Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:5]=1[CH:11]1[N:16]2[N:17]=[CH:18][N:19]=[C:15]2[NH:14][C:13]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)=[CH:12]1>CO.O>[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:5]=1[C@H:11]1[N:16]2[N:17]=[CH:18][N:19]=[C:15]2[NH:14][C@@H:13]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)[CH2:12]1
Reactant: Fc1cccc(Cl)c1C1C=C(c2ccc(Cl)cc2)Nc2ncnn21
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Fc1cccc(Cl)c1[C@@H]1C[C@H](c2ccc(Cl)cc2)Nc2ncnn21
Temperature: 25 °C
Yield: 89 %

Procedure:
Sodium borohydride (10 mmol) was added to a suspension of 7-(2-Chloro-6-fluorophenyl)-5-(4-chlorophenyl)-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidine (1 mmol) in methanol (5 mL). The reaction mixture was refluxed for 30 min, then cooled to room temperature, diluted with water (50 mL) and stirred sufficiently. The resulting mixture was filtered and washed with water to give the crude product, which was further purified by recrystallization from a mixture of EtOAc and Hexanes to provide the product as a white solid. Yield: 89%. m.p. 227-228° C. Rf=0.16 (EtOAc/Hexanes 33.3:66.7). MS: MH+=363. 1H NMR (500 MHz, DMSO-d6): δ 7.54-7.15 (m, 8H, CHar), 5.98-5.94 (m, 1H, CH), 4.82-4.78 (m, 1H, CH), 2.47-2.13 (m, 2H, CH2). HPLC: 99.8% (Method A, tR=3.67 min).
Reaction SMILES: S([N:11]1[C:15]2=[N:16][CH:17]=[C:18]([NH:20][NH:21][C:22]([C@@H:24]3[CH2:28][CH2:27][C@@H:26]([CH2:29][NH:30]C(=O)OC(C)(C)C)[CH2:25]3)=O)[N:19]=[C:14]2[CH:13]=[CH:12]1)(C1C=CC(C)=CC=1)(=O)=O.C(OC(NC[C@@H]1CC[C@@H](C(O)=O)C1)=O)(C)(C)C.CCN(C(C)C)C(C)C.O=S(Cl)[Cl:66].[OH-].[Na+]>O1CCOCC1>[ClH:66].[C:22]1([C@@H:24]2[CH2:28][CH2:27][C@@H:26]([CH2:29][NH2:30])[CH2:25]2)[N:19]2[C:14]3[CH:13]=[CH:12][NH:11][C:15]=3[N:16]=[CH:17][C:18]2=[N:20][N:21]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1ccc(S(=O)(=O)n2ccc3nc(NNC(=O)[C@@H]4CC[C@@H](CNC(=O)OC(C)(C)C)C4)cnc32)cc1
Agent: CC(C)(C)OC(=O)NC[C@@H]1CC[C@@H](C(=O)O)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: Cl
Product: NC[C@@H]1CC[C@@H](c2nnc3cnc4[nH]ccc4n23)C1
Temperature: 80 °C
Yield: 33 %

Procedure:
To a solution of tert-butyl ((1R,3R)-3-(2-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarbonyl)cyclopentyl)methylcarbamate (0.60 g, 1.1 mmol, prepared using A from (1R,3R)-3-((tert-butoxycarbonylamino)methyl)cyclopentanecarboxylic acid [AFID] and Preparation #9) and DIEA (0.79 mL, 4.5 mmol) in 1,4-dioxane (5 mL) was added SOCl2 (0.166 mL, 2.27 mmol). The reaction mixture was heated at about 80° C. for about 1 h before it was allowed to cool to ambient temperature. Aqueous NaOH (2 N, 4 mL, 8 mmol) was added to the reaction mixture and heated at about 60° C. for about 2 h. The reaction mixture was allowed to cool to ambient temperature before it was concentrated under reduced pressure. To the residue was added HCl (4N in 1,4-dioxane (20 mL). The organic solution was decanted away from the resulting precipitate to afford ((1R,3R)-3-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)methanamine hydrochloride as a yellow solid (0.11 g, 33%): LC/MS (Table 2, Method a) Rt=1.01 min; MS m/z: 257 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:13]=[C:12]([C:14]3[CH:23]=[CH:22][C:21]4[C:16](=[CH:17][CH:18]=[C:19]([O:24][CH3:25])[CH:20]=4)[CH:15]=3)[N:11]([C@H:26]([C:28]3[CH:38]=[CH:37][C:31]([C:32]([O:34]CC)=[O:33])=[CH:30][CH:29]=3)[CH3:27])[N:10]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[OH-].[Na+].O>CO.O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:13]=[C:12]([C:14]3[CH:23]=[CH:22][C:21]4[C:16](=[CH:17][CH:18]=[C:19]([O:24][CH3:25])[CH:20]=4)[CH:15]=3)[N:11]([C@H:26]([C:28]3[CH:29]=[CH:30][C:31]([C:32]([OH:34])=[O:33])=[CH:37][CH:38]=3)[CH3:27])[N:10]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CCOC(=O)c1ccc([C@H](C)n2nc(-c3cc(Cl)cc(Cl)c3)cc2-c2ccc3cc(OC)ccc3c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Solvent: CO
Product: COc1ccc2cc(-c3cc(-c4cc(Cl)cc(Cl)c4)nn3[C@@H](C)c3ccc(C(=O)O)cc3)ccc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Ethyl 4-{(1S)-1-[3-(3,5-dichlorophenyl)-5-(6-methoxy-2-naphthyl)-1H-pyrazol-1-yl]ethyl}benzoate (3.53 g, 6.48 mmol) was dissolved in MeOH-dioxane (1:1, 100 ml), and a solution of NaOH (1.2 g, excess)/water (10 ml) was added. The reaction was stirred at room temperature overnight. After concentrating the reaction mixture to 50 ml, it was acidified with 2N HCl and extracted with ethyl acetate. The organic layer was washed with brine 2× and dried over Na2SO4. Evaporation of solvent and vacuum drying gave 4-{(1S)-1-[3-(3,5-dichlorophenyl)-5-(6-methoxy-2-naphthyl)-1H-pyrazol-1-yl]ethyl}benzoic acid as a white powder. NMR (500 MHz, CDCl3) δ: 1.97 (d, J=7.0 Hz, 3H); 3.95 (s, 3H); 5.61 (q, J=7.0 Hz, 1H); 6.66 (s, 1H); 7.17 (d, J=2.5 Hz, H); 7.21 (dd, J=2.5, 9.0 Hz, 1H); 7.29 (dd, J=1.6, 8.4 Hz, 1H); 7.31 (t, J=1.9 Hz, 1H); 7.32 (d, J=8.4 Hz, 2H); 7.63 (d, J=1.6 Hz, 1H); 7.67 (d, J=9.0 Hz, 1H); 7.77 (d, J=8.4 Hz, 1H); 7.80 (d, J=1.9 Hz, 2H); 8.05 (d, J=8.4 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]#[N:13])=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:14][CH2:15][CH2:16][NH:17]C(=O)OC(C)(C)C>C(OCC)C.Cl.O1CCOCC1>[Cl-:1].[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]#[N:13])=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:14][CH2:15][CH2:16][NH3+:17]
Reactant: CC(C)(C)OC(=O)NCCOc1ccc2cc(C#N)ccc2c1Cl
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: N#Cc1ccc2c(Cl)c(OCC[NH3+])ccc2c1
Product: [Cl-]
Temperature: 0 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
To a cooled (0° C.) single necked flask containing a solution of tert-butyl {2-[(1-chloro-6-cyanonaphthalen-2-yl)oxy]ethyl}carbamate in 3 mL of ethyl ether, 5 mL of 4 M HCl solution in dioxane were added. The resulting mixture was stirred at room temperature overnight. The solution was concentrated under reduce pressure to afford 2-[(1-chloro-6-cyanonaphthalen-2-yl)oxy]ethanaminium chloride as a white solid (95% yield).
Reaction SMILES: C[Si]([C:5]#[N:6])(C)C.[F:7][C:8]1[C:17]2[O:16][CH2:15][CH2:14][O:13][C:12]=2[C:11]([O:18][CH3:19])=[CH:10][C:9]=1[CH:20]=O.[NH2:22][C:23]1[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][CH:24]=1>C1COCC1.C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.[Yb+3]>[C:5]([CH:20]([NH:22][C:23]1[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][CH:24]=1)[C:9]1[CH:10]=[C:11]([O:18][CH3:19])[C:12]2[O:13][CH2:14][CH2:15][O:16][C:17]=2[C:8]=1[F:7])#[N:6]
Reactant: C[Si](C)(C)C#N
Reactant: COc1cc(C=O)c(F)c2c1OCCO2
Reactant: N#Cc1ccc(N)cc1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: C1CCOC1
Product: COc1cc(C(C#N)Nc2ccc(C#N)cc2)c(F)c2c1OCCO2
Temperature: 25 °C
Reaction time: 14 h

Procedure:
After adding 17 ml of trimethylsilyl cyanide to a suspension of 17.4 g of 5-fluoro-8-methoxy-2,3-dihydrobenzo[1,4]dioxine-6-carbaldehyde (Example 41c), 9.68 g of 4-aminobenzonitrile, 17 g of MS3A, 5 g of Yb(OTf)3 in 400 ml of THF, the mixture was stirred at room temperature for 14 hours. The reaction mixture was filtered through celite, and the celite was washed with ethyl acetate. The organic layer was concentrated under reduced pressure. The residue was washed with an ethyl acetate and heptane mixed solvent to give 4-{[cyano-(5-fluoro-8-methoxy-2,3-dihydrobenzo[1,4]dioxin-6-yl)methyl]amino}benzonitrile (28.01 g).
Reaction SMILES: S(Cl)(Cl)=O.[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:13]=[CH:14][C:15]([C:18]#[C:19][C:20]3[CH:21]=[C:22]4[C:27](=[CH:28][CH:29]=3)[CH:26]=[C:25]([CH2:30]O)[CH:24]=[CH:23]4)=[N:16][CH:17]=2)=[CH:8][CH:7]=1.C([O-])(O)=O.[Na+].[NH:37]1[CH2:41][CH2:40][CH2:39][CH2:38]1>C(Cl)Cl>[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:13]=[CH:14][C:15]([C:18]#[C:19][C:20]3[CH:29]=[CH:28][C:27]4[C:22](=[CH:23][CH:24]=[C:25]([CH2:30][N:37]5[CH2:41][CH2:40][CH2:39][CH2:38]5)[CH:26]=4)[CH:21]=3)=[N:16][CH:17]=2)=[CH:8][CH:7]=1
Reactant: OCc1ccc2cc(C#Cc3ccc(-c4ccc(Cl)cc4)cn3)ccc2c1
Reactant: C1CCNC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: Clc1ccc(-c2ccc(C#Cc3ccc4cc(CN5CCCC5)ccc4c3)nc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
58 μL (0.80 mmol) thionyl chloride are added at 0° C. to a solution of 148 mg (0.40 mmol) {6-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-naphthalen-2-yl}-methanol in 5 mL DCM. The solution is heated to RT and stirred for 1 h at this temperature. The reaction mixture is diluted with 30 mL DCM, combined with ice water, made alkaline with saturated NaHCO3 solution and the organic phase is washed with water. The organic phase is dried over MgSO4 and filtered. 0.10 mL (1.20 mmol) pyrrolidine are added to the filtrate, which is stirred for 2 h at RT and for 1 h at 40° C. The solvent is eliminated i.vac. and the purification is carried out by column chromatography on silica gel (gradient: DCM to DCM/MeOH/NH3 5:1:0.1).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:20][C:21]#[CH:22])[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].O=C1O[C@H]([C@H](CO)O)C([O-])=C1O.[Na+].[N-:36]=[N+:37]=[N-:38].[Na+].[CH:40]1[CH:45]=[CH:44][C:43]([CH2:46]Br)=[CH:42][CH:41]=1>CN(C=O)C.O.O.CCOC(C)=O>[CH2:46]([N:36]1[CH:22]=[C:21]([CH2:20][C@H:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[N:38]=[N:37]1)[C:43]1[CH:44]=[CH:45][CH:40]=[CH:41][CH:42]=1
Reactant: BrCc1ccccc1
Reactant: [N-]=[N+]=[N-]
Reactant: C#CC[C@H](NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Agent: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1cn(Cc2ccccc2)nn1)C(=O)OCc1ccccc1
Temperature: 65 °C
Reaction time: 5 h

Procedure:
To a mixture of (S)-benzyl 2-(tert-butoxycarbonylamino)pent-4-ynoate (0.50 g, 1.65 mmol), sodium ascorbate (0.036 g, 0.18 mmol), CuSO4-5H2O (0.022 g, 0.09 mmol) and NaN3 (0.13 g, 2.1 mmol) in DMF-H2O (5 mL, 4:1) at rt was added BnBr (0.24 mL, 2.02 mmol) and the mixture was warmed to 65° C. After 5 h LCMS indicated low conversion. A further portion of NaN3 (100 mg) was added and heating was continued for 12 h. The reaction was poured into EtOAc and H2O and shaken. The layers were separated and the aqueous layer extracted 3× with EtOAc and the combined organic phases washed (H2O×3, brine), dried (Na2SO4), filtered, and concentrated. The residue was purified by flash (Biotage, 40+M 0-5% MeOH in CH2Cl2; TLC 3% MeOH in CH2Cl2) to afford a light yellow oil which solidified on standing (748.3 mg, 104%). The NMR was consistent with the desired product but suggests the presence of DMF. The material was used as is without further purification. 1H NMR (400 MHz, DMSO-d6) δ 7.84 (s, 1H), 7.27-7.32 (m, 10H), 5.54 (s, 2H), 5.07 (s, 2H), 4.25 (m, 1H), 3.16 (dd, J=1.0, 5.3 Hz, 1H), 3.06 (dd, J=5.3, 14.7 Hz), 2.96 (dd, J=9.1, 14.7 Hz, 1H), 1.31 (s, 9H). LCMS: Anal. Calcd. for C24H28N4O4: 436; found: 437 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:10]=[CH:11][NH:12][CH:13]=2)[CH:5]=[CH:6][C:7]=1[F:8].[OH-].[K+].CS(C)=O.Cl.[CH3:21][N:22]([CH3:26])[CH2:23][CH2:24]Cl>CC(=O)OCC>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:10]=[CH:11][N:12]([CH2:24][CH2:23][N:22]([CH3:26])[CH3:21])[CH:13]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Fc1ccc(-c2c[nH]cn2)cc1Cl
Reactant: CN(C)CCCl
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CN(C)CCn1cnc(-c2ccc(F)c(Cl)c2)c1
Temperature: 45 °C
Yield: 43.3 %

Procedure:
Charge a round bottom flask with 4-(3-chloro-4-fluoro-phenyl)-1H-imidazole (1.85 g; 1.00 equiv; 9.41 mmol), KOH (3.00 equiv; 28.23 mmol; 1.58 g, crushed to a fine powder), in DMSO (281.56 mmol; 20.00 mL). Add 2-dimethylaminoethyl chloride hydrochloride (1.20 equiv; 11.29 mmol; 1.63 g) in one portion and the solution becomes yellow. Heat at 45° C. for 2 days. Dilute the reaction with EA and wash with water, brine and dry the organics over MgSO4; filter, and concentrate to an orange oil. Purify the crude with ISCO chromatography over a Biotage 40M column eluting with a gradient of 5% MeOH/DCM to 10% MeOH/DCM at a flow rate of 40 mL/min to give the title compound (1.09 g; 4.07 mmol; 43.27%) as a light orange oil. MS(ES): (m/z)=268.0 (M+H).
Reaction SMILES: [OH:1][N:2]=[C:3]([C:9](=[O:11])[CH3:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5].C(=O)([O-])[O-].[K+].[K+].[CH2:18](Br)[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]>CN(C)C=O>[CH2:18]([O:1][N:2]=[C:3]([C:9](=[O:11])[CH3:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCOC(=O)C(=NO)C(C)=O
Reactant: CCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCCON=C(C(C)=O)C(=O)OCC

Procedure:
Ethyl 2-hydroxyimino-3-oxobutyrate (syn isomer, 40 g.), N,N-dimethylformamide (200 ml.), potassium carbonate (52 g.) and n-hexyl bromide (41.4 g.) were treated in a similar manner to that of Example F-(1) to give ethyl 2-n-hexyloxyimino-3-oxobutyrate (syn isomer, 60.7 g. oil.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:15][I:16]>CCOCC>[I-:16].[CH2:1]([N+:8]1([CH3:15])[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CI
Reactant: O=C1CCN(Cc2ccccc2)CC1
Solvent: CCOCC
Product: C[N+]1(Cc2ccccc2)CCC(=O)CC1
Product: [I-]
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To 9.79 ml of 1-benzyl-4-piperidone, 16.5 ml of methyl iodide was added and stirred for 16 hours at room temperature. To the resulting yellow suspension, approx. 10 ml of ether was added and the formed yellow solid was recovered by filtration, which solid was washed with ether and dried to provide 13.42 g of the title compound as a yellow powder.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N:8]2[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]2[C:14]2[CH:19]=[CH:18][N:17]=[CH:16][C:15]=2[CH3:20])[C:5]([NH:21][C:22](=O)[CH3:23])=[C:4]([O:25][CH3:26])[CH:3]=1.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.O=P(Cl)(Cl)Cl>CO.ClCCl>[F:1][C:2]1[CH:7]=[C:6]2[C:5]([N:21]=[C:22]([CH3:23])[C:12]3[N:8]2[C:9]([C:14]2[CH:19]=[CH:18][N:17]=[CH:16][C:15]=2[CH3:20])=[N:10][C:11]=3[CH3:13])=[C:4]([O:25][CH3:26])[CH:3]=1
Reactant: COc1cc(F)cc(-n2cc(C)nc2-c2ccncc2C)c1NC(C)=O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: CO
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Product: COc1cc(F)cc2c1nc(C)c1c(C)nc(-c3ccncc3C)n12
Temperature: 120 °C
Reaction time: 6 h
Yield: 58.7 %

Procedure:
To a mixture of intermediate N-(4-fluoro-2-methoxy-6-(4-methyl-2-(3-methylpyridin-4-yl)-1H-imidazol-1-yl)phenyl)acetamide (1.58 g, 4.46 mmol) and P2O5 (3.16 g, 22.3 mmol) was added 60 mL of POCl3 under nitrogen. The resulting mixture was stirred at 120° C. for 6 hours and cooled to room temperature. Majority of solvent was removed under vacuum and the residue was diluted with ethyl acetate. The mixture was transferred very carefully into iced-50% NaOH solution. The mixture was stirred for 10 minutes (make sure pH>7) and extracted with ethyl acetate (3×). Condensation and column purification using 4-8% MeOH in dichloromethane as eluent provided 880 mg (60% yield) of 8-fluoro-6-methoxy-3,4-dimethyl-1-(3-methylpyridin-4-yl)imidazo[1,5-a]quinoxaline as an offwhite powder. 1H NMR (400 MHz, DMSO) δ ppm 8.68 (s, 1H), 8.60 (d, 1H), 7.48 (d, 1H), 7.00 (dd, 1H), 6.16 (dd, 1H), 3.88 (s, 3H), 2.75 (s, 3H), 2.69 (s, 3H), 1.98 (s, 3H). EIMS 337.1 [M+H]+.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([NH:13][O:14][CH3:15])(=[O:12])=[O:11].[N+:16]([C:19]1[CH:24]=[C:23]([N+:25]([O-:27])=[O:26])[CH:22]=[CH:21][C:20]=1Cl)([O-:18])=[O:17].O>CN(C=O)C>[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([N:13]([O:14][CH3:15])[C:20]1[CH:21]=[CH:22][C:23]([N+:25]([O-:27])=[O:26])=[CH:24][C:19]=1[N+:16]([O-:18])=[O:17])(=[O:12])=[O:11]
Reactant: O=[N+]([O-])c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: CONS(=O)(=O)c1ccccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CON(c1ccc([N+](=O)[O-])cc1[N+](=O)[O-])S(=O)(=O)c1ccccc1Cl
Temperature: 25 °C
Yield: 62.6 %

Procedure:
To a suspension of sodium hydride (60%, 0.09 g (2.25 mmol)) in DMF (3.0 ml), 2-chloro-N-methoxybenzenesulfonamide (0.48 g (2.17 mmol)) was added with stirring under cooling with ice. To the resulting mixture, after 15 minutes' stirring under cooling with ice, 2,4-dinitrochlorobenzene (0.41 g (2.02 mmol)) was added. The resulting mixture was then stirred under cooling with ice for one hour and at room temperature for one hour. Water was added to the reaction mixture and the resulting mixture was extracted with diethyl ether. The extract was washed with water, dilute hydrochloric acid and a saturated aqueous solution of sodium chloride, successively, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure, to give 0.49 g (62%) of the title compound as pale yellow crystals.
Reaction SMILES: OC1CC(=O)C(CC[CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=C1.OCCCCOC1CC(=O)C(CCCCCCC(O)=O)=C1.O1C[CH2:42][CH2:41][CH2:40][CH:39]1[O:44][CH:45]1[CH2:49][C:48](=[O:50])[C:47]([CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH:56]([C:63]([OH:65])=[O:64])[CH:57]2[CH2:62][CH2:61][CH2:60][CH2:59][O:58]2)=[CH:46]1.O1C=CCCC1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl>[O:15]1[CH2:10][CH2:11][CH2:12][CH2:13][CH:14]1[O:16][CH2:42][CH2:41][CH2:40][CH2:39][O:44][CH:45]1[CH2:49][C:48](=[O:50])[C:47]([CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH:56]([C:63]([OH:65])=[O:64])[CH:57]2[CH2:62][CH2:61][CH2:60][CH2:59][O:58]2)=[CH:46]1
Reactant: O=C1CC(OC2CCCCO2)C=C1CCCCCC(C(=O)O)C1CCCCO1
Reactant: O=C(O)CCCCCCC1=CC(O)CC1=O
Agent: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C(O)CCCCCCC1=CC(OCCCCO)CC1=O
Solvent: O
Solvent: ClCCl
Product: O=C1CC(OCCCCOC2CCCCO2)C=C1CCCCCC(C(=O)O)C1CCCCO1

Procedure:
In the manner of Example 147 the mixture of 4-hydroxy-2-(6-carboxyhexyl)cyclopent-2-en-1-one and 4-(4-hydroxybutoxy)-2-(6-carboxyhexyl)cyclopent-2-en-1-one (Example 268) is converted to a mixture of the subject compound and 4-tetrahydropyranyloxy-2-(6-tetrahydropyranylcarboxyhexyl)cyclopent-2-en-1-one with dihydropyran and p-toluenesulfonic acid monohydrate in methylene chloride.
Reaction SMILES: [C:1](Cl)(Cl)=[S:2].[C:5]([O:9][C:10](=[O:22])[NH:11][C:12]([CH3:21])([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([NH2:20])[CH:15]=1)[CH3:13])([CH3:8])([CH3:7])[CH3:6].C(=O)([O-])[O-].[Ca+2].[NH3:28]>C(Cl)Cl.O>[C:5]([O:9][C:10](=[O:22])[NH:11][C:12]([CH3:13])([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([NH:20][C:1]([NH2:28])=[S:2])[CH:15]=1)[CH3:21])([CH3:6])([CH3:7])[CH3:8]
Reactant: CC(C)(C)OC(=O)NC(C)(C)c1cccc(N)c1
Reactant: S=C(Cl)Cl
Reactant: N
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC(C)(C)c1cccc(NC(N)=S)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 89 %

Procedure:
Thiophosgene (0.12 ml) and a solution of the compound (284 mg) obtained in Example 2 in methylene chloride (10 ml) were added dropwise to a suspension of calcium carbonate (319 mg) in water (5 ml) at room temperature and stirred at room temperature for 5 h; thereafter, a 28% aqueous ammonia solution (5 ml) was added to the reaction mixture and stirred at room temperature for 16 h. After neutralization with 2 N HCl, the reaction mixture was extracted with ethyl acetate and the organic layer was washed with a saturated aqueous sodium chloride solution, dried with anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent, n-hexane:ethyl acetate=6:4) to yield 351 mg of the titled compound (yield, 89%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:33]=[CH:34][C:35]=1[O:36][CH3:37])[CH2:6][CH2:7][NH:8][CH2:9][CH:10]([OH:32])[CH2:11][O:12][C:13]1[CH:22]=[CH:21][C:20]([O:23]CC2C=CC=CC=2)=[C:19]2[C:14]=1[CH2:15][CH2:16][C:17](=[O:31])[NH:18]2.C(O)C.[ClH:41].[H][H]>CO.[C].[Pd]>[ClH:41].[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:33]=[CH:34][C:35]=1[O:36][CH3:37])[CH2:6][CH2:7][NH:8][CH2:9][CH:10]([OH:32])[CH2:11][O:12][C:13]1[CH:22]=[CH:21][C:20]([OH:23])=[C:19]2[C:14]=1[CH2:15][CH2:16][C:17](=[O:31])[NH:18]2
Reactant: COc1ccc(CCNCC(O)COc2ccc(OCc3ccccc3)c3c2CCC(=O)N3)cc1OC
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: CO
Product: COc1ccc(CCNCC(O)COc2ccc(O)c3c2CCC(=O)N3)cc1OC
Temperature: 25 °C

Procedure:
2.0 g of 5-[3-(3,4-dimethoxyphenethylamino)-2-hydroxypropoxy]-8-benzyloxy-3,4-dihydrocarbostyril was suspended in 50 ml of methanol, and an ethanol solution containing hydrogen chloride was added to the suspension until the mixture showed acidity. After the mixture became homogenous, 0.7 g of 10% palladium carbon was added thereto followed by stirring at room temperature and at atmospheric pressure thereby absorbing hydrogen. The reaction completed when the absorption of hydrogen ceased. The catalyst was removed by filtration, and the methanol evaporated. A small amount of ethanol was added to the residue to crystallize the product. Recrystallization from ethanol gave 1.5 g of 5-[3-(3,4-dimethoxyphenethylamino)-2-hydroxypropoxy]-8-hydroxy-3,4-dihydrocarbostyril hydrochloride as colorless powdery crystals having a melting point of 171°-173° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[O:10][C:11]3[C:17]([CH3:18])=[CH:16][C:15]([CH3:19])=[CH:14][C:12]=3[N:13]=2)=[CH:4][CH:3]=1.FC1C=C([B:27]2[O:31][C:30]([CH3:33])([CH3:32])[C:29]([CH3:35])([CH3:34])[O:28]2)C=CC=1NC1OC2C=CC=CC=2N=1>>[CH3:34][C:29]1([CH3:35])[C:30]([CH3:33])([CH3:32])[O:31][B:27]([C:2]2[CH:7]=[CH:6][C:5]([NH:8][C:9]3[O:10][C:11]4[C:17]([CH3:18])=[CH:16][C:15]([CH3:19])=[CH:14][C:12]=4[N:13]=3)=[CH:4][CH:3]=2)[O:28]1
Reactant: Cc1cc(C)c2oc(Nc3ccc(Br)cc3)nc2c1
Reactant: CC1(C)OB(c2ccc(Nc3nc4ccccc4o3)c(F)c2)OC1(C)C
Product: Cc1cc(C)c2oc(Nc3ccc(B4OC(C)(C)C(C)(C)O4)cc3)nc2c1

Procedure:
N2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-5,7-dimethyl-1,3-benzoxazol-2-amine was prepared from N2-(4-bromophenyl)-5,7-dimethyl-1,3-benzoxazol-2-amine (1.215 g, 3.831 mmol) in a manner similar to that used for the preparation of N2-[2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1,3-benzoxazol-2-amine. The compound was formed as a tan powder (0.880 g, 63%). RP-HPLC (25 to 100% CR3CN in 0.1 N aqueous ammonium acetate over 10 min at 1 mL/min using a Hypersil HS C18, 250×4.6 mm column) Rt=14.48 min, 81%; m/z 365 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Cl:11])[CH:10]=1)[CH:5]1[O:7][CH2:6]1.[C:12]([NH2:16])([CH3:15])([CH3:14])[CH3:13]>C(O)C>[ClH:1].[C:12]([NH:16][CH2:6][CH:5]([OH:7])[C:4]1[CH:3]=[C:2]([Cl:1])[CH:10]=[C:9]([Cl:11])[CH:8]=1)([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)N
Reactant: Clc1cc(Cl)cc(C2CO2)c1
Solvent: CCO
Product: CC(C)(C)NCC(O)c1cc(Cl)cc(Cl)c1
Product: Cl
Temperature: 5 °C

Procedure:
A solution containing 3.5 g of 3,5-dichlorostyrene oxide in 50 ml of absolute ethanol and 20 ml of t-butylamine is heated gently at reflux for 8 hours and the mixture is evaporated to dryness. The clear yellow syrup is dissolved in 75 ml of ethanol and 25 ml of H2O, and the solution is cooled to 5° C. and acidified with 3N HCl. This solution is evaporated to dryness in vacuo and the residual white solid is recrystallized from acetone to afford 2.81 g, m.p. 218°-221° C.