Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S([O-])([O-])=O.[Na+].[Na+].Cl[S:8]([C:11]1[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=1)(=[O:10])=[O:9].C(=O)(O)[O-].[Na+].CO>O>[S:8]([C:11]1[CH:12]=[CH:13][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:19][CH:20]=1)([OH:10])=[O:9]
Reactant: COC(=O)c1ccc(S(=O)(=O)Cl)cc1
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)c1ccc(S(=O)O)cc1
Temperature: 25 °C
Yield: 78.3 %

Procedure:
Sodium sulfite (15.3 g, 121.45 mMole), was dissolved in water (100 mL) and while stirring at room temperature, methyl 4-chlorosulfonylbenzoate (3), (19.0 g, 80.97 mMole) was added a little at a time to the solution. Sodium bicarbonate was added simultaneously in small portions keeping the solution at approximately pH 8. As the reaction proceeds, periodic addition of a little methanol from a wash bottle minimizes foaming. A total of 20 g of sodium bicarbonate were needed to complete the reaction. After complete addition of the reagents, the mixture was then stirred at room temperature for about 30 minutes. The mixture was then filtered. The clear solution was acidified with concentrated hydrochloric acid and treated with sufficient solid sodium chloride to precipitate the product. The white solid was filtered off and air-dried to give 12.7 g of methyl 4-sulfinobenzoate.
Reaction SMILES: Br[CH2:2][C@@H:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[C:7]([F:15])[CH:6]=1)[OH:4].[C-:16]#[N:17].[Na+]>CCO.O>[F:15][C:7]1[CH:6]=[C:5]([C@@H:3]([OH:4])[CH2:2][C:16]#[N:17])[CH:10]=[CH:9][C:8]=1[C:11]([F:14])([F:13])[F:12]
Reactant: [C-]#N
Reactant: O[C@@H](CBr)c1ccc(C(F)(F)F)c(F)c1
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: N#CC[C@H](O)c1ccc(C(F)(F)F)c(F)c1
Temperature: 50 °C
Reaction time: 8 h
Yield: 76.6 %

Procedure:
To a solution of 258 (0.8 g, 2.8 mmol) and EtOH:water (4:1) was heated to 50° C. was added NaCN (0.20 g, 4.2 mmol) and the reaction stirred at 50° C. overnight. The reaction was then cooled and concentrated to dryness then partitioned between H2O and EtOAc. The combined organic fractions were dried (MgSO4), filtered and concentrated in vacuo. The crude product was purified by SiO2 chromatography eluting with a hexane/EtOAc gradient (4:1 to 3:1) to afford 0.5 g (77%) of (S)-3-(3-fluoro-4-(trifluoromethyl)phenyl)-3-hydroxypropanenitrile (282).
Reaction SMILES: [Br:1][CH2:2][C:3](=[O:21])[CH2:4][C:5]([O:7][CH:8]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:6].[N:22]([O-])=[O:23].[Na+].[Cl-].[Na+]>C(O)(=O)C.O>[Br:1][CH2:2][C:3](=[O:21])[C:4](=[N:22][OH:23])[C:5]([O:7][CH:8]([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:6]
Reactant: O=C(CBr)CC(=O)OC(c1ccccc1)c1ccccc1
Reactant: O=N[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=C(CBr)C(=NO)C(=O)OC(c1ccccc1)c1ccccc1

Procedure:
In 30 ml of acetic acid there were dissolved 6.94 g of benzhydryl 4-bromo-3-oxobutyrate and, under ice-cooling and stirring, a solution of 1.588 g of sodium nitrite in 6 ml of water was added dropwise. The mixture was further stirred at that temperature for 20 minutes and, following addition of 60 ml of a saturated aqueous solution of sodium chloride, the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. The solvent was removed under reduced pressure to recover 7.56 g of the captioned compound.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([Cl:10])=[C:6]([CH:9]=1)[CH2:7]Br.[CH2:11]([NH:13][CH2:14][CH3:15])[CH3:12].[C:16](=[O:19])([O-])[O-].[K+].[K+]>C(#N)C>[Cl:10][C:5]1[CH:4]=[CH:3][C:2]([C:16]2([OH:19])[CH2:15][CH2:14][NH:13][CH2:11][CH2:12]2)=[CH:9][C:6]=1[CH2:7][N:13]([CH2:14][CH3:15])[CH2:11][CH3:12]
Reactant: O=C([O-])[O-]
Reactant: Clc1ccc(Br)cc1CBr
Reactant: CCNCC
Agent: [K+]
Solvent: CC#N
Product: CCN(CC)Cc1cc(C2(O)CCNCC2)ccc1Cl
Yield: 90 %

Procedure:
5-Bromo-2-chlorobenzylbromide (1.3 g) was dissolved in acetonitrile (30 ml). Diethylamine (334 mg) and potassium carbonate (2 g) were added thereto, and the mixture was heated under reflux for 1 hr. After completion of the reaction, the reaction mixture was filtrated, and the filtrate was concentrated. The obtained residue was purified by silica gel column chromatography (elution solvent: hexane-ethyl acetate (2:1-1:2)) to give a white solid. By a similar operation as in Starting Material Synthetic Example 45, 4-{4-chloro-3-[(diethylamino)methyl]phenyl}piperidin-4-ol (610 mg, yield 46%) was obtained from this white solid (1.24 g).
Reaction SMILES: [NH2:1][N:2]1[C:10]2[C:6]([N:7]3[N:13]([CH3:14])[C:12](=[O:15])[N:11]([CH2:16][CH2:17][OH:18])[CH:8]3[N:9]=2)=[C:5]([C:19]2[O:20][CH:21]=[CH:22][CH:23]=2)[N:4]=[CH:3]1.[C:24]1([CH3:34])[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1.CCCCCC>N1C=CC=CC=1>[CH3:34][C:24]1[CH:29]=[CH:28][C:27]([S:30]([O:18][CH2:17][CH2:16][N:11]2[CH:8]3[N:9]=[C:10]4[C:6]([N:7]3[N:13]([CH3:14])[C:12]2=[O:15])=[C:5]([C:19]2[O:20][CH:21]=[CH:22][CH:23]=2)[N:4]=[CH:3][N:2]4[NH2:1])(=[O:32])=[O:31])=[CH:26][CH:25]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CN1C(=O)N(CCO)C2N=C3C(=C(c4ccco4)N=CN3N)N21
Solvent: CCCCCC
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCN2C(=O)N(C)N3C4=C(c5ccco5)N=CN(N)C4=NC23)cc1
Temperature: 26 °C
Reaction time: 16 h
Yield: 79.1 %

Procedure:
A mixture of 5-amino-8-(2-furyl)-3-(2-hydroxyethyl)-1-methyl-[1,2,4]triazolo[5,1-f]purin-2-one obtained in step 6 (3.5 g, 11 mmol), p-toluene sulphonylchloride (5.2 g, 27 mmol) were taken in pyridine (30 ml) and stirred at 25-27° C. for 16 hours. To the reaction mixture hexane (100 ml) was added and solid obtained was filtered off and washed with water (100 ml) followed by hexane (100 ml) to obtain 2-[5-amino-8-(2-furyl)-1-methyl-2-oxo-[1,2,4]triazolo[5,1-f]purin-3-yl]ethyl 4-methylbenzenesulfonate (4.1 g, 78%) as a brown solid.
Reaction SMILES: FC1C=CC(N2C(C(O)=O)=CN=C2SCC2C(F)=CC=C(F)C=2F)=CC=1.[F:27][C:28]1[CH:33]=[CH:32][C:31]([N:34]2[C:38]([C:39]([O:41]CC)=[O:40])=[C:37]([CH3:44])[N:36]=[C:35]2[S:45][CH2:46][C:47]2[C:52]([F:53])=[CH:51][CH:50]=[C:49]([F:54])[C:48]=2[F:55])=[CH:30][CH:29]=1.[Li+].[OH-]>C1COCC1.CO>[F:27][C:28]1[CH:33]=[CH:32][C:31]([N:34]2[C:38]([C:39]([OH:41])=[O:40])=[C:37]([CH3:44])[N:36]=[C:35]2[S:45][CH2:46][C:47]2[C:52]([F:53])=[CH:51][CH:50]=[C:49]([F:54])[C:48]=2[F:55])=[CH:30][CH:29]=1
Reactant: CCOC(=O)c1c(C)nc(SCc2c(F)ccc(F)c2F)n1-c1ccc(F)cc1
Agent: O=C(O)c1cnc(SCc2c(F)ccc(F)c2F)n1-c1ccc(F)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1nc(SCc2c(F)ccc(F)c2F)n(-c2ccc(F)cc2)c1C(=O)O

Procedure:
1-(4-Fluorophenyl)-4-methyl-2-((2,3,6-trifluorobenzyl)thio)-1H-imidazole-5-carboxylic acid (59) was prepared in a similar manner as that described for the synthesis of compound 11 using ethyl 1-(4-fluorophenyl)-4-methyl-2-((2,3,6-trifluorobenzyl)thio)-1H-imidazole-5-carboxylate (58) (300 mg, 0.71 mmol), 1N LiOH (5 mL) in THF (5 mL) and MeOH (5 mL).
Reaction SMILES: [C:1]([C:4]1[N+:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=2)=[CH:7][NH:6][C:5]=1[O-:19])(=[O:3])[NH2:2].[C:20]([O:23][C@@H:24]1[C@H:29]([O:30][C:31](=[O:33])[CH3:32])[C@@H:28]([O:34][C:35](=[O:37])[CH3:36])[C@H:27]([CH3:38])[O:26][C@H:25]1Br)(=[O:22])[CH3:21]>>[N+:16]([C:13]1[CH:12]=[CH:11][C:10]([CH2:9][N:8]2[C:4]([C:1]([NH2:2])=[O:3])=[C:5]([O:19][C@@H:25]3[O:26][C@@H:27]([CH3:38])[C@H:28]([O:34][C:35](=[O:37])[CH3:36])[C@@H:29]([O:30][C:31](=[O:33])[CH3:32])[C@H:24]3[O:23][C:20](=[O:22])[CH3:21])[N:6]=[CH:7]2)=[CH:15][CH:14]=1)([O-:18])=[O:17]
Reactant: NC(=O)c1c([O-])[nH]c[n+]1Cc1ccc([N+](=O)[O-])cc1
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](C)O[C@@H](Br)[C@@H]1OC(C)=O
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](C)O[C@@H](Oc2ncn(Cc3ccc([N+](=O)[O-])cc3)c2C(N)=O)[C@@H]1OC(C)=O
Yield: 56.6 %

Procedure:
Following a procedure similar to that of Example 1 but using 2.88 g of 5-carbamoyl-1-(4-nitrobenzyl)imidazolium-4-olate and 7.77 g of 2,3,4-tri-O-acetyl-α-L-rhamnopyranosyl bromide there was obtained 3.32 g of 1-(4-nitrobenzyl)-4-(2,3,4-tri-O-acetyl-α-L-rhamnopyranosyl)oxy-1H-imidazole-5-carboxamide.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10]([O:16][C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24]([NH:26][C:27]4[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=4[F:34])=[O:25])=[C:19]([Cl:35])[CH:18]=3)=[N:11][CH:12]=[N:13]2)=[CH:8][C:7]=1[O:36][CH3:37].C(=O)([O-])[O-].[K+].[K+].[CH3:44][N:45]1[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]1.O>CN(C)C=O>[Cl:35][C:19]1[CH:18]=[C:17]([O:16][C:10]2[C:9]3[C:14](=[CH:15][C:6]([O:5][CH2:4][CH2:3][CH2:2][N:48]4[CH2:49][CH2:50][N:45]([CH3:44])[CH2:46][CH2:47]4)=[C:7]([O:36][CH3:37])[CH:8]=3)[N:13]=[CH:12][N:11]=2)[CH:22]=[CH:21][C:20]=1[NH:23][C:24]([NH:26][C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=1[F:34])=[O:25]
Reactant: COc1cc2c(Oc3ccc(NC(=O)Nc4ccc(F)cc4F)c(Cl)c3)ncnc2cc1OCCCBr
Reactant: CN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2c(Oc3ccc(NC(=O)Nc4ccc(F)cc4F)c(Cl)c3)ncnc2cc1OCCCN1CCN(C)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 95 %

Procedure:
A starting compound (N-(4-{[7-(3-bromopropoxy)-6-methoxy-4-quinazolinyl]oxy}-2-chlorophenyl)-N′-(2,4-difluorophenyl)urea, 59 mg), potassium carbonate (138 mg), and 1-methylpiperazine (0.055 ml) were dissolved in N,N-dimethylformamide (1 ml), and the solution was stirred at room temperature for 18 hr. Water was added to the reaction mixture, and the mixture was extracted with chloroform-propanol (3/1). The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed by distillation under the reduced pressure. The residue was washed with ether to give 58 mg (yield 95%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C@H:13]([CH3:17])[C:14]([OH:16])=[O:15])[CH:7]=[CH:6]2.O[CH2:19][P:20](=[O:27])([O:24][CH2:25][CH3:26])[O:21][CH2:22][CH3:23].Cl.CN(C)CCCN=C=NCC.Cl>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C@H:13]([CH3:17])[C:14]([O:16][CH2:19][P:20]([O:24][CH2:25][CH3:26])([O:21][CH2:22][CH3:23])=[O:27])=[O:15])[CH:7]=[CH:6]2
Reactant: COc1ccc2cc([C@H](C)C(=O)O)ccc2c1
Reactant: CCOP(=O)(CO)OCC
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CCOP(=O)(COC(=O)[C@@H](C)c1ccc2cc(OC)ccc2c1)OCC

Procedure:
A solution of (2S)-2-(6-methoxy(2-naphthyl))propanoic acid (4.8 g, 20.85 mmol), diethyl (hydroxymethyl)phosphonate (3.76 g, 22.36 mmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (4.29 g, 22.38 mmol) and 4-(dimethylamino)pyridine (catalytic amount) in CH2Cl2 (125 mL) were stirred at room temperature for 2 hours. The reaction was taken up with 0.3 N HCl (150 mL) and extracted with CH2Cl2 (3×50 mL). The combined extracts were washed with water (2×50 mL), dried over Na2SO4, and evaporated under reduced pressure. The product was purified by silica gel column chromatography eluting with 2:1 EtOAc:Hex to obtained the title compound as a viscous oil, 5.23 g (66%). 1H NMR (300 MHz, CDCl3) δ 7.70-7.68 (mult, 3H), 7.43-7.37 (mult, 1H), 7.15-7.09 (mult, 2H), 4.38 (d, JH-P=8.6 Hz, 2H), 4.05-3.85 (mult, 5H), 3.95 (s, 3H), 1.60 (d, J=7.2 Hz, 3H), 1.25-1.1 (mult, 6H); 13C NMR (75 MHz, CDCl3) δ 173.5 (d, JC-P=7.9 Hz), 157.7, 134.9, 133.7, 129.1, 128.8, 127.1, 126.1, 119.0, 105.5, 62.71, 62.62, 62.61, 62.52, 57.1 (d, JC-P=167.0 Hz), 55.2, 45.1, 18.3, 16.20, 16.18, 16.12, 16.11; mass spectrum (API-TIS) m/z 381 (M+H). Anal Calcd for C19H25O6P: C, 60.0; H, 6.62. Found: C, 59.83; H, 6.41.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[C:5]([C:9]1[N:14]=[C:13]([N:15]2[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][CH2:23]Cl)[CH2:17][CH2:16]2)[CH:12]=[C:11]([C:25]([F:28])([F:27])[F:26])[N:10]=1)([CH3:8])([CH3:7])[CH3:6]>CN(C)C=O.[Cl-].[Na+].O>[N:1]([CH2:23][CH2:22][CH2:21][N:18]1[CH2:17][CH2:16][N:15]([C:13]2[CH:12]=[C:11]([C:25]([F:27])([F:28])[F:26])[N:10]=[C:9]([C:5]([CH3:6])([CH3:8])[CH3:7])[N:14]=2)[CH2:20][CH2:19]1)=[N+:2]=[N-:3]
Reactant: CC(C)(C)c1nc(N2CCN(CCCCl)CC2)cc(C(F)(F)F)n1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)c1nc(N2CCN(CCCN=[N+]=[N-])CC2)cc(C(F)(F)F)n1
Temperature: 70 °C
Reaction time: 3 h

Procedure:
2.4 g (36.9 mmol) of sodium azide were added to 13.5 g (36.9 mmol) of 2-tert-butyl-4-[4-(3-chloropropyl)piperazin-1-yl]-6-(trifluoromethyl)pyrimidine (DE 197 35 410) in 60 ml of N,N-dimethylformamide (DMF), and the mixture was stirred at 70° C. for 3 hours. The reaction mixture was allowed to cool to room temperature, the mixture was poured into saturated brine, and the aqueous mixture was extracted with ethyl acetate. The organic phase was washed three times with an NaCl solution, dried over Na2SO4, filtered to remove the desiccant and concentrated in vacuo. Yield: 13.7 g.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][C:8]1[CH:17]=[C:16]2[C:11]([C:12](=[O:26])[N:13]([CH2:18][O:19][C:20](=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22])[CH:14]=[N:15]2)=[CH:10][C:9]=1[O:27][CH3:28].[O:29]1[CH2:34][CH2:33][N:32]([CH2:35][CH2:36][CH2:37]Cl)[CH2:31][CH2:30]1>CN(C)C=O>[CH3:28][O:27][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:8]=1[O:7][CH2:37][CH2:36][CH2:35][N:32]1[CH2:33][CH2:34][O:29][CH2:30][CH2:31]1)[N:15]=[CH:14][N:13]([CH2:18][O:19][C:20](=[O:25])[C:21]([CH3:22])([CH3:23])[CH3:24])[C:12]2=[O:26]
Reactant: COc1cc2c(=O)n(COC(=O)C(C)(C)C)cnc2cc1O
Reactant: ClCCCN1CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(=O)n(COC(=O)C(C)(C)C)cnc2cc1OCCCN1CCOCC1
Temperature: 100 °C
Reaction time: 6 h
Yield: 65.4 %

Procedure:
Potassium carbonate (4.51 g) was added to 7-hydroxy-6-methoxy-3-pivaloyloxymethyl-3,4-dihydroquinazolin-4-one (2.0 g) in dimethylformamide (50 ml) followed by 3-morpholinopropyl chloride (1.3 g) and the reaction was stirred at 100° C. for 6 hours. After cooling the solid was removed by filtration and the filtrate was evaporated and was purified by eluting through a silica column with 10% methanol in methylene chloride to yield 6-methoxy-7-(3-morpholinopropoxy)-3-pivaloyloxymethyl-3,4-dihydroquinazolin-4-one as a solid (1.85 g, 65%); NMR: 1.1 (s, 9H), 1.9 (m, 2H), 2.4 (broad m, 6H), 3.55 (m, 4H), 3.88 (s, 3H), 4.16 (m, 2H), 5.89 (s, 2H), 7.13 (s, 1H), 7.47 (s, 1H), 8.32 (s, 1H); m/s: M+H+ 434.
Reaction SMILES: C(OC([NH:8][C:9]1[CH2:10][C:11]([C:33](O)=[O:34])=[CH:12][C:13]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][C:23]([C:26]([N:28]4[CH2:32][CH2:31][CH2:30][CH2:29]4)=[O:27])=[CH:22][CH:21]=3)=[CH:16][C:14]=2[N:15]=1)=O)(C)(C)C.[Si]([O:43][CH:44]([CH3:50])[CH2:45][NH:46][CH2:47][CH2:48][CH3:49])(C(C)(C)C)(C)C>>[NH2:8][C:9]1[CH2:10][C:11]([C:33]([N:46]([CH2:45][CH:44]([OH:43])[CH3:50])[CH2:47][CH2:48][CH3:49])=[O:34])=[CH:12][C:13]2[CH:19]=[CH:18][C:17]([C:20]3[CH:21]=[CH:22][C:23]([C:26]([N:28]4[CH2:32][CH2:31][CH2:30][CH2:29]4)=[O:27])=[CH:24][CH:25]=3)=[CH:16][C:14]=2[N:15]=1
Reactant: CCCNCC(C)O[Si](C)(C)C(C)(C)C
Reactant: CC(C)(C)OC(=O)NC1=Nc2cc(-c3ccc(C(=O)N4CCCC4)cc3)ccc2C=C(C(=O)O)C1
Product: CCCN(CC(C)O)C(=O)C1=Cc2ccc(-c3ccc(C(=O)N4CCCC4)cc3)cc2N=C(N)C1

Procedure:
The title compound was prepared by the procedures as described in Example 101 (Steps H and I) using (1E,4E)-2-(tert-butoxycarbonylamino)-8-(4-(pyrrolidine-1-carbonyl)phenyl)-3H-benzo[b]azepine-4-carboxylic acid and 2-(tert-butyldimethylsilyloxy)-N-propylpropan-1-amine. MS APCI(+) m/z 475 (M+1) detected; 1H-NMR (400 MHz, CDCl3) δ 7.67 (d, 2H), 7.60 (d, 2H), 7.49 (s, 1H), 7.29-7.34 (m, 2H), 6.87 (s, 1H), 4.11 (br s, 1H), 3.48-3.71 (m, 7H), 3.29 (dd, 1H), 2.93 (d, 1H), 2.80 (d, 1H), 1.86-2.01 (m, 4H), 1.61-1.74 (m, 2H), 1.22 (d, 3H), 0.91 (t, 3H).
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:13][C@@H:14]([OH:17])[CH2:15]Cl)([CH2:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)=[O:5])[CH3:2].[C:18]([C:20]1[CH:21]=[C:22]([CH:26]([NH2:28])[CH3:27])[CH:23]=[CH:24][CH:25]=1)#[N:19].CCN(C(C)C)C(C)C>C(O)C>[CH2:1]([O:3][P:4]([CH2:13][C@@H:14]([OH:17])[CH2:15][NH:28][CH:26]([C:22]1[CH:23]=[CH:24][CH:25]=[C:20]([C:18]#[N:19])[CH:21]=1)[CH3:27])([CH2:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)=[O:5])[CH3:2]
Reactant: CC(N)c1cccc(C#N)c1
Reactant: CCOP(=O)(CC1CCCCC1)C[C@@H](O)CCl
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CCOP(=O)(CC1CCCCC1)C[C@@H](O)CNC(C)c1cccc(C#N)c1
Temperature: 25 °C

Procedure:
A mixture of 5.65 g of 3-chloro-2(R)-hydroxy-propyl(cyclohexylmethyl)phosphinic acid ethyl ester, 2.92 g of N-[1-(3-cyanophenyl)ethyl]amine, 2.60 g of Hunig base and 10 ml of ethanol is heated under reflux for 5 days, then cooled to room temperature and concentrated by evaporation. Chromatography of the residue on silica gel gives 3-{N-[1-(3-cyanophenyl)ethyl]amino}-2(S)-hydroxy-propyl(cyclohexylmethyl)phosphinic acid ethyl ester in the form of an oil; [α]D 20 =+8.6 0.8(c=1.225 in trichloromethane).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][CH2:6][CH2:5]2.[I:13]C1C=CC=CN=1.CN[C@@H]1C[CH2:26][CH2:25][CH2:24][C@H:23]1[NH:28][CH3:29].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C(OCC)(=O)C.O1CCOCC1>[I:13][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:29][N:28]=1)[CH2:6][CH2:5]2
Reactant: Ic1ccccn1
Reactant: CN[C@@H]1CCCC[C@H]1NC
Reactant: O=C1NCCc2cc(Br)ccc21
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: O=C1c2ccc(I)cc2CCN1c1ccccn1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
5 mL of 1,4-dioxane was added to 552 mg of 6-bromo-3,4-dihydroisoquinolin-1(2H)-one, 0.521 mL of 2-iodopyridine, 0.077 mL of trans-N,N′-dimethylcyclohexane-1,2-diamine and 622 mg of tripotassium phosphate, and stirred at 100° C. for 2 hours. Ethyl acetate was added to the reaction liquid, washed with aqueous saturated ammonia solution and saturated saline water, and dried with anhydrous magnesium sulfate. The solvent was evaporated away, and the residue was purified through silica gel column chromatography (hexane/ethyl acetate) to obtain 582 mg of a mixture (1/1) of the entitled compound with 6-iodo-2-pyridin-2-yl-3,4-dihydroisoquinolin-1(2H)-one as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:11]([OH:12])=[C:10]([OH:13])[CH:9]=[C:8]2[C:3]=1[C:4](=[O:19])[C:5]([C:16]([OH:18])=[O:17])=[N:6][N:7]2[CH2:14][CH3:15].[C:20](=[O:23])([O-])[O-].[K+].[K+].Cl[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=1.ClCCl>CN(C)C=O>[Cl:1][C:2]1[C:11]([O:12][CH2:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=2)=[C:10]([O:13][CH2:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=2)[CH:9]=[C:8]2[C:3]=1[C:4](=[O:19])[C:5]([C:16]([O:18][CH2:4][C:3]1[CH:8]=[CH:9][C:10]([O:23][CH3:20])=[CH:11][CH:2]=1)=[O:17])=[N:6][N:7]2[CH2:14][CH3:15]
Reactant: COc1ccc(CCl)cc1
Reactant: O=C([O-])[O-]
Reactant: CCn1nc(C(=O)O)c(=O)c2c(Cl)c(O)c(O)cc21
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCn1nc(C(=O)OCc2ccc(OC)cc2)c(=O)c2c(Cl)c(OCc3ccc(OC)cc3)c(OCc3ccc(OC)cc3)cc21
Temperature: 50 °C
Yield: 84.6 %

Procedure:
To a solution of 5-chloro-1-ethyl-6,7-dihydroxy-4-oxo-1,4-dihydrocinnoline-3-carboxylic acid (1.46 g, 5.13 mmol) in N,N-dimethylformamide (DMF) (20 mL) was added potassium carbonate (1.772 g, 12.82 mmol) followed by 1-(chloromethyl)-4-methoxybenzene (1.392 mL, 10.26 mmol). The mixture was heated at 50° C. for 12 h, extracted with ethyl acetate and washed with water, brine, dried over magnesium sulfate. The solvent was removed under vacuum and the residue was chromatographed on ISCO silica column eluting with 0-10% methanol:dichloromethane to afford 4-methoxybenzyl 5-chloro-1-ethyl-6,7-bis((4-methoxybenzyl)oxy)-4-oxo-1,4-dihydrocinnoline-3-carboxylate (1.4 g, 2.170 mmol, 42.3% yield). LCMS: (M+H)+: 645.2
Reaction SMILES: [NH2:1](=S)[NH2:2].[C:4]([OH:7])(=O)[CH3:5].[C:8]1(C)[CH:13]=[CH:12]C=[CH:10][CH:9]=1>C1(C)C(C)=CC=CC=1>[NH:1]1[C:10]2[CH:5]([CH2:12][CH2:13][CH2:8][CH:9]=2)[C:4](=[O:7])[NH:2]1
Reactant: Cc1ccccc1
Reactant: CC(=O)O
Solvent: Cc1ccccc1C
Product: O=C1NNC2=CCCCC12

Procedure:
The aminosulfide (IV) is then reacted with conc. hydrochloric acid at a temperature of 0° to 40° C., followed by reacting the resultant hydrochloride with 1.0 to 1.5 equivalents of sodium nitrite at -10° to 5° C. to form the diazonium salt. The diazonium salt is reduced with 3.0 to 10 equivalents (in regard to the aminosulfide (IV)) of stannous chloride at 0° to -40° C. to obtain the hydrazine hydrochloride, which is neutralized with an equeous alkaline solution (e.g. sodium hydroxide, potassium hydroxide, potassium carbonate) to obtain the hydrazine sulfide (V). The thus obtained hydrazine sulfide (V) is reacted with 1.0 to 1.2 equivalents of 2-alkoxycarbonylcyclohexanone in a solvent (e.g. acetic acid, toluene, xylene) at a temperature of 50° to 200° C. (preferably 80° to 150° C.) optionally while dehydrating by azeotropic distillation or in the presence of molecular sieve to give the hexahydroindazol-3-one (II).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].[CH3:12][C:13]1[CH:14]=[C:15]([CH:17]=[C:18]([CH3:20])[CH:19]=1)[NH2:16]>>[CH3:12][C:13]1[CH:14]=[C:15]([NH:16][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH2:8][C:9]([OH:11])=[O:10])[CH:17]=[C:18]([CH3:20])[CH:19]=1
Reactant: O=C(O)Cc1ccccc1Br
Reactant: Cc1cc(C)cc(N)c1
Product: Cc1cc(C)cc(Nc2ccccc2CC(=O)O)c1

Procedure:
In the manner described in example 3, 2-bromophenylacetic acid is condensed with 3,5-dimethylaniline to yield 2-[(3,5-dimethylphenyl)amino]phenylacetic acid.
Reaction SMILES: [CH3:1][Si](C=[N+]=[N-])(C)C.[CH3:8][C:9]1[CH:10]=[CH:11][C:12]([C:16]([OH:18])=[O:17])=[N:13][C:14]=1[CH3:15]>CCCCCC.CO.ClCCl>[CH3:1][O:17][C:16]([C:12]1[CH:11]=[CH:10][C:9]([CH3:8])=[C:14]([CH3:15])[N:13]=1)=[O:18]
Reactant: Cc1ccc(C(=O)O)nc1C
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: ClCCl
Solvent: CO
Solvent: CCCCCC
Product: COC(=O)c1ccc(C)c(C)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
77.4 ml 2 mol/L trimethylsilyldiazomethan in hexane was added to 5,6-dimethyl-pyridine-2-carboxylic acid in 150 mL methanol and 600 mL dichlormethane at −5° C. and the reaction was stirred for 0.5 h. After warming to RT the solvent was removed and the residue was purified by chromatorgaphie on Silica (cyclohexane/ethyl acetate:7/3) to give 12.8 g of the desired product.
Reaction SMILES: [CH2:1]([C:4]1([CH2:19][CH:20]=O)[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[CH2:8][CH2:7][C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]1=2)[CH:2]=[CH2:3].Cl.[NH2:23][OH:24].N1C=CC=CC=1>ClCCl>[CH2:1]([C:4]1([CH2:19][CH:20]=[N:23][OH:24])[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[CH2:8][CH2:7][C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]1=2)[CH:2]=[CH2:3]
Reactant: C=CCC1(CC=O)c2ccccc2CCc2ccccc21
Reactant: NO
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: C=CCC1(CC=NO)c2ccccc2CCc2ccccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 61.6 %

Procedure:
Dissolved 2-[10,11-dihydro-5-(2-propenyl)-5H-dibenzo[a,d]cyclohepten-5-yl]-ethanal (1.00 g, 3.62 mmol) in 10 mL of dry dichloromethane under a nitrogen atmosphere. Added 3A sieves, hydroxylamine hydrochloride (0.38 g, 5.43 mmol), and pyridine (0.58 mL, 0.57 g, 7.24 mmol). Stirred at room temperature for 16 hours. Filtered to remove sieve dust, and washed solid with water and dichloromethane. Separated layers of filtrate. Dried organic solution with MgSO4, filtered, and evaporated. Purified crude product by flash chromatography on silica gel eluting with 20% EtOAc-CH2Cl2. Combined appropriate fractions and evaporated to give 0.65 g (62% yield) of 2-[10,11-dihydro-5-(2-propenyl)-5H-dibenzo[a,d]cyclohepten-5-yl]-ethanone oxime as a colorless oil.