Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.O[C:7]1[N:8]=[C:9]2[NH:16][C@:15]([CH3:21])([C:17]([F:20])([F:19])[F:18])[CH2:14][N:10]2[C:11](=[O:13])[CH:12]=1.[OH-].[Na+]>ClCCCl.O.C(OCC)(=O)C>[Cl:3][C:7]1[N:8]=[C:9]2[NH:16][C@:15]([CH3:21])([C:17]([F:20])([F:19])[F:18])[CH2:14][N:10]2[C:11](=[O:13])[CH:12]=1
Reactant: C[C@@]1(C(F)(F)F)Cn2c(nc(O)cc2=O)N1
Reactant: O=P(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: ClCCCl
Solvent: O
Product: C[C@@]1(C(F)(F)F)Cn2c(nc(Cl)cc2=O)N1
Temperature: 70 °C
Yield: 53 %

Procedure:
41.60 mL (446.50 mmol) of phosphorus oxychloride are added, at room temperature and under an argon atmosphere, to a suspension of 35 g (148.80 mmol) of (S)-7-hydroxy-2-methyl-2-trifluoromethyl-2,3-dihydro-1H-imidazo[1,2-a]pyrimidin-5-one in 350 mL of 1,2-dichloroethane. The resulting mixture is then heated at 70° C. for 4 hours. After cooling, the reaction mixture is evaporated to dryness under vacuum. The residue obtained is taken up in 35 mL of cold water and 500 mL of ethyl acetate. 32% sodium hydroxide is added to the mixture obtained, to pH=6-7. The organic phase is then separated out and then dried over magnesium sulfate, filtered and concentrated under reduced pressure to give 20 g of (S)-7-chloro-2-methyl-2-trifluoromethyl-2,3-dihydro-1H-imidazo[1,2-a]pyrimidin-5-one, the characteristics of which are as follows:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH2:15][C:16]2[O:20][CH:19]=[C:18]([C:21](O)=[O:22])[CH:17]=2)[CH3:14])(=[O:12])=[O:11])=[C:5]([CH3:24])[CH:4]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[N:37]1([CH2:42][C:43]2[CH:44]=[C:45]([CH2:49][NH2:50])[CH:46]=[CH:47][CH:48]=2)[CH2:41][CH2:40][CH2:39][CH2:38]1.CCN(C(C)C)C(C)C>ClCCCl>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH2:15][C:16]2[O:20][CH:19]=[C:18]([C:21]([NH:50][CH2:49][C:45]3[CH:46]=[CH:47][CH:48]=[C:43]([CH2:42][N:37]4[CH2:41][CH2:40][CH2:39][CH2:38]4)[CH:44]=3)=[O:22])[CH:17]=2)[CH3:14])(=[O:12])=[O:11])=[C:5]([CH3:24])[CH:4]=1
Reactant: COc1cc(C)c(S(=O)(=O)N(C)Cc2cc(C(=O)O)co2)c(C)c1
Reactant: NCc1cccc(CN2CCCC2)c1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: COc1cc(C)c(S(=O)(=O)N(C)Cc2cc(C(=O)NCc3cccc(CN4CCCC4)c3)co2)c(C)c1

Procedure:
The title compound was prepared according to general procedure AE using 5-({[(4-Methoxy-2,6-dimethylphenyl)sulfonyl](methyl)amino}methyl)furan-3-carboxylic acid (60 mg, 0.16 mmol), CDI (48 mg, 0.29 mmol), 1-[3-(pyrrolidin-1-ylmethyl)phenyl]methanamine (28 mg, 0.15 mmol) and DIPEA (0.17 mL, 0.97 mmol) in DCE (2 mL).
Reaction SMILES: CN(C=O)C.[NH:6]1[CH:10]=[CH:9][N:8]=[C:7]1[C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[Na+].[Na+].[N+:23]([C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH2:29]Cl)([O-:25])=[O:24]>O>[N+:23]([C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH2:29][N:6]1[CH:10]=[CH:9][N:8]=[C:7]1[C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1)([O-:25])=[O:24]
Reactant: c1cc(-c2ncc[nH]2)ccn1
Reactant: O=[N+]([O-])c1cccc(CCl)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cccc(Cn2ccnc2-c2ccncc2)c1
Temperature: 50 °C

Procedure:
DMF (20 mL) is added to 4-(1H-Imidazol-2-yl)-pyridine (930 mg, 6.4 mmol), sodium carbonate (1.92 g, 20 mmol), and 3-nitrobenzyl chloride (1.71 g, 10 mmol) and the mixture is warmed to 50° C. for 4 h. Water (100 mL) is added and the corresponding mixture is extracted with EtOAc (100 mL), dried over anhydrous sodium sulfate, and crude solution is concentrated under reduced pressure. The organics are dissolved in DCM and filtered through a plug of silica eluting first with DCM, and then washing with 20% MeOH:80% DCM to afford 4-[1-(3-Nitro-benzyl)-1H-imidazol-2-yl]-pyridine as an off-white solid.
Reaction SMILES: [C:1]([C:4]1[N:8]([CH3:9])[N:7]=[C:6]([CH2:10][CH2:11][CH3:12])[C:5]=1[NH:13][C:14](=O)[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[O:22][CH3:23])(=[O:3])[NH2:2].[OH-].[Na+]>>[CH3:23][O:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[CH2:15][C:14]1[NH:2][C:1](=[O:3])[C:4]2[N:8]([CH3:9])[N:7]=[C:6]([CH2:10][CH2:11][CH3:12])[C:5]=2[N:13]=1
Reactant: CCCc1nn(C)c(C(N)=O)c1NC(=O)Cc1ccccc1OC
Agent: [Na+]
Agent: [OH-]
Product: CCCc1nn(C)c2c(=O)[nH]c(Cc3ccccc3OC)nc12
Temperature: 150 °C

Procedure:
N-(5-carbamoyl-1-methyl-3-propyl-1H-4-pyrazolyl)-2-(2-methoxyphenyl)acetamide (750 mg, 0.00228 mol) was suspended in polyphosphoric acid (10 ml) and heated under nitrogen at 150° C. for 4 hours. On cooling, the solution was added to ice and the pH adjusted to 5 with aqueous 10N sodium hydroxide solution. The aqueous phase was extracted with dichloromethane (3×10 ml), the organic extracts combined, dried (MgSO4), filtered and concentrated under reduced pressure.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][NH:8][C:9](=[O:11])[CH3:10].CC1C=CC=C(C)N=1.[Cl:20][C:21]1[CH:22]=[N+:23]([O-])[CH:24]=[C:25]([Cl:29])[C:26]=1[CH2:27][Cl:28].C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[Cl:20][C:21]1[C:22]([N:8]([CH3:7])[C:9](=[O:11])[CH3:10])=[N:23][CH:24]=[C:25]([Cl:29])[C:26]=1[CH2:27][Cl:28]
Reactant: CNC(C)=O
Reactant: [O-][n+]1cc(Cl)c(CCl)c(Cl)c1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CC(=O)N(C)c1ncc(Cl)c(CCl)c1Cl
Reaction time: 0.33 h

Procedure:
Oxalyl dichloride (45 μL, 0.47 mmol) was added dropwise to a solution of N-methylacetamide (36 μL, 0.47 mmol) and 2,6-dimethyl-pyridine (55 μL, 0.47 mmol) in anhydrous DCM (10 mL) at 0° C. After stirring for 20 min, 3,5-dichloro-4-chloromethyl-pyridine 1-oxide (10 mg, 0.047 mmol) was added to it and stirring was continued overnight at 45° C. Saturated aqueous Na2CO3 solution (20 mL) and DCM (40 mL) were added to the reaction mixture. The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography over silica gel (elution with EA/hexane 1:3) to give the title compound. MS (m/z): 267.4 [M+H+].
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][N:3]=1.B(O)(O)[C:13]1[CH:14]=[CH:15][C:16]([CH3:19])=[CH:17][CH:18]=1.C([O-])([O-])=O.[Na+].[Na+]>COC.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>[C:16]1([CH3:19])[CH:17]=[CH:18][C:13]([C:2]2[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][N:3]=2)=[CH:14][CH:15]=1
Reactant: Cc1ccc(B(O)O)cc1
Reactant: FC(F)(F)c1cccnc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: COC
Agent: O=C([O-])[O-]
Product: Cc1ccc(-c2ncccc2C(F)(F)F)cc1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a de-gassed mixture of 2-chloro-3-(trifluoromethyl)-pyridine (70.1 mmol), p-tolylboronic acid (70.6 mmol), and 2M Na2CO3 (175.0 mmol), in dimethyl ether (DME; 200 mL) under nitrogen add Pd(PPh3)4 (2.8 mmol). Stir the mixture at 80° C. overnight, concentrate, and extract with EtOAc. Dry over Na2SO4, concentrate under vacuum, and pass through a silica gel pad to give 2-p-tolyl-3-trifluoromethyl-pyridine.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:15])=[CH:4][C:5]2[S:9][C:8](=[O:10])[N:7]([CH2:11][C:12]#[CH:13])[C:6]=2[CH:14]=1.[C:16]1(=O)[O:21][C:19](=[O:20])[C:18]2[CH2:22][CH2:23][CH2:24][CH2:25][C:17]1=2.O>C(O)(=O)C>[F:15][C:3]1[C:2]([N:1]2[C:19](=[O:20])[C:18]3[CH2:22][CH2:23][CH2:24][CH2:25][C:17]=3[C:16]2=[O:21])=[CH:14][C:6]2[N:7]([CH2:11][C:12]#[CH:13])[C:8](=[O:10])[S:9][C:5]=2[CH:4]=1
Reactant: C#CCn1c(=O)sc2cc(F)c(N)cc21
Reactant: O=C1OC(=O)C2=C1CCCC2
Solvent: CC(=O)O
Solvent: O
Product: C#CCn1c(=O)sc2cc(F)c(N3C(=O)C4=C(CCCC4)C3=O)cc21
Yield: 18.9 %

Procedure:
5-Amino-6-fluoro-3-(2-propynyl)-2(3H)-benzothiazolone (0.43 g) and 3,4,5,6-tetrahydrophthalic anhydride (0.32 g) were suspended in acetic acid (5 ml), and the resultant suspension was heated under reflux for 5 hours. After being allowed to cool, water was added thereto, and the resultant mixture was extracted with ethyl acetate. The extract was washed with water and an aqueous sodium bicarbonate solution, dried and concentrated. The residue was purified by silica gel thin layer chromatography with a mixture of ethyl acetate and hexane (1:4) to give 2-[6-fluoro-3-(2-propynyl)-2(3H)-benzothiazolon-5-yl]-4,5,6,7-tetrahydro-2H-isoindole-1,3-dione (0.13 g). m.p., 193°-195° C. Recrystallization from 2-propanol gave the purified product. m.p., 198°-199° C.
Reaction SMILES: [NH2:1][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4].[Br:7][C:8]1[CH:9]=[C:10]([S:14](Cl)(=[O:16])=[O:15])[CH:11]=[CH:12][CH:13]=1>>[Br:7][C:8]1[CH:9]=[C:10]([S:14]([NH:1][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4])(=[O:16])=[O:15])[CH:11]=[CH:12][CH:13]=1
Reactant: CC(C)(N)CO
Reactant: O=S(=O)(Cl)c1cccc(Br)c1
Product: CC(C)(CO)NS(=O)(=O)c1cccc(Br)c1
Yield: 88.7 %

Procedure:
Prepared by general procedure III from 2-amino-2-methyl-1-propanol (8.91 g, 100 mmol) and commercially available 3-bromobenzenesulfonyl chloride (2.88 mL, 20 mmol) to give the title compound as a white solid (5.47 g, 89%). MS (ISN) 306.1 [(M−H)−], 308.2 [(M+2−H)−]. mp 138° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[S:20]([CH3:23])(=[O:22])=[O:21])[CH2:5][N:6]1C(=O)C2C(=CC=CC=2)C1=O.O.NN>CO.ClCCl>[F:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[S:20]([CH3:23])(=[O:22])=[O:21])[CH2:5][NH2:6]
Reactant: CS(=O)(=O)c1ccc(CN2C(=O)c3ccccc3C2=O)cc1F
Agent: NN
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: CS(=O)(=O)c1ccc(CN)cc1F
Temperature: 60 °C
Reaction time: 3 h

Procedure:
The purified intermediate 2-(3-fluoro-4-methylsulfonyl-benzyl)-isoindole-1,3-dione (5.50 g, 15.6 mmol) is dissolved in a mixture of methanol (250 mL) and dichloromethane (250 mL). Hydrazine hydrate (4.6 g, 78.4 mmol) is added, and the mixture is stirred at 60° C. for 3 h. The mixture is filtered, and the filtrate is treated with water. The mixture is extracted with ethyl acetate, and the organic layer is dried over Na2SO4 and concentrated under reduced pressure. The residue is purified by preparative reversed-phase HPLC (Luna C18 250*50 mm, gradient of acetonitrile in water, 0.1% TFA). Yield: 3.1 g (81% of theory); ESI mass spectrum: [M+H]+=204; Retention time HPLC: 0.17 min (X012_S01).
Reaction SMILES: [H-].[Na+].[SH:3][C:4]1[N:5]([CH3:9])[CH:6]=[CH:7][N:8]=1.F[C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=1[N+:18]([O-:20])=[O:19].[Cl-].[Na+]>CN(C)C=O.O.C(O)(=O)C>[F:17][C:14]1[CH:15]=[CH:16][C:11]([S:3][C:4]2[N:5]([CH3:9])[CH:6]=[CH:7][N:8]=2)=[C:12]([N+:18]([O-:20])=[O:19])[CH:13]=1
Reactant: Cn1ccnc1S
Reactant: O=[N+]([O-])c1cc(F)ccc1F
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: Cn1ccnc1Sc1ccc(F)cc1[N+](=O)[O-]
Reaction time: 0.5 h
Yield: 27.6 %

Procedure:
To a mixture of 0.6 g of 60% sodium hydride in mineral oil in 25 ml of N,N-dimethylformamide was added 1.1 g (10 mmoles) of 2-mercapto-1-methylimidazole. After stirring for 30 minutes, 1.6 g (10 mmoles) of 2,5-difluoronitrobenzene was added and the mixture stirred at room temperature for 16 hours. After adding 0.5 ml of acetic acid, the mixture was poured into a mixture of ice, water and sodium chloride. After standing for 1 hour the solid was collected by filtration, washed with water and dried. The crude product was purified by chromatography on silica gel using ethyl acetate as the eluent. The fractions containing the product were combined and concentrated to give 0.7 g (28%) of the product as yellow prisms, mp 123°-126° C.
Reaction SMILES: [Sn](Cl)Cl.[Br:4][C:5]1[CH:6]=[CH:7][C:8]([N+:13]([O-])=O)=[C:9]([CH:12]=1)[CH:10]=O.O=[C:17]([CH2:23][CH3:24])[C:18]([O:20][CH2:21][CH3:22])=[O:19]>C(OCC)C.C(O)C.[Cl-].[Zn+2].[Cl-]>[Br:4][C:5]1[CH:12]=[C:9]2[C:8](=[CH:7][CH:6]=1)[N:13]=[C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:23]([CH3:24])=[CH:10]2
Reactant: O=Cc1cc(Br)ccc1[N+](=O)[O-]
Reactant: CCOC(=O)C(=O)CC
Agent: Cl[Sn]Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCOCC
Solvent: CCO
Product: CCOC(=O)c1nc2ccc(Br)cc2cc1C
Temperature: 70 °C
Yield: 17.6 %

Procedure:
A 2.2 M solution of zinc(II)chloride (6.05 mL, 13.32 mmol) in diethyl ether was added to tin(II)chloride (2.53 g, 13.32 mmol) and activated 4 Å molecular sieve pellets (612.8 mg) under argon. Then, 5-bromo-2-nitro-benzaldehyde (612.8 mg, 2.66 mmol) and ethyl 2-oxobutanoate (346.7 mg, 2.66 mmol) in ethanol (13 mL) were added to the reaction mixture via canula. The mixture was heated at 70° C. in an oil bath for three hours, then allowed to cool to room temperature, and carefully quenched with saturated sodium bicarbonate. Ethyl acetate was added and the mixture was filtered through Celite®. The filtrate was extracted with ethyl acetate and the organic layer was dried over anhydrous magnesium sulfate, then filtered and concentrated. The residue was purified by silica gel chromatography eluting with 1:6 ethyl acetate:hexanes to give 137.9 mg (18%) of ethyl 6-bromo-3-methyl-2-quinolinecarboxylate as a solid. 1H NMR (400 MHz, d6-DMSO): δ 8.30 (s, 1H), 8.27 (d, J=2 Hz, 1H), 7.99 (d, J=9 Hz, 1H), 7.88 (dd, J=9, 2 Hz, 1H), 4.41 (q, J=7 Hz, 2H), 2.54 (s, 3H), 1.35 (t, J=7 Hz, 3H). ESI-LCMS m/z 294 (M+H)+.
Reaction SMILES: C[Si](C)(C)[CH2:3][CH2:4][O:5]CCl.[N+:10]([C:13]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:14]=1[N:15]=CC(=O)[NH:18]2)([O-:12])=[O:11]>O1CCCC1>[N+:10]([C:13]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:14]=1[NH:15][C:4](=[O:5])[CH:3]=[N:18]2)([O-:12])=[O:11]
Reactant: O=c1cnc2c([N+](=O)[O-])cccc2[nH]1
Reactant: C[Si](C)(C)CCOCCl
Solvent: C1CCOC1
Product: O=c1cnc2cccc([N+](=O)[O-])c2[nH]1

Procedure:
Chloromethyl 2-(trimethylsilyl)ethyl ether (10.0 mL, 56.3 mmol) was added to tetrahydrofuran solution (500 mL) containing a mixture (21.6 g) of the 5-nitroquinoxalin-2-one derivative and the 8-nitroquinoxalin-2-one derivative obtained in the above (1), and then sodium hydride (2.30 g, 60% dispersion in oil, 57.3 mmol) was added thereto under ice-cooling. After the resulting reaction solution was stirred at room temperature for 1.5 hours, aqueous ammonium chloride solution was added thereto, and the mixture was extracted with chloroform. After the organic layer was washed with saturated brine, it was dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. To the resulting residue was added 4N hydrogen chloride/1,4-dioxane solution (100 mL), and the solution was stirred at room temperature for 1 hour. After removal of the insolubles by filtration, the filtrate was concentrated in vacuo. The resulting residue was purified by a column chromatography on silica gel to obtain the above 5-nitroquinoxaline-2-one derivative (11.6 g) protected with SEM, as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][NH:10]C(OC(C)(C)C)=O)=[CH:5][CH:4]=1.[Cl:18][C:19]1[C:24]([C:25]([N:27]=[C:28]=[O:29])=O)=[C:23]([F:30])[C:22]([CH2:31][NH:32][C:33](=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35])=[CH:21][CH:20]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([CH2:31][NH:32][C:33](=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35])=[C:23]([F:30])[C:24]=1[C:25]1[NH:27][C:28](=[O:29])[N:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[N:10]=1
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)N=C=O)c1F
Reactant: COc1ccc(NNC(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(-n2nc(-c3c(Cl)ccc(CNC(=O)C(C)(C)C)c3F)[nH]c2=O)cc1

Procedure:
The title compound was prepared by following the procedure as described for Example-83 by using tert-butyl 2-(4-methoxyphenyl)hydrazinecarboxylate (Intermediate-55, 0.060 g, 0.21 mmol), 6-chloro-2-fluoro-3-(pivalamidomethyl)benzoyl isocyanate (Intermediate-51, 0.101 g, 0.32 mmol), DCM (10 mL) and TFA (3 mL) to afford 0.018 g of pure product. 1H NMR (400 MHz, CDCl3): δ 1.20 (s, 9H), 3.82 (s, 3H), 4.46 (d, J=5.8 Hz, 2H), 6.12 (m, 1H), 6.95 (d, J=8.9 Hz, 2H), 7.26-7.30 (m, 1H), 7.43 (t, J=7.9 Hz, 1H), 7.82 (d, J=8.9 Hz, 2H), 11.01 (br s, 1H); MS (m/z): 433.20 (M+H+).
Reaction SMILES: C(OC([N:6]([CH2:13]/[CH:14]=[CH:15]/[P:16](=[O:27])([O:22]C(C)(C)C)[O:17]C(C)(C)C)[O:7]C(OCC)=O)=O)C.Cl.C.[OH-].[Na+]>O.C(O)C.CO.N1C=CC=CC=1>[OH:7][NH:6][CH2:13]/[CH:14]=[CH:15]/[P:16](=[O:17])([OH:27])[OH:22]
Reactant: CCOC(=O)ON(C/C=C/P(=O)(OC(C)(C)C)OC(C)(C)C)C(=O)OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: c1ccncc1
Product: O=P(O)(O)/C=C/CNO
Yield: 8.7 %

Procedure:
A mixture of di-tert.-butyl 3-(N-ethoxycarbonyl-N-ethoxycarbonyloxyamino)trans-1-propenylphosphonate (8.60 g.) and 1 N hydrochloric acid (250 ml.) was refluxed for 15 hours. The resultant mixture was concentrated under reduced pressure to give a residue, which was dissolved in water (100 ml.) and treated with activated charcoal. The solution was concentrated under reduced pressure to give a residue (4 g.), which was dissolved in water (10 ml.) and adjusted to pH 4 with 1 N aqueous sodium hydroxide solution. The aqueous solution was passed through a column of anion exchange resin, Amberlite IRA-400 (trade name, made by Rhom & Hass Co.) (OH- form). The object compound was eluted from the resin with 1 N hydrochloric acid and then the eluate was concentrated under reduced pressure to give an oily residue (3.4 g.), which was dissolved in a mixture of water (0.5 ml.) and ethanol (20 ml.). The solution was adjusted to pH 4 with pyridine and concentrated under reduced pressure to give a residue, which was pulverized with methanol to give powder (1 g.). The powder was dissolved in water (0.5 ml.). To the aqueous solution was added methanol to give precipitates which were separated by filtration and dried to give powdery 3-(N-hydroxyamino)-trans-1-propenylphosphonic acid (280 mg.). Furthermore, the same object compound (120 mg.) was recovered from the mother liquor.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:8]([N:15]1[CH2:20][CH2:19][CH:18]([NH2:21])[CH2:17][CH2:16]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[CH2:8]([N:15]1[CH2:20][CH2:19][CH:18]([NH:21][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)[CH2:17][CH2:16]1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: Brc1ccccn1
Reactant: NC1CCN(Cc2ccccc2)CC1
Product: c1ccc(CN2CCC(Nc3ccccn3)CC2)cc1

Procedure:
Prepared from 2-bromopyridine and 1-benzyl-4-aminopiperidine using Method A-B.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[O:11]([C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][CH:24]=1)[NH2:21])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C([O-])(C)(C)C.[K+]>CS(C)=O>[N+:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:21][C:20]1[CH:22]=[CH:23][CH:24]=[C:18]([O:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:19]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: Nc1cccc(Oc2ccccc2)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ccccc1Nc1cccc(Oc2ccccc2)c1

Procedure:
The product (2.08 g) is obtained according to the method of stage 1 of Example 4, by using 1.23 mL of 2-fluoronitrobenzene and 3.3 g of 3-phenoxyaniline in the presence of 2.13 g of potassium tert-butanolate in 10 mL of DMSO.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8](=[O:10])[CH3:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:11](O)[CH2:12][OH:13].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:7]([C:8]2([CH3:9])[O:13][CH2:12][CH2:11][O:10]2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: OCCO
Reactant: CC(=O)c1cccnc1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC1(c2cccnc2Cl)OCCO1
Temperature: 25 °C
Yield: 77.3 %

Procedure:
1-(2-Chloro-pyridin-3-yl)-ethanone (2.21 g, 14.2 mmol, 1.0 equiv), ethylene glycol (4.41 g, 71.0 mmol, 5.0 equiv) and p-toluenesulfonic acid monohydrate (1.35 g, 7.1 mmol, 0.5 equiv) are dissolved in toluene (100 mL). The resulting mixture is heated overnight under Dean Stark conditions. After cooling to room temperature the mixture is washed twice with saturated NaHCO3 solution, brine, dried over Na2SO4 and evaporated in vacuo. The residue is purified by flash column chromatography (10% to 50% ethyl acetate in heptane) to yield 2.19 g of the title compound.
Reaction SMILES: C([Si]([O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[C:11](I)[CH:10]=1)(C)C)(C)(C)C.[CH2:17]([S:19]([C:22]1[CH:27]=[CH:26][C:25](B2OC(C)(C)C(C)(C)O2)=[C:24]([O:37][CH3:38])[CH:23]=1)(=[O:21])=[O:20])[CH3:18].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[Cl:15][C:12]1[C:11]([C:25]2[CH:26]=[CH:27][C:22]([S:19]([CH2:17][CH3:18])(=[O:21])=[O:20])=[CH:23][C:24]=2[O:37][CH3:38])=[CH:10][C:9]([OH:8])=[CH:14][CH:13]=1
Reactant: CCS(=O)(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)c(OC)c1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(Cl)c(I)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CCS(=O)(=O)c1ccc(-c2cc(O)ccc2Cl)c(OC)c1
Temperature: 100 °C
Reaction time: 40 h
Yield: 72 %

Procedure:
A solution of tert-butyl(4-chloro-3-iodophenoxy)dimethylsilane (Preparation 53, 102 mg, 0.28 mmol), 2-(4-(ethylsulfonyl)-2-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Preparation 21) (90 mg, 0.28 mmol) and aqueous caesium carbonate solution (1M, 0.55 mL, 0.55 mmol) in dioxane (4 mL) was degassed with nitrogen for 10 minutes, followed by the addition of 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride (11.0 mg, 0.014 mmol). The resulting mixture was heated at 100° C. for 3 hours and then cooled to room temperature. The mixture was partitioned between water (15 mL) and EtOAc (15 mL), the aqueous layer then extracted with EtOAc (2×15 mL). The organic layers were combined and washed with brine (25 mL), dried over MgSO4 and then concentrated in vacuo. 4M HCl in dioxane (4 mL) was added to the residue, and the mixture stirred at room temperature for 40 hours. After concentration in vacuo, NH3 solution (7M in MeOH, 2 mL) was added to the residue, and the mixture re-concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with cyclohexane/EtOAc 70:30 to afford the title compound as yellow gum in 72% yield, 65 mg.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:9]1[C:10]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)=[C:11]2[C:16](=[CH:17][C:18]=1[CH3:19])[N:15]=[C:14]([CH2:20][N:21](C)[CH3:22])[CH:13]=[CH:12]2)[CH2:7][OH:8])([CH3:4])([CH3:3])[CH3:2].C(OC[C@@H](OC(C)(C)C)C1C(C2C=CC(Cl)=CC=2)=C2C(=CC=1C)N=C(CNC)C=C2)(=O)C(C)(C)C>>[C:1]([O:5][C@@H:6]([C:9]1[C:10]([C:24]2[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][CH:29]=2)=[C:11]2[C:16](=[CH:17][C:18]=1[CH3:19])[N:15]=[C:14]([CH2:20][NH:21][CH3:22])[CH:13]=[CH:12]2)[CH2:7][OH:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc2nc(CN(C)C)ccc2c(-c2ccc(Cl)cc2)c1[C@@H](CO)OC(C)(C)C
Agent: CNCc1ccc2c(-c3ccc(Cl)cc3)c([C@@H](COC(=O)C(C)(C)C)OC(C)(C)C)c(C)cc2n1
Product: CNCc1ccc2c(-c3ccc(Cl)cc3)c([C@@H](CO)OC(C)(C)C)c(C)cc2n1

Procedure:
Following the procedure used to prepare compound (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-2-((dimethylamino)methyl)-7-methylquinolin-6-yl)ethanol of Example 9, except that (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-((methylamino)methyl)quinolin-6-yl)ethyl pivalate was used instead of (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-2-((dimethylamino)methyl)-7-methylquinolin-6-yl)ethyl pivalate. LCMS-ESI+ (m/z): 413.3, 415.3 (M+H)+.