbo Spray): m/z=599.194 [M+H].
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6](=[O:19])[CH2:7][CH2:8][N+:9]([O-:18])=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])[C:4]=2[CH:3]=1.CO[CH:24](OC)[N:25]([CH3:27])[CH3:26]>CCOCC>[Cl:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6](=[O:19])[C:7](=[CH:24][N:25]([CH3:27])[CH3:26])[CH2:8][N+:9]([O-:18])=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])[C:4]=2[CH:3]=1
Reactant: O=C1CC[N+]([O-])=C(c2ccccc2F)c2cc(Cl)ccc21
Reactant: COC(OC)N(C)C
Solvent: CCOCC
Product: CN(C)C=C1C[N+]([O-])=C(c2ccccc2F)c2cc(Cl)ccc2C1=O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of 3.4 g (11 mmole) of 8-chloro-1-(2-fluorophenyl)-3,4-dihydro-5H-2-benzazepin-5-one-2-oxide and 26 ml of dimethylformamide dimethyl acetal was stirred at room temperature for 12 hr. The mixture was diluted with ether and the precipitate collected to give a yellow solid, mp 175°-178° C. Recrystallization from a mixture of ether and ethyl acetate gave yellow needles, mp 193°-194° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=2[Cl:19])=[NH:11])=[CH:5][CH:4]=1.Br[CH:21]([CH3:29])[C:22](=O)[C:23]([O:25][CH2:26][CH3:27])=[O:24].C([O-])(O)=O.[Na+]>CC(O)C>[Cl:19][C:13]1[CH:14]=[C:15]([Cl:18])[CH:16]=[CH:17][C:12]=1[C:10]1[N:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[C:21]([CH3:29])=[C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[N:11]=1
Reactant: COc1ccc(NC(=N)c2ccc(Cl)cc2Cl)cc1
Reactant: CCOC(=O)C(=O)C(C)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: CCOC(=O)c1nc(-c2ccc(Cl)cc2Cl)n(-c2ccc(OC)cc2)c1C
Yield: 41.8 %

Procedure:
Part A: N-(4-methoxyphenyl)-2,4-dichlorobenzenecarboxamidine (15.0 gram, 50.8 mmol) is dissolved in 2-propanol and ethyl 3-bromo-2-oxobutanoate (23.5 g, 2 molar equivalents) and NaHCO3 (8.5 gram, 2 molar equivalents) are successively added. The resulting mixture is heated at reflux temperature for 40 hours and allowed to attain room temperature. The 2-propanol is removed in vacuo, ethyl acetate is added to the residue and the resulting organic layer is washed with NaHCO3 (5% aqueous solution). The ethylacetate layer is collected, dried over Na2SO4, filtered and concentrated in vacuo. The resulting oil is purified by column chromatography (diethyl ether/petroleum ether=1/3 (v/v), silicagel) to give ethyl 2-(2,4-dichlorophenyl)-5-methyl-1-(4-methoxy-phenyl)-1H-imidazole-4-carboxylate (8.61 g, 42% yield) as a solid. 1H-NMR (200 MHz, CDCl3): δ 7.33 (d, J=8 Hz, 1H), 7.27 (d, J=2 Hz, 1H), 7.18 (dd, J=8 Hz, J=2 Hz, 1H), 7.03 (dt, J=8 Hz, J=2 Hz, 2H), 6.85 (dt, J=8 Hz, J=2 Hz, 2H), 4.42 (q, J=7 Hz, 2H), 3.80 (s, 3H), 2.43 (s, 3H), 1.43 (t, J=7 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][C:11]([C:14]3[CH2:15][CH2:16][N:17]([CH3:20])[CH2:18][CH:19]=3)=[N:12][CH:13]=2)=[CH:4][CH:3]=1.CO.C(O)(=O)C>C(OCC)(=O)C.[Pt](=O)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][C:11]([CH:14]3[CH2:15][CH2:16][N:17]([CH3:20])[CH2:18][CH2:19]3)=[N:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: CN1CC=C(c2ncc(-c3ccc(Cl)cc3)cn2)CC1
Agent: O=[Pt]=O
Solvent: CO
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CN1CCC(c2ncc(-c3ccc(Cl)cc3)cn2)CC1
Reaction time: 18 h
Yield: 44.8 %

Procedure:
Platinum(IV) oxide (30 mg) was added to a solution of 5-(4-chlorophenyl)-2-(1-methyl-1,2,3,6-tetrahydropyridin -4-yl)pyrimidine (0.31 g) in a mixture of ethyl acetate (20 ml), methanol (3 ml) and acetic acid (1 ml) and the mixture was hydrogenated at atmospheric pressure for 18 h. The mixture was then filtered through celite, washing with 10% methanol/ethyl acetate, and evaporated under reduced pressure. The residue was treated with 2 M sodium hydroxide (15 ml) and extracted with diethyl ether (2×25 ml), and the organic extracts were washed with water (2×10 ml), saturated brine (20 ml), dried (Na2SO4) and evaporated under reduced pressure and the residue purified by silica gel column chromatography with 10% methanol/dichloromethane with 0.5% concentrated aqueous ammonia as eluent, to yield the title compound as a white solid (0.14 g, 45%).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].S(=O)(=O)(O)O.[CH2:10]([P:17](=[O:22])([CH2:20][CH3:21])[CH2:18][CH3:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.N>>[N+:1]([C:14]1[CH:15]=[CH:16][C:11]([CH2:10][P:17](=[O:22])([CH2:18][CH3:19])[CH2:20][CH3:21])=[CH:12][CH:13]=1)([O-:4])=[O:2]
Reactant: CCP(=O)(CC)Cc1ccccc1
Reactant: O=[N+]([O-])O
Agent: N
Agent: O=S(=O)(O)O
Product: CCP(=O)(CC)Cc1ccc([N+](=O)[O-])cc1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
To a mixture of nitric acid (0.4 ml) and concentrated sulfuric acid (3 ml) was added benzyldiethylphosphine oxide (1.05 g) at 0° C., and the mixture was stirred at 50° C. for 1 hour. The reaction mixture was added to ice-water, and ammonia solution was added to the solution to neutralize the solution, which was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with magnesium sulfate and concentrated. The residue was separated and purified with column chromatography (ethyl acetate/ethanol=3:2→1:1) to give 4-nitrobenzyldiethylphosphine oxide (518 mg) as pale yellow crystals.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH2:10][C:9]2([CH2:15][CH2:14][CH:13]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:12][CH2:11]2)[O:8][N:7]=1)=[O:5])C.O.[OH-].[Li+]>CO.O>[C:16]([CH:13]1[CH2:14][CH2:15][C:9]2([O:8][N:7]=[C:6]([C:4]([OH:5])=[O:3])[CH2:10]2)[CH2:11][CH2:12]1)([CH3:19])([CH3:17])[CH3:18]
Reactant: CCOC(=O)C1=NOC2(CCC(C(C)(C)C)CC2)C1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(C)C1CCC2(CC1)CC(C(=O)O)=NO2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 8-tert-butyl-1-oxa-2-azaspiro[4.5]dec-2-ene-3-carboxylic acid ethyl ester (2.4 g, 9 mmol) in MeOH (50 ml) and lithium hydroxide monohydrate (1 g, 13.5 mmol) in H2O (8 ml) was stirred overnight at RT. After removal of the solvent under vacuum, the residue was taken up in 10% aq. citric acid solution and EtOAc and the phases were separated. The aqueous phase was extracted several times with EtOAc, dried over magnesium sulphate and desolventised under vacuum. 2.17 g (100% of the theoretical amount) of the free acid 8-tert-butyl-1-oxa-2-azaspiro[4.5]dec-2-ene-3-carboxylic acid was obtained in the form of a colourless solid.
Reaction SMILES: [CH:1]1([C:4]([NH:6][NH:7][C:8]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[N:15]([S:19]([C:22]2[CH:28]=[CH:27][C:25]([CH3:26])=[CH:24][CH:23]=2)(=[O:21])=[O:20])[CH:14]=[C:13]3[I:29])=[O:9])=O)[CH2:3][CH2:2]1.O=P(Cl)(Cl)Cl>O>[CH:1]1([C:4]2[O:9][C:8]([C:10]3[CH:11]=[C:12]4[C:16](=[CH:17][CH:18]=3)[N:15]([S:19]([C:22]3[CH:28]=[CH:27][C:25]([CH3:26])=[CH:24][CH:23]=3)(=[O:20])=[O:21])[CH:14]=[C:13]4[I:29])=[N:7][N:6]=2)[CH2:2][CH2:3]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(C(=O)NNC(=O)C4CC4)ccc32)cc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(-c4nnc(C5CC5)o4)ccc32)cc1
Temperature: 110 °C
Yield: 52.2 %

Procedure:
In a 50 mL RBF, N′-(cyclopropanecarbonyl)-3-iodo-1-tosyl-1H-indole-5-carbohydrazide (1.13 g, 2.159 mmol) was treated with POCl3 (5 mL, 53.6 mmol), under argon. The flask was fitted with a reflux condenser. The reaction was stirred and heated at 110° C. for 1.25 h. The crude material was treated with water and extracted with EtOAc. The organic layer was washed with brine, dried, filtered and concentrated to 20 mL of solvent. When about 20 mL of solvent remained, a brown solid precipitated and was collected by filtration. The mother liquor was purified with flash chromatography to give 2-cyclopropyl-5-(3-iodo-1-tosyl-1H-indol-5-yl)-1,3,4-oxadiazole (570 mg, 1.128 mmol, 52.2). MS (ESI, pos. ion) m/z: 506.0 (M+1). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.23 (s, 1H), 8.15 (d, J=8.6 Hz, 1H), 7.94-8.03 (m, 3H), 7.85 (s, 1H), 7.43 (d, J=8.0 Hz, 2H), 2.28-2.37 (m, 4H), 1.09-1.21 (m, 4H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([CH3:13])[CH:7]=[CH:6]2.[C:14]1(=[O:24])[NH:18][C:17](=[O:19])[C:16]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:15]12.[K]>CN(C=O)C>[CH3:13][C:8]1[CH:7]=[CH:6][C:5]2[C:10](=[CH:11][CH:12]=[C:3]([CH2:2][N:18]3[C:14](=[O:24])[C:15]4[C:16](=[CH:20][CH:21]=[CH:22][CH:23]=4)[C:17]3=[O:19])[CH:4]=2)[N:9]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: Cc1ccc2cc(CBr)ccc2n1
Agent: [K]
Solvent: CN(C)C=O
Product: Cc1ccc2cc(CN3C(=O)c4ccccc4C3=O)ccc2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.3 %

Procedure:
The compound (421.7 mg) obtained in Example 119-1 was dissolved in anhydrous DMF (12.6 ml) and added with potassium phthalimide (663.1 mg), followed by stirring at room temperature for 2 hours. After the reaction, the solvent was distilled off and the residue was then added with water. The mixture was extracted with chloroform and the extract was dried with magnesium sulfate. The solvent was distilled off and the residue was then purified through silica gel column chromatography (chloroform/ethyl acetate), thereby obtaining the subject compound (536.0 mg) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH3:19])[C@@H:12]([CH2:17]O)[C:13]([O:15]C)=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[OH-].[Na+]>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]([CH3:19])[C:12](=[CH2:17])[C:13]([OH:15])=[O:14])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: COC(=O)[C@H](CO)N(C)S(=O)(=O)c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: C=C(C(=O)O)N(C)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 80 °C
Yield: 56.5 %

Procedure:
A solution of 3C (8.5 g, 27.6 mmol) in dioxane (20 mL) was added with 20% NaOH aq. solution (30 mL) and the mixture heated at 80° C. for 5 h. The organic solvent was removed under reduced pressure and the aqueous phase acidified with 10% HCl and extracted with CH2Cl2 (3×50 mL). The combined organic phases were dried over Na2SO4 and evaporated under reduced pressure to afford 4C as a pale yellow deliquescent solid (4.3 g, 62% yield). 1HNMR (DMSO, 200 MHz) δ 2.91 (s, 3H), 5.58 (s, 1H), 6.09 (s, 1H), 7.72-7.60 (m, 4H), 13.05 (bs, 1H).
Reaction SMILES: Cl.[N:2]1([C:8]2[CH:9]=[CH:10][CH:11]=[C:12]3[C:17]=2[NH:16][C:15](=[O:18])[CH2:14][CH2:13]3)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[O:19]=[C:20]1[NH:29][C:28]2[N:27]=[C:26]([O:30][CH2:31][CH2:32][CH2:33][CH:34]=O)[CH:25]=[CH:24][C:23]=2[CH:22]=[CH:21]1>>[O:18]=[C:15]1[CH2:14][CH2:13][C:12]2[C:17](=[C:8]([N:2]3[CH2:7][CH2:6][N:5]([CH2:34][CH2:33][CH2:32][CH2:31][O:30][C:26]4[N:27]=[C:28]5[C:23]([CH:22]=[CH:21][C:20](=[O:19])[NH:29]5)=[CH:24][CH:25]=4)[CH2:4][CH2:3]3)[CH:9]=[CH:10][CH:11]=2)[NH:16]1
Reactant: O=C1CCc2cccc(N3CCNCC3)c2N1
Reactant: O=CCCCOc1ccc2ccc(=O)[nH]c2n1
Agent: Cl
Product: O=C1CCc2cccc(N3CCN(CCCCOc4ccc5ccc(=O)[nH]c5n4)CC3)c2N1

Procedure:
In a manner similar to that of other examples above, 8-piperazin-1-yl-3,4-dihydro-1H-quinolin-2-one hydrochloride (Chem. Pharm. Bull. 1984, 32, 2100–2110) was coupled by reductive amination to 4-(7-oxo-7,8-dihydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde followed by typical workup and purification to give the title compound. MS: APCI: M+1: 448.3 (Exact Mass: 447.23).
Reaction SMILES: [OH:1][CH2:2][C@@:3]12[C@@H:20]3[C@H:11]([C@H:12]4[C@@:16]([CH2:18][CH2:19]3)([CH3:17])[C:15](=[O:21])[CH2:14][CH2:13]4)[C@H:10]([CH3:22])[CH2:9][C:8]1=[CH:7][C:6](=[O:23])[CH2:5][CH2:4]2.[OH:24][CH2:25][C@@:26]12[C@@H:43]3[C@H:34]([C@H:35]4[C@@:39]([CH2:41][CH2:42]3)([CH3:40])[C:38](=[O:44])[CH2:37][CH2:36]4)[CH2:33][CH2:32][C:31]1=[CH:30][C:29](=[O:45])[CH2:28][C@@H:27]2[CH3:46].O[CH2:48][C@@]12[C@@H]3[C@H]([C@H]4[C@@](CC3)(C)C(=O)CC4)CCC1=CC(=O)CC2>>[OH:1][CH2:2][C@@:3]12[C@@H:20]3[C@H:11]([C@H:12]4[C@@:16]([CH2:18][CH2:19]3)([CH3:17])[C:15](=[O:21])[CH2:14][CH2:13]4)[C@H:10]([CH3:22])[CH2:9][C:8]1=[C:7]([CH3:25])[C:6](=[O:23])[CH2:5][CH2:4]2.[OH:24][CH2:25][C@@:26]12[C@@H:43]3[C@H:34]([C@H:35]4[C@@:39]([CH2:41][CH2:42]3)([CH3:40])[C:38](=[O:44])[CH2:37][CH2:36]4)[CH2:33][CH2:32][C:31]1=[C:30]([CH3:48])[C:29](=[O:45])[CH2:28][C@@H:27]2[CH3:46]
Reactant: C[C@@H]1CC2=CC(=O)CC[C@]2(CO)[C@H]2CC[C@]3(C)C(=O)CC[C@H]3[C@H]12
Reactant: C[C@H]1CC(=O)C=C2CC[C@@H]3[C@H](CC[C@]4(C)C(=O)CC[C@@H]34)[C@]21CO
Reactant: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43CO)[C@@H]1CCC2=O
Product: CC1=C2CC[C@@H]3[C@H](CC[C@]4(C)C(=O)CC[C@@H]34)[C@@]2(CO)[C@@H](C)CC1=O
Product: CC1=C2C[C@@H](C)[C@@H]3[C@H](CC[C@]4(C)C(=O)CC[C@@H]34)[C@@]2(CO)CCC1=O

Procedure:
Substituting 19-hydroxy-7α-methyl-4-androstene-3,17-dione and 19-hydroxy-1α-methyl-4-androstene-3,17-dione for the 19-hydroxy-4-androstene-3,17-dione above results in the preparation of 19-hydroxy-4,7α-dimethyl-4-androstene-3,17-dione and 19-hydroxy-1α,4-dimethyl-4-androstene-3,17-dione.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[O:14][C:13]([SH:15])=[N:12][N:11]=3)=[CH:9][C:4]=2[CH2:3][CH2:2]1.[F:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH2:20]Cl.[OH-].[Na+]>O>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[O:14][C:13]([S:15][CH2:20][C:19]4[CH:22]=[CH:23][CH:24]=[C:17]([F:16])[CH:18]=4)=[N:12][N:11]=3)=[CH:9][C:4]=2[CH2:3][CH2:2]1
Reactant: Fc1cccc(CCl)c1
Reactant: Sc1nnc(-c2ccc3c(c2)CCO3)o1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Fc1cccc(CSc2nnc(-c3ccc4c(c3)CCO4)o2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.3 %

Procedure:
A mixture of 5-(2,3-dihydro-1-benzofuran-5-yl)-1,3,4-oxadiazole-2-thiol (0.20 g, 0.91 mmol), 3-fluorobenzyl chloride (0.11 mL, 0.91 mmol), 1 M aqueous sodium hydroxide solution (1.00 mL, 1.00 mmol) and water (4 mL) was stirred overnight at room temperature. The precipitate was collected by filtration and recrystallized from hexane/ethyl acetate to give the title compound (0.21 g, yield 74%) as colorless crystals.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH:25](OC)[O:26]C)=[C:5]([C:21]([O:23][CH3:24])=[O:22])[CH:6]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N+:18]([O-:20])=[O:19])[C:7]=1[C:8]([O:10][CH3:11])=[O:9].C(=O)(O)[O-].[Na+]>CC(C)=O.Cl>[CH3:1][C:2]1[NH:3][C:4]([CH:25]=[O:26])=[C:5]([C:21]([O:23][CH3:24])=[O:22])[CH:6]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N+:18]([O-:20])=[O:19])[C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)C1=C(C)NC(C(OC)OC)=C(C(=O)OC)C1c1ccccc1[N+](=O)[O-]
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Product: COC(=O)C1=C(C)NC(C=O)=C(C(=O)OC)C1c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.5 %

Procedure:
A mixture of a solution of dimethyl 2-methyl-4-(2-nitrophenyl)-6-dimethoxymethyl-1,4-dihydropyridine-3,5-dicarboxylate (10.68 g) in acetone (110 ml) and 6 N hydrochloric acid (10 ml) was stirred at 25° C. for 3 hours, which was neutrallized with an aqueous sodium bicarbonate solution and acetone was distilled off under reduced pressure. The resultant reddish yellow oily precipitates were solidified, which were cracked finely, collected by filtration, washed with water and air dried over-night to give crude crystals of dimethyl 2-methyl-4-(2-nitrophenyl)-6-formyl-1,4-dihydropyridine-3,5-dicarboxylate (9.33 g).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[C:7]([CH2:20][CH2:21][CH3:22])[C:8]3[O:15][C:14]([C:16]([OH:18])=[O:17])=[CH:13][C:12](=[O:19])[C:9]=3[CH:10]=2)[N:5]=[C:4]([C:23]([OH:25])=[O:24])[CH:3]=1.C(=O)(O)[O-].[Na+:30]>O>[Cl:1][C:2]1[C:11]2[C:6](=[C:7]([CH2:20][CH2:21][CH3:22])[C:8]3[O:15][C:14]([C:16]([O-:18])=[O:17])=[CH:13][C:12](=[O:19])[C:9]=3[CH:10]=2)[N:5]=[C:4]([C:23]([O-:25])=[O:24])[CH:3]=1.[Na+:30].[Na+:30]
Reactant: CCCc1c2nc(C(=O)O)cc(Cl)c2cc2c(=O)cc(C(=O)O)oc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CCCc1c2nc(C(=O)[O-])cc(Cl)c2cc2c(=O)cc(C(=O)[O-])oc12
Yield: 85.1 %

Procedure:
6-Chloro-4-oxo-10-propyl-4H-pyrano[3,2-g]quinoline-2,8-dicarboxylic acid (0.629 g) suspended in water was treated with sodium bicarbonate (0.292 g) and stirred until complete dissolution occurred. The solution was filtered then treated with acetone. The precipitated product was collected by filtration and dried to give (0.6 g) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]([N:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]2[CH2:22][F:23])[C:9]2[C:4](=[C:5]([O:24][CH3:25])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[F:26][C:27]1[CH:33]=[CH:32][C:30]([NH2:31])=[C:29]([CH3:34])[CH:28]=1>CN(C)C=O>[ClH:1].[F:26][C:27]1[CH:33]=[CH:32][C:30]([NH:31][C:2]2[N:11]=[C:10]([N:12]3[CH2:21][CH2:20][C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[CH:13]3[CH2:22][F:23])[C:9]3[C:4](=[C:5]([O:24][CH3:25])[CH:6]=[CH:7][CH:8]=3)[N:3]=2)=[C:29]([CH3:34])[CH:28]=1
Reactant: Cc1cc(F)ccc1N
Reactant: COc1cccc2c(N3CCc4ccccc4C3CF)nc(Cl)nc12
Solvent: CN(C)C=O
Product: COc1cccc2c(N3CCc4ccccc4C3CF)nc(Nc3ccc(F)cc3C)nc12
Product: Cl
Yield: 15 %

Procedure:
In accordance with the same procedures as in Example 18, except that to a mixture of 3.3 g of the compound (9.0 mM) prepared in Example 9 and 15 ml of dimethylform-amide, 2.2 ml of 4-fluoro-2-methylaniline(20 mM) was added, 0.65 g of the title compound was prepared.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:23][C:24]([O:26][CH:27]([CH3:29])[CH3:28])=[O:25])[CH2:6][C@@H:5]1[CH3:30])(=[O:3])[CH3:2].[CH3:31][N:32]([CH3:37])[CH2:33][CH2:34][CH2:35]O.Cl.C(N=C=NCCCN(C)C)C>CN(C=O)C.CN(C)C1C=CN=CC=1.O.CCOC(C)=O>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:22]=[CH:21][C:17]([C:18]([O:20][CH2:35][CH2:34][CH2:33][N:32]([CH3:37])[CH3:31])=[O:19])=[CH:16][CH:15]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:23][C:24]([O:26][CH:27]([CH3:29])[CH3:28])=[O:25])[CH2:6][C@@H:5]1[CH3:30])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccc(-c3ccc(C(=O)O)cc3)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Reactant: CN(C)CCCO
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)N1c2ccc(-c3ccc(C(=O)OCCCN(C)C)cc3)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 15 %

Procedure:
To a solution of 4-((2S,4R)-1-acetyl-4-((isopropoxycarbonyl)amino)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)benzoic acid (for a preparation see Intermediate 21) (164 mg, 0.400 mmol) and 3-(dimethylamino)propan-1-ol (206 mg, 1.998 mmol) in DMF (3 mL) were added N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (153 mg, 0.799 mmol) and N,N-dimethylpyridin-4-amine (4.88 mg, 0.040 mmol). The resulting mixture was stirred at room temperature for 2 h, the reaction mixture was diluted with water and EtOAc was added. The layers were separated and the aqueous phase was extracted with EtOAc (×3). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was dissolved in a 1:1 MeOH/DMSO mixture and was purified by MDAP (HpH). The appropriate fractions were combined and concentrated under reduced pressure to give 3-(dimethylamino)propyl 4-((2S,4R)-1-acetyl-4-((isopropoxycarbonyl)amino)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)benzoate (29.3 mg, 15%) as a viscous colourless oil. LCMS (Formate, 2 min), Rt=0.75 min, MH+=476.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([C:6]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=3)[C:10]([CH2:19][CH2:20][O:21][NH2:22])=[C:9]2[CH3:23])=[O:7])=[CH:4][CH:3]=1.[O:26]=[CH:27][CH:28]([CH2:30]O)[OH:29]>>[Cl:1][C:2]1[CH:25]=[CH:24][C:5]([C:6]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=3)[C:10]([CH2:19][CH2:20][O:21][N:22]=[CH:30][CH:28]([CH2:27][OH:26])[OH:29])=[C:9]2[CH3:23])=[O:7])=[CH:4][CH:3]=1
Reactant: O=CC(O)CO
Reactant: COc1ccc2c(c1)c(CCON)c(C)n2C(=O)c1ccc(Cl)cc1
Product: COc1ccc2c(c1)c(CCON=CC(O)CO)c(C)n2C(=O)c1ccc(Cl)cc1

Procedure:
The title compound is prepared by reaction of O-2-[1-(4-chlorobenzoyl)-5-methoxy-2-methylindol-3-yl]ethylhydroxylamine with glyceraldehyde by the method of Example 1.
Reaction SMILES: [CH2:1]1[C:3]2([CH2:9][CH2:8][CH2:7][CH2:6][C:5]([CH2:10][OH:11])=[CH:4]2)[CH2:2]1.[H][H]>C(O)C.[Pt]=O>[CH2:1]1[C:3]2([CH2:9][CH2:8][CH2:7][CH2:6][CH:5]([CH2:10][OH:11])[CH2:4]2)[CH2:2]1
Reactant: OCC1=CC2(CCCC1)CC2
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CCO
Product: OCC1CCCCC2(CC2)C1
Yield: 95.2 %

Procedure:
To a solution of spiro[2.6]non-4-en-5-yl-methanol (170 mg) obtained in Step 4 in ethanol (3.4 mL) was added platinum oxide (35 mg), followed by stirring the reaction mixture at room temperature under normal pressure in an atmosphere of hydrogen for 2 hours. Then, the reaction mixture was filtered through Celite. The filtrate was concentrated and the residue was purified by column chromatography on silica gel (ethyl acetate:hexane (volume ratio)=1:7) to give spiro[2.6]non-5-yl-methanol (164 mg).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[O:9][C:8]([CH2:10][S:11][CH2:12][CH2:13][NH2:14])=[CH:7][CH:6]=1)[CH3:3].[C:15]([NH:17][C:18](SC)=[N:19][CH2:20][CH2:21][O:22][CH3:23])#[N:16]>>[C:15]([NH:17][C:18]([NH:14][CH2:13][CH2:12][S:11][CH2:10][C:8]1[O:9][C:5]([CH2:4][N:2]([CH3:1])[CH3:3])=[CH:6][CH:7]=1)=[N:19][CH2:20][CH2:21][O:22][CH3:23])#[N:16]
Reactant: COCCN=C(NC#N)SC
Reactant: CN(C)Cc1ccc(CSCCN)o1
Product: COCCN=C(NC#N)NCCSCc1ccc(CN(C)C)o1
Yield: 41.3 %

Procedure:
A mixture of 2-[[[5-(dimethylamino)methyl-2-furanyl]methyl]thio]ethanamine (2.14 g) and N-cyano-N'-(2-methoxyethyl)-carbamimidothioic acid, methyl ester (1.73 g) was heated on a steam bath for 6.5 hr. Vacuum was applied occasionally to remove methanethiol. The crude product was purified by chromatography (silica gel/methanol) to give N-cyano-N'-[2-[[[5-(dimethylamino)methyl-2-furanyl]methyl]thio]ethyl]-N"-(2-methoxyethyl)guanidine (1.4 g). Analysis Found: C, 50.51; H, 7.20; N, 19.41, C15H25N5O2S.H2O requires: C, 50.42; H, 7.50; N, 19.60%.